Shift Workers’ Body Clocks Studied To Prevent Certain Cancers
Does shift work predispose you to cancer by altering the body’s response to hormones? And if so, can a dietary supplement help? Those are the questions researchers at The Cancer Institute of New Jersey (CINJ) hope to answer through a new study, which recently received $600,000 in funding from The V Foundation for Cancer Research. CINJ is a Center of Excellence of UMDNJ-Robert Wood Johnson Medical School.
The V Foundation Grant in Translational Clinical Research will support the work of the team led by Helmut Zarbl, PhD, ATS, associate director for Public Health Science at CINJ, and professor of toxicology at UMDNJ-Robert Wood Johnson Medical School, in the area of cancer prevention and circadian rhythms. Circadian rhythms are best described as one’s “body clock,” which controls sleep, hunger, hormones, and activity among other things in all living cells.
According to Dr. Zarbl, epidemiological studies have consistently shown that women and men, who serve the community by working at night, have a significantly elevated risk of breast cancer and possibly prostate cancer. In fact, shift work that alters circadian rhythm is now classified as a probable carcinogen by the International Agency for Research Cancer. Zarbl and his team have recently found that chemical carcinogens also disrupt circadian rhythm, leading to what he considers an imbalance in a protein that prevents cancer by regulating the cell’s response to hormones. More importantly, they found that a naturally occurring compound, methylselenocysteine (MSC), found in many foods, prevents cancer in rats by restoring circadian rhythm and the cell’s response to estrogens. MSC contains the trace mineral selenium, which a number of epidemiological studies have shown can reduce the incidence of several types of cancer.
During the course of the three-year grant period, the team will determine if shift work also disrupts the cell’s response to estrogens, and if this effect can be reversed by dietary MSC. The team will address these questions in two groups of participants. The first group comprised of primarily hospital workers will be asked to donate blood while working the day shift, and again after working at least one week on the night shift. This group will determine the effect of shift work on various biomarkers related to circadian rhythm and estrogen response.
In the second phase of the study, 100 volunteers who engage in traditional “shift work” professions, such as firefighters, police, airline and factory personnel, will be recruited through the New Jersey Family Medicine Research Network. For 30 days, this group will take an over-the-counter MSC supplement. Blood taken from these study participants will be used to determine if the MSC supplement can reverse the harmful effects of shift work on circadian rhythms and estrogen response. If so, the results will form the basis for a prospective study to determine if MSC supplements can prevent breast and prostate cancer in those who serve the community by working at night.
Zarbl, who also is the director of the NIEHS Center for Environmental Exposures and Disease at the Environmental & Occupational Health Sciences Institute (jointly administered by UMDNJ-Robert Wood Johnson Medical School and Rutgers, The State University of New Jersey), notes he is greatly appreciative of such support. “The V Foundation has long been committed to unlocking the mysteries of cancer through the funding of novel research. Through their generous support of this translational study, we have an opportunity to determine whether a supplementation of the diet with the amount of MSC found in a single Brazil nut can prevent two of the most common forms of cancer. The implications from such findings could be far reaching,” he noted.
“We’re very excited about this project,” said Nick Valvano, CEO of The V Foundation for Cancer Research. “Through this important research, we’re working toward a future where we can help people by preventing breast and prostate cancers.”
Co-investigators include Howard Kipen, MD, MPH, CINJ member and professor of environmental and occupational medicine at UMDNJ-Robert Wood Johnson Medical School; Benjamin Crabtree, PhD, co-program leader of the Population Science Program at CINJ and professor of epidemiology at UMDNJ-School of Public Health; and Pamela A. Ohman Strickland, PhD, who is an associate professor of biostatistics in the UMDNJ-School of Public Health. Mingzhu Fang, PhD, a senior staff scientist in the Zarbl laboratory and Terry Falco, who is the coordinator for the New Jersey Family Medicine Research Network, also are included on the team.
The award period runs through October 31, 2011.
About The Cancer Institute of New Jersey
The Cancer Institute of New Jersey (http://www.cinj.org) is the state’s first and only National Cancer Institute-designated Comprehensive Cancer Center, and is dedicated to improving the prevention, detection, treatment and care of patients with cancer. CINJ’s physician-scientists engage in translational research, transforming their laboratory discoveries into clinical practice quite literally bringing research to life. The Cancer Institute of New Jersey is a center of excellence of UMDNJ-Robert Wood Johnson Medical School.
The Cancer Institute of New Jersey Network is comprised of hospitals throughout the state and provides a mechanism to rapidly disseminate important discoveries into the community. Flagship Hospital: Robert Wood Johnson University Hospital. Affiliate Hospitals: Bayshore Community Hospital, Carol G. Simon Cancer Center at Morristown Memorial Hospital, Carol G. Simon Cancer Center at Overlook Hospital, CentraState Healthcare System, Cooper University Hospital*, Jersey Shore University Medical Center, JFK Medical Center, Raritan Bay Medical Center, Robert Wood Johnson University Hospital at Hamilton (CINJ at Hamilton), Saint Peter’s University Hospital, Somerset Medical Center, Southern Ocean County Hospital, The University Hospital/UMDNJ-New Jersey Medical School, and University Medical Center at Princeton.
