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Addgene: CRISPR References and Information

This table lists gRNA sequences that have been experimentally validated for use in CRISPR experiments.

gRNA design tool with extensive selection of eukaryotic pathogen genomes (200+) that can predict gRNA targets in gene families, HDR oligonucleotide design, and batch processing for designing genome-wide gRNA libraries. PubMed PMID 28348817.

This tool helps design (10 different prediction scores), clone (primer design), and evaluate gRNAs, as well as predict off-targets, for CRISPR in 180+ genomes. PubMed PMID: 27380939.

sgRNA Scorer 2.0From the Church Lab: a tool that identifies putative target sites for S. pyogenes Cas9, S. thermophilus Cas9, or Cpf from your input sequence or list of sequences.

Quilt Universal guide RNA designerSearch for gRNAs via gene name or by genomic location. Database includes gRNAs from popular CRISPR libraries and from more than two million DNAse hypersensitive sites for intergenic guide RNAs in hg19, filtered for off-target effects.

From the Kim Lab, Cas-OFFinder identifies gRNA target sequences from an input sequence and checks for off-target binding. Currently supports: Drosophila, Arabidopsis, zebrafish, C. elegans, mouse, human, rat, cow, dog, pig, Thale cress, rice (Oryza sativa), tomato, corn, monkey (macaca mulatta).

Cas-Designer searches for targets that maximize knockout efficiency while having a a low probability of off-target effects. Cas-Designer integrates information from the Kim Lab’s Cas-OFFinder and Microhomology predictor.

From the Qi Lab, a sgRNA design tool for genome editing, as well as gene regulation (repression and activation). Genome support for bacteria (E. coli, B. subtilis), yeast (S. cerevisiae), worm (C. elegans), fruit fly, zebrafish, mouse, rat, and human.

Identifies candidate sgRNA target sites by off-target quality. Validated for gene inactivation, NHEJ, and HDR. Reference genomes include Arabidopsis, C. elegans , sea squirt, cavefish, Chinese hamster, fruit fly, human, rice fish, mouse, silk worm, stickleback, tobacco, tomato, frog (X. laevis and X. tropicalis), and zebrafish.

Program for designing optimal gRNAs. Provides feedback on number of potential off-targets, target’s genomic location, and genome annotation. Available genomes are human (hg19 & hg38), mouse (mm10), and yeast (strain w303).

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Addgene: CRISPR References and Information

Recommendation and review posted by Rebecca Evans

Endo Pharmaceuticals | Hypogonadism

Male hypogonadism (or Low-T) is a condition in which the body doesn’t produce enough testosterone the hormone that plays a key role in masculine growth and development during puberty or has an impaired ability to produce sperm or both.

You may be born with male hypogonadism, or it can develop later in life from injury or infection. The effects and what you can do about them depend on the cause and at what point in your life male hypogonadism occurs. Some types of male hypogonadism can be treated with testosterone replacement therapy.

Doctors base a diagnosis of hypogonadism on symptoms and results of blood tests that measure testosterone levels. Because testosterone levels vary and are generally highest in the morning, blood testing is usually done early in the day, near 8 a.m.

If tests confirm you have low testosterone, further testing can determine if a testicular disorder or a pituitary abnormality is the cause. Based on specific signs and symptoms, additional studies can pinpoint the cause.

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Endo Pharmaceuticals | Hypogonadism

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Here’s Why CRISPR Therapeutics Lost 18.8% in July — The …

What happened

Shares of CRISPR Therapeutics (NASDAQ:CRSP) fell nearly 19% last month, according to data provided by S&P Global Market Intelligence, after yet another study reminded Wall Street and investors that there’s still much for scientists to understand about the use of CRISPR gene-editing tools in human cells. Previously, in June, two studies surfaced that suggested certain uses of CRISPR could trigger faulty DNA repair mechanisms to activate and turn a cell cancerous.

That was followed up last month by a new study suggesting that certain uses of CRISPR tools “seriously underestimated” the number of off-target changes made to a genome. CRISPR Therapeuticssaid to Reutersthat “[w]e do not use the methods described in this Nature Biotech paper … nevertheless, in our work, we do not see similar findings.” While that wasn’t enough to appease Wall Street in July, shareholders have still enjoyed a year-to-date gain of 103%.

Image source: Getty Images.

The study published last month came from researchers at the prestigious Wellcome Sanger Institute, an affiliation that helped the results to be taken more seriously. But considering CRISPR Therapeutics says it doesn’t use the specific techniques identified, investors may be wondering why the company’s shares were impacted at all. Well, it has to do with increasing uncertainty over an important part of using certain gene-editing tools.

More specifically, the most recent study detailing off-target changes to DNA and those identifying the potential to activate cancerous mutations already present in cells all seem to imply the same thing: Scientists may have gotten a little ahead of themselves by assuming DNA repair mechanisms would work in a simple fashion. While CRISPR tools intend to fix genetic defects by cutting one or both strands of human DNA, all rely on DNA repair mechanisms already present in a cell to stitch the genome back together. If those fail, then CRISPR tools might be less effective or could even end up having significant unintended effects.

Right now, it appears that the most troubling side effects are observed when CRISPR tools cut both strands of DNA (a “double-strand break”). The lead drug candidates of all three major CRISPR companies deploying the technology for medical applications avoid that headache, although all companies are exploring preclinical therapeutics that will have to navigate that obstacle eventually.

Investors can likely expect gene-editing stocks such as CRISPR Therapeutics to experience a higher-than-normal amount of volatility. The technology has received an incredible amount of attention in the media and even popular culture, and the potential to cure diseases has Wall Street understandably excited. Those forces have combined to hand the pioneering companies premium market valuations, but it’s important to remember that CRISPR is a relatively new technology. Investors in it for the long haul will simply need to buckle up and remain patient as results from the first clinical trials (yet to get started) begin to trickle in within the next few years.

Maxx Chatsko has no position in any of the stocks mentioned. The Motley Fool owns shares of CRISPR Therapeutics. The Motley Fool has a disclosure policy.

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Here’s Why CRISPR Therapeutics Lost 18.8% in July — The …

Recommendation and review posted by Bethany Smith

WHO Classification of Tumours of the Urinary System and …

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WHO Classification of Tumours of the Urinary System and …

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Gene Therapy Research | Ophthotech

Gene Therapy Research Programs

Ophthotech initiated an innovative gene therapy program focused on applying novel gene therapy technology to discover and develop new therapies for ocular diseases. We intend to investigate promising gene therapy product candidates and other technologies through collaborations with leading companies and academic institutions in the United States and internationally.

As we evaluate the unmet medical need for the treatment of orphan ophthalmic diseases, we have considered that many of these diseases are caused by one or more genetic mutations and currently have no approved treatment options available. Further, the potential to achieve an extended treatment effect and possibly a cure through a single gene therapy administration is particularly appealing to patients who do not have any treatment options, as well as for patients with age-related retinal diseases who currently require chronic therapy over years, if not decades.

Gene therapy consists of delivering DNA encoding for a functional protein to a target tissue to facilitate protein synthesis using a recipients existing cellular machinery. Gene therapy can be used to replace a non-functional protein produced innately by the subject as a result of a genetic mutation or simply as a means of producing and delivering a therapeutic protein that would not otherwise be produced within the body. The DNA, which is generally delivered by a viral vector, is governed by a promoter sequence which controls transcription of the gene of interest, or transgene, into RNA to initiate protein synthesis. Some of the challenges that gene therapy faces are producing vectors that transfect, or deposit the transgene, in only specific cell types, producing the desired protein at the therapeutic dose levels, and avoiding inducing an inflammatory response that leads to tissue damage. We are particularly interested in adeno-associated virus, or AAV, gene therapy delivery vehicles, as AAV vectors are relatively specific to retinal cells and their safety profile in humans is relatively well-documented as compared to other delivery vehicles and gene therapy technologies currently in development.

University of Massachusetts Medical School and its Horae Gene Therapy Center

For our first gene therapy collaboration, we entered into a series of sponsored research agreements with the University of Massachusetts Medical School (UMMS) and its Horae Gene Therapy Center to utilize their minigene therapy approach and other novel gene delivery technologies to target retinal diseases. As a condition of each research agreement, UMMS has granted the Company an option to obtain an exclusive license to any patent or patent applications that result from this research.

The use of minigenes as a novel therapeutic strategy seeks to deliver a shortened but still functional form of a large gene packaged into a standard-size AAV delivery vector commonly used in gene therapy. The minigene strategy may offer an innovative solution for diseases that would otherwise be difficult to address through conventional AAV gene replacement therapy where the size of the gene of interest exceeds the transgene packaging capacity of conventional AAV vectors. Research in this newly evolving area of gene therapy is led by Prof. Hemant Khanna and colleagues in the Horae Gene Therapy Center and was described in a recent journal article in Human Gene Therapy, Gene Therapy Using a miniCEP290 Fragment Delays Photoreceptor Degeneration in a Mouse Model of Leber Congenital Amaurosis by Wei Zhang, Linjing Li, Qin Su, Guangping Gao, and Hemant Khanna, all at the University of Massachusetts Medical School.

The collaboration with UMass Medical School will also focus on developing the next generation of gene therapy vectors to allow novel delivery approaches for treatment of retinal diseases.

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Gene Therapy Research | Ophthotech

Recommendation and review posted by Jack Burke

How Bone Marrow and Stem Cell Transplants Work

If you or a loved one will be having a bone marrow transplant or donating stem cells, what does it entail? What are the different types of bone marrow transplants and what is the experience like for both the donor and recipient?

A bone marrow transplant is a procedure in which when special cells (called stem cells) are removed from the bone marrow or peripheral blood, filtered and given back either to the same person or to another person.

Since we now derive most stem cells needed from the blood rather than the bone marrow, a bone marrow transplant is now more commonly referred to as stem cell transplant.

Bone marrow is found in larger bones in the body such as the pelvic bones. This bone marrow is the manufacturing site for stem cells. Stem cells are “pluripotential” meaning that the cells are the precursor cells which can evolve into the different types of blood cells, such as white blood cells, red blood cells, and platelets.

If something is wrong with the bone marrow or the production of blood cells is decreased, a person can become very ill or die. In conditions such as aplastic anemia, the bone marrow stops producing blood cells needed for the body. In diseases such as leukemia, the bone marrow produces abnormal blood cells.

The purpose of a bone marrow transplant is thus to replace cells not being produced or replace unhealthy stem cells with healthy ones. This can be used to treat or even cure the disease.

In addition to leukemias, lymphomas, and aplastic anemia, stem cell transplants are being evaluated for many disorders, ranging from solid tumors to other non-malignant disorders of the bone marrow, to multiple sclerosis.

There are two primary types of bone marrow transplants, autologous and allogeneic transplants.

The Greek prefix “auto” means “self.” In an autologous transplant, the donor is the person who will also receive the transplant. This procedure, also known as a “rescue transplant” involves removing your stem cells and freezing them. You then receive high dose chemotherapy followed by infusion of the thawed out frozen stem cells. It may be used to treat leukemias, lymphomas, or multiple myeloma.

The Greek prefix “allo” means “different” or “other.” In an allogeneic bone marrow transplant, the donor is another person who has a genetic tissue type similar to the person needing the transplant. Because tissue types are inherited, similar to hair color or eye color, it is more likely that you will find a suitable donor in a family member, especially a sibling. Unfortunately, this occurs only 25 to 30 percent of the time.

If a family member does not match the recipient, the National Marrow Donor Program Registry database can be searched for an unrelated individual whose tissue type is a close match. It is more likely that a donor who comes from the same racial or ethnic group as the recipient will have the same tissue traits. Learn more about finding a donor for a stem cell transplant.

Bone marrow cells can be obtained in three primary ways. These include:

The majority of stem cell transplants are done using PBSC collected by apheresis (peripheral blood stem cell transplants.) This method appears to provide better results for both the donor and recipient. There still may be situations in which a traditional bone marrow harvest is done.

Donating stem cells or bone marrow is fairly easy. In most cases, a donation is made using circulating stem cells (PBSC) collected by apheresis. First, the donor receives injections of a medication for several days that causes stem cells to move out of the bone marrow and into the blood. For the stem cell collection, the donor is connected to a machine by a needle inserted in the vein (like for donating blood). Blood is taken from the vein, filtered by the machine to collect the stem cells, then returned back to the donor through a needle in the other arm. There is almost no need for a recovery time with this procedure.

If stem cells are collected by bone marrow harvest (much less likely), the donor will go to the operating room and while asleep under anesthesia and a needle will be inserted into either the hip or the breastbone to take out some bone marrow. After awakening, there may be some pain where the needle was inserted.

A bone marrow transplant can be a very challenging procedure for the recipient.

The first step is usually receiving high doses of chemotherapy and/or radiation to eliminate whatever bone marrow is present. For example, with leukemia, it is first important to remove all of the abnormal bone marrow cells.

Once a person’s original bone marrow is destroyed, the new stem cells are injected intravenously, similar to a blood transfusion. The stem cells then find their way to the bone and start to grow and produce more cells (called engraftment).

There are many potential complications. The most critical time is usually when the bone marrow is destroyed so that few blood cells remain. Destruction of the bone marrow results in greatly reduced numbers of all of the types of blood cells (pancytopenia). Without white blood cells there is a serious risk of infection, and infection precautions are used in the hospital (isolation). Low levels of red blood cells (anemia) often require blood transfusions while waiting for the new stem cells to begin growing. Low levels of platelets (thrombocytopenia) in the blood can lead to internal bleeding.

A common complication affecting 40 to 80 percent of recipients is graft versus host disease. This occurs when white blood cells (T cells) in the donated cells (graft) attack tissues in the recipient (the host), and can be life-threatening.

An alternative approach referred to as a non-myeloablative bone marrow transplant or “mini-bone marrow transplant” is somewhat different. In this procedure, lower doses of chemotherapy are given that do not completely wipe out or “ablate” the bone marrow as in a typical bone marrow transplant. This approach may be used for someone who is older or otherwise might not tolerate the traditional procedure. In this case, the transplant works differently to treat the disease as well. Instead of replacing the bone marrow, the donated marrow can attack cancerous cells left in the body in a process referred to as “graft versus malignancy.”

