The Dangerous Zohydro Hits the Market This Week

A few months ago, we wrote about Zohydro – the controversial painkiller approved by the FDA last October. Despite its controversy and attempts to block its release, the opiate hits the market this week. Health care and addiction recovery advocates are still pushing for an appeal, as they fear widespread abuse of the painkiller while opiate abuse has reached epidemic levels in the US.The controversy over Zohydro lies in the fact that it is a pure hydrocodone drug, without acetaminophen or other drugs added to it, making it 5 times stronger than other popularly abused opiates. In addition, it is crushable when most crushable painkillers were taken off the market a few years ago. Large scale efforts were made to remanufacture opiates like Percocet and OxyContin to …

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Dermatologists overuse antibiotics in treatment of skin, soft tissue infections, study shows

Results of a new survey to assess treatment of skin and soft tissue infections shows 90% of dermatologists said they would initially prescribe an antibiotic for a routine, uncomplicated cutaneous abscess; however, guidelines recommend antibiotic use only in complicated cases. Research shows the use of antibiotics for uncomplicated abscesses may contribute to the increased incidence of multi-drug resistant pathogens in the general population. These findings, from researchers at Montefiore Medical Center, were published today in the Journal of Drugs in Dermatology.Methicillin resistant Staphyloccus aureus (MRSA) is now the major source of skin infection in the U.S. These infections are generally uncomplicated at the time of initial presentation and can be managed in the outpatient setting. National guidelines for clinical care indicate incision and drainage (I+D) alone for the primary treatment of uncomplicated skin and soft tissue infections. Antibiotic treatment is recommended after I+D only in certain populations, including those who present with symptoms such as fever, patients who are elderly or very young, patients with abscesses in difficult to drain areas, or patients who do not respond to I+D alone. Nearly all dermatologists surveyed (99%) were capable of performing I+D and were likely to incorporate I+D into their initial treatment alongside antibiotic use.”Dermatologists are reluctant to rely on incision and drainage alone, despite the fact that studies spanning more than 30 years fail to show antibiotics provide added benefit in the treatment of routine skin infections,” said Adam Friedman, M.D., director of dermatologic research, Montefiore, assistant professor of medicine, Albert Einstein College of Medicine of Yeshiva University, and lead author. “These findings shine a light on discrepancies between clinical guidelines and clinical practice at a time when widespread misuse of antibiotics is contributing to the increased role of antibiotic resistance across the country.”This is the first published data on the extent to which dermatologists follow national guidelines in the treatment of abscesses. Other key takeaways reveal gaps in dermatologist adherence to clinical guidelines including the frequent prescription of antibiotics that are ineffective against MRSA and the decreased likelihood of performing I+D procedures on infants.”These results add to a growing body of research suggesting that, across specialties, antibiotics are being used as a safety net in the management of routine skin infections even though incision and drainage alone is the gold standard,” said Dr. Friedman. …

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Researcher turns sights on prostate cancer, tissue engineering, blood vessel repair

When biology and materials science converge, the results can be new materials that can be used to deliver targeted drugs, repair damaged arteries or rebuild failing tissues, such as the anterior cruciate ligament, the ACL injury that can end sports careers. Penn State bioengineer Jian Yang is developing polymers designed to target all three.Tissue engineering with click chemistryFinding the right balance between mechanical strength and elasticity in artificial tissue scaffolding has been problematic, as has been the need to add in the desirable traits of biocompatibility and controlled biodegradability. In a recent article in Advanced Materials, Yang and his colleagues in Penn State’s Department of Biomedical Engineering and the Academy of Orthopedics of Guangdong Province in China report on the use of thermal click chemistry to make crosslinked citrate-based biodegradable elastomers with high mechanical strength (up to 40 MPa of tensile stress) with easy surface biofunctionalization. In comparison, the ACL has a tensile strength of 38 MPa and most biodegradable elastomers have a dry tensile strength below 10MPa. Click chemistry is a relatively new technique used primarily in drug discovery that uses a few reliable reactions to lock or “click” together small units of biomaterials in simple processes. Yang believes that this is the first reported use of click chemistry to design versatile biodegradable elastomers for tissue engineering.Beyond superior mechanical strength, Yang’s click polymers provide user-friendly and site-specific functionalization with bioactive molecules to, for instance, promote cell growth. In addition the click polymers show a desirable type of biodegradability he calls “first slow then fast.” In many tissue engineering applications the preservation of mechanical strength of the artificial scaffolding during the early period of tissue regeneration is important. Yet many elastomeric polymers begin to degrade at a steady rate after implantation. The click polymer in this study, called POC-click-3, had low degradation for a sustained period compared to other polymers, but then rapidly degraded.Yang and colleagues believe that their clickable biodegradable elastomer design will greatly expand the application of biodegradable polymers in areas such as drug delivery, orthopedic fixation devices, tissue engineering and other types of medical implants. The paper, “Click Chemistry Plays a Dual Role in Biodegradable Polymer Design,” was coauthored by Jinshan Guo, Zhiwei Xie, Richard T. …