Cancer Institute of New Jersey
New Brunswick
NJ 08901
United States
http://www.cinj.org
Stress May Hasten Growth Of Melanoma Tumors
For patients with a particularly aggressive form of skin cancer malignant melanoma stress, including that which comes from simply hearing that diagnosis, might amplify the progression of their disease.
But the same new research that infers this also suggests that the use of commonly prescribed blood pressure medicines might slow the development of those tumors and therefore improve these patients’ quality of life.
The study, the third by Ohio State University scientists in the last two years that looked for links between stress hormones and diseases like cancer, is published in the February 2009 issue of the journal Brain, Behavior and Immunity.
Eric V. Yang, a research scientist at the Institute for Behavioral Medicine Research (IBMR), exposed samples of three melanoma cell lines to the compound norepinephrine, a naturally occurring catecholamine that functions as a stress hormone. In times of increased stress, levels of norepinephrine increase in the bloodstream.
Yang and colleague Ronald Glaser were looking for changes in the levels of three proteins released by the cells. Glaser is a professor of molecular virology, immunology and medical genetics, member of the university’s Comprehensive Cancer Center and director of the IBMR.
One of the proteins vascular endothelial growth factor, or VEGF plays a key role in stimulating the growth of new blood vessels needed to feed a growing tumor, a process called angiogenesis. The other two proteins, Interleukin-6 and Interleukin-8, are both involved in fostering tumor growth.
All three of the cell lines were grown from tissues taken from secondary tumors that had metastasized from a primary site and they signify aggressive forms of cancer. But one of them C8161 – represented the most aggressive and advanced form of melanoma.
“We noticed that all three of these proteins increased in response to the norepinephrine,” Yang explained, adding that in the C8161 cells, “we got a 2,000 percent increase in IL-6. In untreated samples from this cell line, you normally can’t detect any IL-6 at all.
“What this tells us is that stress might have a worse effect on melanoma that is in a very aggressive or advanced stage, and that one marker for that might be increased levels of IL-6,” he said.
The researchers ruled out cell proliferation – an increase in the number of cells present – as a reason for the increase in all three proteins. That meant that the only other answer was that the cells were increasing their expression of the genes responsible for producing these compounds.
The researchers showed that the norepinephrine molecule binds to receptors on the surface of cancer cells and once this linkage occurs, it stimulates the release of the proteins that support angiogenesis and tumor growth.
Yang and Glaser first confirmed that the receptors were present on cells in all three cell lines and then tested what would happen when the receptors were blocked by common blood pressure medicine – the so-called “beta-blockers.”
When the beta-blockers did bind to the receptors, the production of the three proteins reduced significantly, suggesting that in patients with melanoma, using these types of medications might be used to slow the progression of the disease in patients.
While the study was restricted to tumor cell lines, rather than using animal models or human patients, the findings are still exciting. The researchers found strong evidence that the same receptors are expressed on the surface of tumor cells from biopsies that were taken from melanoma patients. That supports the clinical importance of the results.
Two earlier studies on different tumor cell lines – one prepared from a multiple myeloma and the other from a nasopharyngeal carcinoma – also showed that exposure to norepinephrine increased the levels of proteins responsible for accelerating tumor growth.
The research is showing not only that different forms of cancer react differently to stress hormones but also that those reactions can vary within a specific form of the disease, with the possibility of a more aggressive form of the disease reacting more strongly to the stressors.
For melanoma patients, that can be very important since these tumors are able to metastasize, or spread, when they are much smaller than most other solid cancers. The American Cancer Society estimates that nearly 48,000 cases of melanoma are diagnosed each year and nearly 8,000 people are killed each year by the disease.
This research was supported in part by the National Cancer Institute. Other collaborators in the study included Sanford Barsky, professor and chair of pathology; and IBMR members Elise Donovan, Min Chen, Amy Gross, Jeanette Webster Marketon and Seung-jae Kim.
Ohio State University
1125 Kinnear Rd.
Columbus
OH 43212-1153
United States
http:// www.osu.edu
Early-Stage Multiple Sclerosis Reversed By Stem Cell Transplant
Researchers from Northwestern University’s Feinberg School of Medicine appear to have reversed the neurological dysfunction of early-stage multiple sclerosis patients by transplanting their own immune stem cells into their bodies and thereby “resetting” their immune systems.
“This is the first time we have turned the tide on this disease,” said principal investigator Richard Burt, M.D. chief of immunotherapy for autoimmune diseases at the Feinberg School. The clinical trial was performed at Northwestern Memorial Hospital where Burt holds the same title.
The patients in the small phase I/II trial continued to improve for up to 24 months after the transplantation procedure and then stabilized. They experienced improvements in areas in which they had been affected by multiple sclerosis including walking, ataxia, limb strength, vision and incontinence. The study will be published online January 30 and in the March issue of The Lancet Neurology.