If you’d like to become a volunteer donor, the process is straightforward and simple. Anyone between the ages of 18 and 60 and in good health can become a donor. There is a form to fill out and a blood sample to give; you can find all the information you need at the National Marrow Donor Programwebsite. You can join a donor drive in your area or go to a local Donor Center to have the blood test done.

When a person volunteers to be a donor, his or her particular blood tissue traits, as determined by a special blood test (histocompatibility antigen test,) are recorded in the Registry. This “tissue typing” is different from a person’s A, B, or O blood type. The Registry record also contains contact information for the donor, should a tissue type match be made.

Bone marrow transplants can be either autologous (from yourself) or allogeneic (from another person.) Stem cells are obtained either from peripheral blood, a bone marrow harvest or from cord blood that is saved at birth.

For a donor, the process is relatively easy. For the recipient, it can be a long and difficult process, especially when high doses of chemotherapy are needed to eliminate bone marrow. Complications are common and can include infections, bleeding, and graft versus host disease among others.

That said, bone marrow transplants can treat and even cure some diseases which had previously been almost uniformly fatal. While finding a donor was more challenging in the past, the National Marrow Donor Program has expanded such that many people without a compatible family member are now able to have a bone marrow/stem cell transplant.

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How Bone Marrow and Stem Cell Transplants Work

Recommendation and review posted by Jack Burke

Induced Pluripotent Stem Cell (iPS Cell): 2018-2022 …

Dublin, Aug. 02, 2018 (GLOBE NEWSWIRE) — The “Global Induced Pluripotent Stem Cell (iPS Cell) Industry Report 2018-19” report has been added to ResearchAndMarkets.com’s offering.

Groundbreaking experimentation in 2006 led to the introduction of induced pluripotent stem cells (iPSCs). These are adult cells which are isolated and then transformed into embryonic-like stem cells through the manipulation of gene expression, as well as other methods. Research and experimentation using mouse cells by Shinya Yamanaka’s lab at Kyoto University in Japan was the first instance in which there was a successful generation of iPSCs.

In 2007, a series of follow-up experiments were done at Kyoto University in which human adult cells were transformed into iPSCs. Nearly simultaneously, a research group led by James Thomson at the University of Wisconsin-Madison accomplished the same feat of deriving iPSC lines from human somatic cells.

Since the discovery of iPSCs a large and thriving research product market has grown into existence, largely because the cells are non-controversial and can be generated directly from adult cells. While it is clear that iPSCs represent a lucrative product market, methods for commercializing this cell type are still being explored, as clinical studies investigating iPSCs continue to increase in number.

iPS Cell Therapies

2013 was a landmark year in Japan because it saw the first cellular therapy involving the transplant of iPS cells into humans initiated at the RIKEN Center in Kobe, Japan. Led by Masayo Takahashi of the RIKEN Center for Developmental Biology (CDB). Dr. Takahashi was investigating the safety of iPSC-derived cell sheets in patients with wet-type age-related macular degeneration.

Although the study was suspended in 2015 due to safety concerns, in June 2016 RIKEN Institute announced that it would resume the clinical study using allogeneic rather than autologous iPSC-derived cells, because of the cost and time efficiencies.

In a world-first, Cynata Therapeutics received approval in September 2016 to launch the world’s first formal clinical trial of an allogeneic iPSC-derived cell product, called CYP-001. The study involves centers in the UK and Australia. In this trial, Cynata is testing an iPS cell-derived mesenchymal stem cell (MSC) product for the treatment of GvHD.

On 16 May 2018, Nature News then reported that Japan’s health ministry gave doctors at Osaka University permission to take sheets of tissue derived from iPS cells and graft them onto diseased human hearts. The team of Japanese doctors, led by cardiac surgeon Yoshiki Sawa at Osaka University, will use iPS cells to create a sheet of 100 million heart-muscle cells. From preclinical studies in pigs, the medical team determined that thin sheets of cell grafts can improve heart function, likely through paracrine signaling.

Kyoto University Hospital in Kobe, Japan also stated it would be opening an iPSC therapy center in 2019, for purposes of conducting clinical studies on iPS cell therapies. Officials for Kyoto Hospital said it will open a 30-bed ward to test the efficacy and safety of the therapies on volunteer patients, with the hospital aiming to initiate construction at the site in February of 2016 and complete construction by September 2019.

iPS Cell Market Competitors

In 2009 ReproCELL, a company established as a venture company originating from the University of Tokyo and Kyoto University was the first to make iPSC products commercially available with the launch of its human iPSC-derived cardiomyocytes, which it called ReproCario.

Cellular Dynamics International, a Fujifilm company, is another major market player in the iPSC sector. Similar to ReproCELL, CDI established its control of the iPSC industry after being founded in 2004 by Dr. James Thomson at the University of Wisconsin-Madison, who in 2007 derived iPSC lines from human somatic cells for the first time ever (the feat was accomplished simultaneously by Dr. Shinya Yamanaka’s lab in Japan).

A European leader within the iPSC market is Ncardia, formed through the merger of Axiogenesis and Pluriomics. Founded in 2001 and headquartered in Cologne, Germany, Axiogenesis initially focused on generating mouse embryonic stem cell-derived cells and assays. After Yamanaka’s groundbreaking iPSC technology became available, Axiogenesis was the first European company to license and adopt Yamanaka’s iPSC technology in 2010.

Ncardia’s focus lies on preclinical drug discovery and drug safety through the development of functional assays using human neuronal and cardiac cells, although it is expanding into new areas. Its flagship offering is its Cor.4U human cardiomyocyte product family, including cardiac fibroblasts.

In summary, market leaders have emerged in all areas of iPSC development, including:

iPS Cell Commercialization

Key Findings

Key Topics Covered

1. SCOPE AND METHODOLOGY

2. EXECUTIVE SUMMARY

3. BACKGROUND – iPSC RESEARCH

4. MARKET ANALYSIS BY PRODUCT CATEGORY

5. MARKET ANALYSIS BY APPLICATION

6. MARKET ANALYSIS BY GEOGRAPHY

7. PATENTS

8. COMPANIES

9. COMPANY PROFILES

10. CONCLUSIONS

For more information about this report visit https://www.researchandmarkets.com/research/njhzjc/induced?w=12

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Induced Pluripotent Stem Cell (iPS Cell): 2018-2022 …

Recommendation and review posted by sam

Physician Assistant Studies (masters degree) | University …

What is a Physician Assistant?Physician assistants (PA) are health professionals who practice medicine as members of a team with their supervising physicians. PAs deliver a broad range of medical and surgical services to diverse populations in rural and urban settings. As part of their comprehensive responsibilities, PAs conduct physical exams, diagnose and treat illnesses, order and interpret tests, counsel on preventive health care, assist in surgery, and prescribe medications. PAs promote quality, cost effective medical care to all members of society. Physician assistants are certified by the National Commission on Certification of Physician Assistants (NCCPA) and state-licensed.

How do PA graduates become eligible to practice?Physician Assistant Studiesgraduates are eligible to take the Physician Assistant National Certifying Examination. After successful completion of the examination, they are eligible for state certification and licensure to practice as certified physician assistants.

Program LocationsThe University of Kentucky PAS Program has two campuses: the Lexington campus is located in the Charles T. Wethington Building at the University of Kentucky and the Morehead Campus, which is housed in the Center for Health Education and Research (CHER Building) at Morehead State University.

AccreditationAt its 2017 March meeting, the Accreditation Review Commission on Education for the Physician Assistant (ARC-PA) placed the University of Kentucky Physician Assistant program sponsored by University of Kentucky on Accreditation-Probation status until its next review in 2019 March.Probation is a temporary status of accreditation conferred when a program does not meet the Standards and when the capability of the program to provide an acceptable educational experience for its students is threatened.Once placed on probation, programs that still fail to comply with accreditation requirements in a timely manner, as specified by the ARC-PA, may be scheduled for a focused site visit and/or risk having their accreditation withdrawn.Specific questions regarding the Program and its plans should be directed to the Program Director and/or the appropriate institutional official(s).

Program Director’s Response to Accreditation Status

UKPAS Program PANCE PerformanceUKPA Program PANCE Pass Rates please click here for the full report: UKPA PANCE Results

This document is subject to change due to changing tuition costs each academic year. You may check the University of Kentucky Registrar’swebsitefor the current tuition fees of the academic year. TheUKPAprogram will update the tuition and fee document for each new incoming cohort before matriculation in January.

Contact UsPhysician Assistant ProgramCollege of Health Sciences900 S. LimestoneLexington, KY 40536-0200

General InquiriesLexington 859- 218-0567Morehead 606-783-2051

Admissions AdvisementLexington 859-257-5001Morehead 606-783-2558

Transfer Credit859-218-0473

Clinical Placement859-218-0498

Program Information Sheet(pdf)

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Physician Assistant Studies (masters degree) | University …

Recommendation and review posted by Rebecca Evans

cryonics Meaning in the Cambridge English Dictionary

Any opinions in the examples do not represent the opinion of the Cambridge Dictionary editors or of Cambridge University Press or its licensors.

They say current cryonics procedures can preserve the anatomical basis of mind, and that this should be sufficient to prevent information-theoretic death until future repairs might be possible.

The advantages and disadvantages of neuropreservation are often debated among cryonics advocates.

Resuscitation of a postembryonic human from cryonics is not possible with current science.

Cryonics is another method of life preservation but it cryopreserves organisms using liquid nitrogen that will preserve the organism until reanimation.

A moral premise of cryonics is that all terminally ill patients should have the right, if they so choose, to be cryopreserved.

Cryonics patients need a professional response team to stand ready for suspended animation, when the patients are legally declared as dead.

The term is used in cryonics.

Some scientific literature supports the feasibility of cryonics.

The word is also used as a synonym for cryostasis or cryonics.

Rather, it is an examination of different philosophies and perspectives on life, offering viewers a glimpse into the science and commercialism in fields like funeral planning, cryonics, and anti-aging practices.

While cryonics is sometimes suspected of being greatly profitable, the high expenses of doing cryonics are well documented.

Cryonics procedures ideally begin within minutes of cardiac arrest, and use cryoprotectants to prevent ice formation during cryopreservation.

Unlike cryopreservation or cryonics, chemical techniques do not require freezing and storage at extremely low temperatures.

Cryonics organizations use cryoprotectants to reduce this damage.

Cryonics is the preservation through cold storage, usually with liquid nitrogen, of humans (and sometimes non-human animals) after legal death.

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cryonics Meaning in the Cambridge English Dictionary

Recommendation and review posted by Bethany Smith

Cryonics :: essays research papers

Cryonics

If youve ever seen the Austin Powers movie Im sure you remember the part where they cryogenically freeze Austin and then thirty years later thaw him out to save the world. While we all know Austin Powers isnt real, Im sure you wondered if this freezing could be done in real life. Today we will look at what exactly cryonics is, what businesses claim to provide it, the procedure and its risks.Cryonics is the freezing of humans to preserve them for a later time. Yes, it is a possibility. In fact there are several businesses that offer these services. Two of these businesses are The Cryonics Institute and The Alcor Life Extension Foundation. Alcor Life Extension Foundation calls this process Cryotransport. The cryotransport process begins, according to their website, as soon as possible after legal death. The patient is prepared and cooled to a temperature where decay stops, and is then kept in this cooled state called cryostasis until medical science has advanced enough to bring the person back to life when life extension and anti-aging have become a reality. However, there is a lot of damage done to the body during this freezing, says Dr. Ralph Merkle, a professional in the field of cryonics. First there are fractures that form in the frozen tissues caused by thermal strain, if you were warmed up youd fall into pieces as if cut by thousands of sharp knives. And Second, the Cryotransport is used as a last resort because legally the Cryotransport cant even begin until the patient is legally dead. So when the patient comes out he is already sick and may have a hard time coming back from the injuries of being frozen. Even after knowing all this Dr. Merkle says Cryotransport will almost surely work. Why? He says because basically people are made up of molecules and if they are arranged right then the person is healthy, if not the person is either sick or dead. With technological advances he thinks we will be able to make and rearrange the molecular structure of the frozen tissue. In the future, we will be able to stack and unstack these molecules like Lego blocks. Once the molecules are arranged correctly the person is healthy. Death, once we have this technology, really wont be the same. You couldnt be truly dead unless cremated; torn apart or destroyed in some other way that there would be no way to tell where these molecules are supposed to go.

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Cryonics :: essays research papers

Recommendation and review posted by Bethany Smith

Cryonics – H+Pedia – hpluspedia.org

Cryonics is a controversial life extension technique that aims to preserve neural activity and life typically of a recently deceased person through use of preservation techniques and low temperatures so that resurrection may be possible in the future when technologies have improved.

and with strange aeons even death may die.

Cryonics is the preservation of dead persons at temperatures low enough to practically stop decomposition, with the intent of future revival. While there is experimental evidence attesting to the conservation of vitrified tissue and the possibilities of repair; the decision to undergo cryonic preservation after death is an act of faith, not of science.

The two main ideas behind cryonics are Information-Theoretic Death and the technology vitrification. The first idea is the idea that our criteria for death has changed as our technology and our understanding of biology has changed. In the 1800s, a person who drowned was considered dead. Information-theoretic death is the ‘ultimate’ death, the one that we know as fact is irreversible, and does not depend upon a changing understanding of nature. Information theoretic death is reached when the body (Especially the brain) has been damaged to the point that it is beyond repair; where repair means having enough structure and contextual information to bring the brain, along with the personality, memories and attitudes that it contains, back to a functioning state. If tissues have been properly preserved, this revival could be accomplished through a variety of ways, but even the best methods leave behind irreparable damage, which means memory loss and personality changes, and other neurological (Motor control) damage. The latter is sufficiently generic to be repaired when that kind of technology arrives, the former is unique to each person and impossible to recover.

The second idea, vitrification, is a process through which tissue is lowered to cryogenic temperatures without freezing or forming ice. The most widely believed myth about cryonics is that when people are frozen, ice inside their cells bursts and destroys tissue irreparably. This is false on two points: Modern cryonics uses cryoprotectants which prevent ice damage by vitrifying instead of freezing, and the water that forms ice is mostly outside the cells. A common argument against cryoprotectants is that they are toxic: While true, this only affects the prospects of suspended animation through vitrification, since cryonics patients would probably be revived through more complicated means than just thawing them and applying CPR once a cure for what killed them is found.

