HOUSTON, June 25, 2012 /PRNewswire/ --Veracyte, Inc., a molecular diagnostics company that is pioneering the emerging field of molecular cytology, today announced results from a large, prospective, multicenter study, which demonstrated the potential for the Afirma Gene Expression Classifier, a gene expression test, to reduce the large number of unnecessary surgeries in thyroid cancer diagnosis by more than half.

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The results are being shared during a late-breaking data presentation at The Endocrine Society's ENDO 2012: The 94th Annual Meeting & Expo in Houston, Texas, and coincide with online publication by the New England Journal of Medicine. The study is scheduled to appear in the journal's August 23, 2012 print issue.

The two-year study involved 265 indeterminate thyroid FNA samples collected from 49 academic and community sites around the United States. The findings showed that the Afirma Gene Expression Classifier can reclassify as "benign" with a high degree of accuracy thyroid nodule fine needle aspirate (FNA) samples that were originally deemed inconclusive by cytopathology review using a microscope. When applied to the major categories of indeterminate samples (those with cytology labeled: "atypical of an undetermined significance" or "follicular neoplasm"), the genomic test had a negative predictive value (NPV) of 95 and 94 percent, respectively. Overall, the NPV was 93 percent, based on the study's cancer prevalence rate of 32 percent. The overall NPV increases to 95 percent when a lower cancer prevalence rate of 24 percent, which is more representative of thyroid cases across the U.S., is applied. The test had a sensitivity of 92 percent and a specificity of 52 percent.

"Presently, patients with cytologically indeterminate thyroid nodules are usually referred for thyroid surgery to ensure that thyroid cancer is not present," said co-principal study investigator Erik K. Alexander, M.D., of Brigham and Women's Hospital and Harvard Medical School. "The gene expression test, when benign, should now enable physicians to consider recommending against surgery and confidently monitor patients in a more conservative fashion. Approximately half of all patients with indeterminate thyroid nodule cytology will have a benign gene expression test. This means that tens of thousands of thyroid nodule patients in the U.S. each year can potentially be spared a thyroid surgery they do not need."

Indeterminate thyroid nodule cytology results are a significant problem in thyroid cancer diagnosis. Thyroid nodules are common and, while most are benign, 5-15 percent prove malignant, prompting diagnostic evaluation, typically via FNA sampling. Approximately 450,000 thyroid nodule FNAs a minimally invasive procedure to extract cells for examination under a microscope are performed in the U.S. each year. Such cytology samples, however, produce indeterminate results in 15-30 percent of cases, or approximately 100,000 patients each year in the U.S. Current medical guidelines recommend that most of these patients have all or part of their thyroids removed for final diagnosis. However, the majority (70-80 percent) prove to have benign conditions. These surgeries are invasive, costly and typically result in lifelong hormone therapy for the patient. Additionally, these patients are unnecessarily exposed to a 2-10 percent risk of surgical complications.

"Our results showed that the gene expression test can substantially reclassify otherwise inconclusive thyroid nodule cytology results," said co-principal study investigator Bryan R. Haugen, M.D., professor of medicine and pathology head, Division of Endocrinology, Metabolism & Diabetes at the University of Colorado. "When the gene expression test is benign, this conveys the same level of predictive accuracy comparable to patients who had a benign cytopathology result."

An accompanying New England Journal of Medicine editorial concludes, "In this era of focusing on high-quality outcomes at lower cost, this new gene-expression classifier test is a welcome addition to the tools available for informed decision making about the management of thyroid nodules."

The two-year study enrolled 3,789 patients and prospectively collected 4,812 thyroid FNA samples from nodules larger than or equal to 1.0 cm. Samples were simultaneously collected for local cytopathology analysis, as well as for the study. If the local cytopathology result was indeterminate, the study sample was then analyzed using the gene expression test. Thyroid surgery was performed based on the judgment of the treating physician who was blinded to the genomic test results. At completion of the study, the gene expression test results were compared to gold-standard histopathology diagnosis provided by two blinded experts following review of surgically removed tissue samples.

"This rigorous study is the largest of its kind ever conducted to assess thyroid diagnosis and further confirms the strength and utility of our Afirma Gene Expression Classifier to help prevent avoidable surgeries," said Bonnie Anderson, Veracyte's cofounder and chief executive officer. "Ultimately, these results should underscore the potential of the genomic test to help physicians make more informed treatment decisions early, thus improving patient care and helping to take significant costs out of the healthcare system."

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Veracyte Announces Study Results Published Online in New England Journal of Medicine Which Suggest that Its Afirma® ...

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

Contact: Kim Menard kim.menard@uphs.upenn.edu 215-662-6183 University of Pennsylvania School of Medicine

PHILADELPHIA - A new test can be used to identify low-risk thyroid nodules, reducing unnecessary surgeries for people with thyroid nodules that have indeterminate results after biopsy. The results of the multi-center trial, which includes researchers from the Perelman School of Medicine at the University of Pennsylvania, appear online in the New England Journal of Medicine.

Ultrasound-guided fine-needle aspiration biopsies (FNA) accurately identify 62-85 percent of thyroid nodules as benign. For those deemed malignant or unclassifiable, surgery is currently required. However, about 20-35 percent of nodules have inconclusive results after FNA. This novel test classifies genes from the thyroid nodule tissue obtained through FNA.

"This test, currently available at Penn Medicine, can help us determine whether these nodules with indeterminate biopsy results are likely to be benign," said Susan Mandel, MD, MPH, professor of Medicine in Endocrinology, Diabetes and Metabolism in the Perelman School of Medicine at Penn."If so, patients may be able to avoid unnecessary surgeries and lifelong thyroid hormone replacement treatment."

In an accompanying NEJM editorial, J. Larry Jameson, MD, PhD, Dean of the Perelman School of Medicine and Executive Vice President for the Health System at the University of Pennsylvania, notes that the gene expression test is able to identify nodules at low risk of malignancy, making it possible to avoid approximately 25,000 thyroid surgeries per year. "In this era of focusing on high-quality outcomes at lower cost, this new gene expression classifier test is a welcome addition to the tools available for informed decision making about the management of thyroid nodules," writes Jameson.

The gene expression classifier was tested on 265 indeterminate thyroid nodules, and was able to correctly identify 92 percent of cases as suspicious. The test demonstrated a 85 - 95 percent negative predictive value, effectively ruling out a malignancy.

The Penn research team included Dr. Mandel, Zubair Baloch, MD, PhD, and Virginia A. LiVolsi, MD, both professors of Pathology and Laboratory Medicine. The investigation was funded by a research grant provided by Veracyte, Inc., the maker of the gene expression classifier.

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Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.

