BreakThrough Digest Medical News |
- Study finds link between commonly prescribed statin and memory impairment
- Adjusting bacteria in intestines may lead to obesity treatments
- Penn Medicine researchers harness the immune system to fight pancreatic cancer
- Breakthrough offers first direct measurement of spinal cord myelin in multiple sclerosis
- Johns Hopkins researchers erase human brain tumor cells in mice
| Study finds link between commonly prescribed statin and memory impairment Posted: 24 Sep 2013 09:00 PM PDT New research that looked at whether two commonly prescribed statin medicines, used to lower low-density lipoprotein (LDL) or ‘bad cholesterol’ levels in the blood, can adversely affect cognitive function has found that one of the drugs tested caused memory impairment in rats.
Between six and seven million people in the UK1 take statins daily and the findings follow anecdotal evidence of people reporting that they feel that their newly prescribed statin is affecting their memory. Last year, the US Food and Drug Administration (FDA) insisted that all manufacturers list in their side effects that statins might affect cognitive function. The study, led by scientists at the University of Bristol and published in the journal PLOS ONE, tested pravastatin and atorvostatin (two commonly prescribed statins) in rat learning and memory models. The findings show that while no adverse cognitive effects were observed in rat performance for simple learning and memory tasks for atorvostatin, pravastatin impaired their performance. Rats were treated daily with pravastatin (brand name – pravachol) or atorvostatin (brand name – Lipitor) for 18 days. The rodents were tested in a simple learning task before, during and after treatment, where they had to learn where to find a food reward. On the last day of treatment and following one week withdrawal, the rats were also tested in a task which measures their ability to recognise a previously encountered object (recognition memory). The study’s findings showed that pravastatin tended to impair learning over the last few days of treatment although this effect was fully reversed once treatment ceased. However, in the novel object discrimination task, pravastatin impaired object recognition memory. While no effects were observed for atorvostatin in either task. The results suggest that chronic treatment with pravastatin impairs working and recognition memory in rodents. The reversibility of the effects on stopping treatment is similar to what has been observed in patients, but the lack of effect of atorvostatin suggests that some types of statin may be more likely to cause cognitive impairment than others. Neil Marrion, Professor of Neuroscience at Bristol’s School of Physiology and Pharmacology and the study’s lead author, said: “This finding is novel and likely reflects both the anecdotal reports and FDA advice. What is most interesting is that it is not a feature of all statins. However, in order to better understand the relationship between statin treatment and cognitive function, further studies are needed.” ### Further information 1. BBC: http://www.bbc.co.uk/news/health-18101554 What are statins used for? Statins are medicines that are prescribed to help protect healthy, but high-risk, people from heart disease and to prevent repeated problems in people who have already had a heart attack, a stroke or peripheral artery disease. How do statins work? The cells in our body make a fatty substance called cholesterol. The liver makes the cholesterol mostly from the saturated fats in the food we eat. Cholesterol plays a vital role in how every cell works, throughout the body, and the body uses cholesterol to make other vital chemicals. However, having too much cholesterol in the blood can increase your risk of getting heart and circulatory disease. Statins reduce the amount of cholesterol produced by cells all over our body. This forces them to get their supply by removing it from the bloodstream. So this lowers the blood cholesterol level. Source: British Heart Foundation Paper The paper ‘Chronic Pravastatin but Not Atorvastatin Treatment Impairs Cognitive Function in Two Rodent Models of Learning and Memory’ by Stuart SA, Robertson JD, Marrion NV, Robinson ESJ is published in PLOS ONE : e75467. doi:10.1371/journal.pone.0075467 http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0075467 Funding The study was partially funded by a Wellcome Trust grant. Contact: Caroline Clancy |
| Adjusting bacteria in intestines may lead to obesity treatments Posted: 23 Sep 2013 09:00 PM PDT A drug that appears to target specific intestinal bacteria in the guts of mice may create a chain reaction that could eventually lead to new treatments for obesity and diabetes in humans, according to a team of researchers.