To whom it may concern,

Cryonics is a legitimate science-based endeavor that seeks to preserve human beings, especially the human brain, by the best technology available. Future technologies for resuscitation can be envisioned that involve molecular repair by nanomedicine, highly advanced computation, detailed control of cell growth, and tissue regeneration.

With a view toward these developments, there is a credible possibility that cryonics performed under the best conditions achievable today can preserve sufficient neurological information to permit eventual restoration of a person to full health.

The rights of people who choose cryonics are important, and should be respected.

Most criticism of cryonics arises from fundamental misconceptions (For example, that cryonics involves freezing) and ignorance of current cryopreservation techniques and procedures.

While definitely great progress from most cryonics ‘criticism’ to date, the paper seems to address the well-known fact that reanimation from cryopreservation is impossible (Or nearly so) due to the toxicity of cryoprotectant solutions. The most discussed methods of revival, Molecular Nanotechnology and Whole Brain Emulation are not discussed.

While it’s sad that people focus on philosophical issues instead of the myriad technical and social problems that plague cryonics, along with its attachment to a history of failure and incompetence, philosophical concerns should still be addressed.

By far the biggest philosophical concern people put forward against cryonics is the issue of continuity of consciousness. In these debates, people can easily talk past each other by using different definitions of what constitutes consciousness and how this relates to personal identity. In general, we have two definitions of consciousness:

But what is relevant is not the definition of consciousness, but how this matters to personal identity. Again, here we have two opinions:

Under Definition 1, cryonics patients will be the same person ( brain damage). Under the second definition, when they are repaired, the patients are fundamentally different people who claim to be the same as the original and only shre personality and memories.

The Prospect of Immortality by Robert Ettinger, 1962

The First Immortal: A Novel Of The Future by James L. Halperin, 1998

Man into Superman: The Startling Potential of Human Evolution — And How To Be Part of It by Robert Ettinger, 1972

Connectome: How the Brain’s Wiring Makes Us Who We Are by Sebastian Seung, 2012

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Cryonics – Transhumanism

what is cryonic suspension?

Cryonic suspension is a scientific approach at extending the life of humans, essentially leading them to immortality. Cryonic suspension is a process in which the human body is preserved at very low temperatures with the hope that in the future it will be revived and able to function again. After a person dies, if they wish to be preserved, their body is injected with preserving chemicals. After the body is frozen from these chemicals, it is suspended in liquid nitrogen until it is time for revival. The purpose of cryonics is to preserve a body in the best state possible so that once it is revived in the future it can be treated with advanced medicine and technology. Scientists begin the preserving process as soon as possible, after legal death is declared, in order to prevent any loss of information from the brain.

In order for a person to be suspended, they must be declared legally dead and the procedure must be legally documented in a will. This is necessary to ensure cryonics is desired and approved by the patient. The small time frame for a person to get to a cryonics lab is necessary to ensure that the brain will remain fully functional when the person is injected. If too much time passes, the brain will start to diminish and if the person is revived, their brain may not function correctly, making the revival pointless. Scientists have been working for decades, and continue working today, to preserve these humans in a way that will leave them unharmed by the time a revival process is discovered. The topic of cryonics has become much more serious to scientists and whose who wish to be preserved. People who plan to preserve their bodies try to ensure a comfortable life in the future. It is important to make sure that the person will not have to worry about living in a different time after they are revived. These individuals create a plan for themselves so they will have everything they need once they are revived. They set up financial plans, ensure that their money will be available to them in the future, and some even seek the help of insurance companies to make sure they are covered for the future. There are some insurance companies that will even cover the cost of the cryonic suspension process.

So why choose cryonic suspension?

Cryonics could specifically be beneficial to individuals who are sick with disease or fatal injuries. It is hopeful that cryonics will give these individuals a second chance at life. For those who may have died at a young age, cryonic suspension could allow them to continue living after not having the chance to fully experience life. For others who died from disease or illness, cryonics is fundamentally trying to preserve their bodies until the future can find a cure. Scientists are hopeful that if a person chooses to suspend their bodies because they are sick or diseased, the future will have a means of curing them to rid them of their illness. Many scientists believe that cryonic suspension will be prosperous in the future based on other scientific analyses. More recently, microscope sized computers and cell repair machines have shown that revival is likely to be a success. This nanotechnology circulates the body and looks for problems and ways to prevent or improve them. With the growing help from technology, scientists believe cryonics will prove to be successful in the future.

The picture above displays the processofcryonicsuspension beng performedas atrial runon a dummy for cryonicsworkers topracticethe procedure stepby step. It iscrucialthatcryonics workershave plenty ofexperiencewith the procedure to avoid anymalfunctionsor damgage to the individual.

There are currently thousands of bodies in line for cryonic suspension. Over the next few decades, it is possible that there could potentially be hundreds of thousands of people suspended in liquid nitrogen. In the future, it is highly unlikely that scientists will have the time or effort to unfreeze that many people. Realistically, only the first few people will be interesting to converse with and the rest after that will be repetitive and unexciting. Scientists are worried that this process could also cause potential problems for the futuristic world. If the world is already overpopulated, why would scientists unfreeze a few hundred thousand more? The future is bound to be different from the current world in many ways. Impending problems such as overpopulation, war and scarcity of natural resources, arise when looking toward the future. It may also be hard for the unfrozen individuals to adapt to life in the future. Other scientists are skeptical of the amount of damage that could possibly be done to the frozen bodies since they are frozen at such low temperatures. Cryonics labs freeze bodies initially at negative eighty degrees and later cool them to around negative two hundred degrees. There are no known species that can survive at temperatures that low, which makes cryonics seem senseless. Ken Storey, a professor of biochemistry at Canadas Carleton University, explains that cryonics practitioners freeze bodies so slowly all the cells would be dead from lack of oxygen long before they freeze (Luntz 2009). If cells cannot withstand the temperatures at which they are frozen, then revival will be nearly impossible. If it is possible for scientists to discover a method of preserving the cells without damage, cryonic suspension will not only be feasible but could prove to be one of the greatest scientific breakthroughs of all time.

advancements in brain tissue damage

Before 1992, when going through the process of cryonic suspension, the amount of damage to the brain tissue was very large and uncontrollable. There was little advancement in technology to prevent damage to the tissue, so the formation of ice crystals and freezing damage were simple unavoidable.

Today, the amount of damage done to the braintissue is almost nonexistent when going throughthe process of cryonic suspension. There havebeen many advancements in technology toprevent the formation of icecrystals in thebrain.The cryonic suspensionprocess cannowbe donewith the assurance oflittle to no freezing damageto the brain.

a closer look at cryonic suspension…

There are currently over a hundred bodies in cryonic suspension and there are a few thousand more in line to preserve their bodies at the time of their death. Scientists are working hard and aiming toward advancements in discovering a revival technique to return these preserved individuals to their living state with as minimal damage as possible. Cryonics researchers are hopeful that once a revival process is discovered, the individuals who have been preserved will be cured of their illnesses due to the future advancements in technology and medicine. The revived patients would then be able to begin their new lives and settle themselves in a new, future environment. As the future becomes a reality, cryonics is becoming more pertinent to individuals who are seeking life extension.

For more information on cryonics visit:http://www.alcor.org/AboutCryonics/index.html

http://www.alcor.org/AboutCryonics/index.html

University of the Sciences in PhiladelphiaWriting 102 -04Amanda Martillotti

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Cryonics – Transhumanism

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Cryonics | Halo Nation | FANDOM powered by Wikia

Though often mistaken for cryogenics, which is merely the study of cold on materials, Cryonics is the science of cryo-preservation, using a mixture of factors to preserve a Human or other organism in stasis for periods of time.

Essentially, extremely low temperatures are created, preserving the human body almost indefinitely. Preserving the human brain is more problematic, but UNSC technology has apparently overcome the obstacles of neural tissue damage and resuscitation, but with tissue damage still being a problem, causing what is colloquially called “Freezer burn.”[1] However as stated in Halo: Contact Harvest, the UNSC seems to use certain types of drugs to prevent “Freezer burn.”

The UNSC uses cryonic storage pods in long-range warships, storing personnel for long periods to prevent aging during the journey and to preserve life-vital systems, maintaining only skeleton crews until nearing their target zone.[2] A bronchial surfactant is ingested, intended to replace nutrients lost during the journey, but the process is unpleasant and often induces vomiting.[3]

It is unknown whether the Covenant use a version of this technology. Given the dramatically higher speeds their warships can achieve, though, it is unlikely that it is necessary. The Forerunners used a system similar in practice, but using slipspace to store the personnel within the pod instead of merely freezing them.[4]In some cases UNSC marines can be placed in cryostasis to help ration food and oxygen as they don’t need it if they are frozen.

Cytoprethaline, a drug used by the UNSC during cryo-sleep, prevents damage to the occupants cell membranes caused by ice crystal formation.

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Life Extension | Superpower Wiki | FANDOM powered by Wikia

Life ExtensionPower/Ability to:

extend one’s life

The power to extend one’s life. Sub-power of Lifespan Manipulation. Variation of Immortality. Opposite to Life Reduction.

User can somehow extend their or others’ lifespan significantlyor maybe even indefinitelyin order to live longer.

By continuously bathing in the Lazarus Pits, Ra’s al Ghul (DC Comics) has extended his life for over 600 years.

Toki (Fist of the North Star) was able to use his knowledge of pressure points to extend the mortally wounded Rei’s life by a few days.

By continuously lengthening her telomeres, Tomiko Asahina (From the New World) has extended her life for over 200 years.

Lachesis (Valkyrie Crusade) can extend the years of life of anyone she wants as much as she wants.

Heart of Atlantis (Atlantis: The Lost Empire) provides phenomenal longevity, with the ability to extend an individual’s lifespan by almost 500 times.

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Life Extension | Superpower Wiki | FANDOM powered by Wikia

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Main Inheritance Patterns | Genes in Life

Genetictraitscan be passed from parent to child in different ways. As you will see, people can carry agenebut not be affected directly by it themselves. These patterns help to explain why a condition can seem to skip a generation or be more common in boys than in girls. Making a family health portrait, as described inHow Do I Collect My Family History?, can help to uncover these patterns.

Ourgenesare grouped into collections calledchromosomes. Most people have 46 chromosomes, in 23 pairs. One of the pairs is the sex chromosomes, called X and Y. Your sex chromosomes carry the genes that make you male or female. Women have two X chromosomes, and men have an X and a Y. The rest of your chromosomes are calledautosomalchromosomes. Let’s see what happens when you have a gene that does not work the way it is supposed to on these chromosomes.

Autosomal Inheritance Patterns

Autosomal dominant

Autosomal dominant means that only one copy of the gene that does not work correctly is needed for someone to have the condition.

If one parent has an autosomal dominant condition, they have one functional copyof the gene and one copy that does not work properly. If the other parent has two copies of the gene that work correctly:

Autosomal dominant conditions, such as Huntingtons disease, affect males and females equally.

Autosomal recessive means that a person needs two copies of a gene that do not work properly to have the condition. In this pattern, people with one working copy of the gene and one copy of the gene that does not function correctly are called carriers. Carriers do not have any signs or symptoms of the condition, but they can still pass on the gene that does not function properly to their children. Usually, parents of children with anautosomal recessivecondition are carriers.

If both parents are carriers of a condition:

Autosomal recessive conditions, such as cystic fibrosis, affect males and females equally.

Your sex chromosomes carry the genes that make you a male or female. A female has two X chromosomes. A male has oneX chromosomeand oneY chromosome. If a gene for a condition is carried on the sex chromosomes, we say it is X-linked. X-linked patterns are not as simple as autosomal patterns, because they show up differently in males and females.

X-linked dominantinheritanceoccurs when a gene that does not work correctly on a single X-chromosome results in a condition. Conditions caused by X-linked dominance are rare, and the same condition can vary considerably in severity, especially among women.

The odds of passing down a condition that is X-linked dominant are different depending on whether the mother or father has the gene that does not function properly and on the sex of the child.

If a father has the condition:

If a mother has one working copy of the gene and one copy of the gene that does not work correctly:

Males are often more seriously affected than females by disorders inherited through X-linked dominance. Sometimes, even if a female inherits the gene change on one of her X chromosomes, she will not show symptoms or her symptoms will be less severe. It is thought that if a female has a working copy of the gene on one X-chromosome in addition to the altered copy on the other X-chromosome, the effects of the condition may be dampened. This has led some scientists to suggest that X-linked inheritance should not be described in terms of dominant and recessive, but rather simply be explained as X-linked inheritance.

Incontinentia pigmentiis an X-linked dominantdisorderthat affects multiple systems, but especially the skin.

X-linked recessive means that if there is one working copy of the gene, a person will not have the condition. The gene for these conditions is on the X chromosome. X-linked recessive conditions affect males more often than females. If a male has a copy of the gene that does not function the way it should on his only X chromosome, then he will be affected by the condition.

Some forms of hemophilia are X-linked recessive conditions.

If a father has an X-linked recessive condition:

If a female has two copies of the gene that do not function correctly, then she will be affected by the condition. If she has a working copy on one X chromosome and a copy of the gene that does not work the way it should on her other X chromosome, then she is called a carrier. Carriers are not affected by the condition, but they can still pass the gene that does not work correctly on to their children.

If a mother has an X-linked recessive condition, then she has two copies of the gene that do not function properly:

If a mother is a carrier of an X-linked recessive condition, she has one functional copy of the gene and one copy that does not function correctly:

If the mother is a carrier and the father has the condition, then there is a 1 in 2 chance (50%) that a daughter would be affected. She would always get the gene that does not work properly from her father, but she might get a working gene from her mother.

Most of our genes are stored in our chromosomes, which sit in each cells headquartersthe nucleus. We also have some genes in small structures in the cell called mitochondria. Mitochondria are sometimes called the power plants of the cell: they work on molecules to make them ready to give us the energy we need for our body functions. The mitochondrial genes always pass from the mother to the child. Fathers get their mitochondrial genes from their mothers, and do not pass them to their children.

Mitochondrial inheritance, also called maternal inheritance, refers to genes in the mitochondria. Although these conditions affect both males and females, only mothers pass mitochondria on to their children.

Diabetes mellitus and deafness, a rare form of diabetes, follows the mitochondrial inheritance pattern.