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Gene expression test identifies low-risk thyroid nodules

ScienceDaily (June 24, 2012) Hemimegalencephaly is a rare but dramatic condition in which the brain grows asymmetrically, with one hemisphere becoming massively enlarged. Though frequently diagnosed in children with severe epilepsy, the cause of hemimegalencephaly is unknown and current treatment is radical: surgical removal of some or all of the diseased half of the brain.

In a paper published in the June 24, 2012 online issue of Nature Genetics, a team of doctors and scientists, led by researchers at the University of California, San Diego School of Medicine and the Howard Hughes Medical Institute, say de novo somatic mutations in a trio of genes that help regulate cell size and proliferation are likely culprits for causing hemimegalencephaly, though perhaps not the only ones.

De novo somatic mutations are genetic changes in non-sex cells that are neither possessed nor transmitted by either parent. The scientists' findings -- a collaboration between Joseph G. Gleeson, MD, professor of neurosciences and pediatrics at UC San Diego School of Medicine and Rady Children's Hospital-San Diego; Gary W. Mathern, MD, a neurosurgeon at UC Los Angeles' Mattel Children's Hospital; and colleagues -- suggest it may be possible to design drugs that inhibit or turn down signals from these mutated genes, reducing or even preventing the need for surgery.

Gleeson's lab studied a group of 20 patients with hemimegalencephaly upon whom Mathern had operated, analyzing and comparing DNA sequences from removed brain tissue with DNA from the patients' blood and saliva.

"Mathern had reported a family with identical twins, in which one had hemimegalencephaly and one did not. Since such twins share all inherited DNA, we got to thinking that there may be a new mutation that arose in the diseased brain that causes the condition," said Gleeson. Realizing they shared the same ideas about potential causes, the physicians set out to tackle this question using new exome sequencing technology, which allows sequencing of all of the protein-coding exons of the genome at the same time.

The researchers ultimately identified three gene mutations found only in the diseased brain samples. All three mutated genes had previously been linked to cancers.

"We found mutations in a high percentage of the cells in genes regulating the cellular growth pathways in hemimegalencephaly," said Gleeson. "These same mutations have been found in various solid malignancies, including breast and pancreatic cancer. For reasons we do not yet understand, our patients do not develop cancer, but rather this unusual brain condition. Either there are other mutations required for cancer propagation that are missing in these patients, or neurons are not capable of forming these types of cancers."

The mutations were found in 30 percent of the patients studied, indicating other factors are involved. Nonetheless, the researchers have begun investigating potential treatments that address the known gene mutations, with the clear goal of finding a way to avoid the need for surgery.

"Although counterintuitive, hemimegalencephaly patients are far better off following the functional removal or disconnection of the enlarged hemisphere," said Mathern. "Prior to the surgery, most patients have devastating epilepsy, with hundreds of seizures per day, completely resistant to even our most powerful anti-seizure medications. The surgery disconnects the affected hemisphere from the rest of the brain, causing the seizures to stop. If performed at a young age and with appropriate rehabilitation, most children suffer less language or cognitive delay due to neural plasticity of the remaining hemisphere."

But a less-invasive drug therapy would still be more appealing.

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Gene mutations cause massive brain asymmetry

By Ryan Flinn - 2012-06-25T14:30:00Z

A gene test made by closely held Veracyte Inc. may determine whether cancer exists in thyroid tumor samples that were inconclusive after biopsies, a study found, potentially ending thousands of unnecessary surgeries.

From 15 percent to 30 percent of thyroid nodules evaluated by fine-needle biopsies cant clearly be defined as malignant or benign, leading most doctors to recommend removing part or all of the gland as a precaution, said Erik Alexander, the lead study author and a doctor with the Dana-Farber Cancer Institute and Brigham and Womans Hospital in Boston.

Nobody wants surgery if they dont need it, Alexander said in a telephone interview. This test, when it returns with a benign result, implies there is a very small risk of any cancer.

The test from South San Francisco, California-based Veracyte screens for genes expressed by thyroid tumors. Researchers used the test on 265 indeterminate nodules, finding it correctly identified 78 out of 85 of malignant samples, and predicted benign results accurately in 95 percent of samples that were atypical of an undetermined significance and 94 percent with follicular neoplasm, according to the study funded by the company and published today by the New England Journal of Medicine.

About 56,500 new cases of thyroid cancer will be diagnosed in the U.S. this year and about 1,780 patients will die of the disease, according to the National Cancer Institute.

Widespread use of the gene test may eliminate one-third of the 75,000 surgeries performed in the U.S. on indeterminate thyroid nodules, J. Larry Jameson, professor at the University of Pennsylvanias Perelman School of Medicine, wrote in an editorial accompanying the study.

Veracytes test, which costs about $3,500, is covered by Medicare and is being promoted globally by Paris-based Sanofi (SAN)s Genzyme unit.

This is a key step forward for us, Bonnie Anderson, Veracytes co-founder and chief executive officer, said in an interview. The strength of this study underscores the real value of the test.

To contact the reporter on this story: Ryan Flinn in San Francisco at rflinn@bloomberg.net

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Veracyte Gene Test May Limit Thyroid Cancer Surgeries

DUBLIN--(BUSINESS WIRE)--

Research and Markets (http://www.researchandmarkets.com/research/skdhnn/translational_rege) has announced the addition of the "Translational Regenerative Medicine - Oncology, CNS and Cardiovascular-Rich Pipeline Features Innovative Stem Cell and Gene Therapy Applications" report to their offering.

More Guidelines Needed to Grow Regenerative Medicine Market, Report Finds

Standardized research guidelines are needed to control and encourage the development of gene therapy and stem cell treatments, according to a new report by healthcare experts GBI Research.

The new report* shows how regenerative medicine is seen as an area with high future potential, as countries need ways to cope with the burden of an aging population.

The stem cell market alone is predicted to grow to around $5.1 billion by 2014, while gene therapy has also shown promise despite poor understanding of some areas of regenerative medicine and a lack of major approvals (the only approvals to date being made in Asia).

Up until now, securing research within clinics has been difficult, with a high number of failures and discontinuations throughout all phases of clinical study. Stem cell therapy uses bone marrow transplants as an established treatment method, but the development of the therapy into further applications and has not yet become common practice.

Similarly, tissue engineering has been successful in the areas of skin and bone grafts, but translation into more complex therapies has been an issue for researchers. Although scientific possibilities are ever-increasing, the true potential of regenerative medicine has yet to be demonstrated fully.

A desire to discover new and innovative technologies has encouraged governments in the UK and Singapore to focus directly on regenerative medicine as a future potential economy booster.

Companies Mentioned:

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Research and Markets: Translational Regenerative Medicine - Oncology, CNS and Cardiovascular-Rich Pipeline Features ...

