Archive for February, 2021

Stem Cell Therapy Market: Snapshot

Of late, there has been an increasing awareness regarding the therapeutic potential of stem cells for management of diseases which is boosting the growth of the stem cell therapy market. The development of advanced genome based cell analysis techniques, identification of new stem cell lines, increasing investments in research and development as well as infrastructure development for the processing and banking of stem cell are encouraging the growth of the global stem cell therapy market.

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One of the key factors boosting the growth of this market is the limitations of traditional organ transplantation such as the risk of infection, rejection, and immunosuppression risk. Another drawback of conventional organ transplantation is that doctors have to depend on organ donors completely. All these issues can be eliminated, by the application of stem cell therapy. Another factor which is helping the growth in this market is the growing pipeline and development of drugs for emerging applications. Increased research studies aiming to widen the scope of stem cell will also fuel the growth of the market. Scientists are constantly engaged in trying to find out novel methods for creating human stem cells in response to the growing demand for stem cell production to be used for disease management.

It is estimated that the dermatology application will contribute significantly the growth of the global stem cell therapy market. This is because stem cell therapy can help decrease the after effects of general treatments for burns such as infections, scars, and adhesion. The increasing number of patients suffering from diabetes and growing cases of trauma surgery will fuel the adoption of stem cell therapy in the dermatology segment.

Global Stem Cell Therapy Market: Overview

Also called regenerative medicine, stem cell therapy encourages the reparative response of damaged, diseased, or dysfunctional tissue via the use of stem cells and their derivatives. Replacing the practice of organ transplantations, stem cell therapies have eliminated the dependence on availability of donors. Bone marrow transplant is perhaps the most commonly employed stem cell therapy.

Osteoarthritis, cerebral palsy, heart failure, multiple sclerosis and even hearing loss could be treated using stem cell therapies. Doctors have successfully performed stem cell transplants that significantly aid patients fight cancers such as leukemia and other blood-related diseases.

Global Stem Cell Therapy Market: Key Trends

The key factors influencing the growth of the global stem cell therapy market are increasing funds in the development of new stem lines, the advent of advanced genomic procedures used in stem cell analysis, and greater emphasis on human embryonic stem cells. As the traditional organ transplantations are associated with limitations such as infection, rejection, and immunosuppression along with high reliance on organ donors, the demand for stem cell therapy is likely to soar. The growing deployment of stem cells in the treatment of wounds and damaged skin, scarring, and grafts is another prominent catalyst of the market.

On the contrary, inadequate infrastructural facilities coupled with ethical issues related to embryonic stem cells might impede the growth of the market. However, the ongoing research for the manipulation of stem cells from cord blood cells, bone marrow, and skin for the treatment of ailments including cardiovascular and diabetes will open up new doors for the advancement of the market.

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Global Stem Cell Therapy Market: Market Potential

A number of new studies, research projects, and development of novel therapies have come forth in the global market for stem cell therapy. Several of these treatments are in the pipeline, while many others have received approvals by regulatory bodies.

In March 2017, Belgian biotech company TiGenix announced that its cardiac stem cell therapy, AlloCSC-01 has successfully reached its phase I/II with positive results. Subsequently, it has been approved by the U.S. FDA. If this therapy is well- received by the market, nearly 1.9 million AMI patients could be treated through this stem cell therapy.

Another significant development is the granting of a patent to Israel-based Kadimastem Ltd. for its novel stem-cell based technology to be used in the treatment of multiple sclerosis (MS) and other similar conditions of the nervous system. The companys technology used for producing supporting cells in the central nervous system, taken from human stem cells such as myelin-producing cells is also covered in the patent.

Global Stem Cell Therapy Market: Regional Outlook

The global market for stem cell therapy can be segmented into Asia Pacific, North America, Latin America, Europe, and the Middle East and Africa. North America emerged as the leading regional market, triggered by the rising incidence of chronic health conditions and government support. Europe also displays significant growth potential, as the benefits of this therapy are increasingly acknowledged.

Asia Pacific is slated for maximum growth, thanks to the massive patient pool, bulk of investments in stem cell therapy projects, and the increasing recognition of growth opportunities in countries such as China, Japan, and India by the leading market players.

Global Stem Cell Therapy Market: Competitive Analysis

Several firms are adopting strategies such as mergers and acquisitions, collaborations, and partnerships, apart from product development with a view to attain a strong foothold in the global market for stem cell therapy.

Some of the major companies operating in the global market for stem cell therapy are RTI Surgical, Inc., MEDIPOST Co., Ltd., Osiris Therapeutics, Inc., NuVasive, Inc., Pharmicell Co., Ltd., Anterogen Co., Ltd., JCR Pharmaceuticals Co., Ltd., and Holostem Terapie Avanzate S.r.l.

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Stem Cell Therapy Market Evaluation of Industry Trends, Growth Drivers and Forecast To 2025 NeighborWebSJ - NeighborWebSJ

INTRODUCTION

Myocardial infarction (MI) remains one of the leading causes of death worldwide. The inflammatory response caused by MI sets the stage for fibrous tissue and often progresses to chronic heart failure (1), resulting in a more than 50% 5-year mortality after MI (2). An immunomodulation strategy, which prevents an excessive inflammatory response, can be beneficial to reduce scar tissue formation. Immunomodulation alone can likely prevent ongoing damage but fails to restore the compromised heart function. Promoting angiogenesis in the infarct area has the potential to reperfuse and salvage the surviving ischemic myocardium (3). Therefore, we hypothesize that long-term improvements in heart function after MI can be achieved by the combination of resolving inflammation and promoting angiogenesis in the infarct area.

Various therapeutics, such as cell transplant, exosomes, and nucleic acids, have been explored to treat MI and restore cardiac function, with varying degrees of success. Cell transplantation could enhance the functions of the infarcted heart (4), but only cardiomyocytes derived from pluripotent stem cells have been shown to engraft and generate functional myocardium (5). Limitations in cell sources, potential immune responses, and rigorous regulations hinder the clinical translation of cell-based therapies. Several studies have shown that cell-derived exosomes may be effective in treating cardiovascular diseases (6). However, there are obvious variations in exosomes resulting from multiple factors such as cell phenotype, preparation procedure, and exosome storage conditions (7). MicroRNAs (miRNA) are appealing genetic tools to stimulate cardiac performance, as they could regulate the levels of multiple genes simultaneously. Recently, it has been suggested that the cardiovascular system is regulated via a miRNA network (8). High-throughput screening work revealed that miRNAs, particularly microRNA-21-5p (miR-21-5p), are highly expressed in endothelial cells and stimulate angiogenesis by targeting antiangiogenic genes (9). miRNAs have a unique capacity to simultaneously promote the secretion of multiple endogenous molecules that might enhance vessel regeneration in the ischemic tissue. Negatively charged miRNAs typically cannot cross the cell membrane without a transfection agent. In addition, miRNAs are relatively unstable and can be degraded rapidly in vivo (10). Thus, vectors that protect and deliver miRNAs into cells are crucial to improve the efficacy of miRNA therapy.

Mesoporous silica nanoparticles (MSNs) have been developed as a promising vector for miRNA delivery because of their many excellent properties, such as good biocompatibility and high transfection efficiency. Moreover, studies have shown that inflammation can be modulated by phagocytosis of micro/nanomaterials, such as liposomes (11), polymer particles (12, 13), and inorganic particles (14). Macrophages play a central role in regulating infarct-induced inflammation because they adopt proinflammatory (M1) phenotypes. In this study, we found that MSNs showed great potential in inhibiting M1 polarization following inflammation both in vitro and in vivo (see details in Results). Therefore, we engineered an MSN/miR-21-5p complex by combining MSN, a potential anti-inflammatory nanomaterial, and miR-21-5p, a proangiogenic therapeutic.

RNA interference (RNAi) is a promising therapeutic approach for various diseases (15). An important aspect in RNAi delivery system design is to ensure precise spatiotemporal release (1621). Uncontrolled delivery of miRNA in the heart could result in sudden arrhythmia, as reported by Gabisonia et al. (22). In addition, studies have also identified that a big challenge for RNAi-based therapeutics is to achieve highly localized RNAi delivery (16, 18, 19, 23). Drug release from conventional hydrogels (24, 25) is controlled by passive diffusion and often results in off-target effects (26). In contrast, MSN/miR-21-5p complexes were conjugated within an injectable hydrogel matrix via pH-responsive bonds to form Gel@MSN/miR-21-5p, which accurately released MSN/miR-21-5p complexes only in the acidic infarct area.

Here, we designed an injectable hydrogel loaded with MSN/miR-21-5p complexes (Gel@MSN/miR-21-5p) to deliver miR-21-5p in a two-stage mechanism: The first stage comprises pH-triggered on-demand delivery of MSN/miR-21-5p complexes from the hydrogel matrix in acidic infarct areas, and the second stage involves intracellular delivery of miR-21-5p from MSN/miR-21-5p complexes. This drug delivery system is designed to harness the synergy of inflammation suppression and angiogenesis enhancement in treating MI, the efficacy of which was evaluated in a clinically relevant MI swine model.

Amino (-NH2) and trimethylamine [-N(CH3)3, TMA] functionalized MSNs (MSN-NH2-TMA) were first synthesized (fig. S1A), which had positive charges for miRNA loading (fig. S1B). The miRNA-loading capacity of the MSN-NH2-TMA complex was quantitatively evaluated by a gel retardation assay and potential measurements (fig. S1C), which showed complete encapsulation of miRNA when the mass ratio between the MSN-NH2-TMA complex and miRNA increased to 10:1. Subsequent studies were all using MSN/miRNA complexes with this ratio. Direct evidence of miRNAs loading in MSNs was also provided by transmission electron microscopy (fig. S1D) and energy-dispersive x-ray spectroscopy (EDS) analysis (fig. S1E), which revealed obvious miRNAs residing in MSN pores and signals corresponding to the element P from loaded miRNAs.

Gel@MSN/miR-21-5p was fabricated by mixing the MSN/miR-21-5p complex aqueous solution (30 wt%) with an aqueous solution of -CD (66.7 mg/ml) and aldehyde-capped polyethylene glycol (PEGCHO; 66.7 mg/ml). The hydrogel matrix had a porous structure with pore sizes of around 10 m in diameter and MSN/miR-21-5p complexes covering the wall surface (fig. S1F). Scanning electron microscope image of the injectable colloidal hydrogel (Gel@MSN) showed plenty of MSNs conjugated in the hydrogel (red arrows). The presence of MSNs was also confirmed by EDS, which showed an obvious elemental signal of Si (fig. S1G). Hydrogel formation resulted from two interactions (fig. S2): (i) hydrophobic interaction between cyclodextrins (CDs) along the PEGCHO chains (27) and (ii) Schiff base between the NH2 group from MSNs and the aldehyde (CHO) group from PEGCHO/CD complexes. The stepwise gelation was confirmed by comparing different gelation processes between the MSN/PEGCHO/CD (group with both Schiff base and hydrophobic interaction) and control groups (PEG/MSN, group without hydrophobic interactions and Schiff bases; PEG/MSN/CD, group only with hydrophobic interactions) (fig. S3A) as well as the different rheological characterization of the resulting hydrogels (fig. S3, B and C). The cross-linking relies on hydrophobic and Schiff interactions, which are relatively weaker than conventional covalent bonds. The liquid-gel transition takes approximately 5 min, after which point the hydrogel is injected into the infarct area. The weak interaction allows the hydrogel to exhibit a shear-thinning property, which permitted it to switch from hydrogel to fluid during injection and subsequently formed a firm hydrogel at the MI area along with the further cross-linking process (fig. S3D). The retention property of the hydrogel in the beating heart was also evaluated. During bench testing, hydrogel (labeled with blue dye) was injected into myocardium tissue, and no detachment or cracks were observed between the hydrogel and tissue after bending, distorting, long-time immersing underwater, or stretching (fig. S3E).

The MSN/miRNA complexes were conjugated onto an injectable hydrogel by Schiff bonds. The Schiff base bond is stable at pH 7.4 but is disrupted in an acidic environment (pH 6.8) (fig. S3, F to H), enabling an on-demand release of MSN/miRNA (step 3 in fig. S2B) (28, 29). The 1H NMR (nuclear magnetic resonance) of 1,6-diaminohexane (HDA) functionalized PEG with Schiff base in between (HDA-PEG-HDA) after incubation in phosphate-buffered saline (PBS) buffer with pH 7.4 (red line) and pH 6.8 (black line) for 24 hours, which presented a clear proton peak of aldehyde only in the pH 6.8 treated group, demonstrating the high stability of Schiff base bonds at pH 7.4 and its gradual cleavage to form an aldehyde group at an acidic environment (fig. S3F). The gel permeation chromatography results of HDA functionalized PEG with Schiff base in between (HDA-PEG-HDA) after incubation in PBS buffer with pH 7.4 (i) and pH 6.8 (ii) for 24 hours, which presented an obvious drop of molecule weight only in the pH 6.8 treated group. Moreover, the molecule weight loss is close to twice the molecule weight of HDA, indicating the separation of HDA with PEG, due to the break of Schiff base (fig. S3H). These data comprehensively demonstrated the high stability of Schiff base bonds at pH 7.4 and its gradual cleavage at the slightly acidic environment.

The on-demand release profile was characterized in PBS buffer with pH 7.4 and pH 6.8 [which respectively simulated the microenvironment of healthy tissue (pH 7.4) and infarcted myocardium (pH 6.8)] (30, 31). There was a sustained release of MSN/miRNA complexes from the hydrogel matrix with ~75% release after 7 days at pH 6.8 (fig. S3I). In contrast, only ~6% MSN/miRNA was released from the hydrogel after 7 days at pH 7.4, which could be attributed to the diffusion of MSN/miR-21-5p at the different hydrogel degradation rates under different pH conditions (fig. S3I). The miRNA release from the MSN/miRNA complexes is presented in fig. S3J, which shows that a further decrease in the pH value to 5 (simulated intracellular endosomes and lysosomes environment) (32) could trigger miRNA release from MSN/miRNA complexes, leading to a cumulative release of miRNA of up to 60% over 48 hours.

Hydrogel degradation in vitro was monitored by measuring dry weight loss as a function of time following incubation in PBS (pH 6.8) at 37C (fig. S3K). As shown in fig. S3K, Gel@MSN/miRNA lost approximately 93% of the initial gel mass within 20 days. For in vivo measurements, the PEG frame of the hydrogel was labeled by fluorescent dye. Following injection, the fluorescence signal in the injected area was detected at the indicated time points. Figure S4 shows that the fluorescence signal decay is down to 67% at day 3 and 16% at day 14. At day 28, we could not detect any fluorescence signal, indicating that the hydrogel was completely degraded.

The retention of MSNs in vivo was monitored by fluorescence in vivo imaging system (IVIS) imaging at the indicated time points. Figure S5 shows that the fluorescence signal decay is down to 54% at day 3, 18% at day 14, and 2% at day 28, indicating that accumulation of MSNs was gradually decreased at tissue. At day 36, no positive signal was observed, indicating that almost no residual MSNs could be detectable at tissue.

To assess the in vitro uptake of the MSN/miR-21-5p complex by endothelial cells, the miR-21-5p was labeled with Cy3 (orange-red), the MSNs were labeled with fluorescein isothiocyanate (FITC) (green), and the cell nuclei were stained with 4,6-diamidino-2-phenylindole (DAPI) (blue). For in vitro uptake analysis, endothelial cells were cocultured with MSN/miR-NC complexes or MSN/miR-21-5p complexes. The confocal images and quantification analysis showed that MSN/miR-21-5p complexes showed high transfection efficiency of miR-21-5p and resulted in an approximately 37-fold enhanced miR-21-5p levels in endothelial cells compared to that of control cells (Fig. 1, A and B). Representative profiles from the flow cytometry analysis revealed that the CD31 expression level was 96.5% in endothelial cells (Fig. 1C). Flow cytometry analysis indicated that more than 70% of endothelial cells internalized the MSN/miR-21-5p complexes (identified by the CD31+Cy3+) (Fig. 1D). The cytokine levels were determined by Western blot and real-time quantitative polymerase chain reaction (PCR) assay. Figure 1E shows that compared to the endothelial cell group and the MSN/miR-NCtreated group, MSN/miR-21-5p significantly promoted the expression of proangiogenic cytokines (VEGFA and PDGF-BB) from endothelial cells. MSN/miR-21-5ptreated endothelial cells also had increased capillary tube network formation (as measured by branch points and total tube length via tube formation assay) (as shown in Fig. 1G). We then simulated serum-free and hypoxic infarct-like conditions in vitro to assess the protective effect of MSN/miR-21-5p on the hypoxia/ischemia-induced cardiomyocyte apoptosis (Fig. 1H). The cardiomyocytes were exposed to a combination of ischemic/hypoxic conditions for 24 hours. Endothelial cells were pretreated with MSN/miR-21-5p or MSN/miR-NC and then cocultured with cardiomyocytes subjected to hypoxia/ischemia. Notably, at 24 hours of coculture, we found that coculture with MSN/miR-21-5ptreated endothelial cells reduced the apoptosis of hypoxia/ischemia-induced cardiomyocytes. This correlated with increased secretion of proangiogenic cytokines (VEGFA and PDGF-BB) from endothelial cells treated with MSN/miR-21-5p (Fig. 1, I and J). Previous studies demonstrated that VEGFA or PDGF-BB inhibits apoptosis (33, 34). These data may suggest that miR-21-5pinduced expression of proangiogenic factors in endothelial cells could prevent cardiomyocytes from undergoing apoptosis under ischemic and hypoxic conditions.

(A) In vitro uptake of the MSN/miR-21-5p complex by adherent endothelial cells (ECs) and macrophages (MCs). (B) In vitro transfection efficiency of miR-21-5p was determined by quantifying the miRNA level using real-time quantitative PCR. (C) Representative flow cytometry analysis of CD31 levels in ECs and F4/80 levels in MCs. (D) In vitro uptake of the MSN/miR-21-5p complex by ECs and MCs was determined by quantifying the double-positive cells (CD31 or F4/80 and Cy3) using flow cytometric analysis. The protein expression levels of VEGFA and PDGF-BB in endothelial cells (E) and tumor necrosis factor- (TNF-), interleukin-1 (IL-1), and IL-6 in macrophages (F) were determined by the real-time quantitative PCR and Western blot analysis. (G) The endothelial cells that formed three-dimensional (3D) capillary-like tubular structures were evaluated at indicated times (8 and 16 hours). (H) Schematic diagram of the experimental setup. TUNEL, terminal deoxynucleotidyl transferasemediated deoxyuridine triphosphate nick end labeling. (I) Apoptosis-positive cardiomyocytes from these treatment groups were further quantified. (J) Protein levels of secreted proangiogenic factors were determined by enzyme-linked immunosorbent assay (ELISA) analysis of cell supernatants from the MSN/miRNA-treated ECs (scale bars, 50 m). *P < 0.05 and ***P < 0.01. All experiments were carried out in triplicate. n = 5 per group. The data are shown as means SD. Photo credit: Yan Li, Shanghai Ninth Peoples Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.

To understand the in vitro immunomodulatory effect of MSN/miR-21-5p complexes, MSN/miR-NC complexes or MSN/miR-21-5p complexes were cocultured with isolated macrophages. MSNs were labeled with FITC (green), and miR-21-5p was labeled with Cy3 (red). Representative profiles from the flow cytometry analysis revealed that the F4/80 expression level was 98.2% in isolated macrophages (Fig. 1C). The confocal images and quantification analyses showed that MSN/miR-21-5p complexes had high uptake efficiency in macrophages. Flow cytometry analysis indicated that more than 80% of macrophages took up the MSN/miR-21-5p complexes (identified by the F4/80+Cy3 + staining pattern) (Fig. 1D). We then examined whether the uptake of the MSN/miR-21-5p complexes by macrophages could reduce the inflammatory response. For this purpose, a proinflammatory response was induced by injection of lipopolysaccharide (LPS), a potent inducer of inflammatory response (35), into the peritoneum of mice, and macrophages from the treated mice were collected. Figure 1F shows that the inflammation of the LPS-treated macrophages (LPS-macrophages) was markedly suppressed following uptake of the MSN/miR-21-5p complexes, as indicated by the notable decrease in the expression of tumor necrosis factor- (TNF-), interleukin-1 (IL-1), and IL-6, which are typical cytokines involved in the inflammatory response. These data suggest that the MSN/miR-21-5p complexes released from Gel@MSN/miR-21-5p simultaneously reduced proinflammatory cytokines and increased proangiogenic factors in vitro. The enhanced proangiogenic factors from endothelial cells could effectively prevent cardiomyocytes from apoptosis under ischemic and hypoxic conditions.

To obtain insight into the mechanism by which the MSN/miR-21-5p complex acts on macrophages to modulate the immune response, we performed a proteome analysis of protein alterations in macrophages. We collected three replicates of LPS-induced macrophages (inflammatory stage macrophages) treated with MSN/miR-NC, MSN/miR-21-5p, or pure MSNs. Untreated LPS-macrophages were used as a negative control. We used a label-free quantitative proteomic approach. Hierarchical clustering analysis of the data revealed that the protein expression patterns of the three treatment groups (MSN/miR-NC, MSN/miR-21-5p, or pure MSNs) were obviously different from that of LPS-macrophages without treatment, while the protein expression patterns of the three groups were similar (Fig. 2A). This consistently indicated that the function of immunomodulation originates from the MSNs themselves.

