Biomedical Careers Initiative Internship with Medimmune, LLC
Amy Anderson, a PhD candidate with the Cellular and Molecular Medicine (CMM) graduate program, talks about her internship with MedImmune, LLC. Anderson was s...
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Newswise ATLANTADr. Ming-Hui Zou, an internationally recognized researcher in molecular and translational medicine at the University of Oklahoma Health Science Center, has been named the founding director of the new Center for Molecular and Translational Medicine at Georgia State University.
He is also a Georgia Research Alliance (GRA) Eminent Scholar in Molecular Medicine, becoming the seventh eminent scholar at the university.
Zous research focuses on cardiovascular complications related to diabetes, atherosclerosis and hypertension.
Georgia State is excited to welcome Dr. Zou as the founding director of the universitys new Center for Molecular and Translational Medicine, said Dr. James Weyhenmeyer, vice president for research and economic development. This center is designed to meet healthcare needs by converting significant research findings into diagnostic tools and medicines that will help improve the health of individuals. Dr. Zou has made tremendous achievements in cardiovascular research, and he will certainly be an asset as he leads research efforts that could potentially help millions of people suffering from heart disease, diabetes and other illnesses.
At the University of Oklahoma Health Science Center, Zou held two endowed chairs and was chief of the Section of Molecular Medicine, vice chair for research in the Department of Medicine, Warren Chair in diabetes research and professor of medicine, biochemistry and molecular biology. He holds a doctorate and medical degree.
He has received prestigious awards from the American Heart Association, including the Career Development Award, Irvin H. Page Atherosclerosis Research Award and National Established Investigator Award. He has also received the Juvenile Diabetes Research Foundations Independent Investigator Award and the Regents Award for Superior Research & Creative Activity from the University of Oklahoma. He was awarded the George Lynn Cross Research Professor position, the highest research honor a faculty member may receive from the University of Oklahoma, in 2013.
In addition, he was elected in 2008 to the American Society for Clinical Investigation, the most prestigious society for young physician-scientists in the United States.
Zou studies the role of oxidative stress in vascular biology and disease. He is recognized for making influential discoveries in cardiovascular research, including identifying the role of two key proteins involved in the vessel pathology that leads to vascular disease. He has previously collaborated with the pharmaceutical companies Eli Lilly and Merck to develop new drugs and conduct clinical trials, and he plans to develop new therapeutics for cardiovascular disease and diabetes.
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Prof Dean Nizetic: Isogenic Induced Pluripotent Stem Cell Line
LKCMedicine Professor of Molecular Medicine Dean Nizetic sharing about his recently published Stem Cells paper entitled, "Stem Cells: Isogenic Induced Plurip...
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Prof Dean Nizetic: Isogenic Induced Pluripotent Stem Cell Line - Video
During pregnancy, the mother supplies the fetus with nutrients and oxygen via the placenta. If placental development is impaired, this may lead to growth disorders of the embryo or to life-threatening diseases of the mother such as preeclampsia, a serious condition involving high blood pressure and increased urinary protein excretion. Now, Dr. Katharina Walentin and Professor Kai Schmidt-Ott of the Max Delbrck Center for Molecular Medicine (MDC) Berlin-Buch have discovered a new molecular signaling pathway which regulates the development of the placenta. Perturbations of this pathway in mice cause developmental defects of the placenta (Development 2015 142:1125-1136; doi:10.1242/dev.113829)*.
The study focused on the gene regulator grainyhead-like 2 (GRHL2), which the research group has been investigating for a several years. As Dr. Walentin and Professor Schmidt-Ott have now shown, this regulator plays a key role in the development of the placenta. In a previous study, Professor Schmidt-Ott and his team discovered that it regulates the differentiation of epithelial cells - they line the cavities and surfaces of structures throughout the body - in the mouse embryo.
In the current study, the researchers noted that GRHL2 is very active in the healthy placenta, especially in trophoblast cells, which are responsible for the development of the labyrinth. This placental labyrinth forms the interface between the blood circulation of the embryo and the mother. It ensures the exchange of nutrients and oxygen as well as the removal of embryonic metabolic end products. The trophoblast cells branch out to form the labyrinth, and they are accompanied by fetal blood vessels. Thereby, a large interface is created to facilitate the exchange of metabolites between mother and fetus.
In mice, when the researchers inactivated the gene regulator GRHL2 in the fetal part of the placenta and in the embryo, the development of the labyrinth was severely disrupted. In particular, the branching of the trophoblast cells and the migration of the fetal blood vessels into the placenta were impaired. When the researchers inactivated the gene regulator only outside the placenta in the embryo, the labyrinth developed normally. Using genome-wide analyses, the MDC researchers found that GRHL2 regulates a defined gene program. Components of this program are critically involved in the development of the placenta.
During their studies, which were funded by the German Research Foundation (DFG) and the Urological Research Foundation, the researchers additionally discovered that GRHL2 and its target genes also display activity in the human placenta. They hope that these findings could be significant for the understanding of developmental abnormalities of the placenta and related pregnancy disorders in humans.