Mice fed a high-fat diet and provided tempol, an anti-oxidant drug that may help protect people from the effects of radiation, were significantly less obese than those that did not receive the drug, according to Andrew Patterson, assistant professor of molecular toxicology, Penn State, who worked with Frank J. Gonzalez, laboratory metabolism chief, and James B. Mitchell, radiation biology branch chief, both of the National Cancer Institute. “The two interesting findings are that the mice that received tempol didn’t gain as much weight and the tempol somehow impacted the gut microbiome of these mice,” said Patterson. “Eventually, we hope that this can lead to a new line of therapeutics to treat obesity and diabetes.” The microbiome is the biological environment of microorganisms within the human body. The researchers, who reported their findings in the current issue of Nature Communications, said that tempol reduces some members of a bacteria — a genus of Lactobacillus — in the guts of mice. When the Lactobacillus levels decreases, a bile acid — tauro-beta-muricholic acid — increases. This inhibits FXR — farnesoid X receptor, which regulates the metabolism of bile acids, fats and glucose in the body, according to the researchers. “The study suggests that inhibiting FXR in the intestine might be a potential target for anti-obesity drugs,” said Gonzalez. The researchers said that tempol may help treat type 2 diabetes symptoms. In addition to lower weight gain, the tempol-treated mice on a high-fat diet had lower blood glucose and insulin levels. “Previously, Dr. Mitchell observed a significant difference in weight gain in mice on tempol-containing diet,” said Patterson. “He approached us to help figure out what was going on, and it had been an interesting journey wading through the complexities of the microbiome.” Other studies hinted at the relationship between tempol, the gut microbiome and obesity, but did not focus on why the drug seemed to control weigh gain, according to Patterson. The researchers said these studies are demonstrating how integrated the 100 trillion microbes that make up the human microbiome are with metabolism and health and how the microbiome may provide more pathways to treating other disorders. “There is a tremendous interest in how the microbiome can be manipulated in a therapeutic way,” said Patterson. “And we need to look at these microbiome management techniques in a good, unbiased way.” In the study, the researchers dissolved the tempol in drinking water, or delivered it directly to the mice. Within three weeks, tempol reduced the weight gain for the mice in that group. The mice showed significant reduction in weight gain even after 16 weeks. To further test the role of FXR in obesity, the researchers placed mice that were genetically modified so that they lack FXR on the same high-fat diet. This group was resistant to the effects of tempol and taura-beta-muricholic acid, which further strengthened the importance of FXR in mediating the anti-obesity effect. Gonzalez said that there are indications that FXR plays a similar role in human obesity and diabetes. The researchers must now test the treatments to ensure it is effective in humans, as well as check for any potential side effects, including cancer. ### Patterson worked with Istvan Albert, associate professor of biochemistry and microbiology, and Yunfei Li, bioinformatics specialist, both of Penn State; Fei Li and Changtao Jiang, postdoctoral fellows; Haipin Hao, visiting scholar; Kristopher W. Krausz, research biologist; Kristin Fabre, scientific program manager, all of the National Cancer Institute; The work was supported by the Center for Cancer Research, National Institutes of Health and the Pennsylvania Department of Health, using Tobacco CURE funds. Contact: Matthew Swayne |
| Penn Medicine researchers harness the immune system to fight pancreatic cancer Posted: 23 Sep 2013 09:00 PM PDT Pancreatic cancer ranks as the fourth-leading cause of cancer death in the United States, and is one of the most deadly forms of cancer, due to its resistance to standard treatments with chemotherapy and radiation therapy and frequently, its late stage at the time of diagnosis. A group of researchers led by the University of Pennsylvania’s Perelman School of Medicine and Abramson Cancer Center, in collaboration with scientists from the University of Pittsburgh and University of Washington, published results of a clinical trial in which the standard chemotherapy drug for this disease, gemcitabine, was paired with an agonist CD40 antibody, resulting in substantial tumor regressions among some patients with advanced pancreatic cancer. By using a novel, real-time imaging approach to monitor tumor response to the immunotherapy, the team also found differences how primary and metastatic disease sites shrank. Their work appears online this month in Clinical Cancer Research.