Check outGenetics Home Referencefor more about genetic conditions and inheritance.

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Main Inheritance Patterns | Genes in Life

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Gene Therapy – Genetics Generation

What is Gene Therapy?

Gene therapy is a technique used to correct defective genes genes that are responsible for disease development. Specifically, according to the American Society of Gene and Cell Therapy-

Gene therapy is defined as a set of strategies that modify the expressionof an individuals genes or that correct abnormal genes. Each strategyinvolves the administration of a specific DNA (or RNA).

Gene therapy is the manipulation of the expression of specific genes in a persons body, in hopes of treating a disease or disorder. Gene therapy is still considered experimental and only available via clinical trial. Although many successful trials have been documented (see Interesting Links below), gene therapy has a checkered history. In some gene therapy trials, there were cases of leukemia as an unintended side-effect, and even cases of death (see link on Jesse Gelsinger below).

Image courtesy of Wikimedia Commons

How Does Gene Therapy Work?

Although there are several strategies for gene therapy, the most commonly used method involves inserting a therapeutic gene into the genome to replace the abnormal or disease-causing gene. The gene that is inserted is delivered into a target cell via a vector. Usually, this vector is a virus, although non-viral vectors are in development. Viruses are a good choice for introducing genes into a cell because they typically operate by transferring their own genetic material while replicating themselves. Once target cells are infected with the viral vector, the vector releases its therapeutic gene which then incorporates into the cells DNA. The goal is that the cell will start using the new gene to make functional, healthy proteins.

There are three main strategies for using gene therapy to restore the target cells or target tissues to a normal, healthy state.

1. Insert the functional version of a gene in hopes of replacing the abnormal form. This is used to treat single-gene disorders like hemophilia A and B and cystic fibrosis.

2. Insert a gene that encodes for a therapeutic protein that treats a disease. This is used to treat acquired diseases likeinfection or ischemic heart disease.

3. Use gene transfer to down-regulate gene expression in hopes of decreasing the activity of a harmful gene.

Current Areas of Research

Although gene therapy is still experimental, many diseases have been targets for gene therapy in clinical trials. Some of these trials have produced promising results. Diseases that may be treated successfully in the future with gene therapy include (but are not limited to):* Anemias* Cardiovascular diseases* Cystic Fibrosis* Diabetes* Diseases of the bones and joints* Eye disease and Blindness* Gauschers Disease* Hemophilia* Huntingtons Disease* Lysosomal storage diseases* Muscular Dystrophy* Sickle cell disorder

The main challenges facing gene therapy are the identification of disease causing genes, the targeted delivery of the therapeutic gene specifically to the affected tissues, and the prevention of side effects (such as an immune response) in the patient.

Gene Therapy for Enhancement Purposes

If gene therapy becomes routine medical practice, then it is reasonable to believe that some will seek it out for enhancement purposes. For example, a gene therapy designed to help patients with Alzheimers disease may be appealing to a normal individual hoping to boost memory. One potential area of enhancement that has been discussed is gene doping in sports. Gene doping is defined by the World Anti-Doping Agency (WADA) as the non-therapeutic use of genes, genetic elements and/or cells that have the capacity to enhance athletic performance. The purpose of gene doping is toenhancea given gene rather thancorrecta faulty one. Potential targets of gene doping include:

* Erythropoietin (EPO) for increased production of red blood cells* Insulin-like Growth Factor-1 gene for increased muscle mass* Myostatin for increased muscle mass* Vascular Endothelial Growth Factor (VEGF) for an increase in blood flow

This form of doping would be hard to detect because the doping substances are produced directly in an individuals own cells after these genes with performance-enhancing effects have been expressed. Whether or not to use gene therapy in the future for enhancement purposes, and how to regulate it, will require a complex discussion of ethics in which there will likely be many differing opinions.

Interesting Links*The American Society of Gene and Cell Therapy* National Geographic articleon gene doping* Science Daily article onrecent gene therapy news* New York Times article on the death of Jesse Gelsinger* Scientific American article on treating blindness with gene therapy

CLICK HERE to read our case study involving ethical issues associated with gene therapy

REFERENCES

Gene Therapy and Cell Therapy Defined. American Society of Gene and Cell Therapy, n.d. Web. 04 Nov. 2012. .

Gene Therapy..Human Genome Project Information, n.d. We. 04 Nov. 2012.

Pawliuk R et al. Correction of sickle cell disease in transgenic mouse models by gene therapy. Science. 2001; 294:2368-2371.

Unal M, Unal DO. Gene doping in sports. Sports Medicine. 2004; 34:357-362.

Wells DJ. Gene doping: the hype and the reality. British Journal of Pharmacology. 2008 January; 154: 623-631.

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Gene Therapy – Genetics Generation

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OMIM Entry – # 146510 – PALLISTER-HALL SYNDROME; PHS

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Demurger, F., Ichkou, A., Mougou-Zerelli, S., Le Merrer, M., Goudefroye, G., Delezoide, A.-L., Quelin, C., Manouvrier, S., Baujat, G., Fradin, M., Pasquier, L., Megarbane, A., and 40 others. New insights into genotype-phenotype correlation for GLI3 mutations. Europ. J. Hum. Genet. 23: 92-102, 2015. [PubMed: 24736735] [Full Text: https://dx.doi.org/10.1038/ejhg.2014.62%5D

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Galasso, C., Scire, G., Fabbri, F., Spadoni, G. L., Killoran, C. E., Biesecker, L. G., Boscherini, B. Long-term treatment with growth hormone improves final height in a patient with Pallister-Hall syndrome. Am. J. Med. Genet. 99: 128-131, 2001. [PubMed: 11241471] [Full Text: http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0148-7299&date=2001&volume=99&issue=2&spage=128%5D

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Hall, J. G., Pallister, P. D., Clarren, S. K., Beckwith, J. B., Wiglesworth, F. W., Fraser, F. C., Cho, S., Benke, P. J., Reed, S. D. Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus, and postaxial polydactyly–a new syndrome? Part I: clinical, causal, and pathogenetic considerations. Am. J. Med. Genet. 7: 47-74, 1980. [PubMed: 7211952] [Full Text: http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0148-7299&date=1980&volume=7&issue=1&spage=47%5D

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Iafolla, K., Fratkin, J. D., Spiegel, P. K., Cohen, M. M., Jr., Graham, J. M., Jr. Case report and delineation of the congenital hypothalamic hamartoblastoma syndrome (Pallister-Hall syndrome). Am. J. Med. Genet. 33: 489-499, 1989. [PubMed: 2688416] [Full Text: http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0148-7299&date=1989&volume=33&issue=4&spage=489%5D

Johnston, J. J., Olivos-Glander, I., Killoran, C., Elson, E., Turner, J. T., Peters, K. F., Abbott, M. H., Aughton, D. J., Aylsworth, A. S., Bamshad, M. J., Booth, C., Curry, C. J., and 36 others. Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations. Am. J. Hum. Genet. 76: 609-622, 2005. [PubMed: 15739154] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)62872-9%5D

Kang, S., Allen, J., Graham, J. M., Jr., Grebe, T., Clericuzio, C., Patronas, N., Ondrey, F., Green, E., Schaffer, A., Abbott, M., Biesecker, L. G. Linkage mapping and phenotypic analysis of autosomal dominant Pallister-Hall syndrome. J. Med. Genet. 34: 441-446, 1997. [PubMed: 9192261] [Full Text: http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=9192261%5D

Kang, S., Graham, J. M., Jr., Abbott, M., Schaffer, A., Green, E. D., Rosenberg, M., Allen, J., Clericuzio, C., Grebe, T., Haskins-Olney, A., Biesecker, L. G. Autosomal dominant Pallister-Hall syndrome maps to 7p13. (Abstract) Am. J. Hum. Genet. 59 (suppl.): A17 only, 1996.

Kang, S., Graham, J. M., Jr., Olney, A. H., Biesecker, L. G. GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome. Nature Genet. 15: 266-268, 1997. [PubMed: 9054938] [Full Text: https://dx.doi.org/10.1038/ng0397-266%5D

Killoran, C. E., Abbott, M., McKusick, V. A., Biesecker, L. G. Overlap of PIV syndrome, VACTERL and Pallister-Hall syndrome: clinical and molecular analysis. Clin. Genet. 58: 28-30, 2000. [PubMed: 10945658] [Full Text: http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=2000&volume=58&issue=1&spage=28%5D

Kletter, G. B., Biesecker, L. G. Male-to-male transmission of the Pallister-Hall syndrome. (Abstract) Am. J. Hum. Genet. 51 (suppl.): A100 only, 1992.

Kuller, J. A., Cox, V. A., Schonberg, S. A., Golabi, M. Pallister-Hall syndrome associated with an unbalanced chromosome translocation. Am. J. Med. Genet. 43: 647-650, 1992. [PubMed: 1605268] [Full Text: http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0148-7299&date=1992&volume=43&issue=3&spage=647%5D

Low, M., Moringlane, J. R., Reif, J., Barbier, D., Beige, G., Kolles, H., Kujat, C., Zang, K. D., Henn, W. Polysyndactyly and asymptomatic hypothalamic hamartoma in mother and son: a variant of Pallister-Hall syndrome. Clin. Genet. 48: 209-212, 1995. [PubMed: 8591673] [Full Text: http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=1995&volume=48&issue=4&spage=209%5D

Lurie, I. W. Pallister-Hall and McKusick-Kaufmann syndromes. (Letter) J. Med. Genet. 32: 668-672, 1995. [PubMed: 7473667] [Full Text: http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=7473667%5D

Lurie, I. W., Wulfsberg, E. A. The McKusick-Kaufmann syndrome: phenotypic variation observed in familial cases as a clue for the evaluation of sporadic cases. Genet. Counsel. 5: 275-281, 1994. [PubMed: 7811428]

Narumi, Y., Kosho, T., Tsuruta, G., Shiohara, M., Shimazaki, E., Mori, T., Shimizu, A., Igawa, Y., Nishizawa, S., Takagi, K., Kawamura, R., Wakui, F., Fukushima, Y. Genital abnormalities in Pallister-Hall syndrome: report of two patients and review of the literature. Am. J. Med. Genet. 152A: 3143-3147, 2010. [PubMed: 21108399] [Full Text: https://dx.doi.org/10.1002/ajmg.a.33720%5D

Ondrey, F., Griffith, A., Van Waes, C., Rudy, S., Peters, K., McCullagh, L., Biesecker, L. G. Asymptomatic laryngeal malformations are common in patients with Pallister-Hall syndrome. Am. J. Med. Genet. 94: 64-67, 2000. [PubMed: 10982485] [Full Text: http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0148-7299&date=2000&volume=94&issue=1&spage=64%5D

Pallister, P. D., Hecht, F., Herrman, J. Three additional cases of the congenital hypothalamic ‘hamartoblastoma’ (Pallister-Hall) syndrome. (Letter) Am. J. Med. Genet. 33: 500-501, 1989. [PubMed: 2596511] [Full Text: http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0148-7299&date=1989&volume=33&issue=4&spage=500%5D

Penman Splitt, M., Wright, C., Perry, R., Burn, J. Autosomal dominant transmission of Pallister-Hall syndrome. Clin. Dysmorph. 3: 301-308, 1994. [PubMed: 7894735]

Sama, A., Mason, J. D. T., Gibbin, K. P., Young, I. D., Hewitt, M. The Pallister-Hall syndrome. (Letter) J. Med. Genet. 31: 740 only, 1994. [PubMed: 7815447] [Full Text: http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=7815447%5D

Say, B., Gerald, P. S. A new polydactyly–imperforate-anus–vertebral-anomalies syndrome? (Letter) Lancet 292: 688 only, 1968. Note: Originally Volume II. [PubMed: 4175523] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0140-6736(68)92549-X%5D

Sills, I. N., Rapaport, R., Desposito, F., Lieber, C. Familial Pallister-Hall syndrome: three affected offspring. (Letter) Am. J. Med. Genet. 52: 251 only, 1994. [PubMed: 7802025] [Full Text: http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0148-7299&date=1994&volume=52&issue=2&spage=251%5D

Sills, I. N., Rapaport, R., Robinson, L. P., Lieber, C., Shih, L. Y., Horlick, M. N. B., Schwartz, M., Desposito, F. Familial Pallister-Hall syndrome: case report and hormonal evaluation. Am. J. Med. Genet. 47: 321-325, 1993. [PubMed: 8135274] [Full Text: http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0148-7299&date=1993&volume=47&issue=3&spage=321%5D

Stoll, C., de Saint Martin, A., Donato, L., Alembik, Y., Sauvage, P., Messer, J. Pallister-Hall syndrome with stenosis of the cricoid cartilage and microphallus without hypopituitarism. Genet. Counsel. 12: 231-235, 2001. Note: Erratum: Genet. Counsel. 13: 69 only, 2002. [PubMed: 11693785]

Thomas, H. M., Todd, P. J., Heaf, D., Fryer, A. E. Recurrence of Pallister-Hall syndrome in two sibs. J. Med. Genet. 31: 145-147, 1994. [PubMed: 8182722] [Full Text: http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=8182722%5D

Topf, K. F., Kletter, G. B., Kelch, R. P., Brunberg, J. A., Biesecker, L. G. Autosomal dominant transmission of the Pallister-Hall syndrome. J. Pediat. 123: 943-946, 1993. [PubMed: 8229528]

Unsinn, K. M., Neu, N., Krejci, A., Posch, A., Menardi, G., Gassner, I. Pallister-Hall syndrome and McKusick-Kaufmann (sic) syndrome: one entity? J. Med. Genet. 32: 125-128, 1995. [PubMed: 7760322] [Full Text: http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=7760322%5D

Verloes, A. Numerical syndromology: a mathematical approach to the nosology of complex phenotypes. Am. J. Med. Genet. 55: 433-443, 1995. [PubMed: 7762583] [Full Text: http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0148-7299&date=1995&volume=55&issue=4&spage=433%5D

Verloes, A., David, A., Ngo, L., Bottani, A. Stringent delineation of Pallister-Hall syndrome in two long surviving patients: importance of radiological anomalies of the hands. J. Med. Genet. 32: 605-611, 1995. [PubMed: 7473651] [Full Text: http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=7473651%5D

Verloes, A., Gillerot, Y., Langhendries, J.-P., Fryns, J.-P., Koulischer, L. Variability versus heterogeneity in syndromal hypothalamic hamartoblastoma and related disorders: review and delineation of the cerebro-acro-visceral early lethality (CAVE) multiplex syndrome. Am. J. Med. Genet. 43: 669-677, 1992. [PubMed: 1621756] [Full Text: http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0148-7299&date=1992&volume=43&issue=4&spage=669%5D

Verloes, A., Narcy, F., Fallet-Bianco, C. Syndromal hypothalamic hamartoblastoma with holoprosencephaly sequence, microphthalmia, pulmonary malformations, radial hypoplasia and mullerian regression: further delineation of a new syndrome? Clin. Dysmorph. 4: 33-37, 1995. [PubMed: 7735503]

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OMIM Entry – # 146510 – PALLISTER-HALL SYNDROME; PHS

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Mending a Broken Heart: Stem Cells and Cardiac Repair …

Charles A. Goldthwaite, Jr., Ph.D.

