Utilizing MRI to Measure Blood Flow Over Atherosclerotic Plaques May Aid in Detection of Dangerous Plaques
(Boston) – Researchers from Boston University School of Medicine (BUSM) have shown...
BUSM Study Reveals B cells as Therapeutic Targets to Alter Obesity-Associated Inflammation and Type 2 Diabetes
Barbara Nikolajczyk, PhD
New research from Boston University School of Medicine (BUSM) reveals that B cells regulate obesity-associated inflammation and type 2 diabetes through two specific mechanisms. The study, published in the Proceedings of the National Academies of Sciences, indicates the importance of continuing to explore B cells as a therapeutic target to treat these diseases. Barbara Nikolajczyk, PhD, associate professor of microbiology at BUSM, is the study’s senior author.
The incidence of diabetes continues to rise at alarming rates. According to the National Institute of Diabetes and Digestive and Kidney Diseases, the disease now affects approximately 25.8 million Americans. In 2007, the National Institutes of Health estimated that the direct and indirect costs of diabetes were a staggering $174 billion.
Type 2 diabetes, which is a common result of obesity, occurs when the body produces insulin but cannot use it properly (insulin resistance) or the body does not produce enough insulin. The body needs insulin to absorb glucose and generate energy. If the body does not produce and respond to insulin appropriately, it can, over time, lead to various complications such as cardiovascular disease, nerve damage, kidney disease and blindness.
Previous research has shown that B cells, which are white blood cells of the immune system, promote inflammation and can lead to the development of type 2 diabetes, but the mechanisms underlying B cell function were unclear.
The results of this study shed light on that question and indicate that B cells secrete a pro-inflammatory ratio of proteins called cytokines, which directly promote the insulin resistance that characterizes type 2 diabetes. The researchers also demonstrated that B cells directly regulate inflammatory T cells, an immune cell type known to cause insulin resistance in animal models of disease.
“Now that we have identified the specific mechanisms by which B cells promote inflammation, we can help develop novel, targeted approaches to treat type 2 diabetes,” said Nikolajczyk. “Our study supports the continued exploration of FDA-approved B cell depletion drugs, which are known to be generally safe and effective, as novel agents to prevent obesity-associated inflammation and type 2 diabetes.”
Research included in this study was supported in part by the National Institutes of Health’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) under grant award numbers R21DK089270 and R56DK096525 (PI: Nikolajczyk) and R56DK090455 (PI: Gerald Denis); the NIDDK’s Boston Area Diabetes Endocrinology Research Center Pilot Program and the Boston Nutrition Obesity Research Center under grant award number DK046200; the NIH’s National Institute of Dental and Craniofacial Research under grant award number 5R21DE021154 (PI: Nikolajczyk); the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) Immunology Training Program under grant award number AI007309; the NIH’s National Heart, Lung, and Blood Institute’s Hematology Training Program under grant award number HL007501; and the Evans Center for Interdisciplinary Biomedical Research at BUSM (PI: Nikolajczyk and Denis).
BUSM Study Reveals Potential Target to Better Treat, Cure Anxiety Disorders
Subimal Datta
Researchers at Boston University School of Medicine (BUSM) have, for the first time, identified a specific group of cells in the brainstem whose activation during rapid eye movement (REM) sleep is critical for the regulation of emotional memory processing. The findings, published in the Journal of Neuroscience, could help lead to the development of effective behavioral and pharmacological therapies to treat anxiety disorders, such as post-traumatic stress disorder, phobias and panic attacks.
There are two main stages of sleep – REM and non-REM – and both are necessary to maintain health and to regulate multiple memory systems, including emotional memory. During non-REM sleep, the body repairs tissue, regenerates cells and improves the function of the body’s immune system. During REM sleep, the brain becomes more active and the muscles of the body become paralyzed. Additionally, dreaming generally occurs during REM sleep, as well as physiological events including saccadic eye movements and rapid fluctuations of respiration, heart rate and body temperature. One particular physiological event, which is a hallmark sign of REM sleep, is the appearance of phasic pontine waves (P-waves). The P-wave is a unique brain wave generated by the activation of a group of glutamatergic cells in a specific region within the brainstem called the pons.