ScienceDaily (June 22, 2012) The gene p53 is the most commonly mutated gene in cancer. p53 is dubbed the "guardian of the genome" because it blocks cells with damaged DNA from propagating and eventually becoming cancerous. However, new research led by Ute M. Moll, M.D., Professor of Pathology at Stony Brook University School of Medicine, and colleagues, uncovers a novel role for p53 beyond cancer in the development of ischemic stroke. The research team identified an unexpected critical function of p53 in activating necrosis, an irreversible form of tissue death, triggered during oxidative stress and ischemia.

The findings are detailed online in Cell.

Ischemia-associated oxidative damage leads to irreversible necrosis which is a major cause of catastrophic tissue loss. Elucidating its signaling mechanism is of paramount importance. p53 is a central cellular stress sensor that responds to multiple insults including oxidative stress and is known to orchestrate apoptotic and autophagic types of cell death. However, it was previously unknown whether p53 can also activate oxidative stress-induced necrosis, a regulated form of cell death that depends on the mitochondrial permeability transition pore (PTP) pore.

"We identified an unexpected and critical function of p53 in activating necrosis: In response to oxidative stress in normal healthy cells, p53 accumulates in the mitochondrial matrix and triggers the opening of the PTP pore at the inner mitochondrial membrane, leading to collapse of the electrochemical gradient and cell necrosis," explains Dr. Moll. "p53 acts via physical interaction with the critical PTP regulator Cyclophylin D (CypD). This p53 action occurs in cultured cells and in ischemic stroke in mice. "

Of note, they found in their model that when the destructive p53-CypD complex is blocked from forming by using Cyclosporine-A type inhibitors, the brain tissue is strongly protected from necrosis and stroke is prevented.

"The findings fundamentally expand our understanding of p53-mediated cell death networks," says Dr. Moll. "The data also suggest that acute temporary blockade of the destructive p53-CypD complex with clinically well-tolerated Cyclosporine A-type inhibitors may lead to a therapeutic strategy to limit the extent of an ischemic stroke in patients."

"p53 is one of the most important genes in cancer and by far the most studied," says Yusuf A. Hannun, M.D., Director of the Stony Brook University Cancer Center, Vice Dean for Cancer Medicine, and the Joel Kenny Professor of Medicine at Stony Brook. "Therefore, this discovery by Dr. Moll and her colleagues in defining the mechanism of a new p53 function and its importance in necrotic injury and stoke is truly spectacular."

Dr. Moll has studied p53 for 20 years in her Stony Brook laboratory. Her research has led to numerous discoveries about the function of p53 and two related genes. For example, previous to this latest finding regarding p53 and stroke, Dr. Moll identified that p73, a cousin to p53, steps in as a tumor suppressor gene when p53 is lost and can stabilize the genome. She found that p73 plays a major developmental role in maintaining the neural stem cell pool during brain formation and adult learning. Her work also helped to identify that another p53 cousin, called p63, has a critical surveillance function in the male germ line and likely contributed to the evolution of humans and great apes, enabling their long reproductive periods.

Dr. Moll's Cell study coauthors include: Angelina V. Vaseva and Natalie D. Marchenko, Department of Pathology, Stony Brook University School of Medicine; Kyungmin Ji and Stella E. Tsirka, Department of Pharmacological Sciences, Stony Brook University School of Medicine; and Sonja Holzmann, Department of Molecular Oncology, University of Gottingen in Germany.

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Most commonly mutated gene in cancer may have a role in stroke

Public release date: 21-Jun-2012 [ | E-mail | Share ]

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

Researchers at the University of California, San Diego School of Medicine have uncovered a new signal transduction pathway specifically devoted to the regulation of alternative RNA splicing, a process that allows a single gene to produce or code multiple types of protein variants. The discovery, published in the June 27, 2012 issue of Molecular Cell, suggests the new pathway might be a fruitful target for new cancer drugs.

Signal transduction in the cell involves kinases and phosphatases, enzymes that transfer or remove phosphates in protein molecules in a cascade or pathway. SRPK kinases, first described by Xiang-Dong Fu, PhD, professor of cellular and molecular medicine at UC San Diego in 1994, are involved in controlling the activities of splicing regulators in mammalian cells.

Prior studies have implicated SRPK1 in cancer and other human diseases. For example, it has been shown that SRPK1 plays a critical role in regulating the function of Vascular Endothelial Growth Factor or VEGF, which stimulates blood vessel growth in cancer. SRPK1 has been found to be dysregulated in a number of cancers, from kidney and breast to lung and pancreatic.

Conversely, studies suggest the absence of SRPK1 may be problematic as well, at least in terms of controlling some specific cancer phenotypes. Reduced SRPK1, for example, has been linked to drug resistance, a major problem in chemotherapy of cancer.

In their new paper, Fu and colleagues place SRPK1 in a major signal transduction pathway in the cell. "The kinase sits right in the middle of the PI3K-Akt pathway to specifically relay the growth signal to regulate alternative splicing in the nucleus," said Fu. "It's a new signaling branch that has previously escaped detection."

As such, the SRPK offers a new target for disease intervention and treatment, researchers say. "It's a good target because of its central role and because it can be manipulated with compounds that suppress its activity, which appears quite effective in suppressing blood vessel formation in cancer," Fu said.

###

Co-authors of the paper are Zhihong Zhou, Jinsong Qiu, Yu Zhou and Hairi Li, Department of Cellular and Molecular Medicine, UC San Diego; Liu Wen, Qidong Hu and Michael G. Rosenfeld, Howard Hughes Medical Institute, Department of Medicine; Ryan M. Plocinik and Joseph A. Adams, Department of Pharmacology, UC San Diego; and Gourisanker Ghosh, Department of Chemistry and Biochemistry, UC San Diego.

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Enzyme offers new therapeutic target for cancer drugs

Public release date: 21-Jun-2012 [ | E-mail | Share ]

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

UCLA researchers have combined two tools gene expression and the use of peripheral blood -- to expand scientists' arsenal of methods for pinpointing genes that play a role in autism. Published in the June 21 online edition of the American Journal of Human Genetics, the findings could help scientists zero in on genes that offer future therapeutic targets for the disorder.

"Technological advances now allow us to rapidly sequence the genome and uncover dozens of rare mutations," explained principal investigator Dr. Daniel Geschwind, the Gordon and Virginia MacDonald Distinguished Professor of Human Genetics and a professor of neurology at the David Geffen School of Medicine at UCLA. "But just because a particular genetic mutation is rare doesn't mean it's actually causing disease. We used a new approach to tease out potential precursors of autism from the occasional genetic glitch."

Geschwind and his colleagues studied DNA contained in blood samples from 244 families with one healthy child and one child on the autism spectrum. The team used a hybrid method that blended tests that read the order of DNA bases with those that analyze gene expression, the process by which genes make cellular proteins.

