Archive for June, 2021

ABU DHABI, 22nd June, 2021 (WAM) -- The Ministry of Health and Prevention (MoHAP) and the Emirates Health Services (EHS) recently revealed innovative immunotherapy for cancer and viral infections in cooperation with Japans Kyoto University.

This came during the participation of the ministry and the EHS at the Arab Health 2021 which began in Dubai on 21st June and concludes on 24th June.

The treatment is based on the clinical application of the therapy using T cell preparation after it was discovered that such cells can fight cancer and viral infections. The T cell medicine will be produced using the iPS cell technology.

T Cell makes up a group of lymphocytes present in the blood and plays a major role in cellular immunity. It is possible to produce T cells in large numbers and store them in appropriate conditions to be administered to patients when needed.

Thus, by the success of this project, patients with cancer or viral infection may have great merit in which they can make very easy access to T cell therapy.

Strategic partnerships Dr. Youssef Mohamed Al Serkal, Director-General of the Emirates Health Services, spoke about the commitment of the ministry and the EHS to having strategic partnerships with the most prestigious medical research centres while keeping an eye on the sustainable investment in future healthcare services.

"Although the prevalence of cancer in the UAE is considered lower than in other parts of the world, we work hard to make a qualitative shift in cancer and viral infection healthcare," Al Serkal stated, adding, "This is part of our strategy to provide healthcare services in innovative and sustainable ways and implement the national strategy to reduce cancer mortality rates."

Al Serkal pointed out that the ministry and EHS support the National Cancer Control Programme and prepare a road map to achieve the target indicator. They also analyse the current status of cancer diseases and their diagnostic and therapeutic pathways, support research and studies on the control of cancer diseases and viral infections, and back workshops and educational and training activities. awareness campaigns, and innovative initiatives.

Dr. Kalthum Al Balushi, Director of Hospitals Department, said, "The ground-breaking treatment technology for cancer and viral infections, in cooperation with the Kyoto University, represents a paradigm shift in health services provided by the Ministry and the EHS."

The treatment is based on stimulating immune cells to fight cancer cells using pluripotent stem cells, which is a recent global trend that has begun to open great prospects for improving the quality of life of patients, Al Balushi added.

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MoHAP, EHS reveal immunotherapy for cancer, viral infections at Arab Health 2021 - WAM EN

New York, June 01, 2021 (GLOBE NEWSWIRE) -- Reportlinker.com announces the release of the report "Stem Cell Market - Growth, Trends, COVID-19 Impact, and Forecasts (2021 - 2026)" - https://www.reportlinker.com/p06079777/?utm_source=GNW According to a 2020 research article published in the scientific journal Aging and Disease (2020), mesenchymal stem cells are a safe and effective approach to the treatment of COVID-19. At least 10 projects have been registered in the official international registry for clinical trials, implicating the use of mesenchymal stem cells to patients with coronavirus pneumonia. However, it is still at an initial stage of study in relation to the market studied.

Stem cells are majorly used in regenerative medicine, especially in the field of dermatology. However, oncology is expected to grow at the highest rate due to a large number of pipeline products present for the treatment of tumors or cancers. With the increase in the number of regenerative medicine centers, the stem cell market is also expected to increase in the future.

One of the richest sources of stem cells is the umbilical cord, which possesses unique qualities and has greater advantages over embryonic stem cells or adult stem cells. There are an increasing number of stem cell banks, which collaborate with hospitals and increase awareness about the storage of cord blood units in families, particularly in the emerging markets. The support is increasing with the rising number of medical communities and government initiatives active in promoting the use of stem cells for the treatment of more than 100 diseases. Currently, there is an increase in the number of clinical trials for testing future treatment possibilities of cord blood. Over 200 National Institutes of Health (NIH)-funded clinical trials with cord blood are currently being conducted in the United States alone.

Key Market TrendsThe Oncology Disorders Segment is Expected to Exhibit the Fastest Growth Rate Over the Forecast Period

The global cancer burden has been increasing, and thus, cancer therapies must be modified according to regional and national priorities. According to the World Cancer Research Fund, in 2018, there were an estimated 18 million cancer cases around the world. According to the World Health Organization (WHO), cancer is the second-leading cause of death across the world, with an estimated number of 9.6 million deaths in 2018, accounting for nearly one in six deaths.

Bone marrow transplant or stem cell transplant is a treatment for some types of cancer, like leukemia, multiple myeloma, neuroblastoma, or some types of lymphoma. For cancer treatments, both autologous and allogeneic stem cell transplants are done. Autologous transplants are preferred in the case of leukemias, lymphomas, multiple myeloma, testicular cancer, and neuroblastoma.

The major disadvantage associated with autologous stem cell transplants in cancer therapy is that cancer cells sometimes also get collected, along with stem cells, which may further put it back into the body during the therapy.

In case of allogeneic stem cell transplants, the donor can often be asked to donate more stem cells or even white blood cells, as per the requirement, and stem cells from healthy donors are free of cancer cells. However, the transplanted donor stem cells could die or be destroyed by the patients body before settling in the bone marrow.

Moreover, due to the growing focus of stem cell-based research and the rising demand for novel treatments, several companies, such as Stemline Therapeutics, have been focusing on developing technologies and treatments to attack cancer cells, which may help the market grow. However, owing to the COVID-19 pandemic, the detection and treatment of new cancer cases are impended, which may slightly impact the segment growth in the year.

North America Captured The Largest Market Share and is Expected to Retain its Dominance

North America dominated the overall stem cell market, with the United States contributing to the largest share in the market. The United States and Canada have developed and well-structured healthcare systems. These systems also encourage research and development. The increasing number of cancer cases is providing opportunities for market players. The major market players are focusing on R&D activities to introduce new stem cell therapies in the market.

For instance, the National Cancer Institute (NCI) had stated that the national expenditure on cancer care was expected to reach USD 156 billion by 2020. This factor is expected to boost the growth of the market in the future. In December 2019, the researchers at the National Eye Institute (NEI) launched a clinical trial to test the safety of a novel patient-specific stem cell-based therapy to treat geographic atrophy, the advanced dry form of age-related macular degeneration (AMD), a leading cause of vision loss among people aged 65 years and above.

In addition, the current situation of COVID-19 is another factor driving the growth of the market in the country, as research activities are undergoing for the treatment of COVID-19. Stem cell therapy can also be a promising approach for the treatment of COVID-19 in the future. For instance, on May 6, 2020, Lineage Cell Therapeutics received a grant of USD 5 million from the California Institute for Regenerative Medicine (CIRM) to support the use of VAC, Lineages allogeneic dendritic cell therapy for the development of a potential vaccine against SARS-CoV-2, the virus that causes COVID-19.

Competitive LandscapeThe stem cell market is highly competitive and consists of several major players. In terms of market share, few of the major players currently dominate the market. The presence of major market players, such as Thermo Fisher Scientific (Qiagen NV), Sigma Aldrich (a subsidiary of Merck KGaA), Becton, Dickinson and Company, and Stem Cell Technologies, is in turn, increasing the overall competitive rivalry in the market. The product advancements and improvement in stem cell technology by the major players are also increasing the competitive rivalry.

Reasons to Purchase this report:- The market estimate (ME) sheet in Excel format- 3 months of analyst supportRead the full report: https://www.reportlinker.com/p06079777/?utm_source=GNW

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The stem cell market was valued at USD 14.7 billion in 2020, and it is expected - GlobeNewswire

Brave Nathaniel Nabena smiles from his hospital bed moments before a life-saving procedure.

The nine-year-old had a vital stem cell transplant at Great Ormond Street Hospital on Wednesday after Sunday People readers helped raised more than 215,000.

Nathaniel, battling acute myeloid leukaemia, was on a drip for 30 minutes as umbilical cord stem cells were fed into his body.

Afterwards, dad Ebi said: Nathaniel is very happy. It was amazing to finally get to this point we have all been waiting for.

The youngster was admitted a fortnight ago and had five doses of chemo over ten days to prepare him for the procedure.

How brave has Nathaniel been? Have your say in comments below

Mum Modupe, 38, was able to spend time with him before his transplant.

Consultants warn he faces weeks of sickness as his body reacts to the new cells with symptoms including vomiting and a fever.

Ebi, 45, said: His doctors hope to see improvements after five weeks. It is so hard to see him so exhausted but I dont have a choice. We are grateful to have this done. Our fingers are crossed to see what happens.

For now, Nathaniel has a compromised immune system and is susceptible to falling ill, so he will be staying on the ward.

Stars including Simon Cowell, David Walliams, Katie Price and JLS singer Aston Merrygold rallied to support him after we told of the desperate race to fund treatment.

Nathaniels left eye was removed in his home country of Nigeria a year ago, due to myeloid sarcoma cancer. He was diagnosed with AML in the UK in November after coming here to have a prosthetic eye fitted.

Nathaniel was told a stem-cell transplant was his only hope for survival but it would cost 201,000 as he is not a British citizen. Ebi and Modupe were initially told it could cost as much as 825,000 but the figure was revised after doctors waived their fees and offered to treat him in their own time.

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The lad was admitted to GOSH on May 24 after generous Brits rushed to help the family raise cash.

Business analyst Ebi, who is staying at the hospitals family quarters, said: Ive been there the whole time. When he is not sleeping he is passing the time playing his games.

We sometimes talk about when he gets better and how exciting that will be. This is a difficult thing for him to go through, but Nathaniel is being brave, he is well in himself.

In acute myeloid leukaemia, unhealthy blood-forming stem cells grow quickly in the bone marrow.

This prevents it from making normal red blood cells, white blood cells and platelets meaning the body cannot fight infections or stop bleeding.

A stem cell transplant, also known as a bone marrow transplant, can help AML patients stimulate new bone marrow growth and restore the immune system.

Before treatment, patients need high doses of chemo and sometimes radiotherapy.

This destroys existing cancer and bone marrow cells and stops the immune system working, to cut the risk of transplant rejection.

In an allogeneic transplant, stem cells are taken from a family member, unrelated donor or umbilical cord blood. In Nathaniels case, it was from a cord.

They are then passed into the patients body through a line inserted in a large, central vein, in a process that takes up to two hours.

You can also remove stem cells from the patients body and transplant them later, after any damaged or diseased cells have been removed this is called an autologous transplant.

The survival rate after a transplant for patients with acute leukaemia in remission and using related donors is 55% to 68%, according to Medicine Net. If the donor is unrelated, it is 26% to 50%.

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Brave Nathaniel Nabena, 9, all smiles as he has life-saving procedure - thanks to you - The Mirror

Global Hematopoietic Stem Cell Transplantation (HSCT) Market Size, Status And Forecast 2021-2028

MarketInsightsReports, a leading global market research firm, is pleased to announce its new report on Hematopoietic Stem Cell Transplantation (HSCT) market, forecast for 2021-2028, covering all aspects of the market and providing up-to-date data on current trends.

The report covers comprehensive data on emerging trends, market drivers, growth opportunities, and restraints that can change the market dynamics of the industry. It provides an in-depth analysis of the market segments which include products, applications, and competitor analysis. The report also includes a detailed study of key companies to provide insights into business strategies adopted by various players in order to sustain competition in this highly competitive environment.

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With our Hematopoietic Stem Cell Transplantation (HSCT) market research reports, we offer a comprehensive overview of this sector and its dynamics. We have done extensive research on this topic and are confident that our findings will be helpful for anyone who needs some guidance or direction when making important decisions related to their companys future growth strategy.

Top Companies in the Global Hematopoietic Stem Cell Transplantation (HSCT) Market: ViaCord Inc, Cryo-Save AG, CBR Systems Inc, Pluristem Therapeutics Inc, China Cord Blood Corp, Lonza Group Ltd, Escape Therapeutics Inc, Regen Biopharma Inc

This report segments the global Hematopoietic Stem Cell Transplantation (HSCT) market on the basis of Types are:

On the basis of Application, the Global Hematopoietic Stem Cell Transplantation (HSCT) market is segmented into:

For comprehensive understanding of market dynamics, the global Hematopoietic Stem Cell Transplantation (HSCT) market is analyzed across key geographies namely: United States, China, Europe, Japan, South-east Asia, India and others. Each of these regions is analyzed on basis of market findings across major countries in these regions for a macro-level understanding of the market.

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Key Takeaways from Hematopoietic Stem Cell Transplantation (HSCT) Report

Browse the report description and TOC: https://www.marketinsightsreports.com/reports/06022956528/2016-2028-global-hematopoietic-stem-cell-transplantation-hsct-industry-market-research-report-segment-by-player-type-application-marketing-channel-and-region?mode=dj

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Customization of the Report: This report can be customized as per your needs for additional data up to 3 companies or countries or 40 analyst hours.

MarketInsightsReports provides syndicated market research on industry verticals including Healthcare, Information and Communication Technology (ICT), Technology and Media, Chemicals, Materials, Energy, Heavy Industry, etc.MarketInsightsReports provides global and regional market intelligence coverage, a 360-degree market view which includes statistical forecasts, competitive landscape, detailed segmentation, key trends, and strategic recommendations.

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Hematopoietic Stem Cell Transplantation (HSCT) Market Competitive Analysis with Global Trends and Demand 2021 to 2028:ViaCord Inc, Cryo-Save AG, CBR...

Abstract

Immunomodulatory drugs (IMiDs) have markedly improved patient outcome in multiple myeloma (MM); however, resistance to IMiDs commonly underlies relapse of disease. Here, we identify that tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) knockdown (KD)/knockout (KO) in MM cells mediates IMiD resistance via activation of noncanonical nuclear factor B (NF-B) and extracellular signalregulated kinase (ERK) signaling. Within MM bone marrow (BM) stromal cell supernatants, TNF- induces proteasomal degradation of TRAF2, noncanonical NF-B, and downstream ERK signaling in MM cells, whereas interleukin-6 directly triggers ERK activation. RNA sequencing of MM patient samples shows nearly universal ERK pathway activation at relapse on lenalidomide maintenance therapy, confirming its clinical relevance. Combination MEK inhibitor treatment restores IMiD sensitivity of TRAF2 KO cells both in vitro and in vivo. Our studies provide the framework for clinical trials of MEK inhibitors to overcome IMiD resistance in the BM microenvironment and improve patient outcome in MM.

Multiple myeloma (MM) is characterized by the infiltration of abnormal plasma cells in the bone marrow (BM) and monoclonal protein in serum and/or urine, associated with hypercalcemia, renal dysfunction, anemia, and bone disease (1). The development of high-dose therapy and autologous stem cell transplantation (2, 3) and, more recently, of novel agents including proteasome inhibitors (4), histone deacetylase inhibitor (5, 6), immunomodulatory drugs (IMiDs) (79), and monoclonal antibodies (Abs) (1012), has transformed therapy and markedly improved patient outcome.

The IMiD thalidomide (Thal) was banned because of its teratogenicity when prescribed to treat morning sickness of pregnant women 50 years ago (13). However, Thal and its analogs lenalidomide (Len) and pomalidomide (Pom), initially used empirically predicated upon their antiangiogenic activity (14), have demonstrated remarkable clinical efficacy in MM and other B cell malignancies (15). Our early studies showed that IMiDs trigger direct MM cytotoxicity via activation of caspase-8mediated extrinsic apoptotic pathway, as well as enhancing immune effector antitumor responses while inhibiting T regulatory cells (1619). Multiple groups have subsequently reported that IMiDs directly bind cereblon (CRBN), a substrate adaptor of Cullin4 RING Ligase (CRL4) (20, 21) and activate CRL4CRBN ligase, thereby selectively targeting two B cell transcription factors IKAROS Family Zinc Finger 1 (IKZF1) and IKAROS Family Zinc Finger 3 (IKZF3) for ubiquitination and proteasomal degradation (22, 23). We have also shown that IMiDs directly bind and inhibit TP53-regulating kinase activity in MM cells, followed by MM cell growth inhibition (24). IMiDs trigger additive or synergistic anti-MM activity when combined with proteasome inhibitors and monoclonal Abs in preclinical models (25, 26) and are now used in combinations to treat both newly diagnosed and relapsed MM. However, development of resistance to IMiDs commonly underlies relapse of disease.

To delineate mechanisms of IMiD resistance, the majority of previous studies have focused on CRBN. The expression level of CRBN, CRBN-binding proteins, and CRL4CRBN ligase have been associated with IMiD sensitivity (2730). For example, our prior studies used CRISPR-Cas9 screening to identify signalosome genes regulating expression of CRBN and IMiD sensitivity (31). Although down-regulation or mutations in CRBN have been associated with IMiD resistance (32, 33), MM cells can manifest resistance without CRBN dysfunction (34), indicating potential alternative mechanisms of IMiD resistance. We and others have also shown that MM cell adhesion to extracellular matrix proteins and accessory cells triggers cell adhesionmediated drug resistance to conventional therapeutic agents (35, 36). Moreover, secretion of soluble factors [i.e., tumor necrosis factor (TNF-) and interleukin-6 (IL-6)] from celluar components [i.e., BM stromal cells (BMSCs), osteoclasts, and vascular endothelial cells] activates intracellular signaling pathways including nuclear factor B (NF-B), Rafmitogen-activated protein kinase (MAPK) kinase (MEK)extracellular signalregulated kinase (ERK), Janus kinasesignal transducer and activator of transcription, and phosphatidylinositol 3-kinaseAkt, thereby promoting migration, proliferation, survival, and drug resistance of MM cells (37). Resistance to dexamethasone-induced MM cell apoptosis, for example, is completely abrogated by coculture with BMSCs, IL-6, or insulin-like growth factor 1 (IGF-1). To date, however, the molecular mechanisms mediating IMiD resistance have not been fully delineated.

In this study, we used our in vitro and in vivo preclinical model systems of MM in the BM milieu to delineate molecular mechanisms underlying sensitivity to IMiDs. Genome-wide CRISPR-Cas9 knockout (KO) screening identified TRAF2, a member of TNF receptorassociated factor (TRAF) protein family, to regulate IMiD sensitivity. We show that TRAF2 KO-induced IMiD resistance is mediated via activation of noncanonical NF-B and downstream MEK-ERK signaling, independent of CRBN-IKZF1/3 axis. Within MM BMSC supernatants (SC-sup), TNF- induces proteasomal degradation of TRAF2, followed by noncanonical NF-B and downstream ERK signaling, whereas IL-6 directly triggers ERK activation. Combination MEK inhibitor treatment restores IMiD sensitivity of TRAF2 KO cells with high phosphorylated ERK (p-ERK) both in vitro in the presence of SC-sup and in vivo in an inducible TRAF2 knockdown (KD) MM xenograft model. These data, coupled with RNA sequencing (RNA-seq) showing enrichment of ERK signaling in patients with MM at the time of relapse while on single-agent Len maintenance therapy, provide the framework for clinical trials of MEK inhibitors to overcome IMiD resistance and improve patient outcome in MM.

We first carried out genome-wide CRISPR-Cas9 KO screening to identify genes and/or pathways mediating IMiD sensitivity (Fig. 1A and fig. S1, A and B). As expected, most of the positively selected genes are associated with activity of CRL4CRBN E3 ligase, the main target of IMiDs mediating their anti-MM activity. Among these genes, we have previously validated that COP9 signalosome complex regulates sensitivity to IMiDs by modulating CRBN expression (31). TRAF2 was identified in our top 10 genes list (Fig. 1A and fig. S1A), and we demonstrated that three different single-guide RNAs (sgRNAs) targeting TRAF2 were enriched after IMiD treatment (Fig. 1, B and C). To confirm that TRAF2 modulates IMiD sensitivity, we individually cloned the TRAF2 sgRNAs into the LentiCRISPRv2 vector (38) and reintroduced them into MM cells. As expected, TRAF2-KO MM cells acquired notable resistance to Pom and Len treatment (Fig. 1, D and E, and fig. S2, A to C). Conversely, IMiD-resistant RPMI 8226 MM cell line showed increased sensitivity to Pom when TRAF2 was overexpressed (fig. S2D). In patient samples, TRAF2 mRNA was expressed in samples from patients relapsing on Len [Dana-Farber Cancer Institute (DFCI)/Intergroupe Francophone du Myelome (IFM)] and on other therapies (CoMMpass database) (fig. S2E). However, TRAF2 immunohistochemical analysis of BM biopsies from six patients at the time of diagnosis with disease sensistive to Len compared to the time of relapse with disease resistant to single-agent Len maintenance demonstrated lower expression of TRAF2 protein in five of six samples at the time of relapse (Fig. 1F), suggesting that posttranslational modification of TRAF2 may account for clinical resistance. These data demonstrate that TRAF2 expression modulates sensitivity of MM cells to IMiDs.

(A) Volcano plot showing both positively and negatively selected genes in the CRISPR-Cas9 screen at day 21 after Pom treatment. Genes shown in red and blue represent positively and negatively selected genes, respectively. NS, not significant. (B) Normalized reads of sgTRAF2 from cells treated with either dimethyl sulfoxide (DMSO) control or Pom at the indicated time points. Veh, DMSO control. (C) Enrichment of TRAF2 and CRBN sgRNAs after Pom treatment. Each dot specifies one sgRNA. (D and E) Dose-dependent survival of Pom-treated (D) and Len-treated (E) MM.1S cells infected with individually cloned lentiCRISPR viruses targeting the selected gene candidates. Controls were null-targeting lentiCRISPR viruses. Error bars represent SEM (n = 3). IC50, half maximal inhibitory concentration. (F) Representative images of TRAF2 protein expression assessed by immunohistochemical staining of BM biopsies from six patients at time of diagnosis with disease sensitive to Len and at time of relapse with disease resistant to single-agent Len maintenance therapy. Scale bar, 20 M. (G) Representative Western blot analysis of control and TRAF2 KO MM.1S cells treated with DMSO, 0.5 M Pom, or 1 M Len for 72 hours. Whole-cell lysates (WCLs) were collected and probed with indicated Abs. GAPDH, glyceraldehyde-3-phosphate dehydrogenase; NT, non-targeting.

Because previous studies showed that CRBN-IKZF1/3 axis plays a crucial role in IMiD-induced MM cell growth inhibition, we next examined whether TRAF2 KO-induced IMiD resistance was CRL4CRBN ligase activity dependent. TRAF2 KO showed no effect on CRBN expression or IMiD-induced degradation of IKZF1/IKZF3 and down-regulation of interferon regulatory factor 4 (IRF4), the main effector of MM cell survival (Fig. 1G). Together, these data suggest that TRAF2 KOmediated IMiD resistance is independent of CRBN-IKZF1/3 axis.

We next investigated the molecular mechanism underlying IMiD resistance in TRAF2 KO cells. TRAF2 KO inhibited cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP) triggered by Pom and Len (Fig. 2, A and B, and fig. S3, A and B), indicating that TRAF2 KO inhibits apoptotic cell death triggered by IMiDs. We further confirmed that TRAF2 was required for IMiD-induced cytotoxicity using CellTiter-Glo Luminescent Cell Viability Assay (Fig. 2C and fig. S3C) and flow cytometric analysis with annexin V staining (fig. S3D). Notably, TRAF2 KO has no effect on MM cell growth and cell cycle (fig. S3, E and F). We also examined cross-resistance of TRAF2 KO cells to other therapeutic agents. Viability assays showed that TRAF2 KO cells were also resistant to dexamethasome and melphalan treatment (fig. S3G) but remained sensitive to bortezomib (BTZ) (fig. S3H). These data indicate that TRAF2 KOinduced drug resistance is not specific to IMiDs and independent of ubiquitin-proteasome pathway.