Multiple sclerosis (MS) is an autoimmune disease in which the immune system attacks the central nervous system. In its early stages, the disease is characterized by intermittent neurological symptoms, called relapsing-remitting MS. During this time, the person will either fully or partially recover from the symptoms experienced during the attacks. Common symptoms are visual problems, fatigue, sensory changes, weakness or paralysis of limbs, tremors, lack of coordination, poor balance, bladder or bowel changes and psychological changes.
Within 10 to 15 years after onset of the disease, most patients with this relapsing-remitting MS progress to a later stage called secondary progressive multiple sclerosis. In this stage, they experience a steady worsening of irreversible neurological damage.
The 21 patients in the trial, ages 20 to 53, had relapsing-remitting multiple sclerosis that had not responded to at least six months of treatment with interferon beta. The patients had had MS for an average of five years. After an average follow-up of three years after transplantation, 17 patients (81 percent) improved by at least one point on a disability scale. The disease also stabilized in all patients.
In the procedure, Burt and colleagues treated patients with chemotherapy to destroy their immune system. They then injected the patients with their own immune stem cells, obtained from the patients’ blood before the chemotherapy, to create a new immune system. The procedure is called autologous non-myeloablative haematopoietic stem-cell transplantion.
“We focus on destroying only the immune component of the bone marrow and then regenerate the immune component, which makes the procedure much safer and less toxic than traditional chemotherapy for cancer,” Burt said. After the transplantation, the patient’s new lymphocytes or immune cells are self-tolerant and do not attack the immune system.
“In MS the immune system is attacking your brain,” Burt said. “After the procedure, it doesn’t do that anymore.”
In previous studies, Burt had transplanted immune stem cells into late-stage MS patients. “It didn’t help in the late stages, but when we treat them in the early stage, they get better and continue to get better,” he said.
“What we did is promising and exiting, but we need to prove it in a randomized trial,” Burt noted. He has launched a randomized national trial.
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Article adapted by Medical News Today from original press release.
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For more information visit : http://clinicaltrials.gov/ct2/show/NCT00273364
Source: Marla Paul
Northwestern University
Improved Understanding Of Circadian Clocks
Scientists from Queen Mary, University of London have discovered a new part of the mechanism which allows our bodyclocks to reset themselves on a molecular level.
Circadian clocks regulate the daily fluctuations of many physiological and behavioural aspects in life, and are synchronised with our surrounding environment via light or temperature cycles. Natural changes in the length of the day mean that an animal’s circadian clock often has to reset itself on a molecular level, to avoid getting out of sync with the changing calendar.
Professor Ralf Stanewsky and his team from Queen Mary’s School of Biological and Chemical Sciences study the circadian clocks of Drosophila, a type of fruit fly. Writing in the journal Current Biology, they report that the resetting process is governed by three factors, called Cryptochrome, Jetlag and Timeless.
The team’s findings suggest that the light responses of circadian clocks are fine tuned on a molecular, by small differences in the binding affinities of clock proteins.
Professor Stanewsky explains: “A circadian photoreceptor called Cry is activated by light in the blue spectrum. Once active, Cry then becomes able to bind to a protein called Jetlag. The Jetlag protein then helps to destroy another protein called Timeless, which is used to reset the bodyclock.
“Crucially though, we found that Jetlag also helps to destroy the original photoreceptor Cry itself. This allows the Timeless protein to reaccumulate during the next day, making sure that the clock mechanism continues to tick.”
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Article adapted by Medical News Today from original press release.
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Source: Sian Halkyard
Queen Mary, University of London
Key Component In Cell Replication Identified By Stanford Scientists
Last week, a presidential limousine shuttled Barack Obama to the most important job in his life. Scientists at the Stanford University School of Medicine have now identified a protein that does much the same for the telomerase enzyme – ferrying the critically important clump of proteins around to repair the ends of chromosomes that are lost during normal replication. Without such ongoing maintenance, stem cells would soon cease dividing and embryos would fail to develop.
“This is the first new protein component of telomerase that has been identified in 10 years,” said Steven Artandi, MD, PhD, associate professor of hematology. “And it’s likely to be a valuable target for anti-cancer therapies.”
Artandi is the senior author of the research, which will be published in the Jan. 30 issue of Science. Graduate student Andrew Venteicher is the first author. The two collaborated with scientists at the National Cancer Institute-Frederick and the University of Georgia to conduct the research.
Telomerase is normally expressed in adult stem cells and immune cells, as well as in cells of the developing embryo. In these cells, the enzyme caps off the ends of newly replicated chromosomes, allowing unfettered cell division. Without telomerase, cells stop dividing or die within a limited number of generations. Unfortunately, the enzyme is also active in many cancer cells. Artandi and his collaborators found that blocking the inappropriate expression of the protein, called TCAB1, in human cancer cells keeps telomerase from reaching its DNA targets, called telomeres, and may limit the cell’s life span.
