Researchers Identify Treatment Target For Liver Cancer Recurrence And Survival
April 11, 2008
Deadly and difficult to treat, liver cancer has long resisted attempts by researchers to develop ways to prolong life and prevent recurrence. But Mayo Clinic Cancer Center, in collaboration with the National Cancer Institute, reports in the April issue of Hepatology that the protein sulfatase 2 (SULF2) may provide one of the keys needed to begin the design of new therapies.
Mayo Clinic Cancer Center leads the field in researching the impact and effect of SULF1, a protein whose normal role is to degrade heparin sulfate proteoglycans — molecules that are part sugar and part protein. Mayo scientists have found that the protein also helps inhibit tumor growth. Now, Mayo researchers are studying a related gene, SULF2. The role of the SULF2 gene and protein has not been fully defined, but in this study, researchers investigated the effect of SULF2 on liver tumor growth in the laboratory. They found that increased expression of SULF2 enhances cancer cell growth and migration, whereas decreased expression reduces both.
“The liver is designed to excrete toxins, and its tumors are no exception,” says Mayo Clinic gastroenterologist Lewis Roberts, M.B.Ch.B., Ph.D., the study’s primary investigator. “Our problem is that the tumors tend to excrete chemotherapeutic agents rather than be affected by them. So we are looking for ways to get around that.”
The researchers sought answers by examining a protein related to one they already knew had a role in suppressing liver tumors. SULF1 and SULF2 are similar proteins, but cause opposing results. SULF1 removes sulfate groups that allow growth factors to bind to cells, thus inhibiting growth. The investigators found that SULF2 did the opposite — it increased binding of a specific growth factor, fibroblast growth factor 2 (FGF2), to tumor cells, and also increased expression of the heparan sulfate proteoglycan glypican 3 (GPC3), which plays an important role in cell division and growth. These findings were confirmed in mouse models.
This discovery indicates if scientists can decrease the levels or activity of SULF2 in a tumor, they might be able to stop its development. Mayo researchers are exploring use of an agent that mimics heparin and inhibits SULF2. They are also examining whether preventing heparin sulfate synthesis would inhibit tumor growth.
“If something has a very broad effect on signaling by growth factors, it may lead to an effective treatment,” says Jinping Lai, M.D., Ph.D., a Mayo oncology researcher and the lead author of the study. “SULF2 has a number of characteristics that make it an attractive target, such as the fact that it is widely present in tumors. We are exploring a number of options with SULF2 as a focal point for treatment not only in liver cancer, but also in head and neck, pancreas, breast and other types of cancer.”
The researchers hope to identify drugs that block SULF2, and seek to thoroughly understand the mechanisms involved, including the determination of what other growth signaling pathways are affected by SULF2. They are also looking further at GPC3 as a potential biomarker for liver cancer or as a possible therapeutic target.
In 2007, Dr. Lai presented information at the annual meeting of the American Association for Cancer Research on the role of SULF2 in survival of patients with head and neck cancer — the first concrete link to survival of patients with a specific tumor type.
Additional Mayo researchers on this study include: Catherine Moser; Ruben Bonilla Guerrero, M.D.; Ileana Aderca, Megan Garrity-Park; Hongzhi Zou, M.D., Ph.D.; Abdirashid Shire, Ph.D.; David Nagorney, M.D.; and Schuyler Sanderson, M.D.; also former fellows: Dalbir Sandhu, M.D.; Tao Han, M.D., Ph.D.; Kenard Jackson; and Hajime Isomoto, M.D.; and former staff member Alex Adjei, M.D., Ph.D., and Chunrong Yu, Ph.D., both currently of Roswell Park Cancer Institute, Buffalo, N.Y. Other collaborators included Ju-Seog Lee, Ph.D., and Snorri Thorgeirsson, M.D., Ph.D., of the National Cancer Institute, Bethesda, Md.
This research was supported by the National Institutes of Health, The Richard M. Schulze Family Foundation, and both Mayo Clinic’s Miles and Shirley Fiterman Center for Digestive Diseases and the Cancer Center. For more information on liver cancer research at Mayo Clinic, visit: http://mayoresearch.mayo.edu/mayo/research/gastro_cancer/hepatobiliary.cfm.
Mayo Clinic
200 First St. SW
Rochester, MN 55902
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Researchers Discover ‘Modus Operandi’ Of Heart Muscle Protein
April 11, 2008
Researchers at the University of Pennsylvania School of Medicine have discovered that a protein called leiomodin (Lmod) promotes the assembly of an important heart muscle protein called actin. What’s more, Lmod directs the assembly of actin to form the pumping unit of the heart. The findings appear in this week’s issue of Science.