“We’re now using imaging to understand the treatment heterogeneity that one can see in immunotherapy ? not all tumors within a patient’s body react the same way, even in the face of powerful treatments, and now we have a way to follow these unique treatment responses in patients in real-time,” said lead author Gregory Beatty, MD, PhD, an assistant professor in the division of Hematology/Oncology in the Abramson Cancer Center. The report builds on preliminary results of findings in both humans and mice published in Science in 2011. The new approach exploits an immune reaction in the microenvironment of the patient’s primary tumor by targeting an immune cell surface molecule CD40 to turn a type of white blood cell known as macrophages against the tumor by causing them to attack the stroma, the fibrotic supporting tissue of the tumor that acts as a defensive barrier to standard therapies. The treatment ate away at this stroma, ultimately causing substantial shrinkage of some primary tumors, and affecting the metabolic activity of both primary and metastatic lesions. Of 21 patients treated with the drug combination, five patients who received at least one treatment course developed a partial response, defined as a decrease in tumor size of at least 30 percent. The new study also measured the effectiveness of applying a new approach to FDG/PET-CT imaging, to reveal the metabolic responses of individual tumors. FDG/PET-CT uses a radioactive glucose tracer to pinpoint glucose uptake within tumors, revealing the places where cells are metabolically active. Typically physicians and radiologists report only the maximum uptake of glucose within a tumor using this imaging technique; however, the new study showed that glucose metabolism can be quantified within individual tumors or within organs, and throughout the entire body, to provide a measure of total tumor burden. The team found that while primary tumors seemed to respond more or less uniformly with each treatment cycle, tumors varied in their reactions to treatment. “We incorporated imaging as early as two weeks after the first dose of treatment, and we’re able to see changes and responses in terms of glucose metabolism even at this early time point in treatment, which predicted how well patients would respond two months later,” Beatty says. The team hopes to apply the use of FDG/PET-CT to monitoring treatment responses during other immune-based therapies in pancreas cancer. Determining the reasons for these varying responses will be an important next step in this work. The unique imaging approach, Beatty notes, is revealing new insight into the biology of pancreas cancer and its treatment resistance. This allows the research team to expedite progress through a unique model that moves quickly back and forth between the lab and the clinic: “We’re taking it back to the bench and at the same time, applying it at the bedside with additional clinical trials.” The most commonly observed side effect of the treatment was cytokine release syndrome, typically manifested as chills and rigors. One patient with a previous history of vascular disease experienced a stroke shortly after starting therapy. ### The trial was supported by Pfizer Corporation, with partial funding from the American Society of Clinical Oncology Young Investigator Award and by the National Cancer Institute (CA138907-02, CA169123). Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise. The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 16 years, according to U.S. News & World Report’s survey of research-oriented medical schools. The School is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $398 million awarded in the 2012 fiscal year. The University of Pennsylvania Health System’s patient care facilities include: The Hospital of the University of Pennsylvania — recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; and Pennsylvania Hospital — the nation’s first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region. Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2012, Penn Medicine provided $827 million to benefit our community. Contact: Holly Auer |
| Breakthrough offers first direct measurement of spinal cord myelin in multiple sclerosis Posted: 22 Sep 2013 09:00 PM PDT Researchers have made an exciting breakthrough ? developing a first-of-its-kind imaging tool to examine myelin damage in multiple sclerosis (MS). An extremely difficult disease to diagnose, the tool will help physicians diagnose patients earlier, monitor the disease’s progression, and evaluate therapy efficacy.