(A and B) Representative Western blot analyses of control and TRAF2 KO MM.1S cells treated with DMSO or 1 M Pom (A) or 1 M Len (B) for 72 hours. WCLs were collected and probed with indicated Abs. (C) Percentage cell viability of control and TRAF2 KO MM.1S cells treated with 0.5 M Pom for 72 hours. Cell viability was determined using CellTiter-Glo (CTG) cell viability assay. CRBN KO cells were analyzed as a positive control. Data are shown as means SEM. ***P < 0.001 by two-sided Students t test. (D) Gene set enrichment analysis plots of datasets identified comparing TRAF2 KO and wild-type signatures. NES, normalized enrichment score. FDR, false discovery rate. (E) Nuclear and cytoplasmic protein were extracted from MM.1S TRAF2 KO cells and immunoblotted with indicated Abs. Cyto, cytoplasmic; nuc, nuclear. (F) WCLs from control and TRAF2 KO MM.1S cells were probed for p-ERK, ERK, and TRAF2 by immunoblotting. The numbers under the bands of blots indicate band intensity normalized to control.

We next performed RNA-seq to delineate signaling cascades mediating IMiD resistance induced by TRAF2 KO. Both noncanonical NF-B (Fig. 2D, left) and ERK (Fig. 2D, right) pathways were enriched in TRAF2 KO cells, consistent with previous reports that TRAF2 regulates NF-B and ERK signaling pathways (39). TRAF2 KO cells showed significantly increased processing of precursor p100 to p52 (NFB2) (Fig. 2E and fig. S4A) and up-regulation of NF-Binducing kinase (NIK) (fig. S4B), as well as activation of noncanonical NF-B pathway (fig. S4C), with minimal impact on p105 or p50 (NFB1) protein expression (fig. S4D). These results suggest that TRAF2 KO predominantly activated noncanonical NF-B pathway. Consistent with RNA-seq analysis, we also confirmed that phosphorylation of ERK and upstream MEK were significantly up-regulated in TRAF2 KO MM cells (Fig. 2F and fig. S4, E to G).

Because both noncanonical NF-B and MEK-ERK pathways were activated in TRAF2 KO cells, we next examined interaction of these signaling pathways mediating IMiD resistance. p52 (NFB2) KO significantly reduced phosphorylation of MEK and ERK in TRAF2 KO cells (Fig. 3A), suggesting that noncanonical NF-B pathway may regulate MEK-ERK activity in TRAF2 KO cells. Moreover, p52 KO in TRAF2 KO cells resensitized them to IMiD treatment (Fig. 3, B and C, and fig. S4H). To further confirm the role of up-regulation of phosphorylated MEK-ERK in resistance to IMiDs, we overexpressed p-ERK2 in IMiD-sensitive MM.1S cells, which conferred resistance to IMiDs (Fig. 3D and fig. S4I). Together, these results indicate that TRAF2 KO activates noncanonical NF-B and downstream MEK-ERK signaling mediating IMiD resistance in MM cells.

(A) Representative Western blot analysis of control and KO MM.1S cells. WCLs were collected and probed with indicated Abs. (B) Percentage cell viability of sgTRAF2 and/or sgp52 MM.1S cells treated with 0.5 M Pom for 72 hours. Cell viability was determined using CTG assay. (C) KO efficiency of p100, p52, and TRAF2 in MM.1S cells was assessed by immunoblot analysis. (D) MM.1S cells were infected with lentivirus to constitutively express activated ERK2 and then treated with Pom (0 to 180 nM) for 72 hours. Cell viability was determined using CTG assay. Data in (B) and (D) are shown as means SEM. ***P < 0.001 by two-sided Students t test. OE, over-expressed; GFP, green fluorescent protein. (E and F) RNA-seq data from MM patient samples of 69 patients at first relapse on Len maintenance therapy. Enrichment scores for ERK pathway activation (E) and correlation between ERK and noncanonical NF-B pathway activation (F) were analyzed.

We next evaluated the clinical significance of ERK activation in relapsed MM patient samples. RNA-seq data from 69 MM patient samples demonstrated activated ERK pathway in 97% cases at the time of first relapse while receiving Len maintenance therapy (Fig. 3E). There was also a significant positive correlation between ERK and noncanonical NF-B signaling in relapsed MM patient samples (Fig. 3F and fig. S4J). These data suggest a pivotal role of ERK activity in mediating IMiD resistance in the clinical setting.

Because we confirmed that ERK activity mediates IMiD resistance, we next sought to determine whether blockade of ERK pathway can overcome IMiD resistance induced by TRAF2 KO. AZD6244 is a potent and highly selective MEK inhibitor (40), and we examined whether AZD6244 abrogated IMiD resistance in TRAF2 KO cells. We first showed that AZD6244 in combination with IMiDs triggered synergistic cytotoxicity in MM.1S wild-type (WT) cells, evidenced by inhibition of cell proliferation (fig. S5, A and B). Addition of AZD6244 overcame resistance and mediated synergistic cytotoxicity with IMiDs in TRAF2 KO MM cells, evidenced by decreased proliferation and p-ERK1/2, as well as by increased induction of PARP cleavage (Fig. 4, A and B, and fig. S5, C to E). To assess the efficacy of combination treatment in vivo, we first generated inducible TRAF2 KD MM.1S cells and confirmed that TRAF2 KD triggered activation of noncanonical NF-B and ERK pathways (fig. S5F) and Pom resistance (fig. S5G) in vitro. These cells were then subcutaneously injected into severe combined immunodeficient (SCID) mice, allowing for induction of TRAF2 KD by intraperitoneal injection of doxycycline. MM.1S WT cells were sensitive to Pom treatment, whereas MM.1S TRAF2 KD cells demonstrated resistance. The combination of AZD6244 and Pom significantly reduced in vivo tumor growth of TRAF2 KD cells, without associated host weight loss (Fig. 4, C to F). These data indicate that MEK inhibitor can abrogate activation of ERK1/2 and overcome IMiD resistance in vivo. Together, our results show that activation ERK signaling plays a crucial role modulating IMiD sensitivity and that MEK inhibitor can overcome ERK-mediated resistance and restore IMiD-induced MM cytotoxicity.

(A) Percentage cell growth of TRAF2 KO MM.1S cells after 3 days of treatment with Len (0 to 1 M) and ERK inhibitor AZD6244 (0 to 1 M). Cell growth was determined using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. (B) Representative Western blot analysis of TRAF2 KO MM.1S cells treated for 48 hours with AZD6244 (0 to 3 M), Len (0 to 3 M), or both. WCLs were collected and probed with PARP Ab. (C to F) MM.1S cells expressing doxycycline-induced shTRAF2 were injected subcutaneously into CB-17 SCID mice (n = 5 for each group). When tumors reached 100 mm3, mice were randomized and treated with vehicle, Pom (2.5 mg/kg), AZD6244 (12.5 mg/kg), or both drugs for 3 weeks. (C) Macroscopic photographs after 21 days of therapy. (Photo credit: Jiye Liu, DFCI). Tumor volume (D) and body weight (E) were monitored over the indicated time period. Data in (D) and (E) are shown as means SEM. **P < 0.01 by two-sided Students t test. (F) Representative images of TRAF2 and p-ERK1/2 immunohistochemistry stain in tumor tissue sections from each group. Scale bars, 40 M.

We and others have shown that the BM microenvironment plays an important role in promoting proliferation, survival, and drug resistance in MM cells (41). Specifically, we showed that either BMSCs or SC-sup activate NF-B and MEK-ERK pathways (37). We therefore next examined the relevance of TRAF2 KO-induced ERK activation-mediated IMiD resistance in the context of the BM microenvironment. As expected, coculture of MM cells with BMSCs (Fig. 5, A and B, and fig. S6, A and B) conferred resistance to IMiDs. Moreover, BMSC supernatants (SC-sup) similarly enhanced MM cell growth and conferred resistance to IMiDs (Fig. 5, C and D, and fig. S6C) associated with down-regulation of TRAF2 (Fig. 5E) and up-regulation of p-ERK (Fig. 5F). These data suggest that IMiD resistance in the BM microenvironment can be mediated, at least in part, by TRAF2 down-regulationinduced ERK activation.

(A and B) MM.1S cells were treated with indicated concentrations of Pom (A) or Len (B) in the presence or absence of BMSC. Cell growth was determined using MTT assay. (C) Percentage cell growth of MM.1S cells after 3 days culture with stromal cell supernatants (SC-sup). Cell growth (means SEM) was determined using MTT assay and normalized to medium control. SCs were from five patients with MM. (D) Percentage cell growth of MM.1S cells after 3 days of treatment with Pom (1 M), SC-sup, or both. Cell growth was determined using MTT assay and normalized to the DMSO control group. (E) Immunoblot analysis of TRAF2 protein level in MM.1S cells cultured with SC-sup for 48 hours. SCs were from five patients with MM. (F) MM.1S cells were cultured for 0 to 24 hours in the presence or absence of SC-sup. WCLs were collected and probed with p-ERK1/2 and ERK1/2 Abs. The numbers under the bands of blots indicate band intensity normalized to control. Data in (A) to (D) are shown as means SEM. ****P < 0.0001 and **P < 0.01 by two-sided Students t test.

To further delineate the mechanism whereby SC-sup confers IMiD resistance, we next performed cytokine array analysis and identified that TNF- and IL-6 were highly secreted by BMSCs (Fig. 6A). TNF-, but not IL-6, treatment induced TRAF2 down-regulation in MM cell lines (Fig. 6, B and C) and patient MM cells (Fig. 6D). TNF- significantly inhibited IMiD-induced MM cytotoxicity in a dose-dependent manner (Fig. 6E and fig. S7, A to C), and similar to TRAF2 KO, TNF- induced IMiD resistance by activating ERK and noncanonical NF-B pathways (fig. S7, D and E), without altering CRBN expression (fig. S7F).

(A) Representative image of cytokine Ab array screening of SC-sup. Supernatant was collected after 24-hour culture with BMSCs and filtered by a 0.22 M low-protein binding membrane. (B) Representative Western blot analysis of MM.1S cells treated with TNF- or IL-6 for 24 hours. WCLs were collected and probed with TRAF2 Ab. (C) MM cell lines were treated with TNF- (5 ng/ml) for 48 hours. Cell lysates were collected and blotted with TRAF2 Ab. (D) Immunoblot analysis of patient MM cells treated with TNF- (5 ng/ml) for 48 hours. WCL was collected and probed with TRAF2 Ab. (E) Percentage cell growth of MM.1S cells after 5 days of treatment with Pom (0 to 3 M) and/or TNF- (0 to 3 ng/ml). Cell growth (means SEM) was determined using MTT assay. (F) MM.1S cells were treated with TNF- (5 ng/ml) for 0 to 10 hours. WCLs were collected and probed with TRAF2 Ab. (G) MM.1S cells were treated with 0.5 nM BTZ or 2.5 nM CFZ for 2 hours, followed by treatment with TNF- (10 ng/ml) for 24 hours. WCLs were collected and probed with TRAF2 Ab. (H) MM.1S cells were cultured with TNF- (5 ng/ml) for 18 hours and then treated with MG132 (10 M) for 6 hours. WCLs were collected and immunoprecipitated by anti-TRAF2 Ab and probed for polyubiquitinated protein and TRAF2. IP, immunoprecipitated. The numbers under the bands of blots indicate band intensity normalized to control.

To further define the mechanism of TNF-mediated TRAF2 down-regulation, we next showed that TNF- promoted TRAF2 protein degradation in a time- and dose-dependent manner (Fig. 6F and fig. S8A) and that the half-life of TRAF2 was markedly shortened by TNF- treatment (fig. S8B). Because previous studies identified TRAF2 as a substrate of the proteasome (42), we also treated MM cells with TNF- in the presence or absence of proteasome inhibitor BTZ or carfilzomib (CFZ). Notably, TRAF2 down-regulation triggered by TNF- was inhibited by these proteasome inhibitors (Fig. 6G), associated with accumulation of ubiquitinated TRAF2 (Fig. 6H). These data confirm that TNF-induced TRAF2 down-regulation is due, at least in part, to its proteasomal degradation in MM cells. As described above, TRAF2 KO induced MEK-ERK phosphorylation via noncanonical NF-B activation, resulting in IMiD resistance. Consistent with a previous study (43), we also show that TNF- also triggered ERK phosphorylation (fig. S7D). Last, we and others have shown that IL-6 activates ERK signaling and resistance to dexamethasone-induced MM cell apoptosis (44). Here, we show that IL-6 also directly induces IMiD resistance (Fig. 7A). In contrast, IGF-1 does not trigger ERK activation or IMiD resistance (fig. S9). These data therefore indicate that soluble factors which induce MEK-ERK activation can protect MM cells from IMiD-induced cytotoxicity in the BM microenvironment.

(A) Percentage cell growth of MM.1S cells after 5 days of treatment with Len (0 to 3 M) and/or IL-6 (0 to 10 ng/ml). Cell growth (means SEM) was determined using MTT assay. (B) Representative Western blot analysis of MM.1S cells cultured for 72 hours in the presence of BMCS with AZD6244 (1 M), Len (1 M), or both. WCLs were collected and probed with anti-cleaved PARP, IKZF1, p-ERK, and ERK Abs. (C) Percentage MM.1S cell growth in cultures with or without SC-sup after 5 days of treatment with Pom (0 to 1 M), AZD6244 (0 to 1 M), or both. Cell growth (means SEM) was determined using MTT assay. (D) Percentage MM.1S cell growth in cultures with IL-6 (5 ng/ml) after 5 days of treatment with Pom (0 to 1 M), AZD6244 (0 to 1 M), or both. Cell growth (means SEM) was determined using CTG assay. (E) Percentage MM.1S cell growth in cultures with TNF- (5 ng/ml) after 5 days of treatment with Pom (0 to 1 M), AZD6244 (0 to 1 M), or both. Cell growth (means SEM) was determined using CTG assay.

Because SC-sup (Fig. 5F), TNF- (fig. S7D), and IL-6 (Fig. 7A) induced ERK phosphorylation and IMiD resistance in MM cells, we next determined whether MEK inhibitor was able to inhibit ERK1/2 phosphorylation and overcome IMiD resistance in the context of the BM microenvironment. We first showed that SC-supinduced phosphorylation of ERK was completely blocked by a MEK inhibitor, AZD6244 (Fig. 7B). Moreover, PARP cleavage was markedly enhanced by combination treatment of Pom with AZD6244, without affecting IKZF1 degradation (Fig. 7B). Addition of AZD6244 overcame resistance to Pom and Len in SC-suptreated MM cells (Fig. 7C and fig. S10, A and B). We also observed that IMiD resistance triggered by IL-6 or TNF- was similarly abrogated by AZD6244 (Fig. 7, D and E). These data indicate that MEK-ERK inhibitor can overcome IMiD resistance triggered by TNF- and IL-6 in SC-sup and restore MM cell sensitivity to IMiD treatment in the BM millieu.

During the past two decades, IMiDs have demonstrated remarkable anti-MM activity when used alone or combined with proteasome inhibitors and/or monoclonal Abs as initial, salvage, and maintenance therapies (7, 25, 26, 45, 46). More potent IMiDs with enhanced affinity to CRBN have recently been developed to even further increase their clinical efficacy (4749). Moreover, we and others (24) have also identified novel binding protein of IMiDs, such as TP53-regulating kinase, which may broaden their clinical utility. However, most MM cells eventually acquire resistance to IMiDs, which has, to date, been attributed to decreased expression of CRBN and rarely CRBN mutations (50, 51). Defining mechanisms underlying clinical resistance to IMiDs is therefore essential to inform the design of novel strategies to restore and/or enhance IMiD sensistivity and improve patient outcome.

Targeted genome editing technologies have transformed our abilities to discover basic biological mechanisms underlying specific phenotypes (52, 53). Specifically, the development of the CRISPR-Cas9 system and Cas9-based functional genetic screening tools has facilitated the identification of genes essential for drug resistance (54, 55), and we have used genome-wide CRISPR-Cas9 KO screening to delineate mechanisms of IMiD resistance in MM. We found that many CRL4CRBN E3 ubiquitin ligaseassociated genes are enriched in positively selected genes, confirming that CRBN pathway genes mediate sensitivity of MM to IMiDs. Conversely, many genes essential for MM survival and proliferation (31, 5658) are depleted in negatively selected genes. From this screening, we previously identified the signalosome (CSN) family genes to be positively enriched, and validated that CSN genes regulate CRBN expression, suggesting that strategies to up-regulate CSN may restore CRBN levels and IMiD sensitivity (31). In the current study, we identified TRAF2 as one of the top 10 genes positively selected in our genome-wide CRISPR-Cas9 KO screening. TRAF2 is a member of the TRAF protein family functions as a component of TNF receptor complex and mediates activation of NF-B and/or ERK pathways (59, 60). It also functions as a RING domain E3 ligase that is activated by sphingosine-1-phosphate and catalyzes the lysine-63linked polyuniquitination of receptor interacting serine/threonine kinase 1 (RIP1), thereby leading to NF-B activation (61).

An integrated analysis from 155 MM samples identified that inactive mutations of TRAF2 result in constitutive activation of noncanonical NF-B pathway (62). Here, we show that TRAF2 KO significantly induces IMiD resistance, thereby identifying TRAF2 as an essential mediator of IMiD sensitivity in MM cells. However, TRAF2 KO does not alter CRBN expression or IMiD-induced degradation of IKZF1/3 and its downstream targets IRF4 and c-Myc. Our data therefore identify a novel mechanism underlying IMiD resistance, independent of the CRBN-IZKF1/3 axis. We show that IMiD resistance in TRAF2 KO cells is mediated by noncanonical NF-B and its downstream ERK signaling and that MEK inhibitor AZD6244 can restore sensitivity to IMiDs in vitro and in vivo using our inducible TRAF2 KD MM model. This is of great potential clinical interest, because our analyses of RNA-seq data show nearly universal activation of ERK signaling in MM patient samples at the time of first relapse while on Len maintenance therapy, suggesting that ERK inhibitor may restore IMiD sensitivity in the clinic.

We and others have shown that BMSCs and accessory cells (plasmacytoid dendritic cells, myeloid-derived suppressor cells, osteoclasts, and T regulatory cells) in the MM BM microenvironment play a crucial role in MM pathogenesis by promoting tumor cell growth, survival, and immunosuppression, as well as conferring drug resistance. These biologic sequelae are due to direct tumor cellBMSC/accessory cell interaction (35) and/or secretion of soluble factors including IL-6, TNF-, IGF-1, and vascular endothelial growth factor (63, 64) in the BM milieu. Moreover, our early studies showed that TNF- can directly stimulate the production of IL-6 and up-regulate adhesion molecules (65), thereby further promoting tumor/accessory cell interactions. Here, we show that SC-sup, IL-6, and TNF- induce IMiD resistance in MM cells mediated via ERK signaling. Although IL-6 directly activates ERK signaling, we show that TNF- triggers proteasomal degradation of TRAF2 and activation of noncanonical NF-B, with downstream ERK pathway activation. In contrast, IGF-1 neither activates ERK signaling nor triggers IMiD resistance. Therefore, ERK pathway signaling is implicated in mediating IMiD resistance triggered by multiple stimuli in the BM milieu. Combination MEK inhibitor AZD6244 with IMiDs overcomes resistance to Pom and Len conferred by the BM milieu.

In summary, we have identified and validated that activation of MEK-ERK pathway directly by soluble factors (i.e., IL-6) or indirectly by activation of TRAF2 degradationinduced noncanonical NF-B activation mediates IMiD resistance in the BM microenvironment. These studies not only delineate a novel CRBN-independent mechanism of IMiD resistance in the BM milieu but also provide the preclinical rationale for combining inhibitors of MEK/ERK signaling with Len or Pom to overcome IMiD resistance and improve patient outcome in MM.

MM.1S, RPMI 8226, H929, U266, and human embryonic kidney (HEK) 293T cells were purchased from the American Type Culture Collection. AMO-1, JJN-3, OPM2, and KMS-12BM cells were purchased from Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ). All cell lines were verified by short tandem repeat (STR) DNA fingerprinting analysis (Molecular Diagnostic Laboratory, DFCI) and tested for mycoplasma using the MycoAlert Mycoplasma Detection Kit (Lonza). All cells were grown at 37C in 5% CO2 condition: MM.1S, RPMI 8226, H929, U266, AMO-1, JJN-3, OPM2, and KMS-12BM cells were maintained in RPMI 1640 medium; HEK293T cells were maintained in Dulbeccos modified Eagles medium. All media were supplemented with 10% fetal bovine serum (FBS), 1 antibiotic-antimycotic, 1 GlutaMAX, and 1 Hepes.

BM samples were obtained from patients with MM after informed consent and approval by the Institutional Review Board of the DFCI. Mononuclear cells were separated by Ficoll-Paque PLUS (GE Healthcare Life Sciences). MM cells were purified by CD138-positive selection with human CD138 MicroBeads (Miltenyi). Long-term BMSCs were established by culturing CD138-negative BM mononuclear cells for 4 to 6 weeks in RPMI 1640 medium supplemented with 10% FBS and 1 antibiotic-antimycotic.

The culture medium of established BMSCs was replaced with fresh complete medium. Supernatant was collected 24 hours later, followed by centrifugation at 2000 rpm for 10 min to clear cells and debris. Filtration was then performed with a 0.22 M low-protein binding membrane (Millipore Sigma).

Len, Pom, BTZ, CFZ, and MG132 were purchased from Selleck Chemicals; AZD6244 was purchased from Cayman Chemical. All were dissolved in dimethyl sulfoxide (DMSO) and stored at 20C for up to 6 months. For all cell-based experiments, drugs were diluted at least by 1:1000 to ensure that the final DMSO concentration was lower than 0.1%. Cycloheximide solution was purchased from Millipore Sigma. Human recombinant TNF- and IL-6 were purchased from STEMCELL Technologies. Doxycycline was purchased from Boston Bioproducts. Abs were obtained as follows: IKZF1 (no. 5443, Cell Signaling Technology), IKZF3 (no. 15103, Cell Signaling Technology), IRF4 (no. 4299, Cell Signaling Technology), CRBN (no. SAB045910, Sigma-Aldrich), TRAF2 (no. 4724, Cell Signaling Technology and no. ab126758, Abcam), glyceraldehyde-3-phosphate dehydrogenase (no. 5174, Cell Signaling Technology), cleaved PARP (no. 5625, Cell Signaling Technology), caspase-3 (no. 14220, Cell Signaling Technology), NF-B2 p100/p52 (no. 4882, Cell Signaling Technology), histone H3 (no. 4499, Cell Signaling Technology), phosphoNF-B2 p100 (Ser866/870) (no. 4810, Cell Signaling Technology), ubiquitin (no. 3936, Cell Signaling Technology), p44/42 MAPK (Erk1/2) (no. 4695, Cell Signaling Technology), phosphor-p44/42 MAPK (Erk1/2) (Thr202/Tyr204) (no. 4370, Cell Signaling Technology), pan-actin (no. 8456, Cell Signaling Technology), NF-B1 p105/p50 (no. 3035, Cell Signaling Technology), lamin A/C (no. 4777, Cell Signaling Technology), anti-rabbit immunoglobulin G (IgG), horseradish peroxidase (HRP)linked Ab (no. 7074, Cell Signaling Technology), and anti-mouse IgG, HRP-linked Ab (no. 7076, Cell Signaling Technology). Protein G Sepharose was purchased from Millipore Sigma.

