Researchers described the gene as a "medical and scientific trinity"

NYU School of Medicine researchers have found that the connection between inflammation, accelerated aging and cancer lies in one specific gene.

Robert J. Schneider, PhD, study leader from NYU School of Medicine, along with an NYU team, have found that a single gene, AUF1,is responsible for the correlation between inflammation, accelerated aging and cancer, and can control all three.

For years, it was understood that AUF1 controlled inflammation, and it was also known that there was a connection between inflammation, accelerated aging and cancer. However, the reason for the connection was unknown.

Now, Schneider and his team have figured out this mystery connection. According to the team, the AUF1 gene not only controls inflammatory response, but also activates the enzyme telomerase to repair the ends of chromosomes. This decreases inflammation and prevents rapid aging and cancer development.

"This was certainly an unexpected finding," said Schneider. "It is rather uncommon for one gene to have two very different and very significant functions that tie together control of aging and inflammation. The two, if not regulated properly, can eventually lead to cancer development. It's an exciting scientific find.

"AUF1 is a medical and scientific trinity. Nature has designed a way to simultaneously turn off harmful inflammation and repair our chromosomes, thereby suppressing aging at the cellular level and in the whole animal."

The study was published in the journal Molecular Cell.

Source: e! Science News

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Researchers Determine AUF1 Gene Controls Inflammation/Cancer/Accelerated Aging

The Caterpillar got down off the mushroom and crawled away in the grass, remarking as it went, 'One side will make you grow taller, and the other side will make you grow shorter.' -Alice's Adventures in Wonderland, by Lewis Carroll

Newswise UCLA geneticists have identified the mutation responsible for IMAGe syndrome, a rare disorder that stunts infants growth. The twist? The mutation occurs on the same gene that causes Beckwith-Wiedemann syndrome, which makes cells grow too fast, leading to very large children.

Published in the May 27 edition of Nature Genetics, the UCLA findings could lead to new ways of blocking the rapid cell division that allows tumors to grow unchecked. The discovery also offers a new tool for diagnosing children with IMAGe syndrome, which until now has been difficult to accurately identify.

The discovery holds special significance for principal investigator Dr. Eric Vilain, a professor of human genetics, pediatrics and urology at the David Geffen School of Medicine at UCLA.

Nearly 20 years ago, as a medical resident in his native France, Vilain cared for two boys, ages 3 and 6, who were dramatically short for their ages. Though unrelated, both children shared a mysterious malady marked by minimal fetal development, stunted bone growth, sluggish adrenal glands, and undersized organs and genitals.

I never found a reason to explain these patients unusual set of symptoms, explained Vilain, who is also director of the UCLA Institute for Society and Genetics. Ive been searching for the cause of their disease since 1993.

When Vilain joined UCLA as a genetics fellow, the two cases continued to intrigue him. His mentor, then UCLA geneticist Dr. Edward McCabe, recalled a similar case from his previous post at Baylor College of Medicine. The two of them obtained blood samples from the three cases and analyzed the patients DNA for mutations in suspect genes, but uncovered nothing.

Vilain and McCabe approached the Journal of Clinical Endocrinology and Metabolism, and in 1999 published the first description of the syndrome, which they dubbed IMAGe, an acronym of sorts for the conditions symptoms: intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia and genital anomalies.

Over the next decade, about 20 cases were reported around the world. But the cause of IMAGe syndrome remained a mystery.

Help arrived unexpectedly last year when Vilain received an email from Argentinian physician Dr. Ignacio Bergada, who had unearthed the 1999 journal article. He told Vilain about a large family he was treating in which eight members suffered the same symptoms described in the study. All of the family members agreed to send their DNA samples to UCLA for study.

More here:
Scientists Trace Mutation for Disease That Stunts Infants' Growth to Same Gene That Makes Children Grow Too Fast

Editor's Choice Main Category: Cancer / Oncology Also Included In: Genetics Article Date: 28 May 2012 - 16:00 PDT

Current ratings for: 'Chronic Inflammation Gene May Destroy Tumors'

5 (1 votes)

Robert J. Schneider, PhD, the Albert Sabin Professor of Molecular Pathogenesis and associate director for translational research and co-director of the Breast Cancer Program at the NYU Langone Medical Center, who was the principal investigator of the study, declared:

Scientists have known for decades that accelerated ageing, inflammation and cancer are somehow related, yet exactly how these conditions are linked has so far been unknown. The little knowledge available has partly been obtained in Schneider's previous studies, mainly that a gene called AUF1 controls inflammation by switching off the inflammatory response to prevent the onset of septic shock, and although this finding is significant, it fails to shed light on the link to ageing and cancer. The team observed that accelerated ageing occurred when the AUF1 gene was deleted, which led them to investigate further. A decade later, they have finally discovered the link between inflammation, advanced aging and cancer.

They found out that aside from controlling inflammation, AUF1, which belongs to a family of four related genes, also maintains the integrity of chromosomes. It activates telomerase, an enzyme, to repair the ends of chromosomes, and by doing so, it simultaneously reduces inflammation, prevents rapid aging and cancer from developing. Dr. Schneider explained: "AUF1 is a medical and scientific trinity. Nature has designed a way to simultaneously turn off harmful inflammation and repair our chromosomes, thereby suppressing aging at the cellular level and in the whole animal."

Armed with this new discovery, Dr. Schneider and his team are currently researching how the alterations manifest and present themselves clinically. They are examining human populations for specific types of genetic changes in the AUF1 gene, which are associated with rapid ageing, higher risk of cancer and co-developments of certain immune diseases.