(A) A heatmap of selected proteins representing major altered signaling pathways in three datasets of macrophages treated with MSNs, MSN/miR-NC, or MSN/miR-21-5p complexes. Macrophages with no treatment were used as a negative control. The color bar indicates normalized z score intensity-based absolute quantification. (B) KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis of both up- and down-regulated pathways in macrophages after MSN treatment. The most significant pathways in the phosphoproteome are plotted on the x axis as the log10 of the P value, compared with the proteome. (C) KEGG pathway map of Toll-like signaling pathway. Proteins shown with red backgrounds are down-regulated in macrophages after MSN complex treatments when compared with macrophages with no treatment, as determined by pathway analysis. (D) Real-time quantitative PCR and Western blot analysis of TLR1, TLR2, TLR3, TLR8, P-NFB, TNF-, IL-1, and IL-6 protein content alteration in macrophages after treatment with MSNs, MSN/miR-NC, or MSN/miR-21-5p complexes. (E) Real-time quantitative PCR and Western blot analysis of P-NFB, TNF-, IL-1, and IL-6 protein content alteration in MSN/miR-21-5p complextreated macrophages that overexpress TLR2 with the TLR2 overexpression vector. ***P < 0.01. n = 3 per group. The data are shown as means SD. Photo credit: Yan Li, Shanghai Ninth Peoples Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.

Current reports showed that the reduced inflammatory response elicited by MSN resulted from the reduction of transcription factor nuclear B (NFB), caspase-3, and IL-12 (36). The NFB signaling plays a major role in innate immunity and inflammatory responses. It was shown that the NFB signaling pathway plays important roles in MSN-regulated inflammation (37), but the exact mechanism leading to this effect was still obscure.

The present study used the GSEA (gene set enrichment analysis) method to examine the distribution of the functionally related KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway gene sets within the ranked gene list. GSEA showed that there were groups of genes negatively correlated with the immune response after MSN treatments. The majority of genes that were differentially expressed in macrophages after MSN treatments were enriched in several pathways, such as neutrophil degranulation, Toll-like receptor (TLR) signaling pathway, and MyD88 deficiency (Fig. 2B). TLR activation and MyD88 (a downstream adapter of TLR pathways) play important roles in the NFB signaling pathway (37), stimulation of which may lead to activation of NFB signaling and eventually lead to proinflammatory responses and progression to fibrous tissues (38, 39).

We found that abundance of proteins (TLR1, TLR2, TLR4, TLR3, TLR7, TLR8, TLR9, CD14, RAC1, and TAB1) involved in TLR signaling was down-regulated in macrophages after MSN treatments, indicating that TLR signal transduction pathway activity decreased in response to MSN treatment (Fig. 2C). The most significantly down-regulated genes are TLR1, TLR2, TLR3, and TLR8, which had more than threefold change.

To gain further insight into the mechanism by which MSNs modulated the immune response through the TLR signaling pathway, we examined protein alterations of TLR1, TLR2, TLR3, and TLR8 within macrophages after MSN treatment (Fig. 2D). We found that the mRNA and protein expressions of TLR1, TLR2, TLR3, and TLR8 cytokines were substantially lower in all MSN-treated groups. Meanwhile, NFB signaling pathway and downstream proinflammatory cytokines (TNF-, IL-1, and IL-6) were inhibited, which is consistent with previous findings that TLRs act as primary sensors that elicit innate immune responses and activate NFB signaling (Fig. 2D). Among the known TLRs, TLR2 has been characterized extensively as an inducer of proinflammatory cytokines. To determine whether MSNs modulated the immune response by down-regulating TLR2, we first treated macrophages with MSNs and then transfected MSN-treated macrophages with a TLR2 overexpression plasmid vector or empty vectors. We found that the NFB signaling pathway was up-regulated in macrophages transfected with the TLR2 overexpression vector compared to the empty vector control group. Consistently, the amounts of TNF-, IL-1, and IL-6 protein in macrophages were increased by transfection with the TLR2 overexpression vector (Fig. 2E). These comprehensive data suggest that MSNs modulated immune response through down-regulating TLR2, which inhibited the activation of NFB signaling and subsequently decreased the release of proinflammatory cytokines (TNF-, IL-1, and IL-6) (fig. S6).

To obtain insight into the mechanism underlying miR-21-5penhanced angiogenesis, we performed a proteogenomic analysis of protein alterations in endothelial cells after miR-21-5p treatment. We collected three replicates of endothelial cells after treatment with MSN/miR-NC or MSN/miR-21-5p. We applied a label-free quantitative proteomic approach. Hierarchical clustering analysis of the data revealed that the genes could be assigned into two groups based on their protein expression patterns, and the assigned groups matched with the groups by treatment (Fig. 3A). GSEA revealed that there were groups of genes positively correlated with angiogenesis after MSN/miR-21-5p treatment. KEGG analysis suggested that the MSN/miR-21-5p treatment groups were positively associated with key angiogenic signaling pathways (Fig. 3B). Compared to MSN/miR-NCtreated endothelial cells, MSN/miR-21-5ptreated endothelial cells had a larger number of proteins enriched in pathways such as vascular endothelial growth factor (VEGF) signaling pathway and platelet-derived growth factor (PDGF) signaling pathway (Fig. 3B). VEGF is the major mediator in endothelial cells and is considered to be a crucial signal transducer in angiogenesis. The binding of VEGF to the VEGF receptor leads to a cascade of signaling pathways, including ERK-MAPK (extracellular signalregulated kinase/mitogen-activated protein kinase) signaling, which particularly plays a central role in angiogenesis. Therefore, we focused on ERK-MAPK signaling in MSN/miR-21-5ptreated endothelial cells and found that the levels of phospho-Erk1/2, phospho-FAK, phospho-P38, phospho-AKT, VEGFA, and PDGF-BB were up-regulated in the MSN/miR-21-5p treatment group compared to the MSN/miR-NC group, indicating that miR-21-5p could enhance VEGFA expression and subsequently lead to ERK-MAPK signaling activation (Fig. 3C).

(A) A heatmap of selected proteins representing strongly altered signaling pathways in three datasets of endothelial cells treated with MSN/miR-NC or MSN/miR-21-5p complexes. (B) KEGG pathway analysis of both up- and down-regulated pathways in endothelial cells after MSN/miR-21-5p complex treatment. (C) Western blot analysis of changes in SPRY1, P-ERK1/2, P-FAK, P-p38, P-AKT, VEGFA, and PDGF-BB protein content alteration in endothelial cells after treatment with the MSN/miR-21-5p complex. (D) The effect of MSN/miR-21-5p or MSN/miR-NC on SPRY1 mRNA levels (left) and SPRY1 protein levels (right) in endothelial cells. (E) Schematic diagram illustrating the design of luciferase reporters with the WT SPRY1 3 untranslated region (WT 3UTR) or the site-directed mutant SPRY1 3UTR (3UTR-Mut). (F) The effect of MSN/miR-21-5p on luciferase activity in endothelial cells transfected with either the WT SPRY1 3UTR reporter (left) or the mutant SPRY1 3UTR reporter (right). (G) Western blot analysis of P-ERK1/2, P-FAK, P-p38, P-AKT, VEGFA, and PDGF-BB protein level alteration in MSN/miR-21-5p complextreated endothelial cells after overexpressing SPRY1 with the SPRY1 overexpression vector. *P < 0.05 and ***P < 0.01. n = 3 per group. The data are shown as means SD. Photo credit: Yan Li, Shanghai Ninth Peoples Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.

To gain further insight into the mechanism by which miR-21-5p promotes angiogenesis, we used a miRNA database to predict the potential target genes of miR-21-5p and found that SPRY1 has a miR-21-5p binding site in its 3 untranslated region (UTR). The amount of SPRY1 protein in endothelial cells was down-regulated by MSN/miR-21-5p treatment but not by MSN/miR-NC treatment, whereas we found no difference in SPRY1 mRNA levels between the two groups (Fig. 3D). To determine whether miR-21-5p functionally targets SPRY1 to promote angiogenesis, we overexpressed SPRY1 in endothelial cells. We found that phospho-Erk1/2, phospho-FAK, phospho-P38, phospho-AKT, VEGFA, and PDGF-BB levels were down-regulated in MSN/miR-21-5ptreated endothelial cells transfected with SPRY1 overexpression plasmid vector, compared to cells transfected with the empty vector (Fig. 3E). To test whether miR-21-5p directly targets SPRY1, we constructed luciferase reporters that had either the wild-type (WT) SPRY1 3UTR or an SPRY1 3UTR containing mutations at the miR-21-5p binding site (Fig. 3F). First, we found that MSN/miR-21-5p, but not MSN/miR-NC, substantially inhibited the luciferase reporter activity of the WT SPRY1 3UTR. Second, the luciferase reporter activity of the SPRY1mRNA with the mutated 3UTR was not suppressed by MSN/miR-21-5p (Fig. 3G). These comprehensive data suggest that delivery of miR-21-5p using MSN/miR-21-5p complexes promotes angiogenesis by targeting SPRY1 and subsequently activating the VEGF-induced ERK-MAPK signaling pathway (fig. S6). Detailed predicted miR-21-5p targets by Venn diagram analysis were revealed in fig. S7.

The in vivo efficacy of Gel@MSN/miR-21-5p was evaluated in an induced MI swine model. Coronary arteries were identified and ligated to induce a uniform and consistent MI, and the morphology and pumping effectiveness of the heart were evaluated ~45 min after the MI induction. The MI animals were then randomly divided into four groups receiving saline (negative control), agomiR-21-5p (a commercially available agent used to up-regulate endogenous miR-21-5p level), Gel@MSN/miR-NC, and Gel@MSN/miR-21-5p injection. Sham-operated animals served as a positive control. Morphological and functional assessments were performed using the modified Simpson method, which can accurately calculate left ventricular ejection fraction (LV EF) to detect any early echocardiographic changes. Changes in the morphology and pumping effectiveness of the heart were assessed through measurements of LV end diastolic volume (LVEDV), LV end systolic volume (LVESV), EF, and LV end diastolic dimension (LVEDd). Representative echocardiography images of short-axis views for each treatment group at baseline (before MI) and 45 min, 14 days, and 28 days after MI are shown in Fig. 4A. MI caused a substantial reduction in LV function 45 min after induction, as indicated by an absolute 20% decline in the EF. The morphological and functional parameters were slightly improved in the agomiR-21-5p and Gel@MSN/miR-NC groups compared with the saline negative control group at 14 and 28 days after MI, indicating that either miR-21-5p or MSNs alone could improve the morphology and pumping effectiveness of the heart but only to a limited degree (~an absolute 4 to 5% increase in EF values at 28 days, as compared to the saline group). More substantial improvement was achieved in the Gel@MSN/miR-21-5p group, with an approximately absolute 10% increase in the LV EF values at 28 days after MI. Time course echocardiography assessment over the 28-day study period is shown in Fig. 4B. These data suggest the importance of the therapeutic itself (miR-21-5p) as well as the delivery system (a two-stage delivery) in mitigating the negative LV remodeling and improving the morphology and pumping effectiveness of the heart after MI.

(A) Representative echocardiography imaging by the modified Simpson method of short-axis views for each treatment group at baseline and 45 min, 14 days, and 28 days after MI. The site of the infarct zone is shown by arrows. Notable chamber dilation and wall thinning occurred at 28 days following MI, consistent with the adverse remodeling process. (B) Time course analysis of the EF, LVEDV, LVESV, and LVPWd. (C) MI caused a gradual decline in the EF over 28 days, which was notably attenuated by Gel@MSN/miR-21-5p. (D) MI caused a gradual increase in the LVEDV at day 14 and day 28. The LVEDV of the Gel@MSN/miR-21-5p treatment group was substantially attenuated compared with those of the other three treatment groups. (E) MI caused progressive thinning of the LVPWd thickness at the diastole, which was attenuated by Gel@MSN/miR-NC and agomiR-21-5p treatment and further attenuated by Gel@MSN/miR-21-5p treatment at day 14 and day 28. *P < 0.05 and ***P < 0.01. Sham, n = 3; MI/saline, n = 5; MI/agomir, n = 5; MI/Gel@MSN/miR-NC, n = 6; and MI/Gel@MSN/miR-21-5p, n = 6. The data are shown as the means SD. Photo credit: Yan Li, Shanghai Ninth Peoples Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.

Representative delayed-enhancement computed tomography (CT) images of cross-sectional planes of hearts from two-axis (long axis and short axis) slices at day 28 after MI are shown in Fig. 5. The infarct regions in the LV posterior wall were characterized by wall thinning (identified by red counterstain). Analysis of systolic LV wall thickness showed that the wall thickness in the infarcted zone was retained in the agomiR-21-5p and Gel@MSN/miR-NCtreated groups 28 days after MI to a limited degree (marked with white arrows) compared to that in the saline-treated group. LV wall thickness in the infarcted zone was further persevered with the Gel@MSN/miR-21-5ptreated group. Bulls eye plots (Fig. 5A) display LV wall thickness, wall motion, and regional EFs. Global cardiac functional measures such as LVEDV, LVEDV, and EF are shown in the inserted table.

Representative delayed enhancement CT images of cross-sectional planes of hearts from two-axis (long axis and short axis) slices at day 28 after MI are shown. (A) Bulls eye plots display the LV wall thickness, wall motion, and regional EFs. (B) The infarct zone was characterized by wall thinning (identified by white arrows). (C) Global cardiac functional measures such as cardiac output, stroke volume, and EF are shown in the inserted table. Photo credit: Yan Li, Shanghai Ninth Peoples Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.

Infarct size as measured by tetraphenyl tetrazolium chloride (TTC) staining also showed that the Gel@MSN/miR-21-5p group had the smallest infarct size (Fig. 6A; paired multiple slices of an infarcted heart in the same pigs shown in fig. S8). The histological characterization of the LV sections from the infarct region at 28 days after MI showed that the infarcted regions in pigs injected with Gel@MSN/miR-21-5p present preserved distinct and thick muscle layers. However, moderately thickened muscle was observed in the agomiR-21-5p and Gel@MSN/miR-NC groups, and obvious fibrillary layers were observed in the saline group. The muscle layers were verified to be cardiomyocytes by anticardiac troponin-T staining (Fig. 6B). Massons trichrome staining showed approximately two times less fibrous content in the Gel@MSN/miR-21-5p group than in the saline group (Fig. 6D). These observations provided evidence that Gel@MSN/miR-21-5p treatment could effectively attenuate fibrosis and improve cardiac remodeling after MI.

A porcine model of MI was used to investigate the post-MI responsiveness of different groups to treatments. Healing at the infarct zone was analyzed after 28 days after treatment. (A) Representative image of TTC-stained hearts and morphometric measures of the infarct area from each group. White coloring in the TTC-stained sections indicates infarct zone and tissue necrosis. (B) Representative histological analysis of the infarcted myocardium among the treatment groups. H&E (left) staining, Massons trichrome staining (middle), and immunohistochemistry staining for cardiac troponin T (right) 28 days after MI showed a loss of cardiomyocytes and collagen deposition, and interstitial fibrosis was substantially reduced in the infarct zone after the Gel@MSN/miR-21-5p treatment (scale bars, 2000 m in the low-magnification images and 60 m in the high-magnification images). Quantitative analysis showing the percentage of the TTC-negative infarct area (C) and fibrotic area (D). (E) miRNA transfection efficiency was investigated using real-time quantitative PCR at 28 days following MI. *P < 0.05 and ***P < 0.01. Sham, n = 3; MI/Saline, n = 5; MI/Agomir, n = 5; MI/Gel@MSN/miR-NC, n = 6; and MI/Gel@MSN/miR-21-5p, n = 6. The data are shown as the mean SD. Photo credit: Yan Li, Shanghai Ninth Peoples Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine; Shanghai, 200011, China.

The in vivo data relating to drug release duration and efficacy of MSNs and miRNA delivery by Gel@MSN/miR-21-5p were characterized. Confocal images and quantification analysis showed that more than 60% of macrophages (identified by the F4/80+ marker) or endothelial cells (identified by the CD31+ marker) took up the MSN/miR-21-5p complexes 1 day after injection (Fig. 7). Furthermore, the high intracellular transfection efficacy was sustained up to ~28 days, as evidenced by an approximately twofold increase in endogenous miR-21-5p levels (Fig. 7), which could contribute to the improved morphology and pumping effectiveness of the heart.

MSNs were prelabeled with FITC (green), and miR-21-5p was prelabeled with Cy3 (red). The hydrogel (FITC-labeled Gel@MSN/miR-21-5p or Cy3-labeled Gel@MSN/miR-21-5p) was injected into the mid-myocardium of each target site in the pigs. The duration and efficiency of MSNs and miRNA delivery upon Gel@MSN/miR-21-5p injection were monitored using time course analysis at 1, 14, and 28 days after injection. (A) Histological sections of the infarct region in the Gel@MSN/miR-21-5p group were immunolabeled with the hematoxylin and eosin (H&E) macrophage marker F4/80. (B) Histological sections of the infarct region in the Gel@MSN/miR-21-5p group were immunolabeled with the endothelial marker CD31. Cell nuclei were counterstained with DAPI (blue). (C) F4/80+FITC+ and CD31+Cy3+ double-positive cells were quantified from at least eight high-resolution images acquired from at least eight different regions of each heart. (D) miR-21-5p levels were detected using real-time quantitative PCR at different time points. The transfection efficiency was determined by quantifying the miRNA level. Scale bars, 100 m. n = 3 per group. The data are shown as means SD. Photo credit: Yan Li, Shanghai Ninth Peoples Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.

We further compared the effects of MSN/miR-21-5p complexes without a hydrogel matrix (MSN/miR-21-5p alone) and with a hydrogel matrix (Gel@MSN/miR-21-5p) on treating MI. The morphological and functional parameters of the MSN/miR-21-5p group alone were worse than those of the Gel@MSN/miR-21-5p group at 14 and 28 days, and the parameters did not improve over time. The Gel@MSN/miR-21-5p delivery system provided sustained release of miR-21-5p (fig. S9) and sustained a superior therapeutic benefit compared to that from a bolus shot of MSN/miR-21-5p (fig. S10). Histological examination and the quantification of the total infarct size showed similar results. These data suggest that the hydrogel matrix could maintain a long-term drug release, which is important to achieve a persistent therapeutic effect. The hearts were harvested at 28 days after MI for fluorescent imaging, RNA extraction, and real-time quantitative PCR analysis. The fluorescent images showed that the areas of FITC and Cy3 fluorescence enhancement exactly overlapped with the infarct region (Fig. 8A). The confocal images and quantification of miR-21-5p levels showed that MSN/miRNA complexes were effectively transfected into cells within the infarct region in vivo (Fig. 8B). These data indicate that the hydrogel matrix achieved localized sustained drug release, triggered by the acidic microenvironment in the infarct region.

For examination of on-demand delivery, the hearts were harvested at 28 days after MI for fluorescent imaging, RNA extraction, and real-time quantitative PCR analysis. (A) The fluorescent images showed that there were no transfecting cells detected in the sham group. In contrast, it showed that the area of FITC and Cy3 fluorescence exactly overlapped with the infarct region. (B) Quantification of miR-21-5p levels showed that the MSN/miRNA complex could be highly transfected into cells within the infarct region in vivo. Scale bar, 100 m. ***P < 0.01. The data are shown as means SD. Photo credit: Yan Li, Shanghai Ninth Peoples Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.

The three-dimensional (3D) organization of the vascular network within the infarct regions was characterized by micro-CT angiography. The vascular density and volume were significantly improved with Gel@MSN/miR-21-5p (Fig. 9A). CD31 and smooth muscle actin (-SMA) are typical biomarkers of endothelial cells and mural cells in blood vessels. Immunofluorescence characterization showed that expression levels of CD31 and -SMA were significantly enhanced and that more newly formed vessels were observed in the Gel@MSN/miR-21-5p treatment group than in the other groups. These observations provided evidence that Gel@MSN/miR-21-5p treatment enhanced vascularization after MI.

(A) Micro-CT angiography analysis of 3D vascular structures within the infarct zone 28 days after MI indicates that the vascular volume was significantly increased in the Gel@MSN/miR-21-5p treatment group. The vascular volume within the infarct zone was quantitatively analyzed. *P < 0.05 and ***P < 0.01. n = 3 per group. (B) Immunofluorescence staining for CD31 (red) identified the vascular endothelium, and staining for -SMA (green) identified myofibroblasts and pericytes, showing that the cardiac capillary density in histological sections of the healing infarct zone was significantly higher in the Gel@MSN/miR-21-5p treatment group than in the other groups. The CD31 and -SMA staining intensities in the above-described groups were quantitatively analyzed (scale bars, 500 mm). *P < 0.05 and ***P < 0.01. Sham, n = 3; MI/saline, n = 5; MI/agomir, n = 5; MI/Gel@MSN/miR-NC, n = 6; and MI/Gel@MSN/miR-21-5p, n = 6. The data are shown as the means SD. Photo credit: Yan Li, Shanghai Ninth Peoples Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.

Immunofluorescence analysis of LV sections taken from the infarct region 1 day after MI showed that Gel@MSN/miR-21-5p effectively protected cardiomyocytes (fig. S11) and inhibited the expression of several key inflammatory mediators (TNF-, IL-1, and IL-6) (Fig. 10). Furthermore, concordant with reduced fibrotic area in the infarcted region in the Gel@MSN/miR-21-5ptreated group at 28 days after MI, the expression of key inflammatory mediators (TNF-, IL-1, and IL-6) was obviously reduced (fig. S12). These results suggested that Gel@MSN/miR-21-5p treatment modulated the immune response after MI by inhibiting the expression of proinflammatory cytokines.

