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Blood Protein May Be Biomarker for Lung Cancer

Scientists have reported discovery of a protein in the blood of lung cancer patients that could possibly be used in a test for the disease — difficult to diagnose in its earliest and most treatable stages — and to develop drugs that stop lung cancer from spreading. Their study appears in the American Chemical Society’s Journal of Proteome Research. In the report, Dr. Je-Yoel Cho and colleagues in South Korea note that lung cancer is the leading cause of cancer deaths worldwide. Lung cancer is so deadly because of its tendency to metastasize to distant sites in the body, such as the liver or the brain. Early detection could improve survival rates, but it is very difficult to detect lung cancer at early stages with today's technology. To find a better diagnostic tool, the researchers studied the proteins in the blood of lung cancer patients in search of red flags that could signal the disease's presence. They focused on adenocarcinoma, which accounts for one in three cases and is the most rapidly increasing form of lung cancer in women. Dr. Cho and colleagues found elevated levels of a protein called serum amyloid A (SAA) in the blood and lung tissue of lung adenocarcinoma patients, compared to healthy people. Their work showed that high amounts of SAA were unique to lung cancers (compared with other lung diseases or other cancers) and that the protein was involved in metastasis of cancer cells from the original tumor site. The researchers said that the protein could be used as a diagnostic marker for lung cancer and as a target for developing drugs that stop metastasis. [Press release] [Journal of Proteome Research abstract]

Overlooked Enzyme May Be New Target for Lowering Cholesterol

A promising new way to potentially inhibit cholesterol production in the body has been discovered, a way that may yield treatments as effective as existing medications but with fewer side-effects. In a study published in the March 2 issue of the journal Cell Metabolism, a team of researchers from the University of New South Wales (UNSW) School of Biotechnology and Biomolecular Sciences-led by Associate Professor Andrew Brown–report that an enzyme-squalene mono-oxygenase (SM)-plays a previously unrecognized role as a key checkpoint in cholesterol production. SM is one of at least 20 enzymes involved in the assembly line when cholesterol is made throughout the body but only one of these enzymes-HMG-CoA reductase (HMGR)–is currently targeted by medications to lower cholesterol levels in the blood. "The class of drugs most commonly used to lower cholesterol-statins–are the blockbusters of the pharmaceutical world and work by inhibiting HMGR," said Professor Brown. "But HMGR is involved very early on in the assembly line, so inhibiting it affects all the other steps down the line–and other useful products it provides-and that can give rise in some people to unwanted side-effects, such as muscle pain. What's exciting about this previously overlooked SM enzyme is that it acts as a checkpoint much further down the assembly line, which should mean that it can be more specifically targeted at cholesterol production instead and leave the early part of the assembly line undisturbed. Cholesterol has developed something of a bad name, so many people don't realize that it is actually essential for a healthy body. It's needed, for example, to make sex hormones and to help build the walls of every single cell in our bodies."

10 Percent of Type 2 Diabetes Patients Have Mutation in Single Gene

A multinational study has identified four mutations in a single key gene as responsible for type 2 diabetes in nearly 10 percent of patients of white European ancestry. The study, which originated in Italy and was validated at the University of California-San Francisco (UCSF) and the University of Reims, found that defects in the HMGA1 gene led to a major drop in the body’s ability to make insulin receptors – the cell’s sensor through which insulin tells the cell to absorb sugar. This drop in insulin receptors leads to insulin resistance and type 2 diabetes, according to the paper, which was published online on March 2 in JAMA. Until now, no mutations in a single gene have been significantly associated with playing a role in type 2 diabetes. The results provide the unique opportunity for a test to predict potential for the disease in patients, as well as the possibility of identifying which of the current diabetes medications work best for people with one of the gene mutations, the authors said. Ultimately, it also could help drive research to find new and improved drugs for those patients. While the study focused on Caucasians, it also lays the groundwork for similar analyses in patients of Asian, African, and Native American descent, who suffer from higher rates of the disease, according to diabetes researcher Dr. Ira Goldfine, a UCSF professor of medicine and of physiology who led the U.S. arm of these studies. “This is a major breakthrough in type 2 diabetes,” said Dr. Goldfine, noting that 26 million Americans have diabetes and an estimated 79 million have pre-diabetes. “Many of our current diabetes drugs are very effective in some patients and not in others.