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*A Grhl2-dependent gene network controls trophoblast branching morphogenesis
Katharina Walentin,1,2 Christian Hinze,1,2 Max Werth,1,2,3 Nadine Haase,2 Saaket Varma,4 Robert Morell,5 Annekatrin Aue,1,2 Elisabeth Ptschke,1 David Warburton,4 Andong Qiu,3 Jonathan Barasch,3 Bettina Purfrst,1 Christoph Dieterich,6 Elena Popova1, Michael Bader1, Ralf Dechend,2 Anne Cathrine Staff,7 Zeliha Yesim Yurtdas,1,8,9 Ergin Kilic,10 and Kai M. Schmidt-Ott1,2,11,*
1Max Delbrck Center for Molecular Medicine, Robert-Rssle-Str. 10, 13125 Berlin, Germany.2Experimental and Clinical Research Center, a collaboration between the Max Delbrck Center and the Medical Faculty of the Charit, Robert-Rssle-Str. 10, 13125 Berlin, Germany. 3Department of Medicine, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA. 4Department of Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles, 4650 Sunset Blvd., Los Angeles, CA 90027, USA. 5Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders (NIDCD)/National Institutes of Health (NIH), 5Research Court, Rockville, MD 20850, USA.6Bioinformatics, Max Planck Institute for Biology of Ageing, Robert-Koch-Str. 21, 50931 Cologne, Germany. 7Department of Gynecology and Obstetrics, Institute of Clinical Medicine, Oslo University Hospital and University of Oslo, Kirkeveien 166, 0450 Oslo, Norway. 8Department of Urology, Charit-Universittsmedizin Berlin, Charitplatz 1, 10117 Berlin, Germany. 9Berlin Institute of Urologic Research, Berlin, Germany. 10Department of Pathology, Charit-Universittsmedizin Berlin, Charitplatz 1, 10117 Berlin, Germany. 11Department of Nephrology, Charit-Universittsmedizin Berlin, Charitplatz 1, 10117 Berlin, Germany.
A photo of the placenta of a mouse can be downloaded from the Internet at News: https://www.mdc-berlin.de/en
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MDC researchers discover new signaling pathway in embryonic development
A molecular biologist testifying for the defence in double murder-accused Mark Lundy's retrial says forensic science uses lower testing standards than other scientific fields.
Lundy, 56, has pleaded not guilty to bludgeoning to death his wife Christine, 38, and the couple's seven-year-old daughter at the family's Palmerston North home in 2000.
His High Court retrial in Wellington is in its fifth week and on Wednesday his defence team recalled one of its expert witnesses who had earlier contested a key piece of forensic evidence.
Stephen Bustin is a professor of molecular medicine in the United Kingdom.
This week he said RNA analysis by a Dutch forensic scientist which infers the presence of brain tissue in a stain on Lundy's shirt was fundamentally flawed.
Laetitia Sijen from the Netherlands Forensic Institute had testified tests on the sleeve sample showed "it's more probable than not that it's central nervous system tissue".
The court has been told the shirt was found inside-out in a suit bag in Lundy's Ford Fairmont by police examining the car days after his wife and daughter's bodies were discovered on August 30, 2000.
One stain was found on the left sleeve, the other on the shirt pocket.
A New Zealand forensic scientist has already testified the stains on the shirt matched Mrs Lundy's DNA.
Dr Bustin said even though he is not a forensic scientist, his extensive research in molecular medicine meant he could assess the methodologies used in RNA analysis.
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Patents are an important way of protecting inventions in the pharmaceutical and biotechnology industries. However, intellectual property law reforms have not kept pace with the rapid advances in genomics, synthetic biology, and stem cell research. Meanwhile, universities are increasingly spinning off companies that use these technologies, requiring the academic scientists involved to gain an understanding of intellectual property law and the patent system as it applies to biomedical innovations.
Intellectual Property in Molecular Medicine from Cold Spring Harbor Perspectives in Medicine aims to provide a clear, current, and comprehensive understanding of biomedical intellectual property and the laws that protect it. The contributors describe patent laws and practices in the United States, Canada, Australia, and the European Union. They explain the roles of regulatory agencies in intellectual property, various opinions on the patentability of biological materials (e.g., DNA and stem cells), and the implications of recent court decisions (e.g., the Myriad case). Practical issues related to licensing agreements and patent applications are also discussed. The authors offer guidance on the criteria for patent eligibility (e.g., utility, nonobviousness, and novelty), issues related to timing and possession, and rules for determining inventorship.
Other topics include trade secrets, research exemptions, and the protection of traditional knowledge related to biological resources. This volume will serve as an essential reference for all scientists, physicians, and technology transfer professionals seeking to navigate the complex rules, regulations, and procedures concerning intellectual property in biotech and pharma.
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Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.
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New book on 'Intellectual Property in Molecular Medicine ...
Experimental & Molecular Medicine is a monthly peer-reviewed open access medical journal covering biochemistry and molecular biology. It was established in 1964 as the Korean Journal of Biochemistry or Taehan Saenghwa Hakhoe Chapchi and published bi-annually.[1] It was originally in Korean becoming an English-language journal in 1975. In 1994 the journal began publishing quarterly. It obtained its current name in 1996 at which time it also began publishing bi-monthly, switching to monthly in 2009. It is the official journal of the Korean Society for Medical Biochemistry and Molecular Biology. The editor-in-chief is Dae-Myung Jue (Catholic University of Korea). It is published by the Nature Publishing Group. The full text of the journal from 2008 to the present is available at PubMed Central.
The journal is abstracted and indexed in:
According to the Journal Citation Reports, the journal has a 2013 impact factor of 2.462, ranking it 54th out of 122 journals in the category "Medicine, Research & Experimental"[5] and 176th out of 291 journals in the category "Biochemistry & Molecular Biology".[6]
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Patents are an important way of protecting inventions in the pharmaceutical and biotechnology industries. However, intellectual property law reforms have not kept pace with the rapid advances in genomics, synthetic biology, and stem cell research. Meanwhile, universities are increasingly spinning off companies that use these technologies, requiring the academic scientists involved to gain an understanding of intellectual property law and the patent system as it applies to biomedical innovations.