Written By Petra Rattue Copyright: Medical News Today Not to be reproduced without permission of Medical News Today

MLA

Petra Rattue. "Chronic Inflammation Gene May Destroy Tumors." Medical News Today. MediLexicon, Intl., 28 May. 2012. Web. 29 May. 2012. <http://www.medicalnewstoday.com/articles/245916.php>

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Chronic Inflammation Gene May Destroy Tumors

ScienceDaily (May 27, 2012) UCLA geneticists have identified the mutation responsible for IMAGe syndrome, a rare disorder that stunts infants' growth. The twist? The mutation occurs on the same gene that causes Beckwith-Wiedemann syndrome, which makes cells grow too fast, leading to very large children.

Published in the May 27 edition of Nature Genetics, the UCLA findings could lead to new ways of blocking the rapid cell division that allows tumors to grow unchecked. The discovery also offers a new tool for diagnosing children with IMAGe syndrome, which until now has been difficult to accurately identify.

The discovery holds special significance for principal investigator Dr. Eric Vilain, a professor of human genetics, pediatrics and urology at the David Geffen School of Medicine at UCLA.

Nearly 20 years ago, as a medical resident in his native France, Vilain cared for two boys, ages 3 and 6, who were dramatically short for their ages. Though unrelated, both children shared a mysterious malady marked by minimal fetal development, stunted bone growth, sluggish adrenal glands, and undersized organs and genitals.

"I never found a reason to explain these patients' unusual set of symptoms," explained Vilain, who is also director of the UCLA Institute for Society and Genetics. "I've been searching for the cause of their disease since 1993."

When Vilain joined UCLA as a genetics fellow, the two cases continued to intrigue him. His mentor, then UCLA geneticist Dr. Edward McCabe, recalled a similar case from his previous post at Baylor College of Medicine. The two of them obtained blood samples from the three cases and analyzed the patients' DNA for mutations in suspect genes, but uncovered nothing.

Vilain and McCabe approached the Journal of Clinical Endocrinology and Metabolism, and in 1999 published the first description of the syndrome, which they dubbed IMAGe, an acronym of sorts for the condition's symptoms: intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia and genital anomalies.

Over the next decade, about 20 cases were reported around the world. But the cause of IMAGe syndrome remained a mystery.

Help arrived unexpectedly last year when Vilain received an email from Argentinian physician Dr. Ignacio Bergada, who had unearthed the 1999 journal article. He told Vilain about a large family he was treating in which eight members suffered the same symptoms described in the study. All of the family members agreed to send their DNA samples to UCLA for study.

Vilain realized that he had stumbled across the scientific equivalent of winning the lottery. He assembled a team of UCLA researchers to partner with Bergada and London endocrinologist Dr. John Achermann.

Read more:
Disease that stunts infants' growth traced to same gene that makes kids grow too fast

Public release date: 27-May-2012 [ | E-mail | Share ]

Contact: Elaine Schmidt eschmidt@mednet.ucla.edu 310-794-2272 University of California - Los Angeles Health Sciences

The Caterpillar got down off the mushroom and crawled away in the grass, remarking as it went, 'One side will make you grow taller, and the other side will make you grow shorter.' -Alice's Adventures in Wonderland, by Lewis Carroll

UCLA geneticists have identified the mutation responsible for IMAGe syndrome, a rare disorder that stunts infants' growth. The twist? The mutation occurs on the same gene that causes Beckwith-Wiedemann syndrome, which makes cells grow too fast, leading to very large children.

Published in the May 27 edition of Nature Genetics, the UCLA findings could lead to new ways of blocking the rapid cell division that allows tumors to grow unchecked. The discovery also offers a new tool for diagnosing children with IMAGe syndrome, which until now has been difficult to accurately identify.

The discovery holds special significance for principal investigator Dr. Eric Vilain, a professor of human genetics, pediatrics and urology at the David Geffen School of Medicine at UCLA.

Nearly 20 years ago, as a medical resident in his native France, Vilain cared for two boys, ages 3 and 6, who were dramatically short for their ages. Though unrelated, both children shared a mysterious malady marked by minimal fetal development, stunted bone growth, sluggish adrenal glands, and undersized organs and genitals.

"I never found a reason to explain these patients' unusual set of symptoms," explained Vilain, who is also director of the UCLA Institute for Society and Genetics. "I've been searching for the cause of their disease since 1993."

When Vilain joined UCLA as a genetics fellow, the two cases continued to intrigue him. His mentor, then UCLA geneticist Dr. Edward McCabe, recalled a similar case from his previous post at Baylor College of Medicine. The two of them obtained blood samples from the three cases and analyzed the patients' DNA for mutations in suspect genes, but uncovered nothing.

Vilain and McCabe approached the Journal of Clinical Endocrinology and Metabolism, and in 1999 published the first description of the syndrome, which they dubbed IMAGe, an acronym of sorts for the condition's symptoms: intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia and genital anomalies.

See the original post here:
Same gene that stunts infants' growth also makes them grow too big

CAMBRIDGE, Mass.--(BUSINESS WIRE)--

Vertex Pharmaceuticals Incorporated (VRTX) announced today that the European Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion by consensus recommending the approval of KALYDECO (ivacaftor) for people with cystic fibrosis (CF) ages 6 and older who have at least one copy of the G551D mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. KALYDECO is the first medicine to treat the underlying cause of CF, a rare, genetic disease caused by defective or missing CFTR proteins resulting from mutations in the CFTR gene. In people with the G551D mutation, KALYDECO helps the defective CFTR protein function more normally. An estimated 1,100 people in Europe have this mutation.

