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Researchers Find Potential Breast Cancer Application for Widely Used, Anti-Sodium-Channel-Targeting Epilepsy Drug (Phenytoin)

Scientists at the University of York in the UK have discovered that a drug used widely to combat epilepsy has the potential to reduce the growth and spread of breast cancer. Researchers in the Department of Biology at York studied phenytoin, a drug that inhibits epilepsy by targeting sodium channels. These channels, known as VGSCs, exist in the membranes of excitable cells, such as neurons, where they are involved in transmission of electrical impulses. They are also present in breast cancer cells where they are thought to help the spread of tumors. In research published in Molecular Cancer, the York team found that “repurposing” anti-epileptic drugs, such as phenytoin, that effectively block the sodium channels, could provide a novel therapy for cancer. Despite extensive work to define the molecular mechanisms underlying the expression of VGSCs and their pro-invasive role in cancer cells, there is little clinically relevant in vivo data exploring their value as potential therapeutic targets. The researchers found that treatment with phenytoin, at doses equivalent to those used to treat epilepsy significantly reduced tumor growth in a preclinical model. Phenytoin also reduced cancer cell proliferation in vivo and aslso reduced invasion into surrounding mammary tissue. Dr. Will Brackenbury, who led the research, said, “This is the first study to show that phenytoin reduces both the growth and spread of breast cancer tumor cells. This indicates that re-purposing antiepileptic and antiarrhythmic drugs is worthy of further study as a potentially novel anti-cancer therapy.” The research was funded by the Medical Research Council and the University of York. Some of the analysis was carried out by the proteomics team in the University’s Bioscience Technology Facility. The research team also included Michaela Nelson, Ming Yang, Adam A.

The Origin of Life: Water-Filled Pores in Hot Rocks on Sea Floor May Have Served As Crucibles for Formation of First RNA Molecules

Water-filled micropores in hot rock may have acted as the nurseries in which life on Earth began. A team at Ludwig-Maximilians-Universitaet (LMU) in Munich, Germany has now shown that temperature gradients in pore systems promote the cyclical replication and emergence of nucleic acids. How and in what habitats did the first life-forms arise on the young Earth? One crucial pre-condition for the origin of life is that comparatively simple biomolecules must have had opportunities to form more complex structures, which were capable of reproducing themselves and which could store genetic information in a chemically stable form. But this scenario requires some means of accumulating the precursor molecules in highly concentrated form in solution. In the early oceans, such compounds would have been present in vanishingly low concentrations. But LMU physicists, led by Professor Dieter Braun, now describe a setting that provides the necessary conditions. They show experimentally that pore systems on the seafloor that were heated by volcanic activity could have served as reaction chambers for the synthesis of RNA molecules, which serve as carriers of hereditary information in the biosphere today. “The key requirement is that the heat source be localized on one side of the elongated pore, so that the water on that side is significantly warmer than that on the other,” says Dr. Braun. Pre-formed biomolecules that are washed into the pore can then be trapped, and concentrated, by the action of the temperature gradient– thus fulfilling a major prerequisite for the formation and replication of more complex molecular structures. The molecular trapping effect is a consequence of thermophoresis: Charged molecules in a temperature gradient preferentially move from the warmer to the cooler region, allowing longer polymers in particular to be securely trapped.

Structure of Mitochondrial Complex I Determined

Mitochondria produce ATP, the energy currency of the body. The driver for this process is an electrochemical membrane potential, which is created by a series of proton pumps. These complex, macromolecular machines are collectively known as the respiratory chain. The structure of the largest protein complex in the respiratory chain, that of mitochondrial complex I, has now been elucidated by scientists from the Frankfurt "Macromolecular Complexes" cluster of excellence, working together with the scientists at University of Freiburg, by X-ray diffraction analysis. The results were published in the January 2, 2015 issue of Science. "Mitochondrial complex I plays a critical role in the production of cellular energy and has also been associated with the onset of diseases, such as Parkinson's disease," explains Dr. Volker Zickermann, an Assistant Professor at the Institute for Biochemistry II at the Goethe University in Frankfurt am Main, Germany. In order for the respiratory chain to function, there must be consistently sufficient amounts of oxygen available in all the cells in our bodies. The energy released during biological oxidation is used to transport protons from one side of the inner mitochondrial membrane to the other. The resulting proton gradient is the actual "battery" for ATP synthesis. What surprised the researchers was that previous studies had suggested that redox reactions and proton transport in complex I occurred spatially isolated from one another. The Frankfurt scientists in Dr. Zickermann's working group at Goethe University, and the working groups led by Professor Harald Schwalbe and Professor Ulrich Brandt, both also at Goethe University, have now been able to deduce how the two processes are connected to one another from the detailed analysis of the structure.