Intellectual Property in Molecular Medicine from Cold Spring Harbor Perspectives in Medicine aims to provide a clear, current, and comprehensive understanding of biomedical intellectual property and the laws that protect it. The contributors describe patent laws and practices in the United States, Canada, Australia, and the European Union. They explain the roles of regulatory agencies in intellectual property, various opinions on the patentability of biological materials (e.g., DNA and stem cells), and the implications of recent court decisions (e.g., the Myriad case). Practical issues related to licensing agreements and patent applications are also discussed. The authors offer guidance on the criteria for patent eligibility (e.g., utility, nonobviousness, and novelty), issues related to timing and possession, and rules for determining inventorship.
Other topics include trade secrets, research exemptions, and the protection of traditional knowledge related to biological resources. This volume will serve as an essential reference for all scientists, physicians, and technology transfer professionals seeking to navigate the complex rules, regulations, and procedures concerning intellectual property in biotech and pharma.
###
Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.
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New book on 'Intellectual Property in Molecular Medicine' from CSHLP
IMAGE:Omid Akbari, Ph.D. (left), and Hadi Maazi, D.V.M., Ph.D., of the Keck School of Medicine of USC led a study in the journal Immunity that identifies a molecule critical to... view more
Credit: Keck Medicine of USC
Scientists led by molecular immunologists at the Keck School of Medicine of the University of Southern California (USC) have identified a way to target a recently discovered cell type that causes asthma, paving the way to cure the chronic respiratory disease that affects 25 million Americans.
The team, which includes investigators from Janssen Research and Development, Dana-Farber Cancer Institute and Harvard Medical School, will publish its results in the March 17 edition of the peer-reviewed scientific journal Immunity.
Asthma is a chronic lung disease that irritates and narrows the airways, according to the Centers for Disease Control and Prevention. With no known cure for the 7 million children who suffer from this disease in the United States, as well as millions of adults, the goal of asthma treatment is to control the symptoms. The exact causes of this chronic disease are unknown, but researchers believe a combination of genetic and environmental factors contribute to developing asthma. Discovered within the last decade, type 2 innate lymphoid cells, or ILC2s, are a subset of immune cells that trigger primary asthma symptoms such as mucus production and hypersensitive airways. ILC2s do not express previously identified immune cell markers, however, making them tough to target.
"If we can target ILC2s, we might be able to cure asthma or exacerbations caused by these particular cells," said Omid Akbari, Ph.D., associate professor of molecular and cellular immunology at the Keck School of Medicine of USC and principal investigator of the study. "In this study, we discovered molecules critical to ILC2 homeostasis, survival and function. We believe that targeting these molecules or related pathways could one day cure a patient with ILC2-dependent asthma."
Akbari's team used mouse and human cells to show that inducible T cell costimulator molecules (ICOS) and their interaction with ICOS-ligand (ICOS-L) are crucial for ILC2 function and survival. ICOS and ICOS-L are proteins that influence cell behavior and cell response. Akbari's team developed a humanized mouse model to show how human ILC2s function in vivo; the model is currently being used to study how ILC2s contribute to human asthma and test potential therapies in preclinical studies.
"Because ILC2s are the only cells that express both ICOS and ICOS-L, our research sets the stage for designing new therapeutic approaches that target ILC2s to treat asthma," said Hadi Maazi, D.V.M., Ph.D., a research associate in Akbari's lab and the study's first author.
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Other USC co-authors include Nisheel Patel, Ishwarya Sankaranarayanan, Yuzo Suzuki and Diamanda Rigas. The study was supported by the National Institutes of Health (grants R01AI066020, R01ES021801, R21ES024707, and P01AI056299) and American Association of Immunology.
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Keck School of Medicine of USC scientists open door for asthma cure
Does the child of a person with a heritable form of cancer have the right to access their parent's genetic information after death? What if no consent was ever established? In the March 2 issue of Trends in Molecular Medicine, biomedical ethicists review current arguments about how to disclose genetic information of the deceased and offer suggestions that may help clinicians and officials develop their own policies.
A number of arguments exist both for and against such postmortem disclosure. Disclosure could promote a relative's health or well-being and could help them take more control over their lives. At the same time, it could also violate family members' right not to know and could cause psychological, financial, or other harm. Disclosure efforts might also face logistical challenges as healthcare professionals work to contact, inform, and counsel at-risk relatives.
"The first question that comes to mind is whether a clinician should communicate findings at all," says lead author Sarah Boers, MD, a PhD candidate at the University Medical Center Utrecht in The Netherlands. "This could mean a breach of confidentiality; however, we conclude that sometimes findings are so important that this overrides confidentiality."
Second, should the clinician only communicate findings if family members ask for it, or should they actively approach family members to inform them? "For now, it is too far-reaching to actively approach family members, for example because of confidentiality and a family member's interest in not knowing," Boers says. "In addition, more public awareness about new sequencing techniques should be raised first, and proper guidelines should be developed."
Boers and her colleagues argue for passive postmortem disclosure policies, meaning that under certain circumstances access to genetic information should be provided to a deceased patient's family members at their request. They recommend that policies be crafted by clinicians and clinical institutions, as well as by professional, national, and ethics committees. The investigators also propose some urgent topics for further research, including patients' and family members' attitudes towards communication of genetic findings after death. Cultural differences across countries may make it inappropriate to adopt a single international policy.