For RNA-seq, total RNA of WT and TRAF2 KO cells was extracted using the RNeasy Mini Kit (Qiagen). Library was prepared, and samples were sequenced on NovaSeq 6000 PE150. RNA-seq datasets were aligned to human reference genome hg38 using Homo sapiens steroidogenic acute regulatory protein (STAR). RNA-seq by expectation-maximization was used to do the transcript quantification, and differential expression analysis was performed with DESeq2. Gene set enrichment analysis (GSEA) was performed to identify significantly enriched pathways. The biologically defined gene sets were obtained from the Molecular Signatures Database (http://software.broadinstitute.org/gsea/msigdb/index.jsp). Genes used for GSEA analysis were preranked on the basis of log2 fold change of TPM (transcripts per kilobase million) between WT and TRAF2 KO cells.

Cells were plated in medium (8000 cells per well, 100-l final volume) in white, 96-well opaque plates (no. 3917, Corning). Cells were incubated for indicated intervals at 37C in a 5% CO2 incubator. Assay plates were removed from the incubator and equilibrated to room temperature before addition of 50 l of CellTiter-Glo reagent (Promega), according to the manufacturers instructions. Plates were shaken on an orbital shaker for 2 min at 500 rpm and then incubated at room temperature on the bench top for at least 10 min. Luminescence was detected using a spectrophotometer (SpectraMax M3, Molecular Devices).

The growth-inhibitory effect was assessed by measuring 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) (Sigma-Aldrich) dye absorbance, as previously described (56). Cells were cultured in 96-well plates (100 l) with or without drug treatment; for the last 4 hours, cells were pulsed with 10 l of MTT, followed by addition of 100 l of isopropanol containing 0.04 N HCl. Absorbance was measured at 570 nm, with 630 nm as a reference wavelength, using a spectrophotometer (SpectraMax M3, Molecular Devices).

Cells were treated, harvested, washed with phosphate-buffered saline, and lysed in radioimmunoprecipitation assay buffer (no. R0278, Millipore Sigma) containing protease inhibitor and phosphatase inhibitor (no. 78440, Thermo Fisher Scientific). The suspension was incubated for 15 min on ice and vortexed for 5 min. Then, samples were centrifuged at 13,000 rpm at 4C for 10 min. The supernatant was used as whole-cell lysates. Protein concentrations were quantified with a BCA protein assay kit (no. 23227, Thermo Fisher Scientific). Samples were mixed with 4 LDS sample buffer (no. NP0007, Thermo Fisher Scientific), and boiled at 95C for 8 min. Equal amounts of protein were run on NuPAGE Bis-Tris gels (Thermo Fisher Scientific) at a constant voltage. Proteins were transferred onto nitrocellulose membrane by iBlot Gel Transfer Device (Thermo Fisher Scientific). Then, the membranes were blocked in 5% nonfat dry milk for 1 hour at room temperature and incubated with primary Abs in 5% bovine serum albumin at 4C overnight. Blots were then washed three times with 1 Tris Buffered Saline with Tween (TBS-T), before incubation with secondary Abs for 1 hour. SuperSignal chemiluminescent substrate (Thermo Fisher Scientific) was used for signal detection. For reblotting the membranes, blots were stripped in stripping buffer (no. 46428, Thermo Fisher Scientific) according to the manufacturers instruction and reblocked. The intensity of band was quantified by ImageStudio (LI-COR).

On day 0, HEK293T cells were plated in a T150 flask. On day 1, for each flask, 20 g of lentiviral vector, 15 g of psPAX2 (no. 12260, Addgene), and 10 g of pMD2.G (no. 12259, Addgene) diluted in 3 ml of Opti-MEM were combined with 150 l of Lipofectamine 2000 diluted in 3 ml of Opti-MEM. The mixture was left for 20 min and then added to the cells. Twelve hours after transfection, the medium was replaced by fresh complete medium. The supernatant containing virus was collected 72 hours after transfection, followed by centrifugation at 2000 rpm for 10 min to pellet cell debris. Filtration was then performed with a 0.45-m low-protein binding membrane (no. SE1M003M00, Millipore). Then, the virus was concentrated by the Lenti-X Concentrator (no. 631231, Takara).

For generation of CRISPR KO cell lines, oligonucleotides (table S1) targeting different genes were annealed and subcloned into LentiCRISPRv2 vectors (38). Constructs were packaged into lentivirus in HEK293T cells. Target cells were seeded in 12-well plates and spinfected with virus for 1.5 hours at 2000 rpm at 35C, supplemented with Polybrene (8 g/ml). Medium was then aspirated, and fresh complete medium was added to exclude Polybrene. After 1 day, cells were selected for stable KO using puromycin (0.5 g/ml). After 7 days, cells were collected for immunoblotting or other experiments. To generate inducible TRAF2 KD cells for in vivo study, the SMARTvector inducible human TRAF2 lentivirus plasmid (Horizon Dharmacon) was transfected into HEK293T cells with packaging vectors. Cells were spinfected for 1 hour with viral particles at 2000 rpm at 35C, supplemented with Polybrene (8 g/ml). After 1 day, cells were selected with puromycin (0.5 g/ml) for 7 days. For the constitutive expression of ERK2-MEK1 fusion protein, the sequence of full length of ERK2-MEK1 was cloned from pCMV-myc-ERK2-L4A-MEK1_fusion vector (no. 39197, Addgene) into plenti-CMV-Puro-DEST (no. 17452, Addgene). The expression plasmid was transfected into HEK293T cells with the packaging vectors. Cells were spinfected for 1.5 hours with viral particles at 2000 rpm at 35C, supplemented with Polybrene (8 g/ml). After 1 day, cells were selected with puromycin (0.5 g/ml) for 7 days.

The cytokine array assay was performed using a Human Cytokine Array C5 kit (no. AAH-CYT-5-2, RayBiotech), according to the manufacturers instruction.

MM cells were treated with TNF- (5 ng/ml) for 24 hours and then 10 M MG132 for 6 hours. Cells were lysed in IP lysis buffer (no. 87787, Thermo Fisher Scientific). TRAF2 protein was pulled down by Protein G Agarose with TRAF2 Ab overnight at 4C and washed with IP lysis buffer. Protein was eluted by incubation with LDS loading buffer at 100C for 5 min, separated by SDSpolyacrylamide gel electrophoresis, transferred to nitrocellulose membrane, and probed with indicated Abs.

Cells were cultured in 12-well plates with or without TNF- and treated with cycloheximide (100 g/ml) for the indicated time periods before harvest. Cell lysates were analyzed by Western blotting.

A total of 6 106 Tet-inducible TRAF2 KD MM.1S cells were suspended in 100 l of RPMI 1640 medium and injected into the flanks of 200 cGyirradiated female SCID mice. Tumor size was measured every 2 days with an electrical caliper. The tumor volume was determined with the formula: (length width2) 0.5, where length is the longest diameter and width is the shortest diameter. When the tumor volume reached 100 to 150 mm3, xenografted mice were randomized to treatment and control cohorts. In the TRAF2 KD group, mice received doxycycline (2.5 mg/kg) via intraperitoneal injection to induce TRAF2 KD. AZD6244 (12.5 mg/kg per day) and Pom (2.5 mg/kg for 5 days/week) administrated by oral gavage. All care and treatment of experimental animals was conducted under a protocol approved by DFCI Institutional Animal Care and Use Committee guidelines. All mice were housed in a pathogen-free environment at a DFCI animal facility and were handled in strict accordance with Good Animal Practice, as defined by the Office of Laboratory Animal Welfare.

Cells were harvested and concentrations adjusted to 1 106 cells/ml. After washing, cells were suspended in 50 l of Hanks balanced salt solution (HBSS) containing 2% FBS; 1 ml of ice-cold 70% ethanol was then added in a dropwise manner while mixing gently on a vortex, with storage on ice for no less than 2 hours. Pelleted cells were washed with HBSS containing 2% FBS twice, and then 1 ml of 4,6-diamidino-2-phenylindole (DAPI) working solution was added, followed by incubation in the dark for 15 to 30 min at room temperature. Cells were filtered through a 40-m mesh filter and then analyzed by flow cytometry.

MM cells (1 106) were treated with Pom for 5 days and then stained with the LIVE/DEAD Fixable Aqua Dead Cell Staining Kit (no. L34957, Thermo Fisher Scientific) and annexin Vphycoerythrin conjugate (no. 640908, BioLegend), according to the manufacturers instruction. Cells were analyzed in BD FACSCanto II (BD Biosciences) using the FACSDiva software (BD Biosciences).

Tissue specimen sections of formalin-fixed, paraffin-embedded BM biopsies from six patients at diagnosis with MM sensitive to Len and at the time of relapse with disease resistant to single-agent Len were prepared and precessed for immunohistochemistry to detect TRAF2 protein expression by using TRAF2 Ab (no. ab126758, Abcam). Tumor samples from mice were harvested and fixed in formalin and then embedded in paraffin and cut in 4 M sections. Sections were stained with TRAF2, p-ERK1/2, and DAPI. Tissues were imaged using a microscope.

RNA-seq data from 69 patients with MM at the time of first relapse while on single-agent Len maintenance (DFCI/IFM) were collected after study participants provided written informed consent. After RNA extraction, RNA quantity was evaluated, and only samples with 100 ng of RNA with RNA integrity number (RIN) value 7 were sequenced with stranded 50base pair paired-end sequencing. After quality control, raw samples were quantified using Salmon and Gencode transcripts. Single-sample GSEA (ssGSEA), an extension of GSEA, was used to calculate separate enrichment scores for ERK pathway. R and ggpubr were used for statistical test and visualization. Pearson correlation analysis and Fishers exact test were used for association analysis and enrichment in relapse samples. The DFCI/IFM and CoMMpass patient sample RNA-seq databases were used to analyze correlation between noncanonical NF-B and ERK pathway activation in relapsed patient samples. TPM-level gene expression data were used only for patients who had CD138+ BM samples profiled at the time of relapse. We downloaded the Biocarta ERK pathway and Gene Ontology NIK NF-B signaling pathways from the Molecular Signatures Database website, and with ssGSEA, we quantified the enrichment score for each patient. Spearman correlation between the two pathways were evaluated using R and ggpubr.

Students t test or analysis of variance followed by Dunnetts test was used to compare differences between the treated group and the relevant control group. A value of P < 0.05 was considered significant.

Acknowledgments: We thank E. Campeau, M. Robinson, and F. Zhang for expression vectors. We also thank D. Chauhan and E. Morelli for helpful comments. We thank the staff from the hematologic neoplasia core facilities at DFCI for technical assistance. We also thank the Genome Center of WuXi AppTec Inc. for the initial data analysis of the CRISPR screening. Funding: This work was supported by the National Institutes of Health grants SPORE-P50100707 (to K.C.A.), R01-CA050947 (to K.C.A.), R01-CA178264 (to T.H. and K.C.A.), and P01-155258 (K.C.A. and N.M.). K.C.A. is an American Cancer Society Clinical Research Professor. This study was also supported, in part, by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Riney Family Myeloma Initiative, and the National Natural Science Foundation of China (NSFC grant no. 81800204). Author contributions: K.C.A. conceived the project, designed the research, analyzed the data, wrote the manuscript, and supervised the project. J.L. and T.H. designed and performed the research, analyzed data, and wrote the manuscript. J.L. and L.X. performed xenograft experiments. S.W. and W.Z. performed CRISPR-Cas9 screening data analysis. M.K.S. analyzed RNA-seq data from patients with MM. T.S. performed immunohistochemistry. D.O. provided assistance in some cell-based assays. G.A. and G.B. provided BM sections. S.G. and L.Y. performed immunohistochemistry. T.J. performed some Western blot experiments. K.W. helped process the human samples. R.C. provided biological materials and performed immunohistochemistry. Y.-T.T. provided biological material and analyzed data. N.M. and P.R. helped collect patient samples and analyzed data. Y.C. helped analyze data and revised the manuscript. Competing interests: K.C.A. serves on advisory boards to Millennium, Janssen, Sanofi, Bristol Myers Squibb, Gilead, Precision Biosciences, and Tolero and is a scientific founder of OncoPep and C4 Therapeutics. The authors declare that they have no other competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. All sequencing data were uploaded to Gene Expression Omnibus with accession no. GSE171341.

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Lymph nodes are part of the lymphatic system, which is a complex network of nodes and vessels.

In certain areas of the body, such as the neck, armpit, and groin, lymph nodes sit close to the skin. This means a person may feel them swell when an infection develops.

Lymph nodes are also present in the stomach and between the lungs. However, there are no lymph nodes in the brain or spinal cord.

The name of a lymph node depends on its location in the body.

Lymph nodes form clusters throughout the body. Their main function is to filter out potentially harmful substances.

All tissues and cells in the body excrete lymphatic fluid, or lymph, in order to eliminate waste products. The lymph then travels through vessels in the lymphatic system and passes through lymph nodes for filtering.

Lymph nodes contain lymphocytes. These are a type of white blood cells that help destroy pathogens, such as bacteria, viruses, and fungi. When lymph nodes detect a pathogen in the lymph, they produce more lymphocytes, which causes them to swell.

Upon encountering bacteria or damaged cells, lymph nodes destroy them and turn them into a waste product.

When the lymph reenters the bloodstream, waste products travel to the kidneys and liver. The body then excretes waste products in the urine and feces.

Learn more about how the lymphatic system works here.

Swollen lymph nodes do not always indicate cancer. Below, we list some of many conditions that can cause lymph node swelling.

Lymphadenitis occurs when bacteria, viruses, or fungi in the lymph infect lymph nodes. When this happens, lymph nodes swell and are painful to the touch.

If multiple clusters of nodes become infected, a person may feel pain and swelling in both their neck and groin.

The most common type of lymphadenitis is localized lymphadenitis. This means the condition only affects a few nodes. If the infection occurs in several node clusters, a doctor will likely diagnose generalized lymphadenitis.

The condition usually results from an infection elsewhere in the body.

Symptoms of lymphadenitis include:

Lymphadenitis treatments include:

The type of treatment necessary will depend on a variety of factors, such as the severity of the disease and a persons underlying conditions and allergies. A doctor will help a person choose the most suitable treatment based on these factors.

Learn more about swollen lymph nodes in the neck here.

Swollen lymph nodes in the neck may be due to a viral or bacterial throat infection, such as strep throat.

Viral throat infections, such as colds, can present with swollen lymph nodes, a runny nose, and pinkeye.

These infections usually resolve on their own. However, a person can take over-the-counter pain relievers to alleviate pain they may experience when swallowing.

Strep throat is a bacterial infection that develops in the throat and tonsils due to group A streptococcus. People may contract strep throat if they come into contact with droplets containing the strep bacteria.

A person with strep throat may experience swollen lymph nodes on the neck, a sore throat, a fever, and red spots on the roof of the mouth.

Doctors treat strep throat with antibiotics.

Impetigo is an infection that develops due to group A streptococcus and may cause lymph nodes in the armpits and groin to swell.

A person can contract impetigo when the bacteria enter the body through a break in the skin. This can happen through sharing a towel, razor, or yoga mat.

Symptoms of impetigo include:

If a person has impetigo, they should seek medical attention to address their symptoms and prevent the condition from spreading to others.

Treatment will usually involve antibiotics.

Ringworm, or jock itch, is a fungal infection that can affect many areas of the body. If the fungus develops in the groin, a person may experience lymph node swelling in that area.

Typically, ringworm starts as a fungal lesion. The fungus often transmits when people share towels or razors.

Ringworm thrives in moist environments, and therefore a person should take care to dry thoroughly after a wash and try not to stay in damp clothes.

Common ringworm symptoms include:

A doctor will prescribe an antifungal treatment to address ringworm.

The best way to prevent ringworm is to wear breathable fabrics, avoid sharing towels and razors, and dry thoroughly after bathing.

Learn more about swollen lymph nodes in the groin here.

Lymphoma is a type of cancer that affects the lymphatic system. The two main types of lymphoma are Hodgkin lymphoma and non-Hodgkin lymphoma.

Hodgkin lymphoma occurs when cancer cells spread from one cluster of lymph nodes to another. By contrast, in non-Hodgkin lymphoma, there is no order in how cancer cells spread throughout the lymphatic system.

Typical symptoms of lymphoma include:

These are also common symptoms of viral infections, which can make lymphoma hard to diagnose. However, in people with lymphoma, symptoms tend to persist for longer periods of time.

It is of note that these symptoms do not clearly indicate cancer. If a person experiences any of these, they should contact a doctor to identify the cause of their symptoms.

Treatment options for lymphoma include:

A person should contact a healthcare professional if they are experiencing persistent swelling of lymph nodes.

Swelling usually indicates an infection, and therefore a person should not immediately worry about lymphoma.

After reaching a diagnosis, a doctor will recommend the appropriate course of treatment.

Lymph nodes are a part of the lymphatic system. They filter lymph, which contains pathogens and damaged cells, and send the dead cells to the kidneys and liver.

Lymph node swelling usually results from an infection. In rare cases, however, it may be due to lymphoma.

If a person is concerned about swelling and other symptoms they have, they should contact a doctor.

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Lymph nodes: Purpose, location, and disease warning signs - Medical News Today

Living to be 100 used to be a novelty, so much so that Willard Scott, the Today Show weatherman, would announce your name on air in awe (Al Roker still does). Yet, these days it's not so uncommon to live that long. We're all living longer than ever. The Centers for Disease Control and Prevention currently pegs 78 years of age as the average life expectancy. That's not too shabby considering a century ago people lived to be around 39 (due to an influenza outbreak).

But what if we could push it 25 years more?

Worldwide, there are nearly 500,000 people who have made, or surpassed, the 100-mark, and this number is projected to grow to 3.7 million by 2050. Here, Eat This, Not That! Health rounds-up the latest research that'll not only help you to live to be triple digits, but ensure you're happy doing so. Read onand to ensure your health and the health of others, don't miss these 19 Ways You're Ruining Your Body, Say Health Experts.

Don't down a bottle of Jgermeister in hopes of a long life ahead. But a glass of red wine, by all means. "Our research shows that light-to-moderate drinking might have some protective effects against cardiovascular disease," says Bo Xi, MD, associate professor at the Shandong University School of Public Health in China and the lead author of a study published in the Journal of the American College of Cardiology, "while heavy drinking can lead to death. A delicate balance exists between the beneficial and detrimental."

The Rx: Red wine contains antioxidants, can lower cholesterol, reduces the risk of stroke and increases bone density. Enjoy one to two glasses a day if you wish.

Eating meat less than once a week may increase longevity by 3.6 years, according to a study published in the American Journal of Nutrition. Another 22-year study out of Finland found increased mortality and disease among individuals with higher animal protein intakes.

The Rx: If you must eat meat, opt for leaner proteins (chicken, turkey, lean cuts of beef) and keep off the bacon and sausages since diets heavy in processed meats are linked to higher risk of cancer and heart disease. Otherwise, explore the exciting new world of plant-based nutrition, with a product like Beyond Meat, made with pea protein.

Be mindful of your surroundings, and what you're breathing in. Everything from Benzene (found in gasoline), smoke, and other toxins can lead to cell degeneration and increase mortality rates, studies show.

The Rx: Don't miss this essential list of 100 Ways Your Home Could be Making You Sick.

Olive oil, veggies, fruits, nuts, seafood and a moderate amount of wine and cheesewe've all heard the Mediterranean diet is the secret to a longer life. In fact, numerous studies have linked the diet to improving brain health and function, lower risk of cancer and other diseases.

The Rx: Now it's time you tried it. Eat almonds, hummus, wild salmon, garlic, lemon, quinoa, cauliflower, chia seeds and olives frequently. Eat eggs, Skyr, and chicken moderately. And eat red meat rarely. Avoid entirely the packaged, processed, store-bought items that are loaded with additives.

RELATED: 9 Everyday Habits That Might Lead to Dementia, Say Experts

Gene variants found in centenarians have been linked to their longer lives. A healthy lifestyle can help people live into old age, but these genes help maintain basic maintenance and function of the body's cells in individuals of advanced age, in their 80s and beyond.

The Rx: You can't outrun genetics but you can learn about yours. Consider taking a DNA test, in which you'll learn about your proclivity to certain diseases.

Japan is doing something right! It currently holds the title of longest life span, according to the World Health Organization. This may have something to do with the size of their plates. When it comes to diet, the Japanese tend to eat smaller portionsspecifically the size of a salad plateand don't overstuff themselves. Centenarians studied in Okinawa stop eating when they are 80 percent full. They also tend to live seven years longer than Americans, according to a study, and have fewer cases of heart disease and cancer.

The Rx: Experiment with the 80% rule. Or at the very least, don't keep eating when you feel full.

Don't work so hard; your life depends on it. A Finnish study followed male businessman born between 1919 and 1934, and found that those who didn't sleep enough, were overworked, and didn't take enough time off (i.e. vacation) were 37 percent more likely to die between the years of 1974 and 2004. By 2015, some of the oldest participants, who always took their vacay, reached 81 to 96 years of age.

The Rx: Our current culture rewards non-stop go-and-do work. But at what cost? If you have vacation days, use them to unplug, and be firm with your boss if you must. He'll value your work more if you're alive than dead.

RELATED: The #1 Reason You Could Get Cancer, According to Science

Each hour you binge Netflix, Hulu, HBOthe list goes onafter the age of 25 may cut your life by 22 minutes, according to research out of the University of Queensland, Australia. Those who spent an average of six hours in front of the tube per day were also likely to die five years earlier than those that didn't watch TV at all.

The Rx: There are other reasons to stop clicking "next episode." They can be addictive and eat up your time. (Robert De Niro is currently suing an ex-employee because he watched 55 episodes of Friends in a row.) Enjoy your One Day at a Timeone episode at a time.

A study out of the University of Naples found that too little or too much sleepsleeping less or more than six to eight hours on averageis linked to a 30 percent higher chance of premature death.

The Rx: Seven to eight hours of shuteye is the sweet spot.

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Packed with vitamin C and other nutrients, studies have found mustards, also known as Brassicaceae, will keep you around longer, according to researchers.

The Rx: Enojy cabbage, broccoli, cauliflower, kale, radishes, watercress, Brussels sprouts and a few spices like horseradish, wasabi and, yes, white, Indian and black mustard.

Hey, none of us are getting out of this alive, but that's no reason to keep that sour mug. Researchers examined smile intensity among photos of baseball players from the 1950s. Of the players who had died in the years 2006 to 2009, those who were not smiling in those photos lived an average of 72.9 years, while the big smilers lived nearly 80 years. They concluded that there's a clear link between smiling intensity and longevity.

The Rx: Men, stop telling women to smile. It's demeaning and implies they're subservient. However, given the impact on our health (mental and otherwise), we could all stand to turn that frown upside down.

Old dogs can't learn new tricks but you can. Education, coupled with a healthy weight, leads to a longer life expectancy, revealed a study out of the University of Edinburgh, with almost a year added to your life for each year spent studying beyond school.

The Rx: Pull a Dangerfield and go back to schooleven if it's just an herbalism course, knitting class or continuing ed program.

RELATED: I'm A Doctor And Warn You Never Take This Supplement

Avoid certain jobs, some of the deadliest out there, according to the Bureau of Labor Statistics National Census of Fatal Occupational Injuries, if you want to stick around longer. On the flip side, find a job you love. You'll be happier, longer, which can impact you positively long-term.

The Rx: Truck driver, farmers and construction laborers are among the most dangerous, mainly owing to vehicular accidents.

Country life is serene, but the Milken Institute Center for the Future of Aging found that living in a major city can also support longer life spans because of stronger health systems, and more access to learning, arts, culture, and other healthy stimulants.

The Rx: Eat This, Not That! Health is based in New York City and our editors can attest living here indeed makes you feel young, although struggling to afford it might age you. Weigh the fantasy versus reality before any leaps.