“Very little was known about Lmod when we began this study,” says lead author Roberto Dominguez, PhD, Associate Professor of Physiology.
“It appeared that this protein was present in muscle cells but this had not been demonstrated directly and nobody knew what it did,” explains Dominguez. “We compared the amino acid sequence of Lmod with the sequence of another protein called tropomodulin [Tmod] that was already known to bind actin filaments in muscle cells. We found that one part of Lmod was very similar to Tmod, but Lmod was a bigger protein than Tmod and contained unique features that made us suspect that it could assemble the actin filaments of the heart muscle. This is exactly what we found.”
The results answer a question that scientists studying the heart have long asked: What controls the assembly of the pumping unit of the heart?
Actin is the most abundant protein in most animal cells and forms long polymers, or filaments, that make up the cell skeleton. In the cells that make up muscles and the heart, interactions of actin filaments with motor proteins produce the contractions that pump blood through the body.
Actin spontaneously forms polymers in test tubes, but living cells use nucleator proteins to control the time and place where actin filaments forms. “For a long time, physiologists have wondered what serves as the nucleator protein in cardiac muscle cells,” says co-author Professor Thomas Pollard, PhD, of Yale University. “It was very satisfying after all these years to discover that Lmod can serve as the nucleator protein to initiate the forming of actin polymers in heart muscle cells.”
Lmod also directs actin filaments to the sarcomere, the part of the heart that controls contractions or pumping. When Lmod was knocked down in cardiac muscle cells by an RNA silencing technique, the sarcomeres became completely disorganized and could not direct muscles to contract.
Proper localization of Lmod in heart cells is critical, because even moderately elevated levels promote the formation of abnormal actin bundles in the nuclei of cardiac muscle cells where actin does not belong. A similar disorganization of actin bundles is characteristic of a disease of skeletal muscle weakness called intranuclear rod myopathy. Although this disease is caused by a mutation in a skeletal muscle-specific actin gene, the similarity in appearance suggests that mutations in Lmod could cause the same type of disease in cardiac muscle cells.
The Penn team is currently studying how the heart regulates the level of Lmod and how Lmod might be relevant to cardiac muscle disease. In addition, the team is attempting to crystallize Lmod in order to study its structure directly.
Malgorzata Boczkowska of Penn and David Chereau of Boston Biomedical Institute are co-first authors of this study. Other key contributors are Pekka Lappalainen and Aneta Skwarbek-Maruszewska of the University of Helsinki; Ikuko Fujiwara of Yale; David B. Hayes of Boston Biomedical Institute; and Grzegorz Rebowski of Penn. The study was supported by grants from the National Heart Lung and Blood Institute and the National Institute of General Medical Sciences.
PENN Medicine is a $3.5 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System.
Penn’s School of Medicine is currently ranked #3 in the nation in U.S.News & World Report’s survey of top research-oriented medical schools; and, according to most recent data from the National Institutes of Health, received over $379 million in NIH research funds in the 2007 fiscal year. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.
The University of Pennsylvania Health System includes three hospitals its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation’s “Honor Roll” hospitals by U.S.News & World Report; Pennsylvania Hospital, the nation’s first hospital; and Penn Presbyterian Medical Center a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.
University of Pennsylvania School of Medicine
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House Committee Asks Industry For Input On FDA Approval Process Of Follow-On Biologics
April 11, 2008
House Energy and Commerce Health Subcommittee leaders last week sent health industry stakeholders a six-page list of questions about how to create a pathway for FDA to approve follow-on biologics, CongressDaily reports. The request is the “first major movement on the issue” from subcommittee leaders since Chair Frank Pallone (D-N.J.) and ranking member Nathan Deal (R-Ga.) began compromise negotiations in the fall, according to CongressDaily. Other lawmakers have introduced follow-on biologics legislation, but the measures “vary wildly on how to best task FDA with approving the low-cost versions of biologic drugs,” CongressDaily reports.
The questions were sent by Pallone and Deal to more than 30 trade associations, big businesses, major biotechnology companies, unions and other organizations, including the Generic Pharmaceutical Association and the Biotechnology Industry Organization. The questions also were sent to FDA, the Federal Trade Commission and CMS. The questions focused on potential safety issues, market exclusivity, mandated clinical trials, interchangeability at pharmacies, patent protection and possible savings generated by follow-ons.