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Use of testosterone therapy linked to heart attacks in men under 65, study shows

You may have seen one of the many advertisements geared toward men asking if they suffer from “low T” — low testosterone levels that, according to the ads, can result in lost sex drive, diminished energy and moodiness. The answer, they suggest, may be as simple as applying testosterone through a gel or patch.So successful has the marketing for this testosterone therapy been that, according to Drugs.com, an independent medicine website, sales of the testosterone gel Androgel in 2013 exceeded sales of Viagra.Now, a new joint study by UCLA, the National Institutes of Health and Consolidated Research Inc., has shown there is a twofold increase in the risk of a heart attack shortly after beginning testosterone therapy among men under 65 who have a history of heart disease. Further, the study confirmed earlier studies that found a twofold increase in heart attack risk shortly after treatment began in men older than 65.The study, the largest to date examining heart disease in men using testosterone supplements, appears in the Jan. 29 online edition of the journal PLOS ONE.The research was prompted by three small, earlier studies that raised concerns about possible adverse cardiovascular outcomes associated with testosterone therapy. These included a randomized clinical trialofmen older than 65, which was reported in the New England Journal of Medicine and was stopped in 2010 due to a variety of cardiovascular events.”We decided to investigate cardiovascular risks of this therapy in a large health care database since these previous studies were modest in size and only focused on men 65 and older,” said the study’s senior author, Sander Greenland, a professor of epidemiology at the UCLA Fielding School of Public Health and a professor of statistics in the UCLA College of Letters and Science. “Our study allowed us to examine cardiovascular risk in men under the age of 65 and to replicate the findings in men over 65.”Greenland and his colleagues used data from Truven Health Analytics, which aggregates information on patient care. They examined the health care records of 55,593 men who had been prescribed testosterone therapy — 48,539 under the age of 65 and 7,054 who were 65 or older. Their research led to the finding of a twofold increase in men under 65 with heart disease and confirmed the earlier findings of a twofold increase in men over 65 with or without heart disease.”The extensive and rapidly increasing use of testosterone treatment and the evidence of risk of heart attack underscore the urgency of further large studies of the risks and the benefits of this treatment,” Greenland said. “Patients and their physicians should discuss the risk of heart attacks when considering testosterone therapy.”Story Source:The above story is based on materials provided by University of California – Los Angeles. The original article was written by Mark Wheeler. …

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New Harm Reduction Measure: Medication to Fight HIV Transmission in IDUs

New Harm Reduction Measure: Medication to Fight HIV Transmission in IDUsOctober 2nd 2013 | By: Staff | Posted In: Drugs and Alcohol, Recent NewsA treatment called pre-exposure prophylaxis (PrEP) has proven to be a significant assistance in protecting those individuals who use needles to inject drugs, also known as intravenous drug users, or IDUs. Addicts who utilize needles are at continual risk for a myriad of diseases, including HIV.A study conducted with 2,400 drug users in Bangkok, Thailand concluded that those individuals who ingested tenofovir pills or the PrEP treatment on a daily basis decreased their chance of acquiring the HIV virus by 74 percent. The exciting findings from this study will likely lead to other studies on the safety and validity of the PrEP treatment in acting …

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5 Patients Dead in 2 Years: Is Dr. Drew to Blame for the Loss of Celebrities From Celebrity Rehab?

5 Patients Dead in 2 Years: Is Dr. Drew to Blame for the Loss of Celebrities From Celebrity Rehab?October 6th 2013 | By: Staff | Posted In: Drugs and Alcohol, Recent NewsCritics of Dr. Drew Pinsky (known to viewers as just Dr. Drew) say that rehabilitation should be a private matter and not one that is aired on radio or television. With the recent suicide of Mindy McCready, former country singer, Dr. Drew has found himself the subject of a sudden onslaught of outrage. Many say that his televised rehab reality show is tantamount to exploitation and may only exacerbate the problems of his troubled patients.Ms. McCready was on Dr. Drew’s VH1 reality show Celebrity Rehab and is the fifth participant of that show to die due to…

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Patient embraces personalized approach to lung cancer diagnosis