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Trends in Molecular Medicine, Boers et al.: "Postmortem disclosure of genetic information to family members: active or passive?"
Trends in Molecular Medicine (TMM), published by Cell Press, is a monthly review journal that facilitates communication between groups of highly trained professionals with distinct backgrounds and skills, whose common goals are to understand and explain the molecular basis of disease with a view to new clinical practice. For more information, please visit http://www.cell.com/trends/molecular-medicine. To receive media alerts for TMM or other Cell Press journals, please contact press@cell.com.
Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.
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You can't take your genes with you: Strategies to share genetic information after death
A public-private research collaboration leads to an unexpected discovery in patients with drug-resistant leukemia
Helsinki - February 9, 2015 - A study led by researchers at the Institute for Molecular Medicine Finland FIMM and Faculty of Medicine, University of Helsinki and the Helsinki University Central Hospital Comprehensive Cancer Center, in close collaboration with researchers at Pfizer, has identified a previously unrecognized action of Pfizer's axitinib as a potent inhibitor of the dominant mutation that confers drug resistance to all well tolerated treatments in patients with certain types of leukemia. The findings of this international joint effort were published online today, 9 February, 2015, in the journal Nature.
The FIMM research team studied cancer cells from patients with chronic myelogenous and acute lymphoblastic leukemia (CML and ALL) that had developed resistance to currently available treatments. These cancers are driven by the BCR-ABL1 fusion protein, and resistance to treatment developed due to a new genetic mutation in the BCR-ABL1 fusion gene in the cancer cells.
There were two critical factors that were integral to the outcome of this study. First, the Drug Sensitivity and Resistance Testing (DSRT) method developed at FIMM made it possible to study the response of these cancer patients' leukemia cells to a large panel of drugs simultaneously, thus identifying axitinib as a promising drug candidate. Using this approach, the researchers found that axitinib, a tyrosine kinase inhibitor currently approved to treat certain patients with advanced renal cell carcinoma, effectively eliminated these patient-derived drug resistant leukemia cells.
"This screening method is a key component of FIMM's Individualized Systems Medicine strategy. The drug panel covers all approved and many emerging cancer therapeutics, and thus enables an individualized selection of potentially effective therapies for leukemia patients," explains Krister Wennerberg, FIMM-EMBL Group Leader and a corresponding study author.
Second, by coupling this screening method with Pfizer's deep oncology and structure-based drug discovery expertise, the researchers were also able to define the mechanism by which axitinib binds to the drug resistant version of the BCR-ABL1 protein, providing fundamental new molecular insights into how cancer causing kinases can be blocked.
"If you think of the targeted protein as a lock into which the cancer drug fits in as a key, the resistant protein changes in such a way that we need a different key. In the case of axitinib, it acts as two distinct keys - one for renal cell carcinoma and one for leukemia" says Brion Murray, Pfizer Research Fellow and one of the lead authors of the study.
"Since axitinib is already used to treat cancer, its safety is known and a formal exploration of its clinical utility in drug resistant leukemia can now be done in a fast-track mode. Thus, the normally very long path from lab bench to bedside is now significantly shortened," says Kimmo Porkka, Head of Hematology at Helsinki University Central Hospital Comprehensive Cancer Center and one of the lead authors.
"Our findings highlight the power of drug repositioning, in other words, searching for novel uses for existing, emerging and abandoned drugs. This study shows what can be achieved when academic institutions and pharmaceutical companies team up to study effects of drugs using cells directly obtained from patients," says Olli Kallioniemi, the Director of FIMM.
"This high caliber publication is a great example of Pfizer's strong collaboration with academia to further advance research for patients with cancer," adds Murray. "Further research will determine whether these findings have the potential to significantly improve the standard of care for this select group of CML patients and patients with other related leukemias."
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A new opportunity to treat drug-resistant leukemia discovered
BETHESDA, Md., Feb. 26, 2015 /PRNewswire-USNewswire/ --The National Foundation for Cancer Research (NFCR) announced today that Frederick Alt, Ph.D., Professor of Genetics at Harvard Medical School, Director of the Program in Cellular and Molecular Medicine at Boston Children's Hospital, and Howard Hughes Medical Institute Investigator has been awarded the 2015 Szent-Gyrgyi Prize for Progress in Cancer Research. Dr. Alt's groundbreaking work in cancer genetics over four decades has helped to shape the very roots of modern cancer research. Today, that work continues to bear fruit, profoundly impacting the approaches that doctors use to diagnose and treat cancer.
NFCR's selection committee was unanimous in its decision to recognize Dr. Alt, whose work has proved foundational to the modern understanding of cancer not only how the lethal disease forms, but also how it can become resistant to treatment. In particular, his seminal discoveries of gene amplification and his pioneering work on molecular mechanisms of DNA damage repair have helped to usher in the era of genetically-targeted therapy and personalized medicine.
"Dr. Alt has been a consistently outstanding scientist throughout his career, and this award recognizes his entire body of work," said Dr. James Allison, Executive Director of the Immunotherapy Platform at MD Anderson Cancer Center, winner of the 2014 Szent-Gyrgyi Prize, and Chair of this year's Prize Selection Committee. "The genetic processes he described are central to understanding the mechanisms that cause cancer, and have ultimately led to an entire class of targeted therapy and associated diagnostics that are providing benefit to countless cancer patients."