Case Western Reserve University School of Medicine scientists have developed a novel molecular probe detectable by positron emission tomography (PET) imaging. The new molecular marker, MeDAS, offers the first non-invasive visualization of myelin integrity of the entire spinal cord at the same time, as published today in an article in the Annals of Neurology. “While MS originates in the immune system, the damage occurs to the myelin structure of the central nervous system. Our discovery brings new hope to clinicians who may be able to make an accurate diagnosis and prognosis in as little as a few hours compared to months or even years,” said Yanming Wang, PhD, senior author of study and associate professor of radiology at Case Western Reserve University School of Medicine. “Because of its shape and size, it is particularly difficult to directly detect myelin damage in the spinal cord; this is the first time we have been able to image its function at the molecular level.” As the most common acquired autoimmune disease currently affecting more than two million people worldwide, MS is characterized by destruction of myelin, the membrane that protects nerves. Once damaged, it inhibits the nerves’ ability to transmit electrical impulses, causing cognitive impairment and mobility dysfunction. So far, there is no cure for MS, therapies are only available that modify the symptoms. In addition to its role in monitoring the effects of myelin-repair drugs currently under development, the new imaging tool offers a real-time quantitative clinical diagnosis of MS. A long lag exists between the onset of disease, physical symptoms in the patient and diagnosis via behavioral testing and magnetic resonance imaging (MRI). The lesions, or plaques, as detected by a MRI in the brain and spinal cord are not myelin specific and thus poorly associated with a patient’s disease severity or progression. There is an urgent need to find a new imaging marker that correlates with a patient’s pathology. “This discovery has open the door to develop new drugs that can truly restore nerve function, not just modify the symptoms,” said Robert Miller, PhD, co-author on the study, vice president for research for Case Western Reserve and the Allen C. Holmes Professor of Neurological Diseases at the School of Medicine. “A cure for MS requires both repairing myelin and a tool to measure the mechanism.” For the past 20 years, Miller’s lab has been working tirelessly to create new myelin-repair therapies that would restore nerve function. Successful translation of new drugs from animal studies to human clinical trials is contingent upon researchers’ ability to measure and evaluate the effectiveness of a therapy. Created by Wang’s laboratory, the MeDAS molecular probe works like a homing device. Injected into the body intravenously, it is programmed to seek out and bind only to myelin in the central nervous system, i.e., the brain, spinal cord and optic nerves. A positron-emitting radioisotope label on the molecule allows a PET scanner to detect the targets and quantify their intensity and location. The data can then be reconstructed into an image as shown in the article: http://onlinelibrary.wiley.com/doi/10.1002/ana.23965/abstract. “This is an indispensable tool to help find a new way to treat MS down the road” said Chunying Wu, PhD, first author of the study and instructor of radiology at Case Western Reserve. “It can also be used as a platform technology to unlock the mysteries of other myelin related diseases such as spinal cord injury.” ### The Case Western Reserve research team has completed preclinical studies in animals and has begun the process of initiating human trials. This study was supported by grants from the Department of Defense (W81XWH-10-1-0842), National Multiple Sclerosis Society (RG 4339-A-2), and the National Institutes of Health (R01 NS061837). About Case Western Reserve University School of Medicine Founded in 1843, Case Western Reserve University School of Medicine is the largest medical research institution in Ohio and is among the nation’s top medical schools for research funding from the National Institutes of Health. The School of Medicine is recognized throughout the international medical community for outstanding achievements in teaching. The School’s innovative and pioneering Western Reserve2 curriculum interweaves four themes–research and scholarship, clinical mastery, leadership, and civic professionalism–to prepare students for the practice of evidence-based medicine in the rapidly changing health care environment of the 21st century. Nine Nobel Laureates have been affiliated with the School of Medicine. Annually, the School of Medicine trains more than 800 MD and MD/PhD students and ranks in the top 25 among U.S. research-oriented medical schools as designated by U.S. News & World Report’s “Guide to Graduate Education.” The School of Medicine’s primary affiliate is University Hospitals Case Medical Center and is additionally affiliated with MetroHealth Medical Center, the Louis Stokes Cleveland Department of Veterans Affairs Medical Center, and the Cleveland Clinic, with which it established the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in 2002. http://casemed.case.edu Contact: Jessica Studeny |
| Johns Hopkins researchers erase human brain tumor cells in mice Posted: 22 Sep 2013 09:00 PM PDT Working with mice, Johns Hopkins researchers have discovered that weeks of treatment with a repurposed FDA-approved drug halted the growth of ? and ultimately left no detectable trace of ? brain tumor cells taken from adult human patients.