“There are currently no effective telomerase inhibitors,” said Artandi. “We’ve never really understood before how the enzyme gets to the telomeres; it’s been a complete black box. Now we’re starting to piece together how it happens, and that gives us more opportunities to interfere with its function.”
Telomerase has been subject of intense research for years, but scientists have been stymied by the enzyme’s large size and extreme rarity. Few cells in the adult body make the huge protein complex, and even they make only tiny amounts. As a result, only some members have been identified.
“It’s been incredibly challenging to figure out all the protein components of telomerase,” said Artandi, who refers to the unknown members of the complex as “dark matter.” “We know how big the enzyme is, and it’s clear that the known components don’t add up to the total. Now we’ve identified one more member.”
The researchers used a highly sensitive protein identification technique called mass spectrometry to ferret out TCAB1’s presence in telomerase based on its ability to bind to another, known component of the enzyme. Early last year, Artandi’s lab used the same technique to identify for the first time two other proteins – pontin and reptin – that are important for assembling the massive complex. This time around they identified TCAB1, a protein of previously unknown function.
Unlike pontin and reptin, TCAB1 is a true component of telomerase. But it’s not required for the enzyme’s activity. Rather, it recruits the telomerase complex to processing and holding areas in the nucleus of the cell called Cajal (pronounced “cuh-hall”) bodies. Like a high-end garage, Cajal bodies apply the finishing touches to a variety of proteins that use small molecules of RNA to conduct their activities (telomerase, for example, uses an RNA molecule as a template for the DNA chain it tacks onto the ends of chromosomes). When appropriate, TCAB1 then chauffeurs the telomerase complex to the waiting end of a newly replicated chromosome.
“TCAB1 is absolutely necessary for the telomerase to make this jump from Cajal bodies to telomeres,” said Artandi. “When we inhibited its activity in human cancer cells, the telomeres grew shorter,” implying the cancer cells would die more quickly.
Prior to this study, TCAB1 had no known function. “Andy [Venteicher] found that TCAB1 binds not only telomerase, but also a specific class of small, non-coding RNA molecules that also end up in the Cajal bodies,” said Artandi. He added that the protein may be a common biological shuttle responsible for delivering a variety of molecules to their destinations. He and his collaborators plan to continue their study of TCAB1 and also to identify other telomerase components.
“This is a story that’s been unfolding over decades,” said Artandi. “Telomerase is such a high-priority target for many diseases, but it’s hard to attack when you know very little about it. But that’s changing now.”
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Article adapted by Medical News Today from original press release.
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The research was funded by the National Cancer Institute and the Leukemia and Lymphoma Society. Stanford graduate student Kelly McCann also participated in the research.
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.
Source: Krista Conger
Stanford University Medical Center
Periodontal Treatment Not Found To Reduce Preterm Birth Risk
The study, involving researchers from Duke University Medical Center and the University of North Carolina at Chapel Hill, is one of the largest randomized trials to date to look at the link between the two conditions.
Previous research had suggested that gum disease was associated with very preterm deliveries (defined as less than 32 weeks gestation). That led insurance policies and healthcare providers to recommend scaling and root planing, sometimes referred to as “deep cleaning,” in pregnant women. It was thought that such care had the potential to reduce preterm delivery risk.
These new findings, based on a randomized trial of 1,800 pregnant women with periodontal disease, indicate that routine gum treatments do not reduce the risk of early delivery.
“I’m always asked whether we should mandate dental treatment for all pregnant women,” said Amy Murtha, MD, director of obstetrics research at Duke University Medical Center in Durham, NC, who presented the findings at the annual meeting of the Society for Maternal-Fetal Medicine in San Diego. “The biggest implication of this study is that this level of standard periodontal care will not affect the birth outcome.”
That’s not to say pregnant women should not get dental exams and treatment as needed; they should, Murtha added. “Our study emphasizes that treating periodontal disease during pregnancy is safe, but that standard periodontal care is not enough.”
Progression, or worsening of periodontal disease occurs in about 25 percent of pregnancies, said Steven Offenbacher, DDS, PhD, the study’s lead investigator and director of the UNC-Chapel Hill School of Dentistry-based Center for Oral and Systemic Diseases. The bacterial infection attacks the teeth-supporting tissues below the gum line. Left untreated, it can lead to tooth loss as well as a host of other problems.
This study, conducted at Duke, the University of Alabama at Birmingham and the University of Texas at San Antonio, was overseen by the UNC-Chapel Hill School of Dentistry. Pregnant women with periodontal disease were randomly assigned to two groups: one received periodontal treatment before 23 weeks gestation; the other did not. Overall, no significant differences were reported regarding obstetric or neonatal outcomes when the two groups were compared.
Despite the findings, Murtha said much remains unknown about the relationship between the two conditions. “Periodontal disease and poor pregnancy outcomes travel together, but we don’t know why.”
Nor do researchers understand how or why pregnancy appears to jumpstart the onset and progression of the disease. Murtha said it may be that preterm birth and periodontal disease share a common underlying trait, such as an exaggerated inflammatory response, but more studies are needed to fully explain the connection.
