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Archive - 2012 - Story

October 22nd

Protein Signal from Microenvironment May Trigger Metastasis in Breast Cancer

A new study from Johns Hopkins researchers and colleagues suggests that the lethal spread of breast cancer is as dependent on a tumor’s protein-rich environment as on genetic changes inside tumor cells. In a report in the September 25, 2005 issue of PNAS, the scientists conclude that a molecular signal in the protein meshwork surrounding the breast cancer cells may provide the critical trigger to initiate the life-threatening process of metastasis to distant sites in the body. Moreover, their experiments suggest that the environment surrounding a tumor can even coax healthy breast cells to invade surrounding tissue just as cancer cells do, and that a healthy environment can cause cancer cells to stay put and not spread as they usually do. “The most dangerous aspect of breast cancer is its ability to spread to distant sites, and most tumors are initially unable to do that,” says Andrew Ewald, Ph.D., assistant professor of cell biology at the Johns Hopkins School of Medicine and member of the Institute for Basic Biomedical Sciences’ Center for Cell Dynamics. Learning more specifically what triggers metastases may provide additional targets for preventing and treating the malignant process that causes cancer deaths, Dr. Ewald adds. It’s widely accepted that cancers acquire the ability to spread through the gradual accumulation of genetic changes, and experiments have also shown that these changes occur in parallel with changes in the protein content and 3-dimensional patterning of the protein meshwork that creates the cancer’s immediate surroundings. What has been unclear is whether those immediate surroundings play a role in initiating and encouraging cancer’s spread, or whether they are more “effect” then “cause.” To sort out the contributions of both the genetic changes and the environment, Dr.

October 16th

Cold Viruses Provide Clues to New Cancer Therapies

Cold viruses generally get a bad rap----which they've certainly earned----but new findings by a team of scientists at the Salk Institute for Biological Studies, and collaborators, suggest that these viruses might also be a valuable ally in the fight against cancer. Adenovirus, a type of cold virus, has developed molecular tools----proteins----that allow it to hijack a cell's molecular machinery, including large cellular machines involved in growth, replication, and cancer suppression. The Salk scientists identified the construction of these molecular weapons and found that they bind together into long chains (polymers) to form a three-dimensional web inside cells that traps and overpowers cellular sentries involved in growth and cancer suppression. The findings, published in the October 12, 2012 issue of Cell, suggest a new avenue for developing cancer therapies by mimicking the strategies employed by the viruses. "Cancer was once a black box," says Dr. Clodagh O'Shea, an assistant professor in Salk's Molecular and Cell Biology Laboratory, who led the study. "The key that opened that box was revealing the interactions between small DNA tumor virus proteins and cellular tumor suppressor complexes. But without knowing the structure of the proteins they use to attack cells, we were at a loss for how these tiny weapons win out over much larger tumor suppressors." Dr. O'Shea's team studied E4-ORF3, a cancer-causing protein encoded by adenovirus, which prevents the p53 tumor suppressor protein from binding to its target genes. Known as the "guardian of the genome," p53 normally suppresses tumors by causing cells with DNA damage----a hallmark of cancer----to self-destruct.

October 15th

Curcumin Curbs Metastases in Prostate Cancer

Powdered turmeric has been used for centuries to treat osteoarthritis and other illnesses. Its active ingredient, curcumin, inhibits inflammatory reactions. A new study, led by a research team at Ludwig-Maximilians-Universität (LMU) in Munich, now shows that it can also inhibit formation of metastases. The study was published online in Carcinogenesis on October 5, 2012. Prostate cancer is one of the most prevalent malignancies in the Western world, and is often diagnosed only after metastatic tumors have formed in other organs. In three percent of cases, these metastases are lethal. A research team led by Dr. Beatrice Bachmeier at LMU Munich has been studying the mode of action of a natural product that inhibits the formation of metastases. The compound is found in turmeric, a plant that has been used for medicinal purposes for thousands of years, and is a major ingredient of curry. Dr. Bachmeier's research centers on curcumin, the polyphenol responsible for the characteristic color of curry. Curcumin is well tolerated and is therefore, in principle, suitable both for prophylactic use (primary prevention) and also for the suppression of metastases in cases where an established tumor is already present (secondary prevention). In a previous study, Dr. Bachmeier and her colleagues had demonstrated that the substance reduces statistically significantly the formation of lung metastases in an animal model of advanced breast cancer. The new study was designed to investigate the efficacy of curcumin in the prevention of prostate cancer metastases, and to determine the agent's mechanism of action. The researchers first examined the molecular processes that are abnormally regulated in prostate carcinoma cells.