"Monitoring gene expression provides us with another line of data to inform our understanding of how autism develops," said Geschwind, who is also director of the Center for Autism Research and Treatment at the Semel Institute for Neuroscience and Behavior at UCLA. "Integrating this method with the sequencing of DNA bases expands our ability to find mutations leading to the disease."

Gene expression offers a molecular signpost pointing scientists in the right direction by narrowing the field and highlighting specific areas of the genome. For example, if a gene is expressed at substantially higher or lower levels in a patient, researchers will review the patient's DNA to check if that gene has changed.

"We found that we can use gene expression to help understand whether a rare mutation is causing disease or playing a role in disease development," said Geschwind. "A true mutation will alter a gene's sequence, modifying the protein or RNA it produces -- or preventing the gene from producing them entirely.

"A gene mutation accompanied by a change in expression clues us to a hot spot on the genome and directs us where to look next," he added. "Not all mutations will influence gene expression, but this approach improves our ability to pinpoint those that do."

The researchers used the combined method to prioritize gene targets that merit closer investigation, potentially explaining why one person develops autism and their sibling does not.

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UCLA study uncovers new tools for targeting genes linked to autism

Single treatment produces long-term improvement in animal models

Newswise With a single drug treatment, researchers at the Ludwig Institute for Cancer Research at the University of California, San Diego School of Medicine can silence the mutated gene responsible for Huntingtons disease, slowing and partially reversing progression of the fatal neurodegenerative disorder in animal models.

The findings are published in the June 21, 2012 print issue of the journal Neuron.

Researchers suggest the drug therapy, tested in mouse and non-human primate models, could produce sustained motor and neurological benefits in human adults with moderate and severe forms of the disorder. Currently, there is no effective treatment.

Huntingtons disease afflicts approximately 30,000 Americans, whose symptoms include uncontrolled movements and progressive cognitive and psychiatric problems. The disease is caused by the mutation of a single gene, which results in the production and accumulation of toxic proteins throughout the brain.

Don W. Cleveland, PhD, professor and chair of the UC San Diego Department of Cellular and Molecular Medicine and head of the Laboratory of Cell Biology at the Ludwig Institute for Cancer Research, and colleagues infused mouse and primate models of Huntingtons disease with one-time injections of an identified DNA drug based on antisense oligonucleotides (ASOs). These ASOs selectively bind to and destroy the mutant genes molecular instructions for making the toxic huntingtin protein.

The singular treatment produced rapid results. Treated animals began moving better within one month and achieved normal motor function within two. More remarkably, the benefits persisted, lasting nine months, well after the drug had disappeared and production of the toxic proteins had resumed.

For diseases like Huntington's, where a mutant protein product is tolerated for decades prior to disease onset, these findings open up the provocative possibility that transient treatment can lead to a prolonged benefit to patients, said Cleveland. This finding raises the prospect of a huntingtin holiday, which may allow for clearance of disease-causing species that might take weeks or months to re-form. If so, then a single application of a drug to reduce expression of a target gene could reset the disease clock, providing a benefit long after huntingtin suppression has ended.

Beyond improving motor and cognitive function, researchers said the ASO treatment also blocked brain atrophy and increased lifespan in mouse models with a severe form of the disease. The therapy was equally effective whether one or both huntingtin genes were mutated, a positive indicator for human therapy.

Cleveland noted that the approach was particularly promising because antisense therapies have already been proven safe in clinical trials and are the focus of much drug development. Moreover, the findings may have broader implications, he said, for other age-dependent neurodegenerative diseases that develop from exposure to a mutant protein product and perhaps for nervous system cancers, such as glioblastomas.

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Proposed Drug May Reverse Huntington's Disease Symptoms

Reported in CELL, Stony Brook pathologist uncovers new p53 mechanism triggering necrosis

Newswise STONY BROOK, N.Y., June 22, 2012 The gene p53 is the most commonly mutated gene in cancer. p53 is dubbed the guardian of the genome because it blocks cells with damaged DNA from propagating and eventually becoming cancerous. However, new research led by Ute M. Moll, M.D., Professor of Pathology at Stony Brook University School of Medicine, and colleagues, uncovers a novel role for p53 beyond cancer in the development of ischemic stroke. The research team identified an unexpected critical function of p53 in activating necrosis, an irreversible form of tissue death, triggered during oxidative stress and ischemia. The findings are detailed online in Cell.

Ischemia-associated oxidative damage leads to irreversible necrosis which is a major cause of catastrophic tissue loss. Elucidating its signaling mechanism is of paramount importance. p53 is a central cellular stress sensor that responds to multiple insults including oxidative stress and is known to orchestrate apoptotic and autophagic types of cell death. However, it was previously unknown whether p53 can also activate oxidative stress-induced necrosis, a regulated form of cell death that depends on the mitochondrial permeability transition pore (PTP) pore.

We identified an unexpected and critical function of p53 in activating necrosis: In response to oxidative stress in normal healthy cells, p53 accumulates in the mitochondrial matrix and triggers the opening of the PTP pore at the inner mitochondrial membrane, leading to collapse of the electrochemical gradient and cell necrosis, explains Dr. Moll.

"p53 acts via physical interaction with the critical PTP regulator Cyclophylin D (CypD). This p53 action occurs in cultured cells and in ischemic stroke in mice."

Of note, they found in their model that when the destructive p53-CypD complex is blocked from forming by using Cyclosporine-A type inhibitors, the brain tissue is strongly protected from necrosis and stroke is prevented.

The findings fundamentally expand our understanding of p53-mediated cell death networks, says Dr. Moll. The data also suggest that acute temporary blockade of the destructive p53-CypD complex with clinically well-tolerated Cyclosporine A-type inhibitors may lead to a therapeutic strategy to limit the extent of an ischemic stroke in patients.

p53 is one of the most important genes in cancer and by far the most studied, says Yusuf A. Hannun, M.D., Director of the Stony Brook University Cancer Center, Vice Dean for Cancer Medicine, and the Joel Kenny Professor of Medicine at Stony Brook. Therefore, this discovery by Dr. Moll and her colleagues in defining the mechanism of a new p53 function and its importance in necrotic injury and stoke is truly spectacular.

Dr. Moll has studied p53 for 20 years in her Stony Brook laboratory. Her research has led to numerous discoveries about the function of p53 and two related genes. For example, previous to this latest finding regarding p53 and stroke, Dr. Moll identified that p73, a cousin to p53, steps in as a tumor suppressor gene when p53 is lost and can stabilize the genome. She found that p73 plays a major developmental role in maintaining the neural stem cell pool during brain formation and adult learning. Her work also helped to identify that another p53 cousin, called p63, has a critical surveillance function in the male germ line and likely contributed to the evolution of humans and great apes, enabling their long reproductive periods.