Chemogenetic Inhibition Shows That Different Areas of Brain Govern Unique Aspects of Vocalization in Singing Zebra Finches

New research published by the Neuronal Mechanism for Critical Period Unit at the Okinawa Institute of Science and Technology Graduate University (OIST) in Okinawa, Japan, together with collarborators, has shown the effectiveness of chemogenetic inhibition used to suppress neuronal activity, as well as interesting results on how vocalization can be controlled through this technique’s application in zebra finches. The research conducted by Professor Yoko Yazaki-Sugiyama and Dr. Shin Yanagihara of the OIST was done in collaboration with scientists from the International Institute for Integrative Sleep Medicine at Tsukuba University and the Division of Sleep Medicine at Harvard University and shows that different areas of the brain govern unique aspects of vocalization. The results were pubished in the January 2015 issue of the European Journal of Neuroscience. The research showed that by silencing neurons in the arcopallium, a region in the brain known to be responsible for song generation, zebra finch songs would become erratic and incomplete. Previous studies that used micro lesions on this area of the brain showed a diminished ability to sing almost all components of a song. The chemogenetic inhibition method revealed, however, that the song was only diminished at specific parts, with only some syllables being affected or absent. The syllables affected differed from bird to bird, however the order of syllables did not change. This suggests that the portion of the brain studied, the arcopallium, is in control of the composition of acoustic structure of songs and not their order or timing. It also demonstrated how precise this neuronal suppression method can be in determining the function of very small groups of neurons.

Researchers Pinpoint Two Genes (ARID1A and PIK3CA ) That Triigger IL-6 and Cause Severest Form of Ovarian Cancer; Show How Known Drug (BKM120) Can Suppress Tumor Growth

In the battle against ovarian cancer, University of North Carolina (UNC) School of Medicine researchers have created the first mouse model of the worst form of the disease and found a potential route to better treatments and much-needed diagnostic screens. Led by Terry Magnuson, Ph.D., the Sarah Graham Kenan Professor and Chair of the Department of Genetics, a team of UNC genetics researchers discovered how two genes interact to trigger cancer and then spur on its development. "It's an extremely aggressive model of the disease, which is how this form of ovarian cancer presents in women," said Dr. Magnuson, who is also a member of the UNC Lineberger Comprehensive Cancer Center. Not all mouse models of human diseases provide accurate depictions of the human condition. Dr. Magnuson's mouse model, though, is based on genetic mutations found in human cancer samples. Mutations in two genes -ARID1A and PIK3CA - were previously unknown to cause cancer. "When ARID1A is less active than normal and PIK3CA is overactive," Dr. Magnuson said, "the result is ovarian clear cell carcinoma 100 percent of the time in our model." The research also showed that a drug called BKM120, which suppresses PI3 kinases, directly inhibited tumor growth and significantly prolonged the lives of mice. The drug is currently being tested in human clinical trials for other forms of cancer. The work, published online on January 27, 2015 in Nature Communications, was spearheaded by Ron Chandler, Ph.D., a postdoctoral fellow in Dr. Magnuson's lab. Dr. Chandler had been studying the ARID1A gene, which normally functions as a tumor suppressor in people, when results from cancer genome sequencing projects showed that the ARID1A gene was highly mutated in several types of tumors, including ovarian clear cell carcinoma. Dr.