The scientists targeted a mutation in the IDH1 gene first identified in human brain tumors called gliomas by a team of Johns Hopkins cancer researchers in 2008. This mutation was found in 70 to 80 percent of lower-grade and progressive forms of the brain cancer. The change occurs within a single spot along a string of thousands of genetic coding letters, and is disruptive enough to keep the seemingly innocuous protein from playing its role in converting glucose into energy. Instead, the mutation hijacks the protein to make a new molecule not normally found in the cell, which is apparently a linchpin in the process of forming and maintaining cancer cells. Encouraged by the new findings, described online Sept. 16 in the open-access journal Oncotarget, the Johns Hopkins researchers say they want to work quickly to design a clinical trial to bring what they learned in mice to humans with gliomas. Despite the growing understanding of IDH1 mutant gliomas, the development of effective therapies has proven challenging, they say. “Usually in the lab, we’re happy to see a drug slow down tumor growth,” says Alexandra Borodovsky, a graduate student in the Cellular and Molecular Medicine Program at the Johns Hopkins University School of Medicine who performed the experiments. “We never expect tumors to regress, but that is exactly what happened here.” “This therapy has worked amazingly well in these mice,” says study leader Gregory J. Riggins, M.D., Ph.D., a professor of neurosurgery and oncology at the Johns Hopkins University School of Medicine. “We have spoken with neurosurgeons here, and as soon as possible, we want to start discussing the parameters of a clinical trial to see if this will work in our patients as a follow-up to surgery.” The researchers caution that many treatments have cured cancers in mice, and then failed in humans. The IDH1 gene, whose name stands for isocitrate dehydrogenase 1, produces an enzyme that regulates cell metabolism. Mutations, or changes in the DNA code, force the IDH1 gene to increase production of a flawed version of the enzyme. The flawed enzyme produces large amounts of an entirely new molecule, called 2-hydroxyglutarate. This molecule is believed to cause groups of atoms called methyl groups to latch onto the DNA strand. Although methylation is a normal cellular process, when too many methyl groups glom onto the DNA, Riggins says, this can interfere with normal cell biology and eventually contribute to cancer formation and growth. Borodovsky, Riggins and their colleagues ? including Timothy A. Chan, M.D., Ph.D., of Memorial Sloan-Kettering Cancer Center in New York ? thought that a drug that could strip those methyl groups might be able to reverse the cancer process in those cancers with IDH1 mutations. They chose 5-azacytidine, which is approved to treat a pre-leukemia condition called myelodysplastic syndrome and is being tested on lung and other cancers at Johns Hopkins and elsewhere. Riggins notes that one of the difficulties in developing treatments for IDH1 mutant brain cancers is finding a model in which to study them. Cell lines containing the IDH1 mutation are difficult to grow in the laboratory, for example. Borodovsky worked with Johns Hopkins neurosurgeons to obtain tumor cells from glioma patients likely to have IDH1 mutations and injected them under the skins of mice. She did this for months, before finally getting the tumor cells to grow. Once the tumors grew, the researchers injected the mice with 5-azacytidine for 14 weeks and saw a dramatic reduction in growth and what appeared to be complete regression. Then they withdrew therapy. Seven weeks later, the tumors had not regrown. The researchers, however, said they do expect the tumors to regrow at some point, and are still monitoring the mice. The type of tumor targeted by the researchers eventually progresses to a subtype of glioblastoma multiform ? the deadliest form of brain cancer ? known as progressive or secondary glioblastoma. They arise as a lower-grade glioma and are initially treated with surgery alone, but eventually they progress to the more lethal form of tumor. Survival is longer than with glioblastoma, but it is found in younger patients, those under the age of 50. While both types of tumor look the same at the end, they look very different at the molecular level, Riggins says, leading researchers to believe they may have a better chance at targeting the progressive tumors, which are more likely to have the IDH1 mutation. Chan’s team at Sloan-Kettering simultaneously published a paper in Oncotarget, along with Borodovsky and Riggins, which describes similar results in a different animal model using a similar drug. This is further evidence that the strategy is a sound one, Riggins says. ### Other Johns Hopkins researchers involved in the Borodovsky paper include Charles G. Eberhart, M.D., Ph.D.; Jon D. Weingart, M.D.; Gary L. Gallia, M.D., Ph.D.; and Stephen B. Baylin, M.D. The work was supported by the Conrad N. Hilton Foundation, the Virginia and D.K. Ludwig Fund for Cancer Research, Margaret H. Riggins, and the Irving J. Sherman Research Professorship in Neurosurgery. Funding also came from grants from the National Institutes of Health’s National Cancer Institute (P30 CA006973) and the National Center for Research Resources (UL1 RR025005 and 1S10RR026824-01). For more information: Contact: Stephanie Desmon |
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