Histological sections of the infarct zone (day 1 after MI) were immunolabeled with antibodies targeting TNF- (A), IL-6 (B), or IL-1 (C) and colabeled with the macrophage marker F4/80 (green). Cell nuclei were counterstained with DAPI (blue). (D) The percentages of cells double positive for F4/80 and TNF-, IL-1, or IL-6 (TNF-, IL-1, or IL-6expressing macrophages, respectively) were quantified. Quantification was performed in at least eight high-resolution images acquired from at least eight different regions of each heart. Scale bars, 100 m. ***P < 0.01. n = 3 per group. The data are shown as the means SD. Photo credit: Yan Li, Shanghai Ninth Peoples Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.

The use of large-animal models of MI provides valuable information regarding the safety and efficacy of new therapies. Pig models offer an alternative because of their anatomical and physiological similarities to humans (40, 41). The treatment groups used materials such as PEG derivatives, CD, silica, and miRNA, and an obvious inflammatory response to foreign bodies was not observed in the treated pigs, indicating its potential for clinical transition.

Here, we report the potential for an efficient miRNA delivery system that simultaneously integrates immune modification and angiogenesis enhancement in the field of MI therapy. This study demonstrates the efficacy and feasibility of a delivery system in a clinically relevant porcine MI model, where both the pathophysiology and the administration mimic what would be observed and performed in humans.

Current therapeutic strategies (angiogenic therapy or anti-inflammatory therapy) involving protein delivery or gene therapy for treating MI have limited success in reducing infarct size (42, 43). The results of our study suggest that therapeutic outcome relies on both immunomodulation and angiogenesis. This study demonstrated that MSNs could reduce the inflammatory responses that can modify tissue remodeling and prevent fibrous tissue formation for improved repair after MI. Specifically, the effect of the resultant microenvironment can be further enhanced with sustained miR-21-5p delivery via MSNs and synergistically stimulate angiogenesis as well as changes in the morphology and pumping effectiveness of the heart after MI.

To date, the study to use miRNA for the treatment of ischemic cardiovascular disease in a preclinical pig model was performed by Gabisonia et al. (22). Gabisonia et al. used miR-199a therapy in an attempt to stimulate cardiomyocyte proliferation. The approach enabled the induction of preexisting cardiomyocytes to reenter the cell cycle and rebuild the injured heart (44). Substantial improvements in cardiac function and structure were attributed to this process. However, there are potential limitations of cardiomyocyte proliferation after birth including cardiomegaly or hypertrophy, as well as possible arrhythmias due to the immaturity of myocyte conduction or poor coupling with existing myocardium (45). As reported by Gabisonia, the generation of areas of poorly differentiated cardiomyocytes might cause tachyarrhythmias and eventually determine fatal reentry electric circuits. The adverse effects were also observed in several other studies, that long-term stimulation of cardiomyocyte proliferation might result in impaired cardiac function or arrhythmic events (4648). In the current study, we attempted to use specific miR-21-5pbased therapies to promote angiogenesis in infarct areas, which may further facilitate rescuing resident cardiomyocytes in an injured heart. We focused on myocardial salvage rather than replacement. The proangiogenic effects of miR-21-5p were characterized with multiple in vitro and in vivo experiments and could be attributed to targeting SPRY1. Loss of SPRY1 leads to the expression of proangiogenic cytokines (VEGFA and PDGF-BB) in endothelial cells. While manipulation of proteins in the Hippo pathway (identified as miR-199a targets) promotes adult cardiomyocyte cell cycling, animals subjected to this type of treatment also exhibit cardiac dysfunction and heart failure in the long term (47, 48). Our strategy represents another direction to promote MI repair. Until now, no major case of arrhythmias has been reported to be associated with long-term proangiogenic therapies in either animal studies or clinical trials. In addition, Gabisonia et al. used adeno-associated virus vectors as therapeutic and investigational tools, which have advantages such as high transfection efficiency. However, such virus-based delivery systems could lead to uncontrollable continuous miR-199a expression and unrestrained cardiac growth in the long term, which would eventually result in sudden death due to arrhythmia at weeks 7 to 8 in most of the treated pigs because controlled miRNA delivery was beyond the current capabilities of virus-mediated gene transfer. Therefore, the treatment needs to be carefully dosed, which could be achieved through the delivery of naked, synthetic miRNA mimics. In our study, a local on-demand and controlled delivery system was described. The system provided a controlled miR-21-5p mimic delivery, with ~75% release over 7 days at pH 6.8 in vitro. In addition, considering the limitation of current RNAi-based therapy associated with potential off-target accumulation, multiple works have been done in this area to optimize the RNAi delivery system (16, 18, 19, 23). For example, a hydrogel system used ultraviolet as the external stimulus to achieve on-demand controlled localized release of RNA at designated time points to induce human mesenchymal stem cell (hMSC) osteogenesis (18, 19). In the present study, the hydrogel is designed to be pH stimuli responsive to achieve on-demand miRNA delivery for persistent and accuracy therapeutic effect on MI. The miRNA delivery system (Gel@MSN/miR-21-5p) specifically released MSN/miR-21-5p only at the infarct region without affecting the surrounding healthy tissues, which addresses the safety issue associated with miRNA-based therapy. As shown in fig. S15, two pigs survived out to 11 months after Gel@MSN/miR-21treatment, and electrocardiography (ECG) was performed. ECG analysis of Q wave and T wave showed that ECG signal at 11 months is similar to that at 4 weeks after Gel@MSN/miR-21 treatment, indicating that Gel@MSN/miR-21 was not likely to pose a long-term safety risk.

Acute inflammation caused by MI is a protective response that kills invading pathogens, should be self-limiting, and leads to healing (49). However, excess activation of the acute inflammatory response leads to cardiac myocyte death. Macrophages play a central role in regulating inflammation. Modulation of macrophage activation may contribute to the resolution of cardiac injury after MI. The results of this study indicate that MSNs can be used to inhibit proinflammatory polarization (M1) in an inflammatory microenvironment following ischemic muscle injury in vivo (50). Gulin-Sarfraz et al. (13) also noticed that empty mesoporous silica particles could reduce the number of neutrophils and down-modulate the inflammatory response in a mouse airway inflammation model. In addition, our data showed that MSNs modulated immune response through down-regulating TLR2, which inhibited the activation of NFB signaling and subsequently decreased the release of proinflammatory cytokines (TNF-, IL-1, and IL-6). Our results are similar to the findings of Lee et al. (51), who demonstrated that exposure to MSNs decreased the expression of proinflammatory cytokines such as TNF-, IL-1, and IL-6 in macrophages. Consistent with these results, a more recent study indicated that MSNs inhibit lymphocyte proliferation, suppress the killing activity of natural killer cells, and decrease proinflammatory cytokine and nitric oxide production in macrophage cells (36).

Previous studies have demonstrated that angiogenesis can be promoted by the fine-tuned delivery of multiple growth factors and cells with biomaterials (52, 53). It relies on the precisely controlled sequential release or direct serial delivery, which are unfavorable for clinical use. The present study has provided a relatively simple approach that shows not only equivalent efficacy in promoting angiogenesis but also a modified cardiac inflammatory response in pigs after MI, suggesting that achieving cardiac repair through the stimulation of angiogenesis in the infarct region with a miRNA (miR-21-5p)based strategy is attainable in large mammals. The vascular volume was significantly improved within the infarct region in pigs treated with Gel@MSN/miR-21-5p. The enhanced vessels within the infarct region were associated with the accumulation of endothelial cells (identified by CD31+) and mural cells (identified by -SMA+) 28 days after MI. The mechanism by which miR-21-5p exerts its cardiac proangiogenic effects in the myocardium was also studied. KEGG analysis suggested that treatment with miR-21-5p complex was positively associated with key angiogenic signaling pathways such as VEGF signaling and PDGF signaling. Multiple experiments were further conducted and concluded that the delivery of miR-21-5p promoted angiogenesis by targeting SPRY1 and subsequently activating VEGF-induced ERK-MAPK signaling. Together, these data suggest that endogenous cardiac repair may be facilitated by the miR-21-5pinduced angiogenic network.

Increasing reports have revealed the advantage and importance of biomaterials in cardiac tissue engineering. Despite the enthusiasm, there are relatively few ongoing clinical trials using injected materials for cardiac repair, perhaps due to a lack of evidence in large-animal studies, which are necessary before progressing to human trials. Pig models offer an alternative because of their anatomical and physiological similarities to humans. The use of a pig model of MI may provide valuable information regarding the safety and efficacy of therapeutic strategies for MI in clinic. We performed a large-animal study with a pig model to demonstrate the translational potential. However, because the immediate treatment after MI may not be relevant to clinical situations, whether this approach also works in chronic cases and whether there exists an optimal therapeutic time window require further evaluation. There are also human-specific issues to consider including PEG immunity and species-specific interactions. Thus, understanding the factors that affect PEG immunity is crucial for both researchers and clinicians to ensure the treatment safety in clinic. Optimization of Gel@MSN/miR-21-5p dose and long-term studies are also needed for clinical translation.

In summary, the two-stage gene delivery system Gel@MSN/miR-21-5p developed in this study consists of three key components, pH-responsive hydrogel matrix, MSNs, and miR-21-5p. The responsive hydrogel serves as a matrix to achieve a highly localized drug release triggered by an acidic microenvironment and a 1-week sustained drug release (first stage release); MSN is the gene transfection vector (second stage release) and itself alone also resolves early inflammation by suppressing the TLR/NFB signaling pathway; and miR-21-5p promotes angiogenesis and mature vessel formation by targeting SPRY1 and subsequently activating VEGF-induced ERK-MAPK signaling. The synergy among these three elements demonstrated significance in treating MI in a swine model via a combination of anti-inflammatory and proangiogenic effects. Clinically relevant positive outcomes were observed upon Gel@MSN/miR-21-5p treatment, such as improved cardiac remodeling, reduced fibrosis formation and infarct size, and increased vascularization. The injectable property of Gel@MSN/miR-21-5p makes it potentially translatable to minimally invasive transcatheter-based surgery. In addition, this study is a proof of concept for controlled gene delivery and can serve as a technological platform to better elucidate the dose-dependent response of genes in MI treatment or deliver any other nucleic acids (such as DNAs, mRNAs, siRNAs, and miRNAs) or treat any other disease.

The purpose of this study was to design a controlled on-demand miR-21-5p delivery system (Gel@MSN/miR-21-5p) using MSNs combined with a hydrogel matrix, simultaneously integrating immune modification and angiogenesis enhancement in the field of MI therapy. Gel@MSN/miR-21-5p was fabricated by embedding MSN/miR-21-5p complexes into an injectable hydrogel matrix. We performed studies to determine the mechanical properties, structure, and on-demand release profile of Gel@MSN/miR-21-5p.

For the in vitro experiment, real-time quantitative PCR, Western blot, and enzyme-linked immunosorbent assay (ELISA) were performed to assess the immunomodulatory effect of MSNs. Real-time quantitative PCR, Western blot, ELISA, and tube formation assays were performed to determine the proangiogenic effect of miR-21-5p. The mechanisms underlying MSN-mediated inflammatory effects and miR-21-5pmediated proangiogenic effects were studied by proteogenomic analysis, real-time quantitative PCR, and Western blot.

For the in vivo experiments, pigs were randomly assigned to treatment groups, and, wherever applicable, treatment conditions were kept blinded until statistical analysis. Group sizes of at least five animals were chosen, which indicated that the therapeutic efficacy and safety of the Gel@MSN/miR-21-5p could be robustly identified. MI was characterized using multiple methods including echocardiography, delayed enhancement CT, TTC staining, and histological examination. The potential cardiac-protective effect against apoptosis induced by ischemia was analyzed by immunofluorescence analysis. The duration and efficiency of MSNs and miRNA delivered by Gel@MSN/miR-21-5p injection were monitored using time course analysis.

Animal protocols related to this study were reviewed and approved by the Institutional Animal Care and Use Committee at the School of Medicine of Shanghai Jiao Tong University. All experiments were performed in accordance with the guidelines published by the Institutional Animal Care and Use Committee at the School of Medicine of Shanghai Jiao Tong University, Shanghai. All animals were obtained from the Ninth Peoples Hospital Animal Center (Shanghai, China).

Yucatan mini pigs (male, 45 to 50 kg) were anesthetized with tiletamine hydrochloride and zolazepam hydrochloride (4 mg/kg). To establish the porcine MI model, transthoracic 2D echocardiographic measurement by Simpsons method (S5-1 transducer, PHILIPS Medical Systems) was performed to ensure that the animal was healthy before instrumentation and MI induction. Following baseline echocardiographic measurements, light anesthesia was maintained by continuous intravenous infusion of propofol (30 to 40 g kg1 min1). ECG, heart rate, and arterial pressure were constantly monitored. The pericardium was opened through a left thoracotomy, and the first two obtuse marginal arteries of the circumflex artery (OM1 and OM2) were identified and ligated to induce MI. Past studies demonstrated that this technique creates a uniform and consistent MI (24). The pericardium was left open. Pigs were randomized to receive a total of six distinct injection of saline, agomiR-21-5p, Gel@MSN/miR-NC, or Gel@MSN/miR-21-5p within a targeted 2 2 cm region of mid-myocardium immediately after MI (six injection sites, 100 l per injection). Sham controls were was processed in an identical fashion with the exception of coronary artery ligation. The injection of each target site is shown in fig. S13. For the Gel@MSN/miR-NC and Gel@MSN/miR-21 treatments, the miR-NC or miR-21 was preloaded in the MSN-NH2-TMA with a mass ratio of 1:10 between miRNA/MSNs. Then, the sterilized aqueous solutions (600 l) containing RNA-loaded MSN-NH2-TMA, CHO-PEG-CHO, and -CD with a mass ratio of 1:5:5 were incubated for 5 min to form an injectable hydrogel precursor with weak interaction, which was further drawn into a separate syringe, and injected into the mid-myocardium to form the final hydrogel at the target site immediately following MI induction. Animals were carefully monitored until they fully recovered from anesthesia.

Pigs were sedated at baseline, and 2D echocardiographic measurements by Simpsons method (IE33 digital ultrasonic scanner, PHILIPS Medical Systems, USA) were performed in right lateral recumbency. Echocardiography measurements were taken before surgery (baseline) and at 45 min, 14 days, and 28 days following MI. Transthoracic echocardiography allowed assessment and further calculation of LV dimensions, cardiac chamber size, wall thicknesses, EF, LVEDV, and LVEDd according to the biplane modified Simpsons rule. For these measurements, standard parasternal long-axis and apical chamber views were obtained.

CT examinations were performed at 28 days after MI. Animals were sedated with a cocktail injection of tiletamine hydrochloride (4 mg/kg) and zolazepam hydrochloride (4 mg/kg) injection. Pigs were placed in a right lateral position.

CT images were acquired with a clinical 320-slice scanner (Aquilion One, TOSHIBA Medical Systems). The heart was scanned along two long-axis views (vertical and horizontal) and with one set of short-axis views covering the entire LV from the atrioventricular valve plane to the apex. The following parameters were used: a tube voltage of 100 kV, a tube current of 75 mA, a gantry rotation time of 330 ms, 0.5-mm section thickness, a resolution of 0.5 0.5 mm, and free breathing. The CT contrast medium (Ultravist 370, Schering) was injected at a flow rate of 3.5 ml/s. To identify the scar and quantify the extent of post-infarction fibrosis, delayed contrast-enhanced multidetector CT images were acquired to assess viability 3 to 5 min after the administration of contrast media for LV function.

Multiphase reconstruction was performed with commercially available software (VITAL, TOSHIBA Medical Systems, Japan) by using short-axis slices from the base of the heart to the apex. The end diastole and end systole were defined as the maximal and minimal LV volume, respectively.

The hearts from each group were harvested, and blood vessels within the heart were imaged by angiography, as previously described (54). Briefly, a 50.8-millimeter, 18-gauge catheter (Surflo Teflon IV Catheter, Terumo Medical, USA) was inserted into the left ventricle of the heart and advanced into the ascending aorta. A 0.9% normal saline solution containing heparin sodium (100 U/ml) was perfused through the vasculature. The vasculature was then fixed by perfusion with 10% neutral buffered formalin (NBF) and cleared with saline. Last, 25 ml of polymerizable, lead chromatebased, radiopaque contrast agent (Microfil MV-122, Flow Tech, USA) was injected using a 30-ml syringe. Samples were stored at 4C for 24 hours to allow polymerization of the contrast agent.

Samples were scanned using micro-CT (Y. Cheetah, YXLON, Germany) with the following settings: 90 kV, 50 A source current, exposure time of 907 ms, and two images every 0.5 of a 360 rotation range at a voxel size of 76 m. 3D reconstruction of the micro-CT image was completed and analyzed using the manufacturers evaluation software (VG studiomax 3.0). The reconstruction was performed using binning mode, providing an isotropic voxel size of 76 m.

Since the infarct area is clearly visible in the heart tissue slice, matching the micro-CT image slices with their corresponding tissue slices could identify the infarct zone within the 3D micro-CT reconstructed model. The sectioning planes of the microtomograph and of the tissue samples are parallel. After sectioning, the infarct areas (infarcted myocardium appears pale) of the heart tissue slices were counterstained in red. After obtaining micro-CT images, the infarct areas of the micro-CT images were identified on the basis of the observation of the tissue slices.

The heart tissue was sectioned starting from the base to the apex. After sectioning, slices were immediately immersed in 2% TTC in 0.9% NaCl at 37C for 30 min for vital staining. Infarcted myocardium appeared pale after TTC staining. The MI area (TTC negative, white) is outlined. The infarcted area and the total area of the LV wall were analyzed using ImageJ software. The infarct size was calculated as follows: counts of TTC-negative area/counts of total LV wall area (%) on short-axial middle LV myocardial slices.

The excised hearts were sectioned through four horizontal planes, and each section was then subdivided into subsections for further histological and molecular analyses, as shown in fig. S14. Briefly, each heart was sectioned into four 1-cm-thick slices, starting from the apex toward the base. Then, two regions (indicated by letters) of each slice were chosen for further histological and molecular analyses. In all quantifications, we considered eight sectors of the four heart sections, and the same regions were chosen in animals with different treatments.

Pig hearts were carefully harvested 28 days following infarction. Samples representing the mid-infarct were sliced. These tissue samples were routinely processed for histologic analysis, and sections (5 m thick) were stained with hematoxylin and eosin (H&E) and Massons trichrome, as previously described (55). Capillary densities were examined by counting the number of capillaries stained with anti-CD31 (ab28364, Abcam, USA) and anti-SMA (ab5694, Abcam, USA) antibodies. For hydrogel immunomodulatory investigation, hearts were collected and processed after 1 and 28 days after MI. Immunofluorescence was used as previously described to identify F4/80+ cells (ab6640, Abcam, USA) colabeling with antiTNF- (ab6671, Abcam, USA), antiIL-6 (ab6672, Abcam, USA), or antiIL-1 antibody (NB600-633, Novas, USA); Alexa Fluor 488labeled donkey anti-rat antibody (Jackson ImmunoResearch Laboratories, USA) and the Alexa Fluor 594labeled anti-rabbit antibody (Jackson ImmunoResearch Laboratories, USA) were used for visualization. Slides were counterstained with DAPI (56). Immunohistochemistry was used to verify cardiomyocytes with anticardiac troponin-T antibody (ab10214). ImageJ software was applied to count blue pixels (positive for collagen) within that region in the trichrome images.

Time course analysis of transfection efficiency of Gel@MSN/miR-21-5p was performed in vivo. MSNs were prelabeled with FITC (green), or miR-21-5p was prelabeled with Cy3 (red). The hydrogel (FITC-labeled Gel@MSN/miR-21-5p or Cy3-labeled Gel@MSN/miR-21-5p) was injected into the mid-myocardium of each target site of pigs. The delivery efficiency of miR-21-5p into endothelial cells was examined by identifying CD31+ cells (ab28364, Abcam, USA) colabeling with Cy3-labeled miR-21-5p. The delivery efficiency of MSNs into macrophages was examined by identifying F4/80+ cells (ab6640, Abcam, USA) colabeled with FITC-labeled MSNs.

To assess whether MSNs could protect against apoptosis in cardiomyocytes, a terminal deoxynucleotidyl transferasemediated deoxyuridine triphosphate nick end labeling assay using an In Situ Cell Death Detection Kit (Roche, Switzerland) was performed at an earlier time (1 day) after MI, which labels broken DNA strands that are often associated with apoptosis. Percentages of positively stained cells were determined by counting the numbers of labeled cells and total cells.

The macrophage activation state was evaluated after intraperitoneal injections of LPS (Sigma-Aldrich, St. Louis, MO; 250 g in 0.5 ml of saline) into mice. Primary peritoneal macrophages were obtained from 20 g of female C57BL6J mice, as previously described (57). Briefly, cell lavage was collected by flushing the peritoneum with cold PBS. The peritoneum was centrifuged (800g, 4C, 9 min), and the pellet was incubated with ACK buffer (Fisher Scientific, Chino, USA) for 1 min to lyse erythrocytes. The remaining cells were cultured in RPMI 1640 medium and 10% fetal bovine serum (FBS) (Gibco, Gaithersburg, USA) at 37C in a 5% CO2 atmosphere and plated to select for adherent macrophages.

