BreakThrough Digest Medical News |
- ‘Network’ analysis of the brain may explain features of autism
- New cancer ‘vaccine’ shows future promise in treating and preventing metastatic cancers
- Good bacteria may expunge vancomycin-resistant bacteria from your gut
- Discovery opens door to multipronged attack against skin common cancer, Stanford study shows
- Novel combination therapy shuts down escape route, killing glioblastoma tumor cells
- Researchers find controlling element of Huntington’s disease
- Fecal microbiota transplantation cures gastrointestinal diseases
| ‘Network’ analysis of the brain may explain features of autism Posted: 26 Feb 2013 09:00 PM PST A look at how the brain processes information finds a distinct pattern in children with autism spectrum disorders. Using EEGs to track the brain’s electrical cross-talk, researchers from Boston Children’s Hospital have found a structural difference in brain connections. Compared with neurotypical children, those with autism have multiple redundant connections between neighboring brain areas at the expense of long-distance links.
The study, using a “network analysis” like that used to study airlines or electrical grids, may help in understanding some classic behaviors in autism. It was published February 27 in BioMed Central’s open access journal BMC Medicine, accompanied by a commentary. “We examined brain networks as a whole in terms of their capacity to transfer and process information,” says Jurriaan Peters, MD, of the Department of Neurology at Boston Children’s Hospital, who is co-first author of the paper with Maxime Taquet, a PhD student in Boston Children’s Computational Radiology Laboratory. “What we found may well change the way we look at the brains of autistic children.” Peters, Taquet and senior authors Simon Warfield, PhD, of the Computational Radiology Laboratory and Mustafa Sahin, MD, PhD, of Neurology, analyzed EEG recordings from two groups of autistic children: 16 children with classic autism, and 14 children whose autism is part of a genetic syndrome known as tuberous sclerosis complex (TSC). They compared these readings with EEGs from two control groups?46 healthy neurotypical children and 29 children with TSC but not autism. In both groups with autism, there were more short-range connections within different brain region, but fewer connections linking far-flung areas. A brain network that favors short-range over long-range connections seems to be consistent with autism’s classic cognitive profile?a child who excels at specific, focused tasks like memorizing streets, but who cannot integrate information across different brain areas into higher-order concepts. “For example, a child with autism may not understand why a face looks really angry, because his visual brain centers and emotional brain centers have less cross-talk,” Peters says. “The brain cannot integrate these areas. It’s doing a lot with the information locally, but it’s not sending it out to the rest of the brain.” Network analysis?a hot emerging branch of cognitive neuroscience?showed a quality called “resilience” in the children with autism?the ability to find multiple ways to get from point A to point B through redundant pathways. “Much like you can still travel from Boston to Brussels even if London Heathrow is shut down, by going through New York’s JFK airport for example, information can continue to be transferred between two regions of the brain of children with autism,” says Taquet. “In such a network, no hub plays a specific role, and traffic may flow along many redundant routes.” This quality of redundancy is consistent with cellular and molecular evidence for decreased “pruning” of brain connections in autism. While it may be good for an airline, it may indicate a brain that responds in the same way to many different kinds of situations and is less able to focus on the stimuli that are most important. “It’s a simpler, less specialized network that’s more rigid, less able to respond to stimulation from the environment,” says Peters. The study showed that both groups of children with tuberous sclerosis complex had reduced connectivity overall, but only those who also had autism had the pattern of increased short-range versus long-range connections (See image). Under a recently announced NIH Autism Center of Excellence Grant, Peters and his colleagues will repeat the analysis as part of a multicenter study, taking EEG recordings prospectively under uniform conditions. The current study builds on recent