Dr. Molls Cell study coauthors include: Angelina V. Vaseva and Natalie D. Marchenko, Department of Pathology, Stony Brook University School of Medicine; Kyungmin Ji and Stella E. Tsirka, Department of Pharmacological Sciences, Stony Brook University School of Medicine; and Sonja Holzmann, Department of Molecular Oncology, University of Gottingen in Germany.

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Study Shows Most Commonly Mutated Gene in Cancer may have a Role in Stroke

Public release date: 20-Jun-2012 [ | E-mail | Share ]

Contact: Summer Freeman summer.freeman@stjude.org 901-595-3061 St. Jude Children's Research Hospital

Researchers studying the genetic roots of the most common malignant childhood brain tumor have discovered missteps in three of the four subtypes of the cancer that involve genes already targeted for drug development.

The most significant gene alterations are linked to subtypes of medulloblastoma that currently have the best and worst prognosis. They were among 41 genes associated for the first time to medulloblastoma by the St. Jude Children's Research Hospital Washington University Pediatric Cancer Genome Project.

"This study provides new direction for understanding what drives these tumors and uncovers totally unexpected new drug targets. There are drugs already in development against these targets aimed at treating adult cancers and other diseases," said Richard Gilbertson, M.D., Ph.D., St. Jude Comprehensive Cancer Center director. Gilbertson and Jinghui Zhang, Ph.D., an associate member of the St. Jude Department of Computational Biology, are the study's corresponding authors. The work appears in the June 20 advance online issue of the scientific journal Nature.

The results mark progress toward more targeted therapies against medulloblastoma and other cancers. While better use of existing drugs and improved supportive care have helped push long-term survival rates for childhood cancer to about 80 percent, drug development efforts have largely stalled for more than two decades, particularly against pediatric brain tumors.

"This study is a great example of the way whole-genome sequencing of cancer patients allows us to dig deep into the biology of certain tumors and catch a glimpse of their Achilles heel," said co-author Richard K. Wilson, Ph.D., director of The Genome Institute at Washington University School of Medicine in St. Louis. "These results help us better understand the disease and, as a result, we will be able to more effectively diagnose and treat these kids."

This study involved sequencing the complete normal and cancer genomes of 37 young patients with medulloblastoma, making it the largest such effort to date involving the cancer. Researchers then checked tumors from an additional 56 patients for the same alterations. The genome is the complete set of instructions needed for human life. It is carried in the DNA found in nearly every cell.

The findings are part of the Pediatric Cancer Genome Project, which launched in 2010 as a three-year effort to decipher the complete normal and tumor genomes of 600 young cancer patients with some of the most challenging tumors. The endeavor has already yielded important clues into the origin, spread and treatment response in childhood cancers of the blood, brain, eye and nervous system.

Medulloblastoma is diagnosed in about 400 U.S. children and adolescents annually. Their outcome varies widely based on the subtype they have. While nearly all patients with the wingless (WNT) subtype survive, just 60 percent of those with subtype 3 medulloblastoma are alive three years after diagnosis. WNT medulloblastoma is named for the pathway disrupted in the tumor subtype.

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Gene sequencing project identifies potential drug targets in common childhood brain tumor

LONDON Scientists have used genome sequencing technology to control an outbreak of the superbug MRSA in a study that could point to faster and more efficient treatment of a range of diseases.

The work adds to a burgeoning body of research into better techniques for diagnosing disease more quickly and at an earlier stage to allow more effective treatment and reduce health care costs.

Much of this is being driven by whole genome sequencing, which has enabled scientists to identify the genetic markers for a range of afflictions.

MRSA, or Methicillin-Resistant Staphylococcus Aureus, is a drug-resistant bacterial infection, or superbug, and major public health problem. When outbreaks occur in hospitals it can lead to the closure of whole wards and lengthy investigations.

The bug kills an estimated 19,000 people in the United States alone each year, and even when the infection is successfully treated it can double the average length of a hospital stay and thereby increase health care costs.

A team of scientists from the Wellcome Trust Sanger Institute, the University of Cambridge and genome sequencing company Illumina Inc, used samples from a 2009 MRSA outbreak in a hospital neo-natal intensive care ward to recreate and respond to it, as if in real time.

They found that genome sequencing produced results in roughly 24 hours, using the latest technology from Illumina, gave much more detailed information.

The researchers were able to identify the particular strain of MRSA causing the outbreak, and which strains were not, quickly enough to feed back into treatment and nip the outbreak in the bud faster than current clinical testing methods.

"I think we are at the very beginning of an explosion of evidence to support the use of whole genome sequencing in public health," Sharon Peacock of Cambridge University, who led the study, told Reuters.

The research, published in the New England Journal of Medicine, comes hot on the heels of similar work done on MRSA and Clostridium difficile by a team from Oxford University with Illumina and a group of hospitals in Britain.

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Real-time gene sequencing used to fight MRSA

Last winter I took note of a major conflict between Pankaj Mishra and Niall Fergusonover a review by the former of the latters most recent book, Civilization: The West and the Rest. Ferguson accused Mishra of attempting to assassinate his character, and even suggested that he would take him to court over libel. This piqued my curiosity, so I added Fergusons latest work to my stack. I recently managed to get to it and finish it. Its a very quick and jaunty read. I enjoyed his The Ascent of Money and The Worlds Banker, but have avoided Fergusons forays into neoconservative intellectual polemic. Im obviously not a neoconservative myself, but normally disagreement with an individuals theses doesnt deter me from grappling with their ideas. Rather, the past decade of American history has been a wasteful experiment in neoconservative nation-building, and Id had enough of that. No need for more o that crap in flowery and more erudite paragraphs. But when it comes to economic history Niall Ferguson seems to be on more legitimate terrain, though his histories of the Rothschild House are much weightier tomes than something like The Ascent of Money. But to be frank The Ascent of Moneyis War and Peace next toCivilization.

So what of Mishras review? After reading Civilization I read it, and I quite understand where Fergusons anger was coming from. Panjak Mishra basically suggests that Ferguson is a racist, throwing sneering asides to Charles Murray so that the reader can be assured of the intent. In particular, an analogy is clearly made between Ferguson and Lothrop Stoddard, author of works such as The rising tide of color against white world-supremacy. Stoddards opinion, the rising tide of color, bad, white supremacy, good. A normal Westerner in this day and age would find the comparison offensive, but in Fergusons case its particularly galling, because he has a mixed-race son with Ayaan Hirsi Ali.