Cardiovascular disease (CVD), which includes hypertension, coronary heart disease (CHD), stroke, and congestive heart failure (CHF), has ranked as the number one cause of death in the United States every year since 1900 except 1918, when the nation struggled with an influenza epidemic.1 In 2002, CVD claimed roughly as many lives as cancer, chronic lower respiratory diseases, accidents, diabetes mellitus, influenza, and pneumonia combined. According to data from the 19992002 National Health and Nutrition Examination Survey (NHANES), CVD caused approximately 1.4 million deaths (38.0 percent of all deaths) in the U.S. in 2002. Nearly 2600 Americans die of CVD each day, roughly one death every 34 seconds. Moreover, within a year of diagnosis, one in five patients with CHF will die. CVD also creates a growing economic burden; the total health care cost of CVD in 2005 was estimated at $393.5 billion dollars.

Given the aging of the U.S. population and the relatively dramatic recent increases in the prevalence of cardiovascular risk factors such as obesity and type 2 diabetes,2,3 CVD will continue to be a significant health concern well into the 21st century. However, improvements in the acute treatment of heart attacks and an increasing arsenal of drugs have facilitated survival. In the U.S. alone, an estimated 7.1 million people have survived a heart attack, while 4.9 million live with CHF.1 These trends suggest an unmet need for therapies to regenerate or repair damaged cardiac tissue.

Ischemic heart failure occurs when cardiac tissue is deprived of oxygen. When the ischemic insult is severe enough to cause the loss of critical amounts of cardiac muscle cells (cardiomyocytes), this loss initiates a cascade of detrimental events, including formation of a non-contractile scar, ventricular wall thinning (see Figure 6.1), an overload of blood flow and pressure, ventricular remodeling (the overstretching of viable cardiac cells to sustain cardiac output), heart failure, and eventual death.4 Restoring damaged heart muscle tissue, through repair or regeneration, therefore represents a fundamental mechanistic strategy to treat heart failure. However, endogenous repair mechanisms, including the proliferation of cardiomyocytes under conditions of severe blood vessel stress or vessel formation and tissue generation via the migration of bone-marrow-derived stem cells to the site of damage, are in themselves insufficient to restore lost heart muscle tissue (myocardium) or cardiac function.5 Current pharmacologic interventions for heart disease, including beta-blockers, diuretics, and angiotensin-converting enzyme (ACE) inhibitors, and surgical treatment options, such as changing the shape of the left ventricle and implanting assistive devices such as pacemakers or defibrillators, do not restore function to damaged tissue. Moreover, while implantation of mechanical ventricular assist devices can provide long-term improvement in heart function, complications such as infection and blood clots remain problematic.6 Although heart transplantation offers a viable option to replace damaged myocardium in selected individuals, organ availability and transplant rejection complications limit the widespread practical use of this approach.

Figure 6.1. Normal vs. Infarcted Heart. The left ventricle has a thick muscular wall, shown in cross-section in A. After a myocardial infarction (heart attack), heart muscle cells in the left ventricle are deprived of oxygen and die (B), eventually causing the ventricular wall to become thinner (C).

2007 Terese Winslow

The difficulty in regenerating damaged myocardial tissue has led researchers to explore the application of embryonic and adult-derived stem cells for cardiac repair. A number of stem cell types, including embryonic stem (ES) cells, cardiac stem cells that naturally reside within the heart, myoblasts (muscle stem cells), adult bone marrow-derived cells, mesenchymal cells (bone marrow-derived cells that give rise to tissues such as muscle, bone, tendons, ligaments, and adipose tissue), endothelial progenitor cells (cells that give rise to the endothelium, the interior lining of blood vessels), and umbilical cord blood cells, have been investigated to varying extents as possible sources for regenerating damaged myocardium. All have been tested in mouse or rat models, and some have been tested in large animal models such as pigs. Preliminary clinical data for many of these cell types have also been gathered in selected patient populations.

However, clinical trials to date using stem cells to repair damaged cardiac tissue vary in terms of the condition being treated, the method of cell delivery, and the primary outcome measured by the study, thus hampering direct comparisons between trials.7 Some patients who have received stem cells for myocardial repair have reduced cardiac blood flow (myocardial ischemia), while others have more pronounced congestive heart failure and still others are recovering from heart attacks. In some cases, the patient’s underlying condition influences the way that the stem cells are delivered to his/her heart (see the section, quot;Methods of Cell Deliveryquot; for details). Even among patients undergoing comparable procedures, the clinical study design can affect the reporting of results. Some studies have focused on safety issues and adverse effects of the transplantation procedures; others have assessed improvements in ventricular function or the delivery of arterial blood. Furthermore, no published trial has directly compared two or more stem cell types, and the transplanted cells may be autologous (i.e., derived from the person on whom they are used) or allogeneic (i.e., originating from another person) in origin. Finally, most of these trials use unlabeled cells, making it difficult for investigators to follow the cells’ course through the body after transplantation (see the section quot;Considerations for Using These Stem Cells in the Clinical Settingquot; at the end of this article for more details).

Despite the relative infancy of this field, initial results from the application of stem cells to restore cardiac function have been promising. This article will review the research supporting each of the aforementioned cell types as potential source materials for myocardial regeneration and will conclude with a discussion of general issues that relate to their clinical application.

In 2001, Menasche, et.al. described the successful implantation of autologous skeletal myoblasts (cells that divide to repair and/or increase the size of voluntary muscles) into the post-infarction scar of a patient with severe ischemic heart failure who was undergoing coronary artery bypass surgery.8 Following the procedure, the researchers used imaging techniques to observe the heart’s muscular wall and to assess its ability to beat. When they examined patients 5 months after treatment, they concluded that treated hearts pumped blood more efficiently and seemed to demonstrate improved tissue health. This case study suggested that stem cells may represent a viable resource for treating ischemic heart failure, spawning several dozen clinical studies of stem cell therapy for cardiac repair (see Boyle, et.al.7 for a complete list) and inspiring the development of Phase I and Phase II clinical trials. These trials have revealed the complexity of using stem cells for cardiac repair, and considerations for using stem cells in the clinical setting are discussed in a subsequent section of this report.

The mechanism by which stem cells promote cardiac repair remains controversial, and it is likely that the cells regenerate myocardium through several pathways. Initially, scientists believed that transplanted cells differentiated into cardiac cells, blood vessels, or other cells damaged by CVD.911 However, this model has been recently supplanted by the idea that transplanted stem cells release growth factors and other molecules that promote blood vessel formation (angiogenesis) or stimulate quot;residentquot; cardiac stem cells to repair damage.1214 Additional mechanisms for stem-cell mediated heart repair, including strengthening of the post-infarct scar15 and the fusion of donor cells with host cardiomyocytes,16 have also been proposed.

Regardless of which mechanism(s) will ultimately prove to be the most significant in stem-cell mediated cardiac repair, cells must be successfully delivered to the site of injury to maximize the restored function. In preliminary clinical studies, researchers have used several approaches to deliver stem cells. Common approaches include intravenous injection and direct infusion into the coronary arteries. These methods can be used in patients whose blood flow has been restored to their hearts after a heart attack, provided that they do not have additional cardiac dysfunction that results in total occlusion or poor arterial flow.12, 17 Of these two methods, intracoronary infusion offers the advantage of directed local delivery, thereby increasing the number of cells that reach the target tissue relative to the number that will home to the heart once they have been placed in the circulation. However, these strategies may be of limited benefit to those who have poor circulation, and stem cells are often injected directly into the ventricular wall of these patients. This endomyocardial injection may be carried out either via a catheter or during open-heart surgery.18

To determine the ideal site to inject stem cells, doctors use mapping or direct visualization to identify the locations of scars and viable cardiac tissue. Despite improvements in delivery efficiency, however, the success of these methods remains limited by the death of the transplanted cells; as many as 90% of transplanted cells die shortly after implantation as a result of physical stress, myocardial inflammation, and myocardial hypoxia.4 Timing of delivery may slow the rate of deterioration of tissue function, although this issue remains a hurdle for therapeutic approaches.

Embryonic and adult stem cells have been investigated to regenerate damaged myocardial tissue in animal models and in a limited number of clinical studies. A brief review of work to date and specific considerations for the application of various cell types will be discussed in the following sections.

Because ES cells are pluripotent, they can potentially give rise to the variety of cell types that are instrumental in regenerating damaged myocardium, including cardiomyocytes, endothelial cells, and smooth muscle cells. To this end, mouse and human ES cells have been shown to differentiate spontaneously to form endothelial and smooth muscle cells in vitro19 and in vivo,20,21 and human ES cells differentiate into myocytes with the structural and functional properties of cardiomyocytes.2224 Moreover, ES cells that were transplanted into ischemically-injured myocardium in rats differentiated into normal myocardial cells that remained viable for up to four months,25 suggesting that these cells may be candidates for regenerative therapy in humans.

However, several key hurdles must be overcome before human ES cells can be used for clinical applications. Foremost, ethical issues related to embryo access currently limit the avenues of investigation. In addition, human ES cells must go through rigorous testing and purification procedures before the cells can be used as sources to regenerate tissue. First, researchers must verify that their putative ES cells are pluripotent. To prove that they have established a human ES cell line, researchers inject the cells into immunocompromised mice; i.e., mice that have a dysfunctional immune system. Because the injected cells cannot be destroyed by the mouse’s immune system, they survive and proliferate. Under these conditions, pluripotent cells will form a teratoma, a multi-layered, benign tumor that contains cells derived from all three embryonic germ layers. Teratoma formation indicates that the stem cells have the capacity to give rise to all cell types in the body.

The pluripotency of ES cells can complicate their clinical application. While undifferentiated ES cells may possibly serve as sources of specific cell populations used in myocardial repair, it is essential that tight quality control be maintained with respect to the differentiated cells. Any differentiated cells that would be used to regenerate heart tissue must be purified before transplantation can be considered. If injected regenerative cells are accidentally contaminated with undifferentiated ES cells, a tumor could possibly form as a result of the cell transplant.4 However, purification methodologies continue to improve; one recent report describes a method to identify and select cardiomyocytes during human ES cell differentiation that may make these cells a viable option in the future.26

This concern illustrates the scientific challenges that accompany the use of all human stem cells, whether derived from embryonic or adult tissues. Predictable control of cell proliferation and differentiation requires additional basic research on the molecular and genetic signals that regulate cell division and specialization. Furthermore, long-term cell stability must be well understood before human ES-derived cells can be used in regenerative medicine. The propensity for genetic mutation in the human ES cells must be determined, and the survival of differentiated, ES-derived cells following transplantation must be assessed. Furthermore, once cells have been transplanted, undesirable interactions between the host tissue and the injected cells must be minimized. Cells or tissues derived from ES cells that are currently available for use in humans are not tissue-matched to patients and thus would require immunosuppression to limit immune rejection.18

While skeletal myoblasts (SMs) are committed progenitors of skeletal muscle cells, their autologous origin, high proliferative potential, commitment to a myogenic lineage, and resistance to ischemia promoted their use as the first stem cell type to be explored extensively for cardiac application. Studies in rats and humans have demonstrated that these cells can repopulate scar tissue and improve left ventricular function following transplantation.27 However, SM-derived cardiomyocytes do not function in complete concert with native myocardium. The expression of two key proteins involved in electromechanical cell integration, N-cadherin and connexin 43, are downregulated in vivo,28 and the engrafted cells develop a contractile activity phenotype that appears to be unaffected by neighboring cardiomyocytes.29

To date, the safety and feasibility of transplanting SM cells have been explored in a series of small studies enrolling a collective total of nearly 100 patients. Most of these procedures were carried out during open-heart surgery, although a couple of studies have investigated direct myocardial injection and transcoronary administration. Sustained ventricular tachycardia, a life-threatening arrhythmia and unexpected side-effect, occurred in early implantation studies, possibly resulting from the lack of electrical coupling between SM-derived cardiomyocytes and native tissue.30,31 Changes in preimplantation protocols have minimized the occurrence of arrhythmias in conjunction with the use of SM cells, and Phase II studies of skeletal myoblast therapy are presently underway.

In 2001, Jackson, et.al. demonstrated that cardiomyocytes and endothelial cells could be regenerated in a mouse heart attack model through the introduction of adult mouse bone marrow-derived stem cells.9 That same year, Orlic and colleagues showed that direct injection of mouse bone marrow-derived cells into the damaged ventricular wall following an induced heart attack led to the formation of new cardiomyocytes, vascular endothelium, and smooth muscle cells.11 Nine days after transplanting the stem cells, the newly-formed myocardium occupied nearly 70 percent of the damaged portion of the ventricle, and survival rates were greater in mice that received these cells than in those that did not. While several subsequent studies have questioned whether these cells actually differentiate into cardiomyocytes,32,33 the evidence to support their ability to prevent remodeling has been demonstrated in many laboratories.7

Based on these findings, researchers have investigated the potential of human adult bone marrow as a source of stem cells for cardiac repair. Adult bone marrow contains several stem cell populations, including hematopoietic stem cells (which differentiate into all of the cellular components of blood), endothelial progenitor cells, and mesenchymal stem cells; successful application of these cells usually necessitates isolating a particular cell type on the basis of its’ unique cell-surface receptors. In the past three years, the transplantation of bone marrow mononuclear cells (BMMNCs), a mixed population of blood and cells that includes stem and progenitor cells, has been explored in more patients and clinical studies of cardiac repair than any other type of stem cell.7

The results from clinical studies of BMMNC transplantation have been promising but mixed. However, it should be noted that these studies have been conducted under a variety of conditions, thereby hampering direct comparison. The cells have been delivered via open-heart surgery and endomyocardial and intracoronary catheterization. Several studies, including the Bone Marrow Transfer to Enhance ST-Elevation Infarct Regeneration (BOOST) and the Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI) trials, have shown that intracoronary infusion of BMMNCs following a heart attack significantly improves the left ventricular (LV) ejection fraction, or the volume of blood pumped out of the left ventricle with each heartbeat.3436 However, other studies have indicated either no improvement in LV ejection fraction upon treatment37 or an increased LV ejection fraction in the control group.38 An early study that used endomyocardial injection to enhance targeted delivery indicated a significant improvement in overall LV function.39 Discrepancies such as these may reflect differences in cell preparation protocols or baseline patient statistics. As larger trials are developed, these issues can be explored more systematically.