work by Peters, Sahin and colleagues, which imaged nerve fibers in autistic patients and showed structural abnormalities in brain connectivity. Other recent work at Boston Children’s, led by Frank Duffy, PhD, of Neurology, looked at “coherence,” or the degree of synchrony between any two given EEG signals, and found altered connectivity between brain regions in children with autism. Yet another recent study, led by Boston Children’s informatics researcher William Bosl, PhD, and Charles A. Nelson, PhD, research director of the Developmental Medicine Center, looked at the degree of randomness in EEG signals, an indirect indicator of connectivity, and found patterns that distinguished infants at increased risk for autism from controls. ### The current study was funded by the National Institutes of Health (grant #s R01 RR021885, R01 LM010033, R03 EB008680, UL1 RR025758 to Warfield; P20 RFA-NS-12-006, 1U01NS082320-01 to Sahin and Peters); the National Institute of Mental Health (grant #K23MH094517 to coauthor Shafali Jeste); the National Institute on Deafness and Other Communication Disorders (grant #DC 10290 to Charles Nelson, PhD) and the Department of Defense (grant #W81XWH-11-1-0365 to Nelson). Boston Children’s Hospital is home to the world’s largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 1,100 scientists, including nine members of the National Academy of Sciences, 11 members of the Institute of Medicine and 12 members of the Howard Hughes Medical Institute comprise Boston Children’s research community. Founded as a 20-bed hospital for children, Boston Children’s today is a 395-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Boston Children’s also is a teaching affiliate of Harvard Medical School. Contact: Meghan Weber |
| New cancer ‘vaccine’ shows future promise in treating and preventing metastatic cancers Posted: 26 Feb 2013 09:00 PM PST Preclinical, laboratory studies suggest a novel immunotherapy could potentially work like a vaccine against metastatic cancers, according to scientists at Virginia Commonwealth University Massey Cancer Center. Results from a recent study show the therapy could treat metastatic cancers and be used in combination with current cancer therapies while helping to prevent the development of new metastatic tumors and train specialized immune system cells to guard against cancer relapse.
Recently published in the journal Cancer Research, the study detailed the effects of a molecule engineered by lead author Xiang-Yang Wang, Ph.D., on animal and cell models of melanoma, prostate and colon tumors. The molecule called Flagrp-170 consists of two distinct proteins, glucose-regulated protein 170 (Grp170), known as a “molecular chaperone,” and a “danger signal” derived from flagellin, a protein commonly found in bacteria. The researchers used modified viruses, or adenoviruses, that can no longer replicate to transport Flagrp-170 directly to the tumor site to achieve localized vaccination. The novel therapy caused a profound immune response that significantly prolonged survival in animal models. “Successfully promoting antitumor immunity will help eradicate tumor cells, control cancer progression and help prevent tumor relapse,” says Wang, Harrison Scholar, member of the Cancer Molecular Genetics research program at VCU Massey Cancer Center and associate professor of Human and Molecular Genetics at VCU School of Medicine. “This immunotherapy has the potential to be used alone or in combination with conventional cancer treatments to develop and establish immune protection against cancer and its metastases.” Grp170 is currently being explored for its potential as a “cancer vaccine” because it has been shown to help the immune system recognize cancer antigens. Antigens are molecules from foreign objects such as bacteria, viruses or cancer that, when detected, provoke an immune response aimed at attacking them. However, because cancer cells can alter the microenvironment surrounding a tumor, they are able to suppress immune responses and continue replicating without being attacked by the body’s natural defenses. The chimeric chaperone Flagrp-170, created by strategically fusing a fragment of flagellin to Grp170, not only enhances antigen presentation, it also stimulates additional immune signals essential for functional activation of specialized immune cells, including dendritic cells, CD8+ T lymphocytes and natural killer (NK) cells. Dendritic cells act as messengers between the innate and adaptive immune systems. Once