Sep. 10, 2013 — As a woman in her mid-forties who didn’t smoke, Elizabeth Lacasia never expected to be diagnosed with lung cancer. But in 2006, after she developed a persistent and serious cough, a chest X-ray and CT scan revealed several tumors in her lower left lung.She was eventually diagnosed with stage IV lung cancer, a rare subtype called “bronchioalveolar carcinoma.” Over the next 18 months, she underwent two surgeries followed by a tough combination of a targeted drug treatment and two chemotherapies. Yet the cancer continued to spread. As it turned out, the chemotherapy she was taking was later found to be ineffective against her cancer, although it caused significant side effects.Lacasia, who was an avid rollerblader, a snow skier and had a successful career with a biotech oncology company, was not a woman who gave up easily. She contacted David Gandara, a nationally recognized lung cancer expert and senior advisor for clinical research at the UC Davis Comprehensive Cancer Center.Gandara is known for his emphasis on “personalized treatment” using information available through genetic testing of a patient’s tumor to find the most effective therapies. Lacasia underwent a battery of molecular and genetic tests to help identify whether her cancer would respond to drugs designed to target specific genetic mutations in her cancer. These tests can also reveal which chemotherapies might be most effective in fighting a patient’s tumor.”The genetic testing panel I underwent at UC Davis was very cutting-edge, and it provided important information about how to effectively treat my cancer,” Lacasia now says.In Lacasia’s case, the molecular and genetic tests revealed that her cancer was a “wild type,” meaning it did not have the mutations that can cause some lung cancers to take hold and spread, and which can be effectively targeted by new state-of-the-art medications. So Gandara recommended a clinical trial that used an approach now proven effective for people with Lacasia’s “wild type” cancer.Instead of just one medication, patients like Lacasia in the clinical trial received two drugs, usually considered ineffective when used together. Yet in the clinical trial, Lacasia took the two drugs — erlotinib (Tarceva) and pemetrexed (Alimta) — in a novel alternating schedule that Gandara knew from experience could help treat Lacasia’s cancer. …

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Molecular marker predicts patients most likely to benefit longest from two popular cancer drugs

Sep. 5, 2013 — Johns Hopkins scientists have identified a molecular marker called “Mig 6″ that appears to accurately predict longer survival — up to two years — among patients prescribed two of the most widely used drugs in a class of anticancer agents called EGFR inhibitors.The U.S. Food and Drug Administration-approved drugs, gefitinib (Iressa) and erlotinib (Tarceva), are prescribed for lung and pancreatic cancer patients but only a few who have mutations in the EGFR gene usually benefit with a prolonged reduction of tumor size. The two drugs block the gene’s ramped-up protein production, but patients’ response to the drug varies widely — from no survival benefit to several years. The average is several months.”Clinicians have had no reliable method for distinguishing patients who are not likely to respond to EGFR inhibitors and those who will respond very well,” says David Sidransky, M.D., professor of otolaryngology, oncology, pathology, urology, and genetics at Johns Hopkins. Looking at the precise level of protein production from the EGFR gene alone in specific patients was not proven to be a good indicator of patients’ response to EGFR-blocking drugs, but the presence or absence of Mig 6 might be, he adds.In a preliminary study, described July 31 in the online journal, PLoS ONE, the Johns Hopkins scientists found the genetic marker in a series of experiments that began with laboratory-derived lung and head and neck cancer cell lines resistant to EGFR-inhibitor drugs. In the cell lines, the team found very high levels of protein production from the Mig 6 gene — up to three times the level in sensitive cell lines. Mig 6 is one of the molecules that controls the activity of the EGFR protein.”In the first set of experiments, we found that higher levels of Mig 6 occur often in cells that don’t respond to EGFR inhibitors,” says Sidransky. “Most tumors are known to have high Mig 6 levels and are not expected to respond to EGFR inhibitors.”Next, the research team studied Mig 6 levels in a variety of tumors that were directly engrafted into mice, a research model known as a xenograft, and treated with an EGFR inhibitor. These new models contain a more complete sampling of the tumor that includes “stromal” cells, which surround and interact with the cancer cells. …

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DNA ‘cages’ may aid drug delivery

Sep. 1, 2013 — Nanoscale “cages” made from strands of DNA can encapsulate small-molecule drugs and release them in response to a specific stimulus, McGill University researchers report in a new study.The research, published online Sept. 1 in Nature Chemistry, marks a step toward the use of biological nanostructures to deliver drugs to diseased cells in patients. The findings could also open up new possibilities for designing DNA-based nanomaterials.”This research is important for drug delivery, but also for fundamental structural biology and nanotechnology,” says McGill Chemistry professor Hanadi Sleiman, who led the research team.DNA carries the genetic information of all living organisms from one generation to the next. But strands of the material can also be used to build nanometre-scale structures. (A nanometre is one billionth of a metre — roughly one-100,000th the diameter of a human hair.)In their experiments, the McGill researchers first created DNA cubes using short DNA strands, and modified them with lipid-like molecules. The lipids can act like sticky patches that come together and engage in a “handshake” inside the DNA cube, creating a core that can hold cargo such as drug molecules.The McGill researchers also found that when the sticky patches were placed on one of the outside faces of the DNA cubes, two cubes could attach together. This new mode of assembly has similarities to the way that proteins fold into their functional structures, Sleiman notes. “It opens up a range of new possibilities for designing DNA-based nanomaterials.”Sleiman’s lab has previously demonstrated that gold nanoparticles can be loaded and released from DNA nanotubes, providing a preliminary proof of concept that drug delivery might be possible. But the new study marks the first time that small molecules — which are considerably smaller than the gold nanoparticles — have been manipulated in such a way using a DNA nanostructure, the researchers report.DNA nanostructures have several potential advantages over the synthetic materials often used to deliver drugs within the body, says Thomas Edwardson, a McGill doctoral student and co-author of the new paper. …