Nasal Vaccine Shows Promise for Alzheimer’s, Stroke

Researchers led by Dr. Dan Frenkel of Tel Aviv University's Department of Neurobiology are working on a nasally-delivered 2-in-1 vaccine that promises to protect against both Alzheimer's and stroke. The new vaccine repairs vascular damage in the brain by rounding up "troops" from the body's own immune system. And in addition to its prophylactic effect, study results suggest that the vaccine can have beneficial effects even when Alzheimer's symptoms are already present. The research on this new technology was recently accepted for publication in the journal Neurobiology of Aging. "Using part of a drug that was previously tested as an influenza drug, we've managed to successfully induce an immune response against amyloid proteins in the blood vessels," said Dr. Frenkel, who collaborated on this project with Professor Howard L. Weiner of Brigham and Women's Hospital, Harvard Medical School. "In early pre-clinical studies, we've found it can prevent both brain tissue damage and restore cognitive impairment," Dr. Frenkel added. Modifying a vaccine technology owned by Glaxo Smith Kline, a multinational drug company, Tel Aviv University's new therapeutic approach activates a natural mechanism in our bodies that fights against vascular damage in the brain. The vaccine, Dr. Frenkel explained, activates macrophages — phagocytic cells in the body that swallow foreign antigens. When the vaccine activates large numbers of these macrophages, they clear away the damaging build-up of waxy amyloid proteins in the brain's vascular system. Studies in animal models showed that once these proteins are cleared from the brain, further damage can be prevented, and existing damage due to a previous stroke can be repaired.

Two Genes for "Binge Drinking" Identified

Scientists at the University of Maryland Medical School and the Medical University Vienna have identified two genes associated with binge drinking, a discovery that may pave the way toward new, more effective treatments of excessive alcohol consumption. The scientists found that manipulating two receptors in the brain, GABA receptors and toll-like receptor 4 (TLR4), "caused profound reduction" of binge drinking for two weeks in rodents that had been bred and trained to drink excessively. About 30 percent of Americans who drink do so excessively, and about 75,000 people die each year from the effects of excessive drinking. Current treatments for excessive alcohol drinking include prescription drugs Revia and Campral for controlling cravings. To ease withdrawal symptoms, doctors often prescribe medications such as Valium and Librium that carry their own risks of addiction. Valium and Librium reduce the anxiety alcoholics feel when they stop drinking but do not reduce cravings for alcohol. The new study found that treatments that manipulate both the GABA receptor and TLR4 have the potential to reduce anxiety and control cravings, with little to no risk for addiction, according to lead investigator Dr. Harry June, professor of psychiatry and pharmacology and experimental therapeutics at the University of Maryland School of Medicine.

Stem Cell Study Shows Link Between Rare Lung Disease and Blood Cell Abnormalities

Results from a recent study have revealed a close relationship between pulmonary arterial hypertension (PAH)—a rare and deadly disease characterized by exceedingly high blood pressure in the arteries carrying blood from the heart to the lungs—and abnormalities of the blood-forming cells in the bone marrow (known as myeloid abnormalities). The study, which was conducted by a team of researchers at the Cleveland Clinic and Vanderbilt University, showed that blood progenitor cells (cells that are capable of forming white blood cells, red blood cells, or platelets in the bone marrow and are reported to affect blood vessel formation), are increased in the bone marrow, blood, and lungs of patients with PAH. These findings suggest that the disease processes in the bone marrow and the lungs are related. “This research pieces together a number of previous studies and observations suggesting a very close relationship between PAH and underlying bone marrow abnormalities,” said Dr. Serpil Erzurum, a co-author of the study and Chair of the Department of Pathobiology at the Cleveland Clinic. “Our study honed in on the stem cells involved in blood vessel maintenance to identify factors that might be involved in bone marrow stem cell abnormalities as well as progressive arterial disease.”

Compound Studied in Birth Defects May Be Useful Against Cancer

A compound being studied in the investigation of intestinal birth defects may prove useful in fighting cancer, according to the results of a recent study published in the February 25 issue of Chemistry & Biology. During the screening of chemical compounds created by North Carolina State chemist Dr. Alex Deiters, developmental biologist Dr. Nanette Nascone-Yoder found one of particular interest to her research: a compound that induced heterotaxia, a disordering or mirror-image “flipping” of internal organs, in the frog embryos she was studying. Dr. Nascone-Yoder is particularly interested in the genetic processes involved in proper formation of the gut tube, which later becomes the intestinal tract. “For the intestinal tract to form properly, it has to develop asymmetrically. This compound disrupts asymmetry, so it could be quite useful in helping us to determine when and where intestinal development goes wrong in embryos,” Dr. Nascone-Yoder said. But the compound, dubbed “heterotaxin” by the researchers, had effects beyond just inducing heterotaxia. “We also noticed that the compound prevents normal blood-vessel formation and prevents cells from migrating by increasing cellular adhesion – basically, the cells are stuck together and can’t move.”