activated in response to a stimulus such as Flagrp-170, dendritic cells migrate to lymph nodes where they interact with other immune cells such as T lymphocytes to shape the body’s immune response. CD8+ T lymphocytes and NK cells are known to respond to tumor formation and kill cancer cells by triggering apoptosis, a form of cell suicide. “Overcoming cancer’s ability to suppress the body’s natural immune responses and restore or develop immunity for tumor eradication is the goal of cancer immunotherapy,” says Wang. “More experiments are needed, but we are hoping Flagrp-170 may one day be used in formulating more effective therapeutic cancer vaccines.” Moving forward, Wang and his team are working to better understand the molecular mechanisms responsible for Flagrp-170′s therapeutic effects. Additional studies are underway to more efficiently target and deliver Flagrp-170 to tumor sites in order to provoke a more robust and durable immune response. ### Wang collaborated on this research with Paul Fisher, M.Ph., Ph.D., Thelma Newmeyer Corman Endowed Chair in Cancer Research and program co-leader of Cancer Molecular Genetics at VCU Massey Cancer Center, chairman of VCU’s Department of Human and Molecular Genetics and director of the VCU Institute of Molecular Medicine; Xiaofei Yu; Chunquing Guo, Ph.D.; Huanfa Yi; and Jie Qian, Ph.D., all from VCU’s Department of Human and Molecular Genetics and the VCU Institute of Molecular Medicine; and John R. Subjeck from the Department of Cellular Stress Biology at Roswell Park Cancer Institute. This research was supported by NIH grants CA129111 and CA154708; the American Cancer Society, the Department of Defense and, in part, by funding from VCU Massey Cancer Center’s NIH-NCI Cancer Center Support Grant P30 CA016059. The full manuscript of this study is available online at: http://cancerres.aacrjournals.org/content/early/2013/01/18/0008-5472.CAN-12-1740.long. News directors: Broadcast access to VCU Massey Cancer Center experts is available through VideoLink ReadyCam. ReadyCam transmits video and audio via fiber optics through a system that is routed to your newsroom. To schedule a live or taped interview, contact John Wallace. About VCU Massey Cancer Center: VCU Massey Cancer Center is one of only 67 National Cancer Institute-designated institutions in the country that leads and shapes America’s cancer research efforts. Working with all kinds of cancers, the Center conducts basic, translational and clinical cancer research, provides state-of-the-art treatments and clinical trials, and promotes cancer prevention and education. Since 1974, Massey has served as an internationally recognized center of excellence. It has one of the largest offerings of clinical trials in Virginia and serves patients in Richmond and in four satellite locations. Its 1,000 researchers, clinicians and staff members are dedicated to improving the quality of human life by developing and delivering effective means to prevent, control and ultimately to cure cancer. Visit Massey online at www.massey.vcu.edu or call 877-4-MASSEY for more information. About VCU and the VCU Medical Center: Virginia Commonwealth University is a major, urban public research university with national and international rankings in sponsored research. Located in downtown Richmond, VCU enrolls more than 31,000 students in 222 degree and certificate programs in the arts, sciences and humanities. Sixty-six of the programs are unique in Virginia, many of them crossing the disciplines of VCU’s 13 schools and one college. MCV Hospitals and the health sciences schools of Virginia Commonwealth University compose the VCU Medical Center, one of the nation’s leading academic medical centers. For more, see www.vcu.edu. Contact: John Wallace |
| Good bacteria may expunge vancomycin-resistant bacteria from your gut Posted: 26 Feb 2013 09:00 PM PST Too much antibiotic can decimate the normal intestinal microbiota, which may never recover its former diversity. That, in turn, renders the GI tract vulnerable to being colonized by pathogens. Now researchers from Memorial Sloan-Kettering Cancer Center, New York, NY, and Centro Superior de Investigación en Salud Pública, Valencia, Spain, show that reintroducing normal microbial diversity largely eliminated vancomycin-resistant enterococci (VRE) from the intestinal tracts of mice. The investigators showed further that the findings may apply to humans. The research is published in the March 2013 issue of the journal Infection and Immunity.