Primary cardiomyocytes were obtained from adult C57BL6J mice (8 weeks), as previously described (58). Briefly, the animal is euthanized humanely by cervical dislocation, and the heart is excised, taking care to remove the pericardium. Blood is removed from the coronary vessels after adequate perfusion with EDTA. Next, the heart is perfused with enzyme solution for 8 to 14 min. At the end of the enzyme digestion, the enzyme solution is flushed with 100 M Ca solution for 5 min, after which the heart is excised by dissecting the cannula, atria, and aorta. Once the first digestion was completed, the heart was transferred to a sterile petri dish and a second digestion step is carried out. The ventricular tissue is chopped with small scissors. Fresh digestion buffer was added, and the heart was quickly triturated with fine tweezers and forceps. This second digestion was performed at 37C in an incubator with 5% CO2 for 10 min to facilitate the collagenase activity. The reaction was halted by adding stop buffer containing FBS (Gibco), and the sample was filtered through a 100-m mesh. Following this, cardiomyocytes were purified via gravity separation in a falcon tube for 15 min and washed with Ca solution. After purification, cells were counted in a hemocytometer, seeded in laminin-coated culture dishes, and placed in an incubator with 5% CO2 at 37C.

Endothelial cells were purchased from the cell and stem cell bank (GNO 15, Chinese Academy of Sciences, China) and were maintained in culture with Dulbeccos modified Eagles medium (DMEM) (Gibco) supplied with 10% FBS (BioInd, Israel), as detailed by the manufacturer.

The tube formation assay was performed as previously described (59). Briefly, growth factorreduced Matrigel matrix (Life Technology) was plated in a 24-well plate after thawing at 4C overnight. The plate was then incubated at 37C for 30 min to allow the Matrigel to polymerize. MSNs, MSN/miRNA-NC, and MSN/miRNA-21transfected calcein-labeled endothelial cells in endothelial basal medium 2 (EBM2) supplemented with 0.5% FBS and basic fibroblast growth factor (5 ng/ml) (FGF) final were seeded on the Matrigel-coated well. The plate was then incubated at 37C in a 5% CO2 humidified atmosphere. Tube formation was observed at 8 and 16 hours with confocal microscopy. The tube formation ability was determined by measuring the total tube length of endothelial cells with ImageJ software.

For flow cytometric analyses, cells were blocked with 10% FBS for 10 min on ice and subsequently stained with fluorochrome-tagged anti-F4/80 (BM8, BioLegend) or APC-labeled anti-CD31 (eBioscience, 17-0319-42). All stains were performed in 1% bovine serum albumin PBS buffer for 1 hour in the dark at 4C, followed by two washing steps. Samples were analyzed on a FACSCalibur (BD Biosciences, USA). Dead cells were excluded by forward and side scatter, and data analysis was performed using FlowJo software version 7.6.3 (Tree Star Inc., Ashland, USA).

For in vitro uptake analysis, isolated peritoneal macrophages were cocultured with FITC-labeled nanoparticles (100 g/ml). For in vivo uptake analysis, FITC-labeled Gel@MSN/miR-21-5p was injected into the mid-myocardium of the pigs heart. In vitro and in vivo quantitative uptake of the MSNs by macrophages was determined by quantifying the fluorescence intensity of cells that were positive for F4/80 (ab6640, Abcam, USA) and showed colocalization with FITC.

The growth medium of the hypoxic/ischemia group was replaced with serum-free DMEM. Cells were placed in a hypoxic incubator (Sanyo, O2/CO2 incubator MCO-18M) with oxygen adjusted to 1.0% and CO2 adjusted to 5%. Normal culture (regular medium under 21% oxygen and 5% CO2) served as a control.

The hearts of pigs were collected. Total miRNA from the collected cells or the heart was extracted using the RNeasy Mini Kit (Qiagen) according to the manufacturers instructions. For miRNA level detection, reverse transcription was performed using the Reverse Transcription kit (Takara RR037a, USA) with miRNA-specific stem-loop RT primer (ID: miR8001313, RiboBio, China). Reverse transcriptase reactions contained 0.5 g of RNA samples, 0.2 M stem-loop RT primer, 1 RT buffer, 50 pmol of random primers 6, and PrimerScript Reverse Transcriptase (200 Ul1). The 10-l reactions were incubated in a T100 thermal cycler (Bio-Rad, Hercules, USA) for 15 min at 37C, 5 s at 72C, and then held at 4C. One microliter of cDNA was PCR-amplified using Premix Taq (Takara RR902A) with 1 l of forward primer (0.2 M) and 1 l of reverse primer (0.2 M) for miR-21-5p (RiboBio, ID: miR8001314). The 25-l reaction volume consisted of 1 l of cDNA, 12.5 l of Premix Taq, 9.5 l of ddH2O, 1 l of forward primer (0.2 M), and 1 l of reverse primer (0.2 M). The reactions were performed on a T100 thermal cycler.

The cDNAs were diluted 10 times to perform real-time quantitative PCR using TB Green Premix Ex Taq (Takara RR420A) for miR-21-5p level detection. The 25-l reaction volume consisted of 1 l of cDNA, 12.5 l of Green Premix Ex Taq, 9.5 l of ddH2O, 1 l of forward primer (0.4 M), and 1 l of reverse primer (0.4 M) for miR-21-5p (RiboBio, ID: miR8001314).

For miRNA level detection, cDNAs were synthesized using a reverse transcription kit (Takara, RR037a). Reverse transcriptase reactions contained 0.5 g of RNA samples, 25 pmol of Oligo dT Primer, 1 RT buffer, 50 pmol of random six primers, and PrimerScript Reverse Transcriptase (200 Ul1). The 10-l reactions were incubated in a MyCycler thermal cycler (Bio-Rad, Hercules, CA) for 15 min at 37C and 5 s at 72C and then held at 4C. The cDNAs were then diluted 10 times to perform real-time quantitative PCR for expression confirmation and expression pattern analysis.

The primers used are as follows: -actin (5-CAGGATTCCATACCCAAGAAG-3 and 5-AACCCTAAGGCCAACCGTG-3), IL-1 (5-GAAATGCCACCTTTTGACAGTG-3 and 5-TGGATGCTCTCATCAGGACAG-3), TNF- (5-GACGTGGAACTGGCAGAAGAG-3 and 5-TTGGTGGTTTGTGAGTGTGAG-3), IL-6 (5-TCTATACCACTTCACAAGTCGGA-3 and 5-GAATTGCCATTGCACAACTCTTT-3), TLR1 (5-CCGTCCCAAGTTAGCCCATT-3 and 5-TCCCCCATCGCTGTACCTTA-3), TLR2 (5-TGCGGACTGTTTCCTTCTGA-3 and 5-GCGTTTGCTGAAGAGGACTG-3), TLR3 (5-TACAAAGTTGGGAACGGGGG-3 and 5-GGTTCAGTTGGGCGTTGTTC-3), and TLR8 (5-ACAAACGTTTTACCTTCCTTTGTC-3 and 5-ATGCAGTTGACGATGGTTGC-3).

Western blotting was performed as previously described (56). Total protein was extracted using the EpiQuik whole-cell extraction kit (Epigentek, USA). The protein concentration was measured following the manufacturers instructions (Bio-Rad, USA). Protein was applied to and separated on 4 to 15% NuPAGE gels (Bio-Rad) and transferred to polyvinylidene difluoride membranes (Millipore, USA). The membranes were blocked with 5% bovine serum albumin and incubated with specific primary antibodies against the following: TNF- (AF-410-NA, R&D, USA), IL-1 (Novus, AF-401-NA), IL-6 (bs-0782R, Bioss, USA), VEGFA (DF7470, Affinity, USA), PDGF-BB (bs-1316R, Bioss), TLR1 (NB100-56563, Novus), TLR2 (Abcam, ab209217), TLR3 (NBP2-24875, Novus), TLR8 (NBP2-24917, Novus), NFB (CST8242s, Cell Signaling Technology, USA), p-NFB (CST3033s), SPRY1 (Abcam, ab111523), P-ERK1/2 (AF1018, R&D), ERK1/2 (AF1576, R&D), P-AKT (AF887, R&D), AKT (MAB2055, R&D), P-FAK (MAB4528, R&D), FAK (AF4467, R&D), P-P38 (CST4511), P38 (CST8690), and GAPDH (ab181602) at a ratio of 1:1000 overnight.

Horseradish peroxidaseconjugated IgG (1:10,000 dilution) from Santa Cruz Biotechnology (Santa Cruz, USA) was incubated with the membrane for 1 hour, after which the membranes were enhanced with a SuperSignal West Pico Chemiluminescent Substrate (Thermo Fisher Scientific, USA). The relative amounts of the transferred proteins were quantified by scanning the autoradiographic films. Total protein or nuclear protein was normalized to the corresponding -actin.

For VEGFA and PDGF-BB protein secretion analysis, cells were pretreated with MSN complex loaded with 5 nmol of miR-21-5p as described above. After 6 hours of culture, the medium was replaced with fresh growth medium supplemented with 5.0% serum substitute Nu-Serum (NuS, BD, USA). Samples were collected at 48 hours. VEGFA and PDGF-BB protein levels in the medium were determined using an ELISA according to the manufacturers instructions (R&D Corp., USA). Absorbance was measured at 450 nm with a microplate reader (MTP-800Lab, Corona Electric, Japan). A standard curve was plotted to determine the VEGFA and PDGF-BB concentrations. The values are expressed as picograms per milliliter.

To detect the degradation of Gel@MSN/miR-21 in vivo, the PEG frame of the hydrogel was labeled rhodamine B. Sixty microliters of Gel@MSN/miR-21 was injected into the mid-myocardium of rats after induction of MI. To monitor the residual MSNs in vivo, 60 l of hydrogel containing rhodamine Blabeled MSNs was injected into the mid-myocardium of rats after induction of MI. At the indicated time points, rats were euthanized, and the hearts were removed from the animals. The organs were entirely maintained on ice until ex vivo analysis with Xenogen IVIS imaging system (Alameda, USA). Epifluorescence images of the hearts were acquired. Captured images were then analyzed using the Living Image 4.3.1 software (PerkinElmer Inc., USA). All data obtained by Xenogen IVIS were expressed as radiant efficiency, were assumed to be a calibrated measurement of the photon emission from the subject, and were technically defined as fluorescence emission radiance per incident excitation intensity as follows: photons/s/cm2/sr.

All numerical data are presented as the means SD. Statistical analysis was performed using commercially available software (SPSS 26). Data were first checked for normal distribution, and differences among groups were compared by one-way analysis of variance (ANOVA) followed by the Bonferroni post hoc test. Comparisons between two groups were made using the unpaired t test. For all statistical analyses, significance was accepted at P < 0.05.

Acknowledgments: We thank Y. Zhang and X. Wang (Fudan University) for providing primary cardiomyocytes. The research project was carried out in the Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology. Funding: We acknowledge financial support from the Innovative Research Unit of Chinese Academy of Medical Sciences (2019-12M-5-037) and the National Natural Science Research Program of China (81970977, 31870969, 81870785, 81801039, 81720108011, and 81601606), the Shanghai Municipal Science and Technology Committee research program (number 18DZ2291100), the National Key Research Program of China (2017YFC0840100 and 2017YFC0840109), the Fundamental Research Funds for the Central Universities (2016qngz02), the National Natural Science Foundation of Shaanxi Province (2017JM5023), the Open Fund of the State Key Laboratory of Military Stomatology (2017KA02), and the Knowledge Innovation Program of Shenzhen (JCYJ20170816100941258). Author contributions: Y.L., L.C., D.Z., H.C., and Y.D. carried out animal studies and tissue analyses. X.C. and R.J. carried out the MSN complex synthesis, polyplex development, and Gel@MSN/miR-21-5p hydrogel fabrication and their characterization. Y.L., B.C., J.J.G., G.B., and S.L. contributed to data analysis and interpretation. C.Y., Z.Z., M.D., and Y.L. were responsible for the overall project design and manuscript organization. Competing interests: The authors declare that they have no 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. Additional data related to this paper may be requested from the authors.

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Injectable hydrogel with MSNs/microRNA-21-5p delivery enables both immunomodification and enhanced angiogenesis for myocardial infarction therapy in...

Humans are born with a variety of cells. While all of them are absolutely essential for creating us, some cells are more complex and importantlike the nerve cells forming our brain. After all, what is a human body is nothing if not for its brain.

Once the brain cells start to deteriorate, with ageing or injury, humans start to lose cognitive and motor functions. Often seen in cases of Alzheimer's and schizophrenia.

But looking inside a living human brain is impossible; you can only dissect a dead brain that doesnt function. But a group of researchers have overcome this hurdle by building a brain in a dish.

Scientists have been growing living cells in Petri-dishes for a long time. But this research is leaps and bounds ahead as organoids, grown from stem cells, allowed them to conduct extensive genetic analyses. The organoid was allowed to grow for 20 months. They observed it developed in phases, as if on an internal clock, much like the brain of a human infant. This is beyond the former assumption that dish brain could only develop till foetal stage.

Until now, nobody has grown and characterized these organoids for this amount of time, Nor shown they will recapitulate human brain development in a laboratory environment for the most part, said Daniel Geschwind, author of the study. He adds how this will be incredibly useful as models to study the human brain and diseases as the organoids mature and replicate many aspects of normal human development. The study can be found in the journal Nature Neuroscience.

Studying the organoids is helping them understand the physiology and development of diseases like neurological and neurodevelopmental disorders including autism, epilepsy and schizophrenia.

The scientists developed these organoids using pluripotent stem cells. These cells are born one but have the ability to differentiate into multiple specific cells like neurons or cardiac and so on. They induced these cells, derived from skin and blood, to grow into neurons. By manipulating the chemical balance, cell-dish environment and so on, these cells not just developed a rough neural network but self-organised into a structure similar to a 3-D brain.

Excerpt from:
Scientists have Created a 'Brain in a Dish.' It Could Potentially Cure Alzheimer, Dementia - News18

Exosome therapeutic Market Industry Trends and Forecast to 2028 New Research Report Added to Databridgemarketresearch.com database. The report width of pages: 350 Figures: 60 And Tables: 220 in it. Exosome therapeutic Market describes complete industry Outlook with in-depth analysis. This report also includes the complete analysis of each segment in terms of opportunity, market attractiveness index and growth rate, top players and new comers in industry, competitive landscape, sales, price, revenue, gross margin, market share, market risks, opportunities, market barriers, and challenges. key statistics on the market status. Which give the clear idea about the product differentiation and an understanding of competitive landscape Globally.

Exosome therapeutic Market Research report comprises of a brief summary on the trends and tendency that may help the key market players functioning in the industry to understand the market and strategize for his or her Organization expansion for this reason. This statistical surveying report examines the entire market size, market share, key segments, growth, key drivers, CAGR, historic data, present market trends And End User Demand, environment, technological innovation, upcoming technologies and the technical progress in the industry.

Global Exosome Therapeutic Market By Type (Natural Exosomes, Hybrid Exosomes), Source (Dendritic Cells, Mesenchymal Stem Cells, Blood, Milk, Body Fluids, Saliva, Urine Others), Therapy (Immunotherapy, Gene Therapy, Chemotherapy), Transporting Capacity (Bio Macromolecules, Small Molecules), Application (Oncology, Neurology, Metabolic Disorders, Cardiac Disorders, Blood Disorders, Inflammatory Disorders, Gynecology Disorders, Organ Transplantation, Others), Route of administration (Oral, Parenteral), End User (Hospitals, Diagnostic Centers, Research & Academic Institutes), Geography (North America, Europe, Asia-Pacific and Latin America)

Market Analysis and Insights:Global Exosome Therapeutic Market

Exosome therapeutic market is expected to gain market growth in the forecast period of 2019 to 2026. Data Bridge Market Research analyses that the market is growing with a CAGR of 21.9% in the forecast period of 2019 to 2026 and expected to reach USD 31,691.52 million by 2026 from USD 6,500.00 million in 2018. Increasing prevalence of lyme disease, chronic inflammation, autoimmune disease and other chronic degenerative diseases are the factors for the market growth.

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Exosomes are used to transfer RNA, DNA, and proteins to other cells in the body by making alteration in the function of the target cells. Increasing research activities in exosome therapeutic is augmenting the market growth as demand for exosome therapeutic has increased among healthcare professionals.

Increased number of exosome therapeutics as compared to the past few years will accelerate the market growth. Companies are receiving funding for exosome therapeutic research and clinical trials. For instance, In September 2018, EXOCOBIO has raised USD 27 million in its series B funding. The company has raised USD 46 million as series a funding in April 2017. The series B funding will help the company to set up GMP-compliant exosome industrial facilities to enhance production of exosomes to commercialize in cosmetics and pharmaceutical industry.

Increasing demand for anti-aging therapies will also drive the market. Unmet medical needs such as very few therapeutic are approved by the regulatory authority for the treatment in comparison to the demand in global exosome therapeutics market will hamper the market growth market. Availability of various exosome isolation and purification techniques is further creates new opportunities for exosome therapeutics as they will help company in isolation and purification of exosomes from dendritic cells, mesenchymal stem cells, blood, milk, body fluids, saliva, and urine and from others sources. Such policies support exosome therapeutic market growth in the forecast period to 2019-2026.

This exosome therapeutic market report provides details of market share, new developments, and product pipeline analysis, impact of domestic and localised market players, analyses opportunities in terms of emerging revenue pockets, changes in market regulations, product approvals, strategic decisions, product launches, geographic expansions, and technological innovations in the market. To understand the analysis and the market scenario contact us for anAnalyst Brief, our team will help you create a revenue impact solution to achieve your desired goal.

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Competitive Landscape and Exosome Therapeutic Market Share Analysis

Global exosome therapeutic market competitive landscape provides details by competitor. Details included are company overview, company financials, revenue generated, market potential, investment in research and development, new market initiatives, global presence, production sites and facilities, company strengths and weaknesses, product launch, product trials pipelines, concept cars, product approvals, patents, product width and breadth, application dominance, technology lifeline curve. The above data points provided are only related to the companys focus related to global exosome therapeutic market.

The major players covered in the report are evox THERAPEUTICS, EXOCOBIO, Exopharm, AEGLE Therapeutics, United Therapeutics Corporation, Codiak BioSciences, Jazz Pharmaceuticals, Inc., Boehringer Ingelheim International GmbH, ReNeuron Group plc, Capricor Therapeutics, Avalon Globocare Corp., CREATIVE MEDICAL TECHNOLOGY HOLDINGS INC., Stem Cells Group among other players domestic and global. Exosome therapeutic market share data is available for Global, North America, Europe, Asia-Pacific, and Latin America separately. DBMR analysts understand competitive strengths and provide competitive analysis for each competitor separately.

Many joint ventures and developments are also initiated by the companies worldwide which are also accelerating the global exosome therapeutic market.

For instance,

Partnership, joint ventures and other strategies enhances the company market share with increased coverage and presence. It also provides the benefit for organisation to improve their offering for exosome therapeutics through expanded model range.

Global Exosome Therapeutic Market Scope and Market Size

Global exosome therapeutic market is segmented of the basis of type, source, therapy, transporting capacity, application, route of administration and end user. The growth among segments helps you analyse niche pockets of growth and strategies to approach the market and determine your core application areas and the difference in your target markets.

Based on type, the market is segmented into natural exosomes and hybrid exosomes. Natural exosomes are dominating in the market because natural exosomes are used in various biological and pathological processes as well as natural exosomes has many advantages such as good biocompatibility and reduced clearance rate compare than hybrid exosomes.

Exosome is an extracellular vesicle which is released from cells, particularly from stem cells. Exosome functions as vehicle for particular proteins and genetic information and other cells. Exosome plays a vital role in the rejuvenation and communication of all the cells in our body while not themselves being cells at all. Research has projected that communication between cells is significant in maintenance of healthy cellular terrain. Chronic disease, age, genetic disorders and environmental factors can affect stem cells communication with other cells and can lead to distribution in the healing process. The growth of the global exosome therapeutic market reflects global and country-wide increase in prevalence of autoimmune disease, chronic inflammation, Lyme disease and chronic degenerative diseases, along with increasing demand for anti-aging therapies. Additionally major factors expected to contribute in growth of the global exosome therapeutic market in future are emerging therapeutic value of exosome, availability of various exosome isolation and purification techniques, technological advancements in exosome and rising healthcare infrastructure.

Rising demand of exosome therapeutic across the globe as exosome therapeutic is expected to be one of the most prominent therapies for autoimmune disease, chronic inflammation, Lyme disease and chronic degenerative diseases treatment, according to clinical researches exosomes help to processes regulation within the body during treatment of autoimmune disease, chronic inflammation, Lyme disease and chronic degenerative diseases. This factor has increased the research activities in exosome therapeutic development around the world for exosome therapeutic. Hence, this factor is leading the clinician and researches to shift towards exosome therapeutic. In the current scenario the exosome therapeutic are highly used in treatment of autoimmune disease, chronic inflammation, Lyme disease and chronic degenerative diseases and as anti-aging therapy as it Exosomes has proliferation of fibroblast cells which is significant in maintenance of skin elasticity and strength.

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Exosome therapeutic Market Country Level Analysis

The global exosome therapeutic market is analysed and market size information is provided by country by type, source, therapy, transporting capacity, application, route of administration and end user as referenced above.

The countries covered in the exosome therapeutic market report are U.S. and Mexico in North America, Turkey in Europe, South Korea, Australia, Hong Kong in the Asia-Pacific, Argentina, Colombia, Peru, Chile, Ecuador, Venezuela, Panama, Dominican Republic, El Salvador, Paraguay, Costa Rica, Puerto Rico, Nicaragua, Uruguay as part of Latin America.

Country Level Analysis, By Type

North America dominates the exosome therapeutic market as the U.S. is leader in exosome therapeutic manufacturing as well as research activities required for exosome therapeutics. At present time Stem Cells Group holding shares around 60.00%. In addition global exosomes therapeutics manufacturers like EXOCOBIO, evox THERAPEUTICS and others are intensifying their efforts in China. The Europe region is expected to grow with the highest growth rate in the forecast period of 2019 to 2026 because of increasing research activities in exosome therapeutic by population.