Additional research is also needed to determine whether more intensive periodontal care during pregnancy might make a difference. “Although we did not reduce the risk of preterm births, the level of periodontal care provided in this study was not as effective as compared to earlier studies,” Offenbacher said. It may be that a more aggressive approach to periodontal disease management could have a different outcome, he added.
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Article adapted by Medical News Today from original press release.
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The study was funded by the National Institute of Dental and Craniofacial Research. James D. Beck, PhD, associate dean for research and a Kenan professor within the UNC-Chapel Hill School of Dentistry, was the study’s co-principal investigator. Other UNC-Chapel Hill School of Dentistry researchers include: Luisito Mendoza, DDM and Sally Mauriello, EdD. UNC-Chapel Hill Gillings School of Global Public Health researchers include David Couper, PhD; and Dawn Stewart, MS. Researchers David Cochran, DDS, PhD, and Donald Dudley, MD, are with the University of Texas Health Science Center at San Antonio. Researchers Michael Reddy, DMD, DMSc; Nicolaas Geurs, DDS, and John Hauth, MD, are with the University of Alabama at Birmingham. Heather Jared, MS, formerly with the UNC-Chapel Hill School of Dentistry, also contributed to this research.
Source: Debbe Geiger
Duke University Medical Center
Skin Color Studies On Tadpoles Lead To Cancer Advance
The humble tadpole could provide the key to developing effective anti-skin cancer drugs, thanks to a groundbreaking discovery by researchers at the University of East Anglia (UEA).
The scientists have identified a compound which, when introduced into Xenopus Laevis tadpoles, blocks the movement of the pigment cells that give the tadpoles their distinctive markings and which develop into the familiar greenish-brown of the adult frog.
It is the uncontrolled movement and growth of pigment cells (melanophore) in both tadpoles and humans that causes a particularly dangerous form of skin cancer. By blocking the migration of these cells, the development and spread of cancerous tumours can potentially be prevented.
Published in the Cell Press journal Chemistry & Biology, the findings are the culmination of several years’ work by the UEA team. This unconventional study, which was initiated with funding from the UK Medical Research Council, identifies for the first time an effective new man-made MMP (metalloproteinase) inhibitor, known as ‘NSC 84093′.
The work was led by the University of East Anglia, in partnership with the John Innes Centre (JIC) and Pfizer.
“This is an exciting advance with implications in the fight against cancer,” said lead author Dr Grant Wheeler of UEA’s School of Biological Sciences.
“The next step is to test the compound in other species and, in the longer term, embark on the development of new drugs to fight skin cancer in humans.”
The species Xenopus Laevis (South African clawed frog) is more closely related to humans than one might expect. It only diverged from man 360 million years ago and has the same organs, molecules and physiology. This means that the same mechanisms are involved in causing cancer in both Xenopus tadpoles and humans.
Until the 1960s, Xenopus Laevis frogs were used as the main human pregnancy test. A woman’s urine sample was injected into a live frog. If the urine contained the hCG (human chrionic gonadotropin) hormone, the frog would lay eggs within 24 hours, indicating that the woman was pregnant.
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Article adapted by Medical News Today from original press release.
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‘A chemical genomic approach identifies matrix metallaoproteinases as playing an essential and specific role in Xenopus melanophore migration’ by Grant Wheeler (UEA), Matthew Tomlinson (UEA), Carla Garcia-Morales (UEA), Robert Field (JIC), Pingping Guan ( JIC), Richard Morris (JIC), Martin Rejzek (JIC) and Mark Fidock (Pfizer) is published online on January 29 and in print on January 30.
Source: Simon Dunford, Press Officer
University of East Anglia
Oncogene Inhibits Tumor Suppressor To Promote Cancer: Study Links B-RAF And LKB1
Scientists have uncovered an interesting connection between two important protein kinase signaling pathways that are associated with cancer. The research, published by Cell Press in the January 30th issue of the journal Molecular Cell, may direct new therapeutic strategies for multiple types of cancer.
The protein kinase LKB1 is a known tumor suppressor and the LKB1-AMPK signaling pathway couples energy metabolism with cell growth, proliferation and survival. “Mutations in LKB1 are not frequent in human cancers and it is not clear how tumor cells suppress the signaling pathway to gain growth advantage under conditions of energy stress (common in cancer cells),” explains senior study author Dr. Lewis C. Cantley from Beth Israel Deaconess Medical Center and Harvard Medical School.
Dr. Cantley and colleagues, including Dr. Bin Zheng, designed a study to investigate the molecular mechanisms associated with suppression of the LKB1-AMPK pathway in tumor cells. The researchers used malignant melanoma cells that often have a mutation called “V600E” in the RAF protein B-RAF. The RAF-MEK-ERK pathway is well established as a key regulator of cell growth, proliferation, differentiation and survival.