The CHMP opinion was based on positive findings from two global Phase 3 studies in which KALYDECO demonstrated unprecedented improvements in breathing and other measures of disease for people ages 6 and older with this specific genetic mutation. People treated with KALYDECO experienced significant and sustained improvements in lung function, weight gain and certain quality of life measurements compared to those on placebo. In addition, people who took KALYDECO were 55 percent less likely to have pulmonary exacerbations, or periods of worsening in the signs and symptoms of the disease that often require treatment with antibiotics and hospital visits, than those who received placebo. Fewer people in the KALYDECO treatment groups discontinued treatment due to adverse events than in the placebo groups. The majority of adverse events associated with KALYDECO were mild to moderate. Adverse events most commonly observed in those taking KALYDECO included headache, upper respiratory tract infection (common cold), stomach pain and diarrhea.

While there has been great progress in cystic fibrosis treatment during the last few decades, we are still only treating the symptoms and complications of the disease, said Stuart Elborn, M.D., KALYDECO investigator and President of the European Cystic Fibrosis Society. KALYDECO is a fundamentally different approach to the way we treat cystic fibrosis because it targets the underlying cause of the disease. In clinical trials, KALYDECO helped people with a specific genetic mutation breathe more easily, gain weight and generally feel better.

The CHMPs positive opinion will now be reviewed by the European Commission, which has the authority to approve medicines for the European Union. The European Commission generally follows the recommendation of the CHMP and typically issues marketing approval within three to four months.

Since 1998, Vertex has been committed to developing new medicines to treat the underlying cause of cystic fibrosis, said Peter Mueller, Ph.D., Chief Scientific Officer and Executive Vice President of Global Research and Development at Vertex. KALYDECO represents an important achievement in this ongoing effort. We look forward to working with the European Medicines Agency to bring KALYDECO, our first new medicine in Europe, to people with CF as quickly as possible.

KALYDECO was discovered as part of a collaboration with Cystic Fibrosis Foundation Therapeutics, Inc., the nonprofit drug discovery and development affiliate of the Cystic Fibrosis Foundation.

About Cystic Fibrosis

Cystic fibrosis is a rare, life-threatening genetic disease affecting approximately 35,000 people in Europe and 70,000 people worldwide. Today, the median predicted age of survival for a person with CF is approximately 38 years but the median age of death remains in the mid-20s. There are more than 1,800 known mutations in the CFTR gene. Some of these mutations, which can be determined by a genetic, or genotyping test, lead to CF by creating non-working or too few CFTR proteins at the cell surface. The absence of working CFTR proteins results in poor flow of salt and water into and out of the cell in a number of organs, including the lungs. This leads to the buildup of abnormally thick, sticky mucus that can cause chronic lung infections and progressive lung damage.

In some people, CFTR proteins are present at the cell surface but do not work properly. One type of this dysfunction is known as the G551D mutation.

Read more from the original source:
Vertex Receives European CHMP Positive Opinion for KALYDECO™ (ivacaftor), the First Medicine to Treat the Underlying ...

University of Edinburgh researchers say they've identified a gene crucial to sperm development that could be a target for a new form of male birth control.

Oliver Cleve / Getty Images

Condoms or a vasectomy are basically the only contraceptive options currently available for men. But a new gene discovery by infertility researchers at theCentre for Reproductive Healthat the University of Edinburghsuggests that the development of a male contraceptive pill could someday be possible.

While studying infertility in mice, the researchers identified a gene called Katnal1 that appears to be critical during the late stages of sperm production. In the testes,Katnal1 regulates a protein needed by cells that support sperm maturation; without it, sperm do not develop properly and the body disposes of them.

In lab studies, the research team found that mice with genetic mutations that interrupted Katnal1 became infertile.

(MORE:Male Contraception May Be a Reality Sooner than We Think)

Although the research is still in the preliminary stages, the authors say that if a drug could be developed to hinder Katnal1, it could potentially serve as a reversible contraceptive.

If we can find a way to target this gene in the testes, we could potentially develop a non-hormonal contraceptive, researcherDr. Lee Smith of the University of Edinburgh said in a news release.The important thing is that the effects of such a drug would be reversible because Katnal1 only affects sperm cells in the later stages of development, so it would not hinder the early stages of sperm production and the overall ability to produce sperm.

As Dr. Allan Pacey, a senior lecturer in andrology at the University of Sheffield,told BBC News:

The key in developing a non-hormonal contraceptive for men is that the molecular target needs to be very specific for either sperm or other cells in the testicle which are involved in sperm production.

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The New Era of Contraception, Thanks to Gene Discovery?

24-05-2012 17:00 Obesity has continued to be a growing epidemic in America. The centers for Disease Control and Prevention estimates by the year 2030 obesity could affect over 42% of Americans. Many Americans have tried to lose the pounds by eating healthy and exercising but still cannot find a solution. Could the secret to weight gain or therefore lack of weight loss be answer in our genetics? WSPA 7 on Your Side Weekend Morning News Anchor and Weekday Reporter Laura Thomas tests the theory of The Weight Loss Gene. One simple test could change the overall health outlook for millions of Americans struggling with obesity!

Read more here:
WSPA 7 On Your Side Medical Investigation: The Weight Loss Gene - Video

By Fiona Macrae

PUBLISHED: 16:09 EST, 24 May 2012 | UPDATED: 11:15 EST, 25 May 2012

A breakthrough by British fertility experts could lead to a male pill and even a 'genetic vasectomy'.

Edinburgh University scientists have discovered a gene that is key to the production of sperm.