The lawmakers wrote, “Members of the Subcommittee on Health are committed to this issue and several have introduced legislation to establish an abbreviated approval process,” adding, “We have found it challenging, however, to reach consensus on a single bill that would accomplish this goal.” According to the lawmakers, “In order for the subcommittee to better evaluate the merits, benefits and costs of a biosimilars bill, we wish to understand more fully the range of perspectives, concerns and objectives that might be addressed in such a legislative proposal.” They added, “We are also interested as to where consensus exists within the biotechnology community and among other stakeholders.” Pallone and Deal have requested responses to the questions by April 22 (Edney, CongressDaily, 4/9).
Competition Can Lower Costs, Opinion Piece Says
The cost of biologics can be “expected to remain high for the majority of patients who need them,” unless “Congress allows monopoly-busting competition by creating a regulatory pathway for generic versions of these medicines from other manufacturers,” Insmed CEO Geoffrey Allan writes in a Richmond Times-Dispatch opinion piece. According to Allan, biologics “can cost 20 times more than traditional drugs.” He adds that the costs “reflect the high expenditures for research and development that go into creating these medicines, the complexity of their manufacture, the enormous patient benefit and the need for innovators to make a reasonable profit,” as well as the fact that they “are sold under monopoly conditions that permit prices to remain high.”
According to Allan, more than $10 billion of biologics will lose their patents by 2011 with an additional $9 billion to $10 billion losing patent protection between 2012 and 2015. He continues, “The stakes for patients and their caregivers are significant.” Allan writes, “Bringing competition to the current de facto monopoly will not only lower costs, but also bring competition and advancement to one of our most innovative industries” (Allan, Richmond Times-Dispatch, 4/6).
Reprinted with kind permission from http://www.kaisernetwork.org. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at http://www.kaisernetwork.org/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork.org, a free service of The Henry J. Kaiser Family Foundation© 2007 Advisory Board Company and Kaiser Family Foundation. All rights reserved.
Novel Process Behind Heart Muscle Contraction Discovered
April 10, 2008
Researchers from the University of Pittsburgh and the University of Chicago were able to control heart muscle function in a new way after discovering the previously unknown role of two enzymes in heart muscle contraction, as detailed in the April 11 cover story of the Journal of Biological Chemistry. Although in the early stages, the research provides fresh knowledge of how heart muscle functions and also holds early potential as a treatment for various heart diseases - including congestive heart failure - that is possibly less taxing on the heart than current regimens.
Experiments on slivers of heart muscle revealed that heart muscle contractions can be regulated by the enzymes histone acetyltransferases (HATs) and histone deacetylases (HDACs), explained Pitt professor Sanjeev Shroff, the Gerald McGinnis Chair of Bioengineering in the Swanson School of Engineering. Shroff and Pitt research associate Stephen Smith collaborated with Mahesh Gupta, an associate professor of surgery at the University of Chicago, and his research associate Sadhana Samant. The project was funded by a grant from the National Institutes of Health.
The team found that HATs and HDACs influence acetylation of certain heart muscle proteins, a process wherein a radical cluster of atoms called an acetyl group attach to a protein and change its function. HATs facilitate acetylation, and HDACs remove the acetyl group. The team discovered that acetylation renders the muscle fiber more sensitive to calcium, which causes the muscle to contract.
“This is a completely new process in the area of heart muscle contraction,” Shroff said. “Acetylation is widely known to regulate such events inside the cell nucleus as gene regulation, but it’s never before been associated with heart muscle contraction.”
Furthermore, Shroff and his colleagues could intervene in this microscopic process to control heart muscle contraction. By inhibiting HDACs, they increased the calcium sensitivity of the muscle fibers and strengthened contraction.
As a possible treatment for such conditions as congestive heart failure, this technique could present an alternative to current therapies that counteract heart muscle weakness by boosting cellular calcium content, Shroff said. The heightened calcium improves muscle contraction but also results in more energy consumption in hearts that often are energy-starved to begin with.
In contrast, inhibiting HDAC alters a natural process to make heart muscle more sensitive to the prevailing level of calcium, he said.
“We did not create this process - we are just manipulating what is already there,” Shroff explained. “The physiology to block HDAC is already there, and we just took advantage of that. This perturbation does not require greater mobilization of calcium, so we won’t end up with increased cardiac energy consumption. That’s been the Achilles heel of treatment so far.”
The team’s next step involves examining HAT- and HDAC-driven regulation of cardiac contraction in the whole animal rather than just muscle samples. Then it can better determine the overall significance of the newly discovered process to the intact heart function and its therapeutic potential.
“We want to see how much protein acetylation matters when operating alongside all the other processes in the heart and the body,” Shroff said. “If this process is shown to be significant under these conditions, it will be an exciting finding.”