Mutations in the RAF kinase B-RAF have been found in many types of human cancer but, while oncogenic B-RAF V600E has been linked with tumor induction, growth, maintenance and progression, the specific molecular mechanisms have not been identified. Dr. Cantley’s group found that melanoma cells with the B-RAF V600E mutation had impaired AMPK activation and that inhibition of B-RAF signaling activated AMPK.
The researchers went on to show that LKB1 was phosphorylated by two kinases that are downstream of B-RAF, ERK and Rsk. The phosphorylation of LKB1 interfered with the ability of LKB1 to bind and activate AMPK. Importantly, expression of mutant LKB1 that could not be phosphorylated resulted in activation of AMPK and an inhibition of melanoma cell proliferation.
“Taken together, our results provide a molecular linkage between the LKLB1-AMPK and the RAF-MEK-ERK pathways and suggest that suppression of LKB1 function by B-RAF V600E plays an important role in B-RAF V600E-driven tumorigenesis,” says Dr. Zheng. “It’s conceivable that tumor cells must turn off the LKB1-AMPK signaling pathway to gain a growth advantage under conditions of energy stress.”
Given that B-RAF mutation and loss of LKB1 are associated with multiple types of cancer, the work is likely to have a significant clinical impact. “Further understanding of how the intriguing molecular linkage between LKB1-AMPK and RAF-MEK-ERK functions in tumorigenesis could potentially provide great therapeutic opportunities for cancer treatment,” offers Dr. Cantley.
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Article adapted by Medical News Today from original press release.
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The researchers include Bin Zheng, Harvard Medical School, Boston, MA; Joseph H. Jeong, Dana-Farber Cancer Institute, Boston, MA; John M. Asara, Harvard Medical School, Boston, MA; Yuan-Ying Yuan, Harvard Medical School, Boston, MA; Scott R. Granter, Brigham and Women’s Hospital, Boston, MA; Lynda Chin, Dana-Farber Cancer Institute; and Lewis C. Cantley, Harvard Medical School, Boston, MA.
Source: Cathleen Genova
Cell Press
With Medical School Enrollment Expanding For The First Time In 30 Years, Medical Leaders Urge Educators To Institute Curricula Reform Now
Calling this period “an unparalleled opportunity” for change, an influential group of medical leaders today urged the nation’s medical schools to reform their educational model because it too often fails to give new physicians the right mix of competencies and experiences to practice medicine effectively. The call to action for education reform comes as medical schools are expanding their enrollments for the first time in 30 years to address a shortage of physicians in the United States. In a new report, sponsored by the Josiah Macy, Jr. Foundation, the panel of experts says “medical education has not kept pace with the growing public expectations of physicians or with the novel demands of an increasingly complex healthcare system.”
According to the report “Revisiting the Medical School Educational Mission at a Time of Great Expansion,” medical schools are experiencing an historic growth spurt. By 2020, allopathic medical schools are expected to graduate an additional 5,000 doctors each year. There are nine new allopathic medical schools underway or in the planning stages, and 108 of the nation’s 126 medical schools are increasing class size, some by adding new branches. The number of osteopathic schools is growing as well. Today, there are 28 such schools in the United States, nine more than in 2000, with more planned.
“If we are going to open new schools and expand existing schools, we want to be sure we’re doing it in the most socially responsible way,” says George Thibault, MD, president of the New York-based Josiah Macy, Jr. Foundation. Thibault says this is even more important given the renewed prospects of health reform under the new Obama Administration. If more people have health insurance, there will be a much greater demand for physicians to deliver care. “What we’re saying to medical educators is let’s seize this opportunity to address the mismatch between the kinds of physicians we’re producing and what people want and need,” he says.
The 36-member panel is chaired by Jordan Cohen, MD, the former president of the Association of American Medical Colleges, and composed of medical and institutional leaders from around the country. The group was convened by the Macy Foundation in 2008 to assess ways in which expansion of enrollment could be harnessed to advance the effectiveness of medical education.
“What medical education needs to recognize is that it has a fundamental social mission to train future physicians for a rapidly changing health care system that seeks different competencies than in the past,” says Cohen. “The leaders of medical education institutions need to seize the opportunity that expansion affords to ensure that their institutions are responsive to their public purpose.”
Highlights of what areas schools should focus on:
- Giving student more opportunities to learn the principles of quality improvement, patient safety and patient-centered care;
- Preparing students to work effectively and collaborative as members of health care teams and as part of a system of care;
- Using community-based settings more as classrooms, and hospital settings less, to expose students to a more realistic practice environment;
- Ensuring that physicians have more background in public health education and the role that social factors play in affecting patient health; and
- Emphasizing the importance of problem solving and self-directed learning as a way to keep up with the fast-paced health care environment.
Expanding Diversity and Instilling Professionalism
Increasing the diversity of the applicant pool should be a top priority, the group says. One way to do this would be to relieve the burden of medical student debt. More than 80 percent of medical students today graduate with educational debt that averages $160,000.