The country section of the report also provides individual market impacting factors and changes in regulation in the market domestically that impacts the current and future trends of the market. Data points such as new sales, replacement sales, country demographics, regulatory acts and import-export tariffs are some of the major pointers used to forecast the market scenario for individual countries. Also, presence and availability of global brands and their challenges faced due to large or scarce competition from local and domestic brands, impact of sales channels are considered while providing forecast analysis of the country data.

Huge Investment by Automakers for Exosome Therapeutics and New Technology Penetration

Global exosome therapeutic market also provides you with detailed market analysis for every country growth in pharma industry with exosome therapeutic sales, impact of technological development in exosome therapeutic and changes in regulatory scenarios with their support for the exosome therapeutic market. The data is available for historic period 2010 to 2017.

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Exosome therapeutic Market Segmentation, Parameters, Prospects 2021 And Forecast Research Report To 2027 KSU | The Sentinel Newspaper - KSU | The...

The Latest Released Autologous Stem Cell Based Therapies market study has evaluated the future growth potential of the Global Autologous Stem Cell Based Therapies Industry and provides information and useful stats on market structure and size. The report is intended to provide market intelligence and strategic insights to help decision-makers take sound investment decisions and identify potential gaps and growth opportunities.

Additionally, the Autologous Stem Cell Based Therapies Market report also identifies and analyses changing dynamics, emerging trends along with essential drivers, challenges, opportunities, and restraints in the Autologous Stem Cell Based Therapies market, which will help the future market to grow with promising CAGR and offers an extensive collection of reports on different markets covering crucial details. The report studies the competitive environment of the Autologous Stem Cell Based Therapies Market is based on company profiles and their efforts on increasing product value and production.

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Keep yourself up to date with the latest market trends and changing dynamics due to COVID Impact and Economic Slowdown globally. Maintain a competitive edge by sizing up with available business opportunities in Autologous Stem Cell Based Therapies Market various segments and emerging territory.

The research offers detailed segmentation of the global Autologous Stem Cell Based Therapies market. Key segments analyzed in the research include Type and Application.

By Type:

By Application:

The report will include a market analysis of Autologous Stem Cell Based Therapies which includes Business to Business (B2B) transactions as well as Autologous Stem Cell Based Therapies aftermarket. The market value has been determined by analyzing the revenue generated by the companies solely. R&D, any third-party channel cost, consulting cost and any other cost except company revenue has been neglected during the analysis of the market. A comprehensive analysis will be provided covering the following points in the report:

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Top Key Players included in Autologous Stem Cell Based Therapies Market:

Region Included are: North America, Europe, Asia Pacific, Oceania, South America, Middle East & AfricaCountry Level Break-Up: United States, Canada, Mexico, Brazil, Argentina, Colombia, Chile, South Africa, Nigeria, Tunisia, Morocco, Germany, United Kingdom (UK), the Netherlands, Spain, Italy, Belgium, Austria, Turkey, Russia, France, Poland, Israel, United Arab Emirates, Qatar, Saudi Arabia, China, Japan, Taiwan, South Korea, Singapore, India, Australia and New Zealand, etc.

What benefits does the In4Research study is going to provide?

Key questions answered by Autologous Stem Cell Based Therapies market report

Table of Content For Autologous Stem Cell Based Therapies Market Report

Chapter 1. Research Objective

Chapter 2. Executive Summary

Chapter 3. Strategic Analysis

Chapter 4. Autologous Stem Cell Based Therapies Market Dynamics

Chapter 5. Segmentation & Statistics

Chapter 6. Market Use case studies

Chapter 7. KOL Recommendations

Chapter 8. Investment Landscape

Chapter 9. Competitive Intelligence

Chapter 10. Company Profiles

Chapter 11. Appendix

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2021 Updates in Autologous Stem Cell Based Therapies Industry with Global Market Demand Analysis, Industry Chain, Revenue and Forecast 2026 - The...

SPRINGFIELD, Mo. Beginning Thursday, February 25, 2021, the radar operated by the NOAA National Weather Service will be down for approximately seven days.

The planned outage is to replace the generator, fuel tanks, and accompanying components.

This update is important to support the radars operation during periods of commercial power outages, specifically when hazardous weather is present.

This generator update is the third major project of the NEXRAD Service Life Extension Program, a series of upgrades and replacements that will keep our nations radars viable into the 2030s.

NOAA National Weather Service, the United States Air Force, and the Federal Aviation Administration are investing about $150 million in the seven-year program. The first project was the installation of the new signal processor and the second project was the transmitter refurbishment. The two remaining projects are the refurbishment of the pedestal and equipment shelters. The Service Life Extension Program will complete in 2023.

During the outage, check data from adjacent radars including: Pleasant Hill/Kansas City (KEAX), St Louis (KLSX), Paducah, KY (KPAH), Memphis, TN (KNQA), Little Rock, AR (KLZK), Fort Smith, AR (KSRX), Tulsa, OK (KINX), Wichita, KS (KICT) and Topeka, KS (KTWX).

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Springfield National Weather Service radar scheduled outage coming, will last about a week - KOLR - OzarksFirst.com

Dublin, Feb. 25, 2021 (GLOBE NEWSWIRE) -- The "Global Military Aircraft Modernization and Upgrade and Retrofit Market 2020-2024" report has been added to ResearchAndMarkets.com's offering.

The military aircraft modernization and upgrade and retrofit market is poised to grow by $ 2.61 bn during 2020-2024 progressing at a CAGR of 3% during the forecast period.

The market is driven by the incorporation of CNS systems in aircraft and emergence of SVAB.

The reports on military aircraft modernization and upgrade and retrofit 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 military aircraft modernization and upgrade and retrofit market analysis includes type segment and geographical landscapes.

This study identifies service life extension of military aircraft fleets as one of the prime reasons driving the military aircraft modernization and upgrade and retrofit market growth during the next few years.

The 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 military aircraft modernization and upgrade and retrofit market vendors that include BAE Systems Plc, Elbit Systems Ltd., Honeywell International Inc., Israel Aerospace Industries Ltd., L3Harris Technologies Inc., Lockheed Martin Corp., Northrop Grumman Corp., Raytheon Technologies Corp., Thales Group, and The Boeing Co..

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

Key Topics Covered:

Executive Summary

Market Landscape

Market Sizing

Five Forces Analysis

Market Segmentation by Type

Customer landscape

Geographic Landscape

Vendor Landscape

Vendor Analysis

Appendix

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

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Global Military Aircraft Modernization and Upgrade and Retrofit Markets to 2024: Incorporation of CNS Systems in aircraft and Emergence of SVAB -...

Representational image

Can anyone perceive questions and provide answers in the midst of a vivid dream? It is possible, say researchers of a recent study whose results might sound like a real-life extension of the Hollywood blockbuster Inception.

The findings of the study indicate that it is possible for people while dreaming to follow instructions, do simple math, answer yes-or-no questions, or tell the difference between different sensory stimuli.

"We found that individuals in REM sleep can interact with an experimenter and engage in real-time communication," said researcher Ken Paller from Northwestern University in the US. According to the researcher, dreamers are capable of comprehending questions, engaging in working-memory operations and producing answers.

"Most people might predict that this would not be possiblethat people would either wake up when asked a question or fail to answer and certainly not comprehend a question without misconstruing it," Paller said. But the research shows that people in dreams could respond using eye movements or by contracting facial muscles.

For the study, published in the journal Current Biology, the researchers evaluated 36 people who aimed to have a lucid dream, in which a person is aware they're dreaming. The researchers refer to it as "interactive dreaming."

The researchers said that future studies of dreaming could use these same methods to assess cognitive abilities during dreams versus wake. Outside of the laboratory, the methods could be used to help people in various ways, such as solving problems during sleep or offering nightmare sufferers novel ways to cope, the team noted.

**

The above article has been published from a wire source with minimal modifications to the headline and text.

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Real-Time Communication with Dreaming Person Possible, Says Study | The Weather Channel - Articles from The Weather Channel | weather.com - The...

New York, Feb. 23, 2021 (GLOBE NEWSWIRE) -- Reportlinker.com announces the release of the report "Canned Soups Market Forecast to 2027 - COVID-19 Impact and Global Analysis By Type, Category, Processing, and Distribution Channel" - https://www.reportlinker.com/p06027525/?utm_source=GNW The shelf life of any canned soup is the amount of time it requires to degrade to the non-palatable state. Shelf life extension ingredients added in the canned soup products slow down the process of food degradation and enable longer storage of the food items. They are both organic and conventional in origin. Shelf life extension ingredients also aid in the keeping food logistics decongested, sustain canned soups in frozen areas, and improve consumer confidence over stability of food items. Consumers have become more aware about their diet. Health benefits such as improved immunity, lower caloric intake, and high protein intake are other factors expected to influence the product demand. Moreover, canned soups with high shelf life also comprise high content of nutrition, minerals, vitamins, and proteins. On a global level, youngsters are preferring to purchase premium goods due to health attributes and are ready to change their habits toward healthier nutrition. Canned soup made from fresh vegetables, and bone and meat has gained tremendous popularity as it offers various health benefits and nutrition as well as it has a high shelf life. In addition, consumers are opting for canned soup products over other protein sources owing to its benefits such as the presence of macro and micronutrient in good proportion with a high concentration of protein. Additionally, packed soups are majorly preferred over soups served in the restaurants and food outlets due to ease of access as well as durability of packages. Drinking canned soups or making a simple soup help add more protein into the diet and prevents one from consuming too many calories. Thus, consumers inclination toward nutrition-based canned soup drives the market growth.

In terms of category, the non-vegetarian segment led the global canned soup market in 2019.The demand for non-vegetarian canned soups is high owing to their versatile nutritional composition and high protein content.

Non-vegetarian canned soup is a rich source of protein.It is also a nutritional supplement that offers various health benefits such as weight loss, joint pain reduction, skin aging reduction, and appetite reduction.

These canned soups products contain essential minerals such as calcium and magnesium in larger amounts than other animal protein-based products. Therefore, the rising demand for healthy food & beverage products across the world drives the market growth for the non-vegetarian segment.Campbell soup company, Amys Kitchen Inc, General Mills Inc., The Kraft Heinz Company, Baxters Food Group, Unilever, Struik Foods Europe NV, Vanee Foods Company, BCI Foods Inc., and Hain Celestial Companies are among the players operating in the global canned soup market.At present, most of the regions across the world are under lockdown due to the COVID-19 outbreak.In the most-affected countries in different regions, isolation and social distancing measures have been imposed.

The lesser production of goods and commodities is hampering the growth of the global canned soup market as the demand for these products has been declined since the past couple of months.The outbreak and measures taken to contain the spread of the novel coronavirus are hindering the food & beverages industry across the world, mainly due to disruptions in supply and distribution chain.

In addition, the overall restrictions on manufacturing processes, research, and development activities are restraining the global canned soup market.The overall global canned soup market size has been derived using both primary and secondary sources.To begin the research process, exhaustive secondary research has been conducted using internal and external sources to obtain qualitative and quantitative information related to the market.

The process also serves the purpose of obtaining an overview and forecast for the global canned soup market with respect to all the segments pertaining to the region.Also, multiple primary interviews have been conducted with industry participants and commentators to validate the data, as well as to gain more analytical insights into the topic.

The participants of this process include industry experts such as VPs, business development managers, market intelligence managers, and national sales managers, along with external consultants such as valuation experts, research analysts, and key opinion leaders, specializing in the global canned soup market.Read the full report: https://www.reportlinker.com/p06027525/?utm_source=GNW

About ReportlinkerReportLinker is an award-winning market research solution. Reportlinker finds and organizes the latest industry data so you get all the market research you need - instantly, in one place.

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Canned Soups Market Forecast to 2027 - COVID-19 Impact and Global Analysis By Type, Category, Processing, and Distribution Channel - GlobeNewswire

February 24, 2021 - TheNewswire - Toronto, ON - Star Royalties Ltd. (the Company or Star Royalties) (TSXV:STRR) is pleased to announce the closing of the second installment of its previously announced US$18,000,000 gold purchase and sale agreement (the Streaming Agreement) with Arizona Gold Corp. (Arizona Gold) (TSX: AZG, OTC: AGAUF) (formerly Kerr Mines Inc.) which will be used to finance the restart of underground operations and gold production at the Copperstone Gold Mine (Copperstone) in Arizona, USA.

Alex Pernin, Chief Executive Officer of Star Royalties, commented: With the closing of Tranche 2 and an expected operational restart in less than one year, this gold stream represents significant, near-term cash flow from a highly prospective deposit in a world-class jurisdiction. We have great confidence in both Copperstones potential and Arizona Golds ability to execute a successful restart of operations. We continue to look forward to working closely with their team as we transition Copperstone into Arizonas next producing gold mine.

The US$18 million advance payment under the Streaming Agreement is being provided in three equal installments, with the first two US$6 million installments having now been advanced. The final US$6 million installment will be payable on or before April 30, 2021, subject to certain closing conditions.

Summary of Transaction Terms

Star Royalties will purchase from Arizona Gold an amount of refined gold equal to 9.9% of gold produced at Copperstone until a cumulative 21,000 ounces of refined gold are delivered, then 3.3% of gold produced until a cumulative 27,200 ounces are delivered, and 1.2% of gold produced thereafter for the remaining life of mine.

In addition to the US$18 million advance payment, Star Royalties will provide a cash payment to Arizona Gold for each ounce of gold delivered equal to 25% of the average London Bullion Market Association gold spot price (PM) for the five consecutive trading days prior to delivery. Arizona Gold has granted security over all of its assets to the Company to secure the obligations of Arizona Gold to the Company under the Streaming Agreement.

In connection with the advance of the second tranche of US$6 million, Arizona Gold entered into an amended and restated royalty purchase agreement with Trans Oceanic Mineral Company Ltd. (TOMCL) providing for the purchase of a 3% gross production royalty on Copperstone for US$2.5 million. Upon completion, the purchase will reduce the aggregate gross royalties on Copperstone from 6% to 3%, consisting of a remaining 1.5% royalty which will continue to be held by TOMCL and a 1.5% royalty held by Angie Patch Survivor's Trust. Completion of the repurchase is subject to the satisfaction of all conditions to the advance by Star Royalties of the third US$6 million installment under the Streaming Agreement.

CONTACT INFORMATION

For more information, please visit our website atwww.starroyalties.comor contact:

Alex Pernin, P.Geo.

Chief Executive Officer and Director

This email address is being protected from spambots. You need JavaScript enabled to view it.

Peter Bures

Chief Business Development Officer

This email address is being protected from spambots. You need JavaScript enabled to view it.

+1 647 360 4793 +1 437 997 8088

ABOUT STAR ROYALTIES LTD.

Star Royalties Ltd. is a precious metals royalty and streaming investment company. The companys objective is to provide wealth creation through accretive transaction structuring and asset life extension with superior alignment to both counterparties and shareholders. With a strategy to also invest in green opportunities, Star Royalties pioneered the first forest carbon credit royalty and is pursuing a pipeline of additional green investments.

CAUTIONARY NOTE REGARDING FORWARD-LOOKING INFORMATION

Certain statements in this news release may constitute "forward-looking statements", including those regarding future market conditions for metals and minerals. Forward-looking statements are statements that address or discuss activities, events or developments that the Company expects or anticipates may occur in the future. When used in this news release, words such as "estimates", "expects", "plans", "anticipates", "will", "believes", "intends" "should", "could", "may" and other similar terminology are intended to identify such forward-looking statements. Forward-looking statements are made based upon certain assumptions and other important factors that, if untrue, could cause the actual results, performances or achievements of Star Royalties to be materially different from future results, performances or achievements expressed or implied by such statements. Forward-looking statements should not be read as a guarantee of future performance or results and will not necessarily be an accurate indication of whether or not such results will be achieved. A number of factors could cause actual results, performances or achievements to differ materially from such forward-looking statements, including, without limitation, changes in business plans and strategies, market conditions, share price, best use of available cash, the ability of the Company to identify and execute future acquisitions on acceptable terms or at all, risks inherent to royalty companies, title and permitting matters, metal and mineral commodity price volatility, discrepancies between actual and estimated production, mineral reserves and resources and metallurgical recoveries, mining operation and development risks relating to the parties which produce the metals and minerals Star Royalties will purchase or from which it will receive royalty payments, regulatory restrictions, activities by governmental authorities (including changes in taxation), currency fluctuations, the global social and economic climate, natural disasters and global pandemics, dilution, and competition. These risks, as well as others, could cause actual results and events to vary significantly. Accordingly, readers should exercise caution in relying upon forward-looking statements and the Company undertakes no obligation to publicly revise them to reflect subsequent events or circumstances, except as required by law.

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Star Royalties Closes Second US$6 Million Installment of US$18 Million Stream Financing for the Restart of the Copperstone Gold Mine - Junior Mining...

RNSKLDSVIK, Sweden--(BUSINESS WIRE)--BAE Systems has received an order from the Norwegian Army for 20 additional CV90 Infantry Fighting Vehicles to increase the combat power of its existing fleet. The Norwegian Defense Materiel Agency awarded the more than $50 million contract that will increase the Armys fleet to 164 vehicles as part of its effort to grow and modernize in the face of evolving threats.

Norway is one of seven CV90 users and is the latest customer to enhance its fleet of combat-proven CV90s following significant life extension and mid-life upgrade contracts from Switzerland and the Netherlands. The new Norwegian order for 12 engineering and eight multi-carrier CV90 variants is scheduled for delivery in 2023.

We look forward to fielding another 20 modern CV90 combat support vehicles into the Norwegian Army, said Brigadier yvind Johan Kvalvik, Norwegian Defence Materiel Agencys Land Systems Division. These additional vehicles will provide the Norwegian Army with the room for maneuver and combat power that the Army needs to be able to complete its missions using the most modern IFV vehicles in the world.

BAE Systems Hgglunds, the manufacturer of the CV90 based in rnskldsvik, Sweden, will deliver the new vehicles in cooperation with Ritek, an established Norwegian CV90 partner. With Ritek at the center of the local industrial cooperation hub, up to 30 potential Norwegian suppliers will be responsible for upgrading and repairing components, as well as delivering new subsystems and technology solutions as part of future upgrades for the Norwegian CV90 fleet.

We have a strong track record of delivering on time, at cost, and high quality to the Norwegian Army. This follow-up order demonstrates the importance of successful relationships with in-country industry partners like Ritek, said Tommy Gustafsson-Rask, managing director of BAE Systems Hgglunds. As we work to enhance the Norwegian Armys existing fleet of CV90s, deepening our existing relationships with local industry will naturally benefit our end users.

BAE Systems has a successful history of industrial cooperation projects in Norway that have strengthened industry partnerships, transferred technical know-how, and exceeded customer expectations and requirements. During the latest CV90 procurement and upgrade contract, BAE Systems Hgglunds delivered 100 percent offset obligation five years ahead of schedule.

BAE Systems and Ritek look forward to strengthening their relationship through the successful execution of this contract. Our cooperation with the Norwegian Armed Forces and BAE Systems Hgglunds is based on trust and experience between all parties involved. We are very pleased with this new agreement which brings a positive local employment effect for Ritek as we focus on delivering this critical capacity to the Norwegian Army in the form of more combat support vehicles, said Hilmar Olsen, general manager at Ritek. We also expect the project to provide long-term opportunities for several other Norwegian suppliers across the country.

Norway is one of seven European users operating the CV90. The others are Denmark, Estonia, Finland, Switzerland, Sweden and the Netherlands. With close to 1,300 vehicles in service in multiple variants, the vehicle is combat-proven and designed to accommodate future growth to meet evolving missions.

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Norwegian Army Adding 20 CV90s to Its Fleet - Business Wire

When last years Nobel prize for chemistry was awarded to biochemist Jennifer Doudna and microbiologist Emmanuelle Charpentier for their work in developing the technique of gene editing known as Crispr-Cas9 (pronounced crisper), headlines hailed their discovery as molecular scissors that would allow us to rewrite the book of life with all the complicated ethical questions that ability raises. But much of the excitement has nothing to do with visions of designer babies. The real promise of Crispr is for treating diseases caused by genetic mutations, from muscular dystrophy to congenital blindness, and even some cancers.

The first human trials of Crispr therapies are happening already, and researchers hope that they are on the brink of reaching the clinic. The speed at which Crispr research has progressed has been truly astonishing, says Doudna from the University of California at Berkeley.

Many common diseases, including heart conditions, Alzheimers and diabetes, are partly caused by genes: people who inherit the wrong variants of certain genes are more vulnerable. For many of these conditions the genetic component is complicated: many genes are involved. Other diseases, such as cystic fibrosis, might be caused by the malfunction of just one or a few genes. In that case, the disease might be cured entirely by gene editing: replacing the faulty genes with the healthy variant.

This gene therapy approach has been a goal ever since scientists first began learning how to edit genes in the 1970s. But it has never yet lived up to the hype, because editing one gene among about 21,000 others in the DNA of each of our cells is hard. It requires very accurate tools for finding the gene, snipping the DNA at that point, and then stitching in a new gene (or fragment of one) in its place.

Biologists have been able to make such edits for decades, but not precisely enough for safe clinical use. If editing is too messy or inadvertently alters other genes too, the consequences could be dire in particular, an unintended mutation could trigger cancer.

Crispr changed all that. The technique uses an enzyme molecule called Cas9, first found in bacteria, which can be reliably programmed to find its target. It carries with it a piece of genetic material called RNA, similar to DNA, which holds the sequence of the target site. When the enzyme finds the DNA sequence matching that on its RNA reference strand, it snips the DNA double helix in two. Other enzymes can then insert another piece of DNA encoding the healthy sequence, say into the break.