Good relationships, more than money or fame, are what keep people happy throughout their lives, a Harvard study revealed. Another study in Personal Relationships looked at 270,000 people in nearly 100 countries with a strong link to better health in older age among those with strong friend and family connections.

The Rx: Send a "friend request" to someone you'd like to be closer toand meet them in person, not just online.

Compared with persons with a normal body mass index (18.5 to 25), those who are underweight, overweight, and obese have an increased risk of death over a 30-year period. Being too underweight, or at the extreme, obese, can impact health significantly over time, show studies.

The Rx: A book like Zero Belly Diet can help you cut dairy, reduce bloat, stay plant-based and be leaner for life.

Stay away from men. That's what centenarian Jessie Gallan, at one time Scotland's oldest woman, credited for her longevity. "They're more trouble than they're worth," she said in an interview before her death in 2015. Granted, Gallan was a tough woman without or without a man. She started working at the age of 13 and spent her 109 years staying fit and having good people in her life but never walked down the aisle.

The Rx: There's no definitive research supporting a link between marriage and longevity one way or the other, although one study found that "current marriage is associated with longer survival. Among the not married categories, having never been married was the strongest predictor of premature mortality." Our advice: Marry the person you want to spend your life with, and give one another room to grow.

If you want to live longer, make sure you and your spouse are happy. A study published by the Association for Psychological Science found that a happy marriage can lead to a longer life.

The Rx: A good marriage is linked to a more active life and healthier habits, overall. How's your relationship?

RELATED: The #1 Cause of Obesity, According to Science

As stressful as parenthood gets at times, having kids can actually keep you around longer since it encourages a healthier lifestyleyou're more likely to give up smoking and stay active, shows one study.

The Rx: Don't have children just to live longer. But if you do have or want kids, remember that your habits become theirs. Set the example.

Keep a good pace. Brisk walking will keep your heart healthy and add some years to your life, according to a recent Mayo Clinic study. Researchers reported that women who walked more quickly had a life span of about 87 years compared to 72 years for women who walked slowly. Meanwhile, men who walked quickly had a life span of about 86 years compared to 65 years for men who walked more slowly.

The Rx: "Walking is man's best medicine," said Hippocrates. Get steppin'.

A handful of nuts a day may keep the doctor away, according to Harvard University research, which found that people who crunch some nuts daily lived 20 percent longer than those who didn't.

The Rx: Our favorite is almonds. Besides being an easy go-to snack that you can whip out of your bag during a good ol' 9-5 shift, almonds are also chock-full of essential vitamins and minerals, with vitamin E and biotin being the most predominant. Those nutrients enable your skin to remain smooth and gives your lush hair and strong nails the nutrition they need to flourish.

Don't stopever! The moment you become stagnant, things may go downhill. Stay active. A 2016 study found that elderly people who exercised for just 15 minutes a day, at an intensity level of a brisk walk, had a 22 percent lower risk of early death compared to people who don't exercise.

The Rx: "For most healthy adults, the Department of Health and Human Services recommends these exercise guidelines: Get at least 150 minutes of moderate aerobic activity or 75 minutes of vigorous aerobic activity a week, or a combination of moderate and vigorous activity," reports the Mayo Clinic.

To quote Dr. Nelly of Nellyville: It's getting hot in here. Frequent spicy food consumption is linked to a longer life. Those who eat spicy foods nearly every day have a 14 percent chance of living longer, according to a Harvard study. Capsaicin and other compounds in chili peppers have been linked to fighting cancer, obesity, and more.

The Rx: Sprinkle some cayenne pepper into your eggs every morning, for a one-two punch of protein and spice.

RELATED: Signs You're Getting One of the "Most Deadly" Cancers.

Researchers at the Carleton University in Canada say that having a sense of purpose may add more years to your life, because of positive relations and emotions and overall well-being.

The Rx: Start small. Rather than ask yourself, "Why am I here? What is my place in the Universe" ask yourself, "What can I do today that will make me feel like I've enriched my life, or the lives of others?"

Yoga can help improve digestion, calm the nervous system, lower blood sugar, and so many other tangible benefits. It's no wonder researchers say it will help increase your overall life span.

The Rx: Get your chaturanga on! There's no doubt a yoga studio near you, with teachers who will welcome first-timers. For long-timers, consider a retreat.

Taking care of your teeth and gums isn't just about preventing cavities or bad breath. The mouth is the gateway to the body's overall health. Not flossing allows plaque to build up, which then turns into tartar that can eventually irritate the gums, which can lead to various infections and disease over time. Researchers followed more than 5,400 people for 18 years and found that those who did not brush their teeth daily had a 22 to 65 percent greater risk of dementia than those who brushed three times a day.

The Rx: The American Dental Association recommends brushing your teeth twice a day. Use fluoride toothpaste, and brush for two minutes.

Coffee is packed with tons of healthy compounds, including antioxidants, which can protect the body against cellular damage that can lead to disease, studies show.

The Rx: Drinking four to five cups daily is also associated with a reduced risk of early death.

This one is pretty self explanatory. An active lifestyle will keep you around longer. Exercising at a moderate level for at least 150 minutes can add on 3.4 years to your life, according to the National Institute of Health.

The Rx: Try one of these 25 Easy Exercises That Boost Your Health Fast. They really work.

Helping others can only make you feel good, and it helps boost overall mental health throughout time, which impacts the body's immunity to fight disease, according to a study published in BMC Public Health.

The Rx: Animal rescue shelters, national parks, Habitat for Humanity, local libraries, political campaigns and the YMCA are a few places that rarely say no to help.

RELATED: Sure Signs You Had COVID and Didn't Know It

Studies show sex releases endorphins and hormones in the body, which can help combat feelings of loneliness and depression, keep you physically active, reduce stress relieving, and boost mental wellness.

The Rx: Take this advice seriously. Having sex is one of theSimplest Ways to Avoid a Heart Attack, Say Doctors.

Are there stairs nearby? Good. Use them. The European Society of Cardiology released a study showing how brisk movement, particularly being able to climb three flights quickly, can reduce your risk of early death from cardiovascular and oncologic, and other diseases.

The Rx: Skip the elevators and escalators, and track your steps with a fitness watch, if you need more motivation.

The sweet stuff won't get you far in lifeliterally. Too much sugar is linked to shorter life spans, according to one study. Sugar has even been linked to reprogramming how our genes function. The Centers for Disease Control and Prevention (CDC) reports that about 14% of the daily calories the average Ameican consumes comes from added sugars. And it shows. According to a Population Health Management publication, the number of Americans diagnosed with diabetes increased more than three times between 1990 and 2010. This just so happens to be the same years sugar starting becoming more prevalent in our food.

The Rx: A book like Sugar Free 3 can teach you how to identify added sugarsand how to give them up.

Get in touch with your spiritual side. People who attend religious services, or have some spiritual connection, typically experience lower levels of anxiety, depression, have lower blood pressure, and are generally in better health. An 18-year study published in PLOS One found that regular service attendance was linked to reductions in the body's stress responses, and worshippers were 55 percent less likely to die.

The Rx: You read that right: 55 percent less likely to die. Start by defining what spirituality means to you, and then see if there's a community that supports that common interest.

If you're not connected to a particular religion, you can still find your spiritual balance through meditation. Not only does it improve mental health, but meditating has been linked to a lower risk of cancer and other diseases, according to a study from the University of California-Davis, which found that regular meditation produces higher levels of telomerase, an enzyme that helps lengthen the telomeres in our chromosomes, which impact aging.

The Rx: Apps like Insight Timer, Headspace and Calm have taken meditating mainstream; try one. One of our favorite apps is 10% Happier, from ABC News man-turned-meditator Dan Harris.

If you know how to laugh at things, you'll live longer. A 15-year study out of Norway assessed the link between a sense of humor and mortality rates among 53,556 men and women and found that women who had a good sense of humor lived longer, despite illnesses, including cardiovascular disease; cheerful men faired just as well with laughter protecting them from infection.

The Rx: We've been obsessed with the funniest lines from HBO's Successionand aren't even sure it's a comedy!

RELATED: Everyday Habits That Make You Look Older, According to Science

Want to live to 85 or longer? Optimistic thinking can add years on to your life, say researchers at Boston University School of Medicine. Optimistic people can better regulate emotions so we can bounce back from stressors and difficulties more effectively.

The Rx: Technically, the glass is always half full. The other half is air.

Creativity keeps the brain healthy and may decrease mortality rates. Researchers agree. Creative people just tend to live longer.

The Rx: Remember this, if something's blocking you: You don't have to be "creative" to create.

Be good to yourself. Self compassion goes a long way, say researchers. It's associated with better moods, can improve body image, and is linked to happiness, optimism, wisdom, personal initiative, and more. Overall, it improves our entire mental health, which keeps our body more resilient to stress and illnesses.

The Rx: Did we mention we love that thing you said today? So smart! So funny! So wise.

People who eat fiber-rich foods, including some good 'ole oatmeal or porridge, cut their risk of dying from cardiovascular, infectious, and respiratory diseases by 24 to 56 percent in men and by 34 percent to 59 percent in women, shows one study.

The Rx: Buy "regular" oatmeal and add berries for sweetness. Anything else may be loaded with dangerous added sugars.

Owning a dog is linked to a longer life, according to researchers out of Uppsala University in Sweden, who reviewed national registry records of 3.4. million men and women, ages 40 to 80.

If you're a cat person, you'll get some extra years from kitties as well. A study by the Minnesota Stroke Institute found that people who owned cats were 30 percent less likely to suffer a heart attack.

The Rx: We mentioned volunteering at the ASPCA. If you feel truly capable of caring for a pet, discuss taking one home. We like these questions from Nylabone:

Get back to basics with food. Those who incorporate more whole grains, vegetables, fruits, and fish and limiting too much sodium, unhealthy fats, excess red meat, sugar, and processed foods, improved their overall health and life expectancy.

The Rx: For the web's #1 nutrition resource, and to make the right food choice every time, head to Eat This, Not That!

Does longevity run in your family? Dig deeper into your family history, including lifestyle habits, illnesses, deaths, and beyond. It may help us tap into how long we ultimately have here.

The Rx: Put together a family treewith dates of birth, death, and causes.

Tea contains flavonoids, a compound that works to boost health. One study found that 88 percent of women were 40 percent more likely to live longer because they drank two cups of tea per day.

The Rx: Go green. The most potent catechin in green tea is EGCG, the powerhouse compound that's responsible for most of green tea's weight loss properties. In addition to revving your metabolism and boosting the breakdown of fat, EGCG can also block the formation of new fat cells.

Read more:
Simple Ways to Never Age, According to Experts | Eat This Not That - Eat This, Not That

For Keith Wexelblatt of Massachusetts, it was walking into a full-capacity playoff ice hockey game for his beloved Boston Bruins.

For Eileen Fetterolf of New Jersey, it was smiling at strangers and seeing their whole face smile back.

For Katie Black of California, it was seeing her medical specialists in person.

For many of us, feelings of euphoria are coming quickly as we move back into the things we could do before the COVID-19 pandemic began.

That feeling of joy is chemically based, experts say.

Is it good for us? Like many scientific questions, the answer reads like this: yes, no, or maybe.

There was a layer placed between us and pleasure, Dr. Gail Saltz, a clinical associate professor of psychiatry at the NewYork-Presbyterian Hospital/Weill-Cornell Medical College, told Healthline.

The absence of pain is pleasure, she said. And so many people have been constrained (the basis for much of the pain). The removal of that limitation the unpleasant stimulus is pleasure.

Which means, she said, as we all re-enter normal life, you dont have to summit Mount Everest on your first venture out in the world to feel that joy. With the way weve been locked down and layered away from the world, she said, just about anything triggers joy right now.

For some people, food shopping is pleasure, she said. Looking at the fruits and vegetables set out for us, touching them without worry, when you can do it unrestricted, it is a pleasure for many.

What happens chemically?

Saltz said that the body releases dopamine, which she calls the reward hormone, when it senses a new and pleasurable experience.

This often requires something relatively exciting.

Often in couples counseling, Saltz advises couples to share a new activity or experience for just that reason. Dopamine can trigger that euphoric vibe, something that can help them enjoy one anothers company again.

Dopamine can also pump through the body when a long-time pleasurable experience, simple or grand, is withheld from a person for some time.

The joy we feel is probably intense, too, from the setup we may have experienced over the pandemic year leading up to the experience.

We dont fully realize the toll the loss has taken on us. There is a residue that has built up over the last year, Karen Doll, PsyD, a licensed psychologist in Minnesota, told Healthline.

Lack of stimulation and lack of variety of inputs creates a fog in the brain, she said. As humans, we have a strong need to connect with people in person.

Thats why, beyond dopamine, we may also have more good hormones pumping, and we may feel excited to see just about anyone we know in real life.

The isolation and loneliness have been significant, Doll said. Reconnecting with individuals is having a powerful impact on people and relationships. The increase in oxytocin (love hormone) that occurs when we are connected with people is so important for well-being.

Its not all dopamine and hugs, though.

First, said Saltz, its important we all amp up our compassion mode in real time.

Why? Because, she said, not everyone is at a place of joy.

Its very individual, she said. How close is someone to loss? What psychology did they have heading into this?

She points out that loss has many incarnations. Theres the loss of lives, of jobs, of income, of financial security, and more. Top that off, she said, with the non-pandemic concerns such as racial inequality, and you can see that many may still be having a difficult time.

Realizing and owning that is not only crucial, she said, its humane.

The person you may see who isnt joyful like you, she said, can feel really bad, thinking something is wrong with them (when everyone else seems so happy).

Her advice? As much as you may want to dance through the market aisle hugging everyone you pass, Give yourself and others a lot of space. If youre not feeling it and everyone around you seems to be going woo hoo! it can seem pretty awful.

We could also, said Doll, take the joy vibe too far.

There are risks to letting loose after operating with such restrictions in our environment, Doll said.

She points out that over the pandemic year, our social skills were not put into practice as much and may be languishing a bit.

I heard someone describe it as letting a bunch of caged animals out can be dangerous, she said.

So, we may not be as accurately in tune with our senses and cues that will tell us when we are on the verge of poor choices. Its like our social judgments in public havent been exercised or utilized, so are likely out of tune, Doll said.

What to do? She suggests we remember to take a pause and check in with ourselves, to ensure that we dont overdo it or lose sight of the risks and impact of our behaviors.

It could also, Doll said, lead to letdown.

To avoid a post-joy crash, she said, It can also be helpful to increase our emotional awareness and literacy. Being aware of what we are feeling, how intensely, and what are the triggers can be useful for healthy emotional regulation.

The message? As we savor those hormone highs, we should also take time to adjust.

Coming out of this is going to take time, Saltz said. The idea that we are just flipping a switch is not correct. Set smaller goals.

And if you dont feel a shift toward joy over time? Take action.

The good news? We all, for the most part, should get to joy in time.

These are treatable conditions, she said.

For now, many are savoring the joy of even the most basic.

Its making me so happy to smile at strangers and friends, said Fetterolf.

She works with first graders and has realized a new joy there as well.

I did not realize how much I missed toothless grins and wiggly teeth, she said.

Wexelblatt marvels at how something as joyful all his life as a Bruins playoff game could feel even better. But, he said, it did and it does.

There was an unreal pent-up energy that exploded with fans, he said. A huge sense of almost normalcy. Immense joy.

And for Erin Duggan of Massachusetts, total joy joins with wearing makeup once more.

I can wear lipstick and not just leave it on my mask now, she said. Its the simple things.

Originally posted here:
Post-Pandemic Joy: Why It Feels So Good to Do Simple Things Again - Healthline

Regulators on Friday said a new version of a popular diabetes medicine could be sold as a weight-loss drug in the U.S.

The Food and Drug Administration approved Wegovy, a higher-dose version of Novo Nordisk's diabetes drug semaglutide, for long-term weight management.

In company-funded studies, participants taking Wegovy had average weight loss of 15%, about 34 pounds (15.3 kilograms). Participants lost weight steadily for 14 months before plateauing. In a comparison group getting dummy shots, the average weight loss was about 2.5%, or just under 6 pounds.

"With existing drugs, you're going to get maybe 5% to 10% weight reduction, sometimes not even that," said Dr. Harold Bays, medical director of the Louisville Metabolic and Atherosclerosis Research Center. Bays, who is also the Obesity Medicine Association's chief science officer, helped run studies of the drug.

In the U.S., more than 100 million adults about 1 in 3 are obese.

Dropping even 5% of one's weight can bring health benefits, such as improved energy, blood pressure, blood sugar and cholesterol levels, but that amount often doesn't satisfy patients who are focused on weight loss, Bays said.

Bays said Wegovy appears far safer than earlier obesity drugs that "have gone down in flames" over safety problems. Wegovy's most common side effects were gastrointestinal problems, including nausea, diarrhea and vomiting. Those usually subsided, but led about 5% of study participants to stop taking it.

The drug carries a potential risk for a type of thyroid tumor, so it shouldn't be taken by people with a personal or family history of certain thyroid and endocrine tumors. Wegovy also has a risk of depression and pancreas inflammation.

Wegovy (pronounced wee-GOH'-vee) is a synthesized version of a gut hormone that curbs appetite. Patients inject it weekly under their skin. Like other weight-loss drugs, it's to be used along with exercise, a healthy diet and other steps like keeping a food diary.

The Danish company hasn't disclosed Wegovy's price but said it will be similar to the price of its Saxenda, a weight loss drug injected daily that now typically costs more than $1,300 per month without insurance.

Dr. Archana Sadhu, head of the diabetes program at Houston Methodist Hospital, said Wegovy's usefulness "all depends on what the price will be." She noted patients' health insurance plans sometime don't cover weight-loss treatments, putting expensive drugs out of reach.

Sadhu, who has no connection to Novo Nordisk, plans to switch patients who are obese and have Type 2 diabetes to Wegovy. It makes patients feel full sooner and increases release of insulin from the pancreas to control blood sugar, she said. Patients would then be more likely to get motivated to exercise and eat healthier, she added.

Wegovy builds on a trend in which makers of relatively new diabetes drugs test them to treat other conditions common in diabetics. For example, popular diabetes drugs Jardiance and Novo Nordisk's Victoza now have approvals for reducing risk of heart attack, stroke and death in heart patients.

Phylander Pannell, 49, of Largo, Maryland, joined a patient study after cycles of losing and then regaining weight. She said she received Wegovy, worked out several times a week and lost 65 pounds over 16 months.

"It helped curb my appetite and it helped me feel full faster," said Pannell. "It got me on the right path."

Shortly after she finished the study and stopped receiving Wegovy, she regained about half the weight. She's since lost much of that, started exercise classes and bought home exercise equipment. She's considering going back on Wegovy after it's approved.

Novo Nordisk also is developing a pill version.

___

Follow Linda A. Johnson at https://twitter.com/LindaJ_onPharma.

___

The Associated Press Health and Science Department receives support from the Howard Hughes Medical Institute's Department of Science Education. The AP is solely responsible for all content.

___

This story has been corrected to show the length of time study participants lost weight before plateauing was 14 months, not 16 months, and the last name of the Houston physician to Sadhu, not Sudhu.

The rest is here:
FDA approves obesity drug that helped people cut weight 15% - Minneapolis Star Tribune

On June 1, Florida Gov. Ron DeSantis signed a bill into law that would ban trans athletes from participating on female sports teams at the high school and college level. It states that individuals with a biological sex indicated as male on their birth certificates cannot participate on girls sports teams. Several other states have proposed or passed similar legislation, including Mississippi, Minnesota, Idaho, Ohio and Tennessee.

Politicians who support the bans say that this is an issue of fairness and of protecting girls sports. Experts say that this fear is not well supported.

This argument that trans people are somehow going to ruin sports as we know it is not based on anything connected to fact, said Vinnie Pompei, who conducted a survey of LGBTQ+ youth in California for the Human Rights Campaign Foundation, to The Mercury News.

Physician and geneticist Eric Vilain, who has studied sex differences in athletes and advised the International Olympic Committee and the NCAA, said to NPR that the proposed laws are not based in scientific evidence and "target women who have either a different biology or ... simply look different."

Biologists who study genetics, hormones and performance of the human body haveexaminedthis issue for many years. There might be some advantage that biological men have on average, but this does not mean that there is always such an advantage or that there is a benefit to taking a hard line on banning individuals from sports.

We know that men have, on average, an advantage in performance in athletics of about 10% to 12% over women, which the sports authorities have attributed to differences in levels of a male hormone called testosterone, says Vilain to NPR. But the question is whether there is in real life, during actual competitions, an advantage of performance linked to this male hormone and whether trans athletes are systematically winning all competitions. The answer to this latter question, are trans athletes winning everything, is simple that's not the case.

America is changing faster than ever! Add Changing America to your Facebook or Twitter feed to stay on top of the news.

Although experts have been researching hormones and athletic ability for years, theres no consensus on what really affects a persons ability to perform.

The science of whether testosterone in real life is actually providing an advantage in competition is not clearly established, says Vilain to NPR.

Theres no scientific evidence that someone who was assigned male at birth would definitively have a competitive advantage over someone who was assigned female at birth. Both women and men have a wide range of physical capabilities, and its likely that athletic performance is much more complex than hormones and genetics.

Another important point is that women who may look different may be asked to prove their sex in order to compete under these laws. In a letter to South Dakota Gov. Kristi Noem (R), the National Womens Law Center writes, the proposed ban for the state would not only exclude transgender students from sports but would also harm cisgender girls and women who fall outside stereotypical notions of femininity, simply because they are very tall or muscular, have short hair, wear masculine clothing, or otherwise choose to present in more traditionally masculine ways.

If, as many of these lawmakers claim, fairness is their goal, they should turn their attention to the unfair advantages many cisgender, white athletes receive by virtue of little more than their zip codeincluding the remaining gap in resources between boys and girls programs, according to the National Womens Law Center.

Trans youth are hearing powerful politicians say that their identities are invalid and that they are a threat to their peers, says Jack Turban, a Fellow in Child & Adolescent Psychiatry at the Stanford University School of Medicine, to The Mercury News. Though they may know this is not true, hearing it over and over takes a serious toll and can drive anxiety and depression. As a therapist who treats these young people, it is heartbreaking to see.

In Florida, the Human Rights Campaign plans to sue Gov. DeSantis over the new legislation.

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Laws banning trans athletes from competing in girls' and women's sports not grounded in science, say experts | TheHill - The Hill

Two weeks after saying the breast cancer hopeful amcenestrant could be at the forefront of future treatments, Sanofi has secured partners for a phase 3 trial to study the drug versus the hormone therapy tamoxifen.

The Breast International Group (BIG), the European Organization for Research and Treatment of Cancer (EORTC) and the Alliance Foundation Trials (AFT) will initiate the pivotal trial with the French Big Pharma.

The AMEERA-6 study will look at amcenestrant versus tamoxifen, a hormonal therapy approved by the FDA in 1998 for women with estrogen receptor-positive breast cancer who prematurely ended standard therapy and are susceptible to a return of the disease.

Amcenestrant, which is an oral selective estrogen receptor degrader (SERD), has the potential to become a best-in-class oral endocrine backbone therapy, said Peter Adamson, M.D., global head of oncology development at Sanofi, in a statement.

RELATED: Sanofi says early amcenestrant data could see it be endocrine backbone therapy in breast cancer

The add-on therapy aims to prevent and slow down disease progression. Current adjuvant therapies, like aromatase inhibitors, have side effects that lead some women to end medication early, said David Cameron, BIG executive board chairman, in a statement.