A drug that blocks the gene from working could be used as a contraceptive, liberating women from the burden of family planning.

Scientists from Edinburgh University say they have discovered a gene that is key to the production of sperm

The research could also lead to a 'genetic vasectomy' - a jab of genes that would leave a man permanently sterile.

Ultimately, within just five to ten years, it could even mean new treatments for infertile men, allowing them to achieve their dream of fatherhood.

The hopes come from an early-stage study in which scientists bred mice in which a gene called Katnal1 didn't work.

See the article here:
Found: The breakthrough discovery of the gene that is key to the production of sperm and the male Pill

Dr Lee Smith, from the university, said if the gene was blocked the testes would continue to produce sperm, only releasing immature, ineffective sperm which had not developed into the final stages.

"The important thing is that the effects of such a drug would be reversible because Katnal1 only affects sperm cells in the later stages of development, so it would not hinder the early stages of sperm production and the overall ability to produce sperm.

He added it would be "relatively difficult" to do as the protein lives inside cells, but there was "potential" to find another substance that protein worked with as an easier target.

The research, funded by the Medical Research Council, was based on altering the genetic code of mice to discover mutations which led to infertility.

Dr Allan Pacey, senior lecturer in andrology at the University of Sheffield, told the BBC there was "certainly a need" for a non-hormonal contraceptive for men and that this had been a "Holy Grail" of research for many years.

"The gene described by the research group in Edinburgh sounds like an exciting new possible target for a new male contraceptive, but it may also shed light on why some men are sub-fertile and why their sperm does not work properly, he said.

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Male contraceptive pill hopes after gene discovery

Public release date: 25-May-2012 [ | E-mail | Share ]

Contact: Scott LaFee slafee@ucsd.edu 619-543-6163 University of California - San Diego

Five scientists from the University of California, San Diego and its School of Medicine have been awarded almost $12 million in new grants from the California Institute for Regenerative Medicine (CIRM) to conduct stem cell-based research into regenerating spinal cord injuries, repairing gene mutations that cause amyotrophic lateral sclerosis and finding new drugs to treat heart failure and Alzheimer's disease.

The awards mark the third round of funding in CIRM's Early Translational Awards program, which supports projects that are in the initial stages of identifying drugs or cell types that could become disease therapies. More than $69 million in awards were announced yesterday, including funding for first-ever collaboratively funded research projects with China and the federal government of Australia.

"With these new awards, the agency now has 52 projects in 33 diseases at varying stages of working toward clinical trials," said Jonathan Thomas, JD, PhD and CIRM governing board chair. "Californians should take pride in being at the center of this worldwide research leading toward new cures. These projects represent the best of California stem cell science and the best international experts who, together, will bring new therapies for patients."

The five new UC San Diego awards are:

With a $1.8 million award, Lawrence Goldstein, PhD, professor in the Department of Cellular and Molecular Medicine, Howard Hughes Medical Institute Investigator and director of the UC San Diego Stem Cell Program, and colleagues will continue their work developing new methods to find and test drug candidates for Alzheimer's disease (AD). Currently, there is no effective treatment for AD. The researchers screen novel candidates using purified human brain cells made from human reprogrammed stem cells. Already, they have discovered that these human brain cells exhibit a unique biochemical behavior that indicates early development of AD in a dish.

Mark H. Tuszynski, MD, PhD, professor of neurosciences and director of the Center for Neural Repair at UC San Diego, and colleagues seek to develop more potent stem cell-based treatments for spinal cord injuries. By combining grafts of neural stem cells with scaffolds placed at injury sites, the researchers have reported substantial progress in restoring functional improvement in impaired animal models. The new $4.6 million grant will fund work to identify the optimal human neural stem cells for preclinical development and, in an unprecedented step, test this treatment in appropriate preclinical models of spinal cord injury, providing the strongest validation for human translation.

Amyotrophic lateral sclerosis or ALS (Lou Gehrig's disease) is a progressive neurological condition that is currently incurable. Gene Yeo, PhD, assistant professor in the Department of Cellular and Molecular Medicine, and colleagues will use a $1.6 million grant to exploit recent discoveries that specific mutations in RNA-binding proteins cause neuronal dysfunction and death. They will use neurons generated from patient cells containing the mutations to identify the unique RNA "signature" of these doomed neurons and screen for drug-like compounds that bypass the mutations to correct the RNA signature to obtain healthy neurons.

Eric David Adler, MD, an associate clinical professor of medicine and cardiologist, studies heart failure, including the use of stem cells to treat it. His $1.7 million award will fund research into Danon disease, a type of inherited heart failure that frequently kills patients by their 20s. Adler and colleagues will turn stem cells created from skin cells of patients with Danon disease into heart cells, then screen hundreds of thousands of drug candidates for beneficial effects. The most promising drugs will subsequently be tested on mice with a genetic defect similar to Danon disease, with the ultimate goal of identifying a suitable candidate for human clinical trials. The research may have broader applications for other conditions with similar pathogenesis, such as cancer and Parkinson's disease.

See the original post here:
UC San Diego researchers receive new CIRM funding

OMAHA, Neb.--(BUSINESS WIRE)--

Transgenomic, Inc. (TBIO.OB) today announced it has entered into an agreement with Gene Logic, Inc., an Ocimum Biosolutions Company, to acquire its biorepository assets for $250,000 in cash. The biorepository contains thousands of human biological samples that can be used to validate diagnostic assays developed by Transgenomic. Transgenomic will use the samples to develop and validate its REVEAL family of proprietary ICE COLD-PCR-based oncology assays, as well as its WAVE MCE System and SURVEYOR Scan Mutation Detection Kits.