Dr. Alt's discovery of gene amplification in chemotherapy-resistant cancer cellswhich revealed that cells can produce multiple copies of a genewas revolutionary, coming at a time when the human genome was widely believed to be stable and inflexible. This radical new concept suggested that cancer cells could change their genes, a process that would both allow them to develop more potent cancer-causing genes as well as evolve resistance to treatment. Dr. Alt proved the generality of his initial discoveries when he showed that the gene n-myc is commonly amplified in the childhood cancer neuroblastoma. Today, genomic instability is recognized as one of the hallmarks of cancer.
Equally important is Dr. Alt's work on the critical DNA repair mechanism called "non-homologous end joining" (NHEJ). Dr. Alt not only made the initial experimental findings that led to the discovery of this pathway, but also carried out an ingenious series of experiments over many years in his lab in Boston, taking it apart piece by piece to understand how it works. This work linked NHEJ to protecting against a specific kind of DNA damage called "translocations," which is a major component of many cancers, especially leukemia and lymphoma.
Both amplified genes and translocated genes are key components of the Precision Medicine paradigm, which is at the heart of 21st century medicine. By identifying the source of genetic abnormalities that drive both cancer development and drug resistance, Dr. Alt's insights helped to revolutionize cancer diagnostics and treatment. His discoveries led to a wholly new approach to treating cancer identifying these genetic abnormalities then selecting new drugs that target each specifically.
"I am truly honored to be selected by the National Foundation for Cancer Research to receive this award, and I am humbled to stand with past winners of the Szent-Gyrgyi Prize," said Dr. Alt. "Cancer is a complex and terrible disease, but with each new discovery we are making it less mysterious, more understandable, and ultimately less deadly. We are making progress."
"Dr. Alt's work has uncovered and explained some of the most foundational chemistry of life, and throughout his career he has always been focused on the implications for cancer. His vision and talent were instrumental in bringing cancer research into the modern era, and we are proud to present him with this award," said Sujuan Ba, Ph.D., Co-chair of the 2015 Szent-Gyrgyi Prize Selection Committee and President of NFCR.
Dr. Alt will be honored at an award ceremony held April 29, 2015 at The National Press Club in Washington, D.C. Media and the public are invited and encouraged to attend.
About the Szent-Gyrgyi Prize for Progress in Cancer Research
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BETHESDA, Md., March 5, 2015 /PRNewswire-USNewswire/ -- In an effort to standardize interpretation and reporting of genomic test results, the American College of Medical Genetics and Genomics (ACMG), together with colleagues from the Association for Molecular Pathology (AMP) and the College of American Pathologists (CAP), has developed an evidence-based gene variant classification system and accompanying standard terminology.
The new system, published online ahead of print in ACMG's flagship journal, Genetics in Medicine, is designed to assist genetic testing laboratories and clinical geneticists in the critical task of assigning the disease-causing potential to the many different genetic variants that individuals have in their DNA.
"These updated guidelines provide a systematic and sound way to classify genomic variants so that when Lab A on the east coast and Lab B on the west coast are reporting results, they are using the same method to classify that variant," said Sue Richards, Ph.D., a medical director of the Knight Diagnostic Laboratories, and Professor of Molecular and Medical Genetics at Oregon Health & Science University, Portland, OR. and chair of the workgroup that issued the guidelines. To develop the guidelines the multi-disciplinary workgroup sought input from the clinical genetics community through surveys and workshops at professional society meetings. The result is a consensus document that reflects that input.
"In the past, standard terms such as 'pathogenic' and a consistent strategy for classifying variants have been lacking," Richards said, "leading to wide variation in how laboratories classify individual differences in DNA sequence. Each person carries many thousands of these DNA variants, but determining which of these are causative for disease is a difficult task that requires an abundance of scientific evidence."
"Navigating the complexity of genetic evidence and how to weigh the strength of that evidence is challenging for laboratories and this guidance will help provide a consistent framework for that process," said Heidi Rehm, Ph.D., Chief Laboratory Director at Partners Laboratory for Molecular Medicine and Associate Professor of Pathology, Brigham & Women's Hospital and Harvard Medical School, Boston, Mass., and workgroup co-chair. "Although these guidelines were targeted to clinical laboratories, it is our hope that the same consistent approaches will be applied in the research setting and help improve the quality of published literature and the genetic claims being made."
"Recently, clinical laboratories have more broadly begun sharing their variant interpretations in the public domain through ClinVar, a database that aggregates information about genetic sequence variation and its relationship to human health and human disease, allowing differences of interpretation to be identified. Through this process, laboratories are employing the ACMG guidelines as a best standard in resolving any differences in variant interpretation," said Rehm.
Because genomics is a developing field of research, standards of evidence are also evolving over time and will continue to evolve. Many genetic changes are what's termed "variants of uncertain significance," (VUS), which simply means that not enough is known about them to be able to state whether they cause health problems or not. Under the new guidelines, a variant of uncertain significance (VUS) should not be used in clinical decision-making.
The guidelines provide five standard classifications: "pathogenic," "likely pathogenic," "uncertain significance," "likely benign," and "benign," along with standard definitions for each term. These new standards may place more variants in the VUS category, Richards said, because there is not enough scientific evidence to state with confidence that they do or do not cause disease.
The workgroup stresses that physicians should combine genomic results with other evidence of disease whenever possible. "Likely pathogenic" results provide enough evidence that a physician can act on it when combined with, for example, prenatal ultrasound, enzyme assays, physical findings or imaging studies.
It is important to note that these new guidelines cover only genetic variants that are inherited, not those genetic changes that arise in a specific cell within a tumor. Neither do the guidelines cover genetic changes that may contribute to complex diseases such as diabetes or heart disease. Guidelines for the interpretation of complex disease traits remain under study.