Memories of fearful experiences can lead to enduring alterations in emotion and behavior and sleep plays a natural emotional regulatory role after stressful and traumatic events. Persistence of sleep disturbances, particularly of REM sleep, is predictive of developing symptoms of anxiety disorders. A core symptom of these disorders frequently reported by patients is the persistence of fear-provoking memories that they are unable to extinguish. Presently, exposure therapy, which involves controlled re-exposure to the original fearful experience, is considered one of the most effective evidence-based treatments for anxiety disorders. Exposure therapy produces a new memory, called an extinction memory, to coexist and compete with the fearful memory when the fearful cue/context is re-encountered.
The strength of the extinction memory determines the efficacy of exposure therapy. A demonstrated prerequisite for the successful development of an extinction memory is adequate sleep, particularly REM sleep, after exposure therapy. However, adequate or increased sleep alone does not universally guarantee its therapeutic efficacy.
“Given the inconsistency and unpredictability of exposure therapy, we are working to identify which process(es) during REM sleep dictate the success or failure of exposure therapy,” said Subimal Datta, PhD, director and principle investigator at the Laboratory of Sleep and Cognitive Neuroscience at BUSM who served as the study’s lead author.
The researchers used contextual fear extinction training, which works to turn off the conditioned fear, to study which brain mechanisms play a role in the success of exposure therapy. The study results showed that fear extinction training increased REM sleep. Surprisingly, however, only 57 percent of subjects retained fear extinction memory, meaning that they did not experience the fear, after 24 hours. There was a tremendous increase of phasic P-wave activity among those subjects. In 43 percent of subjects, however, the wave activity was absent and they failed to retain fear extinction memory, meaning that they re-experienced fear.
“The study results provide direct evidence that the activation of phasic P-wave activity within the brainstem, in conjunction with exposure therapy, is critical for the development of long-term retention of fear extinction memory,” said Datta, who also is a professor of psychiatry and neurology at BUSM. In addition, the study indicates the important role that the brainstem plays in regulating emotional memory.
Future research will explore how to activate this mechanism in order to help facilitate the development of new potential pharmacological treatments that will complement exposure therapy to better treat anxiety and other psychological disorders.
According to the National Institute of Mental Health, anxiety disorders affect approximately 40 million American adults each year. While anxiety can sometimes be a normal and beneficial reaction to stress, some people experience excessive anxiety that they are unable to control, which can negatively impact their day to day life.
Research included in this study was supported in part by the National Institutes of Health’s National Institute of Mental Health under grant award number MH 59839 (PI: Datta) and the National Institute of Neurological Disorders and Stroke under grant award number NS 34004 (PI: Datta).
“Safe, long-term opioid therapy is possible” according to BUSM’s Alford in JAMA
Daniel Alford
In a Clinical Crossroads article featured in the March 6, 2013 issue of the Journal of the American Medical Association (JAMA), Dr. Dan Alford from Boston University School of Medicine (BUSM) and Boston Medical Center (BMC) suggests that prescription opioid abuse can be minimized by monitoring patients closely for harm by using urine drug testing (UDT), pill counts, and reviewing prescription drug monitoring program data when available.
Approximately 100 million Americans have chronic pain. The safe and effective use of opioids for the management of chronic pain is complex. Clinicians must balance the goals of relieving pain and suffering while not harming the patient resulting in addiction and overdose.
The JAMA article describes a 71-year old man who had been treated for chronic low back pain since 1981. After getting no pain relief from non-opioids, he achieved pain control with long-term opioids. However a UDT found no opioid in his system on two occasions and his opioid was discontinued. He explained that he occasionally drinks alcohol and does not take his opioid medication when doing so.
“When a patient exhibits behavior for opioid misuse, the clinician should first confirm that the UDT was accurate. If confirmed, the clinician should interview the patient considering the full differential diagnosis for the behavior of concern. Once the etiology has been determined, a change in treatment plan may occur,” explained Alford, an associate professor of medicine at BUSM and the Director of the Addiction Medicine Fellowship program at BMC.
Alford stresses that monitoring for benefit includes measuring improvement in pain, function and quality of life. Monitoring for harm includes detecting opioid misuse through UDT, pill counts and use of state prescription drug monitoring programs.