The reduced diversity of microbiota wrought by antibiotics “allow[s] VRE to invade and thrive in the intestine, suggesting that bacterial species that are wiped out by antibiotics are key to preventing colonization by VRE,” says first author Carles Ubeda of the Centro Superior de Investigacion en Salud Publica, Valencia, Spain. “We hypothesized that repopulating the mice’ intestines with the missing bacteria would promote clearance of the VRE.” In the study, the researchers treated mice with antibiotics. They then gave the mice fecal transplants from untreated mice, or aerobic or anaerobic cultures from the fecal transplants. Following the latter treatments, mice receiving the fecal transplant or the anaerobic culture were able to clear the VRE, while those receiving the aerobic culture failed to do so. The researchers compared the microbiota in each group. The big difference: the mice that had cleared the VRE contained bacteria from the anaerobic genus, Barnesiella, while those that had failed to clear the VRE did not. The researchers then analyzed the fecal microbiota from human patients who had received bone marrow transplants, who were at high risk of being colonized by vancomycin-resistant enterococci. “The presence of Barnesiella in fecal samples was associated with protection against VRE, suggesting that in humans, Barnesiella may also confer protection against dense VRE colonization,” says Ubeda. “The findings could be very useful for development of novel probiotics,” says Ubeda. Additionally, “scientifically, this is a major finding that will help us to understand how the microbiota confer resistance against intestinal colonization by pathogens, an important question that remains incompletely answered.” ### (C. Ubeda, V. Bucci, S. Caballero, et al. Intestinal microbiota containing Barnesiella species cures vancomycin-resistant Enterococcus faecium colonization. Infect. Immun. 81:965-973) Infection and Immunity is a publication of the American Society for Microbiology (ASM). The ASM is the largest single life science society, composed of over 39,000 scientists and health professionals. Its mission is to advance the microbiological sciences as a vehicle for understanding life processes and to apply and communicate this knowledge for the improvement of health and environmental and economic well-being worldwide. Contact: Jim Sliwa |
| Discovery opens door to multipronged attack against skin common cancer, Stanford study shows Posted: 26 Feb 2013 09:00 PM PST Hailed as a major step forward in the effort to develop targeted cancer therapies, a recently approved drug for the most common type of skin cancer has been a mixed blessing for patients. Although the initial response is usually dramatic, the tumors often recur as the cancer becomes resistant to treatment.
Now researchers at the Stanford University School of Medicine have identified a second way to block the activity of the signaling cascade, called the Hedgehog pathway, that is abnormally active in these cancers. The researchers hope the new approach may not only one day help patients with tumors that have become resistant to the first drug, vismodegib (marketed as Erivedge), but may also provide a novel combination therapy for newly diagnosed tumors that may be more effective than either treatment alone. “These new, highly targeted therapies work really well,” said dermatology professor Anthony Oro, MD, PhD, who was one of several Stanford researchers involved in the multiyear effort that brought vismodegib to market in 2012. “But this type of treatment is a race against evolution. Within a year, many of the tumors recur when the cancers become resistant to the inhibitor.” The effect on patients, particularly those with a severe condition called Gorlin syndrome, is a heartbreaking yo-yo as the tumors that cover most of their bodies disappear within weeks, but often recur in force. But Oro and his colleagues’ discovery of another, previously unknown component of the Hedgehog pathway ? a component vital to its cancer-causing ability ? could address this problem. Blocking the activity of this protein, called aPKC, can stop the growth in mice of transplanted skin tumors and tumor cells resistant to vismodegib. The finding, which will be published Feb. 28 in Nature, may pave the way to a future in which cancers are treated with more than one specifically targeted drug. “Although these tumors evolve in response to targeted drug treatment, we believe there’s a limited number of ways they can escape these therapies,” said Oro. “If we were able to hit them at the time of diagnosis with drugs that target more than one step in the pathway, they may be less able to evade treatment. We’ve identified a new target in the Hedgehog pathway and we’ve developed an inhibitor of this target that we hope will work in human cancers.” Oro, who is the senior author of the study, was also one of several authors on a series