For the entire paper, visit the Journal of Biological Chemistry Web site
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4/9/08/tmw
Source: Morgan Kelly
University of Pittsburgh
Secrets Of The Heart Revealed By Molecular Imaging
April 10, 2008
The extraordinary action of a new cellular therapy came to light as a result of powerful PET and SPECT imaging in a recent study reported in the April issue of the Journal of Nuclear Medicine. Researchers in Germany were able to observe the repair action of circulating progenitor cells (CPCs), immature blood-derived cells capable of developing into adult stem cells, as they successfully preserved healthy heart tissue and corrected blood flow imbalance within the heart.
Twenty-six patients took part in the randomized, placebo-controlled and double-blinded study. Following the recanalization of blocked coronary arteries (the surgical reopening or formation of new paths for blood flow), one group received an infusion of progenitor cells. FDG PET and 99mTc-tetrofosmine-SPECT were then used to image relative changes in myocardial perfusion (blood flow through the middle and thickest part of the heart) and glucose metabolism.
The results were compared with a control group that had undergone recanalization but did not receive CPCs. In the CPC group, normalization of glucose metabolism and coronary blood flow was seen in nearly 50 percent of the repaired artery segments.
“PET and SPECT are the only techniques capable of validating the metabolic changes we needed to observe in the heart once we had administered the progenitor cells,” said Kai Kendziorra, M.D., a specialist in Nuclear Medicine at the University of Leipzig in Leipzig, Germany. “The results shown by these imaging modalities provide the evidence needed to expand the use of CPC treatment.”
Earlier research has shown that when a patient’s progenitor cells are activated by growth factors, the result is increased cell division, which is vital to the tissue repair process. In this study, progenitor cells developed from circulating blood were also found to be capable of repairing dysfunctional - yet viable - myocardial tissue, a condition referred to as “hibernating myocardium.”
Kendziorra said he believes that in addition to assisting in monitoring and guiding treatment of heart patients, PET scans may also be helpful in selecting those who would profit the most from CPC administration.
“Early detection of hibernating myocardial tissue via noninvasive imaging modalities such as PET and SPECT will help us to assess a patient’s myocardial metabolism and blood flow,” he said. “Subsequent early coronary recanalization and CPC administration may lead to treatment-specific normalization and reduce the risk of cardiac events over longer periods.”
“For decades, nuclear medicine imaging has contributed functional assessment to the anatomical definition of the presence or absence of disease,” said Alexander J. McEwan, M.D., president of SNM. “Today molecular imaging is on the way to revolutionizing patient care - by integrating information about location, structure, function and biology - leading to a package of non-invasive imaging tools with enormous potential for improving patient care and outcomes.”
Co-authors of “Effect of Progenitor Cells on Myocardial Perfusion and Metabolism in Patients After Recanalizatoin of a Chronically Occluded Coronary Artery” include Henryk Barthel, Osama Sabri and Regine Kluge, Department of Nuclear Medicine; Sandra Erbs and Gerhard Schuler, Heart Center Leipzig GmbH; and Frank Emmrich, Institute of Clinical Immunology and Transfusion Medicine, all with the University of Leipzig, Leipzig, Germany; and Rainer Hambrecht, Department of Nuclear Medicine, University of Leipzig, Leipzig, Germany and Heart Center Bremen, Bremen, Germany.
About SNM - Advancing Molecular Imaging and Therapy
SNM is an international scientific and professional organization of more than 16,000 members dedicated to promoting the science, technology and practical applications of molecular and nuclear imaging to diagnose, manage and treat diseases in women, men and children. Founded more than 50 years ago, SNM continues to provide essential resources for health care practitioners and patients; publish the most prominent peer-reviewed journal in the field (The Journal of Nuclear Medicine); host the premier annual meeting for medical imaging; sponsor research grants, fellowships and awards; and train physicians, technologists, scientists, physicists, chemists and radiopharmacists in state-of-the-art imaging procedures and advances. SNM members have introduced - and continue to explore - biological and technological innovations in medicine that noninvasively investigate the molecular basis of diseases, benefiting countless generations of patients. SNM is based in Reston, Va.; additional information can be found online at http://www.snm.org/.
Source: Kathryn Wiley
Society of Nuclear Medicine
Gene Involved In Blood Stem Cell Replication, Movement, Identified By Joslin Study
April 10, 2008
Researchers at the Joslin Diabetes Center have identified a gene that is responsible for the division and movement of marrow-derived, blood-forming stem cells, a finding that could have major implications for the future of bone marrow and blood cell transplantation.