Decisions to continue or discontinue opioids should be based on the risk-to-benefit ratio. “In this case of the patient with no opioid in his UDT if he was benefiting but taking less than prescribed, I would inquire about the status and safe storage of his extra medication. I would decrease his dose and schedule close follow up with random pill counts and UDT. If there was too much risk (misuse such as diversion) despite benefit, I would discontinue his opioid therapy as was done in this case,” added Alford.
ART DAYS 2013, Share Your Creativity
- ART DAYS 2013
- MONDAY-TUESDAY, April 1-2, 9 a.m.-5 p.m.
- RECEPTIONS BOTH DAYS at 3 p.m.
- BUSM Instructional Building, Hiebert Lounge
All students, faculty and staff from all schools on the BU Medical Campus are encouraged to submit artwork of any medium to the 23rd annual Boston University School of Medicine gallery for the arts. “Art Days” was begun by then Dean Chobanian to foster the support and growth of the creative arts at BUMC. It has been very successful and has shown work from students, faculty and staff and family members. The exhibition is mounted by the Creative Arts Society.
NEW FACET–KEYWORD: This is the second year of a university-wide arts initiative with an annual Keyword to be used as a thematic organizer for various courses and events. The Keyword for this year is RESILIENCE. (“Resilience is marked by flexibility, elasticity, and vivacity in the face of adversity.” Therefore, there may be a special section at Art Days for display of works addressing Resilience. However, it is also fine to submit work not related to the Keyword.
To be placed on the “submit list” or if you have any questions please contact: Dr. Keith Tornheim, 638-8296, email: tornheim@bu.edu
In late March (28 or 29), we will accept paintings, photos, poetry, sculpture, needlework, etc. Pieces should be framed if possible. Security will be provided. Works will be returned April 3. Specific instructions will be sent at a later date to those who respond to this announcement.
BUSM Researchers Use Goal-Oriented Therapy to Treat Diabetic Neuropathies
John D. Otis, MD
Researchers at Boston University School of Medicine (BUSM) and VA Boston Healthcare System (VA BHS) have found that cognitive behavioral therapy (CBT) can help relieve pain for people with painful diabetic neuropathies. The study, which is the first of its kind to examine this treatment for people with type II diabetes mellitus, is published in the March issue of the Journal of Pain.
Type II diabetes mellitus is the most common form of the disease and affects more than 20 million Americans. The onset of type II diabetes mellitus is often gradual, occurring when a person is unable to make or use insulin efficiently. As a result, abnormally high levels of sugar accumulate in the blood, resulting in a condition called hyperglycemia.
Untreated hyperglycemia can develop into diabetic neuropathies, or nerve damage, which causes painful burning and stinging sensations in the hands and feet and permanent nerve damage. Although pain medications for this condition exist, they often have negative side effects such as headaches, dizziness and nausea.
Researchers led by John D. Otis, PhD, an associate professor of psychiatry at BUSM and clinical psychologist at the VA BHS, assessed whether CBT, a psychological, goal-oriented treatment approach aimed at changing maladaptive thoughts and illness supporting behaviors, could be of benefit to veterans with painful diabetic neuropathies.
The study, which was conducted at the VA BHS, compared participants receiving CBT to those receiving treatment as usual. The participants were U.S. veterans age 18 and older who had been diagnosed with type II diabetes and experienced neuropathic pain for more than three months.
Participants attended 11, hour-long CBT sessions, which focused on teaching participants relaxation techniques and how to identify and challenge thoughts that contribute to pain. In addition, participants were taught how to keep active and plan enjoyable activities such as exercise, going for walks or having dinner with friends.
At a four-month follow-up, participants who received CBT reported feeling less pain and reported that pain was less interfering in their daily lives when compared to participants who received treatment as usual.
“This study demonstrates that the millions of people who are experiencing pain and discomfort from type II diabetes mellitus do not need to rely solely on medication for relief,” said Otis. “More broadly, the results of this study add to a growing body of literature demonstrating that cognitive behavioral therapy is an effective psychological treatment approach for chronic pain management,” he added.
This work was supported by a grant from the Veterans of Foreign Wars (VFW) to the diabetes research program at VA BHS.