Mesenchymal stem cells (MSCs) are precursors of non-hematopoietic tissues (e.g., muscle, bone, tendons, ligaments, adipose tissue, and fibroblasts) that are obtained relatively easily from autologous bone marrow. They remain multipotent following expansion in vitro, exhibit relatively low immunogenicity, and can be frozen easily. While these properties make the cells amenable to preparation and delivery protocols, scientists can also culture them under special conditions to differentiate them into cells that resemble cardiac myocytes. This property enables their application to cardiac regeneration. MSCs differentiate into endothelial cells when cultured with vascular endothelial growth factor40 and cardiomyogenic (CMG) cells when treated with the dna-demethylating agent, 5-azacytidine.41 More important, however, is the observation that MSCs can differentiate into cardiomyocytes and endothelial cells in vivo when transplanted to the heart following myocardial infarct (MI) or non-injury in pig, mouse, or rat models.4245 Additionally, the ability of MSCs to restore functionality may be enhanced by the simultaneous transplantation of other stem cell types.43

Several animal model studies have shown that treatment with MSCs significantly increases myocardial function and capillary formation.5,41 One advantage of using these cells in human studies is their low immunogenicity; allogeneic MSCs injected into infarcted myocardium in a pig model regenerated myocardium and reduced infarct size without evidence of rejection.46 A randomized clinical trial implanting MSCs after MI has demonstrated significant improvement in global and regional LV function,47 and clinical trials are currently underway to investigate the application of allogeneic and autologous MSCs for acute MI and myocardial ischemia, respectively.

Recent evidence suggests that the heart contains a small population of endogenous stem cells that most likely facilitate minor repair and turnover-mediated cell replacement.7 These cells have been isolated and characterized in mouse, rat, and human tissues.48,49 The cells can be harvested in limited quantity from human endomyocardial biopsy specimens50 and can be injected into the site of infarction to promote cardiomyocyte formation and improvements in systolic function.49 Separation and expansion ex vivo over a period of weeks are necessary to obtain sufficient quantities of these cells for experimental purposes. However, their potential as a convenient resource for autologous stem cell therapy has led the National Heart, Lung, and Blood Institute to fund forthcoming clinical trials that will explore the use of cardiac stem cells for myocardial regeneration.

The endothelium is a layer of specialized cells that lines the interior surface of all blood vessels (including the heart). This layer provides an interface between circulating blood and the vessel wall. Endothelial progenitor cells (EPCs) are bone marrow-derived stem cells that are recruited into the peripheral blood in response to tissue ischemia.4 EPCs are precursor cells that express some cell-surface markers characteristic of mature endothelium and some of hematopoietic cells.19,5153 EPCs home in on ischemic areas, where they differentiate into new blood vessels; following a heart attack, intravenously injected EPCs home to the damaged region within 48 hours.12 The new vascularization induced by these cells prevents cardiomyocyte apoptosis (programmed cell death) and LV remodeling, thereby preserving ventricular function.13 However, no change has been observed in non-infarcted regions upon EPC administration. Clinical trials are currently underway to assess EPC therapy for growing new blood vessels and regenerating myocardium.

Several other cell populations, including umbilical cord blood (UCB) stem cells, fibroblasts (cells that synthesize the extracellular matrix of connective tissues), and peripheral blood CD34+ cells, have potential therapeutic uses for regenerating cardiac tissue. Although these cell types have not been investigated in clinical trials of heart disease, preliminary studies in animal models indicate several potential applications in humans.

Umbilical cord blood contains enriched populations of hematopoietic stem cells and mesencyhmal precursor cells relative to the quantities present in adult blood or bone marrow.54,55 When injected intravenously into the tail vein in a mouse model of MI, human mononuclear UCB cells formed new blood vessels in the infarcted heart.56 A human DNA assay was used to determine the migration pattern of the cells after injection; although they homed only to injured areas within the heart, they were also detected in the marrow, spleen, and liver. When injected directly into the infarcted area in a rat model of MI, human mononuclear UCB cells improved ventricular function.57 Staining for CD34 and other markers found on the cell surface of hematopoietic stem cells indicated that some of the cells survived in the myocardium. Results similar to these have been observed following the injection of human unrestricted somatic stem cells from UCB into a pig MI model.58

Adult peripheral blood CD34+ cells offer the advantage of being obtained relatively easily from autologous sources.59 Although some studies using a mouse model of MI claim that these cells can transdifferentiate into cardiomyocytes, endothelial cells, and smooth muscle cells at the site of tissue injury,60 this conclusion is highly contested. Recent studies that involve the direct injection of blood-borne or bone marrow-derived hematopoietic stem cells into the infarcted region of a mouse model of MI found no evidence of myocardial regeneration following injection of either cell type.33 Instead, these hematopoietic stem cells followed traditional differentiation patterns into blood cells within the microenvironment of the injured heart. Whether these cells will ultimately find application in myocardial regeneration remains to be determined.

Autologous fibroblasts offer a different strategy to combat myocardial damage by replacing scar tissue with a more elastic, muscle-like tissue and inhibiting host matrix degradation.4 The cells may be manipulated to express muscle-specific transcription factors that promote their differentiation into myotubes such as those derived from skeletal myoblasts.61 One month after these cells were implanted into the post-infarction scar in a rat model of MI, they occupied a large portion of the scar but were not functionally integrated.61 Although the effects on ventricular function were not evaluated in this study, authors noted that modified autologous fibroblasts may ultimately prove useful in elderly patients who have a limited population of autologous skeletal myoblasts or bone marrow stem cells.

As these examples indicate, many types of stem cells have been applied to regenerate damaged myocardium. In select applications, stem cells have demonstrated sufficient promise to warrant further exploration in large-scale, controlled clinical trials. However, the current breadth of application of these cells has made it difficult to compare and contextualize the results generated by the various trials. Most studies published to date have enrolled fewer than 25 patients, and the studies vary in terms of cell types and preparations used, methods of delivery, patient populations, and trial outcomes. However, the mixed results that have been observed in these studies do not necessarily argue against using stem cells for cardiac repair. Rather, preliminary results illuminate the many gaps in understanding of the mechanisms by which these cells regenerate myocardial tissue and argue for improved characterization of cell preparations and delivery methods to support clinical applications.

Future clinical trials that use stem cells for myocardial repair must address two concerns that accompany the delivery of these cells: 1) safety and 2) tracking the cells to their ultimate destination(s). Although stem cells appear to be relatively safe in the majority of recipients to date, an increased frequency of non-sustained ventricular tachycardia, an arrhythmia, has been reported in conjunction with the use of skeletal myoblasts.30,6264 While this proarrhythmic effect occurs relatively early after cell delivery and does not appear to be permanent, its presence highlights the need for careful safety monitoring when these cells are used. Additionally, animal models have demonstrated that stem cells rapidly diffuse from the heart to other organs (e.g., lungs, kidneys, liver, spleen) within a few hours of transplantation,65,66 an effect observed regardless of whether the cells are injected locally into the myocardium. This migration may or may not cause side-effects in patients; however, it remains a concern related to the delivery of stem cells in humans. (Note: Techniques to label stem cells for tracking purposes and to assess their safety are discussed in more detail in other articles in this publication).

In addition to safety and tracking, several logistical issues must also be addressed before stem cells can be used routinely in the clinic. While cell tracking methodologies allow researchers to determine migration patterns, the stem cells must target their desired destination(s) and be retained there for a sufficient amount of time to achieve benefit. To facilitate targeting and enable clinical use, stem cells must be delivered easily and efficiently to their sites of application. Finally, the ease by which the cells can be obtained and the cost of cell preparation will also influence their transition to the clinic.

The evidence to date suggests that stem cells hold promise as a therapy to regenerate damaged myocardium. Given the worldwide prevalence of cardiac dysfunction and the limited availability of tissue for cardiac transplantation, stem cells could ultimately fulfill a large-scale unmet clinical need and improve the quality of life for millions of people with CVD. However, the use of these cells in this setting is currently in its infancymuch remains to be learned about the mechanisms by which stem cells repair and regenerate myocardium, the optimal cell types and modes of their delivery, and the safety issues that will accompany their use. As the results of large-scale clinical trials become available, researchers will begin to identify ways to standardize and optimize the use of these cells, thereby providing clinicians with powerful tools to mend a broken heart.

Chapter 5|Table of Contents|Chapter 7

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Mending a Broken Heart: Stem Cells and Cardiac Repair …

Recommendation and review posted by Jack Burke

Scientists edit heart muscle gene in stem cells, may be …

Story highlights

In other words, the impact certain variants could have on your health remains a guessing game.

“Patients often ask us what do these variants of uncertain significance mean. But in reality, we don’t know most of the time ourselves. So we end up having to follow the patients for the next five, 10, 20, or 30 years to see if the patient manifests the disease or not,” Wu said.

“Here, we now have a way to shorten that time because we can generate patients’ induced pluripotent stem cells from blood.”

How do those stem cells then help predict if a variant is harmful or not? They can be differentiated into heart cells.

If the heart cells look abnormal, that probably means the variant of uncertain significance is pathogenic, meaning it’s capable of causing disease.

If the heart cells look normal, that probably means the variant of uncertain significance is actually benign.

“This is one of the very first proof of principles to show that concept,” Wu said.

‘An important step towards precision medicine’

The researchers found 592 genetic variants across the 54 people. While 78% of the variants were categorized as benign, there were 17 people who each carried a variant categorized as “likely pathogenic.” For four of those people, their variant was hypertrophic cardiomyopathy-related.

So the researchers then took that knowledge and used CRISPR to turn the patient’s stem cells with this MYL3 genetic variant from being heterozygous, meaning they have one normal and one recessive form of the variant, to being homozygous, so that they have two recessive forms of the variant.

Specifically, the researchers took the one study participant’s blood cells, turned them into induced pluripotent stem cells, and then used CRISPR to edit those cells in a petri dish. The researchers then differentiated the edited stem cells so they would become heart muscle cells, and performed a comprehensive analysis to evaluate the variant, determining exactly how harmful the variant was or whether it was benign.

In this case, the study participant’s variant was predicted to be benign.

A risk with using CRISPR is that it could introduce some unintended changes, but no off-target mutations were detected in the gene-edited cells, the researchers reported in their study.

“Much work remains to further develop stepping stones between editing cells in a dish and genome editing therapeutics that can treat patients, but studies such as this one help identify variants that are promising targets for therapeutic editing,” said David Liu, core institute member of the Broad Institute and professor of chemistry and chemical biology at Harvard University, who was not involved in the study.

This gene-editing approach was found to be feasible in this one patient, but more research is needed to determine whether similar results would emerge among more patients.

“While it’s very elegant, the major limitation of this work is that it took years of expensive work by a team of very talented scientists to do this for just one patient,” said Dr. Kiran Musunuru, an associate professor of cardiovascular medicine at the University of Pennsylvania’s Perelman School of Medicine, who was not involved in the new study but has conducted separate research involving CRISPR.

“It’s an important step towards precision medicine, but going forward we will need to scale this up and be able to do this for dozens, hundreds, or even thousands of patients at a time, in a matter of weeks and much more cheaply,” he said.

Time and cost are also limitations of this approach, Wu said.

“Cost-wise, it takes us probably about $10,000 and time-wise about six months,” he said. Those six months would involve making the induced pluripotent stem cells, using CRISPR to edit the cells and then analyzing the differentiated heart cells.

Wu added, “but keep in mind that six months is actually still much better than the current alternative that we have, which is to tell patients that we don’t know what the variant means.”

The alternative would be following a patient with a variant for years, with the worrisome chance of a disease possibly developing or not developing. In either scenario, the patient as well as family members could have anxiety and stress.

Is this the future of gene editing?

“This addresses a major unmet need in patient care by helping determine whether your specific mutation is something to worry about,” said Lagor, who was not involved in the study but has conducted separate research on CRISPR.

Then once a mutation has been identified as disease-causing, “this is an ideal platform for testing potential new drugs or gene therapy approaches in a patient-specific manner. This is truly personalized medicine,” he said.

“The first therapeutic application of this technology would be to correct rare genetic diseases of the heart itself, where the potential benefit far outweighs the risk to the patient. Some of this technology already exists today, and it is now a matter of demonstrating that this can be done safely and effectively,” he said.

“However, present-day forms of CRISPR technology do not work well enough in the actual heart muscle in a living being to correct a mutation for a disease like cardiomyopathy,” he said. “It’s possible that some future generation of gene-editing technology might be able to do the job of treating disease in the heart muscle, years or more likely decades in the future.”

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Scientists edit heart muscle gene in stem cells, may be …

Recommendation and review posted by Jack Burke

Here’s Why CRISPR Stocks Are Down as Much as 11.4% Today …

What happened

Shares of the three leading companies developing human therapeutics based on CRISPR gene-editing technology fell as much as 11.4% today. There was no new news that could be interpreted as detrimental to CRISPR Therapeutics (NASDAQ:CRSP), Editas Medicine (NASDAQ:EDIT), or Intellia Therapeutics (NASDAQ:NTLA). But on July 23, many media outlets published stories commenting on a study released one week earlier.

While the stock moves may seem to be based on the rehashing of old news, there are good reasons investors shouldn’t be too quick to dismiss the concerns. As of 2:44 p.m. EDT, CRISPR Therapeutics stock had settled to a 9.5% loss, while Editas Medicine shares were down 10.4%, and Intellia Therapeutics stock had sunk by 7.2%.