of three papers in the New England Journal of Medicine last June describing the effectiveness of vismodegib in treating the most common type of skin cancer, basal cell carcinoma. Postdoctoral scholar Scott Atwood, PhD, is the lead author of the current study. Taken together, the recent studies illustrate the nature of the constant battle among physicians and the rapidly growing and changing cancer cells they strive to eradicate. Targeted treatments that focus on unique vulnerabilities exhibited by specific types of cancers can be highly effective. They can also minimize the unpleasant side effects of less-specific treatments that kill many other non-cancerous cells. But their very specificity encourages and drives the tumor cells to evolve resistance in a way that might not be possible against a more broad-based therapeutic approach. Many researchers believe that a multipronged attack targeted at more than one point in critical cancer-causing pathways could be an effective way to combat resistance. “Our goal is to provide precision cancer care at the time of diagnosis,” said Atwood. “We’re working toward developing better, more specific single and combination therapies to reduce the chance of resistance through tumor evolution.” The Hedgehog pathway is critical to many aspects of embryo development in animals as diverse as fruit flies and humans. When abnormally activated, it can cause uncontrolled cell growth. The pathway was first linked to human cancer about 16 years ago by researchers, including Stanford professor of developmental biology Matthew Scott, PhD. Since that time, researchers around the world, including a large group at Stanford, have worked to learn more about the pathway and how to inhibit it. That work led to the development of vismodegib, which blocks a protein called Smoothened, or Smo, that acts near the beginning of the Hedgehog pathway. Smo sits in the cell membrane and sends signals into the interior of the cell. When activated, it initiates a biological cascade of signaling molecules that culminates in the cell’s nucleus at a protein called Gli, which governs gene expression. Oro and Atwood discovered another, previously unknown protein player in the Hedgehog pathway called aPKC. This protein perpetuates Gli’s ability to transcribe, or activate, certain genes by giving it a specific molecular tag (a process called phosphorylation). The phosphorylated Gli in turn goads aPKC to higher levels of activity in what’s known as a positive feedback loop. The researchers studied human skin cancer cells removed from patients and grown in a laboratory dish. They also used a model in which basal cell carcinomas were transplanted onto mice. They looked at levels of aPKC activity and gene expression profiles in the tumors. “We’ve found that aPKC is highly active in human basal cell carcinomas that have become resistant to vismodegib,” said Atwood. “This positive feedback with aPKC allows tumors to grow really well even in the presence of vismodegib.” When the researchers used an aPKC inhibitor to treat mice bearing transplanted tumors or tumor cells resistant to Smo inhibitors, the growth of the cancer cells was suppressed and the tumors shrank. The researchers are now working to optimize the selection and design of the aPKC inhibitor. They are also interested in exploring its effect in other cancers in which the Hedgehog pathway is implicated. “There are a host of Hedgehog-dependent cancers,” said Oro, “and we have many researchers and clinicians here at Stanford poised to conduct clinical trials of these types of therapies. It’s very exciting.” ### Other Stanford researchers involved in the work include former undergraduate student Mischa Li, technician Alex Lee and assistant professor of dermatology Jean Tang, MD, PhD. The research was funded by the National Institutes of Health (grants 1F32CA14208701, AR052785 and AR046786). Information about Stanford’s Department of Dermatology, which also supported the work, is available at http://dermatology.stanford.edu/. The Stanford University School of Medicine consistently ranks among the nation’s top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://mednews.stanford.edu. The medical school is part of Stanford Medicine, which includes Stanford Hospital & Clinics and Lucile Packard Children’s Hospital. For information about all three, please visit http://stanfordmedicine.org/about/news.html. Contact: Krista Conger |
| Novel combination therapy shuts down escape route, killing glioblastoma tumor cells Posted: 25 Feb 2013 09:00 PM PST Glioblastoma, the most common and lethal form of brain tumor in adults, is challenging to treat because the tumors rapidly become resistant to therapy. As cancer researchers are learning more about the causes of tumor cell growth and drug resistance, they are discovering molecular pathways that might lead to new targeted therapies to potentially treat this deadly cancer.
