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Archive - 2012

October 24th

Nobel Prize Winner Discovers New Target for Cancer Research

In a new paper published online on October 24, 2012 in Nature, BioFrontiers Institute scientists at the University of Colorado-Boulder, Drs. Tom Cech and Leslie Leinwand, described a new target for anti-cancer drug development that is located at the ends of our DNA. Researchers in the two scientists' laboratories collaborated to find a patch of amino acids that, if blocked by a drug docked onto the chromosome end at this location, may prevent cancerous cells from reproducing. The amino acids at this site are called the "TEL patch" and once modified, the end of the chromosome is unable to recruit the telomerase enzyme, which is necessary for growth of many cancerous cells. "This is an exciting scientific discovery that gives us a new way of looking at the problem of cancer," Dr. Cech said. "What is amazing is that changing a single amino acid in the TEL patch stops the growth of telomeres. We are a long way from a drug solution for cancer, but this discovery gives us a different, and hopefully more effective, target." Dr. Cech is the director of the BioFrontiers Institute, a Howard Hughes Medical Investigator and winner of the 1989 Nobel Prize in chemistry. Co-authors on the study include postdoctoral fellows Drs. Jayakrishnan Nandakumar and Ina Weidenfeld; University of Colorado undergraduate student Caitlin Bell; and Howard Hughes Medical Institute Senior Scientist Dr. Arthur Zaug. Telomeres have been studied since the 1970s for their role in cancer. They are constructed of repetitive nucleotide sequences that sit at the ends of our chromosomes like the ribbon tails on a bow. This extra material protects the ends of the chromosomes from deteriorating, or fusing with neighboring chromosome ends. Telomeres are consumed during cell division and, over time, will become shorter and provide less cover for the chromosomes they are protecting.

Large-Scale Sequencing Study of Pancreatic Cancer Reveals Genetic Clues

A large-scale study that defines the complexity of underlying mutations responsible for pancreatic cancers in more than 100 patients was published online in Nature on October 24, 2012. The analysis represents the first report from Australia’s contribution to the International Cancer Genome Consortium (ICGC), which brings together the world's leading scientists to identify the genetic drivers behind 50 different cancer types. Pancreatic cancer has the highest mortality rate of all the major cancers and is one of the few for which survival has not improved substantially over the past 40 years. It is the fourth-leading cause of cancer death. Professor Sean Grimmond, from the Institute for Molecular Bioscience (IMB) at The University of Queensland, and Professor Andrew Biankin, from The Kinghorn Cancer Centre at Sydney’s Garvan Institute of Medical Research / St. Vincent's Hospital, led an international team of more than 100 researchers that sequenced the genomes of 100 pancreatic tumors and compared them to normal tissue to determine the genetic changes that lead to this cancer. “We found over 2,000 mutated genes in total, ranging from the KRAS gene, which was mutated in about 90 per cent of samples, to hundreds of gene mutations that were only present in 1 or 2 per cent of tumors,” Professor Grimmond said. “So while tumors may look very similar under the microscope, genetic analysis reveals as many variations in each tumor as there are patients. This demonstrates that so-called ‘pancreatic cancer’ is not one disease, but many, and suggests that people who seemingly have the same cancer might need to be treated quite differently.” Professor Biankin said such individual genetic diagnoses and treatments represent the future of healthcare.

Scientists ID Two Receptor Families Used by Dengue Virus to Penetrate Cells

By demonstrating that it is possible to inhibit viral infection in vitro by blocking the bonding between the Dengue virus and TIM and TAM receptors, researchers have opened the way to a new antiviral strategy. Their work was published online in Cell Host & Microbe on October 18, 2012. The Dengue virus circulates in four different forms (four serotypes). It is transmitted to humans by mosquitoes. It is a major public health problem. Two billion people throughout the world are exposed to the risk of infection and 50 million cases of Dengue fever are recorded by the WHO every year. The infection is often asymptomatic, or causes influenza-like symptoms, but its most serious forms can lead to fatal haemorrhagic fevers. At present, there is no preventive vaccine or efficient antiviral treatment for these four Dengue serotypes. So it is of vital importance that new therapeutic strategies be developed. Ali Amara's team at INSERM, together with colleagues, performed genetic screening in order to identify cell receptors used by the virus to penetrate target cells. The researchers have determined the important function played by the TIM receptors (TIM-1, 3, 4) and TAM receptors (AXL and TYRO-3) in the penetration process of the four Dengue serotypes. Mr. Amara's team has succeeded in demonstrating that the expression of these two receptor families makes cells easier to infect. In addition, the researchers observed that interfering RNA or antibodies that target the TIM and TAM molecules considerably reduced the infection of the cells targeted by the Dengue virus. The TIM and TAM molecules belong to two distinct families of transmembrane receptors that interact either directly (TIM) or indirectly (TAM) with phosphatidylserine, an "eat-me" signal that allows the phagocytosis and the elimination of these apoptopic cells.