I suspect that Fergusons first instinct was to track Mishra down and beat the living shit out of him. I know that would be my own instinct in his position. They fuck you up, your kids. To me that explains his outrageous attempt to silence Mishras obnoxious imputations with the threat of the law. Britain has ridiculously pro-plaintiff courts in regards to libel, but Niall Ferguson makes a great show of being American, and in the United States it is totally acceptable to make tenuous accusations against the motives of public figures. Rather than fight with the law Ferguson should probably just have accused Mishra of being a Communist with sympathies toward genocidal Leftist regimes like that of Pol Pot. I know, juvenille, but the Leftist intellectual usage of the term racism is of the same nature as the old red-baiting of the Cold War. If you dont have coherent arguments, simply insult and accuse, with sure knowledge that your ideological allies wont inspect your accusations with any degree of skepticism.

Whats a shame though is that many of Mishras substantive critiques ofCivilizationare spot on. Niall Fergusons story of the rise of the West involves six killer apps. They are:political and economic competition, the scientific revolution, the rule of law, modern medicine, education and the work ethic. Where this argument is persuasive, its not original (e.g., the scientific revolution). Where it is novel, it is not worked out in much detail (e.g., medicine). The book is simply far too ambitious in scope in relation to the thesis being presented. Rather than an argument,Civilizationconsists mostly of bald assertions occasionally sprinkled in with some insight which one wishes would be followed up in more detail. For example, as Mishra notes there is much warmed-over Webberianism in Fergusons narrative, but he does present the idea that Protestantism was not useful for the work ethic in a direct manner, but that it increased in human capital and therefore potential productivity through the spread of literacy due to the shift toward personal reading of the Bible. Yes, there are notes, but I wish Ferguson would have pushed more into this area and fleshed out his thoughts, because he reports that this effect holds true in non-Western societies too (i.e., Protestant areas have higher literacy, all things areas, vis-a-vis Roman Catholic areas).

But I assume that it is in the area of colonialism that Niall Ferguson might rankle many. His enthusiasm for empire is well attested, so its not surprising that he doesnt give a totally negative account of the colonial adventure, in both intent and outcome. A world of post-colonial theory this is a big no-no, and clearly was the reason for why Pankaj Mishra accused Ferguson of being a racialist of yore. Long-time readers know that Im not a fan of post-colonial theory, which makes a fetish of the power of the white race, and totally ignores the agency of colored peoples, for good or ill. In particular I found it interesting howCivilizationoutlined the different natures of Western colonialism. Not only does post-colonial theory tend to reduce the colored experience into one of amorphous subalterns, but there also does not seem to be a deep exploration of the reality that French colonialism was qualitatively different from British colonialism which was qualitatively different from German colonialism. This section of the narrative is worth expanding, but in the interests of covering all his killer apps Ferguson simply moves on hastily.

Finally, there are aspects of the book which are amateurish and tendentious in the extreme. As Mishra notes Ferguson dismisses Kenneth Pommeranzs argument in The Great Divergence with barely a word. I understand thatCivilizationis not a scholarly work, but I also found it frustrating that the reader might not be aware that one of Pommeranzs observations is that too often the most dynamic areas of Europe (e.g., England) are compared to the whole of China, with the appropriate comparison is apples to apples (e.g., England vs. the zone around Shanghai). If you read Fergusons narrative this isnt clear at all, and in fact he regularly does compare England itself to all of China. The section on religion and Christianity was also very hackneyed. Much of the portion on China and Christianity is taken directly from Jesus in Beijing, a work of a journalist, not a scholar. Many of the statistics and projects are basically pulled out of thin-air, though to be fair that is a problem with religion & China more generally thanks to government obstruction. Ferguson regales the reader with the fact that Chinese social scientists are convinced that Christianity is the reason for Western success, and that Jiang Zemin wanted to make Christianity Chinas official religion. The former is unsourced, while Zemin is also rumored to be a private practitioner of Buddhism. In other words, question the veracity of these claims. Not only that, there is a strange juxtapositionbetween the section on the implicit necessity of Christianity for Chinas modernization, and Japans wholesale adoption of Western ways. Ferguson neglects to mention that there was one thing which Japan did not adopt wholesale: Christianity. And last I checked Japan was a modern society, which somehow managed to develop (granted, Christians have been a catalytic force in Japanese society over the past century).

OverallCivilizationgets 2.5 stars from me. If you know a lot of history its a quick read, and you can probably separate the wheat from the chaff easily. Im not quite sure why youd want to read it, as it doesnt get much further than the op-eds which Ferguson has been penning (and the conceit of killer apps gets really annoying in my opinion). If you arent well versed in history you should probably not read this book, because youre too ignorant to figure out where Ferguson is bullshitting, and where hes being a serious scholar (you can check the notes, but he switches between the type of books published by university presses to superficial mass market nonfiction).

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Civilization is not Ferguson’s best | Gene Expression

Public release date: 17-Jun-2012 [ | E-mail | Share ]

Contact: Quinn Eastman qeastma@emory.edu 404-727-7829 Emory University

Scientists have found a master regulator gene needed for the development of M cells, a mysterious type of intestinal cell involved in initiating immune responses.

M cells act like "conveyor belts," ingesting bacteria and transporting substances from the gut into Peyer's patches, specialized tissues resembling lymph nodes in the intestines. Better knowledge of M cells' properties could aid research on oral vaccines and inflammatory bowel diseases.

A team of researchers at Emory University School of Medicine and RIKEN Research Center for Allergy and Immunology in Japan has identified the gene Spi-B as responsible for the differentiation of M cells.

The results are published Sunday, June 17 in the journal Nature Immunology.

"This discovery could really unlock a lot of information about the sequence of events needed for M cells to develop and what makes them distinctive," says co-author Ifor Williams, MD, PhD, associate professor of pathology and laboratory medicine at Emory University School of Medicine. "M cells have been difficult to study because they are relatively rare, they are only found within the Peyer's patches and can't be grown in isolation."

Scientists at RIKEN, led by senior author Hiroshi Ohno, MD, PhD, teamed up with Williams' laboratory, taking advantage of a discovery by Williams that a protein called RANKL, which is produced by cells in Peyer's patches, can induce M cell differentiation. Research scientist Takashi Kanaya is first author of the paper.

Kanaya and colleagues found that the gene Spi-B is turned on strongly at early stages of M cell differentiation induced by RANKL. Their suspicion of Spi-B's critical role was confirmed when they discovered that mice lacking Spi-B do not have functional M cells, and the cells in the intestines lack several other markers usually found on M cells.

"It was somewhat surprising to find Spi-B expressed in intestinal epithelial cells," Williams says. "Because Spi-B is known to be important for the development of some types of immune cells, it was thought to be expressed only in bone marrow-derived cells."