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AMP incidental findings working group recommends that laboratories develop individual policies for analysis and reporting of known and predicted incidental findings
Bethesda, MD, February 12, 2015 The Association for Molecular Pathology (AMP), the premier global, non-profit organization serving molecular laboratory professionals, announced that The Journal of Molecular Diagnostics today published a Special Article titled, "Reporting Incidental Findings in Genomic Scale Clinical Sequencing - A Clinical Laboratory Perspective." This paper offers new and important perspectives from the laboratory highlighting the need for increased understanding and transparency of complex genomic testing. It also outlines important recommendations, including the need for laboratories to establish clear and patient-friendly policies for delivering ancillary information generated from genome-wide genetic tests. A copy of the paper is available online at http://jmd.amjpathol.org/article/S1525-1578%2814%2900245-1/fulltext.
The AMP Incidental Findings Working Group, including authors of this paper, have closely followed the incidental findings debate since early 2013 when the American College of Medical Genetics (ACMG) published its guidelines on incidental findings reporting. These recommendations primarily focused on the content of secondary information obtained from genetic tests, and not the pitfalls of technology limitations, which has placed a significant burden on laboratories to educate patients as well as physicians about the strengths and limitations of genetic testing.
Lead author and Chair of the AMP Incidental Findings Working Group, Madhuri Hegde, Ph.D., from Emory Genetics Laboratory, Department of Human Genetics, Emory University, finds that patient and physician education about how genomic data are interpreted as well an appreciation for technology limitations placed on to the lab have been overlooked.
"Patients have a choice whether or not to receive additional information that may be available as a result of a genetic test that looks across an entire genome of DNA. In most cases, patients are interested in learning more, but it's critical that we educate them, as well as the ordering physician, about their options and what can and cannot be reported," noted Dr. Hegde. "While genetic testing technologies have revolutionized the way we diagnose and treat disease, we must appreciate the technical limitations that still exist today. If a report comes back with no known genetic abnormalities, it doesn't mean that a pathogenic variant might not exist - we just can't see it or interpret it from the data we have right now."
Laboratory regulation also plays an important role in how incidental findings are reported. Clinical Laboratory Improvements Amendments (CLIA) regulations, proficiency testing, lab accreditation, and other quality measures oversee and govern laboratories and the tests that they develop. If the U.S. Food and Drug Administration (FDA) steps in, as proposed in their recent draft framework, it could make access to important tests challenging.
"While we want to underscore the need for continued discussion among stakeholders to improve our understanding of the effect of different test result disclosure policies on patients, providers, and laboratories, we don't want to lose any progress that we have achieved since the completion of the human genome project," said Elaine Lyon, Ph.D., AMP Past President. "The proposed laboratory developed test regulation framework imposes substantially new requirements on clinical laboratories, hospitals, physicians, and other health care providers. This interference with the practice of medicine poses significant impact on patient access to vital molecular testing services necessary for improving patient care."
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About The Journal of Molecular Diagnostics
The Journal of Molecular Diagnostics, the official publication of the Association for Molecular Pathology, co-owned by the American Society for Investigative Pathology, and published by Elsevier, Inc., seeks to publish high quality original papers on scientific advances in the translation and validation of molecular discoveries in medicine into the clinical diagnostic setting, and the description and application of technological advances in the field of molecular diagnostic medicine.
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JMD publishes article on laboratory perspective of incidental findings reporting
Rare Disease Day 2015 Bahrain
Join us in Bahrain City Center on 28 February 2015, to celebrate together the International Day of Rare Diseases. Bahrain rare diseases public awareness camp...
By: Aljawhara Center for Molecular Medicine and Inherited Disorders
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When AbbVie AbbVies CEO Rick Gonzalez described his recently acquired product ibrutinib (Imbruvica) as offering a pipeline in a drug, I imagine every business development executive in biopharma chuckled. No question each of them has used this exact line at some point to characterize a partner-ready product that has been developed for one indication, yet just might be useful in a range of others.
Its tempting to dismiss this concept as slick salesmanship of the Ginsu Knife but wait, theres more variety but dont. While pipeline in a pill may sound like a marketing slogan, it captures important emerging concepts within molecular medicine and pharmaceutical strategy.
Progress in understanding illness at a molecular level has revealedthat seemingly different conditions may share common molecular elements. For example, two very different cancers may be driven, in part, by a common oncoprotein (a signaling molecule stuck in the on position, say), suggesting a drug that effectively targeted this aberrant molecule could find use in a range of different cancers. This framework is one reason why sequencing has secured such a strong foothold in oncology (think Foundation Medicine) the possibility of identifying a drugable target in an otherwise inscrutable cancer.
(Disclosure/reminder: I work at a genomic data company.)
Outside of oncology, perhaps the most common variation on this theme is the use of a single drug to treat a range of seemingly unrelated conditions, especially illnesses that are caused by some sort of autoimmune response (essentially, the body attacking itself). Perhaps the most common therapeutic here are glucocorticoids (steroids like prednisone) to treat conditions ranging from asthma to arthritis. To be sure, no one would consider steroids an example of an especially precise medicine, given their notoriously pleotropic effects. Not surprisingly, theres been a huge amount of effort trying to develop treatments that more selectively restrain the immune system.
One example of such a product, which has enjoyed considerable commercial success, is adalimumab (Humira), a biologic that acts by sequestering a powerful secreted (soluble) mediator of immune response called TNF. Consequently, the medicine has been approved for the treatment of several arthritic conditions, several inflammatory bowel conditions, and couple of other autoimmune diseases.