When the Crispr system was first reported in 2012 by Doudna, Charpentier and other researchers, the unprecedented accuracy of gene-editing it permitted quickly began to transform the possibilities for tailoring a genome the sum of an organisms DNA to order. The roles and effects of genes could be deduced by cutting them out or modifying them.

Some researchers hope we can use Crispr to boost our immune system so that it is better at destroying cancer cells

Crispr also made gene-editing more viable for medicine. The first diseases researchers are looking at, Doudna says, are those that require a simple change in a single gene and in a cell or tissue that we can target easily. As its a new and expensive approach, she adds, it makes sense to prioritise diseases for which no other treatments exist.

Some blood disorders, such as sickle-cell anaemia and beta thalassemia, fit the bill. In sickle-cell disease, a mutation in the gene for haemoglobin (the oxygen-carrying protein in red blood cells) changes the cells shape, causing problems with blood flow. In a procedure developed by a hospital in Tennessee, last year a Mississippi woman named Victoria Gray became the first person to receive an experimental Crispr treatment for sickle-cell anaemia. Blood-forming stem cells from her bone marrow were collected and treated outside her body to alter a gene involved in haemoglobin production, before being transfused back. So far the treatment seems to be successful: Gray has not needed the regular blood transfusions or hospitalisations her condition previously necessitated.

She is now taking part in trials on Crispr treatments of both sickle-cell disease and beta thalassemia conducted in Boston by Crispr Therapeutics in collaboration with Vertex Pharmaceuticals. Doudna warns, however, that the early therapies are going to be quite expensive. Lowering the cost is one of the key aims of her Innovative Genomics Institute at Berkeley. Having a cure for sickle-cell disease that few people can afford is not a solution to the problem, she says.

One great attraction of Crispr, says Niren Murthy, a bioengineer at Berkeley, is that it could be a one-shot affair. You have the treatment and the gene is fixed for good, rather than you having to return to the doctor every few months. Whats more, the gene-editing doesnt have to be particularly efficient to work. With sickle-cell disease, it appears that correcting the mutation in just 5% of a patients stem cells would be enough to have a positive clinical effect, says Doudna. Were aiming for much higher than that, of course the more you can target your treatment, the higher the efficiency.

One key advantage in treating these diseases is that its easy to get the Crispr system to the right place: the blood. For editing other tissues, the challenge is to cross the barrier between the bloodstream, where a drug would be introduced, and the cells of the tissue. If you just inject the molecular components into the blood, they get quickly degraded by the bodys immune system. Its better to load them into some tiny vehicle or vector such as synthetic particles or disabled viruses (thats how the active ingredients of Covid vaccines are delivered). But these tend to be too large to get through membranes and into tissues. The delivery problem is very large, Murthy says. If someone was able to solve it, that would open up a lot more therapeutic opportunities.

Five years ago, the prospect of correcting a single base pair that causes afatal genetic disease seemed like science fiction

Some researchers hope that Crispr can combat cancer. One approach would use gene-editing to boost our immune system so that it is better at destroying tumour cells. Such cancer immunotherapy is already showing great promise, but Crispr could make it more efficient or effective, says Doudna. The basic concept is to edit a patients T-cells [a type of white blood cell central to the immune response] and reintroduce them to the bloodstream so that they can recognise and attack cancer cells.

The first human trial for Crispr-boosted (lung) cancer immunotherapy happened in China in 2016. There have also been efforts to treat some types of blood and bone cancers this way. But its too early to say how effective the treatments are, Doudna says. Another option is to use Crispr to disable cancer cells themselves but again, the challenge is getting the gene-editing machinery into tumours. For blood cancers such as leukaemia, Murthy points out, this delivery problem doesnt arise.

Atherosclerosis (a cause of stroke and heart disease) is another important target. Some people have a genetic vulnerability to it because their cells produce too much of a protein called PCSK9, which stops a molecule called LDL cholesterol from being broken down. High levels of LDL cholesterol can create hardening of the arteries, which in turn may induce heart failure.

Cholesterol breakdown takes place in the liver, which is one of the few tissues for which good drug-delivery vehicles have been developed. That makes PCSK9-related atherosclerosis an ideal target for Crispr therapy. Last year, the US biotech startup Verve, based in Cambridge, Massachusetts, began trialling this approach, using artificial nanoparticles made from fatty lipids to ferry the gene-editing molecules to the liver. Cambridge-based Intellia, meanwhile, is exploring Crispr therapies for sickle-cell, haemophilia and some rare genetic heart conditions.

Yet another Cambridge-based gene-editing company, Editas, has begun a trial in collaboration with Dublin-based Allergan that uses Crispr to treat the most common form of inherited childhood blindness, called LCA10. Unlike the earlier sickle-cell and cancer treatments, this one introduces Crispr directly into the body in this case by injecting it, inside a virus, into the eye. The eye is a good target, Doudna says, because it has certain characteristics that make genome-editing less likely to have unwanted side-effects. Well learn a lot from this trial, she adds, and Im excited to see the results.

Murthy is working on a Crispr treatment for Duchenne muscular dystrophy, one of the most common and severe forms. It is caused by mutations of a gene that produces dystrophin, which is involved in building muscles, and results in the wasting away of muscle fibres, leading to disability and death. But he suspects that Crispr therapy may first see wide clinical use for neurological genetic conditions such as Huntingtons disease, because brain tissue turns out to be easier to edit than muscle.

Treating different diseases might demand different kinds of gene-editing. The simplest approach is to just mess up a gene so it doesnt work. When Cas9 snips a DNA strand, the cells DNA-repair machinery doesnt just stitch it together again; typically it shaves a bit off the strands, as if cleaning up the ragged ends. The rejoined gene is then generally useless and sometimes thats all you need. Some editing jobs call for a more precise molecular scalpel, however.

For most genetic diseases, precise gene correction, rather than disruption, is needed to benefit patients, says David Liu of the Broad Institute of the Massachusetts Institute of Technology and Harvard University. Over the past few years, he has developed a way of using Cas9 to make precise changes to just a single one of the molecular units called bases that encode genetic information. Sometimes, as in sickle-cell disease, thats all it takes to make a mutation dangerous. Lius so-called base editors use a modified version of Cas9 that can target DNA in a programmed way but doesnt cut it, in conjunction with other molecules that then swap a single base at the target site.

Liu and his colleagues are using their base editors to treat a devastating condition called progeria, which causes very rapid ageing and eventually death in children born with a mutation to a gene called lamin A. This too is caused by a single base change, but the mutant protein it produces can damage nearly all the cells in the body. Its not enough to just damage mutant lamin A, since the uncontrolled mixture of products that results could still be lethally toxic. You need instead to precisely correct the lone rogue base.

Lius team has done this in mice genetically altered to carry the human form of mutant lamin A. They treated the animals 14 days after birth equivalent to about age five in humans and found that the mice lived until the beginning of old age for normal mice. As we realised the extent of the disease rescue was well beyond what had been achieved before, we started freaking out, says Liu.

Five years ago, the prospect of correcting a single base pair in a living animal that causes a fatal genetic disease, with a one-time treatment of an engineered molecular machine, seemed like science fiction, he says. His team is now working with Beam Therapeutics (also in Cambridge, MA) and with Verve in Cambridge to develop these tools for clinical applications in humans; Verve is using base editors for its work on atherosclerosis.

Although Murthy says that widespread clinical use of Crispr therapies is still five to 10 years down the line, Doudna admits to being constantly amazed at how quickly Crispr genome-editing has been adopted by researchers around the world. Usually, clinical trials can take a long time, she says. So the fact that, thanks to Crispr, we have people today who appear to be cured of sickle-cell disease is surprising in the best way.

This article was amended on 23 February 2021 to clarify that the guide molecule for Crispr is simply RNA rather than mRNA.

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After the Nobel, what next for Crispr gene-editing therapies? - The Guardian

Fourteen-month old Fatima who was suffering from a killer disease has got a new lease of life after USD 2.1 mn treatment at Bengaluru hospital. Fatima faced a bleak future afflicted with a killer muscular disorder, but a Rs 16 crore 'revolutionary' gene therapy she underwent at a city hospital after winning a 'lottery' has given her a new lease of life.

Fatima, daughter of Mohammed Basil and Khadija from Bhatkal town in the coastal Uttara Kannada district in Karnataka, is recovering after she was given 'Zolgensma', the gene therapy at Bangalore Baptist Hospital late last month, as per a report in PTI.

She emerged "a lucky winner of a lottery" through a compassionate access programme by drug major Novartis that helped her get the costly treatment, affordable only by multi-millionaires, the hospital said.

Rs. 16 crore: Cost of injection

"The cost of this medicine is about 2.1 million US dollars, which is roughly about Rs. 16 crore," hospital Director (CEO) Naveen Thomas said. "There is gradual improvement. She is now able to move her leg. It will take time to become like a normal child," her father Basil said, as per a report in PTI.

Spinal Muscular Atrophy or SMA

The toddler was diagnosed with Spinal Muscular Atrophy or SMA, a disease caused by loss of nerve cells, which carry electrical signals from the brain to the muscles.

The protein needed for this signaling is coded by a gene for which everyone has two copies --- one from the mother and the other from the father, according to Thomas.

He said a child develops this disorder only if both the copies were faulty and without treatment, this disease was ultimately fatal. But the problem is that the treatment is out of reach of most people. "Only multi-millionaires can afford it! Current treatment options range from medicines, which increase these proteins to replacing the faulty gene. Zolgensma, a gene therapy is a revolutionary treatment, which aims at curing the disease by replacing the faulty gene", he said.

"For the first time in Karnataka, Zolgensma was given at Bangalore Baptist hospital to a child who was the lucky winner of a lottery through a compassionate access programme by Novartis", Thomas said.Incidentally, the couple had earlier lost a child, who was also suffering from SMA.

"On the 21st day of the 21st year of the 21st century, the baby was given the injection, which is a one-shot cure for this rare disease, said Dr Ann Agnes Mathew, Consultant Paediatric Neurologist and Neuromuscular Specialist.

At present there were about 200 children getting treatment in the Baptist Hospital which is specialised in genetic diseases, more specifically SMA and Duchenne muscular dystrophy (DMD), said the doctor.She added that previous year alone, 38 children who were getting treatment in the hospital breathed their last in the absence of this expensive treatment.

In Fatima's case, Thomas said: It is a dream come true for doctors in this field. We hope more children receive this treatment and many such treatments will become affordable in the future."

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Lucky winner! Rs 16 crore lottery gives new lease of life to 14-month-old Fatima - Zee Business

Tech is booming, big-time. We saw its strength reflected in the stock market in 2020, despite a global pandemic. In a world gone virtual, it was a lifeline for businesses and people alike.

Seemingly overnight, COVID-19 disrupted our assumptions and forced us to become more adaptable and responsive than we had previously thought possible. Comfortable plans for the future were condensed from years into weeks, said Bill Briggs, the global chief technology officer of Deloitte Consulting, of the acceleration of digital transformation last year. While the growth was uncomfortable at best, its driven important change.

We know the future will look vastly different from today, and technology is a critical path to our tomorrow. As our next normal plays out, emerging tech will continue to reshape how we live and work. In Dallas-Fort Worth, organizations large and small are working to meet new needs and identify rising opportunities.

Heres a look at 14 major trends and some of the key players leading the innovation charge in the region.

[Image: 3disometric/iStockphoto]

Intelligent machines and smart data can transform our world. This tech trioartificial intelligence, machine learning, and data analyticsis the glue behind other trends on our list. Separately and together, they play a role in everything from public safety (Tyler Technologies) to financial services (Capital One, Goldman Sachs, JP Morgan, to name a few). Deloitte, in its 12th annual tech trends report, calls data the art of the possible. Human capacity can be augmented at scale if enterprises can move toward automation and machine-led decision making, the consultancy says. In healthcare, Pieces Technologya startup launched in 2016, spun out of Dallas Parkland Health and Hospital Systemuses cloud-based AI with natural language processing and doctor-supervised machine learning to interpret patient information to support healthier outcomes. Dallas-based Worlds, which emerged from stealth last year, announced a COVID breath-testing device using AI and high-tech sensors that provides nearly instant results. The device could have application for other outbreaks and diseases well beyond Covid-19. Texas-based Hypergiant Industries, with offices in Dallas and Austin, is launching a constellation of satellites with the United State Air Force that can update, collect, and share data in spaceon the fly. For networking and resources in these specialized fields, a local meetup group, WiMLDS, supports and promotes women and gender minorities.

[Image: istockphoto]

IoT, another synergistic cluster of technologies driven by 5G and fueled by data, is ushering in Industry 4.0. An ever-growing number of connected devices make our homes comfortable (Honeywell) and track assets across the globe (Polte). IoT and sensor-based tech has applications in every sector: industrial, healthcare, real estate, and more, according to Cisco, which offers services including remote monitoring with Industrial Asset Vision. AT&T and Microsoft also teamed on an IoT guardian device that connects to the cloudbypassing public internet. IoT Texas, a monthly meetup run by Ed Hightower, recently hosted Taubyte, which emerged from stealth with its smart computing platform.

[Photo: Rawf8/istockphoto]

Hailed as the connectivity of the future, 5G brings speed and capabilities that will boost other technologies including AI and IoT. The orders-of-magnitude performance boost that 5G promises doesnt happen very often, according to a Deloitte report last year. In DFW, youll find major players like AT&T, Verizon, and T-Mobile investing in the technology. Huawei notes 5G makes possible zero-distance computing. Earlier this year, networking pioneer DZS moved from Oakland to Plano, launching a new 5G R&D center. Ericsson also built the countrys first 5G smart factory in Lewisville, producing its first base stations that enable rapid 5G deployments. And in May, Nokia said it achieved world-record 5G speeds in its local lab.

Image: Zapp2Photo via iStock

Banking isnt the only industry that could be transformed by distributed ledger tech, according to CB Insights: Watch for law enforcement, rideshare, insurance, and gaming to be impacted. Beyond its beginnings in cryptocurrency, a virtual ledger is a secure way to store, authenticate, and protect data. This year, Dallas DLT startup Hedera Hashgraph and The Coupon Bureau took the more-than-century-old coupon industry into the digital age by creating universal digital coupons. Another startup, GreenLight Credentials, was chosen to provide its blockchain platform to the Texas College Bridge. Now more than 6,000 students will be able to electronically share records directly with colleges. In cryptocurrency, Dallas startup Zabo builds tech to help financial services companiesbanks, brokerage firms, fintechsconnect to customers crypto wallets.

[Illustration: Selim Dnmez/iStock]

Experimentation that might be too expensive (or risky) in the real world is made possible by digital twin technology that creates a digital copy of a physical object, process, or environment. This year, Jacobs created a twin of a water reclamation plant in Singapore in an R&D project, and River Logic used its supply chain tech to create a twin of multinational tobacco company Philip Morris Internationals global manufacturing footprint. UTD also formed the Digital Twin Health AI Consortium with plans to advance precision medicine. In Fort Worth, Bell opened its new Manufacturing Technology Center. The MTC, a proving ground for Future Vertical Lift aircraft, will twin itself to communicate operational details about its equipment and processes. In Plano, Siemens PMS, which announced a partnership with Team Penske to support its IndyCar series in 2018, has created digital twins of race cars allowing engineers to try out design concepts virtually to streamline designs and speed results

[Illustration: bestbrk/istockphoto]

CRISPR has revolutionized life sciences. Gene editing and genomic breakthroughs coupled with artificial intelligence could change the face of healthcare. At the North Texas Genome Center in Arlington, scientists are unlocking human DNA through genome sequencing to create databases that would inform doctors of the right care approach. During the pandemic, the center has used its testing capabilities to run up to 500 COVID tests a day to serve the campus and community. In Bedford, Nanoscope Therapeutics is advancing gene therapy using light-sensitive molecules and light-assisted gene delivery. Its mission? Giving sight to the blind. In Irving, Caris Life Sciences tech developed a Genomic Profiling Similarity Score to compare molecular characteristics of a patients tumor against Caris extensive database. Caris profiling tool for tumors uses over 6,500 mathematical models in a machine-learning algorithm. Bio North Texas, a Dallas Innovates partner organization, is a hub for connections and resources in life sciences. The nonprofit organization hosts an annual event each fall, the iC3 Life Sciences Summit.

[Image: IgorKirillov via istockphoto]

The field of smart voice, speech, and language processing lets machines recognize human language. From chatbots to Alexa and Siri, its been a game changer for how businesses interact with customers. Next-gen NLP is now being used in industrial IoT. North Texas startups are using the tech for myriad solutions: Illuma Labs offers real-time voice authentication, Briocare helps seniors age in place with the assistance of smart voice tech, and woman-owned SalesBoost uses patented voice tech to train teams with on-demand learning. Enterprises like Toyota see an application for the future of mobility, employing engineers who design, develop, and test voice recognition solutions.

[Photo: metamorworks/istockphoto]

Autonomous vehiclescars, trucks, aircraftare on the way to commercial viability. In DFW, companies in the space range from Toyota to Bell to Waymo. Autonomous activity is coming, says Hillwoods Bill Burton, and DFW is well suited to benefit from it. Driverless tech startup TuSimple recently expanded into AllianceTexas Mobility Innovation Zone. Earlier this month, Hillwood and Bell completed the first point-to-point unmanned aircraft delivery in North Texasshowing the future capabilities of commercial operations. In Dallas, FusionFlight had the first successful flight of its small-but-powerful autonomous drone with vertical take-off and landing called JetQuad, after three years of extensive development.

[Image: WhataWin/istockphoto]

Protecting computers from theft or damage to electronic data, software, or hardware became even more important in 2020 as work-from-home accelerated use of the cloud, which boosts file sharing and potential cyber-attacks. Trend Micro, a Japanese firm with its U.S. headquarters in Dallas, recently announced the worlds first security tool for cloud-native file storage. Other local firms include CRITICALSTART, HCL Technologies, QED Secure Solutions, and Jacobs. In education, UTD and SMU offer masters degrees and cutting-edge intel on stopping cyber threats.

[Photo: metamorworks via iStock]

AI tech allows computers to understand and tag images, including individual faces. Its now used in driverless cars, fintech, retail, medical diagnostics, agriculture, and more. NEC, a Japanese company with its U.S. headquarters in Irving, is an industry leader in advanced recognition systems for retail, government, and travel. Others, such as Omnigo Software, provide facial recognition for police and schools. UTD is pioneering research on racial bias in the technology. Local meetup Amplified Vision shares and creates computer vision projects.

The University of Texas at Arlington has awarded four research grants. Shown is the Buddy social robot. Photo Courtesy University of Texas at Arlington

Cobotscollaborative robots, designed to work with humans in shared spacesand robots, often used in industrial settings, are multiplying thanks in part to the pandemic. Locally, APS uses cobots to clean floors and sanitize offices. Hilti built the ceiling-hole-drilling Jaibot, and RoboKinds robots help children with autism. AT&T worked with San Antonio-based Xenex on germ-zapping robots for hospitals. Richland Hills startup MZ Motion is poised to provide some of the mechanical makings to collaborative robotics with its patented motion systems. In education, UT Arlington Research Institutes Automation and Intelligent Systems efforts focus on advanced robotics, while UTD uses robots to deliver food.

[Image: KrulUA via iStock]

Coming on strong is robotic process automation, which uses computer software robots to do mundane and repetitive digital tasks to free up employees for more complex work. Its used in many industries, including financial services, healthcare, and telecom. Plano-based ABIA uses RPA to streamline workflows. Its automation anywhere provides AI-enhanced RPA solutions. Startup Ant Brains created Krista, a conversational intelligent process RPA platform, for identity management, and more. This year, Dallas-based EPSoft RPA was used to improve COVID-related safety in the workplace.

[Illustration: DKosig/istockphoto]

Quantum computers use the principles of quantum theory to solve complex computational problems. Atos, a French company with its U.S. headquarters in Irving, is a global pioneer in building Quantum Learning Machines for commercial purposes, such as portfolio management and logistics. In education, SMU recently received a $1 million grant to advance quantum-related cybersecurity devices. A team at UT Dallas just developed a technique for atomically precise manufacturing (APM) of silicon quantum devices to scale production. Richardson-based Zyvex Labs also focuses on APM. Quantum computing has game-changing implications for cybersecurity, as well:Math will no longer protect your data, said cyber threat expert Doug Peckover, who is now co-founder of Kloke.ai, in a previous interview. Encryption that would normally take millions of years to crack could be done in seconds with a quantum computer, he said.

Adaptive3D focuses on creating strain-tolerant materials used for additive manufacturing. [Photo: Courtesy Adaptive3D]

Nanotechnology is the use of matter on an atomic or molecular scale for medical or industrial purposes. In 2020, Orthofix Medical got FDA clearance for its 3D-printed bone screw that uses a nano-surface to stabilize the joint. Coppell-based Peak Nanosystems, which closed a $25 million Series C this year, plans to expand the development of its nanolayered film used in optical lenses. OncoNano develops nanotech-enabled fluorescent probes for cancer surgery. UNT and UTA offer degrees in materials science and engineering. Alpine Advanced Materials offers a lightweight alternative to aluminum for aviation and other industries.

WHAT ARE YOU INNOVATING? Let us know.

A version of this story was originally published in Dallas Innovates 2021: The Resilience Issue.

Our fourth annual magazine, Dallas Innovates 2021: The Resilience Issue, highlights Dallas-Fort Worth as a hub for innovation. The collective strength of the innovation ecosystem and intellectual capital in Dallas-Fort Worth is a force to be reckoned with.

Sign up to keep your eye on whats new and next in Dallas-Fort Worth, every day.