International consortium discovers seven new genomic regions associated with AMD
Lindsay Farrer
An international group of researchers has discovered seven new regions of the human genome—called loci—that are associated with increased risk of age-related macular degeneration (AMD), a leading cause of blindness. The AMD Gene Consortium, a network of international investigators representing 18 research groups, also confirmed 12 loci identified in previous studies. The study, which is published online in Nature Genetics and represents the most comprehensive genome-wide analysis of genetic variations associated with AMD, was supported by the National Eye Institute (NEI), a part of the National Institutes of Health.
Lindsay A. Farrer, PhD, chief of the biomedical genetics section and professor at Boston University Schools of Medicine (BUSM) and Public Health (BUSPH), is co-lead author of the study.
“This compelling analysis by the AMD Gene Consortium demonstrates the enormous value of effective collaboration,” said NEI Director Paul A. Sieving, MD, PhD. “Combining data from multiple studies, this international effort provides insight into the molecular basis of AMD, which will help researchers search for causes of the disease and will inform future development of new diagnostic and treatment strategies.”
Since the 2005 discovery that certain variations in the gene for complement factor H—a component of the immune system—are associated with major risk for AMD, research groups around the world have conducted genome-wide association studies to identify other loci that affect AMD risk. These studies were made possible by tools developed through the Human Genome Project, which mapped human genes, and related projects, such the International HapMap Project, which identified common patterns of genetic variation within the human genome.
The AMD Gene Consortium combined data from 18 research groups to increase the power of prior analyses. The current analysis identified seven new loci near genes. As with the previously discovered 12 loci, these seven loci are scattered throughout the genome on many different chromosomes.
“A large number of samples was needed to detect additional genetic variants that have small but significant influences on a person’s disease risk,” said Hemin Chin, PhD, NEI associate director for ophthalmic genetics, who assembled the consortium and helped coordinate the study. “By cataloging genetic variations associated with AMD, scientists are better equipped to target corresponding biological pathways and study how they might interact and change with age or other factors, such as smoking.”
The consortium’s analysis included data from more than 17,100 people with the most advanced and severe forms of AMD, which were compared to data from more than 60,000 people without AMD. The 19 loci that were found to be associated with AMD implicate a variety of biological functions, including regulation of the immune system, maintenance of cellular structure, growth and permeability of blood vessels, lipid metabolism and atherosclerosis.
As with other common diseases, such as type 2 diabetes, an individual person’s risk for getting AMD is likely determined not by one but many genes. Further comprehensive DNA analysis of the areas around the 19 loci identified by the AMD Gene Consortium could turn up undiscovered rare genetic variants with a disproportionately large effect on AMD risk. Discovery of such genes could greatly advance scientists’ understanding of AMD pathogenesis and their quest for more effective treatments.
AMD affects the macula, a region of the retina responsible for central vision. The retina is the layer of light-sensitive tissue in the back of the eye that houses rod and cone photoreceptor cells. Compared with the rest of the retina, the macula is especially dense with cone photoreceptors and is what humans rely on for tasks that require sharp vision, such as reading, driving and recognizing faces. As AMD progresses, such tasks become more difficult and eventually impossible. Some kinds of AMD are treatable if detected early, but no cure exists. An estimated 2 million Americans have AMD.
Scientists have shown that age, diet, and smoking influence a person’s risk of developing AMD. Genetics also plays a strong role. AMD often runs in families and is more common among certain ethnicities, such as Asians and people of European descent. AMD typically presents later in life, but identifying genetic variants associated with the disease, all of which are present at birth, could help future studies determine how to stop the disease from progressing and even from occurring.
“Genetic research allows us to piece together disease pathways that may have their starting point much earlier in life,” said Farrer. “These newly identified genes, individually and collectively, provide novel clues and targets to evaluate for their potential therapeutic benefits.”
For more information about AMD, visit http://www.nei.nih.gov/health/maculardegen/index.asp.
Goncalo Abecasis, DPhil, from the University of Michigan; Iris Heid, PhD, from the University of Regensburg, Germany; and Jonathan L. Haines, PhD, from Vanderbilt University are the study’s other co-lead authors. Funding for the research conducted at BUSM for this study was provided in part by the National Institutes of Health under grant award number R01-EY014458 and the Edward N. & Della L. Thome Memorial Foundation.