Every year, some 45,000 patients undergo bone marrow or peripheral blood progenitor cell transplantation for the treatment of a variety of diseases, including leukemia, lymphoma, and immunodeficiency. Blood cell transplantation may also one day help people with diabetes better tolerate islet cell transplants without the need for prolonged use of powerful immunosuppressive drugs. In addition, transplantation of blood-forming stem cells, also called hematopoietic stem cells, may prove useful in halting the autoimmune process that causes type 1 diabetes.
The success of bone marrow and blood cell transplants depends on the ability of intravenously infused hematopoietic stem cells, which normally reside predominantly in the bone marrow, to accurately and efficiently migrate from the blood to the marrow of the transplant recipient and, once there, to repopulate their pool of mature blood cells.
In studying mice that lack the transcription factor early growth response gene (EGR-1), a team led by Amy Wagers, Ph.D., found that hematopoietic stem cells in the marrow of these animals divided about twice as often as stem cells in mice with the gene. Mice lacking EGR-1 also had higher numbers of such stem cells circulating in their blood.
The paper, published in the April issue of Cell Stem Cell, is the first to identify EGR-1 as a regulator of hematopoietic stem cell migration and proliferation. The transcription factor has already been identified as a tumor suppressor.
“The transcription factor EGR-1 is important in both of these processes,” said Wagers, Principal Investigator in the Joslin Section on Developmental and Stem Cell Biology, principal faculty member at the Harvard Stem Cell Institute and Assistant Professor of Pathology at Harvard Medical School. “This factor gives us a handle on the discovery of new pathways that regulate the movement of stem cells.”
The knowledge that EGR-1 suppression increases blood-forming stem cell production in the marrow and movement into the bloodstream suggests “a unique opportunity to target this pathway” to manipulate stem cell activity in the context of clinical bone marrow transplantation, the paper says.
“The process of cell migration is critical,” Wagers said. Migration of hematopoietic stem cells from the blood to the marrow is essential for effective transplantation, and the reverse process of migration from the marrow to the blood - an event called “mobilization” - is increasingly exploited for the collection of donor cells for transplant.
“By figuring out in future studies which genes this transcription factor is regulating we can find new ways, by targeting those genes, to enhance stem cell mobilization in people whose stem cells don’t mobilize well,” she said.
Bone marrow transplant patients are also vulnerable to infections in the period post-transplant when they may have insufficient numbers of blood cells. A mechanism to speed the recovery of normal levels of circulating blood cells, based on manipulations of EGR-1, would be beneficial in this manner as well, the paper points out.
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The Wagers Lab at Joslin focuses on hematopoietic stem cells, which constantly maintain and can fully regenerate the entire blood system, as well as on skeletal muscle satellite cells, involved in skeletal muscle formation. This work is aimed particularly at defining novel mechanisms that regulate the migration, expansion, and regenerative potential of these two distinct adult stem cells.
The research was funded in part by a Burroughs Wellcome Fund career award, Smith Family New Investigator award, and an NIH/NIDDK training grant.
Other authors include Irene M. Min, Ph.D.; Giorgio Pietramaggio, M.D.; Francis S. Kim, all of Joslin; Emmanuelle Passegue, Ph.D., of the University of California, San Francisco; and Kristen E. Stevenson, Dana-Farber Cancer Institute.
About Joslin Diabetes Center
Joslin Diabetes Center is the world’s largest diabetes clinic, diabetes research center and provider of diabetes education. Joslin is dedicated to ensuring people with diabetes live long, healthy lives and offers real hope and progress toward diabetes prevention and a cure for the disease. Founded in 1898 by Elliott P. Joslin, M.D., Joslin is an independent nonprofit institution affiliated with Harvard Medical School. For more information on Joslin, visit http://www.joslin.org/.
Source: Kira Jastive
Joslin Diabetes Center
Studying Neural Sludge Accumulation In Alzheimer’s
April 10, 2008
Researchers have identified a key mechanism by which the protein sludge that kills brain cells accumulates in Alzheimer’s disease (AD). Their findings in mice offer clues to treating AD and also could explain why memory centers of the brain are most affected in the disease.
John Cirrito and colleagues published their findings in the April 10, 2008, issue of the journal Neuron, published by Cell Press.
Central to the pathology of AD is accumulation of toxic protein plaque in the interstitial fluid (ISF) between brain cells. This plaque, which comprises clumps of a small protein called A”, interferes with transmission of signals among neurons and ultimately kills them.