This transaction significantly strengthens Transgenomics position in translational medicine services, providing a deep source of clinical samples allowing us to validate new drug-associated genetic targets, said Craig Tuttle, Chief Executive Officer of Transgenomic. The biorepository provides not only strategic and operational benefits, but also long-term cost savings. Acquiring specimens on a case-by-case basis is expensive and time-consuming; such expenditure would quickly surpass the cost of acquiring this asset.

The Gene Logic biorepository consists of a high quality, diverse collection of human tissue samples and extracted DNA specimens with linked clinical information. The 60,000 samples and specimens cover multiple disease areas, including many thousands of cancer tissue specimens.

About Transgenomic

Transgenomic, Inc. (www.transgenomic.com) is a global biotechnology company advancing personalized medicine in cancer and inherited diseases through its proprietary molecular technologies and world-class clinical and research services. The Company has three complementary business divisions: Transgenomic Pharmacogenomic Services is a contract research laboratory that specializes in supporting all phases of pre-clinical and clinical trials for oncology drugs in development. Transgenomic Clinical Laboratories specializes in molecular diagnostics for cardiology, neurology, mitochondrial disorders, and oncology. Transgenomic Diagnostic Tools produces equipment, reagents, and other consumables that empower clinical and research applications in molecular testing and cytogenetics. Transgenomic believes there is significant opportunity for continued growth across all three businesses by leveraging their synergistic capabilities, technologies, and expertise. The Company actively develops and acquires new technology and other intellectual property that strengthen its leadership in personalized medicine.

Forward-Looking Statements

Certain statements in this press release constitute forward-looking statements of Transgenomic within the meaning of the Private Securities Litigation Reform Act of 1995, which involve known and unknown risks, uncertainties and other factors that may cause actual results to be materially different from any future results, performance or achievements expressed or implied by such statements. Forward-looking statements include, but are not limited to, those with respect to management's current views and estimates of future economic circumstances, industry conditions, company performance and financial results, including the ability of the Company to grow its involvement in the diagnostic products and services markets. The known risks, uncertainties and other factors affecting these forward-looking statements are described from time to time in Transgenomic's filings with the Securities and Exchange Commission. Any change in such factors, risks and uncertainties may cause the actual results, events and performance to differ materially from those referred to in such statements. Accordingly, the Company claims the protection of the safe harbor for forward-looking statements contained in the Private Securities Litigation Reform Act of 1995 with respect to all statements contained in this press release. All information in this press release is as of the date of the release and Transgenomic does not undertake any duty to update this information, including any forward-looking statements, unless required by law.

Continued here:
Transgenomic Acquires Clinical Sample Biorepository from Gene Logic

ScienceDaily (May 24, 2012) Researchers at NYU School of Medicine have, for the first time, identified a single gene that simultaneously controls inflammation, accelerated aging and cancer.

"This was certainly an unexpected finding," said principal investigator Robert J. Schneider, PhD, the Albert Sabin Professor of Molecular Pathogenesis, associate director for translational research and co-director of the Breast Cancer Program at NYU Langone Medical Center. "It is rather uncommon for one gene to have two very different and very significant functions that tie together control of aging and inflammation. The two, if not regulated properly, can eventually lead to cancer development. It's an exciting scientific find."

The study, funded by the National Institutes of Health, appears online ahead of print May 24 in Molecular Cell and is scheduled for the July 13 print issue.

For decades, the scientific community has known that inflammation, accelerated aging and cancer are somehow intertwined, but the connection between them has remained largely a mystery, Dr. Schneider said. What was known, due in part to past studies by Schneider and his team, was that a gene called AUF1 controls inflammation by turning off the inflammatory response to stop the onset of septic shock. But this finding, while significant, did not explain a connection to accelerated aging and cancer.

When the researchers deleted the AUF1 gene, accelerated aging occurred, so they continued to focus their research efforts on the gene. Now, more than a decade in the making, the mystery surrounding the connection between inflammation, advanced aging and cancer is finally being unraveled.

The current study reveals that AUF1, a family of four related genes, not only controls the inflammatory response, but also maintains the integrity of chromosomes by activating the enzyme telomerase to repair the ends of chromosomes, thereby simultaneously reducing inflammation, preventing rapid aging and the development of cancer, Dr. Schneider explained.

"AUF1 is a medical and scientific trinity," Dr. Schneider said. "Nature has designed a way to simultaneously turn off harmful inflammation and repair our chromosomes, thereby suppressing aging at the cellular level and in the whole animal."

With this new information, Dr. Schneider and colleagues are examining human populations for specific types of genetic alterations in the AUF1 gene that are associated with the co-development of certain immune diseases, increased rates of aging and higher cancer incidence in individuals to determine exactly how the alterations manifest and present themselves clinically.

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Key gene found responsible for chronic inflammation, accelerated aging and cancer

Public release date: 24-May-2012 [ | E-mail | Share ]

Contact: Sarah Jackson press_releases@the-jci.org Journal of Clinical Investigation

Severe combined immunodeficiency is defect in the immune system that results in a loss of the adaptive immune cells known as B cells and T cells. Mutations in several different genes can lead to the development of severe combined immunodeficiency, including mutation of the adenosine deaminase (ADA) gene. Traditional treatment options, such as enzyme replacement therapy, are of limited efficacy, but bone marrow transplant from a compatible donor leads to a better response. A recent clinical trial indicated that gene therapy to insert the correct ADA gene in the patient's own bone marrow cells can also lead to a good response.