Mechanisms Regulating Inflammation Associated with Type 2 Diabetes, Cancer Identified
(Boston) – A study led by researchers at Boston University School of Medicine (BUSM) has identified epigenetic mechanisms that connect a variety of diseases associated with inflammation. Utilizing molecular analyses of gene expression in macrophages, which are cells largely responsible for inflammation, researchers have shown that inhibiting a defined group of proteins could help decrease the inflammatory response associated with diseases such as obesity, type 2 diabetes, cancer and sepsis.
Anna Belkina
The study, which is published online in the Journal of Immunology, was led by first author Anna C. Belkina, MD, PhD, a researcher in the department of microbiology at BUSM, and senior author Gerald V. Denis, PhD, associate professor of pharmacology and medicine at BUSM.
Epigenetics is an emerging field of study exploring how genetically identical cells express their genes differently, resulting in different phenotypes, due to mechanisms other than DNA sequence changes.
Previous studies have shown that a gene, called Brd2, is associated with high insulin production and excessive adipose (fat) tissue expansion that drives obesity when Brd2 levels are low and cancer when Brd2 levels are high. The Brd2 gene is a member of the Bromodomain Extra Terminal (BET) family of proteins and is closely related to Brd4, which is important in highly lethal carcinomas in young people, as well as in the replication of Human Immunodeficiency Virus (HIV).
The BET family proteins control gene expression epigenetically by acting on chromatin, the packaging material for genes, rather than on DNA directly. This mechanism of action is being explored because the interactions are not reflected in genome sequencing information or captured through DNA-based genetic analysis. In addition, this layer of gene regulation has recently been shown to be a potential target in the development of novel epigenetic drugs that could target several diseases at once.
Gerald Denis
The study results show that proteins in the BET family have a strong influence on the production of pro-inflammatory cytokines in macrophages. This indicates that the defined family of proteins govern many aspects of acute inflammatory diseases, such as type 2 diabetes, sepsis and cardiovascular disease, among others, and that they should be explored as a potential target to treat a wide variety of diseases.
“Our study suggests that it is not a coincidence that patients with diabetes experience higher risk of death from cancer, or that patients with chronic inflammatory diseases, such as atherosclerosis and insulin resistance, also are more likely to be obese or suffer from inflammatory complications,” said Belkina. “This requires us to think of diverse diseases of different organs as much more closely related than our current division of medical specialties allows.”
Future research should explore how to successfully and safely target and inhibit these proteins in order to stop the inflammatory response associated with a variety of diseases.
Research included in this press release was supported in part by the National Institutes of Health’s National Institute of Diabetes and Digestive and Kidney Diseases under grant award R56 DK090455 (Principal Investigator: Denis).
Getting Ready for Sequestration: BU Already Tightening the Belt
With Washington stymied over a deficit plan, across-the board cuts affecting BU are scheduled to begin tomorrow. Photo by Heather Reed
How will sequestration affect research at Boston University? The School of Medicine already is taking a 10 percent haircut on some federal grants that were promised, but are being withheld, forcing some lab staff layoffs. David Coleman, a MED professor and chair of the department of medicine, fears a slowdown in its studies of how a variety of diseases work, with delayed hires and cuts in equipment purchases.
On the Charles River Campus, Howard Eichenbaum, a College of Arts & Sciences professor of psychology, is planning for no undergraduate hires, and possibly no new graduate student or postdoctoral fellows, for his studies of how memories are retrieved and processed, with its implications for future dementia treatments.
Those are just two snapshots of academic life on the eve of sequestration, the agreement between President Obama and Congress to make automatic, across-the-board spending reductions if the two fail to agree to a deficit-erasing plan.
In the 2012 fiscal year, federal dollars paid for 90 percent of the $362.5 million in sponsored research spending at BU, according to Andrew Horner, associate vice president for financial affairs. (“Sponsored” research is any funded by a non-University source.) Horner says the rest of the funding came from foundations, industry, the state and city, and the University, which covers researchers’ overhead out of its own revenue.