Targeted Drug Benefits Some Patients with Advanced Lung Cancer

The drug crizotinib (Xalkori) substantially lengthens the amount of time some patients with advanced lung cancer live without their disease progressing, according to findings from the first large clinical trial to test the targeted therapy. Initial results from the trial were presented at the European Society for Medical Oncology Congress (ESMO) in Vienna, Austria, and reported in the October 2, 2012 National Cancer Institute Bulletin. The Food and Drug Administration (FDA) approved crizotinib last year to treat patients with advanced non-small cell lung cancer (NSCLC) whose tumors have a specific genetic mutation. The approval was based on smaller, nonrandomized trials that showed crizotinib could shrink tumors in many patients with the mutation—a genetic rearrangement involving the ALK gene. Until now, crizotinib had not been shown to prolong progression-free or overall survival compared with standard chemotherapy. "The results from the phase I and phase II trials were pretty remarkable," said lead investigator Dr. Alice Shaw of Massachusetts General Hospital. "We had high tumor response rates, which were impressive for just a single agent." A large randomized trial was necessary, Dr. Shaw explained, to confirm that the tumor responses translated into meaningful outcomes and to answer questions about whether patients whose tumors had this genetic mutation were more sensitive to any therapy, not just crizotinib. "Patients who received crizotinib did significantly better," she said. Progression-free survival was more than twice as long in patients treated with crizotinib compared with those who received chemotherapy—docetaxel (Taxotere) or pemetrexed (Alimta)—7.7 months versus 3 months.

Imatinib Effective in Treating Highly Aggressive Lymphoma

The use of carefully chosen animal models often underlies crucial medical advances. A perfect example is provided by the recent demonstration that a known drug, imatinib, can be used to treat a rare, but highly aggressive, type of lymphoma. The work was largely undertaken in the group of Dr. Lukas Kenner at the Ludwig Boltzmann Institute for Cancer Research and the Medical University of Vienna, with the support of Drs. Karoline Kollmann and Veronika Sexl at the University of Veterinary Medicine, Vienna, together with a number of national and international collaborators. The findings were published online on October 14, 2012 in Nature Medicine. So-called anaplastic large cell lymphoma (ALCL) is even less attractive in real life than it is on paper. It is a highly aggressive type of lymphoma that generally occurs in children and young adults and that has, to date, proven extremely difficult to treat. It has long been known that ALCL patients frequently show a genetic alteration (a translocation) that causes expression of nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), a gene known to be capable of giving rise to cancer. But how the NPM-ALK gene works has so far remained largely a matter of conjecture. Working in a mouse model for lymphoma, Dr. Kollmann in Dr. Sexl’s group at the University of Veterinary Medicine, Vienna, and colleagues at the Ludwig Boltzmann Institute for Cancer Research and the Medical University of Vienna were able to show that the development of lymphoma is absolutely dependent on the “platelet-derived growth factor receptor B” (PDGFRB), a protein already associated with the growth of other types of tumors. The scientists demonstrated that the effect was direct, with NPM-ALK stimulating the production of the transcription factors JUN and JUNB, which bind to and activate the PDGFRB promoter.

Japanese and British Scientists Share 2012 Nobel in Physiology or Medicine

Shinya Yamanaka M.D., Ph.D., a senior investigator at the Gladstone Institutes—which is affiliated with the University of California, San Francisco (UCSF)—has won the 2012 Nobel Prize in Physiology or Medicine for his discovery of how to transform ordinary adult skin cells into cells that, like embryonic stem cells, are capable of developing into any cell in the human body. Dr. Yamanaka shares the award with Dr. John Gurdon of the University of Cambridge. A former governor of the Wellcome Trust, Professor Gurdon was awarded the Prize for the discovery that mature cells can be reprogrammed to become immature cells that are capable of developing into all tissues of the body. He is widely regarded as the scientist who kick-started the field of cloning. In 1962, Professor Gurdon was the first to demonstrate that the specialisation of cells is reversible when he successfully 'cloned' the South African frog from a tadpole's intestinal cell. By transplanting the nucleus of the intestinal cell into an empty egg cell, he created an organism genetically identical to the tadpole before. The discovery caused shockwaves around the scientific community, not least because a mere graduate student had disproved previously held dogma developed by more famous and established scientists. "John's seminal work, which was carried out in the 1960s, showing that is possible to reprogram a mature frog cell into a nonspecialised, immature cell, was both counterintuitive and with no conceivable application at the time. Yet it now underpins all of regenerative medicine, an area in which the UK remains at the cutting edge. His recognition by the Nobel Prize is very well deserved,” said Sir William Castell, Chairman of the Wellcome Trust. The awards were announced on October 8, 2012. Dr.

Association of PBRM1 Gene with Bipolar Disorder Replicated in Large Study

One of the biggest challenges in psychiatric genetics has been to replicate findings across large studies. Scientists at King's College London, Institute of Psychiatry, and multiple collaborators have now performed one of the largest ever genetic replication studies of bipolar affective disorder, with 28,000 subjects recruited from 36 different research centers. Their findings provide compelling evidence that the chromosome 3p21.1 locus contains a common genetic risk for bipolar disorder, the PBRM1 gene. The locus at 3p21.1 has also been previously associated with depression and schizophrenia. Using a separate dataset of over 34,000 subjects, the scientists did not confirm association of this same variant with schizophrenia. Thus, they replicated the association of the marker with bipolar disorder, but not with schizophrenia. This is an interesting finding, in that it distinguishes the heritable risk for bipolar disorder and schizophrenia. It contrasts with the majority of studies that have found that schizophrenia risk genes also contribute to the risk for bipolar disorder. "This study adds to the recent rapid progress in identifying genes for mental illness. The last few years have seen the identification of about two dozen genetic loci for bipolar disorder and schizophrenia," commented first author Dr. Evangelos Vassos. "About half of these are shared between these two disorders, indicating they share some, but not all, genetic causes." Due to the conflicting results, it is clear that more work is needed to determine the role this locus plays in psychosis, but the evidence seems solid that it is associated with bipolar disorder.