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Conditions most likely to kill encephalitis patients identified

Aug. 20, 2013 — People with severe encephalitis — inflammation of the brain — are much more likely to die if they develop severe swelling in the brain, intractable seizures or low blood platelet counts, regardless of the cause of their illness, according to new Johns Hopkins research.The Johns Hopkins investigators say the findings suggest that if physicians are on the lookout for these potentially reversible conditions and treat them aggressively at the first sign of trouble, patients are more likely to survive.”The factors most associated with death in these patients are things that we know how to treat,” says Arun Venkatesan, M.D., Ph.D., an assistant professor of neurology at the Johns Hopkins University School of Medicine and leader of the study published in the Aug. 27 issue of the journal Neurology.Experts consider encephalitis something of a mystery, and its origins and progress unpredictable. While encephalitis may be caused by a virus, bacteria or autoimmune disease, a precise cause remains unknown in 50 percent of cases. Symptoms range from fever, headache and confusion in some, to seizures, severe weakness or language disability in others. The most complex cases can land patients in intensive care units, on ventilators, for months. Drugs like the antiviral acyclovir are available for herpes encephalitis, which occurs in up to 15 percent of cases, but for most cases, doctors have only steroids and immunosuppressant drugs, which carry serious side effects.”Encephalitis is really a syndrome with many potential causes, rather than a single disease, making it difficult to study,” says Venkatesan, director of the Johns Hopkins Encephalitis Center.In an effort to better predict outcomes for his patients, Venkatesan and his colleagues reviewed records of all 487 patients with acute encephalitis admitted to The Johns Hopkins Hospital and Johns Hopkins Bayview Medical Center between January 1997 and July 2011. They focused further attention on patients who spent at least 48 hours in the ICU during their hospital stays and who were over the age of 16. Of those 103 patients, 19 died. Patients who had severe swelling in the brain were 18 times more likely to die, while those with continuous seizures were eight times more likely to die. …

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LSD and other psychedelics not linked with mental health problems

Aug. 19, 2013 — The use of LSD, magic mushrooms, or peyote does not increase a person’s risk of developing mental health problems, according to an analysis of information from more than 130,000 randomly chosen people, including 22,000 people who had used psychedelics at least once.Researcher Teri Krebs and clinical psychologist Pål-Ørjan Johansen, from the Norwegian University of Science and Technology’s (NTNU) Department of Neuroscience, used data from a US national health survey to see what association there was, if any, between psychedelic drug use and mental health problems.The authors found no link between the use of psychedelic drugs and a range of mental health problems. Instead they found some significant associations between the use of psychedelic drugs and fewer mental health problems.The results are published in the journal PLOS ONE and are freely available online after 19 August.Symptoms and mental health treatment consideredThe researchers relied on data from the 2001-2004 National Survey on Drug Use and Health, in which participants were asked about mental health treatment and symptoms of a variety of mental health conditions over the past year. The specific symptoms examined were general psychological distress, anxiety disorders, mood disorders, and psychosis.Armed with this information, Krebs and Johansen were able to examine if there were any associations between psychedelic use and general or specific mental health problems. They found none.”After adjusting for other risk factors, lifetime use of LSD, psilocybin, mescaline or peyote, or past year use of LSD was not associated with a higher rate of mental health problems or receiving mental health treatment,” says Johansen.Could psychedelics be healthy for you?The researchers found that lifetime use of psilocybin or mescaline and past year use of LSD were associated with lower rates of serious psychological distress. Lifetime use of LSD was also significantly associated with a lower rate of outpatient mental health treatment and psychiatric medicine prescription.The design of the study makes it impossible to determine exactly why the researchers found what they found.”We cannot exclude the possibility that use of psychedelics might have a negative effect on mental health for some individuals or groups, perhaps counterbalanced at a population level by a positive effect on mental health in others,” they wrote.Nevertheless, “recent clinical trials have also failed to find any evidence of any lasting harmful effects of psychedelics,” the researchers said, which supports the robustness of the PLOS ONE findings.In fact, says Krebs, “many people report deeply meaningful experiences and lasting beneficial effects from using psychedelics.””Other studies have found no evidence of health or social problems among people who had used psychedelics hundreds of times in legally-protected religious ceremonies,” adds Johansen.What’s the bottom line on psychedelic use?Psychedelics are different than most other recreational drugs. Experts agree that psychedelics do not cause addiction or compulsive use, and they are not known to harm the brain.When evaluating psychedelics, as with any activity, it is important to take an objective view of all the evidence and avoid being biased by anecdotal stories either of harm or benefit, the researchers say.”Everything has some potential for negative effects, but psychedelic use is overall considered to pose a very low risk to the individual and to society,” Johansen says, “Psychedelics can elicit temporary feelings of anxiety and confusion, but accidents leading to serious injury are extremely rare.””Early speculation that psychedelics might lead to mental health problems was based on a small number of case reports and did not take into account either the widespread use of psychedelics or the not infrequent rate of mental health problems in the general population,” Krebs explains.”Over the past 50 years tens of millions of people have used psychedelics and there just is not much evidence of long-term problems,” she concludes.Both researchers were supported by the Research Council of Norway.