As for whether BU could tap other sources, from tuition to private gifts, to cover at least some of the lost federal money, Provost Jean Morrison is blunt: “Absolutely not. The loss of federal revenue cannot be made up elsewhere.”
While we know that sequestration will cut domestic spending 5.1 percent, University officials say the bottom-line hit to BU research is hard to predict, because different federal agencies have varying abilities to adjust the rate at which they impose their cuts. For example, the National Institutes of Health accounted for the most ($209 million) federal research money received by BU last year. But the NIH has 27 institutes, and each one will make cuts at its own discretion, says Jennifer Grodsky, the University’s vice president for federal relations. Depending on the federal funding source, Grodsky says, cuts to BU research grants could range between 5 percent and 10 percent.
Horner says damage from cuts will be lessened if Washington rescinds the sequester quickly. “If they come to the deal relatively quickly,” he says, “the impact would be much lower than if it lasted into April, May, and beyond.”
Grodsky says that because other revenue sources, like tuition, are needed for vital operations, “such as educating students,” the University will be unable to cover the federal cuts.
“All of our revenues are spoken for,” says Horner. “We’re a nonprofit institution, and we’re trying to balance the budget on an annual basis.”
Nor can money from BU’s $1 billion comprehensive fundraising campaign cover any shortfall, as donors, not the University, have discretion on how to spend that money, says Scott Nichols, senior vice president for development and alumni relations. “There is very little wiggle room in terms of directing money. Virtually every big donor we have knows exactly what they want to support. Certainly, the campaign strengthens the University’s finances; there is support coming in for research, but it’s for particular projects” specified by donors.
In fiscal year 2012, MED had $140 million in sponsored research expenses, more than any other University school. Karen Antman, dean of MED and provost of the Medical Campus, says the inability of Congress and the White House to agree on a current year budget—the nation is running on a “continuing resolution” that holds spending to last year’s levels—gummed up the research works even before sequestration.
“Federal agencies, such as the NIH, are already being very conservative with spending, because of their uncertain budgets,” says Antman, and funding agencies have withheld grants already awarded the University and delayed decisions on new grants. “We are already slowing important research,” she says. “We are letting laboratory staff go and accepting fewer graduate students, who are the future of innovation.…Research is not like a light switch that can be easily turned on and off. Cuts like these have a devastating impact to the future of health care. We will lose the next generation of leaders in science and medicine.”
Medical schools and teaching hospitals like MED-affiliated Boston Medical Center will be disproportionately affected, according to Antman, because they conduct more than half the research paid for by the NIH. Those studies have “the potential to change our lives,” she says. “We have people looking at the impact of pollution on human development, researchers trying to grow lung cells in order to combat cystic fibrosis, and people figuring out how the body can combat antibacterial-resistant infections.”
Eichenbaum, whose memory research receives almost $25 million in federal funding, mostly from the NIH, says he’s been told to anticipate that one-tenth of that will disappear. He says the types of lab layoffs that MED is imposing “would be a last resort,” one that he would avoid if possible by attrition of student assistants and not hiring new ones.
Coleman oversees about 250 researchers across 3 centers and 16 department sections, and their research attracts more than $100 million a year, 80 percent to 90 percent of it coming from the federal government. “We do not anticipate furloughing investigators unless the sequester lasts more than a few months,” he says. “We are, however, quite concerned about the ability of new investigators to launch their respective careers,” especially when their proposals would qualify for grant money that’s being withheld.
BU and other schools lobbied hard to avert the autopilot cuts regimen that Grodsky says few Washington politicians want. Sequestration was always a doomsday machine, she says, something that was “supposed to be so unpalatable it would force a deal.” BU President Robert A. Brown cosigned a letter last fall from Massachusetts university presidents to the state’s congressional delegation, urging a budget compromise. And after recently joining the Association of American Universities, an organization of leading research universities, BU contributed video commentaries by researchers to a website of the AAU, the Science Coalition, and the Association of Public and Land-grant Universities opposing the sequester.
Grodsky says she is optimistic that the University will weather the sequester. “Our faculty are extraordinarily entrepreneurial” in devising and managing their projects, she says. “Even in difficult circumstances, they tend to do really, really well.”