Sanofi will provide funding and the investigational drug for the global study as the sponsor, while Brussels-based BIG will do the study within its network. EORTC, an academic contract research organization, will manage the study, data analysis and medical management. AFT, a cancer clinical trial research organization, will handle the U.S. portion of the study.

Two weeks ago, Sanofi presented pooled data of amcenestrant from the phase 1 AMEERA-1 trial, which hit an objective response rate of 34% and a clinical benefit rate of 74% when combined with Pfizers approved breast cancer med Ibrance.

As part of the American Society of Clinical Oncology presentation last month, Sanofi said AMEERA-3, a potential registrational study attempting to show amcenestrant is superior to physicians choice in a second-line setting, was delayed from the second quarter to the latter half of this year.

Analysts from Jefferies have been impressed by the early data from the AMEERA-1 program but said the AMEERA-3 delay "does not help build confidence in establishing belief in the pipeline."

Sanofi will not be first in the SERD gameAstraZeneca'sFaslodex holds that titlebut the French drugmaker hopes to avoid the pitfalls of the 20-year-old med that had to be delivered through intramuscular injection. This painful delivery mechanism held back sales.

Jefferies estimates the SERD market is a $2 billion to $3 billionopportunity.Sanofi is going up against Roche in trying to bring a new SERD through the clinic as well as AstraZeneca, which has a second-generation therapy in the works.

Read more here:
Sanofi inks partners for phase 3 pivotal trial of add-on breast cancer therapy - FierceBiotech

Dispatches from the Reproductive Revolution 2. At the request of a leading abortion provider, a doctor in the UK has been banned by the Medical Practitioners Tribunal Service from helping women to reverse the effects of their chemical abortions. He could be deregistered.

As often happens, this story is a tangled one. Bear with us.

During the UKs first lockdown, abortion providers lobbied to send chemical abortion drugs to women through the postal service. They would never see a doctor; instead, they just took two pills and waited for the foetus to be expelled.

Some women regretted their impulsive decision as soon as they had taken the first pill. For them, Dr Dermot Kearney prescribed progesterone, a hormone for treating natural miscarriages, in an attempt to cancel the effects of the abortifacient, mifepristone. This is an off-label use of progesterone.

He claims that of 73 women, 38 of them managed to hold on to their babies -- a success rate of almost 50%.

According to the Daily Mail, MSI Reproductive Choices, formerly known as Marie Stopes International, filed a complaint. It claimed that Dr Kearney inappropriately prescribed progesterone to a patient for a use not backed by evidence, failed to present a balanced picture of its benefits and risks, and imposed his anti-abortion beliefs on her.

Andrea Williams, chief executive of the Christian Legal Centre, said: Babies are alive today because mothers reached out to Dr Kearney and he provided effective and safe abortion rescue. This ruling punishes the life saver, is deeply wrong and needs to be overturned.

Dr Kearney, a cardiologist and emergency physician and the president of the Catholic Medical Association, has been told by the MPTS that he must not prescribe, administer or recommend progesterone for abortion reversal treatments. Otherwise, he can continue practicing until the hearing.

Michael Cook is editor of BioEdge

Read more here:
UK doctor banned from reversing chemical abortions - BioEdge

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Trodelvy More than Doubled Overall Survival as Second-Line Treatment in New ASCENT Subgroup Analysis

FOSTER CITY, Calif.--(BUSINESS WIRE)--Gilead Sciences, Inc. (Nasdaq: GILD) today announced new data from the Phase 3 ASCENT study evaluating Trodelvy (sacituzumab govitecan-hziy) in relapsed or refractory metastatic triple-negative breast cancer (TNBC). In this subgroup analysis of brain metastases-negative patients who received only one line of prior systemic therapy in the metastatic setting in addition to having disease recurrence or progression within 12 months of (neo)adjuvant chemotherapy, Trodelvy improved progression-free survival (PFS), with a 59% reduction in the risk of disease worsening or death (HR: 0.41; 95% CI: 0.22-0.76) and a median PFS of 5.7 months (n=33) versus 1.5 months with chemotherapy (n=32). Trodelvy also extended median overall survival to 10.9 months versus 4.9 months with chemotherapy (HR: 0.51; 95% CI: 0.28-0.91). The results were presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract #1080).

In patients with relapsed or refractory metastatic triple-negative breast cancer, outcomes are typically poor especially among patients who progress within 12 months of (neo)adjuvant chemotherapy, said Lisa Carey, MD, Medical Director of the UNC Breast Center, the Physician-in-Chief of the North Carolina Cancer Hospital and Associate Director of Clinical Research at UNC Lineberger Comprehensive Cancer Center. In the Phase 3 ASCENT study, Trodelvy was the first treatment to demonstrate a proven survival advantage in pre-treated patients with locally advanced or metastatic TNBC, and the analysis presented at ASCO reaffirms this benefit over standard of care with important new data in the second-line setting.

Additional results showed Trodelvy demonstrated a higher overall response rate compared with chemotherapy (30% versus 3%). Efficacy results from this subgroup were consistent with those observed in the overall ASCENT study population.

The safety profile of Trodelvy in this subgroup was consistent with prior reports. The most frequent Grade 3 treatment-related adverse reactions for Trodelvy compared to chemotherapy were neutropenia (61% versus 21%), leukopenia (9% versus 0%), diarrhea (6% versus 0%), anemia (3% versus 6%), and fatigue (3% versus 0%). One patient in this subgroup who received Trodelvy experienced febrile neutropenia. Adverse reactions leading to treatment discontinuation were low across both groups (6% in each). There were no treatment-related deaths with Trodelvy in this subgroup. The Trodelvy U.S. Prescribing Information has a BOXED WARNING for severe or life-threatening neutropenia and severe diarrhea; see below for Important Safety Information.

With Trodelvy, we continue to challenge the standard of care in locally advanced and metastatic TNBC. The efficacy observed in the second-line metastatic setting with Trodelvy is highly meaningful, since many patients will progress quickly following chemotherapy. Among these patients, we see median overall survival more than doubled where need is particularly great, said Daejin Abidoye, MD, Senior Vice President, Head of Oncology Clinical Development, Gilead Sciences. We are committed to improving the prognosis for people with this aggressive cancer, and as we continue to study Trodelvy, we are encouraged by this proven efficacy in TNBC.

Two additional ASCENT subgroup analyses that support the efficacy benefit of Trodelvy were also presented at the meeting one evaluating Trodelvy efficacy by patients age (Abstract #1011) and the other comparing Trodelvy with specific single-agent chemotherapy chosen by the patients treating physicians (Abstract #1077).

About Triple-Negative Breast Cancer (TNBC)

TNBC is an aggressive type of breast cancer, accounting for approximately 15% of all breast cancers. The disease is diagnosed more frequently in younger and premenopausal women and is more prevalent in African American and Hispanic women. TNBC cells do not have estrogen and progesterone receptors and have limited HER2. Medicines targeting these receptors therefore are not typically effective in treating TNBC.

About the ASCENT Study

The Phase 3 ASCENT study, an open-label, active-controlled, randomized confirmatory trial, enrolled more than 500 patients with relapsed/refractory metastatic triple-negative breast cancer who had received two or more prior systemic therapies, including a taxane, at least one of them for metastatic disease. Patients were randomized to receive either Trodelvy or a chemotherapy chosen by the patients treating physicians. The primary efficacy outcome was PFS in patients without brain metastases at baseline, as measured by a blinded, independent, centralized review using RECIST v1.1 criteria. Additional efficacy measures included PFS for the full population, including all patients with and without brain metastases, and overall survival. More information about ASCENT is available at http://clinicaltrials.gov/show/NCT02574455.

About Trodelvy

Trodelvy (sacituzumab govitecan-hziy) is a first-in-class antibody and topoisomerase inhibitor conjugate directed to the Trop-2 receptor, a protein frequently expressed in multiple types of epithelial tumors, including metastatic triple-negative breast cancer and metastatic urothelial cancer, where high expression is associated with poor survival and relapse.

In the U.S., Trodelvy is indicated for the treatment of:

Beyond the regulatory approvals of Trodelvy in the U.S., regulatory reviews for Trodelvy in metastatic triple-negative breast cancer are currently underway in the EU, U.K., Canada, Switzerland and Australia, as well as in Singapore through our partner Everest Medicines. Trodelvy is also being investigated as potential treatment for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer and metastatic non-small cell lung cancer. Additional evaluation across multiple solid tumors is also underway.

U.S. Important Safety Information for Trodelvy

BOXED WARNING: NEUTROPENIA AND DIARRHEA

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

Neutropenia: Severe, life-threatening, or fatal neutropenia can occur and may require dose modification. Neutropenia occurred in 61% of patients treated with Trodelvy. Grade 3-4 neutropenia occurred in 47% of patients. Febrile neutropenia occurred in 7%. Withhold Trodelvy for absolute neutrophil count below 1500/mm3 on Day 1 of any cycle or neutrophil count below 1000/mm3 on Day 8 of any cycle. Withhold Trodelvy for neutropenic fever.

Diarrhea: Diarrhea occurred in 65% of all patients treated with Trodelvy. Grade 3-4 diarrhea occurred in 12% of patients. One patient had intestinal perforation following diarrhea. Neutropenic colitis occurred in 0.5% of patients. Withhold Trodelvy for Grade 3-4 diarrhea and resume when resolved to Grade 1. At onset, evaluate for infectious causes and if negative, promptly initiate loperamide, 4 mg initially followed by 2 mg with every episode of diarrhea for a maximum of 16 mg daily. Discontinue loperamide 12 hours after diarrhea resolves. Additional supportive measures (e.g., fluid and electrolyte substitution) may also be employed as clinically indicated. Patients who exhibit an excessive cholinergic response to treatment can receive appropriate premedication (e.g., atropine) for subsequent treatments.

Hypersensitivity and Infusion-Related Reactions: Serious hypersensitivity reactions including life-threatening anaphylactic reactions have occurred with Trodelvy. Severe signs and symptoms included cardiac arrest, hypotension, wheezing, angioedema, swelling, pneumonitis, and skin reactions. Hypersensitivity reactions within 24 hours of dosing occurred in 37% of patients. Grade 3-4 hypersensitivity occurred in 2% of patients. The incidence of hypersensitivity reactions leading to permanent discontinuation of Trodelvy was 0.3%. The incidence of anaphylactic reactions was 0.3%. Pre-infusion medication is recommended. Observe patients closely for hypersensitivity and infusion-related reactions during each infusion and for at least 30 minutes after completion of each infusion. Medication to treat such reactions, as well as emergency equipment, should be available for immediate use. Permanently discontinue Trodelvy for Grade 4 infusion-related reactions.

Nausea and Vomiting: Nausea occurred in 66% of all patients treated with Trodelvy and Grade 3 nausea occurred in 4% of these patients. Vomiting occurred in 39% of patients and Grade 3-4 vomiting occurred in 3% of these patients. Premedicate with a two or three drug combination regimen (e.g., dexamethasone with either a 5-HT3 receptor antagonist or an NK1 receptor antagonist as well as other drugs as indicated) for prevention of chemotherapy-induced nausea and vomiting (CINV). Withhold Trodelvy doses for Grade 3 nausea or Grade 3-4 vomiting and resume with additional supportive measures when resolved to Grade 1. Additional antiemetics and other supportive measures may also be employed as clinically indicated. All patients should be given take-home medications with clear instructions for prevention and treatment of nausea and vomiting.

Increased Risk of Adverse Reactions in Patients with Reduced UGT1A1 Activity: Patients homozygous for the uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)*28 allele are at increased risk for neutropenia, febrile neutropenia, and anemia and may be at increased risk for other adverse reactions with Trodelvy. The incidence of Grade 3-4 neutropenia was 67% in patients homozygous for the UGT1A1*28, 46% in patients heterozygous for the UGT1A1*28 allele and 46% in patients homozygous for the wild-type allele. The incidence of Grade 3-4 anemia was 25% in patients homozygous for the UGT1A1*28 allele, 10% in patients heterozygous for the UGT1A1*28 allele, and 11% in patients homozygous for the wild-type allele. Closely monitor patients with known reduced UGT1A1 activity for adverse reactions. Withhold or permanently discontinue Trodelvy based on clinical assessment of the onset, duration and severity of the observed adverse reactions in patients with evidence of acute early-onset or unusually severe adverse reactions, which may indicate reduced UGT1A1 function.

Embryo-Fetal Toxicity: Based on its mechanism of action, Trodelvy can cause teratogenicity and/or embryo-fetal lethality when administered to a pregnant woman. Trodelvy contains a genotoxic component, SN-38, and targets rapidly dividing cells. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Trodelvy and for 6 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Trodelvy and for 3 months after the last dose.

ADVERSE REACTIONS

In the ASCENT study (IMMU-132-05), the most common adverse reactions (incidence 25%) were fatigue, neutropenia, diarrhea, nausea, alopecia, anemia, constipation, vomiting, abdominal pain, and decreased appetite. The most frequent serious adverse reactions (SAR) (>1%) were neutropenia (7%), diarrhea (4%), and pneumonia (3%). SAR were reported in 27% of patients, and 5% discontinued therapy due to adverse reactions. The most common Grade 3-4 lab abnormalities (incidence 25%) in the ASCENT study were reduced neutrophils, leukocytes, and lymphocytes.

In the TROPHY study (IMMU-132-06), the most common adverse reactions (incidence 25%) were diarrhea, fatigue, neutropenia, nausea, any infection, alopecia, anemia, decreased appetite, constipation, vomiting, abdominal pain, and rash. The most frequent serious adverse reactions (SAR) (5%) were infection (18%), neutropenia (12%, including febrile neutropenia in 10%), acute kidney injury (6%), urinary tract infection (6%), and sepsis or bacteremia (5%). SAR were reported in 44% of patients, and 10% discontinued due to adverse reactions. The most common Grade 3-4 lab abnormalities (incidence 25%) in the TROPHY study were reduced neutrophils, leukocytes, and lymphocytes.

DRUG INTERACTIONS

UGT1A1 Inhibitors: Concomitant administration of Trodelvy with inhibitors of UGT1A1 may increase the incidence of adverse reactions due to potential increase in systemic exposure to SN-38. Avoid administering UGT1A1 inhibitors with Trodelvy.

UGT1A1 Inducers: Exposure to SN-38 may be substantially reduced in patients concomitantly receiving UGT1A1 enzyme inducers. Avoid administering UGT1A1 inducers with Trodelvy.

Please see full Prescribing Information, including BOXED WARNING.

About Gilead Sciences

Gilead Sciences, Inc. is a biopharmaceutical company that has pursued and achieved breakthroughs in medicine for more than three decades, with the goal of creating a healthier world for all people. The company is committed to advancing innovative medicines to prevent and treat life-threatening diseases, including HIV, viral hepatitis and cancer. Gilead operates in more than 35 countries worldwide, with headquarters in Foster City, California.

Forward-Looking Statements

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including Gileads ability to initiate, progress or complete clinical trials within currently anticipated timelines or at all, including those involving Trodelvy; the possibility of unfavorable results from ongoing or additional trials, including those involving Trodelvy; Gileads ability to receive regulatory approvals in a timely manner or at all, including additional regulatory approvals of Trodelvy for the treatment of metastatic TNBC, metastatic breast cancer, metastatic UC, metastatic non-small cell lung cancer and other solid tumors, and the risk that any such approvals may be subject to significant limitations on use; and any assumptions underlying any of the foregoing. These and other risks, uncertainties and other factors are described in detail in Gileads Quarterly Report on Form 10-Q for the quarter ended March 31, 2021, as filed with the U.S. Securities and Exchange Commission. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. Investors are cautioned that any such forward-looking statements are not guarantees of future performance and involve risks and uncertainties and are cautioned not to place undue reliance on these forward-looking statements. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation and disclaims any intent to update any such forward-looking statements.

U.S. Prescribing Information for Trodelvy including BOXED WARNING, is available at http://www.gilead.com.

Trodelvy, Gilead and the Gilead logo are trademarks of Gilead Sciences, Inc., or its related companies.

For more information about Gilead, please visit the companys website at http://www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

View source version on businesswire.com: https://www.businesswire.com/news/home/20210604005059/en/

Jacquie Ross, Investors(650) 358-1054

Nathan Kaiser, Media(650) 522-1853

Source: Gilead Sciences, Inc.

See original here:
Trodelvy Demonstrates Superior Outcomes to Standard of Care in Second-Line Treatment of Metastatic Triple-Negative Breast Cancer in Phase 3 ASCENT...

You're about to hear advice from the last people you'd ever want to meet. Oncologists specialize in the diagnosis and treatment of cancer. If you're talking to one, and you're not at a dinner party, you might be one of the 100 million folks around the world who have it. With those staggering stats, you might think getting cancer is an inevitably. It isn't. Read onand to ensure your health and the health of others, don't miss these 19 Ways You're Ruining Your Body, Say Health Experts.

"I am very careful about keeping up with proven cancer screening interventions," says Amy Tiersten, MD, clinical breast medical oncologist at Mount Sinai. She stays current on preventative tests like colonoscopy, skin cancer exams, and gynecologic follow-ups.

Late diagnoses are a leading cause of premature death due to cancer. Interventions, like those Dr. Tiersten recommends, allow for early detection and diagnosis where patients can start treatment earlier. This is especially impactful in breast, cervical, and colorectal cancers.

The American Cancer Society recommends:

Ten years after the HPV vaccine was introduced, there is "compelling evidence" that we're on track "to eradicate cervical cancer within decades." A June 2019 study reviewed 60 million individuals', mostly girls and women, eight-year post-vaccination status and found that the vaccine has exceeded expectations.

The CDC recommends both boys and girls get the HPV vaccine at ages 11-12, with the second dose within a year. It's recommended up to age 26 for women and age 21 for men.

Newer versions of the vaccine require two doses instead of three, ensuring adherence to the full vaccination schedule. As well, it's gender-neutral and targets more HPV strains.

Exercise every single day that's the walk Kathryn Schmitz, Ph.D., a leading exercise oncology researcher at Penn State University, walks and talks. "We oncologists run, walk, or roll our way to cancer prevention," she said, citing research that supports a relationship between physical activity and cancer prevention. She's the biggest proponent of strength training, something she introduced in the chemo lab at Penn State Cancer Institute and shares as "exercise snacks" each week on her Instagram. "I try to exercise 30 minutes a day to stay fit. We know that regular physical exercise does reduce cancer risk in many cases. Decreasing your body weight, even by 5%, can make a big difference in terms of cancer risk," says Xavier Llor, MD, Medical Director of the Cancer Screening and Prevention Program.

RELATED: The #1 Reason You Could Get Cancer, According to Science

"Embrace your social networks; recognize who loves you and let them in," is how Dr. Don Dizon, MD, FACP, FASCO, director of medical oncology at Rhode Island Hospital and Professor of Medicine at Brown University prevents cancer. He says it's well-established that whether your social network includes a spouse, kids, best friend, or church, these connections are key to good health and that social isolation is associated with an increased risk of death.

"In one study, social isolation scores were associated with risk of death from heart disease and in all-cause mortality. This was true for men and women, Blacks and whites."

As an oncology clinical pharmacist, there are several things Allison Baxley, PharmD, BCOP of Stephenson Cancer Center does to prevent cancer. She recognizes that many elements are out of our control, like genetics, so she does all she can to reduce the risk through things she can control.

"Working primarily in GI oncology, I'm very aware of the link between colon cancer and processed and red meat consumption. I eat these in moderation, and rarely if ever eat highly processed meat like hot dogs and bacon."

She avoids what Micahel Pollen has called "edible food-like substance," which is the majority of what's in the center aisles of the grocery store.

RELATED: Signs You're Getting One of the "Most Deadly" Cancers.

Our daily diet choices play a powerful role in cancer prevention, reminds Dr. Terry Wahls, author of The Wahls Protocol series. For optimal cancer prevention, she aims for 9 cups of plant-based foods each day: 3 cups of greens, 3 cups of sulfur-rich foods like cabbage, onions, or mushrooms, and 3 cups of color from berries.

"We can choose to eat more greens and non-starchy vegetables and berries to markedly reduce the risk of developing cancer (and surviving cancer if it is diagnosed)," she explains. "Or we can choose the standard American diet, full of sugar and flour, which drives up insulin and insulin-like growth hormone and have a much higher risk of pre-cancers and overt cancers."

LaShyra "Lash" Nolen, an MD candidate at Harvard Medical School, points out that Black women have a disproportionately higher rate of mortality from breast cancer than white women, according to 2016 research.

"Therefore, I think it is so important for me, as a young Black woman, to take agency over my body," shared Nolen. "One way I do this is by regularly performing a physical exam of my breasts to search for abnormalities or unusual lumps."

She adds that, sometimes, women allow others to know their bodies better than they do themselves, but that this has to change in order to detect cancers at earlier stages and improve outcomes.

As an American Cancer Society Research Professor and Associate Dean for Oncologic Sciences at Brown University, Dr. Wafik El-Deiry says it's important to remember that half of all cancer is preventable. One of his preventive efforts is to limit or moderate alcohol consumption, as alcohol has been linked to cancers of the mouth, throat, liver, colon, breast, and others.

"Be aware and keep in the back of your mind that this is a substance that can do harm," he advises. El-Deiry says there's a lot of evolving and emerging data on the association between alcohol and cancer, but that the relationship does exist.

How much is too much? The American Cancer Society advises no more than 2 drinks per day for men and 1 drink per day for women.

Jeffrey Meyerhardt, MD, MPH, medical oncologist for the Dana-Farber Cancer Institute, works hard to maintain a healthy body weight. He cites consistent evidence in observational studies that link obesity and higher BMI with a variety of cancers, including colorectal, ovarian, and pancreatic.

In particular, he cited a 2003 study that analyzed the relationship between body weight and mortality from cancer in nearly one million American adults. When the heaviest participants had a BMI of 40, death rates from all cancers were 62% higher in women and 52% higher in men when compared to those of "normal weight."

RELATED: The #1 Cause of Obesity, According to Science

"I eat a balanced diet of real food. The less processed, the better!" says Allison Betof Warner, MD, Ph.D. of Memorial Sloan Kettering Cancer Center. Of course, this melanoma medical oncologist splurges and doesn't always eat healthy (like the rest of us!), but when she does, moderation is key.

While no single food can prevent cancer, a well-rounded diet with a variety of vegetables, fruits, and grains can go a long way toward risk reduction.

"I try to live by the 80/20 rule," she caveats. That's 80% whole, healthy foods in balanced proportions and 20% treats and other "less" healthy stuff.

"I make sure to get plenty of Vitamin D," says Kevin Dawravoo, MD, hematologist and medical oncologist at Northwestern Medicine Cancer Center Warrenville. He cites numerous studies that support the anti-cancer effects of this nutrient. Anyone can check for a vitamin D deficiency with a simple blood test at their doctor's office. That deficiency was linked in a 2014 study to a greater risk for more aggressive prostate cancer.

The best source for vitamin D is the sun, but new research says sunblock does not compromise the absorption of the vitamin. Fish is the best food source for vitamin D, including salmon, rainbow trout, and swordfish, as well as fish oil/cod liver.

Most Americans are "woefully sleep deprived," says Dr. Stephen C Schimpff, MD, MACP. Board certified in medical oncology, Schimpff is sure to "get enough sleep" each night. It's a subject important enough that he addresses it in his book, Longevity Decoded The 7 Keys to Healthy Aging.

"Inadequate sleep predisposes to high blood pressure, stress, overeating [in general] and the wrong foods, obesity, and hence predisposes to cancer," he continued

Monisha Bhanote, MD, FASCP, FCAP meditates regularly, a practice she says can "help balance life's daily stressors." The most benefit is gained from daily practice, even if just five minutes, than if done sporadically.