However, patients were noted to have defects in B cell tolerance, meaning that some B cells that react to antigens from the body fail to be eliminated, leading to an autoimmune response. Dr. Eric Meffre and colleages at Yale University in New Haven, Connecticut and Alessandro Aiuti in Milan, Italy joined together to better understand why patients developed B cell tolerance problems. They found that loss of the ADA gene directly contributes to B cell tolerance problems and that these defects are mostly corrected after gene therapy. Their results point to a previously unknown role for ADA in B cell response and support the use of gene therapy as an effective treatment option for ADA-deficient severe combined immunodeficiency patients.

###

TITLE:

Defective B cell tolerance in adenosine deaminase deficiency is corrected by gene therapy

AUTHOR CONTACT:

Eric Meffre Yale University School of Medicine, New Haven, CT, USA Phone: 1-203-737-4535; Fax: 1-203-785-7903; E-mail: eric.meffre@yale.edu

ACCOMPANYING COMMENTARY

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Gene therapy can correct forms of severe combined immunodeficiency

ScienceDaily (May 22, 2012) Up to half of all prostate cancer cells have a chromosomal rearrangement that results in a new "fusion" gene and formation of its unique protein -- but no one has known how that alteration promotes cancer growth. Now, Weill Cornell Medical College researchers have found that in these cancer cells, the 3-D architecture of DNA, wrapped up in a little ball known as a chromatin, is warped in such a way that a switch has been thrown on thousands of genes, turning them on or off to promote abnormal, unchecked growth. Researchers also found that new chromosomal translocations form, further destabilizing the genome.

These findings, published in the Proceedings of the National Academy of Sciences (PNAS), are the first to show how this chromosomal mutation likely contributes to early development of prostate cancer -- and suggests a model for how other chromosomal translocations, common to many tumor types, are linked to cancer formation and growth.

"This is likely a phenomenon that occurs in many types of cancers when oncogenic fusion genes are over-expressed," says the study's senior author, Dr. Mark A. Rubin, The Homer T. Hirst Professor of Oncology in Pathology and vice chair for experimental pathology at Weill Cornell Medical College.

Dr. Rubin adds that if such an oncogenic protein has the power to throw the switch on thousands of genes, a novel treatment may be able to turn that switch off. "If we understand how this works, then we may be able to borrow that trick to target many genes simultaneously. This discovery would hold a lot of promise for cancer therapy," he says.

The study also adds to the growing understanding of how remodeling of the chromatin regulates genes linked to cancer, says the study's lead author, Dr. David S. Rickman, assistant professor of pathology and laboratory medicine at Weill Cornell Medical College. The genome's DNA, along with specialized proteins, has to be packed into the chromatin bundle so that it can fit inside a cell's nucleus, and when genes need to be expressed, the chromatin opens up a bit, allowing transcription. Emerging evidence suggests that, within this package, the genome organizes itself according to a non-randomly-assembled, 3-D architecture of hubs and domains that affect when and where individual genes are turned on.

This study shows the oncogenic ERG protein, produced by the ETS prostate cancer fusion gene, binds to specific sites in the genome, which then forces the 3-D genome architecture to vastly change, creating different hubs and domains, Dr. Rickman says. This results in additional chromosomal translocations, as well as a coordinated expression of genes known to be relevant to aggressive prostate cancer, he says.

The research shows just how complex genetic regulation really is and how distortions in this process can lead to cancer, says Dr. Rubin, who is also a professor of pathology and laboratory medicine and professor of pathology in urology at Weill Cornell Medical College.

"We used to think everything related to gene expression was linear, that one promoter affected the gene located right next to it," he says. "Now we are beginning to understand that what happens in the 3-D space of tightly bundled DNA is also important -- how DNA opens up and undergoes changes that efficiently turn on whole sets of genes that aren't located anywhere near each other."

It Takes a Village -- of Scientists

Reaching these findings required a collaborative team of scientists, says Dr. Rubin, who co-discovered the ETS fusion gene. For this project, he sought the expertise of Dr. Rickman and Dr. Olivier Elemento, an assistant professor in the Department of Physiology and Biophysics and assistant professor of computational genomics in the Institute for Computational Biomedicine at Weill Cornell Medical College, and a co-senior author of the paper. Dr. Elemento and his lab provided the expertise in computational biology and mathematical analysis needed to interpret the complex data produced by the experiments run by Dr. Rickman, his lab and members of the Rubin laboratory.

Read more here:
Role of fusion gene in prostate cancer: Mutation found in half of all prostate cancers may lead to disease development

Public release date: 22-May-2012 [ | E-mail | Share ]

Contact: Lauren Woods law2014@med.cornell.edu 212-821-0560 New York- Presbyterian Hospital/Weill Cornell Medical Center/Weill Cornell Medical College

NEW YORK (May 22, 2012) -- Up to half of all prostate cancer cells have a chromosomal rearrangement that results in a new "fusion" gene and formation of its unique protein -- but no one has known how that alteration promotes cancer growth. Now, Weill Cornell Medical College researchers have found that in these cancer cells, the 3-D architecture of DNA, wrapped up in a little ball known as a chromatin, is warped in such a way that a switch has been thrown on thousands of genes, turning them on or off to promote abnormal, unchecked growth. Researchers also found that new chromosomal translocations form, further destabilizing the genome.

These findings, published in the Proceedings of the National Academy of Sciences (PNAS), are the first to show how this chromosomal mutation likely contributes to early development of prostate cancer -- and suggests a model for how other chromosomal translocations, common to many tumor types, are linked to cancer formation and growth.