A” is produced by the snipping apart of a longer amyloid precursor protein (APP) inside the neuron. However, APP originates at the cell surface, and a key question is how the protein is taken into the cell to be cleaved to produce A”.
This question is clinically significant because plaque formation depends on the concentration of A” in ISF, “meaning that elevated levels of ISF A” are likely to hasten the formation of these toxic species,” wrote the researchers.
“Consequently, knowing the factors that regulate ISF A” levels has implications for AD pathogenesis and may provide insights into therapeutic intervention,” they wrote.
In their experiments, the researchers used tiny probes to sample the ISF in mouse brain, in order to measure A” levels. Previous studies in cell cultures had indicated that APP is transported into the neuron through the process called endocytosis. In endocytosis, molecules are enveloped by special structures in the cell membrane and drawn into the cell.
Cirrito and his colleagues showed that endocytosis also transports APP in vivo: When they inhibited endocytosis in the brain cells of the mice, they saw a reduction in A” levels.
In other experiments, the researchers explored why greater activity among neurons in transmitting nerve impulses is connected to an increase in A” - a phenomenon also shown by previous studies. Since nerve impulse transmission depends on endocytosis to transport molecules, the researchers reasoned that this activity-dependent elevation of A” also depends on endocytosis. They found in their experiments that increasing synaptic activity increased ISF A” levels and that this increase depended on endocytosis.
“We estimate that ~70% of ISF A” arises from endocytosis-associated mechanisms, with the vast majority of this pool also dependent on synaptic activity,” concluded the researchers. “These findings have implications for AD pathogenesis and may provide insights into therapeutic intervention,” they wrote.
“Many studies have postulated that the aggregation of A” in both soluble and insoluble forms in the brain is likely a key initiating factor in AD pathogenesis,” they wrote. “Thus, influences on the aggregation process are potentially major treatment targets.”
The researchers also wrote that their finding could help explain why learning and memory are most affected in AD.
“Brain regions that contain the most metabolic activity throughout life, and presumably have the highest levels of neuronal activity, are also the regions most vulnerable to A” accumulation and aggregation in AD patients,” they wrote. “In each of these cases, synaptic activity appears to play a role in regulating A” levels under physiologic conditions. We now identify a cellular pathway, endocytosis, that likely links synaptic activity and A” production.”
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The researchers include John R. Cirrito, Jae-Eun Kang, Jiyeon Lee, Floy R. Stewart, Deborah K. Verges, Luz M. Silverio, Guojun Bu, Steven Mennerick, and David M. Holtzman, of the Washington University School of Medicine, St. Louis, MO.
Source: Cathleen Genova
Cell Press
Mechanism For Meth Addiction Discovered
April 10, 2008
Researchers have identified, for the first time, long-term changes in the brain circuitry of methamphetamine-addicted mice that can explain why the craving of addiction is so stubborn and long-lived. The research could lead to more effective treatments for addiction to methamphetamine and related drugs.
Nigel Bamford and colleagues published their findings in the April 10, 2008, issue of the journal Neuron, published by Cell Press.
In their experiments, the researchers treated mice with methamphetamine and studied how long exposure to the drug affected levels of the brain chemical dopamine. Researchers have long known that methamphetamine and amphetamine enhance release of dopamine at the connections between neurons, called synapses. Dopamine is one of the brain’s major neurotransmitters, the chemical messengers by which one neuron triggers its neighbor to fire a nerve impulse.
The researchers concentrated on the dopamine machinery in the brain’s corticostriatal region, believed to harbor the “habit” circuitry central to the compulsive drug-seeking of addiction to methamphetamine and amphetamine.
To reveal the flow of dopamine, they used a fluorescent tracer dye that is taken up by the same microscopic sacs, called vesicles, that store and release dopamine in the process of signaling between neurons. Using microscopy to follow the movement of the dye, they could study how methamphetamine affected the dopamine transport machinery in the brain.
Their studies revealed that giving the animals the drug long enough to cause chronic effects caused a depression of the synaptic dopamine machinery in the corticostriatal region that lasted for months after the drug was withdrawn. However, giving the animals a dose of methamphetamine reversed the depressive effects on the synaptic machinery.
The researchers’ experiments also revealed details of how the drug produced its long-term effect - by altering specific types of receptors for dopamine and another neurotransmitter, acetylcholine.
They concluded that the mechanism they discovered “might provide a synaptic basis that underlies addiction and habit learning and their long-term maintenance.”
In a preview of the article in the same issue of Neuron, Jeremy Day and Regina Carelli speculated that the drug effects that the researchers discovered might disrupt the normal machinery for learning in the brain, “leading to aberrant reward processing and action selection. If so, the discovery of methods to reverse this plasticity may be a promising avenue for addiction treatment,” they wrote.