The triple board certified physician at Baptist MD Anderson Cancer Center says, "Managing stress is important for preventing chronic disease and predisposing one to cancer. Stress weakens the immune system and lowers its defenses to fight diseases." Consistent meditation can move the body into a parasympathetic state (rest and energy conservation) as opposed to a continuous sympathetic state (aka fight or flight).

Bhanote cited a 2004 study that found chronic stress can impair the body's immune response and contribute to the development of cancer.

A variety of sources like cell phones, wifi, power lines, and battery-powered cars bombard us every day with EMFs, or electromagnetic fields. Dr. Jonathan Stegall, an integrative oncologist and medical director of The Center for Advanced Medicine in Atlanta, says he tries to limit his exposure to EMFs.

"I recommend that my patients not hold a cell phone up to the ear, and instead hold it away from the body using speaker phone. This significantly minimizes the amount of radiation absorbed by the body," advises the author of the bestselling book Cancer Secrets. He also recommends installing a timer on any WiFi modem/router at home so that it turns off while you are sleeping.

RELATED: The #1 Reason You Could Get Cancer, According to Science

It's family first for Dr. Timothy S. Pardee, chief medical officer, Rafael Pharmaceuticals and oncologist and director of Leukemia Translational Research at Wake Forest Baptist Health. He believes this time is super important, and notes that familial relationships can reduce stress and increase overall well being.

A global study found that larger families, those with many children, have a reduced risk of cancer. And that's not just the nuclear family. Larger household sizes with multiple generations living together enjoy that same protective benefit. The study authors cite the "special emotional environment" as having a positive effect that contributes to disease resistance, as well as the benefit of family members supporting each other in a healthy lifestyle.

Did you know you can get paid to prevent cancer? Roshni Rao, MD, Chief of the Division of Breast Surgery at New-York Presbyterian Hospital and Columbia University Medical Center and says even she participates in clinical trials. "I was part of an MRI trial where I was in [the] machine for over an hour, and I got paid $25!," she said.

She's also participating in the T-MIST trial, a national study working to identify how often women should get mammograms and what type of mammogram to get. Rao says this trial is currently open at Columbia and seeking up to 165,000 women to participate.

"I drink a few cups of green tea or coffee every day," says William W. Li, MD, author of Eat to Beat Disease: The New Science of How Your Body Can Heal Itself. After 20 years of cancer prevention research, he says he's well aware of the scientific evidence that points to tea and coffee doing the body good.

They each "contain different types of polyphenols (micronutrients from plant-based food), but they all activate our body's key health defense systems (starving cancer, feeding our healthy gut bacteria, repairing damaged DNA, improving immunity) that help us resist cancer. From lab studies to clinical trials to large-scale public health studies showing that tea or coffee lowers risk across different forms of cancers, I consider it a no-brainer to drink these beverages." And it's a cherry on top that he loves the taste!

The lead authors of a large-scale study from the University of Glasgow in 2018 now know it's best to keep screentime to a minimum. They analyzed nearly 400,000 people and found a strong correlation between higher screentime and a higher risk of all-cause mortality, cardiovascular disease, and cancer. This was independent of known cancer-causing factors like smoking, BMI, and diet.

The more discretionary, or leisure, time spent on tablets, smartphones, and other media devices directly contributes to a sedentary lifestyle, the result of which is lower physical fitness, grip strength, and overall poor health.

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Nearly half the deaths from an astounding 12 different cancers can be attributed to smoking cigarettes: liver, colorectal, lung, oral and throat, esophageal, larynx, stomach, pancreas, bladder, kidney, cervix, and acute myeloid leukemia. That's why it's a smoke-free life for Dr. Wafik El-Deiry, Associate Dean for Oncologic Sciences at Brown University. While fewer people smoke in 2019, plenty are still addicted to one of the single-most unhealthy habits.

He does note that quitting smoking can have a positive impact, but that the risk never fully goes away compared to the general population. It can take 8-10 years to truly minimize the risks associated with cigarette smoking.

Likewise, Dr. El-Deiry isn't vaping, either.

"The message needs to get out that [vaping] is potentially cancer causing and we have to be aware," he warns. "The more we talk about itto save anyoneis worth it."

He says the more we learn about vaping the more we realize how unsafe it is in different ways. The vapor exposes users to chemicals known to cause cancer, for instance. And while e-cigs have their place for smokers trying to quit, the vape pens aren't benign. El-Deiry reminds that no substantial research has yet been completed on the relationship between vaping and cancer.

The National Institutes of Health warns that teens are vaping in record numbers; higher than opioid or marijuana use.

Dr. Katherine Crew, director of the Clinical Breast Cancer Prevention Program at New York-Presbyterian and Columbia University Medical Center, walks at least a mile every day. "For a busy oncologist, it's not always easy to find time to lead a healthy, active lifestyle, but I try to incorporate it into my daily routine."

Each of those steps is worth the time. Walking a single mile each day at a moderate 20-minute pace can reduce mortality in breast cancer patients by as much as 40% and almost 30% in prostate cancer patients. Risk for endometrial cancer is also reduced by a moderate intensity walking regimen.

Dr. Crew also takes the stairs "whenever it's humanly possible" to gain an extra burst of physical activity in her day.

RELATED: 9 Everyday Habits That Might Lead to Dementia, Say Experts

As an exercise oncologist, Kathryn Schmitz, PhD gets as much movement as she recommends. Before heading outdoors though, "I slap on the sunscreen, since exercise increases the risk of melanoma by 28%." While this 2016 study found that exercise reduces the risk for 10 different cancers, it increased risk for malignant melanoma significantly.

Schmitz echoed the researchers' assumption that increased time exercising or enjoying leisure physical activity increased exposure to the sun, which in turn increased the incidence of skin cancer. If you're spending time outside, be sure to wear a broad spectrum sunblock with SPF 30 or higher and remember that "water resistant" is not the same as "waterproof."

Making "greener" choices can ultimately support everyone's goal to reduce their risk of cancer. Climate change is having a negative impact on more than just the earth's health and sustainability. Human life is taking a negative toll, too.

Stratospheric ozone depletion is implicated in an increase in skin cancer incidence, like melanoma, and scientists expect to see a continuation over the next couple of decades.Exposure to air pollution increases the risk of breast cancer in premenopausal women. And the very air we breathe has been deemed carcinogenic by WHO, citing a direct correlation to nearly a quarter-million lung cancer deaths in 2010 alone.

How much "good" fat do you have in your diet? It's something Dr. Stephen C Schimpff, MD, MACP, author of Longevity Decoded The 7 Keys to Healthy Aging, prioritizes in his own diet. He recommends avocado, nuts and seeds, olive oil, and fish like tuna and salmon.

What makes a fat good for you? These unsaturated fats remaining liquid, not solid, at room temperature and are generally derived from plants.

Tree nuts like almonds, walnuts, and pecans can decrease your risk of colon cancer, which is why Kevin Dawravoo, MD, hematologist and medical oncologist at Northwestern Medicine Cancer Center Warrenville, makes them a regular part of his diet.

For men and women, a 2018 study found a "statistically significant" link between eating nuts three times per week and a reduction in colorectal cancer risk.

Another 2018 study found that stage 3 colon cancer patients who had two 1-ounce servings of tree nuts (which included walnuts, cashews, almonds, pistachios, hazelnuts, pecans macadamia nuts, and Brazil nuts) each week were 42% more likely to experience disease-free survival and 57% greater chance of overall survival.

Turn up the flavor experience of roasted vegetables, rice, soup, smoothies, and tea by adding turmeric. This Indian spice, most common in curries, has an earthy sweet-pungent flavor and bright orange hue that can truly transform any food. That, and the cancer-preventative benefits, are why Roshni Rao, MD, Chief of the Division of Breast Surgery at New-York Presbyterian Hospital and Columbia University Medical Center, loves to eat turmeric-laden foods.

"Most of the studies do show a benefit from this anti-inflammatory, and there is no study that shows that it is detrimental," she says.

A 2015 study reviewed the multifaceted role of curcumin (the source of turmeric) in cancer prevention, and found that it can "suppress initiation, progression, and metastasis of a variety of tumors."

The plastics we brush our teeth with, eat and drink from, build toys with, type on, and so much more inundate every aspect of our lives, but the chemicals within are taking away our health and mortality. Especially when plastics are heated or scratched, they can leach the chemicals used to develop the products. Once inside our bodies, these chemicals, like BPA, disrupt the natural role of hormones and create an imbalance that can ultimately lead to cancer.

"BPA has been shown to play a role in the [development of]hormone-dependent tumors such as breast and prostate cancer," states a 2015 study that reviewed the health risks associated with exposure to bisphenol A.

Avoid plastics whenever possible by looking for BPA-free products and carrying reusable glass or steel drinking vessels. Do not cook or reheat food nor store hot food in plastic containers.

"Especially important in the summertime is decreasing charred food consumption," says Kevin Dawravoo, MD of Northwestern Medicine Cancer Center Warrenville. Reminding that the blackened char marks on grilled meat is a known carcinogen. It's something he rarely eats.

The concern is that when meat is cooked over open flame, and burned or blackened, chemicals known as HCAs and PAHs develop. When consumed these can alter a person's DNA which increases the risk of cancer.

In rodent studies, HCAs developed tumors breast, colon, liver, skin, lung, prostate, and other tumors. Similar rodent studies found that PAHs caused leukemia, and identified gastrointestinal and lung tumors. In epidemiologic studies, higher consumption of well-done and "barbecued" meat was linked to increased risk of colorectal, pancreatic, and prostate cancers.

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You might be bored answering all of your doctor's questions about your parents' and grandparents' health, but it truly matters. Dr. Wafik El-Deiry, Associate Dean for Oncologic Sciences at Brown University, knows his family history and strongly recommends that you do the same.

"Illnesses that are found in the family can be a major clue to what risks there are," he says, adding that a history of cancer is usually well known and not difficult to learn about.

Sharing your family history with your doctor means they can do additional screening sooner, and work to catch symptoms and tumors earlier, which is key in treating and curing cancer.

"This knowledge may also direct patients to genetic testing that can further help to figure out different options to manage the risks," he added.

"Read your mammography results letter. In many states, including Connecticut, we, as radiologists are required to inform the patient whether or not her breast tissue is dense. If your breast tissue is dense, talk to your doctor about whether you need additional tests: a screening ultrasound or possibly even a screening MRI, the latter being a useful complementary screening tool in some women at higher than average risk of developing breast cancer. Please note that screening ultrasounds and screening MRIs do not replace mammography; rather, they are a complement to it," says Liva Andrejeva-Wright, MD, a Yale Medicine radiologist who specializes in breast imaging.

"It is important to know that screening mammograms do not prevent breast cancer. They do help by detecting cancer early in many cases, before it becomes palpable, however, and therefore prevent disease and treatment related morbidity that would have occurred if the cancer was detected later by the patient or her doctor," she added. And to get through this pandemic without catching coronavirus, don't miss this essential list: Most COVID Patients Did This Before Getting Sick.

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Slash Your Cancer Risk in Seconds, Say Cancer Experts | Eat This Not That - Eat This, Not That

Cases of type 2 diabetes have been significant and on the rise within the past decade. This condition is restrictive in some ways. Individuals are deprived of the ability to enjoy their preferred foods and are likely to experience intense symptoms (i.e., thirst, hunger, faintness, and blurred vision, among others). Several solutions have come and gone, but one natural supplement appears to have taken a unique approach that might end up reversing diabetes altogether. This supplement is none other than Glucofort.

Glucofort is an advanced blood sugar support that eliminates the supposed root cause of type 2 diabetes: ceramides. As explained by the creators of this solution, Andrew Freeman and Dr. Jun, ceramides push fat cells into the bloodstream, forcing vital organs to clog up. This prevents the pancreas from producing the insulin hormone, a crucial component that redistributes glucose to other body areas. It is only when these foreign invaders are eliminated from the body that diabetes might be reversed altogether. Hence, the reason for Glucofort.

The Glucofort formula has been split into a vitamins and minerals blend and a proprietary blend. The first includes Vitamin C (50mg), Vitamin E (15mg), Biotin (300mcg), Magnesium (125mg), Zinc (7.5mg), Manganese (1mg), Chromium (76mcg) and Vanadium. As for the proprietary ingredients blend, individuals can familiarize themselves with Guggul, Bitter Melon, Licorice, Cinnamon, Gymnema Sylvestre, Alpha Lipoic Acid, Banaba, Yarrow, Juniper, White Mulberry, L-Taurine, and Cayenne.

Guggul: According to a 2020 article in the International Journal of Research in Pharmaceutical Sciences, Guggul divided into nine groups, rats were given Diabetes mellitus, over a 28 week period, Blood collected showed that guggul did not reveal toxicity in the rats, and guggul formulations improved oral glucose tolerance in the diabetes-induced rats and after the end of the study resulted in significant reductions in serum glucose levels.

Bitter Melon: The US National Library of Medicine National Institutes of Health states that medicinal plants are important cost-effective worldwide to treat diabetes and are considered therapeutic aids in alleviating ailments in humans. Bitter melon is reported to possess pancreatic cell regeneration, insulin-releasing, and fighting insulin resistance.

Licorice Root: An herb that has been used for decades to treat many health ailments. Scientists have identified a group of natural substances with anti-diabetic effects found in the licorice root.

Cinnamon Bark: Known as true cinnamon, studies show that cinnamon can effectively manage blood sugar issues, such as lower blood sugar, and may help control high blood glucose levels in the brain.

Gymnema Sylvestre: Supports lowering of high blood sugar levels. And may play a role in diabetes treatment, as it may regenerating pancreas islet cells and stimulate insulin secretion, which help lower blood sugar levels.

Alpha Lipoic Acid: Can break down carbs and make energy for use in other organs in the body, and an antioxidant.

Banaba: The banaba leaf has been used in folk medicine for decades to treat diabetes used for its impressive anti-diabetic properties, antioxidant, cholesterol-lowering, and anti-obesity health benefits.

Yarrow: Used to regulate blood sugar in diabetes, protect the gallbladder and liver, and as immune-system support.

Juniper Berry: May hold antidiabetic properties and used in traditional medicine to treat diabetes, with recent studies confirming that they may have anti-diabetic properties.

White Mulberry: Used to treat high cholesterol, common colds, high blood pressure, joint, and muscle pain caused by arthritis. White mulberry can be used against hair loss and premature graying, constipation, dizziness, and ringing in the ears.

L-Taurine: Taurine can helps by avoiding the damaging effects of fat, glucose, and excess insulin levels; it also protects and strengthens the heart muscle cells.

Cayenne: Scientifically proven to boost metabolism, lower blood pressure with the capsaicin found in cayenne peppers can also reduce hunger.

Generally speaking, Glucofort is deemed 100% natural, safe, and effective to take. In fact, this formula has supposedly undergone testing with 160 men and women who were either pre-diabetic, diabetic, or have had diabetes for some time now. The study results suggest that glucose levels improved, weight and fat loss were attained, blood pressure and sugar levels were lowered, and cardiovascular and cognitive health bettered with time. That said, no side effects were reported. All things considered, a health practitioners opinion should be gathered before adding any extra supplements.

Given that one capsule should be taken per day and each bottle contains 30 capsules, individuals can expect to invest roughly $69 per bottle. Bulk orders such as purchasing 3 or 6 bottles at once will come out to $59 and $49 each, respectively. Luckily, all unused bottles have been protected by a 60-day money-back guarantee, making Glucofort risk-free.

Blood sugar is a health biomarker that needs to be taken care of, as it can easily worsen and lead to unwanted health implications. With a solution like Glucofort, symptoms may be eased in the short run and reversed in the long run. In this case, patience is key, and everyone will need to consider their health conditions and possible medication interactions beforehand. To find out more about Glucofort, visit here>>>.

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Please understand that any advice or guidelines revealed here are not even remotely a substitute for sound medical advice from a licensed healthcare provider. Make sure to consult with a professional physician before making any purchasing decision if you use medications or have concerns following the review details shared above. Individual results may vary as the statements made regarding these products have not been evaluated by the Food and Drug Administration. The efficacy of these products has not been confirmed by FDA-approved research. These products are not intended to diagnose, treat, cure or prevent any disease.

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GlucoFort Reviews: Does GlucoFort Work? What They Won't Say! - Homer News

Introduction

Prostate cancer is the fifth most common cancer in Thai men,1 and the number of cases continues to increase despite active screening. Radical prostatectomy (RP) is the standard of care in the management of clinically localised cancer and also an option for the treatment of locally advanced prostate cancer. RP can be performed using open radical prostatectomy (ORP), laparoscopic radical prostatectomy (LRP), or robotic-assisted laparoscopic radical prostatectomy (RALRP) techniques.

Another recognised treatment for regional and metastatic prostate cancer is androgen deprivation therapy (ADT). ADT is also a beneficial supplement to external beam radiation therapy (EBRT).2 However, the use of neoadjuvant androgen deprivation therapy (NADT) prior to RP as a perioperative treatment is still controversial.2 Previous research has demonstrated that NADT lowers the positive margin status, but this benefit has not translated into improvements in long-term PSA-free survival.3 NADT is also associated with worrisome side effects, such as osteoporosis, hot flashes, sexual dysfunction, metabolic syndrome, gynecomastia, anaemia and cardiovascular mortality. For all these reasons, current guidelines recommend against the use of NADT prior to RP.2,4,5

In the past few years, a growing trend has emerged towards the utilization of NADT, as it can provide a pathological complete response,6 a potentially positive impact on recurrence rates,7 a significant decrease in prostate cancerrelated death8 and fewer long-term effects on quality of life.9 The aim of the present study was to determine the benefit of NADT prior to RP in terms of perioperative outcomes.

Between January 2008 and July 2018, 718 prostate cancer patients were treated by RP at Ramathibodi Hospital in Thailand. Of these patients, 138 had undergone NADT (NADT group) and 580 had not undergone neoadjuvant ADT (non-NADT group). The remaining 2 patients were excluded from the study due to incomplete data. The principles of the Helsinki Declaration were followed during the study, consent and the confidentiality of the patients data was maintained by the authority of the Committee for Research of the Faculty of Medicine, Ramathibodi Hospital, Mahidol University (date of approval: 20 February 2020, ID MURA2020/298).

The ORP was performed in a retropubic fashion via low midline incision (Figure 1). A retzius space was approached with blunt and sharp dissection along the outside of left umbilical ligament. Endopelvic fascia on both sides were bluntly opened, puboprostatic ligament was dissected and dorsal venous complex was sutured and ligated using Vicryl No.1. The bladder neck was incised with monopolar cautery then foleys catheter was pull and traction. The seminal vesicle and vas deferens were dissected. Denonvilliers fascia was opened and the posterior surface of prostate was freed. The lateral prostatic pedicles were dissected with monopolar cautery and ligated without nerve sparing, followed by incised of urethra by Metzenbaum scissor. An urethrovesical anastomosis was performed with interrupted sutures, using Vicryl 3/0 6 stitches. Before the last stitch was performed, new 20 Fr Foleys catheter was inserted via urethra into bladder. Bleeding was checked and stopped. Silastic drain was placed in cul-de-sac.

Figure 1 Incision of open radical prostatectomy.

The LRPs were performed in an extraperitoneal fashion using 5 trocars with some modification in port position to facilitate the prevention to graft injury (Figure 2). Subumbilical incision was done and extraperitoneal space was created using kidney-shaped balloons with (PDB, Covidien, United States). Retropneumoperitoneum was performed by CO2 insufflation to create at an abdominal pressure of 15 mmHg, followed by port placement as Figure 2, all trocars were inserted under direct visualization. Thirty-degree standard Trendelenburg position was used with cushioning for dependent zone. A Retzius space was developed. Endopelvic fascia on both sides were opened, followed by puboprostatic ligament was dissected and dorsal venous complex was controlled using Vicryl No.1 CT-1 needle. The bladder neck was incised with monopolar cautery then foleys catheter was pull and traction. The seminal vesicle and vas deferens were dissected. Denonvilliers fascia was opened and the posterior surface of prostate was freed. The lateral prostatic pedicles were controlled by Hem-o-lock clip and dissected with vessel sealing device (LigaSure Impact Curved, Large jaw, Medtronic, United Kingdom) without nerve sparing, followed by incised of urethra by cold scissor. An urethrovesical anastomosis was performed with continuous watertight sutures, using Vicryl 3/0. Before passing the anterior stitch, the 20 Fr Foleys catheter was passed into the bladder and the anastomosis was completed. A closed suction drain was placed in cul-de-sac. The specimen was retrieved with the use of laparoscopic bag through a subumbilical incision.

Figure 2 Port placement of laparoscopic radical prostatectomy.

The RALRPs were performed with transperitoneal fashion using the da Vinci Si Surgical System, with 5 trocars. We place the trocars medially than the standard port site to deliver sufficient access without graft injury (Figure 3). The pneumoperitoneum pressure of 15 mmHg was created after subumbilical puncture with Veress needle. A 12 mm subumbilical trocar was inserted into abdominal space and was used as a camera port. Two robotic trocars were placed on the right side with at least 8 cm apart from each other (Arm 1, Arm 3). On the left side, a robotic trocar was placed (Arm 2), and the assistance 12 mm trocar was inserted between the second port and camera port as Figure 3, all trocars were inserted under direct visualization. Each arm was equipped with Monopolar scissor (Arm 1), Bipolar Maryland (Arm 2) and Prograpse (Arm 3). Thirty-degree standard Trendelenburg position was used with cushioning for dependent zone. A Retzius space was developed. Endopelvic fascia on both sides were opened, followed by puboprostatic ligament was dissected and dorsal venous complex was controlled using barbed suture No.1 (V-Loc PBT wound closure device, Medtronic, United Kingdom). The bladder neck was incised with monopolar and bipolar cautery then foleys catheter was pull and traction. The seminal vesicle and vas deferens were dissected. Denonvilliers fascia was opened and the posterior surface of prostate was freed. The lateral prostatic pedicles were controlled by Hem-o-lock clip and dissected with monopolar and bipolar cautery with 1 case of interfacial nerve sparing and 2 case of non-nerve sparing, followed by incised of urethra by cold scissor. An urethrovesical anastomosis was performed with continuous watertight sutures, using barbed suture 3/0 (V-Loc PBT wound closure device, Medtronic, United Kingdom). Before passing the anterior stitch, the 20 Fr Foleys catheter was passed into the bladder and the anastomosis was completed. A closed suction drain was placed in cul-de-sac. The specimen was retrieved with the use of laparoscopic bag through a subumbilical incision.

Figure 3 Port placement of robotic-assisted radical prostatectomy.

Nerve-sparing RPs were performed in some cases, except when biopsy specimens revealed extensive cancer or in cases of preoperative poor-quality erections, current and future lack of a sexual relationship, or other medical conditions that could adversely affect erections (eg, hypertension, diabetes mellitus, neurologic diseases, psychiatric diseases or medications that produce erectile dysfunction). However, we shared the decision-making with the patients and the surgeon.

Six instructor surgeons participated in this study. Two surgeons always performed ORPs over 25 years, while the other four surgeons performed all three techniques as shown in Table 1. The procedure techniques were decided by shared decision-making with patients.

Table 1 Surgeons Participation

In this study, both gonadotropin-releasing hormone (GnRH) analogues, such as degarelix, and GnRH antagonists, such as leuprolide, goserelin and triptorelin, were used for the ADT. The choice of medication depended on the patients insurance and the surgeon preference. The duration of NADT was 3 months, since some evidence indicates that this is the optimum duration.10,11

The decision was made upon the discussion between patients and physicians. Since the specific criteria for selection have not been officially stated, we typically advise the NADT for those patients who a. associated with high or very high-risk disease and b. are on the waitlist for surgery longer than three months.