New T Cell Treatment Targets Advanced Melanoma in Mouse Model

Cancers arise in the body all the time. Most are nipped in the bud by the immune response, not least by its T cells, which detect telltale molecular markers—or antigens—on cancer cells and destroy them before they grow into tumors. Cancer cells, for their part, evolve constantly to evade such assassination. Those that succeed become full-blown malignancies. Yet, given the right sort of help, the immune system can destroy even these entrenched tumors. In the October 22, 2012 issue of the Journal of Experimental Medicine, researchers led by Jedd Wolchok, M.D., Ph.D., of the Ludwig Center for Cancer Immunotherapy at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York describe one way in which that might be achieved. The paper relates how the cancer drug cyclophosphamide (CTX) and OX86—an antibody that activates a molecule named OX40 on T cells—were combined with a cutting-edge therapy known as adoptive T cell transfer to eradicate advanced melanoma tumors in mice. Dr. Wolchok and his colleagues had previously shown that CTX and OX86 treatment caused the regression of such tumors. Now they wanted to see if adding T cell transfer to the mix would further improve outcomes. T cell transfer is an investigative immunotherapy in which T cells that target tumors are isolated from patients, manipulated, expanded, and then transfused back into those patients. A variety of T cells are of relevance to this approach. One is the CD8+ T cell, which can directly kill diseased and cancerous cells. Another is the CD4+ T cell, whose general role is to orchestrate the immune assault. It comes in several varieties — examples are the T helper 1 (Th1) and T helper 2 (Th2)—each of which elicits a distinct sort of immune response. And then there is the regulatory T cell, which keeps a lid on the last two responses.

October 23rd

Telomere Length in White Blood Cells Linked to Pancreatic Cancer

A new study shows that a blood marker is linked to pancreatic cancer, according to a study published today by scientists at the University of Wisconsin Carbone Cancer Center and the Mayo Clinic. First author Dr. Halcyon Skinner, assistant professor of population health sciences at the University of Wisconsin School of Medicine and Public Health, says the study is the first time pancreatic cancer risk has been linked to differences in telomere length in blood cells. "This suggests a new avenue to identify those with pancreatic cancer or those at risk of developing the cancer in the future,'' he says. Dr. Skinner's colleagues at the Mayo Clinic took blood samples from more than 1,500 people – 499 of them with a diagnosis of pancreatic cancer and 963 of them cancer-free control subjects. Specifically, the scientists were interested in the length of the telomeres – the end caps on chromosomes – found in white blood cells. They found a direct relationship with the risk of pancreatic cancer: the shorter the telomeres, the more likely a person was to have pancreatic cancer. Telomeres maintain the stability of genes, and are known to shorten with age as cells divide. People of the same chronological age can have vastly different telomere lengths. In other words, some people's cells can by viewed as biologically older than cells from other people the same age. "We know that people with many factors that are classically unhealthy also tend to have shorter telomeres. Those who have had stressful lives, exposed to chronic inflammation, have poor glucose control or smoked cigarettes tend to have shorter telomeres, and that can set the stage for genetic damage,'' Dr. Skinner explains. Shortened telomeres in the blood have already been associated with other types of cancer, including colon cancer.

Family History of Schizophrenia Is a Risk Factor for Autism

Autism Spectrum Disorders (ASD), a category that includes autism, Asperger syndrome, and Pervasive Developmental Disorder, are characterized by difficulty with social interaction and communication, or repetitive behaviors. The U.S. Centers for Disease Control and Management says that one in 88 children in the U.S. is somewhere on the autism spectrum — an alarming ten-fold increase in the last four decades. New research by Dr. Mark Weiser of Tel Aviv University’s Sackler Faculty of Medicine and the Sheba Medical Center has revealed that ASD appears to share a root cause with other mental illnesses, including schizophrenia and bipolar disorder. At first glance, schizophrenia and autism may look like completely different illnesses, he says. But closer inspection reveals many common traits, including social and cognitive dysfunction and a decreased ability to lead normal lives and function in the real world. Studying extensive databases in Israel and Sweden, the researchers discovered that the two illnesses have a genetic link, representing a heightened risk within families. They found that people who have a schizophrenic sibling are 12 times more likely to have autism than those with no schizophrenia in the family. The presence of bipolar disorder in a sibling showed a similar pattern of association, but to a lesser degree. A scientific leap forward, this study sheds new light on the genetics of these disorders. The results will help scientists better understand the genetics of mental illness, says Dr. Weiser, and may prove to be a fruitful direction for future research. The findings were published online during July 2012 in the Archives of General Psychiatry. Researchers used three data sets, one in Israel and two in Sweden, to determine the familial connection between schizophrenia and autism.