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Research shows negative effects of half-siblings

Aug. 11, 2013 — Adolescents who have half-siblings with a different father are more likely to have used drugs and had sex by age 15 than those who have only full siblings. That’s according to new research from Karen Benjamin Guzzo, an assistant professor of sociology at Bowling Green State University, and Cassandra Dorius, an assistant professor of human development and family studies at Iowa State University.Using data from the National Longitudinal Study of Youth, they examined a phenomenon known as “multi-partnered fertility” or MPF. This happens when parents who are not romantically involved with each other form new relationships and have another child with a new partner.”It’s not new behavior, but it’s happening more often as more people are having children outside of marriage,” said Guzzo.According to Guzzo, this is one of the first studies to examine the effect of parental MPF on children over the long-term, and the only study that takes into account background factors (such as the mother’s level of education and household poverty) and the number of changes in family structure the adolescent experienced.The researchers looked at the connections between this re-partnering and additional childbearing on adolescent drug use and early sex. They focused on mothers and first-born children who lived with their mother most of their lives.”For children, MPF means having a half-sibling, but it also means, for first-born children, that they usually experienced their biological parents splitting up — if they were together at all, lived in a single mother household for some time, experienced their mother finding a new partner at least once and perhaps lived with a stepfather, and finally experienced their mother having a baby with a new partner,” Guzzo explained.Researchers looked at the mother’s educational background, her own family structure growing up, and whether the child experienced bouts of poverty. They also examined family factors — whether the father lived with them at birth, how many family transitions the adolescents experienced, and whether the mother ever married or cohabited, with the child’s father or another partner.”We find that first-born adolescents with half-siblings with the same mother but a different father do have less favorable outcomes compared to their peers with only full siblings, even after accounting for the mother’s background characteristics, socioeconomic factors the child experienced growing up, and family instability and structure,” Guzzo said.”Adolescents with a half-sibling with a different father are about 65 percent more likely to have used marijuana, uppers, inhalants, cocaine, crack, hallucinogens, sedatives, or other drugs by the time of their 15th birthday than those who have only full siblings. They are also about 2.5 times more likely to have had sex by their 15th birthday than their peers with only full siblings.”Guzzo said it’s not clear yet what drives these outcomes, but that in the future she and Dorius plan to explore differences in maternal behaviors, father and stepfather involvement, and adolescent perceptions of their relationship with their mother to see if these factors explain the association between having half-siblings with a different father and risky adolescent behavior.”We are also planning to look at whether this association holds for children other than the first-born, who tend to experience the most instability,” Guzzo said.

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Why tumors become drug-resistant

Aug. 6, 2013 — Cancer drugs known as ErbB inhibitors have shown great success in treating many patients with lung, breast, colon and other types of cancer. However, ErbB drug resistance means that many other patients do not respond, and even among those who do, tumors commonly come back.A new study from MIT reveals that much of this resistance develops because a protein called AXL helps cancer cells to circumvent the effects of ErbB inhibitors, allowing them to grow unchecked. The findings suggest that combining drugs that target AXL and ErbB receptors could offer a better way to fight tumors, says Doug Lauffenburger, the Ford Professor of Bioengineering, head of MIT’s Department of Biological Engineering and an affiliate member of MIT’s Koch Institute for Integrative Cancer Research.”Drug resistance is the major challenge in cancer these days. People are coming up with a lot of targeted therapies for particular genes and identifying drugs that work against them, but resistance is just invariably the issue,” says Lauffenburger, the senior author of a paper describing the findings in the Aug. 6 issue of Science Signaling.ErbBs, a family of epithelial growth factor receptors (EGFRs), are proteins that are often overactive in cancer cells, causing them to grow and divide uncontrollably. The drug Iressa is used to treat lung cancer patients whose tumors overexpress one type of ErbB mutant, and Herceptin targets another ErbB family member that is found in certain types of breast cancer.”There are a lot of excellent drugs that target EGFR itself or other members of that family, yet they have these limitations,” Lauffenburger says.Systems analysisIn the new study, Lauffenburger and colleagues set out to identify factors that help tumor cells become resistant to EGFR and other ErbB inhibitors. To do this, they developed a new computer model and applied it to a large dataset called the Cancer Cell Line Encyclopedia, which includes information on about 1,000 human cancer lines and their responses to different drugs.Led by biological engineering graduate student Aaron Meyer, lead author of the paper, the researchers created a machine learning program that can sift through the data and look for pairs of overexpressed proteins that make tumor cells resistant to EGFR inhibitors. In this case, they searched for the EGFR protein in combination with every other possible protein in the database, one pair at a time.Through this analysis, the researchers found that EGFR paired with the AXL receptor appears to be the strongest marker for EGFR inhibitor resistance. They found this pattern across many types of cancer, including lung, breast and pancreatic.A few previous studies have shown that overexpression of AXL is associated with resistance to EGFR inhibitors in a particular tumor, but this is the first systematic study to demonstrate the correlation, Lauffenburger says. …