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The researchers include Nigel S. Bamford, University of Washington, Seattle, WA, University of Washington and Children’s Hospital and Regional Medical Center, Seattle, WA; Hui Zhang, Columbia University College of Physicians and Surgeons, New York, NY; John A. Joyce, University of Washington, Seattle, WA; Christine A. Scarlis, University of Washington, Seattle, WA; Whitney Hanan, University of Washington, Seattle, WA; Nan-Ping Wu, Mental Retardation Research Center, The David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA; Veronique M. Andre, Mental Retardation Research Center, The David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA; Rachel Cohen, Mental Retardation Research Center, The David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA; Carlos Cepeda, Mental Retardation Research Center, The David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA; Michael S. Levine, Mental Retardation Research Center, The David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA; Erin Harleton, Columbia University College of Physicians and Surgeons, New York, NY; and David Sulzer, Columbia University College of Physicians and Surgeons, New York, NY, Columbia University College of Physicians and Surgeons, New York, NY, New York State Psychiatric Institute, New York, NY.
Source: Cathleen Genova
Cell Press
Technique Developed At Stanford Enables Creation Of Cancer Stem Cells
April 10, 2008
With a bit of genetic trickery, researchers at the Stanford University School of Medicine have turned normal skin cells into cancer stem cells, a step that will make these naturally rare cells easier to study.
Cancer stem cells are thought to be the ones that drive a cancer, and are therefore the targets of any cancer therapy that must kill them in order to be effective. Understanding these cells has been a challenge, however, because they are rare, difficult to isolate and don’t grow well in the lab.
Howard Chang, MD, PhD, assistant professor of dermatology and senior author of the work, said being able to generate cancer stem cells from normal cells will help move that research forward. “The upshot is that there may be a way to directly create cancer stem cells in the lab so you don’t always have to purify these rare cells from patients in order to study them directly,” he said. The work will be published in the April 10 issue of Cell Stem Cell.
The study also demonstrated that cancer stem cells are much more similar to the stem cells found in embryos, which can develop to form all tissue types, than they are to the more-restricted adult stem cells. This finding has important implications for understanding how cells go awry when they become cancerous.
Cancer stem cells were first discovered in 1994 by researchers at the University of Toronto. In 2003, Michael Clarke, PhD, who was then at the University of Michigan, discovered cancer stem cells in the first solid tumor, breast cancer in this case, showing that the concept of cancer stem cells wasn’t restricted to blood cancers. Clarke has since moved to Stanford, where he is the Karel H. and Avice N. Beekhuis Professor in Cancer Biology, and Stanford has become a leader in cancer stem cell research, with teams finding cancer stem cells in head and neck cancer, colorectal cancer and additional blood cancers. Laboratory researchers at the medical school are also beginning to work with clinical groups to apply cancer stem cell findings to patient care.
One question among cancer stem cell researchers has been how those cells originate. “By the time a patient comes to a hospital, they already have a cancer, so that process has already happened,” Chang said. Generating cancer stem cells in the lab gives scientists insight into how the transformation happens and could lead to new ways of either stopping the transformation early on or detecting and destroying those cells once they form.
Chang and first author David Wong, MD, PhD, postdoctoral scholar, began to answer the question of how cancer stem cells originate by comparing genetic activity in embryonic stem cells with the activity in normal adult stem cells. They found a large group of genes that were active only in embryonic cells. They then looked at which genes were active in cancer stem cells and found that the pattern resembled that of embryonic stem cells.
The finding was a surprise, given that once embryonic stem cells become committed to forming adult cells, such as skin, brain or blood, they were thought to forever deactivate those embryonic genes. Instead, Chang said this work suggests that when those adult cells become cancerous, they turn those embryonic genes back on.
The group also noticed that the genes active in both embryonic and cancer stem cells are controlled by a few biological master regulators. One of those genes, called Myc, has also been shown recently to help convert normal skin cells into embryonic-like cells.
By activating two genes in addition to Myc in normal skin cells, those cells were transformed into what appeared to be cancer stem cells. When transplanted into laboratory mice, the cells formed tumors, one hallmark of a true cancer stem cell.
From here, Chang and Wong hope to learn more about how these genes activate a cancerous state. “Our particular interest is in using this approach to find the mechanism that turns a normal cell into a cancer stem cell,” said Chang, who is also the Kenneth G. and Elaine A. Langone Scholar of the Damon Runyon Cancer Research Foundation.