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Control gene for 'conveyor belt' cells could help improve oral vaccines, treat intestinal disease

Public release date: 14-Jun-2012 [ | E-mail | Share ]

Contact: Jim Ritter jritter@lumc.edu 708-216-2445 Loyola University Health System

MAYWOOD, Il. -- Loyola University Chicago researchers are taking advantage of a quirk in the evolution of fruit fly genes to help develop new weapons against cancer.

A newly discovered fruit fly gene is a simplified counterpart of two complex human genes that play important roles in the development of cancer and some birth defects. As this fruit fly gene evolved, it split in two. This split has made it easier to study, and the resulting insights could prove useful in developing new cancer drugs.

"Evolution has given us a gift," said Andrew K. Dingwall, PhD, senior author of a paper that describes how his team identified and analyzed the split gene. Their findings are published in the June issue of the prestigious journal Development. Based on the importance of the findings, the paper was recently selected as an "Editor's Choice" in Science Signaling, published by the American Association for the Advancement of Science (AAAS).

When normal cells develop, they differentiate into particular types, such as bone cells or muscle cells, and reproduce in an orderly manner. The process is governed by genes and hormones that work in concert. Two of these genes are known as MLL2 and MLL3. Cancer cells, by contrast, undergo uncontrolled division and reproduction.

Since 2010, a growing number of cancers have been linked to mutations in the MLL2 and MLL3 genes. These cancers include non-Hodgkin's lymphoma, colorectal cancer, kidney cancer, bladder cancer and a brain tumor called medulloblastoma. There also is evidence that MLL2 and MLL3 mutations are involved in breast and prostate cancers.

The MLL2 and MLL3 genes are similar to one another. Each has more than 15,000 building blocks called base pairs -- more than 10 times the number found in a typical gene. Because these genes are so large and complex, they are difficult to study.

In the fruit fly, the counterpart gene to MLL2 and MLL3 split into two genes named TRR and CMI. Each carried information critical for normal gene regulation, and they wound up on different chromosomes. The parsing of the MLL2/MLL3 genetic information into smaller genes in the fruit fly made study of the gene functions much easier; it allowed the researchers unprecedented opportunities to explore the role the human genes play in the development of cancers.

"This fruit fly gene gives us unique insight into the massive human MLL2 and MLL3 genes that are almost impossible to study because they are so large," Dingwall said.

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Quirky fruit fly gene could point way to new cancer drugs

By Eddie Wrenn

PUBLISHED: 10:29 EST, 13 June 2012 | UPDATED: 10:29 EST, 13 June 2012

Research in Italy suggests that a 'gay gene' survive through the generations via family members

Researchers believe that male homosexuality may be due to a gene carried by mothers.

Evolution suggests that homosexuality as a trait would not last long, as it discourages sex, with women and therefore procreation.

But a study by Andrea Camperio Ciani, from the University of Padova in Italy, spots a correlation between gay men and their mothers and maternal aunts, who tend to have significantly more children than the relatives of straight men.

They theorise that this leads credence to the 'balancing selection hypothesis', which suggest that a gene which leads to homosexuality also leads to high reproduction among their female relatives.

As such, while the 'gay gene' may not get passed down directly, it will survive through the generations via the family.

The gene or genes which causes this behaviour is not yet known, but the report by Ciani suggests that it resides on the X chromosone, of which men inherit one.

Originally, the team considered the hypothesis that the gene would affect men and women in different ways - making the man homosexual, and making females more promiscuous.

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'Gay gene' survives through generations as female relatives of homosexual men 'have more babies'

OTTAWA The Ottawa Hospital is looking to gain a foothold in the fast-growing field of personalized medicine, which involves using gene sequencing to help doctors predict which drugs would work best for a particular patient.

The hospital has drawn up plans to set up a molecular diagnostics lab with the technology to decode hundreds of genes, or even the entire genomes of patients, which could yield new approaches for treating cancer and other serious diseases.

Details of the plan are still being worked out, and no funding has yet been committed to the project. The hospital is looking to raise $380,000 in seed money to get the lab off the ground. Another $1 million would have to be raised to buy the gene-sequencing equipment.

Hospital officials say the lab would mark a key step in making the relatively new technology of DNA sequencing a standard part of medical care. It would also position the hospital for an emerging field in which the medical establishment has placed great hope: studying entire genomes all of a patients DNA and identifying every mutation involved in a particular disease.

Experts say the approach would enable treatments to be customized to an individual patients genetic profile, which is miles away from the traditional trial-and-error method of giving every patient the same drugs in the hope of benefiting the fortunate few.

Down the road, the hospital wants to establish a teaching program that would train a new generation of pathologists with the skills to practise personalized medicine.

This is a very realistic vision, and I want Ottawa to be positioned as a provincial centre of excellence for molecular diagnostics, said Paula Doering, the hospitals vice-president of clinical programs.

Currently, the use of gene sequencing is most advanced in cancer care. Doctors use the information to guide more precise treatment, or to tailor drugs to the genetic traits of patients, with the goal of giving them a better chance of survival.

The idea is to avoid wasting precious time and money on potentially ineffective treatments, which expose countless patients to harmful side effects and inflate the nations drug spending.

Of the 7,000 cancer patients who are treated annually at The Ottawa Hospital, a high proportion receive testing for selective genes or chemical markers, especially if they have certain types of breast, lung, colorectal or gastrointestinal cancer, said Dr. David Stewart, the hospitals head of medical oncology.

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Ottawa Hospital eyes expansion into cutting-edge ‘molecular medicine’

ScienceDaily (June 12, 2012) A team led by investigators at the Stanford University School of Medicine has found that the most common genetic risk factor for Alzheimer's disease disrupts brain function in healthy, older women but has little impact on brain function in healthy, older men. Women harboring the gene variant, known to be a potent risk factor for Alzheimer's disease, show brain changes characteristic of the neurodegenerative disorder that can be observed before any outward symptoms manifest.

Both men and women who inherit two copies (one from each parent) of this gene variant, known as ApoE4, are at extremely high risk for Alzheimer's. But the double-barreled ApoE4 combination is uncommon, affecting only about 2 percent of the population, whereas about 15 percent of people carry a single copy of this version of the gene.

The Stanford researchers demonstrated for the first time the existence of a gender distinction among outwardly healthy, older people who carry the ApoE4 variant. In this group, women but not men exhibit two telltale characteristics that have been linked to Alzheimer's disease: a signature change in their brain activity, and elevated levels of a protein called tau in their cerebrospinal fluid.