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Genes that drive brain cancer revealed

Aug. 5, 2013 — A team of researchers at the Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center has identified 18 new genes responsible for driving glioblastoma multiforme, the most common — and most aggressive — form of brain cancer in adults.The study was published August 5, 2013, in Nature Genetics.”Cancers rely on driver genes to remain cancers, and driver genes are the best targets for therapy,” said Antonio Iavarone, MD, professor of pathology and neurology at Columbia University Medical Center and a principal author of the study.”Once you know the driver in a particular tumor and you hit it, the cancer collapses. We think our study has identified the vast majority of drivers in glioblastoma, and therefore a list of the most important targets for glioblastoma drug development and the basis for personalized treatment of brain cancer.”Personalized treatment could be a reality soon for about 15 percent of glioblastoma patients, said Anna Lasorella, MD, associate professor of pediatrics and of pathology & cell biology at CUMC.”This study — together with our study from last year, Research May Lead to New Treatment for Type of Brain Cancer — shows that about 15 percent of glioblastomas are driven by genes that could be targeted with currently available FDA-approved drugs,” she said. “There is no reason why these patients couldn’t receive these drugs now in clinical trials.”New Bioinformatics Technique Distinguishes Driver Genes from Other MutationsIn any single tumor, hundreds of genes may be mutated, but distinguishing the mutations that drive cancer from mutations that have no effect has been a longstanding problem for researchers.The Columbia team used a combination of high throughput DNA sequencing and a new method of statistical analysis to generate a short list of driver candidates. The massive study of nearly 140 brain tumors sequenced the DNA and RNA of every gene in the tumors to identify all the mutations in each tumor. A statistical algorithm designed by co-author Raul Rabadan, PhD, assistant professor of biomedical informatics and systems biology, was then used to identify the mutations most likely to be driver mutations. The algorithm differs from other techniques to distinguish drivers from other mutations in that it considers not only how often the gene is mutated in different tumors, but also the manner in which it is mutated.”If one copy of the gene in a tumor is mutated at a single point and the second copy is mutated in a different way, there’s a higher probability that the gene is a driver,” Dr. Iavarone said.The analysis identified 15 driver genes that had been previously identified in other studies — confirming the accuracy of the technique — and 18 new driver genes that had never been implicated in glioblastoma.Significantly, some of the most important candidates among the 18 new genes, such as LZTR1 and delta catenin, were confirmed to be driver genes in laboratory studies involving cancer stem cells taken from human tumors and examined in culture, as well as after they had been implanted into mice.A New Model for Personalized Cancer TreatmentBecause patients’ tumors are powered by different driver genes, the researchers say that a complicated analysis will be needed for personalized glioblastoma treatment to become a reality. First, all the genes in a patient’s tumor must be sequenced and analyzed to identify its driver gene.”In some tumors it’s obvious what the driver is; but in others, it’s harder to figure out,” said Dr.Iavarone.Once the candidate driver is identified, it must be confirmed in laboratory tests with cancer stem cells isolated from the patient’s tumor.About 15 percent of glioblastoma driver genes can be targeted with currently available drugs, suggesting that personalized treatment for some patients may be possible in the near future. Personalized therapy for glioblastoma patients could be achieved by isolating the most aggressive cells from the patient’s tumor and identifying the driver gene responsible for the tumor’s growth (different tumors will be driven by different genes). …

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Close-up view of water pores needed in the eye’s lens: Aquaporins could hold clues to cataract