October 11th

Chemistry Nobel Awarded for Work on G-Protein-Coupled Receptors (GPCRs)

Robert J. Lefkowitz M.D., a Howard Hughes Medical Institute investigator who has spent his entire 39-year research career at the Duke University Medical Center, is sharing the 2012 Nobel Prize in Chemistry with Brian K. Kobilka, M.D., of Stanford University School of Medicine, who was a post-doctoral fellow in Dr. Lefkowitz’s lab in the 1980s. The Nobel announcement of the prize was made on October 10, 2012. The two scientists are being recognized for their work on a class of cell surface receptors that have become the target of prescription drugs, including antihistamines, ulcer drugs, and beta blockers to relieve hypertension, angina, and coronary disease. The receptors receive chemical signals from the outside and transmit their messages into the cell, providing the cell with information about changes occurring within the body. These particular receptors are called seven-transmembrane G protein-coupled receptors, or just "G-coupled receptors" for short. Serpentine in appearance, G-coupled receptors weave through the surface of the cell seven times. The human genome contains code to make at least 1,000 different forms of these trans-membrane receptors, all of which are quite similar. The receptors also bear a strong resemblance to receptors that detect light in the eyes, smells in the nose, and taste on the tongue. "Bob's seminal discoveries related to G-protein coupled receptors ultimately became the basis for a great many medications that are in use today across many disease areas," said Victor J. Dzau, M.D., Chancellor for Health Affairs and CEO, Duke University Health System. "He is an outstanding example of a physician-scientist whose impact can be seen in the lives of the countless patients who have benefited from his scientific discoveries.

Breakthrough in Fighting Pompe Disease

Adding a third anti-cancer agent to a current drug cocktail appears to have contributed to dramatic improvement in three infants with the most severe form of Pompe disease -- a rare, often-fatal genetic disorder characterized by low or no production of an enzyme crucial to survival. Duke researchers previously pioneered the development of the first effective treatment for Pompe disease via enzyme replacement therapy (ERT). ERT relies on a manufactured enzyme/protein to act as a substitute for the enzyme known to be lacking in patients with a particular disease. In Pompe disease, ERT has been found to reduce heart and muscle damage caused by the absence of the enzyme. In the new study, appearing online on Oct. 11, 2012, in Genetics in Medicine, the Duke team, and collaborators, added a new step to the therapeutic regimen to address complications suffered by a subset of infants with Pompe disease who are treated with ERT. Some infants with Pompe disease who have certain combinations of genetic mutations develop a severe immune response to ERT. Very high levels of antibodies become directed against the enzyme and greatly reduce its therapeutic effect, leading to rapid clinical decline and death. In a January 2012 publication in Genetics in Medicine, the researchers reported success in preventing the immune rejection in Pompe infants who were just beginning ERT. They treated them with a drug cocktail that included low doses of the cancer chemotherapy drugs rituximab and methotrexate, plus the immune booster gammaglobulin to prevent the immune response to the ERT.

October 1st

Laser Scissors and Next-Gen Sequencing Allow Analysis of Gene Activty in Entire Fungal Genomes

With a combination of microscopic laser scissors and modern sequencing methods, biologists at the Ruhr-Universität Bochum (RUB) in Germany have analyzed the activity of genes in the entire genomes of a certain fungi in one fell swoop. Especially with organisms in the millimetre size range, this is a particular challenge because little cell material is available. The scientists of the RUB Department of General and Molecular Botany took advantage of the combined methods to investigate the development of small, multicellular fungi. The results were reported on September 27, 2012 in the open-access journal BMC Genomics. In multicellular organisms, each cell contains the same genetic material, however, often only a fraction of the genes are active (expressed). These differences in gene expression are the cause of variations in the structure and physiology of cells. Gene expression is therefore the key to understanding the development of multicellular organisms. "In large organisms such as plants, it is usually not a problem to get enough starting material to study gene expression," explains Dr. Minou Nowrousian. "In the case of microorganisms, organs often consist of only a few cells, and might be embedded in other tissues from which they are difficult to separate." Therefore, biologists of the research groups of Professor Ulrich Kück and Dr. Nowrousian combined laser microdissection with modern sequencing technologies to analyze the gene activity during the development of certain, just 0.5 millimeters large, sexual structures of fungi. In laser microdissection, scientists cut defined regions of a sample under the light microscope with a laser beam.