AbbVies newly-acquired ibrutinib (see here for my detailed story of the medicines wild history) represents yet another variation on this theme, targeting a signalling molecule within an immune cell specifically, a protein involved in the activation of B-cells (which are responsible for the production of antibodies). Ibrutinib was initially considered as a potential treatment for rheumatoid arthritis, an autoimmune disease with incompletely understood pathophysiology that seems to include an antibody component. However, researchers also recognized that a drug blocking B-cell activation might be useful in the treatment of B-cell cancers; this proved to be the indication for which iburtinib ultimately was developed and approved. In a sense, Gonzalezs apparent interest in pursuing the autoimmune possibilities of ibrutinib has a sense of completing the circle, returning the development of the drug to the indication from which it began.
Of course, development doesnt always proceed as anticipated; AstraZeneca AstraZeneca partnered with Rigel to evaluate a similar inhibitor of B-cell activation, fostamatinib, in the treatment of rheumatoid arthritis. However, when a phase 2b study suggested the new product was likely to be less effective than adalimumab, AstraZeneca returned the rights to Rigel and absorbed a $140M writedown in the process. The potential of a precisely targeted molecule to be used for a range of indications reflects an evolution of the blockbuster ambition. Rather than relying on a single, broadly defined indication (think statins to treat high cholesterol), the industry now often looks to demonstrate the efficacy of a pathway-targeted product in a range of conditions involving the implicated pathway This distinction was elegantly pointed out (as Ive discussed) at a recent Xconomy forum by Rick Morrison of Comprehend Systems, who suggested the increasing need to identify promising indications represented an important application for big data and sophisticated analytics.
Bottom line for pipeline in a pill: while overused as a sales pitch, the concept reflects a legitimate scientific aspiration that is often pursued, and increasingly realized.
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Newswise NORTHFIELD, ILL. When Kimberly Jewett, a young mother of two, received a breast cancer diagnosis of ER-PgR positive, HER2-negative, it seemed like a foreign language to her. She wasnt sure what these words meant and how the molecular profile of her cancer would affect her treatment.
To help patients, such as Kimberly, the College of American Pathologists (CAP), the worlds leading organization for board-certified pathologists, is teaming with the National Patient Safety Foundation (NPSF) during National Patient Safety Awareness Week, March 8-14, 2015. Supporting this years special focus of patient and family engagement, the CAP will offer education resources, including a video and handout, How to Read Your Pathology Report, to help patients and their loved ones better understand their diagnoses.
With advancements in molecular medicine, the pathology report can provide patients with information from specialized tests used to identify tumor biomarkers that guide individualized treatment, said CAP president Gene N. Herbek, MD, FCAP, and medical director at Nebraska Methodist Health System. When a patient understands their pathology report and what the molecular markers mean for their diagnosis, it allows them to ask the appropriate questions regarding targeted therapies available for their type of cancer. We hope the CAPs participation in National Patient Safety Awareness Week will help encourage these meaningful conversations between patients and physicians.
Pathologists are medical doctors who specialize in the diagnosis of disease by looking at tissue or cells under a microscope and by interpreting medical laboratory tests. Based on the pathologists careful and accurate examination of a patients tissue sample, a pathologist generates a pathology report, which gives the patients diagnosis. Pathologists review the pathology report with the patients medical care team to formulate a treatment plan.
The CAPs participation in National Patient Safety Awareness Week is another example of our theme, United in Safety, said Tejal K. Gandhi, MD, MPH, CPPS, president and CEO of NPSF. Recognizing where our goals align and creating partnerships with other medical organizations, such as the CAP, help advance the work necessary to truly make health care safer for patients.
Advice to Patients Today, Kimberly is a two-time breast cancer survivor who is enjoying life with her family and friends.
My advice to someone who has been recently diagnosed with an illness, such as cancer, is to be your own advocate, said Ms. Jewett. Ask for a copy of your pathology report and seek accurate and credible resources, such as those provided by the CAP, to help you understand your pathology report and your diagnosis.
Resources Learn more about Kimberlys story and how a patients medical care team relies on the pathologists report to guide treatment and create safe and meaningful patient experiences. Details about Patient Safety Awareness Week, including CAP resources, are available on the NPSF website.
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Knowledge Is Power. Understand Your Pathology Report to Make Informed Health Decisions
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Experimental & Molecular Medicine (EMM) is Koreas first biochemistry journal and is relaunched as an Open Access, fully peer-reviewed international journal devoted to publishing the latest and most important advances in genetic, molecular and cellular studies of human physiology and diseases. The journal aims to communicate the improved clinical benefits for human health from the experimental and translational research performed using molecular tools. Areas that are covered include, but are not limited to, cancer biology, immunology, neuroscience, cardiovascular diseases, genetics and genomics, gene therapy and stem cells and regenerative medicine.
In March 2014, EMM published a special feature on Mucosal Immunity and Vaccines with a series of reviews providing an overview of current understanding in this area and covering a range of key topics including regulatory T cell vaccination, antigen targeting to M cells, mucosal mast cells and the role mucosal dendritic cells play in shaping mucosal immunity.