The group suggests several ways schools can ease that burden including making additional funds available from endowments or other sources; organizing the curriculum to allow students the option of meeting graduation requirements in three rather than four years; capping tuition at current or reduced levels; and advocating the creation or support of more government programs that provide debt forgiveness in return for limited public service such as the National Health Service Corps.
The high price tag of medical schools discourages too many college students of high potential but modest means from even considering medical careers, the panel adds. The high debt also affects the kinds of physician’s medical students choose to become, which is helping to fuel a shortage of lower paid primary care doctors, such as family physicians and geriatricians.
There also is strong support for re-examining the medical school admissions process to make it more flexible, which would be an important step to attract and produce a more diverse workforce that is more culturally competent and reflective of society. The panel says schools should reduce their reliance on standardized tests, college grade point averages, and traditional undergraduate course requirements as part of the admissions process, and instead employ a more balanced, comprehensive set of admissions criteria to attract, matriculate and support students.
When it comes to professionalism, the group says there is a “conspicuous gap” between what educators say about their commitment to high professional standards and the actual behavior on display in many student learning environments. The panel says schools need to more aggressively commit to professionalism during training and expose students to positive role models that espouse the ethic of putting patients first.
What Barriers Stand in the Way?
Despite the possibility of reform, the panel admits there are substantive barriers to overcome, including:
- The need to capture the attention and active participation of institutional leaders, without which meaningful change won’t happen.
- The perception that current accreditation standards for both undergraduate and graduate medical education are overly rigid. The panel acknowledges that this perceived rigidity may keep educators from considering changes that would shift away from traditional training experiences they have grown comfortable with.
Barriers aside, the panel says schools should not let this opportunity pass them by – especially those medical schools that are just opening their doors or still in the planning stages. “They are in an optimal position to think freshly about how they are constructing their programs so they can be better aligned with societal needs,” says Cohen.
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Article adapted by Medical News Today from original press release.
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Copies of the report “Revisiting the Medical School Educational Mission at a Time of Expansion” can be obtained by visiting http://www.macyfoundation.org
The Josiah Macy, Jr. Foundation is a privately endowed philanthropy located in the borough of Manhattan, New York City. The Foundation supports programs designed to improve the education of health professionals in the interest of the health of the public.
Source: Janet Firshein
Burness Communications
Cymbalta(R) Significantly Reduced Osteoarthritis Knee Pain In New Study
In a new study, Cymbalta (duloxetine HCl) 60-120 mg, taken once daily, reduced pain severity significantly, compared with placebo, in patients with osteoarthritis pain of the knee. Data from the 13-week randomized, double-blind, placebo-controlled clinical trial(1) were presented at the annual meeting of the American Academy of Pain Medicine (AAPM) in Honolulu, Hawaii.
Duloxetine-treated patients showed greater reductions from baseline on the primary endpoint, the 24-hour average pain score on the Brief Pain Inventory (BPI), compared with placebo-treated patients. In the study, 65 percent of duloxetine-treated patients experienced a clinically significant (at least 30 percent) improvement in pain, compared with 44 percent of placebo-treated patients.
The duloxetine-treated patients also showed improved physical function, compared with placebo-treated patients, as measured by the Western Ontario and McMaster Osteoarthritis Index (WOMAC). In this study, patients on duloxetine did not show statistically significant improvements on the WOMAC pain and stiffness subscales compared with placebo.
“The disabling nature of osteoarthritis pain can greatly impact a person’s life,” said Vladimir Skljarevski, M.D., a study author and medical fellow at Eli Lilly and Company. “As our population ages, osteoarthritis of the knee is likely to become an increasing problem.”
The most common adverse events in the study (occurred at a rate of greater than or equal to 5 percent and at least twice the rate of placebo) included nausea, constipation and excessive sweating (hyperhidrosis). Adverse events were similar to those seen in previous duloxetine studies.
Additional Study Highlights
– Compared with patients receiving placebo, patients receiving duloxetine experienced additional improvements associated with osteoarthritis pain of the knee, including:
– Decreased interference from pain in general activity and normal work, as measured by the BPI Pain Interference (BPI-I) scales.
– Duloxetine-treated patients did not show statistically significant improvements compared with placebo-treated patients according to BPI-I measures of mood, walking ability, relations with other people, sleep, enjoyment of life and average interference.
– Weekly mean of the 24-hour average pain severity and worst pain severity.
– PGI-Improvement (PGI-I).
– Duloxetine-treated patients showed statistically significant improvements compared with placebo as measured by PGI-I at each office visit, but not at study endpoint.
– CGI-Severity.
– A total of 31 patients in the study discontinued due to adverse events – seven in the placebo-treated group and 24 in the duloxetine-treated group.
It is estimated that 27 million adults in the United States have osteoarthritis and the prevalence increases with age.(2) Osteoarthritis of the knee is a common subtype of this disorder, impacting the lives of approximately 10 million Americans.(2) In addition to pain, other symptoms of osteoarthritis include aching, stiffness and limited range of motion of the joint.(3) Duloxetine is being studied to manage the pain associated with this disorder.