One implication of the study, published June 13 in the Journal of Neuroscience, is that men revealed by genetic tests to carry a single copy of ApoE4 shouldn't be assumed to be at elevated risk for Alzheimer's, a syndrome afflicting about 5 million people in the United States and nearly 30 million worldwide. The new findings also may help explain why more women than men develop this disease, said Michael Greicius, MD, assistant professor of neurology and neurological sciences and medical director of the Stanford Center for Memory Disorders. Most critically, identifying the prominent interaction between ApoE4 and gender opens a host of new experimental avenues that will allow Greicius' team and the field generally to better understandhow ApoE4 increases risk for Alzheimer's disease.

For every three women with Alzheimer's disease, only about two men have the neurodegenerative disorder, said Greicius, the study's senior author. (The first author is Jessica Damoiseaux, PhD, a postdoctoral scholar in Greicius' laboratory. They collaborated with colleagues at the University of California-San Francisco and UCLA.) True, women live longer than men do, on average, and old age is by far the greatest risk factor for Alzheimer's, Greicius said. "But the disparity in Alzheimer's risk persists even if you correct for the difference in longevity," he said. "This disparate impact of ApoE4 status on women versus men might account for a big part of the skewed gender ratio."

Besides age, another well-studied major risk factor is genetic: possession of a particular version of the gene known as ApoE. This gene is a recipe for a protein involved in transporting cholesterol into cells -- an important job, as cholesterol is a crucial constituent of all cell membranes including those of nerve cells. And nerve cells are constantly responding to experience by developing or enhancing small, bulblike electrochemical contacts to other nerve cells, or diminishing or abolishing them. For all these processes, efficient cholesterol transport is critical.

The ApoE protein comes in three versions, each the product of a slightly differing version of the ApoE gene: E2, E3 or E4. Most people have two copies of the E3 version of ApoE. A small percentage carries one copy of E3 and one of E2, and even fewer two copies of E2. The protein specified by the E4 gene version seems to be somewhat defective in comparison to the one encoded by either E2 or the much more common E3. Thus, while only about 10-15 percent of the population carries one copy of E4 (or, much less commonly, two), more than 50 percent of people who develop Alzheimer's are E4 carriers.

But, as it turns out, the heightened risk E4 imposes may be largely restricted to women.

To demonstrate this, the scientists first obtained functional MRI scans of 131 healthy people, with a median age of 70, to examine connections in the brain's memory network. They used sophisticated brain-imaging analysis to show that in older women carrying the E4 variant, this network of interconnected brain regions, which normally share a synchronized pattern of activity, exhibit a loss of that synchrony -- a pattern typically seen in Alzheimer's patients. In healthy, older women (but not men) with at least one E4 allele, activity in a brain area called the precuneus appeared be out of synch with other regions whose firing patterns generally are closely coordinated.

The brain-imaging technique Greicius and his colleagues used is known as functional-connectivity magnetic resonance imaging, or fcMRI. Performed on "resting" subjects, who remain in the scanner awake but not focusing on any particular task, fcMRI can discern on the order of 20 different brain networks, each consisting of a set of dispersed brain regions that are physically connected by nerve tracts and whose pulses of activity are synchronized, or in phase. Greicius, Damoiseaux and their associates have previously shown that the synchronous firing pattern of one network in particular, critical to memory function and known as the "default mode network," is specifically targeted by Alzheimer's and deteriorates as the disease progresses.

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Alzheimer's risk gene disrupts brain function in healthy older women, but not men

Newcastle University scientists welcome ethics council backing for IVF gene switching

8:00am Tuesday 12th June 2012 in News By Barry Nelson, Health Editor

WORLD-BEATING North- East scientists have welcomed the findings of an independent report that makes it more likely they will be able to resume controversial, but potentially life-saving, research.

The Nuffield Council on Bioethics said the technique, sometimes described as threeparent IVF, would be an ethical treatment option for families affected by mitochondrial diseases if it could be shown to be safe and effective.

Alison Murdoch, professor of reproductive medicine at Newcastle University, said: We welcome the findings of the Nuffield Council report. It is very reassuring that they support our aims and we hope the Government will also give support.

In 2010, scientists from the university proved it was possible to use a form of IVF to prevent a group of deadly inherited diseases being passed to the next generation.

The discovery was hailed by the Muscular Dystrophy Campaign as a ray of hope for families who fear they might pass on mitochondrial disease to their children.

However, some campaigners are concerned at the technique, which involves taking part of a human egg donated by a healthy individual to replace the faulty mitochondria of the affected mother.

About one in every 6,500 children born in the UK has severe mitochondrial disease.

Mitochondria are located in every human cell and provide the energy for cells to function.

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Newcastle University scientists welcome ethics council backing for IVF gene switching

Public release date: 11-Jun-2012 [ | E-mail | Share ]

Contact: Dagny Stuart Dagny.stuart@vanderbilt.edu 615-936-7245 Vanderbilt University Medical Center

A study led by Vanderbilt-Ingram Cancer Center (VICC) investigators has identified a gene expression pattern that may explain why chemotherapy prior to surgery isn't effective against some tumors and suggests new therapy options for patients with specific subtypes of breast cancer.

The study by lead author Justin Balko, Pharm.D., Ph.D., was published online June 10, 2012 in Nature Medicine in advance of print publication. Balko is a postdoctoral fellow in the laboratory of Carlos L. Arteaga, M.D., associate director for Clinical Research and director of the Breast Cancer Program at VICC, who led the study.

About 30 percent of breast cancer patients have a pathological complete response when chemotherapy is used to shrink tumors prior to surgery. However, many patients still have residual cancer in the breast after neoadjuvant chemotherapy (NAC) is completed. These patients are at a higher risk of cancer recurrence and death.

The investigators suspected that profiling tumors after neoadjuvant chemotherapy would identify genes associated with resistance to this form of treatment. They studied gene expression patterns in 49 breast tumors obtained during surgery after four months of NAC.

They identified and analyzed specific groups of genes associated with high-grade, chemotherapy-resistant tumors, labeling their 244 unique genes the CLUSTER signature, and combined this panel with previously identified gene signatures to search for distinctive patterns of behavior.

The investigators found that low concentrations of dual specificity protein phosphatase 4 (DUSP4) is strongly correlated with faster tumor cell growth following neoadjuvant chemotherapy. Low DUSP4 was also correlated with a type of breast cancer known as basal-like breast cancer (BLBC). DUSP4 promoter methylation and gene expression patterns of Ras-ERK pathway activation were also higher in BLBC relative to other breast cancer subtypes.

When DUSP4 was present, chemotherapy was effective against cancer cells, whereas when DUSP4 was experimentally deleted, there was a much lower response to chemotherapy.

"These data suggest that cells with low DUSP4 expression are enriched during NAC and that low DUSP4 expression in residual resected breast tumors is a potential biomarker for drug resistance and a high likelihood of tumor recurrence," said Balko.

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Vanderbilt-led study identifies genes linked to resistance to breast cancer chemotherapy