Volume 47, February 2015 ISSN (online): 2092-6413
2013 Impact Factor 2.462* 54/122 Medicine, Research & Experimental 176/291 Biochemistry & Molecular Biology
Editor-in-Chief: Dae-Myung Jue
*2013 Journal Citation Reports Science Edition (Thomson Reuters, 2014)
A key regulatory protein provides a potential new therapeutic target for difficult-to-treat breast cancer. Around 10-20% of breast cancers are known as triple-negative because they don't show any of the three markers commonly found in breast cancer cells and don't respond well to common therapies. A team led by Yeon-Sun Seong and Insoo Bae from Dankook University in South Korea and Georgetown Univiersity in U.S. treated triple-negative breast cancer cells with PI-103, a drug known to block a key pathway regulating cell division and tumor formation. The researchers observed a decrease in the expression of -TrCP1, a subunit of a larger protein complex involved in ubiquitin proteasome pathway. Experimentally reducing levels of -TrCP1 was sufficient to slow the growth of the breast cancer cells. These results raise the possibility of inhibiting -TrCP1 in novel ways to combat triple-negative breast cancer.
An anti-rheumatic drug can protect hearing in mice from the damage wrought by platinum-containing chemotherapeutic agents. A research team led by Raekil Park of the Wonkwang University College of Medicine in Iksan, South Korea, investigated whether bucillamine, a drug used to treat rheumatoid arthritis, can lessen the degree of hearing loss caused by the cancer chemotherapy drug cisplatin. In cisplatin-treated mice, bucillamine led to better scores on a standard hearing test. Bucillamine also reduced cisplatin-induced sensory hair cell loss in cochlear explants grown in a lab dish. The researchers analyzed the molecular response using a mouse auditory cell line treated with cisplatin. They observed that bucillamine lowered the activity of proteins involved in cell death, suppressed the generation of damaging free radicals, and increased the expression of various proteins involved in detoxification.
Special Feature on Epstein-Barr Virus (EBV)
It has been 50 years since Michael Anthony Epstein and Yvonne Barr discovered Epstein-Barr Virus (EBV) particles in cell lines cultured from tumor tissue from a Burkitt lymphoma. Since the initial discovery of the virus, more than 20,000 scientific papers on the characteristics, functions and oncogenic mechanisms of viral genes, the spectrum of EBV-associated diseases, and treatment of patients have been published. Experimental & Molecular Medicine contains six review articles that provide an overview of our current understanding of Epstein-Barr virology and oncogenesis and of EBV-associated neoplasm.
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Released: 27-Feb-2015 4:00 PM EST Embargo expired: 2-Mar-2015 11:00 AM EST Source Newsroom: Johns Hopkins Medicine Contact Information
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Newswise The cascade of events leading to bacterial infection and the immune response is mostly understood. However, the molecular mechanisms underlying the immune response to the bacteria that causes tuberculosis have remained a mystery until now. Researchers at the Johns Hopkins University School of Medicine have now uncovered how a bacterial molecule controls the bodys response to TB infection and suggest that adjusting the level of this of this molecule may be a new way to treat the disease. The report appears this week as an advance online publication of Nature Medicine.
We unraveled part of the cat-and-mouse game that plays out when TB bacteria infect human cells. The microbes release a small piece of DNA that resembles viral DNA, and this tricks the human cells to react as if they were responding to a virus instead of a bacterium; this may explain in part why the human immune response is often unable to combat TB, says William Bishai, M.D., Ph.D., co-director of the Johns Hopkins Center for Tuberculosis Research Laboratory and corresponding author on the paper. The exciting part is that with the knowledge of this molecular trickery, we may be able to come up with better drugs and vaccines for TB tools that are sorely needed.
After tuberculosis bacteria infect a host, the bacteria release a molecule called c-di-AMP into the hosts cells. Those cells have built-in early detection systems that recognize these foreign molecules and start an inflammatory response, which then leads to a complex reaction to combat the infection. The research team first measured c-di-AMP levels in the bacteria and found that its levels increase when the bacteria are actively multiplying.
To determine if c-di-AMP is indeed altering the host immune response, the researchers infected mouse immune cells with TB bacteria engineered to make different levels of c-di-AMP and compared how much of an immune response the cells mounted by measuring levels of INF-beta protein. They found that the more c-di-AMP released into the mouse cell, the higher the INF-beta levels.
But, according to Bishai, INF-beta levels may not reveal the whole picture of what transpires during infection. So they then looked at how well the bacteria themselves grow when releasing different amounts of c-di-AMP into the cells theyve infected. The bacteria making the highest levels of c-di-AMP, it turns out, showed the slowest growth rates.
Others had suggested that molecules of the same class as c-di-AMP can trigger autophagy, when a cell chews up and disposes of its insides, says Bishai. So we set out to see if overproducing c-di-AMP was causing the infected host to eat the TB bacteria. Using cells marked with glowing proteins, the researchers saw under microscopes that cells infected with TB bacteria making high levels of c-di-AMP indeed underwent more autophagy than those with lower levels of c-di-AMP.
The team then examined whether differences in c-di-AMP could alter the severity of the disease in mice. Infection with normal bacteria causes death at about 150 days, whereas infection with bacteria engineered to overproduce c-di-AMP led to longer survival times 321 days.
We still dont know if altering c-di-AMP levels can be linked to different outcomes in humans with TB, but this study does suggest that it would be well worth looking into, says Bishai. The study was funded by the National Institute of Allergy and Infectious Diseases (grant numbers AI037856, AI097138 and AI036973), and Bishai is supported by the Howard Hughes Medical Institute. Other authors on the paper include Bappaditya Dey, Ruchi Jain Dey, Laurene S. Cheung, Supriya Pokkali, Ph. D., Haidan Guo and Jong-Hee Lee, Ph.D.
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Johns Hopkins Researchers Identify Key to Tuberculosis Resistance