That resilience notwithstanding, Morrison sees a rougher road ahead. Sequester or no sequester, she says, “the long-term outlook for federal funding for the research enterprise, given our national debt and deficit, is not rosy.” And Brown, citing an inevitable drop in funding in his State of the University letter this week, announced plans to eliminate administrative redundancies, review academic programs for quality and impact, and make “difficult but necessary decisions” to scale back some of them.
This BU Today story was written by Rich Barlow.
Wainford Recognized by American Physiological Society
Richard Wainford
Richard Wainford, PhD, is the recipient of the American Physiological Society 2013 Shih-Chun Wang Young Investigator Award. This award was established in 1998, in memory of Shih-Chun Wang, to recognize an individual demonstrating outstanding promise in the field of central nervous system physiology. In addition, the award includes $4000 for use in support of Wainford’s research. This award will be presented at the American Physiological Society Annual Business Meeting on April 23 in Boston.
Wainford is an Assistant Professor in the Departments of Pharmacology & Experimental Therapeutics and Medicine, Division of Cardiovascular Medicine and a member of The Whitaker Cardiovascular Institute. His research interests focus on the central neural control of fluid and electrolyte homeostasis and blood pressure regulation in both health and disease.
BUSM Researchers Propose Potential Epigenetic Mechanisms for Improved Cancer Therapy
(Boston) – A review article by BUSM researchers proposes a new epigenetic hypothesis linked to tumor production and novel ideas about what causes progenitor cells to develop into cancer cells. Published in the February 2013 issue of Epigenomics, the article provides examples of how epigenetic drug treatments could be beneficial in treating cancers while also decreasing the likelihood of cancer relapse.
Sibaji Sarkar
The article was written by researchers at the Boston University Cancer Center. Sibaji Sarkar, PhD, adjunct instructor of medicine at BUSM, is the article’s corresponding author.
Cancer is a complex disease characterized by uncontrolled cell growth, division and invasion into other tissues. A 2004 review article published in Nature Medicine suggests that epigenetics, which is the phenomena whereby genetically identical cells express their genes differently resulting in different phenotypes, and other factors play an important role in the formation of cancer originating from cancer stem cells.
Sarkar and colleagues propose that epigenetic processes, specifically DNA methylation, may trigger cancer progenitor cell formation from somatic cells in coordination with other cellular and environmental events. DNA methylation is a process that changes the DNA and causes genes to be silenced. In the absence of definitive proof of the existence of cancer stem cells, this hypothesis discusses a possible explanation for the formation and existence of cells that may develop into cancer. The researchers also explore why only some individuals develop cancer, despite identical genetic predispositions.
In cancer cells, the enzyme that maintains high levels of methylation in tumor suppressor genes is highly expressed, allowing uncontrolled growth. At the same time, many oncogenes, or genes with the potential to cause cancer, are activated and have lower levels of methylation. The apparent anomaly of the existence of both low and high rates of methylation could be explained with either the compartmentalization of these two processes and/or by the existence of both a methylation and demethylation system operating simultaneously at specific locations with the help of various accessory proteins.
The authors hypothesize the existence of both DNA methylating and demethylating enzymes in cells that regulate the methylation and demethylation process. Accessory proteins and/or small RNA factors could lead these enzymes to their sites of actions, resulting in some genes remaining methylated and others not methylated simultaneously within the same cellular environment. DNA sequences around the regions that are methylated and demethylated may also play role in these events. During drug treatments, the demethylating system dominates while the methylating enzyme is down-regulated, resulting in re-expression of silenced genes.
Recent studies have shown that epigenetic drug treatments prior to and with standard chemotherapy reduce the chance of cancer relapse.
“Progenitors are known to cause cancer relapse, and because epigenetic drugs can help destroy progenitor cells, these drugs could help reduce the chance of cancer relapse and improve the long-term outcomes of people with cancer,” said Sarkar. “While our hypotheses are based on current knowledge, we are proposing important and exciting areas to be explored in the future.”
Sarah Goldgar, Shannon Byler, Shoshana Rosenthal and Sarah Heerboth are co-authors of the article.
Research included in this review article was funded in part by the American Cancer Society.