Scientists at the Ludwig Institute for Cancer Research in San Diego worked collaboratively across the laboratories of Drs. Paul Mischel, Web Cavenee and Frank Furnari to investigate one such molecular pathway called the mammalian target of rapamycin or mTOR. This signaling pathway is hyperactivated in close to 90 percent of glioblastomas and plays a critical role in regulating tumor growth and survival. Therapies that inhibit mTOR signaling are under investigation as drug development targets, but results to date have been disappointing: mTOR inhibitors halt the growth but fail to kill the tumor cells. A study published this week in the Proceedings of the National Academy of Sciences uncovers an unexpected but important molecular mechanism of mTOR inhibitor resistance and identifies a novel drug combination that reverses this resistance. The story begins with a closer look at a gene-encoded protein called promyleocytic leukemia gene or PML. The study investigators explored the role of PML in causing resistance to mTOR inhibitor treatment. They found that when glioblastoma patients are treated with drugs that target the mTOR pathway, the levels of PML rise dramatically. Further, they showed that PML upregulation made the tumor cells resistant to mTOR inhibitors, and that if they suppressed the ability of the tumor cells to upregulate the PML protein, the tumor cells died in response to the mTOR inhibitor therapy. “When we looked at cells in in vivo models and patients treated in the clinic, it became clear that the glioblastoma cells massively regulated PML enabling them to escape the effects of mTOR inhibitor therapy,” reported senior author Paul Mischel, MD, Ludwig Institute member based at the University of California at San Diego. “Our team hypothesized that if we could use a pharmacological approach to get rid of PML and combine it with an mTOR inhibitor, it could change the response from halting growth to cell death. The question was how?” added Mischel. Previous research had shown that the use of low-dose arsenic could cause degradation of the PML protein in patients with leukemia. The team hypothesized that if arsenic could degrade PML, it may reverse resistance to mTOR inhibitors. The combination of mTOR and low-dose arsenic in mice indeed showed a synergistic effect, with massive tumor cell death along with very significant shrinkage of the tumor in mice with no ill side effects. “Current therapy upregulates PML, turning off the mTOR signaling pathway. The tumor cells hide, waiting for the target signal to return,” said Mischel. “When low-dose arsenic is added, not only does it stop the cell from returning, it shuts down the escape route killing the tumor cell.” These results present the first clinical evidence that mTOR inhibition promotes PML upregulation in mice and patients, and that it mediates drug resistance. The clinical relevance was confirmed when researchers looked at before- and after-treatment tissue samples from patients treated with mTOR inhibitors, confirming that PML goes up significantly in post treatment of mTOR inhibitors. “These data suggest a new approach for potential treatment of glioblastoma,” said Mischel. “We are moving forward to test that possibility in people.” Post-doctoral students Akio Iwanami and Beatrice Gini from the Mischel lab as well as Ciro Zanca from the Furnari/Cavenee lab, also contributed significantly to this paper. ### This work was supported by the Japan Society for the Promotion of Science, the Uehara Memorial Foundation, three NIH grants: NS73831, CA 119347 and P01-CA95616, the Ziering Family Foundation in Memory of Sigi Ziering and the Ben and Catherine Ivy Foundation. About The Ludwig Institute for Cancer Research
The Ludwig Institute for Cancer Research is an international non-profit organization committed to improving the understanding and control of cancer through integrated laboratory and clinical discovery. Leveraging its worldwide network of investigators and the ability to sponsor and conduct its own clinical trials, Ludwig is actively engaged in translating its discoveries into applications for patient benefit. Since its establishment in 1971, the Ludwig Institute has expended more than $1.5 billion on cancer research. Contact: Rachel Steinhardt |
| Researchers find controlling element of Huntington’s disease Posted: 25 Feb 2013 09:00 PM PST Huntington’s disease, also known as Huntington’s chorea, is a hereditary brain disease causing movement disorders and dementia. In Germany, there are about 8,000 patients affected by Huntington’s disease, with several hundred new cases arising every year. The disease usually manifests between the ages of 35 and 50. To date, it is incurable and inevitably leads to death. It is caused by a specific genetic defect: In the patient’s DNA, which is the carrier of genetic information, there are multiple copies of a certain motif. “Repeats like this are also found in healthy people. However, in cases of Huntington’s disease, these sequences are longer than usual,” explains Dr. Sybille Krauss from the DZNE in Bonn.