Methods
In this 13-week double-blind trial, patients were at least 40 years of age without a current diagnosis of major depressive disorder; with no confounding painful conditions or diagnosis of inflammatory arthritis or autoimmune disorders; and with no invasive therapy of the knee in the past three months, knee arthroscopy within the past year or joint replacement of the index knee at anytime. Patients were randomized to duloxetine (n=128) or placebo (n=128) and stratified by whether or not they used nonsteroidal anti-inflammatory drugs. At week seven, patients who showed suboptimal response to the 60 mg (33 patients) dose had their dose increased to 120 mg. The primary efficacy endpoint of the study was the Brief Pain Inventory (BPI) 24-hour average pain rating, which was analyzed using a mixed-model repeated measures (MMRM) approach. Secondary outcomes included the BPI-Severity and Interference items, weekly mean of the 24-hour worst pain and average pain scores, response rates on BPI average pain and weekly 24-hour average pain, the Patient Global Impressions of Improvement, the Western Ontario and McMaster Universities Index (WOMAC) total and subscales, Clinical Global Impressions of Severity, health survey Short Form-36 (SF-36) and EuroQoL Questionnaire – 5 Dimension.
About Cymbalta
Serotonin and norepinephrine in the brain and spinal cord are believed to both mediate core mood symptoms and help regulate the perception of pain. Based on preclinical studies, Cymbalta is a balanced and potent reuptake inhibitor of serotonin and norepinephrine that is believed to potentiate the activity of these chemicals in the central nervous system (brain and spinal cord). While the mechanism of action of Cymbalta is not known in humans, scientists believe its effects on depression and anxiety symptoms, as well as its effect on pain perception, may be due to increasing the activity of serotonin and norepinephrine in the central nervous system.
Cymbalta is approved in the United States for the acute and maintenance treatment of major depressive disorder, the acute treatment of generalized anxiety disorder, the management of diabetic peripheral neuropathic pain and the management of fibromyalgia, all in adults (18+). Cymbalta is not approved for use in pediatric patients.
Important Safety Information
Cymbalta is approved to treat major depressive disorder and generalized anxiety disorder and manage diabetic peripheral neuropathic pain. Antidepressants can increase suicidal thoughts and behaviors in children, adolescents and young adults. Patients should call their doctor right away if they experience new or worsening depression symptoms, unusual changes in behavior, or thoughts of suicide. Be especially observant within the first few months of treatment or after a change in dose. Cymbalta is approved only for adults 18 and over.
Cymbalta is not for everyone. Patients should not take Cymbalta if they have recently taken a type of antidepressant called a monoamine oxidase inhibitor (MAOI), are taking Mellaril(R) (thioridazine) or have uncontrolled glaucoma. Patients should speak with their doctor about any medical conditions they may have, including liver or kidney problems, glaucoma, or diabetes. Patients should tell their doctor about all their medicines, including those for migraine, to avoid a potentially life-threatening condition. Taking Cymbalta with NSAID pain relievers, aspirin, or blood thinners may increase bleeding risk. They also should talk to their doctor about their alcohol consumption. Patients should consult with their doctor before stopping Cymbalta or changing the dose and if they are pregnant or nursing.
Patients taking Cymbalta may experience dizziness or fainting upon standing. The most common side effects of Cymbalta include nausea, dry mouth, sleepiness and constipation.
This is not a complete list of side effects.
For full Patient Information, visit http://www.cymbalta.com.
For full Prescribing Information, including Boxed Warning and medication guide, visit http://www.cymbalta.com.
About Eli Lilly and Company
Lilly, a leading innovation-driven corporation, is developing a growing portfolio of first-in-class and best-in-class pharmaceutical products by applying the latest research from its own worldwide laboratories and from collaborations with eminent scientific organizations. Headquartered in Indianapolis, Ind., Lilly provides answers — through medicines and information — for some of the world’s most urgent medical needs. Additional information about Lilly is available at http://www.lilly.com.
P-LLY
This press release contains forward-looking statements about the potential of Cymbalta for chronic pain including the management of osteoarthritis pain of the knee and reflects Lilly’s current beliefs. However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of development and commercialization. There is no guarantee that the product will continue to be commercially successful. For further discussion of these and other risks and uncertainties, see Lilly’s filings with the United States Securities and Exchange Commission. Lilly undertakes no duty to update forward-looking statements.
References
(1) Chappell, A, et al. Duloxetine 60 to 120 mg Once Daily Versus Placebo in the Treatment of Patients with Osteoarthritis Knee Pain. Poster presented at the American Academy of Pain Medicine Annual Meeting. 29 January 2009.
(2) Lawrence, RC, et al. Estimates of the Prevalence of Arthritis and Other Rheumatic Conditions in the United States. 2008. Arthritis and Rheumatism (58):26-35.
(3) National Pain Foundation Web site – http://www.nationalpainfoundation.org/MyTreatment/articles/Arthritis_Types.asp , accessed on 22 December 2008.
Eli Lilly and Company
http://www.lilly.com
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