Aug. 5, 2013 — Researchers have achieved dynamic, atomic-scale views of a protein needed to maintain the transparency of the lens in the human eye. The work, funded in part by the National Institutes of Health, could lead to new insights and drugs for treating cataract and a variety of other health conditions.Aquaporin proteins form water channels between cells and are found in many tissues, but aquaporin zero (AQP0) is found only in the mammalian lens, which focuses light onto the retina, at the back of the eye. The lens is primarily made up of unique cells called lens fibers that contain little else besides water and proteins called crystallins. Tight packing of these fibers and of the crystallin proteins within them helps create a uniform medium that allows light to pass through the lens, almost as if it were glass.Abnormal development or age-related changes in the lens can lead to cataract — a clouding of the lens that causes vision loss. Besides age, other risk factors for cataract include smoking, diabetes, and genetic factors. Mutations in the AQP0 gene can cause congenital cataract and may increase the risk of age-related cataract.”The AQP0 channel is believed to play a vital role in maintaining the transparency of the lens and in regulating water volume in the lens fibers, so understanding the molecular details of how water flows through the channel could lead to a better understanding of cataract,” said Dr. Houmam Araj, who oversees programs on lens, cataract and oculomotor systems at NIH’s National Eye Institute (NEI), which helped fund the research.Closing of AQP0 channels is regulated by a calcium-sensitive protein called calmodulin, but the precise mechanism has been unclear. Some models have suggested that calmodulin simply acts as a plug to fill the open channel. The new study, published in Nature Structural and Molecular Biology, reveals a more nuanced process in which calmodulin essentially grasps the open channel and forces it to close.The research was a collaboration between investigators at the University of California, Irvine and the Janelia Farm Research Campus in Ashburn, Va., a part of the Howard Hughes Medical Institute (HHMI). …

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Statins suppress Rett syndrome symptoms in mice

July 29, 2013 — Statins, a class of cholesterol-lowering drugs found in millions of medicine cabinets, may help treat Rett Syndrome, according to a study published today in Nature Genetics. The Rett Syndrome Research Trust (RSRT) funded this work with generous support from the Rett Syndrome Research Trust UK and Rett Syndrome Research & Treatment Foundation.Rett Syndrome is a neurological disorder that affects girls. A seemingly typical toddler begins to miss developmental milestones. A regression follows as young girls lose speech, mobility, and hand use. Many girls have seizures, orthopedic and severe digestive problems, as well as breathing and other autonomic impairments. Most live into adulthood and require total, round-the-clock care. Rett Syndrome affects about 1 in 10,000 girls born in the U.S. each year.The new study screened for randomly induced mutations in genes that modify the effect of the Rett gene, MECP2 (methyl-CpG-binding protein 2), in a mouse model. MECP2 turns other genes on or off by disrupting chromatin, the DNA-protein mix that makes up chromosomes.The challenge of treating Rett Syndrome is what drove senior author Monica Justice, Ph.D., Professor in the Departments of Molecular and Human Genetics and Molecular Physiology and Biophysics at the Baylor College of Medicine, to look beyond MECP2, hoping to find new drug targets that might improve symptoms or even reverse the course of the disease. In 2007, Adrian Bird, Ph.D., Buchanan Professor of Genetics at the Wellcome Trust Centre for Cell Biology at the University of Edinburgh, showed that symptoms in mice are reversible regardless of the age of the animal.Exploring cholesterol metabolism in neurological diseases is an emerging area, with statin drugs being tested in fragile X syndrome, neurofibromatosis, amyotrophic lateral sclerosis, and other conditions. …

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Water molecules control inactivation and recovery of potassium channels

July 28, 2013 — Just 12 molecules of water cause the long post-activation recovery period required by potassium ion channels before they can function again. Using molecular simulations that modeled a potassium channel and its immediate cellular environment, atom for atom, University of Chicago scientists have revealed this new mechanism in the function of a nearly universal biological structure, with implications ranging from fundamental biology to the design of pharmaceuticals.Their findings were published online July 28 in Nature.”Our research clarifies the nature of this previously mysterious inactivation state. This gives us better understanding of fundamental biology and should improve the rational design of drugs, which often target the inactivated state of channels” said Benoît Roux, PhD, professor of biochemistry and molecular biology at the University of Chicago.Potassium channels, present in the cells of virtually living organisms, are core components in bioelectricity generation and cellular communication. Required for functions such as neural firing and muscle contraction, they serve as common targets in pharmaceutical development.These proteins act as a gated tunnel through the cell membrane, controlling the flow of small ions into and out of cells. After being activated by an external signal, potassium channels open to allow ions through. Soon after, however, they close, entering an inactive state and are unable to respond to stimuli for 10 to up to 20 seconds.The cause of this long recovery period, which is enormously slow by molecular standards, has remained a mystery, as structural changes in the protein are known to be almost negligible between the active and inactivated states — differing by a distance equivalent to the diameter of a single carbon atom.To shed light on this phenomenon, Roux and his team used supercomputers to simulate the movement and behavior of every individual atom in the potassium channel and its immediate environment. After computations corresponding to millions of core-hours, the team discovered that just 12 water molecules were responsible for the slow recovery of these channels.They found that when the potassium channel is open, water molecules quickly bind to tiny cavities within the protein structure, where they block the channel in a state that prevents the passage of ions. The water molecules are released slowly only after the external stimulus has been removed, allowing the channel to be ready for activation again. This computer simulation-based finding was then confirmed through osmolarity experiments in the laboratory.”Observing this was a complete surprise, but it made a lot of sense in retrospect,” Roux said. “Better understanding of this ubiquitous biological system will change how people think about inactivation and recovery of these channels, and has the potential to someday impact human health.”