Image source: Getty Images.

On July 16, scientists published a study in Nature Biotechnology demonstrating that using CRISPR tools to edit faulty DNA sequences can lead to unintended deletions and rearrangements of genetic material. The lead author, Dr. Allan Bradley, issued a cautious summary of the study:

This is the first systematic assessment of unexpected events resulting from CRISPR/Cas9 editing in therapeutically relevant cells, and we found that changes in the DNA have been seriously underestimated before now. It is important that anyone thinking of using this technology for gene therapy proceeds with caution, and looks very carefully to check for possible harmful effects.

The researchers, who hail from the prestigious Wellcome Sanger Institute, found that some of the genetic changes occurred far away from where CRISPR tools cut a genome, locations which would elude existing diagnostic tools used to gauge off-target effects. In other words, the field has “seriously underestimated” the potential for unintended genetic alterations because it hasn’t been looking in the right places.

All three companies made statements to Reuters last week regarding the study. CRISPR Therapeutics commented: “We do not use the methods described in this Nature Biotech paper … nevertheless, in our work, we do not see similar findings.” Editas Medicine said it was “not specifically concerned.” Intellia Therapeutics said it didn’t think the findings would affect the future of CRISPR-based therapies.

While it’s important for investors not to panic over the latest study showing potentially unintended consequences of using gene-editing tools, it is worth noting that most of the recent uncertainty injected into CRISPR stocks has come from observations of DNA repair mechanisms — one thing gene-editing tools have little to no control over. While companies focus on developing safe and effective ways to cut a genome, they must rely on natural cellular processes to stitch up the genome afterwards.

For instance, in June, investors worried over two studies showing that CRISPR tools could activate a faulty DNA repair mechanism and result in cancerous cells. The latest study from the Wellcome Sanger Institute was not concerned with the same question, but demonstrated that researchers may be overlooking the details of how genomes get stitched back up.

An open-minded approach to investing in CRISPR Therapeutics, Editas Medicine, and Intellia Therapeutics would nod to the awesome potential of the technology while acknowledging the risks of an early-stage investment. Recent stock moves hint that the hype may need to come back down to earth, as there’s much left to understand about using CRISPR tools in human cells. To date researchers have focused mostly on the ability to cut DNA, but it may be time to start paying closer attention to what happens after that.

Maxx Chatsko has no position in any of the stocks mentioned. The Motley Fool owns shares of CRISPR Therapeutics. The Motley Fool recommends Editas Medicine. The Motley Fool has a disclosure policy.

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Here’s Why CRISPR Stocks Are Down as Much as 11.4% Today …

Recommendation and review posted by sam

Hypogonadism disease: Malacards – Research Articles, Drugs …

Drugs for Hypogonadism (from DrugBank, HMDB, Dgidb, PharmGKB, IUPHAR, NovoSeek, BitterDB): (show top 50) (show all 199) # Name Status Phase Clinical Trials Cas Number PubChem Id 1 Methyltestosterone Approved Phase 4,Phase 3,Phase 2,Phase 1,Early Phase 1 58-18-4 6010

Synonyms:

17alpha-Methyl-3-oxo-4-androsten-17beta-ol

17alpha-methyl-delta-androsten-17beta-ol-3-one

17alpha-methyltestosterone

17alpha-Methyltestosterone

17beta-Hydroxy-17-methylandrost-4-en-3-one

17-beta-Hydroxy-17-methylandrost-4-en-3-one

17-methyltestosterone

17-Methyltestosterone

17-methyltestosterone

17-methyl-4-androsten-17-ol-3-one

4-Androstene-17alpha-methyl-17beta-ol-3-one

Methyltestosteronum

Metiltestosterona

Synonyms:

(+-)-8-iso-testosterone

(+-)-retrotestosterone

(+)-testosterone

(+-)-testosterone

(17b)-17-hydroxy-androst-4-en-3-one

(17beta)-17-Hydroxyandrost-4-en-3-one

(8R,9S,10R,13S,14S,17S)-17-hydroxy-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one

13-Iso-testosterone

17?-Hydroxy-4-androsten-3-one

17a-Hydroxy-(13a)-androst-4-en-3-one

17a-Hydroxy-13a-androst-4-en-3-one

17a-Hydroxy-14b-androst-4-en-3-one

17a-Hydroxy-androst-4-en-3-one

17beta-Hydroxy-3-oxo-4-androstene

17beta-hydroxy-4-androsten-3-one

17beta-Hydroxy-4-androsten-3-one

17beta-Hydroxyandrost-4-en-3-one

17-beta-Hydroxyandrost-4-en-3-one

17beta-Hydroxyandrost-4-ene-3-one

17-beta-Hydroxy-delta(sup 4)-androsten-3-one

17beta-Hydroxy-delta(sup4)-androsten-3-one

17b-Hydroxy-(10a)-androst-4-en-3-one

17b-Hydroxy-(13a)-androst-4-en-3-one

17b-Hydroxy-(8a)-androst-4-en-3-one

17b-Hydroxy-(8a,10a)-androst-4-en-3-one

17b-Hydroxy-(9b)-androst-4-en-3-one

17b-Hydroxy-(9b,10a)-androst-4-en-3-one

17b-Hydroxy-13a-androst-4-en-3-one

17b-hydroxy-4-androsten-3-one

17b-Hydroxy-8a-androst-4-en-3-one

17b-Hydroxy-androst-4-en-3-on

17b-Hydroxyandrost-4-en-3-one

17b-Hydroxy-androst-4-en-3-one

17b-Hydroxyandrost-4-ene-3-one

17b-Hydroxy-D4-androsten-3-one

17b-Testosterone

17-Hydroxy-(17beta)-androst-4-en-3-one

17-Hydroxy-(17-beta)-androst-4-en-3-one

17-Hydroxy-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-cyclopenta[a]phenanthren-3-one

17-Hydroxy-androst-4-en-3-one

17-Hydroxy-D4-androsten-3-one

46923_FLUKA

46923_RIEDEL

4-Androsten-17?-ol-3-one

4-Androsten-17beta-ol-3-one

4-androsten-17-ol-3-one

4-Androsten-3-one-17b-ol

4-androstene-17beta-ol-3-one

58-22-0

7-beta-Hydroxyandrost-4-en-3-one

8-Iso-testosterone

9b,10a-Testosterone

9b-Testosterone

AA 2500

AC-14899

AC1L1LM0

Andriol

Andro

Andro 100

Andro L.A. 200

Androderm

Androderm (TN)

Androgel

AndroGel

Androgel (TN)

Android 10

Android 25

Android 5

Androlin

Andronaq

Andronate 100

Andronate 200

Andropatch

Andropository 200

Androsorb

Androst-4-en-17beta-ol-3-one

Androst-4-en-17b-ol-3-one

Androst-4-ene-17b-ol-3-one

Andrusol

Andryl 200

B5DEE83F-632B-48A1-A0ED-A51E7F13DF2E

beta testosterone

Beta Testosterone

BIDD:ER0555

Read more from the original source:
Hypogonadism disease: Malacards – Research Articles, Drugs …

Recommendation and review posted by simmons

Our Programs – CRISPR

Gene Editing to Treat Disease

The majority of medical therapies available today are directed at managing disease processes, the pathogenic or mis-regulated proteins or molecules associated with disease. However, these pathogenic molecules themselves are typically encoded in or affected by changes in genes or other sequences in the human genome, which encompasses the DNA in all our cells. Gene editing technologies, including CRISPR/Cas9, now offer us the ability to directly modify or correct the underlying disease-associated changes in our genome. Successfully editing or correcting a gene that encodes the dysfunctional or missing protein can in principle result in the expression of a fully normal protein and full correction of the disease.

Gene therapy and other technologies to modify the genome have been in development for many years, and a small number of gene therapies have been approved to treat patients. However, these older approaches have been burdened by challenges to their safety and efficacy and have not yet provided the ability to precisely control a range of different genetic changes.

We believe that CRISPR/Cas9 offers just such an opportunity, particularly to correct DNA changes in somatic (non germ line) cells in patients with serious disease.

CRISPR/Cas9 is a rapid and easy to use gene editing technology that can selectively delete, modify or correct a disease causing abnormality in a specific DNA segment. CRISPR refers to Clustered Regularly Interspaced Short Palindromic Repeats occurring in the genome of certain bacteria, from which the system was discovered; Cas9 is a CRISPR-associated endonuclease (an enzyme), the molecular scissors that are easily programmed to cut and edit, or correct, disease-associated DNA in a patients cell. The location at which the Cas9 molecular scissors cut the DNA to be edited is specified by guide RNA, which is comprised of a crRNA component and a tracrRNA component, either individually or combined together as a single guide RNA (sgRNA). For example, a guide RNA can direct the molecular scissors to cut the DNA at the exact site of the mutation present in the genome of patients with a particular genetic disease. Once the molecular scissors make a cut in the DNA, additional cellular mechanisms and exogenously added DNA will use the cells own machinery and other elements to specifically repair the cut DNA.

There are more than 10,000 known single-gene (or monogenic) diseases, occurring in about 1 out of every 100 births1. Scientists and clinicians are now conducting pioneering research using CRISPR/Cas9 to address both recessive and dominant genetic defects, opening up the potential of gene editing to provide novel transformative gene-based medicines for patients with a large number of both rare and common diseases.

Dr. Emmanuelle Charpentier, one of CRISPR Therapeutics scientific founders, co-invented the CRISPR/Cas9 technology.

The clustered repeats of CRISPR were discovered in 1987 in bacteria2, but their function was unknown. In 2000, these clustered repeat elements were found to be relatively common in bacteria3 hinting to an important role of these elements. The clustered repeats were given the name CRISPR in 2002 and multiple CRISPR-associated (Cas) genes were discovered adjacent to the repeat elements in that same year4.

CRISPR/Cas9 is a rapid and easy to use gene editing technology that can selectively delete, modify or correct a disease causing abnormality in a specific DNA segment. CRISPR refers to Clustered Regularly Interspaced Short Palindromic Repeats occurring in the genome of certain bacteria, from which the system was discovered; Cas9 is a CRISPR-associated endonuclease (an enzyme), the molecular scissors that are easily programmed to cut and edit, or correct, disease-associated DNA in a patients cell. The location at which the Cas9 molecular scissors cut the DNA to be edited is specified by guide RNA, which is comprised of a crRNA component and a tracrRNA component, either individually or combined together as a single guide RNA (sgRNA). For example, a guide RNA can direct the molecular scissors to cut the DNA at the exact site of the mutation present in the genome of patients with a particular genetic disease. Once the molecular scissors make a cut in the DNA, additional cellular mechanisms and exogenously added DNA will use the cells own machinery and other elements to specifically repair the cut DNA.

There are more than 10,000 known single-gene (or monogenic) diseases, occurring in about 1 out of every 100 births1. Scientists and clinicians are now conducting pioneering research using CRISPR/Cas9 to address both recessive and dominant genetic defects, opening up the potential of gene editing to provide novel transformative gene-based medicines for patients with a large number of both rare and common diseases.

Dr. Emmanuelle Charpentier, one of CRISPR Therapeutics scientific founders, co-invented the CRISPR/Cas9 technology.

The clustered repeats of CRISPR were discovered in 1987 in bacteria2, but their function was unknown. In 2000, these clustered repeat elements were found to be relatively common in bacteria3 hinting to an important role of these elements. The clustered repeats were given the name CRISPR in 2002 and multiple CRISPR-associated (Cas) genes were discovered adjacent to the repeat elements in that same year4.

The function of the CRISPR-Cas system in bacteria as an immune defense mechanism was hypothesized by Mojica in 20055 and experimentally validated at the food ingredient company, Danisco, in 20076.

In 2011, Dr. Charpentiers lab discovered an essential component of the CRISPR-Cas system, tracrRNA, in bacteria7. The following year she and colleagues described how the Cas9 endonuclease works together with crRNA and tracrRNA to form functional molecular scissors to cut at a specific DNA sequence in the genome8. In this same publication the authors also described how to modify, or re-program, the system to direct the molecular scissors to cut at essentially any DNA sequence; how to modify the RNA components into a single guide RNA, simplifying the system into only 2 components; and how to modify the Cas9 molecular scissors to make nicks in the DNA by only cutting one of the two DNA strands. These foundational discoveries enabled transformative gene editing in a wide range of cells, tissues and species, including for the potential benefit of patients suffering from serious genetic diseases.

CRISPR/Cas9 is an easy, effective technology for gene editing that has enabled a wide range of new studies and transformed many areas of research. Thousands of academic laboratories across the world are carrying out research using the technology. Rapid adoption of CRISPR/Cas9 by the broader academic community and the collective efforts of their research are in turn driving tremendous progress in the field.

We have licensed the foundational CRISPR/Cas9 patent estate for human therapeutic use from our scientific founder, Dr. Emmanuelle Charpentier. This IP is directed broadly to CRISPR/Cas9 genome editing and includes many different applications of the technology. We have filed additional IP and will continue to do so in support of our mission to bring transformative gene-based medicines to patients with serious diseases.

In 2011, Dr. Charpentiers lab discovered an essential component of the CRISPR-Cas system, tracrRNA, in bacteria7. The following year she and colleagues described how the Cas9 endonuclease works together with crRNA and tracrRNA to form functional molecular scissors to cut at a specific DNA sequence in the genome8. In this same publication the authors also described how to modify, or re-program, the system to direct the molecular scissors to cut at essentially any DNA sequence; how to modify the RNA components into a single guide RNA, simplifying the system into only 2 components; and how to modify the Cas9 molecular scissors to make nicks in the DNA by only cutting one of the two DNA strands. These foundational discoveries enabled transformative gene editing in a wide range of cells, tissues and species, including for the potential benefit of patients suffering from serious genetic diseases.

CRISPR/Cas9 is an easy, effective technology for gene editing that has enabled a wide range of new studies and transformed many areas of research. Thousands of academic laboratories across the world are carrying out research using the technology. Rapid adoption of CRISPR/Cas9 by the broader academic community and the collective efforts of their research are in turn driving tremendous progress in the field.