October 22nd

Sequencing Used in Study of Gut Bacteria/Diet in Kittens

For animals as well as people, diet affects what grows in the gut. The gut microbial colonies, also known as the gut microbiome, begin to form at birth. Their composition affects how the immune system develops and is linked to the later onset of metabolic diseases such as obesity. Common wisdom is that cats, by nature carnivorous, are healthiest when fed high-protein diets. Researchers at the University of Illinois, and collborators, wanted to find out if this is true. "There are a lot of diets now, all natural, that have high protein and fat and not much dietary fiber or carbohydrates," said animal sciences researcher Dr. Kelly Swanson. He and his team examined the effect of dietary protein:carbohydrate ratio on the gut microbiomes of growing kittens and reported their results online on August 31, 2012 in the British Journal of Nutrition. One month before mating, eight domestic shorthair female cats were randomly assigned to one of two dry diets: high-protein, low-carbohydrate (HPLC) or moderate-protein, moderate-carbohydrate (MPMC). When the kittens were born, they were housed with their mothers until they were 8 weeks old, weaned, and then fed the same diets as their mothers. After weaning, the 30+ kittens were twin- and triple-housed within the dietary-group cages. They were allowed to go into a common area furnished with toys and scratching posts to play with people and each other. "It became quite a party right away," said Dr. Swanson. "It was a bit chaotic but fun as well." Twelve of the kittens became part of the study. The researchers took fecal samples at weaning and 4 and 8 weeks after weaning. They extracted bacterial DNA and used bioinformatics techniques to estimate total bacterial diversity.

3D Structure of an Unmodified GPCR in Its Natural Enviroment

Scientists have determined the three-dimensional structure of a complete, unmodified G-protein-coupled receptor in its native environment: embedded in a membrane in physiological conditions. Using NMR spectroscopy, the team mapped the arrangement of atoms in a protein called CXCR1, which detects the inflammatory signal interleukin 8 and, through a G protein located inside the cell, triggers a cascade of events that can mobilize immune cells, for example. Because G-protein-coupled receptors are critical for many cellular responses to external signals, they have been a major target for drugs. More precise knowledge of the shapes of these receptors will allow drugmakers to tailor small molecules to better fit specific targets, avoiding collateral hits that can cause detrimental side effects. "This finding will have a major impact on structure-based drug development since for the first time the principal class of drug receptors can be studied in their biologically active forms where they interact with other proteins and potential drugs," said Dr. Stanley Opella, professor of chemistry and biochemistry at the University of California, San Diego, who led the work, which Nature published online on October 21, 2012, in advance of the print edition. Protein structures are most often determined by reading the diffraction patterns of X-rays beamed at their crystalline form, but crystallizing such large, unwieldy molecules is a challenge often met with strategies such as snipping off floppy ends. Those changes can alter the shape of critical regions of the protein. "Our approach was to not touch the protein," Dr. Opella said. "We are working with molecules in their active form." Their strategy has revealed a new view of these receptors. Previous reports have all noted seven helices weaving through the membrane.

How Bacteria Recognize and Exclude Arsenate

Not long ago, some unassuming bacteria found themselves at the center of a scientific controversy: a group claimed that these microorganisms, which live in an environment that is rich in the arsenic-based compound arsenate, could take up that arsenate and use it – instead of the phosphate on which all known life on Earth depends. The claim, since disproved, raised another question: How do organisms living with arsenate pick and choose the right substance? Chemically, arsenate is nearly indistinguishable from phosphate. Professor Dan Tawfik of the Biological Chemistry Department at the Weizmann Institute of Science in Israel says: “Phosphate forms highly stable bonds in DNA and other key biological compounds, while bonds to arsenate are quickly broken. But how does a microorganism surrounded by arsenate distinguish between two molecules that are almost the same size and have identical shapes and ionic properties?” To investigate, Dr. Tawfik, postdoctoral fellow Dr. Mikael Elias, Ph.D. student Alon Wellner, and lab assistant Korina Goldin, in collaboration with Drs. Tobias Erb and Julia Vorholt of ETH Zurich, looked at a protein in bacteria that takes up phosphate. This protein, called PBP (short for phosphate binding protein), sits near the bacteria’s outer membrane, where it latches onto phosphates and passes them on to pumps that transport them into the cell. In research published online on October 3, 2012 in Nature, the team, which also included Dr. Eric Chabriere from the CNRS-Université de la Méditerranée, compared the activity of several different PBPs – some from bacteria like E. coli that are sensitive to arsenate and others, like those from the arsenic-rich environment, which are tolerant of the chemical.

New X-Ray Approach May Permit Early Detection of Severe Lung Diseases

Severe lung diseases are among the leading causes of death worldwide. To date, they have been difficult to diagnose at an early stage. Within an international collaboration, scientists from Munich have now developed an X-ray technology to do just that. Their results were published online on October 16, 2012 in PNAS. Now they are working on bringing the procedure into medical practice. Chronic obstructive pulmonary disease (COPD) is considered the fourth most common cause of death in the United States. Usually the precursor to this life-threatening lung disease is a chronic bronchitis. Partially destroyed alveoli and an over-inflation of the lungs, known as emphysema, are serious side effects. However, the subtle differences in the tissue are barely discernable in standard X-ray images. In addition to the conventional X-ray images, the Munich scientists analyzed the radiation scattered by the tissue. From these data they calculated detailed images of the lungs of the investigated mice. Using such images, physicians can see not only if a patient is diseased, but also how strongly which parts of the lung are affected. “Especially in early stages of the disease, identification, precise quantification, and localization of emphysema through the new technology would be very helpful”, says Professor Maximilian Reiser, head of the Institute for Clinical Radiology at Ludwig-Maximilians-University Munich.