North Texas research universities will offer their expertise in artificial intelligence, composite materials, wireless vehicle tech, IOT, big data, and more. Under the umbrella of the Texas Research Association, the new center aims to solve mobility challenges faced by industry, nonprofits, municipalities, and transportation agencieshere and beyond.

The collective strength of the innovation ecosystem and intellectual capital in Dallas-Fort Worth is a force to be reckoned with.

There are plenty of things to do withyourphysically distanced time. Here are a few from our curated selection.

From Amazon hiring in Oak Cliff to great places to work in DFW and Texas, here are our 10 most-read stories in May.

In the fourth installment of a five-part series, Capital One shines a spotlight on nonprofit innovation in 2020.

Link:
14 Emerging Tech Trends for 2021and Dallas-Area Companies That Are Innovating for the Future Dallas Innovates - dallasinnovates.com

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var fullDuration = rawVideoElem.duration * 1000; var current_time = Math.floor(rawVideoElem.currentTime); console.log("raw timeupdate: " + fullCurrent + " out of " + fullDuration); if ( current_time > 0 && ( fullCurrent >= (fullDuration - 50) )){ var currId = playerState.VIDEO_ID; var newMediaId = WVM.getNextPlaylistIndex(currId); if(newMediaId){ console.log("loading new video from rawtimeupdate"); WVM.load_video(newMediaId, true, playerState.ORIGINAL_ID); } } if(!$('.vjs-loading-spinner').hasClass('badspinner')){ $('.vjs-loading-spinner').addClass('badspinner') } }; } WVM.reinitRawEvents = function(playerId){ var playerState = WVM['player_state' + playerId]; var rawVideoElem = document.getElementById('html5-video-' + WVM['player_state' + playerId]['ORIGINAL_ID'] + '_html5_api'); //COMPLETE EENT if( WVM['player_state' + playerId].COMPLETE_EVENT){ rawVideoElem.removeEventListener('ended', WVM.rawCompleteEvent, false); } rawVideoElem.addEventListener('ended', WVM.rawCompleteEvent, false); //TIME UPDATE EVENT if( WVM['player_state' + playerId].TIMEUPDATE_EVENT){ rawVideoElem.removeEventListener('ended', WVM.rawTimeupdateEvent, false); } rawVideoElem.addEventListener('ended', WVM.rawTimeupdateEvent, false); WVM['player_state' + playerId].COMPLETE_EVENT = true; WVM['player_state' + playerId].TIMEUPDATE_EVENT = true; };

MILWAUKEE (CBS 58) --- Our genes tell the story of us - who we are at the molecular level.

Recent advances in genetic testing are giving patients and their doctors insight about their bodies that would have been impossible a generation ago.

Joining CBS 58 Morning News is 23-And-Me genetic trends expert Jhulianna Cintron and Marc Lovicott, a Madison man who has benefitted from the technology.

Excerpt from:
Experts say genetic testing can play a role in your overall health and well-being - WDJT

This article was originally published here

Gynecol Oncol. 2021 Feb 19:S0090-8258(21)00150-5. doi: 10.1016/j.ygyno.2021.02.013. Online ahead of print.

ABSTRACT

OBJECTIVES: Genetic testing (GT) companies have developed patient education videos to supplement or replace pre-test genetic counseling (GC) by certified genetic counselors (CGC). The aim of this study was to assess the quality of these videos compared to the standard of care (SOC).

METHODS: Videos from four major GT companies were selected from an internet search identifying pre-test patient education videos. A scoring rubric with 22 questions and 36 total points was devised to assess quality metrics, as described by the National Cancer Institute and National Society of Genetic Counselors. Twenty-two individuals with varying genetics expertise (3 gynecologic oncologists, 3 academic generalists, 4 CGC, a genetics community health worker, 3 cancer care navigators, and 8 medical students) scored each video. Scorers were blinded to others assessments.

RESULTS: Invitae had the highest median score (26/36), followed by Myriad (22/36), Ambry (17.5/36), and Color (15/36). All videos scored highly in explaining DNA basics, cancer development, and hereditary cancer predisposition. All addressed benefits of GT but failed to address potential disadvantages. All scored poorly in explaining medical terms and different GT options. There was variability in addressing patient concerns including cost, privacy, and procedure.

CONCLUSIONS: There is significant variation in the content of pre-test patient education videos between GT companies. None of the videos met the SOC for pre-test GC, and none addressed disadvantages of GT, possibly due to a conflict of interest. With improvement in content, accessibility, and use of interactive platforms, these videos may serve as an adjunct to in-person pre-test GC.

PMID:33618842 | DOI:10.1016/j.ygyno.2021.02.013

View original post here:
The role of the genetic testing industry in patient education of hereditary cancer: An observational study assessing the quality of patient education...

Othman Laraki, the chief executive of Color, is tired of having his company pigeonholed.

Often grouped into the broader personal-DNA-testing space with 23andMe and Ancestry, the company formerly known as Color Genomics now prides itself on its efforts in population health that provide software to public health entities and health systems with genetic screening tests as part of a larger package deal. In January, Color raised $167 million in a Series D round that valued the company at $1.5 billion, giving it "unicorn" status.

"From our perspective, we have actually thought about genetics in a way that's different from almost any other company on the market," Laraki told Insider. "Our business strategy has never been about direct-to-consumer testing."

Before the pandemic, Color had already secured high-profile partnerships including with the National Institutes of Health, Chicago's NorthShore University Health System, and Alphabet's life sciences arm Verily, giving consumers access to genetic testing through hospitals and employers. Color's genetic database that it shares with researchers includes 54,000 individual genomes, according to the company's research arm.

When coronavirus hit the US last March, the Burlingame, California-based company made major pivots to fight the pandemic, starting with offering testing in San Francisco. In September, its self-swab COVID-19 test received the FDA's OK for emergency use.

Expanding on its existing health technology platform, Color now provides the software infrastructure for all of California's COVID-19 testing labs, as well as other major cities, school systems, and corporate employers like Foster Farms. To date, it's processed over 3.5 million COVID-19 tests.

"We're doing what is probably actually the biggest rollout in the country of COVID testing access points," Laraki said, adding that Color has also begun coordinating data for California vaccination sites as part of the statewide vaccination campaign.

With Insider, Laraki went deep on the future of personal genetic testing and how genetics will integrate into a larger push to address population health. Color's expansion into handling logistics and supply chain considerations via software is indicative of the company's shift.

Going forward, Laraki considers Color a health services company that contributes to larger-scale public health initiatives, rather than simply a personal genomics company.

In January 2020, Laraki told Insider that the consumer testing market boom had essentially run its course.

Today, he feels exactly the same. Companies in the space have needed to diversify their offerings, recent 23andMe SPAC deal aside, and Color is no exception.

For Laraki, the pandemic has made him realize Color's main product isn't genetic tests it's the health tech infrastructure. Through software coordinating the collection of health data from typically hard-to-reach communities and genetic screening, he said he believes Color has the ability to increase access to preventive care, a major goal of public health.

When the company began working to deliver and process COVID-19 tests, Laraki said the team realized that the software they had built to process genetic tests could also deliver basic health care services to underserved populations. Color's expansion into health care infrastructure can be seen as part of a broader public health mission, he said, because it expands access to healthcare via technology that will scale faster and become cheaper in the future.

It's not the first time Color has turned to this approach. Color worked with Alaska Railroad Company and the Philadelphia area's Teamsters Health and Welfare Fund to offer genetic testing and follow-up preventive care services to these blue collar workforces. Laraki said that led a huge percentage effectively ended up using Color's tests as effectively a technology-first version of a basic health screen.

"We were able to reach these people that were outside of the healthcare envelope, if you will," Laraki said, with Color's genetic screens providing information and guidance on how to prevent major conditions like cancer, cardiovascular disease, and diabetes.

Right now, Color operates COVID-19 testing for California's K-12 public school system.

"I don't know of any health service that's distributed in 20,000 locations," he said.

To Laraki, the adoption of Color's infrastructure demonstrates that the company can expand by providing basic healthcare access in underserved communities.

Genetic testing can't replace one-on-one interaction with a doctor, Laraki said, but it can supply broad populations with data and an additional, typically more convenient access point for the healthcare system.

For Laraki, genetic testing being a buzzy, highly touted healthcare tool or even a source of "infotainment" is beside the point. Although others in the space like 23andMe have doubled down on personalized drug development, Color's chief executive believes genetic testing's greatest value lies in the fact it serves as an easily scalable, low-cost preventative health measure.

"From my perspective, genomics will have the biggest impact when we forget it's even there," Laraki said. As long as people view genetic tests for high-risk conditions like cancer as a special add-on, that means it's not weaved into a general conceptualization of what constitutes healthcare, he added.

By selling to health systems, public health bodies, and large employers, Color has found an efficient way to get genetic tests in the hands of people in a manner that will hopefully help keep people healthier.

"What Color in particular has been somewhat successful at doing is aligning patients, providers, and payers," said CB Insights analyst Kedar Karkare. Companies like Color and its competitor, Helix, have made the bet that genetic screenings will fundamentally save on long-term disease management.

Thus far, Karkare said he agreed it's paid off. Like other companies that began sequencing people's DNA at large scale, Color hasn't yet shown evidence that its preventive genetic screens are helpful in a primary care setting. Its peer-reviewed publications using its data have contributed to preliminary research on how genetic data correlates with health conditions like cancer and liver failure.

Comparatively, Laraki sees the push into personalized drugs, like 23andMe's partnerships, as feeding into the US healthcare system's acute-care overspending problem.

"I don't think that is the highest value utilization of something like genetics," he said. "I think the biggest value creation that will come out of genetics is going to be in the actual care of people."

According to Karkare, the partnership model that Color has used has more clearly married the goals of public health and for-profit companies, relative to other players in the consumer genomics space hoping to pivot to drug development.

Laraki is firm in his faith that basic genetic screenings will one day become seamlessly integrated into primary care to the point that people will not even care about it or be aware of it.

Though broader consumer DNA testing has raised alarm bells about companies owning and profiting off personal genetic data, he said he believes the larger concern is about health data, more broadly speaking. He pointed to large-scale patient billing information data breaches and STD test results as examples of more alarming data that could fall into the wrong hands.

"Genetics itself, relative to the rest of your health data portfolio, is actually not necessarily the scariest," Laraki said. More harm comes from the right data not being used to help people, he said.

From its start in 2015 at the height of the direct-to consumer DNA testing boom to now, Color has made clear it wants to ensure individual genetic testing is more than just a passing fad. By partnering with both public and private players, Laraki hopes his company will outlive even the very last waves of hype.

Nearly a year into the pandemic, Laraki says COVID-19 has made Color realize that its efforts in preventative health-based genetic testing are part of a larger category of population health and the infrastructure that goes into making that happen.

"What is the approach to make basic healthcare services extremely accessible? I think that's the big transition that we went through last year," he said.

Some of that just happens to involve genetics.

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Color's CEO thinks genetics will help expand healthcare access - Business Insider

Most of us go through life thinking were blessedand dingedby the genes weve inherited. Maybe you got your moms gorgeous eyes but also her astigmatism, or you scored the tall-and-slender genes from your fathers side of the family but worry that you also have their predisposition to Alzheimers.

Though we cannot change our genetic makeup, we can positively influence how our DNA gets expressed, says Brandon Colby, M.D., the author of Outsmart Your Genes and a clinical geneticist in Beverly Hills. You can think of your genes like a road map of possible routes, explains Dr. Colby. While your genes may mean your road map has paths that go toward heart disease or Alzheimers, those paths arent set in stonetheyre just possibilities laid out by your genes.

And there are a number of things you can do to program your genetic GPS so it takes you down a road toward health. Most diseases are determined by a combination of genetic and nongenetic factors, which means you can make changes that will minimizeand maybe even eliminateyour chances of contracting diseases for which your genes put you at risk, says Dr. Colby. Its empowering.

Taking what we know about our own genetic predisposition, how can we reroute ourselves so were on a path toward better health and maybe even sidestep issues our parents and grandparents faced? While the majority of our insight comes from genetic research, we are starting to get some guidance from the tens of thousands of studies in the emerging field of epigenetics, which looks at how lifestyle and environment can modify the ways genes function.

Before you take steps that can tweak your gene expression for the better, its important to have a basic understanding of what genes are and how they work beyond giving you traits like eye and hair color.

Heres a fact that will bring you back to Biology 101: Despite how vastly different humans seem from one another, we all inherit the same 20,000-plus genes, all made up of DNA. In every single one of the trillions of cells in your body, your DNA is organized into pairs of chromosomes. While both chromosomes in any given pair contain the same genes, the genetic code within those genes may be slightly different, says Dr. Colby. And when a cell divides, gene mutationsalso known as variantscan come about. Differences within our genetic code are responsible for everything from what we look like to our personality traits to our predisposition to disease, says Dr. Colby.

A rare mutation that occurs in one of the cells that combine to form an embryo, either the egg or the sperm, becomes a new genetic variant that neither parent has, but the child will. That child can then pass it along to future offspring. Sometimes this is a great thing: The fact that our genes have mutated over time is the reason humans have evolved to be smarter and live longer.

On the flip side, sometimes a change in a gene can cause it to wreak havoc, explains Dr. Colby, which is why particular genes are associated with particular diseases. Some changes are prompted by factors such as too much sunlight, poor diet, smoking, and other environmental and lifestyle choiceswhich can lead to diseases like cancer. Other mutations occur as a result of aging or because of occasional mistakes made as the bodys cells go through their normal process of dividing and multiplying. However, these generally dont pose any health risks. Luckily, your body detects and corrects most errorsand even if it doesnt, many gene mutations are harmless and wont affect your health, says Dr. Colby. However, some mutations are harmfuland those are the ones we can now detect and try to outsmart.

Joshua Selsby, Ph.D., a muscle physiologist and a professor at Iowa State University, likes to compare our 20,000 genes to recipes in a big cookbook. While we get our genetic makeup (DNA) from our parents, with fixed ingredients, through lifestyle choices we can exert control over how often we make certain recipes. And while you cant change your cookbook, you can decide which recipes you cook the most.

Say, for example, you exercise regularly. That healthy lifestyle choice is like making a good-for-you recipe over and over againso many times that your cookbook will automatically open to the page for that recipe, says Keith Baar, Ph.D., a professor of molecular exercise physiology at the University of California, Davis. When it comes to the genes you use a lot, its as if youre pushing on your genome like youd push down the pages of the recipes you use repeatedly, he says. Thats a great thing if what youre doing is something positive like exercising or eating 12 servings of fruits and veggies a day, choices that change your genes in helpful ways.

The converse is also true. Things like smoking and sitting for 12 hours a day can push on genes you dont want turned on. How you move, what you eat, and a number of other factors will affect your DNA, says Selsby, which means you can favor the genes that will help you live a long, healthy life and work to suppress the ones that put you at increased risk for disease: While you cant control your genetics, you can impact what you do with those genetics, Selsby says.

With advances in genetic testing, its possible to understand your specific gene mutationsinformation that can help doctors, say, predict your risk of certain diseases and more precisely prescribe medication (you could even be offered truly targeted nutritional recommendations). Yet even most geneticists agree that genetic testing isnt a must for most people, especially because most clinicians wont know how to support you with this kind of precision medicine.

However, a handful of strategies will work across the board to turn on your health- promoting genes and turn off ones that could cause problems. Below are several ideas for how to start.

Amp up your exercise intensity.

You already know that working out is one of the best things you can do for your health, and research shows that exercisespecifically, weight trainingcan actually change your genes so they mimic those of someone much younger. In a study, men and women older than 65 did twice-weekly resistance training for six months. Researchers then compared their muscle tissue to that of a group of 20-somethings, and they found a real change: The older adults genetic fingerprint had actually reversed, reaching levels similar to those seen in the younger adults.

The best way to defeat disease will always be to prevent it.

Cardio workouts are still important too; in fact, when it comes to risk of breast cancer, exercise has been shown to have a significant and positive effect. Doing four or more hours per week of cardio exercise lowers the risk of breast cancer by about 30%, and experts think this is due to changes in the genes themselves. Also, an interesting study on breast cancer survivors suggested that increasing physical activity might affect genes that suppress tumors, which could boost survival outcomes.

Think back to when you were a kidyou probably sprinted as fast as you could, pulled yourself up on the jungle gym, and tried to lift or push heavy things, and all this activity turned certain genes on, says Baar. Doing strenuous activity as an adult sparks your epigenetic memory, prompting those genes that respond well to exercise to respond again.

Keep in mind that the key to triggering this reaction is to stress your body. That means that a couple of times a week you should do activity that goes beyond brisk-walk-around-the-block intensity, adds Baar. If you really push yourself, the genetic response will be bigger.

What we eat serves as an epigenetic signal that can actually prompt changesand these changes adjust important chemical tags on DNA, potentially influencing our health for better or worse.

For example, a diet loaded with refined grains and lacking in fruits and veggies has been linked to DNA changes that stifle gene expression and cause disease. On the other hand, polyphenols (found in fruits, vegetables, green tea, coffee, and red wine) have been shown to reduce DNA damage, ultimately protecting against disease. Its also important to eat foods you enjoy, be conscious of what youre eating, and maintain a caloric intake at or slightly below what you need, Baar says.

When it comes to outsmarting gene mutations that might lead to cognitive decline, exercising your mind on a regular basis is especially important. This has been shown to stimulate the growth of new brain cells and strengthen the synapses between those cellstwo things that keep you sharp as you age. And mental exercises you really enjoy have the added benefit of reducing stress, also key when it comes to programming your genetic GPS.

Playing card games or chess, doing puzzles, attending lectures, learning a new language, and starting a new hobby all count, Dr. Colby says. And the best types of mental exercises appear to be those involving social interaction. A strong social network of friends has also been associated with a protective effect against Alzheimers, possibly because it helps ease stress. Aim to do any of those brain-boosting activities for about an hour three or more times a week.

Many geneticists believe that whole-genome sequencing as a regular part of health care is the wave of the future and that this will ultimately help health care practitioners create a precise personalized medical plan for every patient. But until then, theres still a lot you can do to alter, minimize, and even entirely avoid your current genetic destiny, says Dr. Colby.

You dont have to wait until illness appears and then try to treat it, he says. The best way to defeat disease will always be to prevent it, and were learning how to do that by studying our genetic code and using the information it provides.

These are three of the biggies, and the gene mutations to be aware of for each.

What we know: The BRCA1 and BRCA2 mutations are inherited from your mother or father and can increase your risk of developing breast cancer by 70%. The PIK3CA gene mutation isnt inherited and is more likely to tell docs how a patient might respond to cancer treatment.

What we know: The APOE4 gene variation is the main genetic risk for the disease; it can lead to the buildup of harmful deposits in the brain that can compromise the function of brain cells. One study found that this variation also caused Alzheimers disease to manifest earlier in life, with memory decline before age 60.

What we know: Many of us have genetic variants that increase our risk of cardiovascular disease no matter what our lifestyle. For example, the APOE gene plays a role in how the body processes cholesterol, and variants within this gene are associated with increased risk of premature death. The SCN5A gene is associated with heart arrhythmias, a risk factor for stroke.

Cells from your body (typically via your saliva if its an at-home test, or from blood if its a test your doc ordered) are collected and sent to a lab, which looks at the DNA within those cells. The amount of genetic info reviewed can be small (for example, a test might look only for the APOE gene for Alzheimers disease) or huge (your entire genome may be sequenced). The resulting info goes to a geneticist, who analyzes it and creates a report. Heres where genetic counselors can be incredibly helpful: Theyre trained to look at your specific gene mutations and help you tailor personalized prevention strategies.

In 2008, Congress made it illegal for, say, an insurance company to increase your premiums or refuse you coverage based on genetic infobut its still a good idea to verify that test results will remain confidential, especially when using a personal genomics company such as 23andMe or one of its competitors. Your name and any other identifying info shouldnt be linked to your genetic information, Dr. Colby says. That way, even if a third party somehow managed to access your genetic info, thered be no way to associate it with you.

Doctors and patients are concerned about the potential for that. But Dr. Colby says that while your anxiety may go up in the days and weeks after you learn youre at increased risk of disease, research shows that its likely to return to baseline. Still, think this through and consider your mental health before making the decision.

This article originally appeared in the March 2021 issue of Prevention.

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Do Genes Affect Health? - Tips to Outsmart Genetic Health Risks - Prevention.com

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Curr Breast Cancer Rep. 2020 Sep;12(3):125-131. doi: 10.1007/s12609-020-00364-1. Epub 2020 May 19.

ABSTRACT

PURPOSE OF REVIEW: Despite a steady improvement in breast cancer survival rates over the past several decades, mortality disparities remain among Black women, who have a 42% higher death rate compared to non-Hispanic white (NHW) women. Hereditary breast cancer (HBC) accounts for 5-10% of all breast cancer cases, the majority of which are due to the BRCA1 and BRCA2 (BRCA) genes. Despite the availability of BRCA testing for over 25 years, there remain disproportionately lower rates of genetic testing among Blacks compared to NHW due to a multitude of factors. The intent of this review is to discuss racial disparities focused on HBC across diverse populations and review the existing gaps to be addressed when delivering gene-based care.

RECENT FINDINGS: The factors contributing to the racial survival disparity are undoubtedly complex and likely an interplay between tumor biology, genomics, patterns of care and socioeconomic factors. Advances in genomic technologies that now allow for full characterization of germline DNA sequencing are integral in defining the complex and multifactorial cause of breast cancer and may help to explain the existing racial survival disparities.

SUMMARY: Identification of inherited cancer risk may lead to cancer prevention, early cancer detection, treatment guidance, and ultimately has great potential to improve outcomes. Consequently, advances in HBC diagnosis and treatment without widespread implementation have the potential to further widen the existing breast cancer mortality gap between Black and NHW women.