"This is likely a phenomenon that occurs in many types of cancers when oncogenic fusion genes are over-expressed," says the study's senior author, Dr. Mark A. Rubin, The Homer T. Hirst Professor of Oncology in Pathology and vice chair for experimental pathology at Weill Cornell Medical College.

Dr. Rubin adds that if such an oncogenic protein has the power to throw the switch on thousands of genes, a novel treatment may be able to turn that switch off. "If we understand how this works, then we may be able to borrow that trick to target many genes simultaneously. This discovery would hold a lot of promise for cancer therapy," he says.

The study also adds to the growing understanding of how remodeling of the chromatin regulates genes linked to cancer, says the study's lead author, Dr. David S. Rickman, assistant professor of pathology and laboratory medicine at Weill Cornell Medical College. The genome's DNA, along with specialized proteins, has to be packed into the chromatin bundle so that it can fit inside a cell's nucleus, and when genes need to be expressed, the chromatin opens up a bit, allowing transcription. Emerging evidence suggests that, within this package, the genome organizes itself according to a non-randomly-assembled, 3-D architecture of hubs and domains that affect when and where individual genes are turned on.

This study shows the oncogenic ERG protein, produced by the ETS prostate cancer fusion gene, binds to specific sites in the genome, which then forces the 3-D genome architecture to vastly change, creating different hubs and domains, Dr. Rickman says. This results in additional chromosomal translocations, as well as a coordinated expression of genes known to be relevant to aggressive prostate cancer, he says.

The research shows just how complex genetic regulation really is and how distortions in this process can lead to cancer, says Dr. Rubin, who is also a professor of pathology and laboratory medicine and professor of pathology in urology at Weill Cornell Medical College.

"We used to think everything related to gene expression was linear, that one promoter affected the gene located right next to it," he says. "Now we are beginning to understand that what happens in the 3-D space of tightly bundled DNA is also important -- how DNA opens up and undergoes changes that efficiently turn on whole sets of genes that aren't located anywhere near each other."

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Scientists unravel role of fusion gene in prostate cancer

Gene Findings in African-Americans May Pave Way Toward Better Quit-Smoking Treatments

By Denise Mann WebMD Health News

Reviewed by Laura J. Martin, MD

May 22, 2012 -- A "smoking gun" gene may play a role in how many cigarettes certain smokers puff each day.

Researchers from 50 medical institutions across the country analyzed genetic material of more than 32,000 African-American smokers and non-smokers to see if certain genes predicted when they began smoking, how many cigarettes they smoked, and how easily they were able to quit.

According to the new study, a variant in a nicotine receptor gene predicts about one extra cigarette smoked per day. This same general location has been implicated in smoking behavior among white Europeans. Among African-Americans, the new genetic marker appears on a different spot on the same gene.

The findings appear in the May 22 issue of Translational Psychiatry. They are part of the Study of Tobacco in Minority Populations (STOMP) Genetics Consortium.

"This region is really important for addiction biology, regardless of race or ethnicity," says researcher Helena Furberg, PhD, an assistant attending epidemiologist at Memorial Sloan-Kettering Cancer Center in New York City.

This is somewhat surprising, she says. "Smoking behaviors differ among ethnic groups." For example, African-Americans typically start smoking at later ages than their counterparts of European descent and smoke fewer cigarettes each day. But they have a higher risk for lung cancer and are less likely to quit smoking.

The findings hold potential for tailoring smoking cessation treatments down the road, Furberg says. "The next research step would be to see if currently available smoking cessation medications would work better or differently among people who carry these variants."

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Smoking Gene May Reveal Why Some People Smoke More

Delivering a missing enzyme to the brains of paralyzed children with a rare, life-threatening neurological disease restores movement and builds muscle mass.

An inherited disorder known as aromatic L-amino acid decarboxylase deficiency, or AADC, leaves patients unable to produce the neurotransmitter dopamine, leaving them nearly paralyzed until they die in early childhood. But a new gene therapy, which involves the delivery of the missing L-amino acid decarboxylase enzyme that converts the chemical precursor L-DOPA to dopamine, helped four Taiwanese children, aged 4 to 6 years, move their heads and sit up on their own, according to a study published today (May 16) in Science Translational Medicine.

The children in this study have the most severe form of inherited movement disorder known, and the only treatments so far have been supportive ones, pediatric cardiologist Barry Byrne, director of the University of Floridas Powell Gene Therapy Center, said in a press release. It is gratifying to see it is possible to do something to help them, other than providing feeding tubes and keeping them safe. This absolutely opens the door to the possibility of even earlier treatment of neurological diseases by direct gene transfer, and has implications for Parkinsons disease, ALS, and even cognitive diseases such as dementia when caused by gene defects.

In the phase I trial led by Wuh-Liang Hwu of the National Taiwan University Hospital, doctors injected an adeno-associated virus loaded up with a good copy of the AADC gene into the childrens putamen, a part of the brain where the enzyme works to make dopamine. Within 16 months of the surgery, all the patients showed increased head movements, higher weight, and were able to sit up without assistance. One patient was even able to stand. In the months that followed, the patients continued to gain weight, and scored higher on cognition and motor development tests. Their parents also said that the children slept better and had improved eye coordination and emotional stability.

Given the positive results, the doctors plan to treat eight more childrenfour in Taiwan and four in the United States, Byrne said.

AADC is not the only disease currently being targeted with gene therapy. Recent successes in treating hemophilia B, numerous cancers, and a variety of blindness disorders are stirring excitement around this once-embattled field. Look out for the feature story, Targeting DNA, in the June issue of The Scientist to learn more about the ways that gene therapy could change the face of medicine.