The long DNA sequences in Huntington’s disease lead to changes in a certain protein called “Huntingtin”. The DNA is like an archive of blueprints for proteins. Errors in the DNA therefore result in defective proteins. “Huntingtin is essential for the organism’s survival. It is a multi-talent which is important for many processes,” emphasises Krauss. “If the protein is defective, brain cells may die.” In the spotlight: protein synthesis In the current study, the scientists around Sybille Krauss and the Mainz-based human geneticist Susann Schweiger took a closer look at a critical stage of protein production ? translation. At this step, a copy of the DNA, the so-called messenger RNA, is processed by the cell’s protein factories. In patients with Huntington’s disease, the messenger RNA contains an unusually high number of consecutive CAG sequences ? CAG representing the building plan for the amino acid glutamine. These repetitive sequences have a direct consequence: more glutamine than normal is built into Huntingtin, which is therefore defective. Sybille Krauss and her colleagues have now identified a group of three molecules, which regulate the production of this protein. “We were able to show that this complex binds to the messenger RNA and controls the synthesis of defective Huntingtin,” says Krauss. When the scientists reduced the concentration of this so-called MID1 complex in the cell, production of the defective protein declined. “If we could find a way of influencing this complex, for example with pharmaceuticals, it is quite possible that we could directly affect the production of defective Huntingtin. This kind of treatment would not just treat the symptoms but also the causes of Huntington’s disease,” says Krauss. Background: Three molecules come together The complex consists of MID1, from which it gets its name, and the proteins PP2Ac and S6K. “Every single one of these proteins is known to be important for translation. We have discovered that in the specific case of Huntington’s disease, they together bind to the CAG sequences. This was previously unknown. We also found that binding increases with repeat lengths,” says Krauss. “In sequences of normal length, we found only weak binding or none at all.” The Bonn-based molecular biologist and her colleagues investigated the effect of the MID1 complex and the interaction between its components in a series of elaborate laboratory experiments. “This project took several years of research work,” says Krauss. Along with biochemical procedures, the scientists used cell cultures and analysed proteins from the brains of mice. The mice’s genetic code had been modified in such a way that it contained elongated CAG-repeats as it is typical for Huntington’s disease. From previous studies it was already known that the protein MID1 tends to bind messenger RNAs. The scientists were now able to show that MID1 also attaches to messenger RNAs with excessively long CAG sequences. Furthermore, experiments showed that PP2Ac and S6K also bound the RNA in the presence of MID1. However, if the MID1 was depleted, this binding did not occur. “From this, we can conclude that these three proteins form a molecular complex, which binds to the RNA. MID1 is a key component. It actually seems to keep together its binding partners,” Krauss comments on the results of the experiments. Complex controls protein production The researchers were also able to prove that the MID1 complex controls the translation of RNA with excessively long CAG sequences. For this, they investigated various cell cultures. The cells produced either normal Huntingtin or ? due to excessively long sequences in their DNA ? a defective version of this protein. The scientists reduced the occurrence of MID1 inside the cells using a procedure known as “knock-down”. The elimination of this protein, which is a major part of the MID1 complex, had direct consequences: the production of defective Huntingtin declined. “However, it did not affect the production of normal Huntingtin,” emphazises Krauss. “This further proves that the MID1 complex specifically targets RNAs with excessively long CAG sequences.” Highly specific The Bonn-based molecular biologist sees this specific influence as a chance to treat Huntington’s disease: “The MID1 complex is a promising target for therapy. It indicates a possibility to suppress the production of defective Huntingtin only, while not affecting the production of normal Huntingtin. This is of