The "Fifth Taste" Unami May Play Important & Beneficial Role in Health; Flavour Journal Publishes Provocative Article Series Called “The Science of Taste”

The umami taste could have an important and beneficial role in health, according to research published in the open-access journal Flavour. The journal's special series of articles “The Science of Taste” also finds that “kokumi'”substances, which modify flavor, could improve the taste of low-fat foods. Flavour guest editor Ole Mouritsen, Professor of Biophysics at the University of Southern Denmark, said, "In general, our understanding of taste is inferior to our knowledge of the other human senses. An understanding and description of our sensory perception of food requires input from many different scientific disciplines. In addition to the natural and life sciences, human sciences, social sciences, as well as the arts, each contribute their perspectives on what we call 'taste'. For this special series, we've brought together researchers from a range of different disciplines with the aim of providing a composite mosaic of our current understanding of taste." Despite the widely held belief that monosodium glutamate (MSG) is an unhealthy addition to food, researchers from Tohoku University Graduate School of Dentistry, Japan, show that the taste it triggers, umami, is important for health, especially in elderly people. In a small study of 44 elderly patients, the researchers showed that some elderly patients suffer a loss of the umami taste sensation, and that all of the patients studied complained of appetite and weight loss, resulting in poor overall health. Umami taste receptors also reportedly exist in the gut, suggesting that the umami taste sensation functions in nutrient sensation and modulating digestion in the gut, which could be important for maintaining a healthy daily life.

Using Optogenetics, Columbia Scientists ID Brain's On-Of f Switch for Thirst; Discovery of One SFO Neuron Type Driving Thirst and a Second SFO Neuron Type Suppressing Thirst Could Lead to New Therapies for Dehydration and Excessive Thirst

Neurons that trigger our sense of thirst--and neurons that turn it off--have been identified by Columbia University Medical Center (CUMC) neuroscientists. The paper was published online on January 26, 2014 in Nature. For years, researchers have suspected that thirst is regulated by neurons in the subfornical organ (SFO) in the hypothalamus. But it has been difficult to pinpoint exactly which neurons are involved. "When researchers used electrical current to stimulate different parts of the SFO of mice, they got confusing results," said lead author Yuki Oka, Ph.D., a post-doctoral research scientist in the laboratory of Charles S. Zuker, Ph.D., Professor of Biochemistry and Molecular Biophysics and of Neuroscience, a member of the Kavli Institute for Brain Science and the Mortimer B. Zuckerman Mind Brain Behavior Institute, and a Howard Hughes Medical Institute Investigator at CUMC. The CUMC team hypothesized that there are at least two types of neurons in the SFO, including ones that drive thirst and others that suppress it. "Those electrostimulation experiments were probably activating both types of neurons at once, so they were bound to get conflicting results," said Dr. Oka. To test their hypothesis, Drs. Oka and Zuker turned to optogenetics, a more precise technique for controlling brain activity. With optogenetics, researchers can control specific sets of neurons in the brain after inserting light-activated molecules into them. Shining light onto these molecules turns on the neurons without affecting other types of neurons nearby. These "mind-control" experiments revealed two types of neurons in the SFO that control thirst: CAMKII neurons, which turn thirst on, and VGAT neurons, which turn it off.

FDA Approves Immunotherapy Drug (Opdivo) from Bristol-Myers Squibb for Treatment of Advanced Melanoma