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Other Stanford researchers who contributed to this work include medical student Helen Liu; Todd Ridky, MD, PhD, instructor in dermatology; and David Cassarino, MD, assistant professor of pathology.
The work was funded by grants from the National Institutes or Health, the American Cancer Society and a Dermatology Foundation Research Career Development Award to David Wong.
Stanford University Medical Center integrates research, medical education and patient care at its three institutions - Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children’s Hospital at Stanford. For more information, please visit the Web site of the medical center’s Office of Communication & Public Affairs at http://mednews.stanford.edu/.
Source: Amy Adams
Stanford University Medical Center
Natural Citrus Supplement May Benefit Diabetics
April 10, 2008
Two new studies presented at the Experimental Biology Annual Meeting suggest that an all-natural dietary supplement made from citrus may help people with type 2 diabetes lower their blood glucose numbers after a meal and their LDL-cholesterol levels.
Mal Evans, DVM, MSc, PhD, KGK Synergize Inc’s Scientific Director, said, “Our scientifically validated testing has consistently shown that Diabetinol™ improves blood glucose numbers. This time we saw a sizeable change in glucose intolerance in just a short time. This is good news for many of the 21 million Americans with diabetes. Tighter blood sugar control may mean less diabetic complications like nerve pain and kidney disease. And, that could mean less disability and expense from complications and associated medications and certainly less stress for the patient.
“Although there were no statistically significant changes in fasting blood glucose levels in either group, the Diabetinol™-treated subjects demonstrated an excellent favorable downward trend in their hemoglobin A1C levels. These results suggest that when administered to people with type 2 diabetes over a longer treatment period, Diabetinol™ significantly improves glucose tolerance or the blood glucose numbers following a meal.
“Additionally, the Diabetinol™-treated group showed improvements in LDL-cholesterol levels. An elevated LDL-cholesterol level is a risk factor for heart disease, and having type 2 diabetes increases an individual’s risk for developing heart disease two to four times. In fact, sixty-five percent of deaths from diabetes are related to cardiovascular causes such as heart attack and stroke,” said Evans.
Hemoglobin A1C is an indicator of average blood glucose control over two to three months and is correlated to an individual’s risk of developing diabetic complications such as diseases of the eye, kidney and nerves.
In a pilot study, twenty adults with diabetes who were taking oral diabetes medications were randomly assigned to receive either Diabetinol™ or a placebo twice per day for three months. Each subject had mildly to moderately elevated cholesterol levels at the start of the study as well.
After 84 days, the group receiving Diabetinol™ showed a significant 19 percent reduction in glucose intolerance measured as peak changes in blood glucose over the four hours of a standard oral glucose challenge. The placebo group showed no significant improvements in glucose intolerance. A standard glucose challenge involves ingesting 100 grams of glucose and having blood glucose measurements after 30 minutes and hourly for four hours. Neither the investigators nor the volunteers knew who was receiving the Diabetinol™ or the placebo.
The number of Americans with diabetes has been increasing as obesity rates continue to rise. At least 90% of Americans with diabetes have type 2 diabetes. In type 2 diabetes, the body either produces too little insulin or the cells do not respond properly to the insulin and leave the cells starved for energy while raising the blood glucose level.
Earlier animal studies led researchers to test Diabetinol in humans. Twelve hamsters were treated with a special high-fructose diet to induce diabetes-like symptoms including increased blood glucose, insulin, cholesterol and triglyceride levels. Half of the animals were then given Diabetinol™ for 42 days. The other six hamsters were given no anti-diabetic treatment. At the end of the study, the Diabetinol™-treated animals showed improvements in each blood glucose, insulin, and cholesterol and triglyceride levels.
Taken together, these studies suggest that Diabetinol™ may help lower blood glucose levels and be beneficial in lowering the risks of heart disease and diabetic complications in people with type 2 diabetes.
An additional six-month study is underway to evaluate Diabetinol™ treatment in a larger sample of people with type 2 diabetes.
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About KGK Synergize Inc:
KGK Synergize provides contract research services to the health nutrition, biotechnology and pharmaceutical industries, which include analytical chemistry, in vitro assays, in vivo models, toxicology and human clinical trials.
In addition to its contract research capabilities, KGK has a Product Development Division which brings new and innovative natural health products to the point where they are ready to be manufactured and marketed. These products include SytrinolTM for cardiovascular health, DiabetinolTM for the treatment and/or prevention of Type II Diabetes, and DermytolTM, a new product for the protection of sun damage to the skin.
For further information please go to:
http://www.kgksynergize.com/
Source: Jeff Nedelman
Strategic Communications