Phase 3 Trial for Promising Melanoma Vaccine

Rush University Medical Center in Chicago is leading a nationwide phase 3 clinical trial to determine whether a promising vaccine for advanced melanoma can effectively treat the deadly skin cancer. An earlier phase 2 trial of the experimental drug involving 50 patients with metastatic melanoma had what were referred to as “stunning results.” Eight patients recovered completely and four partially responded to the vaccine, according to the researchers. "Very few treatment options exist for patients with advanced melanoma, none of them satisfactory, which is why oncologists are so excited about the results we found in our phase 2 study," said Dr. Howard Kaufman, associate dean of Rush Medical College and director of the Rush Cancer Program. Dr. Kaufman is leading the phase 3 study. The vaccine being tested is called OncoVEX, initially developed to combat herpes virus. Researchers discovered accidentally that the vaccine attacked cancerous tissue when it was inadvertently placed in a Petri dish of tumor cells. The vaccine includes an oncolytic virus, a reprogrammed virus that has been converted into a cancer-fighting agent that attacks tumor cells while leaving healthy cells undamaged. OncoVEX also carries biological agents that boost the immune response to melanoma. The vaccine is injected directly into lesions that can be felt or seen, with or without ultrasound. The procedure is generally done in a physician's office. "What really surprised, and encouraged, us was that the vaccine worked not just on the cells we injected, but on lesions in other parts of the body that we couldn't reach," Dr. Kaufman said in commenting on the phase 2 results. "In other words, the vaccine prompted an immune response that was circulated through the bloodstream to distant sites.

Vascularization Pathway Mediated by MicroRNA Is Discovered

Researchers at the University of Massachusetts Medical School and colleagues have discovered a critical step for blood vessel growth in zebrafish embryos, providing new insight into how vascular systems develop and offering a potential therapeutic target for preventing tumor growth, which depends on vascularization. The researchers have identified a novel microRNA-mediated genetic pathway responsible for new blood vessel growth (angiogenesis) in zebrafish embryos. The work provides new insights into how vascular systems use the forces of existing blood flow to initiate the growth of new vessels. Focusing on the development of the fifth and sixth aortic arches in the zebrafish, senior author Dr. Nathan Lawson described how the forces exerted by blood flow on endothelial cells are a critical component for expressing a microRNA that triggers new vessel development. In the early stages of development, when blood flow is present in the aortic vessels, but the vascular linkages between the two arches have yet to be established, the stimulus provided by active blood flow leads to expression of an endothelial-cell specific microRNA (mir-126). In turn, this microRNA turns on vascular endothelial growth factor (VEGF), a chemical signal produced by surrounding cells that normally stimulates angiogenesis. Thus, blood flow allows the endothelial cells to respond to VEGF by growing into new blood vessels. However, when blood flow in the aortic arches was restricted, mir-126 failed to be expressed. In the absence of this microRNA, new blood vessels were unable to develop due to a block in VEGF signaling. "We have known for over a hundred years that blood flow makes new vessels grow," said Dr. Lawson. "But we never really knew how cells in a growing vessel interpreted this signal.

Pancreas Alpha-Cells Can Convert to Insulin-Producing Beta-Cells

In a mouse model, scientists have discovered that alpha-cells in the pancreas, which do not produce insulin, can convert into insulin-producing beta-cells, advancing the prospect of regenerating beta-cells as a cure for type 1 diabetes. The research team, led by senior author Dr. Pedro L. Herrera of the University of Geneva, demonstrated that beta-cells will spontaneously regenerate after near-total beta-cell destruction in mice and the majority of the regenerated beta-cells are derived from alpha-cells that had been reprogrammed, or converted, into beta-cells. Using a unique model of diabetes in mice, in which nearly all of the beta-cells are rapidly destroyed, the researchers found that if the mice were maintained on insulin therapy, beta-cells were slowly and spontaneously restored, eventually eliminating the need for insulin replacement. Alpha-cells normally reside alongside beta-cells in the pancreas and secrete a hormone called glucagon, which works in opposition to insulin to regulate the levels of sugar in the blood. Alpha-cells are not attacked by the autoimmune processes that destroy beta-cells and cause type 1 diabetes. Dr. Andrew Rakeman, the Juvenile Diabetes Research Foundation (JDRF) Program Manager in Beta-Cell Therapies and who was not involved in the research, said that the breakthrough in Dr. Herrera's work is the demonstration that alpha-to-beta-cell reprogramming can be a natural, spontaneous process. "If we can understand the signals that are triggering this conversion, it will open a whole new potential strategy for regenerating beta-cells in people with type 1 diabetes," he said. "It appears that the body can restore beta-cell function either through reprogramming alpha-cells to become beta-cells or, as previously shown by others, by increasing growth of existing beta cells.

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