The following data were collected from all patients: age, body weight (kg), height (cm), body mass index (BMI), prostate-specific antigen (PSA) level, underlying disease, clinical stage (TNM classification), prostate cancer risk group (National Comprehensive Cancer Network [NCCN] classification),2 and the Gleason score (GS) of the biopsy specimen.

Perioperative outcomes included operative time (minutes); estimated blood loss (EBL) (mL); perioperative complications, including transfusion rate; adjacent organ injury of the bladder, rectum, ureter, bowel, or blood vessel; and length of hospital stay (days) (determined by subtracting the date of admission from the date of discharge).

All specimens were evaluated in accordance with the NCCN guidelines by an experienced uropathologist, who reported the prostate weight (g), pathological stage, GS of the specimen and the margin status. A positive surgical margin (PSM) was defined as cancer cells extending to the inked surface of the specimen.12

A descriptive study was performed. The data were analysed using a Wilcoxon rank-sum (MannWhitney) and Fishers exact test to identify the statistical significance of the difference in means standard deviation, median (interquartile range), and proportions. Analysis was performed using Stata version 14 software, with a p-value of <0.005 considered to be statistically significant.

The demographic data and preoperative parameters are presented in Table 2. The non-NADT and NADT groups were not statistically different in terms of median age (68 vs 68 years; p = 0.819), median body weight (67.1 vs 67.1 kg; p = 0.807), median height (165 vs 165 cm; p = 0.403) or median BMI (24.4 vs 24.3 kg/m2; p = 0.218). The pre-operative PSA level and GS of the biopsy specimens were statistically significantly higher in the NADT than in the non-NADT group (33.4 [16.256.6] vs 10.1 [7.215.2]; p = <0.001 and 8 [79] vs 7 [67]; p = <0.001). The clinical stage differed significantly between the two groups (p = <0.001).

Table 2 Demographic Data and Pre-Operative Parameters of Non-NADT and NADT

The perioperative outcomes (Table 3) showed that the operative time was significantly lower in the NADT than in the non-NADT group (185 vs 195 minutes; p = <0.018). The EBL was also significantly lower in the NADT than in the non-NADT group (300 vs 500 mL; p = <0.001), but no difference was noted in the blood transfusion rate between the two groups. No statistically significant differences were detected between the NADT and non-NADT groups for adjacent organ injury rate (2.9% vs 2.2%; p = 0.999) or length of hospital stay (6 vs 6 days; p = 0.184). The most common site of injury was the rectum (11 patients).

Table 3 Perioperative Outcomes of Non-NADT and NADT

The pathological outcomes (Table 4) revealed significant differences in pathological stage between the two groups (p = 0.001). The GS of the specimens was significantly higher in the NADT group than in the non-NADT (7 [79] vs 7 [77]; p < 0.001). The specimen weight was significantly lower in the NADT than in the non-NADT group (34.8 vs 39.5; p = 0.014). The PSM did not differ significantly between the NADT and non-NADT group (36.4% vs 43.9%; p = 0.131).

Table 4 Pathological Outcomes of Non-NADT and NADT

Subgroup analysis for perioperative and pathological outcomes of the non-low risk prostate cancer patients are presented in Table 5. The perioperative outcomes, which included operative time, EBL, blood transfusion rate and length of hospital stay, were significantly better in the NADT than in the non-NADT group. Only adjacent organ injury rate showed no significant difference in the two groups. The pathological stage was significantly different in the two groups (p < 0.001). The GS of the specimens was significantly higher in the NADT group (7.5 [79] vs 7 [78]; p < 0.001) and the specimen weight was significantly lower in the NADT group (35 [29.144] mL vs 40 [32.251.5] mL; p = 0.002). However, the PSM still did not show a significant difference between the NADT and non-NADT groups (43.6% vs 47.8%; p = 0.506).

Table 5 Perioperative Outcomes and Pathological Outcomes of PCa Non-Low Risk Group

Neoadjuvant therapy is the current standard of care for several solid tumour malignancies, including bladder, breast, and rectal cancer. NADT prior to surgery may downstage a malignancy to facilitate surgical resection, thereby lowering the positive surgical margin rate and improving perioperative outcomes.13,14 In our study, the median operative time was significantly lower in the NADT than in the non-NADT group (p=0.018) and a lower EBL was also observed in the NADT group (p<0.001).

Androgen deprivation therapy affects tumour behaviour and biology by changing the metabolic patterns of atrophy, lowering serum PSA level and reducing histopathologic atrophy.3 These tumour responses may have contributed to the smaller prostate volume in the NADT group than in the non-NADT group (39.5 vs 34.8 g, p = 0.014), since enlarged prostate glands usually have more vascularity and a wider resection margin.1517

The transfusion rate did not differ significantly between the two groups (p = 0.091). This may reflect the practice in our hospital of having the anaesthesiologist initiate transfusion when the haematocrit drops below 30. Consequently, some patients with a higher baseline haematocrit would be less likely to receive a transfusion.

The length of hospital stay also did not differ statistically between the two groups. However, the hospital stays were longer in the present study than in a previous study by Wallerstedt et al,18 who reported lengths of hospital stay of around 3.34.1 days. This discrepancy can be attributed to an institutional practice where patients are routinely discharged after the closed-suction pelvic drain is removed. However, many other factors, such as socioeconomic status, inexpensive room rates, anxiety and patient pain tolerance, might affect the length of a hospital stay.

No pathological down-staging could be demonstrated in the present study because of the limited pre-operative T clinical staging. In our setting, pre-operative imaging is not generally affordable for all patients, so many patients are classified as T1c (91.4%). Nevertheless, the data show a decrease in the median GS in the NADT group from the pre-operative biopsy specimen score of 879 to the post-operative specimen score of 7.79

The oncological control of RP in prostate cancer can be measured by the PSM, biochemical recurrence (BCR) rate, time to biochemical recurrence, local recurrence and distant metastasis.19 Sachdeva et al20 and other researchers2124 have shown that a PSM in prostate cancer is considered an adverse oncologic outcome and is associated with an increased likelihood of BCR. However, the significant predictors of BCR are tumour volume, a high GS and a high pre-operative PSA level. In our study series, no statistically significant difference was noted in PSM between both groups, which is consistent with the results of many guidelines and the current literature.2,4,5 The PSM rate in large series data ranged from 11% to 50%11 and from 12.1% to 41.3% in a recent meta-analysis.12 The PSM rate in our study was higher, which may reflect the participation of multiple surgeons in this study, as each surgeon may have had a different learning curve. For example, in the present study, two new instructor surgeons had just started performing RALRP in 2016. In addition, after the subgroup analysis, most of the PSMs were in the T3 stage, indicating that PSMs could result from the nature of the cancer that had extended beyond the prostatic capsule.

The subgroup analysis revealed that the perioperative and pathological outcomes significantly better almost all parameters in the non-low risk NADT group. This can be related to the fact that study was heterogenous and not weighted towards those who may benefit the most from NADT.

Patients with PSM are typically given two treatment options: external beam radiation therapy (proton beam radiation) with or without androgen deprivation therapy (ADT) or observation. Unfortunately, data related to the rate of conversion and catheterisation time could not be collected to determine our patient outcomes, as this study was retrospective. The functional outcomes, such as incontinence and erectile dysfunction, are presently being assembled by the authors, who will report on these findings in a subsequent study.

Author want to underline some interesting upcoming trend from the Pignot and Walz,25 and we comply with their findings that the multimodal approach including both local and systemic treatment neoadjuvant may be an option for selected patients especially with non-low risk prostate cancer. However, there is still not enough data to conclude when is the best setting for treatment (Neoadjuvant/adjuvant) and who would really benefit from treatment.

The present study has some limitations. One was its retrospective nature, which compared the effect of NADT with non-NADT but did not include data regarding the type of ADT, since no standard regimens for NADT currently exist. Consequently, the choice of treatment for each patient is highly heterogeneous and depends on patient insurance and physician preference. A second limitation is that all RPs were performed by different surgeons, raising the possibility of bias in the process of evaluating the procedure outcomes. A third limitation is that this study lacked data about the oncological and functional follow-ups. A fourth limitation is that this study had some significant differences in baseline characteristic, approach, PSA pre-op and GS from biopsy (33.4 [16.256.6] vs 10.1 [7.215.2]; p = <0.001 and 8 [79] vs 7 [67]; p = <0.001), as a result of the selection bias by physician typically offer treatment with NADT in high or very high-risk disease and the trend toward the Robotic-assisted era which can confound the effect of NADT. The findings of the present study would be strengthened by conducting a prospective randomised study with a higher case volume, as this would reduce biases and provide much more accurate results.

This study has demonstrated the long-term data on the use of NADT prior to RP and has shown an association between NADT and a positive effect on perioperative outcomes in the prostate cancer non-low risk group. Further randomized, prospective studies are needed to elucidate the true effect of NADT on perioperative outcomes, pathological outcomes and survival benefit.

This work was supported by Wijittra Matang, Yada Phengsalae and Kornkanok Somboonpun. The authors thank Wijittra Matang, Yada Phengsalae and Kornkanok Somboonpun for continued support and encouragement.

The authors declare no conflicts of interest in this work.

1. National cancer institute Doms, Thailand. Hospital base cancer registry 2015. 2017.

2. network NCC. Prostate cancer (Version 1.2020). Available from: https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed May 14, 2021.

3. Meng MV. Treatment of Locally Advance Prostate Cancer. 12th ed. Partin AW, editor. Elsevier; 2020:2.

4. Sanda MG, Chen RC, Crispino T, et al. Clinically localized prostate cancer: AUA/ASTRO/SUO guideline; 2017. Available from: https://www.auanet.org/guidelines/prostate-cancer-clinically-localized-guideline#x14226. Accessed May 14, 2021.

5. Mottet N, Bellmunt J, Briers E, et al. EAU ESTRO ESUR SIOG guidelines on prostate cancer; 2020. Available from: https://uroweb.org/guideline/prostate-cancer/. Accessed May 14, 2021.

6. Montgomery B, Tretiakova MS, Joshua AM, et al. Neoadjuvant enzalutamide prior to prostatectomy. Clin Cancer Res. 2017;23(9):21692176. doi:10.1158/1078-0432.CCR-16-1357

7. McKay RR, Montgomery B, Xie W, et al. Post prostatectomy outcomes of patients with high-risk prostate cancer treated with neoadjuvant androgen blockade. Prostate Cancer Prostatic Dis. 2018;21(3):364372. doi:10.1038/s41391-017-0009-6

8. Tosco L, Laenen A, Briganti A, et al. The survival impact of neoadjuvant hormonal therapy before radical prostatectomy for treatment of high-risk prostate cancer. Prostate Cancer Prostatic Dis. 2017;20(4):407412. doi:10.1038/pcan.2017.29

9. Chen MC, Kilday PS, Elliott PA, et al. Neoadjuvant leuprolide therapy with radical prostatectomy: long-term effects on health-related quality of life. Eur Urol Focus. 2020. doi:10.1016/j.euf.2020.03.001

10. Meyer F, Bairati I, Bedard C, Lacombe L, Tetu B, Fradet Y. Duration of neoadjuvant androgen deprivation therapy before radical prostatectomy and disease-free survival in men with prostate cancer. Urology. 2001;58(2 Suppl 1):7177. doi:10.1016/S0090-4295(01)01245-6

11. Soloway MS, Pareek K, Sharifi R, et al. Neoadjuvant androgen ablation before radical prostatectomy in cT2bNxMo prostate cancer: 5-year results. J Urol. 2002;167(1):112116. doi:10.1016/S0022-5347(05)65393-1

12. Silberstein JL, Eastham JA. Significance and management of positive surgical margins at the time of radical prostatectomy. Indian J Urol. 2014;30(4):423428. doi:10.4103/0970-1591.134240

13. Gmez Veiga F, Lorenzo Patio MJ, Daz Bermdez J, et al. [Effect of complete androgen block before radical prostatectomy for cancer of the prostate]. Arch Esp Urol. 1997;50(4):355363.

14. Polito M, Muzzonigro G, Minardi D, Montironi R. Effects of neoadjuvant androgen deprivation therapy on prostatic cancer. Eur Urol. 1996;30(Suppl 1):2631. doi:10.1159/000474242

15. Frota R, Turna B, Santos BM, Lin YC, Gill IS, Aron M. The effect of prostate weight on the outcomes of laparoscopic radical prostatectomy. BJU Int. 2008;101(5):589593. doi:10.1111/j.1464-410X.2007.07263.x

16. Hsu EI, Hong EK, Lepor H. Influence of body weight and prostate volume on intraoperative, perioperative, and postoperative outcomes after radical retropubic prostatectomy. Urology. 2003;61(3):601606. doi:10.1016/S0090-4295(02)02422-6

17. Kim MS, Jang WS, Chung DY, et al. Effect of prostate gland weight on the surgical and oncological outcomes of extraperitoneal robot-assisted radical prostatectomy. BMC Urol. 2019;19(1):1. doi:10.1186/s12894-018-0434-4

18. Wallerstedt A, Tyritzis SI, Thorsteinsdottir T, et al. Short-term results after robot-assisted laparoscopic radical prostatectomy compared to open radical prostatectomy. Eur Urol. 2015;67(4):660670. doi:10.1016/j.eururo.2014.09.036

19. Akand M, Celik O, Avci E, Duman I, Erdogru T. Open, laparoscopic and robot-assisted laparoscopic radical prostatectomy: comparative analysis of operative and pathologic outcomes for three techniques with a single surgeons experience. Eur Rev Med Pharmacol Sci. 2015;19(4):525531.

20. Sachdeva A, Veeratterapillay R, Voysey A, et al. Positive surgical margins and biochemical recurrence following minimally-invasive radical prostatectomy an analysis of outcomes from a UK tertiary referral centre. BMC Urol. 2017;17. doi:10.1186/s12894-017-0262-y

21. De La Roca RL, Da Cunha IW, Bezerra SM, Da Fonseca FP. Radical prostatectomy and positive surgical margins: relationship with prostate cancer outcome. Int Braz J Urol. 2014;40(3):306315. doi:10.1590/S1677-5538.IBJU.2014.03.03

22. Meeks JJ, Eastham JA. Radical prostatectomy: positive surgical margins matter. Urol Oncol. 2013;31(7):974979. doi:10.1016/j.urolonc.2011.12.011

23. Pettenati C, Neuzillet Y, Radulescu C, Herve JM, Molinie V, Lebret T. Positive surgical margins after radical prostatectomy: what should we care about? World J Urol. 2015;33(12):19731978. doi:10.1007/s00345-015-1580-x

24. Yossepowitch O, Briganti A, Eastham JA, et al. Positive surgical margins after radical prostatectomy: a systematic review and contemporary update. Eur Urol. 2014;65(2):303313. doi:10.1016/j.eururo.2013.07.039

25. Pignot G, Walz J. Identifying the relevant population for neoadjuvant chemo-hormonal therapy combined with radical prostatectomy. Gland Surg. 2020;9(2):495497. doi:10.21037/gs.2019.12.22

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Neoadjuvant Androgen Deprivation Therapy Effects on Perioperative Outc | RRU - Dove Medical Press

Many have heard about the fire that caused $1 million dollars of damage to the very large residential home called Brigadoon Cottage on Mackinac Island on the evening of Sunday, May 30, 2021. What you may not have heard is the great news of the businesses and their staffs on Mackinac Island that came together to save a wedding reception.

A couple had gotten married that day and had just started their wedding reception next door to the Brigadoon Cottage at the Mackinac Island Yacht Club. MLive is reporting just after the guest were seated about a minute into the father-of-the-bride speech they noticed the fire.

What happened next is all good news and something you would see in a movie.

The Yacht Club staff called the Mission Point Resort staff and arranged for the wedding reception to be moved to their facility down the road. They used carriages, bikes and whatever else they could to move all of the necessary items from the Yacht Club to Mission Point.

We are told that within 30 minutes the reception was back on at Mission Point.

Many pitched in to help this couple on their wedding day. Even a local restaurant opened up their kitchen so the Yacht Club chefs could finish preparing the dinner for the guests. The article even states the staff from Mission point who was not working that day heard about what happened and came to help however they could.

The bride, Elizabeth Landuyt said they were very grateful and very blessed.

Her newly minted husband, Jake Landuyt put it this way:

We were blown awayTo see all our guests basically in the same spot as we had set up before. It was disbelief and overwhelming in the positive way. To go from that same state of disbelief to the exact opposite, were just so blessed to have friends and family there that were willing to do it.

Mission Points vice president of sales and marketing, Liz Ware said:

We love being a part of the amazing Mackinac Island community, where people and fellow businesses can come together to make magic happenOur entire team at Mission Point was proud to be a part and followed our brand pillars in delivering hospitality from the heart and to always do the right thing. Our core values include going the extra mile and working hard together with a great sense of Michigan pride, and we believe this is one of the reasons the Landuyts wedding reception was a truly celebratory occasion.

What a great story they will have to remember for the rest of their lives and what a great story to start our Friday and weekend off with.

Share the love and share this story.

The Live with Renk show airs Monday through Friday from 9 a.m. tonoon, to let me know your thoughts call (269) 441-9595

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Mackinac Island Businesses And Staff Save A Wedding Reception - wbckfm.com

DUBLIN--(BUSINESS WIRE)--The "Global Genetic Testing Market 2021-2025" report has been added to ResearchAndMarkets.com's offering.

The genetic testing market is poised to grow by $5.39 billion during 2021-2025, progressing at a CAGR of about 12%.

The market is driven by the rising prevalence of genetic diseases and disorders, rising approval of advanced genetic testing products, and increasing affordability due to reduction in the cost of genetic testing.

The report on the genetic testing market provides a holistic analysis, market size and forecast, trends, growth drivers, and challenges, as well as vendor analysis covering around 25 vendors. The report offers an up-to-date analysis regarding the current global market scenario, latest trends and drivers, and the overall market environment. The genetic testing market analysis includes product segment and geographic landscape.

This study identifies the advancements in next-generation sequencing as one of the prime reasons driving the genetic testing market growth during the next few years. Also, the growing adoption of direct-to-consumer genetic tests in early disease diagnosis and the growing adoption of pharmacogenetic testing in reducing adverse drug events will lead to sizable demand in the market.

The publisher's robust vendor analysis is designed to help clients improve their market position, and in line with this, this report provides a detailed analysis of several leading genetic testing market vendors that include Abbott Laboratories, Agilent Technologies Inc., bioMerieux SA, Bio-Rad Laboratories Inc., F. Hoffmann-La Roche Ltd., Illumina Inc., Myriad Genetics Inc., QIAGEN NV, Quest Diagnostics Inc., and Thermo Fisher Scientific Inc.

Also, the genetic testing market analysis report includes information on upcoming trends and challenges that will influence market growth. This is to help companies strategize and leverage all forthcoming growth opportunities.

The study was conducted using an objective combination of primary and secondary information including inputs from key participants in the industry. The report contains a comprehensive market and vendor landscape in addition to an analysis of the key vendors.

Key Topics Covered:

Executive Summary

Market Landscape

Market Sizing

Five Forces Analysis

Market Segmentation by Product

Segmentation by Application

Customer Landscape

Geographic Landscape

Vendor Landscape

Vendor Analysis

Appendix

For more information about this report visit https://www.researchandmarkets.com/r/pwg97i

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Global Genetic Testing (Equipment & Consumables) Market 2021-2025: Rising Approval of Advanced Genetic Testing Products and Increasing...

Researchers evaluated the clinical utility of genetic testing with MammaPrint 70-gene signature to determine how well this assay works in comparison with clinical assessment to determine the need for chemotherapy in women with breast cancer involving 0 to 3 lymph nodes. The phase 3 MINDACT findings, which included the survival outcomes of patients with an ultralow risk 70-gene signature, were presented during the 2021 American Society of Clinical Oncology Annual Meeting.

The 70-gene signature can identify patients with an ultralow risk of distant recurrence. These 1000 MINDACT patients had an excellent 8-year breast cancerspecific survival (BCSS) above 99%, regardless of clinical risk, and low rates of distant metastasis, explained Josephine Lopes Cardozo, MD, of the Netherlands Cancer Institute.

The median follow-up for disease assessment was 8.7 years. Of the 6693 patients enrolled in the study (ClinicalTrials.gov Identifier: NCT00433589), 1000 patients (15%) were identified as having an ultralow risk using 70-gene signature profiling and 67% of these patients were older than age 50. A majority of the patients were estrogen receptorpositive (99%), lymph nodenegative (80%), had grade 1 or 2 tumors (96%), and tumors below 2 cm in size (81%).

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Systemic therapy was administered in 83% of the study population; 69% of patients received endocrine therapy (ET), 14% received ET in combination with chemotherapy, and 16% did not receive adjuvant systemic therapy (AST). The trials primary endpoint was distant metastasis-free interval (DMFI).

At a median duration of 8 years, excellent DMFI and BCSS was observed in the low-risk and ultralow-risk group of patients. The 8-year DMFI for low-risk and ultralow-risk groups was 94.5% (95% CI, 93.6-95.3) and 97.0% (95% CI, 95.8-98.1), respectively. The 8-year DMFI in the ultralow-risk group who had not received AST was 97.8% (95% CI, 95.3-100). The 8-year DMFI in the ultralow-risk group who had received ET only was 97.4% (95% CI, 96.1-98.7). Based on the preliminary results after adjusting for tumor and treatment characteristics, DMFI for ultralow-risk vs low-risk groups had a hazard ratio (HR) 0.66 (95% CI, 0.46-0.95). The 8-year BCSS for genomic low-risk and ultralow-risk patients was 98.2% (95% CI, 97.7-98.7) and 99.6% (95% CI, 99.1-100), respectively.

We can confirm that the 70-gene signature can identify patients with ultralow risk of distant recurrence and these patients could be candidates for further de-escalation of treatment, further reducing overtreatment and the risk of side effects, concluded Dr Cordozo.

Disclosure: This research was supported by a grant from the EORTC Breast Group and the Netherlands Cancer Institute. Several study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors disclosures

Read more ofCancer Therapy Advisorscoverage of the 2021 ASCO Annual Meeting by visiting the conference page.

Reference

Cardozo JL, Drukker C, Schmidt M, et al. Outcome of patients with an ultralow risk 70-gene signature in the MINDACT trial. J Clin Oncol. 2021;39:(suppl 15; abstr 500). doi:10.1200/JCO.2021.39.15_suppl.500

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MammaPrint 70-Gene Signature Identifies Ultralow-Risk Patients With Outstanding Prognosis in Breast Cancer - Cancer Therapy Advisor

A medicine from AstraZeneca and Merck & Co. has become the first of its type to slow the return of a particularly aggressive, hereditary form of breast cancer, a significant finding that may push doctors to do more genetic testing in patients with the disease.

The results, from a 1,836-patient study of a drug called Lynparza, are being presented at the American Society of Oncology's virtual meeting Sunday and were published Thursday in the New England Journal of Medicine. They've been anticipated ever since AstraZeneca and Merck in February surprisingly said the Phase 3 study succeeded, without giving details. They could help change care for patients with an inherited gene mutation associated with roughly 5% of all breast cancers.

"These results will transform the prognosis, overnight, for [these] patients," said Chatrick Paul, the head of AstraZeneca's U.S. oncology division.