In a December 22, 2014 press release, the U.S. Food and Drug Administration (FDA) announced that it had granted accelerated approval to Opdivo (nivolumab), a new treatment for patients with unresectable (cannot be removed by surgery) or metastatic (advanced) melanoma who no longer respond to other drugs. Three related articles were published in the January 22, 2015 issue of the New England Journal of Medicine (NEJM). Melanoma is the fifth most common type of cancer in the United States. It forms in the body’s melanocyte cells, which develop the skin’s pigment. The National Cancer Institute (NCI) estimates that 76,100 Americans will be diagnosed with melanoma and 9,710 will die from this disease in 2014. Opdivo works by inhibiting the PD-1 protein on cells, which blocks the body’s immune system from attacking melanoma tumors. Opdivo is intended for patients who have been previously treated with ipilimumab and for melanoma patients whose tumors express a gene mutation called BRAF V600, for use after treatment with ipilimumab and a BRAF inhibitor. “Opdivo is the seventh new melanoma drug approved by the FDA since 2011,” said Richard Pazdur, M.D., Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “The continued development and approval of novel therapies based on our increasing understanding of tumor immunology and molecular pathways are changing the treatment paradigm for serious and life-threatening diseases.” Other FDA-approved treatments for melanoma include ipilimumab (2011), peginterferon alfa-2b (2011), vemurafenib (2011), dabrafenib (2013), trametinib (2013), and pembrolizumab (2014).

Researchers Image & Measure Tubulin Transport in Cilia; 400,000 Tubulin Dimers per Minute Transported in Formation of One Cilium, New Study & Video Have Implications for Wide Range of Cilia Dysfunction Diseases, Including PKD

Defective cilia can lead to a host of diseases and conditions in the human body--from rare, inherited bone malformations to blindness, male infertility, kidney disease (e.g., polycystick kidney disease [PKD]), and obesity. Scientists knew that somehow these tiny cell organelles become deformed and cause these diseases because of a problem related to their assembly, which requires the translocation of vast quantities of the vital cell protein tubulin. What they didn't know was how tubulin and another cell organelle known as flagella fit into the process. Now, a new study from University of Georgia (UGA) cell biologists shows the mechanism behind tubulin transport and its assembly into cilia, including the first video imagery of the process (http://jcb.rupress.org/site/biosights/biosights_jan_19_2015.xhtml). The study was published online on January 12, 2015 in the Journal of Cell Biology. "Cilia are found throughout the body, so defects in cilia formation affect cells that line airways, brain ventricles, or the reproductive track," said the study's lead author Julie Craft, a sixth-year doctoral student at UGA. "One of the main causes of male infertility is the cilia won't function properly," Ms. Craft said. An interdisciplinary team from the UGA Franklin College of Arts and Sciences and the UGA College of Engineering collaborated on the research, which used total internal reflection fluorescence microscopy to analyze moving protein particles inside the cilia of Chlamydomonas reinhardtii, a green alga widely used as a model for cilia analysis. The team exploited the natural behavior of the organism--which is to attach by its cilia to a smooth surface, such as a microscope glass cover.

How Pin1 Protein of Tick-Transmitted Tropical Parasite Triggers Formation of Cancer-Like Invasive Cells in Infected Mammals

Scientists from the Université Paris Diderot, Sorbonne Paris Cité, Epigenetics and Cell Fate, in Paris, France, together with collaborators, have pinned down how a dangerous tropical parasite that is transmitted by ticks manages to turn healthy cells into cancer-like invasive cells, according to research published online on January 26, 2015 in Nature. Microscopic Theileria parasites infect the blood of mammals, particularly cattle, causing serious illness. “Evidence that Theileria can infect white blood cells and make them behave like cancer cells was first published In Nature 30 years ago,” says lead researcher Professor Jonathan Weitzman. “Now, we finally think we understand the some important details of how this works. We discovered that, while the parasite is living inside the white blood cell, it secretes a special protein, [a prolyl isomerase] called Pin1. This protein is then able to ‘mess around’ with the cell and trigger mechanisms which control cell behavior –so it starts acting like a cancer cell. We also found that an anti-parasite drug can target this protein and reverse the cancer-like state. This is an exciting example of how parasites hijack the host cell and how these parasite proteins can be targeted by drugs. It also directly links a parasite protein to cancer-causing cell processes, giving us a real insight into how infection with parasites and other organisms might lead to cancer in humans.” Dr. Helen Rippon, Head of Research at Worldwide Cancer Research, which supported the study, said: “Some parasite infections have long been linked to certain types of human cancer. Schistosomiasis, for example, which affects an estimated 240 million people globally, is a known risk factor for bladder cancer - accounting for up to 3 per cent of cases worldwide.

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