particular significance, because the normal protein is also being produced in the patients’ bodies and it is important for the organism.” A suitable active substance has yet to be found, says Krauss. However, the next developments are in sight: “We now want to test potential substances in the laboratory,” she says. ### Original Publication “Translation of HTT mRNA with expanded CAG repeats is regulated by the MID1-PP2A protein complex”, Sybille Krauß, Nadine Griesche, Ewa Jastrzebska, Changwei Chen, Désiree Rutschow, Clemens Achmüller, Stephanie Dorn, Sylvia M. Boesch, Maciej Lalowski, Erich Wanker, Rainer Schneider, Susann Schweiger, Nature Communications, DOI: 10.1038/ncomms2514. Contact: Dirk Förger |
| Fecal microbiota transplantation cures gastrointestinal diseases Posted: 25 Feb 2013 09:00 PM PST Clostridium difficile infections have developed into a virtual pandemic over the past two decades. The outcome of standard antibiotic treatment is unsatisfactory: the recurrence rates are high with every relapse increasing the risk of further follow-ups. Faecal microbiota transplantation offers a rapidly acting and highly effective alternative in treating recurrent Clostridium difficile infections (RCDI), as Professor Lawrence J. Brandt (Montefiore Medical Center, New York, USA) points out. According to him, more than 90 per cent of the patients are being cured within a short period of time. Further information on this issue ? one of many topics presented at the 2nd World Summit “Gut Microbiota For Health” in Madrid, Spain, from 24 to 26 February 2013 ? can be found at http://bit.ly/SUN24PR.
To keep themselves up to date on the rapidly increasing advances in the field of gut microbiota research, scientists and health-care professionals came together at the 2nd Gut Microbiota For Health World Summit. This year, the event was hosted by the Gut Microbiota & Health Section of the European Society of Neurogastroenterology and Motility (ESNM) ? a member of United European Gastroenterology (UEG) ? and the American Gastroenterological Association (AGA), with the support of Danone Dairy. ### About the Gut Microbiota For Health Experts Exchange website The www.gutmicrobiotaforhealth.com Experts Exchange, provided by the Gut Microbiota & Health Section of ESNM, is an online platform for health-care professionals, scientists, and other people interested in the field. Thanks to being an open, independent and participatory medium, this digital service enables a scientific debate in the field of gut microbiota. Connected to www.gutmicrobiotaforhealth.com, the Twitter account @GMFHx, animated by experts, for experts from the medical and scientific community, actively contributes to the online exchanges about the gut microbiota. Follow @GMFHx on Twitter. Join the event on #GMFH2013. About the Gut Microbiota & Health Section of ESNM ESNM stands for the European Society of Neurogastroenterology and Motility, a member of United European Gastroenterology (UEG). The mission of the ESNM is to defend the interests of all professionals in Europe involved in the study of neurobiology and pathophysiology of gastrointestinal function. The Gut Microbiota & Health Section was set up to increase recognition of the links between the gut microbiota and human health, to spread knowledge and to raise interest in the subject. The Gut Microbiota & Health Section is open to professionals, researchers, and practitioners from all fields related to gut microbiota and health. www.esnm.eu/gut_health/gut_micro_health.php?navId=68 About the AGA The American Gastroenterological Association is the trusted voice of the GI community. Founded in 1897, the AGA has grown to include more than 16,000 members from around the globe who are involved in all aspects of the science, practice and advancement of gastroenterology. The AGA Institute administers the practice, research and educational programmes of the organisation. www.gastro.org About Danone Dairy and Gut Microbiota For Health Danone’s conviction is that food plays an essential role in human health namely through the impact that gut microbiota may have on health. That is why Danone Dairy supports the Gut Microbiota For Health World Summit and Experts Exchange web platform with the aim to encourage research and increase knowledge in this promising area, in line with its mission to “bring health through food to as many people as possible. Contact: Aimee Frank |
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