Patients in the so-called OlympiA trial received either Lynparza or placebo for a year of "adjuvant" treatment, meaning after surgery to remove a tumor and standard drugs such as radiation, chemotherapy or hormone therapy. All participants inherited a mutation to a gene, BRCA1 or BRCA2, and were considered at high risk of cancer recurrence because of the size of their tumor or other factors. Their tumors were either HR-positive or triple-negative, two of the three main forms of breast cancer.

Among these patients, researchers found Lynparza reduced the risk of disease progression or death by 42% compared to a placebo after a median of 2.5 years of follow-up. About 86% of Lynparza-treated patients were cancer-free, versus 77% of those who got a placebo.

Patients on Lynparza also had a 43% lower risk of developing or dying from more lethal "distant" tumors that appear elsewhere.

Those numbers are "clinically meaningful and practice changing," said Sayeh Lavasani, an assistant clinical professor at City of Hope's Department of Medical Oncology & Therapeutics Research. Lavasani wasn't involved in the trial.

Follow-up is still limited, however, meaning it's unclear how long a year of Lynparza treatment will extend patients' lives data that Paul acknowledges is a "critical piece" of missing information.

The drug is "no walk in the park," added Debu Tripathy, the chair of MD Anderson Cancer Center's breast medical oncology department, referring to side effects like nausea, vomiting and diarrhea. In rarer cases, treatment was associated with severe anemia that can require a blood transfusion.

The authors of the study also admit they don't know how Lynparza compares to a type of chemotherapy, Xeloda, that has been proven an effective adjuvant treatment for some breast cancer patients.

Nonetheless, "this is a big win," said Tripathy, who also wasn't involved in the trial. Assuming approval from regulators, "patients with higher-risk cancers who have BRCA mutations will now be getting this."

The drugmakers aim to get the results in the hands of regulators "as quickly as possible," said Roy Baynes, Merck's senior vice president of global clinical development.

Breast cancer remains the most commonly diagnosed cancer as well as the second-leading cause of cancer death among women, despite substantial advances in treatment over the past few decades. The death rate associated with the disease declined 40% between 1989 and 2017, according to the American Cancer Society. Better early cancer detection is a big reason why.

A majority of early breast cancer patients are now cured of their disease, according to Tripathy. But about a third relapse. When they do, their cancers become much more deadly. In response, researchers have sought to bring new drugs like immunotherapies and other therapies known as CDK 4/6 inhibitors that have been approved in advanced disease into earlier settings, when they might stop cancers from returning.

Broadening use of these types of drugs comes with trade-offs, though. If cleared to lower the risk of recurrence, high-priced cancer drugs would likely become more widespread, raising costs for uninsured patients and, potentially, insurance premiums for others, Tripathy said. Insurers can block access as well; Lavasani is "hoping" they will cover Lynparza, should it be approved as an adjuvant treatment. Often, the drugs are approved on the likelihood, but not the certainty, that they'll help people live longer.

Clinicians and regulators also have to decide whether the benefits are worth added side effects for patients who tend to be younger and healthier. The FDA, for instance, asked Merck for more data when it rejected its immunotherapy Keytruda in early triple-negative breast cancer. An advisory panel was wary of the side effects associated with treatment, which Tripathy noted, can include permanent liver or kidney injury. (Merck has since gathered more data and intends to re-file for approval.)

Lynparza had what Lavasani, of City of Hope, called "acceptable toxicities," most frequently nausea and fatigue. Consistent with what's been reported in earlier testing, the only severe side effect seen in more than 5% of patients was anemia, which occurred in 79, or about 9%, of those who got Lynparza.

Those side effects were balanced against Lynparza's benefit in slowing breast cancer's return in patients who had inherited mutations to the BRCA1 or BRCA2 genes. These patients tend to develop cancers at a younger age, have faster-moving disease and a much higher risk of relapse, some studies have shown. OlympiA study authors noted, for instance, that almost one-quarter of patients on placebo with HR-positive cancer a typically slow-moving tumor had invasive disease or died within three years.

There were no marketed drugs specifically tailored to BRCA1 and BRCA2 breast cancers for patients with metastatic disease until the FDA approved Lynparza and Talzenna, another, similar PARP inhibitor from Pfizer, in 2018. Those approvals came amid early enthusiasm for PARP inhibitors, which are mainly used as "maintenance" therapies in ovarian cancer.

Testing for BRCA mutations, as a result, has lagged for those with early-stage disease: 60% to 70% of patients with triple-negative tumors, and 25% to 35% of HR-positive patients are being tested, according to Ipsos Healthcare's Global Oncology Monitor.

"It's not where it should be," says Paul, of AstraZeneca.

The OlympiA results, then, could change testing practice. The data are a "call to action" to make sure patients know their BRCA status, said Merck executive Baynes.

Oncologists, Tripathy added, may push to broaden testing guidelines for patients beyond those who get cancer at a young age or have a family history of BRCA mutations.

"We would like to get to a point someday when we take the risk totally away, that having breast cancer is no longer something that can lead to fatality," Tripathy said. "We got a little closer to that with this trial."

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An AstraZeneca, Merck drug slows the return of genetic breast cancer. Will testing speed up? - BioPharma Dive

Eight years later Adam, now 21 and a gymnastics coach, would have high blood pressure and experience a carotid artery blowout. Thankfully, though, his neck muscles saved his life.

The teeth abnormalities, as well as the carotid artery blowout, are likely due to the calcification in the body that patients with this illness can present, said Prasov. With the genetic testing, we were able to conclude this disease was Singleton-Merten syndrome type II an extremely rare, autosomal, dominant condition with only 3 families documented in literature.

With their collective expertise, the team was able to better characterize the familys symptoms: pediatric-onset glaucoma, spontaneous tendon rupture, arthritis, and a psoriasis-looking skin rash. Glaucoma and skin rash were the most prominent symptoms.

There werent many cases in literature to compare the familys disease presentation to, so Prasov, whose research focuses on inherited eye diseases, worked with colleagues at the National Institutes of Health and U-M clinician-scientists Johann Gudjonsson, M.D., Ph.D., a dermatologist, and J. Michelle Kahlenberg, M.D., Ph.D., a rheumatologist, to more deeply phenotype the family.

When looking for new genes, it can take a considerable amount of time. Once we could perform sequencing, we could move a lot faster to get a diagnosis. The Gibson family had an official diagnosis approximately a year after we performed the sequencing. said Prasov.

He adds that working in the field of genetics comes with certain challenges; the provider making the diagnosis wants to be absolutely certain that the genetic change is causing the disease, as it can have a big impact on clinical management.

More certainty came with the identification of another family across the globe in Belm, Brazil, that had a similar peculiar set of clinical findings and the same genetic variant in DDX58. By comparing notes among all of the identified families, Prasov and his team were able to give a definitive diagnosis.

But the final piece of this medical puzzle required additional work in the laboratory.

According to Prasov, very few families with mutations in DDX58 have a multi-system disorder featuring calcification in the body, skin rashes and childhood glaucoma.

Published in the Journal of Medical Genetics, Prasov led an international team, including researchers and clinicians from U-M, the NIH, Brazil, and Harvard, to provide the first complete molecular and histological assessment of the eye and skin findings in Singleton-Merten syndrome type II. Together, they definitively showed that the familys mutation behaves similarly to other mutant proteins in how it sets off an inflammatory cascade in the body in absence of a definitive RNA trigger.

Because of the communication between these doctors, more of this condition is now better understood, said Eryn. Their curiosity led to answers, but also helped us feel like we were finally being heard and cared about. Finally, after generations of unanswered questions and enormous health challenges someone took this seriously and had access to the resources to find answers about this condition.

Since skin is the most available tissue for molecular analysis, Gudjonsson and his team were able to obtain samples from Stan and Adam to compare Stans gene expression to his children. Somewhat surprisingly, they found that the inflammatory response was only active in affected skin, and not in neighboring skin or in the blood.

The study team also found that the family in Brazil had a more severe case of Singleton-Merten syndrome. By working with the Brazilian clinicians and researchers, Prasov was able to compare data and see if other genetic triggers or environmental influences affect the presentation of the disease.

This is something I want to explore more, he said. Rachel and Adam dont have many of the system effects of this disease, but they could develop them in the future. Understanding all the factors that may provoke more severe illness may help us be able to prevent those developments from occurring.

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The study reinforces the idea that genetic triggers or environmental influences may affect the presentation of Singleton-Merten syndrome, as the research team found that some family members carrying the mutation only have the most common feature of childhood glaucoma, while others have more extensive disease features that affect the immune system.

This means there could be other children in the world with this glaucoma that dont have the other features of the disease, said Prasov. But theyre at risk for developing those features later in life and suffer serious health consequences if providers dont know to look out for all these symptoms.

There are drugs like Rinvoq, a medication that Stan now takes, that can help calm the immune system and disrupt the downstream pathway associated with more serious disease. According to Stan, the medication has helped his skin discoloration resolve.

Im so grateful to know what this condition is. Knowing how to treat it would be a miracle, but you have to start somewhere, said Stan. This research will benefit my own children but also their children when they start families of their own. They know what to look out for.

This study highlights how a genetic diagnosis can have a big impact on clinical practice and patient outcomes, said Prasov. Understanding this disease pathogenesis is also important in the field of glaucoma care and research. Prasov now leads a multidisciplinary clinic in which he partners with pediatric medical geneticists to provide ophthalmic genetic care for families like the Gibsons.

The next step for the U-M research team is to generate an animal model to better understand the disease and hopefully find a targeted drug treatment that may have fewer side effects. They also plan to further study the role of DDX58 in the eye, since the RNA binding protein can sense viral infections like Rubella and Zika: viruses known to provoke glaucoma. The hope is that they can find a way to block this receptor or the downstream signaling, in turn preventing the glaucoma from developing.

Stan has a severe case of Singleton-Merten so my hope is that if researchers can crack his case, they can know how to treat anyone with the condition, said Eryn. If it wasnt for Kellogg Eye Center, both of my kids would be blind. Im just grateful beyond words.

This research was supported by the National Eye Institute (NEI K12 EY022299, NEI P30 EY07003, RBH, BG, and BPB), the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (R01-AR060802, P30-AR075043 and K01-AR072129), the National Institute of Allergy and Infectious Diseases (R01-AR069071), the A. Alfred Taubman Medical Research Institute, the Parfet Emerging Scholar Award and the Roche Postdoctoral Fellowship.

Paper cited: DDX58(RIG-I)-related disease is associated with tissue-specific interferon pathway activation, Journal of Medical Genetics. DOI: 10.1136/jmedgenet-2020-10744

Originally posted here:
Family finds answers to rare, genetic glaucoma - University of Michigan Health System News

It is understood that while genes are the bodys blueprint its basic physical and functional unit of heredity not a lot of people pause to think about genetic anomalies or disorders that may be affecting their health.

Women, especially, are unaware of just how much their genes impact their health, and how prevention of certain genetic diseases can be done to ensure a healthy offspring.

Dr Hema Purandarey, consultant medical and reproductive geneticist, MedGenome Centre for Genetic Health Care shares with indianexpress.com some health conditions that women are more prone to through genetics, and the tests available to detect them.

1. Chromosomal aneuploidy in babies of expecting mothers: A condition in which a cell has an incorrect number of chromosomes. If there is an error in the normal processes of fertilization, there can be changes to the number or structures of chromosomes which can lead to an offspring with birth defects due to the abnormal structure or number.

The most commonly seen type of defect is an extra chromosome 21 called trisomy 21 or Down syndrome. Genetic screening and diagnostic tests are available with pre-test and post-test counselling which can identify these changes in the foetal state. These include specific noninvasive screening tests like NIPT and parental karyotypes and invasive diagnostic tests such as amniocentesis and chorionic villus sampling to identify the genetic makeup of the baby.

2. X-linked inherited disorders: Some disorders are X-linked, which means a female with 2X chromosomes will be a carrier, but if she passes this to her male offspring, it will be affected since males only inherit one X chromosome from their mother, the other being a Y chromosome inherited from the father. Finding out about carrier status prior to conception can help to plan genetic counselling. Testing is available for several such disorders like Fragile X, Hemophilia, Duchenne Muscular Dystrophy etc.

3. Hematological disorder screening: Couples have to be screened if they are carriers for common hematological disorders such as thalassemia and sickle cell disease. Consanguinity increases the risk of having any recessive genetic disorder by approximately 25 per cent.

A carrier screening test can help prevent both X-linked and conditions such as thalassemia and sickle cell anemia from being passed on. It also helps couples understand and plan better for their future. This is a comprehensive test screening, with the capability to detect mutations causing disease in more than 2,000 genes.

4. Recurrent pregnancy loss: Three or more consecutive pregnancy losses before 20 weeks from the last menstrual period are defined as recurrent pregnancy loss or RPL. Epidemiological studies show 1 per cent to 2 per cent of pregnant women suffer from RPL. Genetic causes of recurrent pregnancy losses account for about 2-5 per cent. Chromosomal or genetic abnormalities lead to most losses of pregnancy. The abnormality might come from the early embryo, egg, or sperm.

There are genetic tests that can help detect if the pregnancy loss was due to an abnormal number of chromosomes, and provide insights to plan and support a successful pregnancy in future.

5. Implantation failure during IVF: One in two human preimplantation-IVF embryos are chromosomally abnormal. This causes them to implant onto the uterine wall or not stay there long enough for a successful pregnancy. This leads to miscarriages and failed IVFs. If there is a family history of a genetic disorder, the fertilized embryo can be tested using pre-implantation genetic testing. If a donor was used, the donor sperm or the egg can be tested.

6. Hereditary breast and ovarian cancer: In women, approximately 15 per cent of all ovarian cancers and 7 per cent of all breast cancers are caused by mutations in the BRCA1 and BRCA2 genes. At present, we have predictive tests like BRCA1 and BRCA2 gene tests for this. Actor Angelina Jolie had a history of breast and ovarian cancer. So, she asked to be genetically tested and when it was clear she was susceptible, she had the required surgeries. Early detection can not only save life but also reduce the financial burden of advanced treatment.

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Genetic health conditions every woman should know about - The Indian Express

CHICAGO, June 4, 2021 /PRNewswire/ -- According to the new market research report "Animal Genetics Market by Products & Services (Live Animals (Poultry, Porcine, Bovine, Canine) Genetic Material (Semen (Bovine, Porcine), Embryo (Bovine, Equine)) Genetic Testing (DNA Testing, DNA Typing, Genetic Traits Testing)) - Global Forecast to 2026", published by MarketsandMarkets, the global market is projected to reach USD 7.7 billion by 2026 from USD 5.5 billion in 2021, at a CAGR of 7.1% during the forecast period.

Browse in-depth TOC on "Animal Genetics Market"

269 Tables 36 Figures 296 Pages

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The growth of this market is majorly attributed to the increasing consumption of animal-derived protein, growing global population & rapid urbanization, growing focus on identifying superior breeds, increased adoption of genetic services to prevent genetic diseases & business loss, and increased adoption of advanced genetic technologies. On the other hand, the shortage of skilled professionals in veterinary research is a key factor restraining market growth.

By product type segment, the live animals segment accounted for the largest market share during the forecast period.

Based on products and services, the animal genetics market has been segmented into live animals, genetics materials, and animal genetic testing services. The factors attributing to the large revenue of the live animals segment include high demand for live animals for breeding purposes. The introduction of disease-resistant animals has further boosted the demand for live animals, as they are economically viable for owners and increase their profitability.

Poultry accounted for the largest animal genetics marketshare in the live animals segment during the forecast period.

In the live animals segment, poultry accounted for the largest market share during the forecast period. This can be attributed to the strong demand for poultry and eggs in developed countries. Additionally, due to the growing population and rapid urbanization in developed countries, the demand coming from these regions is also increasing significantly.

In the segment of the genetic material, semen accounted for the largest market share during the forecast period.

Under the segment of the genetic material, semen held the largest share, most of which came from bovine semen during the forecast period. Growth in this market is mainly driven by the increasing need for raising highly productive animals to meet the growing demand for meat and other animal-derived products.

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Europe dominates the Animal Genetics market during the forecast period.

Europe accounted for the largest share of the market in 2020. Better accessibility to technologies and well-established distribution channels, the growing demand for livestock food products, high intake of animal-derived proteins, and increasing animal welfare activities are the major factor contributing to this.

The major players in the global animal genetics market include Neogen Corporation (US), Genus (UK), URUS (US), EW Group (Germany), Groupe Grimaud (France), CRV Holding (Netherlands), Topigs Norsvin (Netherlands), Zoetis (US), Envigo (US), Hendix Genetics (Netherlands), Animal Genetics (US), VetGen (US), DanBred (Denmark), Tropical Bovine Genetics (India), Trans Ova Genetics (US), Inguran LLC dba ST Genetics (US), Semex Alliance (Canada), Genetic Veterinary Sciences (US), Cobb-Vantress (US), Milk Source (US), and Eurogene AI Services (Ireland).

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Animal Genetics Market worth $7.7 billion by 2026 - Exclusive Report by MarketsandMarkets - PRNewswire

Top row, left to right: Steve Nelson, 4-year survivor; Anne Shimabukuro, 15-year survivor; Roberta Luna, 19-year survivor Bottom row, left to right: Teona Ducre, 5-year survivor; Cathy Schwandt, 8-year survivor; Nick Pifani, 4-year survivor

Editors note: In honor of National Cancer Survivors Day on June 6, 2021, we invited members of PanCANs Survivor Council to pass along encouraging words to pancreatic cancer patients and to also share what it means to them to be a survivor. The Survivor Council is a group of volunteers created to ensure the survivors voice, experience and expertise are integrated into PanCANs programs and initiatives. Today and every day, we honor all survivors and remember those whove lost their life to the disease. We are here for everyone affected by pancreatic cancer.

PanCAN: Celebrating life is one of the themes of National Cancer Survivors Day. How do you celebrate life?

Teona Ducre: I do my best to practice gratitude every day.Since surviving cancer, I understand that even the little things I may have taken for granted before seeing my children smile, hanging out with friends and family on a random Tuesday afternoon, or just waking up in the morning are really big blessings.

Roberta Luna: I celebrate life by savoring every moment, not taking anyone or anything for granted, trying to be the best person I can.Stop and smell the flowers, dance like nobodys watching, sing like no one is listening! I know these are all clich but when youve been given what seems like a death sentence, the little things really take on new meaning.

Steve Nelson: I celebrate every time I find an opportunity to tell my story of hope.

Nick Pifani: I celebrate life by making memories with the people I love and making a difference for a better tomorrow. I share my story with newly diagnosed patients with the goal of giving them hope.

Anne Shimabukuro: I value my time more. My priorities have shifted my family and my health come first. I am more willing to say no than I was before.

PanCAN: Have you started any new traditions since your cancer diagnosis?

Roberta: On April 9, 2013, a group of survivors, family and friends and I celebrated life by jumping out of an airplane. What we thought was a one-time event has turned into an annual tradition. Every April, for eight years and counting, a group of us skydive from a height of 14,000 feet. Theres always at least one first-time jumper with us.

Nick: Every year we celebrate my Whipple surgery anniversary. I was fortunate to come out of surgery cancer-free and I consider it a second birthday because I got a second chance at life.

PanCAN: What is your advice for people living with pancreatic cancer or for those who are newly diagnosed?

Roberta: My advice to someone newly diagnosed is to get all the information, but dont let it weigh you down. Ask questions, be your own advocate, remember to enjoy life and keep fighting.

Steve: Never give up hope! I have a brother who is a 17-year survivor.And as a member of PanCANs Survivor Council, I know many others who have beaten the odds, and those odds get better every year.You could be next!

Nick: Remember that you are not a number and you dont fall into a specific category or statistic. If youve been recently diagnosed, contact PanCANs Patient Services and get genetic testing.

Anne: If youre living with pancreatic cancer, keep living! Do what you love. And give yourself a break. If youve been recently diagnosed, dont think about thestatistics. Your case is unique and its the only case you should care about. Put yourself first. And dont be afraid to ask for help.

PanCAN: What does it mean to you to be a survivor?

Teona: It means I can accomplish anything. Whenever I am faced with a challenge, I think, This is nothing. You survived one of the deadliest cancers in the world so you can do this, too. I also get the privilege to share my story to encourage others and that means a lot to me.

Roberta: To be a survivor means Ive been given a very special precious gift, the gift of life, the gift to love more deeply, the gift to inspire someone, to make a difference, to give back, to do better.

Steve: Due to genetic testing and a regular screening regimen, my cancer was discovered early. I encourage anyone with first or second-degree relatives who have or have had pancreatic cancer to get tested for genetic mutations. And if they find they have a mutation, to embrace regular screenings. It could save their life, like it did mine!

Nick: My story is different because I lost three family members to the disease I am the lone survivor. As a survivor, I carry a piece of my lost family members with me it inspires me to make a difference in this fight. This is how I honor them and make sure their cancer battle is never forgotten.

Cathy: We, the survivors, need to be the voice for all those who are no longer here.

Anne: As a 15-plus-year survivor, my survivorship is not always top of mind its now a part of me. This journey has given me strength as well as more self-confidence. Ill often remind myself, I conquered pancreatic cancer; I can deal with anything.

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Long-time pancreatic cancer survivors offer inspiration and advice - Pancreatic Cancer News & Stories

The role genetics play in atrial fibrillation (AF) complications such as heart failure and stroke will be investigated as part of new research involving UNSW researchers.

Led by Victor Chang Cardiac Research Institutes scientist and UNSW Conjoint Professor Diane Fatkin, the multicentre research team were awarded $1 million by The Heart Foundation to gain new knowledge about genetic causes of AF.

The condition is a major public health problem with one in three individuals at risk of developing it in their lifetime.

Prof. Fatkin said the research being done by her team is breaking fresh ground, and further advancement would not be possible without the recent financial boost.

This will really allow us to do in-depth genetic analyses on our patients, and we already have a large cohort of [those] available. This will enable us to do these genetic analyses for the first time in Australia, so it really is a major new initiative, she said.

We will use cutting-edge tools for rapid low-cost genetic analyses of AF patient cohorts that will enable us, for the first time, to look at single-gene mutations, genetic risk scores, and genetic effects on anti-arrhythmic drug metabolism. The cost and outcomes of genetic testing, and patient preferences for testing, will also be assessed.

AF is a disorder of the hearts electrical activity that can lead to stroke, heart failure and even early death.

A persons genetic make-up is an important determinant of AF susceptibility, but genetic information is not part of current patient care.

Scientists at the Victor Chang Cardiac Research Institute and UNSW would like that to change.

Prof. Fatkin said those facing choices about their treatment may really benefit from knowledge about genetic influences when selecting appropriate drug therapies or interventions, such as ablation therapy.

Genetics, we are thinking, may also be important for predicting the risk of recurrence of atrial fibrillation after the ablation procedures, she said.

Our data will define high-risk patient subsets and have direct implications for the screening and clinical management of family members.

Prof. Fatkin is looking at different types of patients across the research. Some have a family history of AF and the collated data will help identify family members also at risk of developing AF in the future.

Another group that is part of the research includes those without a clear family history of AF but who still have the condition.

A third group being studied is athletes who have developed AF after a lifetime of competitive sporting activity.

Prof. Fatkin hopes this research will lead to the ability to predict which athletes are likely to have heart problems in the future.

This may inform sports choices even in young kids, and we can advise those who are at high genetic risk to potentially change the type of sport that they participate in, she said.

The Heart Foundations Strategic Grants are awarded with the aim to generate innovative and collaborative research projects in the areas where identified gaps in cardiovascular health exist.

The 2020 Predictive Modelling Grant was awarded to Prof. Fatkin to investigate the role of genetics for risk stratification in AF.

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Genetic links to be investigated in ground-breaking heart rhythm research - UNSW Newsroom