PMID:33603954 | PMC:PMC7885902 | DOI:10.1007/s12609-020-00364-1

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Disparities in Genetic Testing and Care among Black women with Hereditary Breast Cancer - DocWire News

This article was originally published here

Curr Opin Cardiol. 2021 Feb 16. doi: 10.1097/HCO.0000000000000841. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: To highlight the evolving understanding of genetic variants, utility of genetic testing, and the selection of novel therapies for cardiac amyloidosis.

RECENT FINDINGS: The last decade has seen considerable progress in cardiac amyloidosis recognition given the advancement in cardiac imaging techniques and widespread availability of genetic testing. A significant shift in the understanding of a genetic basis for amyloidosis has led to the development of disease-modifying therapeutic strategies that improve survival.

SUMMARY: The systemic amyloidoses are disorders caused by extracellular deposition of misfolded amyloid fibrils in various organs. Immunoglobulin light-chain or transthyretin amyloidosis are the most common types associated with cardiac manifestations. Genetic testing plays a central role in the identification of genotypes that are associated with different clinical phenotypes and influence prognosis. Given the emergence of effective therapies, a systematic approach to the diagnosis of cardiac amyloidosis, with the elucidation of genotype when indicated, is essential to select the appropriate treatment.

PMID:33605615 | DOI:10.1097/HCO.0000000000000841

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Clinical approach to genetic testing in amyloid cardiomyopathy: from mechanism to effective therapies - DocWire News

SAN FRANCISCO, Feb. 24, 2021 /PRNewswire/ --Invitae Corporation (NYSE: NVTA), a leading medical genetics company, today announced the addition of tools from Medneon, a digital health AI company, to its robust clinical workflow and patient education tools. The additional capabilities further support clinicians and patients with cancer by making it easier to determine who should get testing and how to use genetic information to individualize treatment.

"While utility of genetic information in cancer care is well established, it remains challenging for clinicians to navigate varying guidelines and research findings that inform them about which patient, which test and what results mean for patient care," said Robert Nussbaum, M.D., chief medical officer at Invitae. "The addition of Medneon's risk assessment tool, which was developed by experts in the field, makes it easier for clinicians to make sure testing is considered and findings are acted upon for all patients who could benefit from genetic-informed care. The frequent updating of Medneon's recommendations based on the most current recommendations and newest research findings means that providers and patients will have the most up-to-date information at their disposal."

Medneon's Predictive Risk Assessment combines several factors, including current guidelines, real-world evidence, and personal and family history, to rapidly identify an individual's elevated short-term and lifetime cancer risk. Clinicians are quickly informed of their patient's eligibility for genetic testing and supplemental imaging, so that preventative action may be taken. In addition, the platform can assist clinicians in confirming and documenting the clinician's determination that the patient met medical necessity qualifying criteria to help navigate insurance coverage. When test results are returned, the company's Personalized Genetic Insights curates information from an array of published expert resources, including the AI knowledge base ASK2ME, medical experts, and genetic counselors, to generate custom reports that support patients and clinicians in shared decision-making.

"For clinicians who are learning to manage care through telemedicine during the ongoing pandemic, the Medneon platform distills the rapidly growing amount of published genetic and genomic information into digestible reports to help determine when to order a test, how to interpret results and how to personalize a care plan," said Noel Pugh, Ph.D., JD, MHA, head of commercialization at Medneon. "We hope by utilizing these tools, preventable cancers will be caught earlier to ultimately deliver better outcomes for patients and their families."

Medneon's technologies are another addition to the tools Invitae offers, anchored by its Gia platform, that support patients and providers by providing patient education and clinical support throughout the genetic testing process across a wide array of clinical areas.

About Medneon

Medneon's mission is to prevent cancer and optimize treatment by empowering individuals and their care team with DNA insights and decision support tools throughout the cancer journey. The innovative Medneon digital platform combines AI and human insights with actionable information regarding an individual's cancer risk to inform precision prevention and management over time at the point-of-care or through telemedicine. For more information, visitthe company's website at http://www.medneon.com.

About Invitae

Invitae Corporation(NYSE: NVTA) is a leading medical genetics company, whose mission is to bring comprehensive genetic information into mainstream medicine to improve healthcare for billions of people. Invitae's goal is to aggregate the world's genetic tests into a single service with higher quality, faster turnaround time, and lower prices. For more information, visit the company's website atinvitae.com.

Safe Harbor Statement

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including statements relating to the capabilities and potential benefits of the tools provided by Medneon. Forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially, and reported results should not be considered as an indication of future performance. These risks and uncertainties include, but are not limited to: the company's history of losses; the company's ability to compete; the company's failure to manage growth effectively; the company's need to scale its infrastructure in advance of demand for its tests and to increase demand for its tests; the company's ability to use rapidlychanging genetic data to interpret test results accurately and consistently; security breaches, loss of data and other disruptions; laws and regulations applicable to the company's business; and the other risks set forth in the company's filings with the Securities and Exchange Commission, including the risks set forth in the company's Quarterly Report on Form 10-Q for the quarter ended September 30, 2020. These forward-looking statements speak only as of the date hereof, and Invitae Corporation disclaims any obligation to update these forward-looking statements.

Contact:Laura D'Angelo[emailprotected](628) 213-3283

SOURCE Invitae Corporation

http://www.invitae.com

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Invitae adds Medneon's risk assessment tools to its education and clinical support offerings - PRNewswire

BEIJING, Feb. 24, 2021 /PRNewswire/ --Berry Oncology Corporation, the shareholding subsidiary of Berry Genomics, announced the results of a case-control study on the effectiveness of a novel diagnostic method for detecting hepatocellular carcinoma (HCC) in patients with liver cirrhosis, demonstrating the new model had greater accuracy and sensitivity compared to existing screening methods.

The study, published in Cell Research, featured both China and the U.S.-based authors and research teams led separately by Prof. Hong-Yang Wang of the National Center for Liver Cancer, Prof. Jin-Lin Hou of Nanfang Hospital, Southern Medical University and Dr. Lin Wu and Dr. Jian Bai of Berry Oncology. The researchers collected cell-free DNA (cfDNA) samples from a total of 3,234 individuals, including 2,250 patients with liver cirrhosis (LC), 508 with HCC, and 476 healthy controls (CTRL) from 13 hospitals in 11 provinces in China.

Scientists employed a state-of-the-art next-generation sequencing (NGS) technology to acquire genome-wide 5-hydroxymethylcytosine (5-hmc), nucleosome footprint (NF), 5 end motif and fragmentation profiles of cfDNAs from all enrolled individuals. Researchers then used a logistic regression method to construct a weighted diagnostic model based on the performance of these four features.

The novel diagnostic model, called HIFI, achieved a sensitivity of 95.42%, a specificity of 97.83%, and an AUC of 0.996 in the study, a higher accuracy in differentiating HCC from liver cirrhosis than existing diagnosis tests measuring AFP or PIVKA-II. The method was also able to detect signs of liver cancer with 93.9% accuracy among individuals that had tested negative using an AFP test, and with 90.9% accuracy among those that tested negative using a PIVKA-II test.

These results can be achieved regardless of a patient's age, HBV status, Child-Pugh score, BCLC stage, tumor size, or AFP status. Furthermore, the HIFI model can also be used to screen for other major cancers, such as lung cancer.

HCC, the most common form of liver cancer, is the second most deadly cancer worldwide. Patients with liver cirrhosis are at the highest risk of developing HCC, and diagnosis at an early stage contributes to an improved prognosis with the possibility of curative treatment.

"Due to the low accuracy of current diagnostic methods, new non-invasive strategies for early HCC diagnosis in cirrhotic patients are urgently needed," said authors of the study. "The HIFI method exhibited an excellent performance for early-stage HCC diagnosis compared to other non-invasive methods, and has huge potential of HCC detection for cirrhotic patients."

According to Berry Oncology CEO Jun Zhou, the result of this study is a milestone for Berry Oncology in tumor screening and early detection. As the forerunner in the field of genomic testing of cancers in China, this research aligns with Berry's strategic road map will accelerate Berry's advances in early screening of high-risk and high-incidence tumors and can also contribute to similar goals set out in China's 13th Five-Year Plan.

In addition to Berry Oncology, authors of the study also hail from the National Center for Liver Cancer, Shanghai Eastern Hepatobiliary Surgery Hospital in Shanghai, the Memorial Sloan Kettering Cancer Center in New York, Mengchao Hepatobiliary Hospital of Fujian Medical University in Fuzhou, the Second Hospital of Shandong University in Jinan, Ningbo Hwamei Hospital in Ningbo, Nanfang Hospital in Guangzhou and more.

About Berry Oncology

Berry Oncology, founded in 2017 as a member company of Berry Genomics, focuses on genetic testing of cancers. Driven by the mission of "Diagnose all cancers early, treat all patients precisely", we have established for cancer patients and high-risk population a complete system of genetic testing products and services, including tumor genetic susceptibility analysis, early screening, as well as as companion diagnostics, response monitoring and prognosis prediction of both targeted and immune therapies. For cancer early detection, we have launched a series of clinical research projects for early screening and early diagnosis, covering liver cancer, lung cancer, gynecologic cancer, and etc. Berry Oncology has three centers (manufacture, supercomputing, R&D) located in Fuzhou and Beijing. We serve and cooperate with more than 600 Class 3A hospitals across the country, and have provided valuable genetic testing services for hundreds of thousands of patients.

For more information please visit:http://en.berryoncology.com/

About Berry Genomics

Founded in May 2010, Berry Genomics is a leading company in clinical genomics and life science in China. Berry Genomics is dedicated to research, development and commercialization of genetic test technologies in clinical applications. Berry Genomics aims to assist accurate diagnosis of diseases throughout the full human life circle, and to improve human health.

As a company with strong R&D capability, Berry Genomics pioneered the first NGS-based genetic test, NIPT, in China back in 2010. The company currently provides NGS- based tests for many genetic diseases and cancers from preconception to adulthood. Berry Genomics is leading in the clinical study of early clinical detection of liver cancer in the world. Exploring the use of the third-generation sequencing technology in both clinical field and scientific study is ongoing.

Berry Genomics has around 1500 employees dedicating to developing products and providing services for over 4000 organizations and facilities home and abroad, including hospitals, research institutions, universities and corporations.

Berry Genomics has been listed on A-share market in China since 2017 under the stock code: 000710.

For more information please visit:http://www.berrygenomics.com/

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SOURCE Berry Oncology Corporation

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Berry Oncology Announces Novel Diagnostic Method for Liver Cancer Achieved Greater Accuracy and Sensitivity Compared to Existing Non-Invasive Methods...

According to the World Health Organization (WHO) and the American Cancer Society, cancer accounts for about 1 in 6 deaths worldwide - more than HIV/AIDS, tuberculosis, and malaria combined. The report states that by 2040, the global burden is expected to reach 27.5 million new cancer cases and 16.2 million cancer deaths. A WHO estimate in 2018 projected that 1 in 10 Indians will develop cancer during their lifetime and 1in 15 will die of the disease.

About 5-10% of all cancers are hereditary and occur due to inheritance of a genetic variation/mutation within families, especially in close family members. Examples of such hereditary cancer syndromes, also called familial cancer syndromes, are hereditary breast and ovarian cancer syndrome, Li-Fraumeni syndrome, Cowden syndrome, and Lynch syndrome.

Unlike localized (somatic) genetic variations that are acquired over the course of one's life, inherited or familial variations are transmitted from one generation to another and can thus predict the increased lifetime risk of developing cancer. The presence of such variations can also indicate the early onset of the disease.

From a comprehensive cancer treatment point of view, the knowledge of hereditary gene mutations has a plethora of applications including better disease management and application of preventive strategies such as risk-reducing surgeries, which can improve survival. Asymptomatic carriers can also be benefitted from chemoprevention and enhanced surveillance approaches.

There are about 100 genes that are associated with hereditary cancer development and information about mutations in these genes can be used to tailor prevention, surveillance, and treatment of cancer. Genetic testing to detect such inherited variations helps an Oncologist in making a well-informed treatment decision.

Hereditary cancers are known to have a poor-prognosis- meaning these cancers are comparatively more aggressive. This information can aid in better clinical management decisions. Further, mutations in certain genes increase response to drugs and thus contribute to precision/personalized medicine wherein patients are treated based on the mutations identified in them.

For example, women diagnosed with HBOC (Hereditary Breast and Ovarian Cancer syndrome), with a mutation in the BRCA1/2 gene, respond to targeted treatment using Poly ADP-ribose polymerase (PARP) inhibitors.

Considering the multiple advantages of identifying genetic variations in hereditary cancers, the health care fraternity globally, has been trying to make genetic testing more affordable and widely available to the public, enabling easier diagnosis, management, and treatment of this disease.

Sequencing of multiple cancer susceptibility genes simultaneously has now become available through multi-gene panel testing in a rapid and cost-effective manner. This is a breakthrough that will result in a new era of personalized healthcare for hereditary cancers in the decades to come.

-Article by Dr. Lakshmi Mahadevan, Principal Scientist, MedGenome Labs Ltd

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What genes tell us about the risk of developing cancer - India Today

Pune, India, Feb. 22, 2021 (GLOBE NEWSWIRE) -- Gene Panel Market Overview

As per Market Research Future (MRFR), the Global Gene Panel Marketis expected to register aCAGR of12.16%to reachUSD4.34 Billion by 2025.

Increased cancer rates and genetic testing benefits will drive growth in the global market for genetic testing. Due to increased incidences of chronic illnesses and the increase in tailor-made gene panels for specific diseases, the market growth is exponential. In addition to market growth, a rise in initiatives across the world and DNA analysis benefits are anticipated to drive the gene panel market.

The thriving biotechnology industry coupled with increased awareness of advanced technologies is one of the main reasons the region has become a primary medical service provider. Although the gene panel testing is accurate, the test's limitations and inaccuracy are expected to impede the growth of the market. Furthermore, the stringent regulations and safety concerns regarding gene panels are likely to stifle this market in the immediate future. Regardless, ongoing research and development of gene sequencing are expected to lead to the rising need for genetic testing.

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COVID-19 Analysis:

The COVID-19 pandemic has heightened interest in the complex interaction between human host factors and pathogen factors. The spectrum of phenotypes associated with the SARS-CoV-2 infection, ranging from the absence of symptoms to severe systemic complications, raised the question of the extent to which the variable response to coronaviruses (CoVs) is influenced by the variability of the hosts' genetic background. Thus, the covid 19 pandemic has led to a rise in the research and development initiatives and investments towards genetics that could be helpful to design and conduct effective studies and, in turn, to find possible healthcare strategies aimed at facing the current COVID-19 pandemic, consequently creating new opportunities for market players of the global gene panel market.

Competitive Landscape:

The Prominent Players in the Global Gene Panel Market are:

The players operating in the global market have tried to innovate, develop, and acquire properties.

Browse In-depth Market Research Report (220 Pages) on Gene Panel: https://www.marketresearchfuture.com/reports/gene-panel-market-6100

Segmental Analysis:

The Global Gene Panel Market has been segmented by product & service, Technique, Design, Application, and End User.

Based on product & service, the market has been bifurcated into test kits and testing services.

The global gene panel market has been bifurcated into an amplicon-based approach and a hybridization-based approach based on technique.

The global gene panel market has been bifurcated into predesigned gene panels and customized gene panels based on design.

Based on application, the global gene panel market has been classified as cancer risk assessment, diagnosis of congenital disorders, and pharmacogenetics.

The global gene panel market based on end-user has been divided into hospitals, diagnostic laboratories, and others.

Regional Insights:

North America Leads with Established Sectors while APAC to Rise Substantially.

The Americas would be the largest market for gene testing at the end of the forecast period. The increasing prevalence of cancer and the growing presence of well-established players support the Americas' dominance in the coming years. North America dominated the global gene panel market due to its dominant position in cancer and rare diseases and the increase in applications for NGS-based and clinical research in the region. Such as many leading genomics researches and leading NGS providers in this region.

Europe created significant growth in the cancer medication market because of rising cancer rates. The rising incidence of cancer in people will, in part, drive the development of the cancer market. Moreover, the presence of a well-established healthcare sector and global market players leads to growth opportunities in Europe over the review period.

The Asia-Pacific region is projected to be the fastest-growing due to projected increases in life expectancy and the number of those who need healthcare. With increasing cancer prevalence and its resulting health care costs and the federal government's investment in cancer research and development, the market is likely to grow. Companies involved in genetic services can target India and China due to increased prevalence of infectious diseases.

Inability to fully advance in the biotechnology industry would have decreased business growth in the Middle East and Africa due to a lack of technological expertise. Due to the limited number of biotech consulting services available worldwide, the Middle East and Africa have the smallest global market share. Nevertheless, the gene panel market is expected to experience gradual growth in the Middle East and Africa due to the increased spending on healthcare and the growing number of people seeking genetic tests. The UAE, Saudi Arabia and Kuwait are expected to push the Middle East & African market. In comparison, the African region will see modest growth over the next decade.

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Industry Updates:

January 2021: Swift Biosciences released an S-gene panel for SARS-CoV-2 that covered the majority of viral genes even with very low levels of virus detection. The S gene controls the spike protein which allows the virus to attach to cells and affect transmissibility; mutations in the concerning variants have been discovered in the U.K., South Africa, Brazil, Denmark, and the United States. The panel will enable rapid scaling of the new strains' surveillance efforts by labs using the Illumina system and can be run by any lab using the Illumina system (NGS).

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Gene Panel Market Is Estimated to Reach USD 4.34 Billion by 2025 at CAGR of 12.16% | Market Research Future (MRFR) - GlobeNewswire

Researchers at University of California San Diego School of Medicine have launched a first-in-human Phase I clinical trial to assess the safety and efficacy of a gene therapy to deliver a key protein into the brains of persons with Alzheimers disease (AD) or Mild Cognitive Impairment (MCI), a condition that often precedes full-blown dementia.

The protein, called brain-derived neurotrophic factor or BDNF, is part of a family of growth factors found in the brain and central nervous system that support the survival of existing neurons and promote growth and differentiation of new neurons and synapses. BDNF is particularly important in brain regions susceptible to degeneration in AD.

In previous published research, principal investigator Mark Tuszynski, MD, PhD, professor of neuroscience and director of the Translational Neuroscience Institute at UC San Diego School of Medicine, and colleagues described the prevention and reversal of brain cell degeneration and death in animal models.

Mark Tuszynski, MD, PhD, professor of neuroscience and director of the Translational Neuroscience Institute at UC San Diego School of Medicine.

We found that delivering BDNF to the part of the brain that is affected earliest in Alzheimers disease the entorhinal cortex and hippocampus was able to reverse the loss of connections and to protect from ongoing cell degeneration, said Tuszynski. These benefits were observed in aged rats, aged monkeys and amyloid mice.

Amyloid mice are genetically engineered to inherit a mutation in the gene encoding the amyloid precursor protein, and as a result develop amyloid plaques aggregates of misfolded proteins in the brain that are considered a hallmark characteristic of AD.

BDNF is normally produced throughout life in the entorhinal cortex, an important memory center in the brain and one of the first places where the effects of AD typically appear in the form of short-term memory loss. Persons with AD have diminished levels of BDNF.

But BDNF is not easy to work with. It is a large molecule and cannot pass through the blood-brain barrier. As a result, researchers will use gene therapy in which a harmless adeno-associated virus (AAV2) is modified to carry the BDNF gene and injected directly into targeted regions of the brain, where researchers hope it will prompt production of therapeutic BDNF in nearby cells.

The injections are precisely controlled to contain exposure to surrounding degenerating neurons since freely circulating BDNF can cause adverse effects, such as seizures.

The three-year-long trial will recruit 12 participants with either diagnosed AD or MCI to receive AAV2-BDNF treatment, with another 12 persons serving as comparative controls over that period.

This is the first safety and efficacy assessment of AAV2-BDNF in humans. A previous gene therapy trial from 2001 to 2012 using AAV2 and a different protein called nerve growth factor (NGF) found heightened growth, axonal sprouting and activation of functional markers in the brains of participants.

The BDNF gene therapy trial in AD represents an advance over the earlier NGF trial, said Tuszynski. BDNF is a more potent growth factor than NGF for neural circuits that degenerate in AD. In addition, new methods for delivering BDNF will more effectively deliver and distribute it into the entorhinal cortex and hippocampus.

Despite billions of dollars of research investment and decades of effort, there are only two symptomatic treatments for AD. There is no cure or approved way to slow or stop progression of the neurological disorder that afflicts more than 5 million Americans and is the sixth leading cause of death in the United States.

Numerous clinical trials are ongoing to assess pharmaceutical remedies. Tuszynski said gene therapy, which debuted in 1980 and has been tested on multiple diseases and conditions, represents a different approach to a disease that requires new ways of thinking about the disease and new attempts at treatments.

We hope to build on recent successes of gene therapy in other diseases, including a breakthrough success in the treatment of congenital weakness in infants (spinal muscular atrophy) and blindness (Leber Hereditary Optic Neuropathy, a form of retinitis pigmentosa), Tuszynski said.

BDNF gene therapy has the potential, unlike other AD therapies currently under development, to rebuild brain circuits, slow cell loss and stimulate cell function. We are looking forward to observing the effects of this new effort in patients with AD and MCI.

For more information on this Phase I clinical trial, contact Michelle Mendoza at 858-249-3015 or email alphastemcellclinic@ucsd.edu

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First-in-Human Clinical Trial to Assess Gene Therapy for Alzheimer's Disease - UC San Diego Health