We have licensed the foundational CRISPR/Cas9 patent estate for human therapeutic use from our scientific founder, Dr. Emmanuelle Charpentier. This IP is directed broadly to CRISPR/Cas9 genome editing and includes many different applications of the technology. We have filed additional IP and will continue to do so in support of our mission to bring transformative gene-based medicines to patients with serious diseases.

Read the rest here:
Our Programs – CRISPR

Recommendation and review posted by Bethany Smith

iPSC | Induced Pluripotent Stem Cells | Human | HiPSC …

Consistency

Quality Control and Testing

Product Selection & Support

HiPSC Custom Services

Human Induced Pluripotent Stem Cells (HiPSC)Top:HiPSC express pluriotency markers OCT4, Nanog, LIN28 and SSEA-4.Bottom:HiPSC differentiate into cell derivatives from the 3 embryonic layers: Neuronal marker beta III tubulin (TUJ1), Smooth Muscle Actin (SMA) and Hepatocyte Nuclear Factor 3 Beta (HNF3b).

Cutting-edge development and manufacturing provides high quality, thoroughly-characterized HiPSC cells to researchers around the world. HiPSC are generated from somatic cells, eliminating ethical considerations associated with scientific work based on embryonic stem cells. Furthermore, being donor/patient-specific, they open possibilities for a wide variety of studies in biomedical research. Donor somatic cells carry the genetic makeup of the diseased patient, hence HiPSC can be used directly to model disease on a dish.

Thus, one of the main uses of HiPSC has been in genetic disease modeling in organs and tissues, such as the brain (Alzheimers, Autism Spectrum Disorders), heart (Familial Hypertrophic, Dilated, and Arrhythmogenic Right Ventricular Cardiomyopathies), and skeletal muscle (Amyotrophic Lateral Sclerosis, Spinal Muscle Atrophy). The combination of HiPSC technology and gene editing strategies such as the CRISPR/Cas9 system creates a powerful platform in which disease-causing mutations can be created on demand and sets of isogenic cell lines (with and without mutations) serve as convenient tools for disease modeling studies.

Other applications of HiPSC and iPSC-differentiated cells include drug screening, development, efficacy and toxicity assessment. As an example, through the FDA-backed CiPA (Comprehensive in vitro Pro-Arrhythmia Assessment) initiative, HiPSC-derived cardiac muscle cells (cardiomyocytes) are poised to constitute a new standard model for the evaluation of cardiotoxicity of new drugs, which is the main reason of drug withdrawal from the market. Finally, HiPSC-differentiated cells are being used in early stage technology development for applications in regenerative medicine. Bio-printing and tissue constructs have also been considered as attractive applications for HiPSC.

Human iPSC and Derived Cells are forResearch Use Only (RUO). Not for human clinical or therapeutic use.

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iPSC | Induced Pluripotent Stem Cells | Human | HiPSC …

Recommendation and review posted by Jack Burke

Gay genetics | Science Focus

WANTED! Gay Men with a Gay Brother, reads the banner. Its held aloft by Dr Alan Sanders and a group of colleagues from NorthShore University near Chicago who are attending a gay pride festival. Theyre recruiting volunteers for a groundbreaking study that sets out to answer fundamental questions about who we are.

Were trying to locate genes that may influence variation in male sexual orientation, Sanders says. Volunteers from over 700 families responded. Researchers asked them questions about their sexuality, the size and structure of their families, and took DNA samples. Sanders is now analysing that data and the results could tell us once and for all whether theres such a thing as a gay gene.

The people participating in our study are interested in contributing to this kind of scientific knowledge and want to understand at least part of how they came to be the way they are, Sanders says.

The search for gay genes goes back to 1993, when a US team led by Dr Dean Hamer described a region of DNA located on the X chromosome called Xq28. The region also goes by another name: GAY-1, a genetic marker linked to male homosexuality.

The discovery caused Hamer to be attacked from all sides. Conservative, right-wing people hated it because they felt that it was saying that being gay is like being black, that it was in-born, that it would somehow excuse gay people or give them more rights, says Hamer. On the other hand, gay people hated it too because, at that time, there were fears that the discovery would be misused to abort gay babies and wipe gay people off the face of the Earth.

Although these fears remain, in recent years the search for gay genes has become more accepted by the gay community, in no small part because a biological explanation wouldundermine arguments that being gay is a social or lifestyle choice. Conservative attitudes remain unchanged, however. They continue to be vehemently opposed to any notion that homosexuality is something natural, says Hamer.

Despite their objections, theres a lot of evidence that homosexuality has a biological basis. While there hasnt been much research on lesbians, there has been on gay men. For instance, identical twin brothers (siblings derived from the same fertilised egg) are more likely to both be gay than fraternal twins (twins that develop from separate eggs). The fact that identical twins have the same DNA and fraternal twins share 50 per cent suggests that male homosexuality is hereditary.

It was scrutinising family trees to see how homosexuality is inherited that led Hamer to the discovery of Xq28. Now chief of the gene structure and regulation section at the US National Cancer Institute, his study revealed a curious pattern: gay men tended to have more gay uncles and gay male cousins on their mothers side of the family than on their fathers.

For geneticists thats fascinating because it suggests it could be due to X chromosome linkage those types of traits tend to run on the female side for males, says Hamer. This is because males inherit their X chromosome from their mother.

To track down the DNA region linked to the gay trait, Hamer used a technique called linkage mapping, an approach that lets geneticists find a gene even when they dont know what it does or where its located. Linkage mapping works because close relatives like brothers share not only a particular trait, such as homosexuality, but also the genes underlying the trait. When comparing bits of DNA from two brothers, the sequences will, on average, be the same 50 per cent of the time. So, if you study many pairs of gay brothers and find a DNA region thats the same in more than 50 per cent of cases, its likely to be linked to homosexuality. In this case, Hamer compared the X chromosomes from 40 pairs of gay brothers, and Xq28 stood out.

Inheriting the gay version of Xq28 wont necessarily make you homosexual. Our studies showed that it significantly increased the odds of being gay, but it was not determinative, says Hamer. Many people who are gay dont have any history of homosexuality in their families. He points out that some heterosexual men in his 1993 study also had the so-called gay gene. A subsequent study in 1999 failed to replicate Hamers results and other researchers are sceptical that Xq28 is linked to homosexuality at all.

Many scientists believe that exposure to hormones during pregnancy heavily influences sexuality. Hormones are chemical messengers, released by certain cells to affect the growth and development of other cells in the body. During pre-natal development, for example, the sex organs in a foetus can recognise testosterone, which will switch on genes to make it male.

Aside from a few superficial differences (among them penis and ring-finger length both longer in homosexuals), gay and straight mens bodies appear the same. The exception is homosexual mens brains, which show remarkable similarities to the brains of heterosexual women, suggesting that sexual orientation depends on the effect hormones have on the developing brain.

But these two factors only go so far in explaining how homosexuality develops. People assume that all of the biological influence on sexual orientation is either genes or hormones, says sexologist Ray Blanchard from the University of Toronto. They might account for the lions share of variance in sexual orientation, but it looks like theres some other bit that requires a third biological mechanism.

In 1996 Blanchard and Professor Tony Bogaert revealed a peculiar phenomenon: the more older brothers a boy has, the greater their chances of being homosexual. This fraternal birth order effect meant that each subsequent brother increases the odds of being gay by 33 per cent. An only child has a two per cent chance, but with 10 brothers the odds are over 20 per cent. But why the increasing odds? Blanchard believes its related to how a mothers body protects itself when pregnant with a son.

Theres only one system in the mother that would have the memory to know how many male foetuses shes previously carried: the immune system, says Professor Blanchard. According to his theory, a mothers immune system keeps track of the number of sons shes already had, producing antibodies to protect her against male-specific proteins entering her bloodstream, which often occurs during childbirth. As the mothers level of immunisation increases with each son, so too do the chances of variation from typical sexual orientation as, in theory, the mothers antibodies could cross the placenta and neutralise proteins that her son needs for normal sexual development.

Many of these male-specific proteins are found on the Y chromosome, DNA thats foreign to females. A lot of male-specific proteins are preferentially expressed in the testes and have a crucial role in sperm development, says Blanchard. Some are expressed in the foetal brain for reasons that no-one has established, but you wouldnt expect them to be expressed without a reason.

Blanchard believes that homosexuality is 100 per cent biological, and estimates that the fraternal birth order effect accounts for 15-30 per cent of gay men in the population. So what explains the rest?

Professor Andrea Camperio Ciani at the University of Padova in Italy has tested various hypotheses by studying 100 families of gay men. Not only did he replicate Blanchards birth order effect, he also detected inheritance of homosexuality on the mothers side, supporting Hamers idea of a gay gene on chromosome X. The maternal inheritance effect seems most important too.

Genetics explains 20-25 per cent for the moment, says Camperio Ciani. The rest is unknown. A part is environment; a part can be other genetic elements that we cannot perceive with our study. In principle, the genetic component might even be the Xq28 region.

Regardless of which regions of DNA are linked to homosexuality, the very existence of gay genes creates a Darwinian paradox. How would genes that cause homosexuality pass from one generation to the next, given that gay people reproduce less than heterosexuals? Natural selection opposes anything that might cause even a small reduction in the number of offspring you produce, so a gay trait would soon disappear from the gene pool. If you carry a trait that reduces your fecundity [the number of offspring you produce] by 10 per cent, in seven to eight generations your trait and all your descendents disappear, says Camperio Ciani.

The paradox was finally resolved by his 15-year-old daughter. After Camperio Ciani described the observed patterns in pedigrees of homosexuality the effects of maternal inheritance and birth order his daughter suggested that he re-check his data to see if the female relatives of gay men had more children on the mothers side. When Camperio Ciani went back to the lab, thats exactly what he found. Mothers and aunts on the maternal line of homosexuals had around one-fifth to one-fourth more kids than the heterosexual comparison, and also than the paternal line.

He thinks that the evolution of homosexuality is driven by a process called sexually antagonistic selection. Its where a genetic factor confers an advantage when expressed in one sex, but incurs an evolutionary cost in the other. In this instance, the gay genes dont exist to make men homosexual, instead theyre a consequence of fertility factors that help women reproduce.

Nipples are another example of a sexually antagonistic trait: theyre needed for feeding babies, but developing nipples in men is a waste of the bodys resources and allow errors leading to breast cancer.

Even if Camperio Cianis fecundity factors are the same as Hamers gay genes, it doesnt tell us what the specific genes actually do. Hamer speculates the genes might boost the size or connections from parts of the brain used in reproduction such as the hypothalamus to make people more libidinous.

Alan Sanderss study at NorthShore University could finally reveal the identity and function of gay genes. Sanders, director of the Behavior Genetics Unit, is comparing DNA from gay brothers to find shared genes that underlie sexual orientation. Hes initially using linkage mapping to find candidate regions. The large sample size over 700 families provides huge statistical power for detecting regions significantly linked to homosexuality. Sanders will then use sequences from databases like the Human Genome Project to pinpoint which genes are in these regions.

So what happens if gay genes are found? While they may confirm the idea that homosexuality has a biological basis, many people fear that the results could be used to discriminate against gay people. It is a valid concern, says Sanders. People we talked to at gay pride festivals have designer-baby kind of worries a genetic test employed in a pre-natal way, or for employment and insurance discrimination, maybe in the military too. Its not just an issue in sexual orientation, but intelligence or disease screening .

A test for gay genes also has a flipside: homosexual couples might exploit reproductive technology to have gay kids. This has been a huge debate in other areas, like deaf parents wanting to have deaf children, says Hamer, who has fathered a daughter with a woman from a lesbian couple. One of them said, If I had my choice, Id select the sexual orientation of my child. But this is all theoretical for now, as its not actually happening yet.

Genes that influence our sexual orientation further fuel the debate over what makes us who we are. For Hamer at least, sexual orientation is determined at birth. Its mostly biological, he says. The way a person acts is altered by culture, society and individual choice, but thats a different issue than the underlying deep-seated orientation.

Link:
Gay genetics | Science Focus

Recommendation and review posted by Jack Burke

Hypopituitarism in Children | Children’s Hospital of Philadelphia

Hypopituitarism is a condition in which the pituitary gland in the brain is not working properly. Normally, the pituitary gland produces hormones some of which affect growth, blood pressure, blood sugar and other body processes. Effects of hypopituitarism may be gradual, or sudden and dramatic.

Hypopituitarism, in children, is often caused by a benign (noncancerous) pituitary tumor, an injury, an autoimmune process, or an infection. Often, no exact cause can be determined.

Symptoms vary depending on what hormones are insufficiently producedfrom the pituitary gland. The symptoms of hypopituitarism may resemble other conditions or medical problems. Always consult yourdoctor for a diagnosis. Common symptoms include:

Small penis in males

Very low blood sugar (hypoglycemia)

Slowed growth and short stature

Slowed sexual development

Prolonged jaundice at birth

Poor appetite

Weight loss or weight gain

Sensitivity to cold

Facial puffiness

The symptoms of several underactive glands may help your child’sdoctor diagnose hypopituitarism. In addition to a complete medical history and physical exam, diagnostic procedures for hypopituitarism may include:

Computed tomography scan (also called a CT or CAT scan).A diagnostic imaging procedure that uses a combination of X-rays and computer technology to producehorizontal, or axial,images (often called slices)of the body. A CT scan shows detailed images of any part of the body, including the bones, muscles, fat, and organs. CT scans are more detailed than general X-rays.

Magnetic resonance imaging (MRI).A diagnostic procedure that uses a combination of large magnets, radiofrequencies, and a computer to produce detailed images of organs and structures within the body.

Blood tests. Blood tests are used to measure hormone levels.

Bone X-rays of the hand. X-rays of the left hand and wrist willdetermine bone age, which is often delayed compared with chronologic age inchildren with hypopituitarism..

Specific treatment for hypopituitarism will be determined by your child’sdoctor based on:

Your child’s age, overall health, and medical history

Extent of the disease

Your child’s tolerance for specific medications, procedures, or therapies

Expectations for the course of the disease

Your opinion or preference

Treatment of hypopituitarism depends on its cause. The goal of treatment is to restore the pituitary gland to normal function, producing normal levels of hormones. Treatment may include specific hormone replacement therapy, surgical tumor removal, and/or radiation therapy.

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Hypopituitarism in Children | Children’s Hospital of Philadelphia

Recommendation and review posted by simmons


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