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Chemical reaction could streamline manufacture of pharmaceuticals and other compounds

July 22, 2013 — Researchers at The University of Texas at Austin have discovered a new chemical reaction that has the potential to lower the cost and streamline the manufacture of compounds ranging from agricultural chemicals to pharmaceutical drugs.The reaction resolves a long-standing challenge in organic chemistry in creating phenolic compounds from aromatic hydrocarbons quickly and cheaply.Phenolic compounds, or phenols, are broadly used as disinfectants, fungicides and drugs to treat many ailments such as Parkinson’s disease. Creating a phenol seems deceptively simple. All it requires is replacing a hydrogen molecule on an aromatic hydrocarbon with an oxygen molecule.”This is a chemical transformation that is underdeveloped and at the same time pivotal in the production of many chemicals important to life as we know it,” said Dionicio Siegel, an assistant professor of chemistry in the College of Natural Sciences at The University of Texas at Austin.The secret that Siegel and his colleagues discovered is a substance called phthaloyl peroxide. This chemical was studied in the late 1950s and early 1960s, but it has been largely ignored during the intervening years.The scientists were conducting basic studies on phthaloyl peroxide, building on previous research, and decided to use it to tackle the age-old problem of transforming aromatic hydrocarbons into phenols.The advantage to using phthaloyl peroxide is that the reaction does not require the use of acids or catalysts to work, and it can add oxygen to a wide variety of starting materials.”There are no special conditions,” said Siegel. “You just combine the reagents, mix them and go. It’s very simple and straight forward.”The paper describing this discovery was published last week in Nature.The new process can be applied to other problems in organic chemistry. One particular area of interest is creating metabolites to drugs. Metabolites are the products left after the body finishes breaking down, or metabolizing, a substance. When testing drugs, scientists need to take into account not just how the drug itself reacts in the body, but also how the metabolites react.”We’ve had a long-standing interest in accessing metabolites of drugs or compounds that are used in biological systems,” said Siegel. “Just as it’s important that the drug doesn’t have deleterious side effects, it’s equally important that the metabolite doesn’t have an effect. …

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Study lays groundwork for norovirus anti-viral treatments

July 22, 2013 — An animal model of the human norovirus created at the University of Michigan Health System lays the groundwork for understanding the biology of the pesky virus and developing antiviral drug treatment.Well-known as the virus that impacts cruise ship vacations, norovirus leads to misery on land too. The virus spreads quickly from person to person in any closed-in space, such as schools, nursing homes, or day-care centers.”The first virus in this group was discovered in 1972 following a disease outbreak at a school in Norwalk, Ohio in 1968. Since then research has been underway to culture noroviruses in the laboratory and develop animal models,” says lead researcher Christiane Wobus, Ph.D., assistant professor in the Department of Microbiology and Immunology at the University of Michigan Medical School.An international group of scientists from the U.S. and Germany authored the study published in mBIO, a journal of the American Society of Microbiology.”Norovirus research has been hampered by the absence of a norovirus cell culture and a genetically manipulable small animal model,” Wobus says. “This new model gives us the tool to test potential antiviral compounds and may lay the foundation to culture these viruses in the lab.”The new model was developed by determining whether human noroviruses can infect “humanized” mice, that is mice containing human immune cells. These mice are widely used for study of the human immunodeficiency virus (HIV), a virus which can only infect human cells.The study identified macrophages, a vital immune cell in the body, as the cell type infected by the virus.Very few particles of the virus can lead to infection. Estimates are as few as 18 particles can cause gastroenteritis (inflammation of the stomach and intestines) and lead to diarrhea, vomiting and stomach pain. In the U.S. norovirus causes approximately 21 million cases of acute gastroenteritis a year, and 800 deaths.”Most people can cope with the symptoms, but deaths are more likely among the elderly mainly because of dehydration,” Wobus says.Only the common cold is more widespread than the norovirus, which can remain on surfaces for weeks, ready to cause more infections. Because it lacks a lipid envelope, norovirus is not susceptible to common disinfectants and alcohol-based sanitizers.The economic impact of these infections is staggering with an economic cost for norovirus associated food-borne outbreaks alone of $5.8 billion in the U.S.There is no vaccine for preventing norovirus infection and no drug to treat it. …

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