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Gene Therapy for Brain Disease

ScienceDaily (May 14, 2012) A new study consisting of inducing cells to express telomerase, the enzyme which -- metaphorically -- slows down the biological clock -- was successful. The research provides a "proof-of-principle" that this "feasible and safe" approach can effectively "improve health span."

A number of studies have shown that it is possible to lengthen the average life of individuals of many species, including mammals, by acting on specific genes. To date, however, this has meant altering the animals' genes permanently from the embryonic stage -- an approach impracticable in humans. Researchers at the Spanish National Cancer Research Centre (CNIO), led by its director Maria Blasco, have demonstrated that the mouse lifespan can be extended by the application in adult life of a single treatment acting directly on the animal's genes. And they have done so using gene therapy, a strategy never before employed to combat aging. The therapy has been found to be safe and effective in mice.

The results were recently published in the journal EMBO Molecular Medicine. The CNIO team, in collaboration with Eduard Ayuso and Fatima Bosch of the Centre of Animal Biotechnology and Gene Therapy at the Universitat Autonoma de Barcelona (UAB), treated adult (one-year-old) and aged (two-year-old) mice, with the gene therapy delivering a "rejuvenating" effect in both cases, according to the authors.

Mice treated at the age of one lived longer by 24% on average, and those treated at the age of two, by 13%. The therapy, furthermore, produced an appreciable improvement in the animals' health, delaying the onset of age-related diseases -- like osteoporosis and insulin resistance -- and achieving improved readings on aging indicators like neuromuscular coordination.

The gene therapy consisted of treating the animals with a DNA-modified virus, the viral genes having been replaced by those of the telomerase enzyme, with a key role in aging. Telomerase repairs the extreme ends or tips of chromosomes, known as telomeres, and in doing so slows the cell's and therefore the body's biological clock. When the animal is infected, the virus acts as a vehicle depositing the telomerase gene in the cells.

This study "shows that it is possible to develop a telomerase-based anti-aging gene therapy without increasing the incidence of cancer," the authors affirm. "Aged organisms accumulate damage in their DNA due to telomere shortening, [this study] finds that a gene therapy based on telomerase production can repair or delay this kind of damage," they add.

'Resetting' the biological clock

Telomeres are the caps that protect the end of chromosomes, but they cannot do so indefinitely: each time the cell divides the telomeres get shorter, until they are so short that they lose all functionality. The cell, as a result, stops dividing and ages or dies. Telomerase gets around this by preventing telomeres from shortening or even rebuilding them. What it does, in essence, is stop or reset the cell's biological clock.

But in most cells the telomerase gene is only active before birth; the cells of an adult organism, with few exceptions, have no telomerase. The exceptions in question are adult stem cells and cancer cells, which divide limitlessly and are therefore immortal -- in fact several studies have shown that telomerase expression is the key to the immortality of tumour cells.

It is precisely this risk of promoting tumour development that has set back the investigation of telomerase-based anti-aging therapies.

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First gene therapy successful against aging-associated decline: Mouse lifespan extended up to 24% with a single ...

Public release date: 16-May-2012 [ | E-mail | Share ]

Contact: Tom Rickey tom_rickey@urmc.rochester.edu 585-275-7954 University of Rochester Medical Center

A well-known genetic risk factor for Alzheimer's disease triggers a cascade of signaling that ultimately results in leaky blood vessels in the brain, allowing toxic substances to pour into brain tissue in large amounts, scientists report May 16 in the journal Nature.

The results come from a team of scientists investigating why a gene called ApoE4 makes people more prone to developing Alzheimer's. People who carry two copies of the gene have roughly eight to 10 times the risk of getting Alzheimer's disease than people who do not.

A team of scientists from the University of Rochester, the University of Southern California, and other institutions found that ApoE4 works through cyclophilin A, a well-known bad actor in the cardiovascular system, causing inflammation in atherosclerosis and other conditions. The team found that cyclophilin A opens the gates to the brain assault seen in Alzheimer's.

"We are beginning to understand much more about how ApoE4 may be contributing to Alzheimer's disease," said Robert Bell, Ph.D., the post-doctoral associate at Rochester who is first author of the paper. "In the presence of ApoE4, increased cyclophilin A causes a breakdown of the cells lining the blood vessels in Alzheimer's disease in the same way it does in cardiovascular disease or abdominal aneurysm. This establishes a new vascular target to fight Alzheimer's disease."

The team found that ApoE4 makes it more likely that cyclophilin A will accumulate in large amounts in cells that help maintain the blood-brain barrier, a network of tightly bound cells that line the insides of blood vessels in the brain and carefully regulates what substances are allowed to enter and exit brain tissue.

ApoE4 creates a cascade of molecular signaling that weakens the barrier, causing blood vessels to become leaky. This makes it more likely that toxic substances will leak from the vessels into the brain, damaging cells like neurons and reducing blood flow dramatically by choking off blood vessels.

Doctors have long known that the changes in the brain seen in Alzheimer's patients the death of crucial brain cells called neurons begins happening years or even decades before symptoms appear. The steps described in Nature discuss events much earlier in the disease process.

The idea that vascular problems are at the heart of Alzheimer's disease is one championed for more than two decades by Berislav Zlokovic, M.D., Ph.D., the leader of the team and a neuroscientist formerly with the University of Rochester Medical Center and now at USC. For 20 years, Zlokovic has investigated how blood flow in the brain is affected in people with the disease, and how the blood-brain barrier allows nutrients to pass into the brain, and harmful substances to exit the brain.

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Alzheimer's gene causes brain's blood vessels to leak, die