News 27 juli 2009
Bcl6 gene sculpts helper T cell to
boost antibody production
Expression of a single gene programs an immune system helper T cell that fuels rapid
growth and diversification of antibodies in a cellular structure implicated in autoimmune
diseases and development of B cell lymphoma, scientists at The University of Texas M. D.
Anderson Cancer Center reported today in Science Express, the advance online publication
of the journal Science. The gene is Bcl6, which the team found plays the crucial role in
differentiating a naïve T cell into a T follicular helper cell (Tfh). "Tfh cells
were first noticed in structures called germinal centers found in the lymphoid system - in
lymph nodes and the spleen," said senior author Chen Dong, Ph.D., professor in M. D.
Anderson's Department of Immunology. Germinal centers are powerful machines that churn out
lots of antibodies. In the adaptive immune system, B cells present an antigen - a
distinctive piece of an invading bacterium or virus - to T cells. The bound antigen
converts a naïve T cell to a helper T cell that secretes cytokines which help the B cells
expand and produce a large volume of antibodies to destroy an intruder. Tfh cells are
concentrated with B cells in germinal centers, where they play a helper T cell's
traditional role in B cell proliferation and antibody development. "In germinal
centers, the B cells not only proliferate but they also undergo hypermutation in their
immunoglobulin genes so they can produce a diverse class of antibodies," Dong said.
"These mutations also allow production of antibodies with stronger affinity for their
target antigens." There are pitfalls to this process. Tfh cells and germinal centers
have been implicated in antibody-mediated autoimmune diseases such as lupus and rheumatoid
arthritis, Dong noted. In these diseases, the germinal centers are likely producing the
wrong type of antibody at great volume. Genetic hypermutation among B cells in germinal
centers creates a hotbed of genomic instability, which gives rise to some types of B cell
lymphoma, Dong said.
Bone from Blood - Circulating Cells
Form Bone Outside the Normal Skeleton, Penn Study Finds
The accepted dogma has been that bone-forming cells, derived from the body’s
connective tissue, are the only cells able to form the skeleton. However, new research
shows that specialized cells in the blood share a common origin with white blood cells
derived from the bone marrow and that these bloodstream cells are capable of forming bone
at sites distant from the original skeleton. This work, published online this month in the
journal Stem Cells, represents the first example of how circulating cells may contribute
to abnormal bone formation.
Human cells secrete cancer-killing
protein, UK study finds
Human cells are able to secrete a cancer-killing protein, scientists at the University of
Kentucky's Markey Cancer Center have found. Researchers led by Vivek Rangnekar, UK
professor of radiation medicine, have determined that the tumor-suppressor protein Par-4,
initially thought to be active only within cells expressing the Par-4 gene, is in fact
secreted by most human and rodent cells and can target large numbers of cancer cells by
binding to receptors on the cell surface. This discovery, published today in the leading
journal Cell, makes Par-4 a very attractive molecule for future research aimed at
developing new cancer treatments. "It was a pleasant surprise, when we noticed that
Par-4 protein is secreted by cells," Rangnekar said. "This new finding means it
is not necessary to make genetic modifications, or to employ recombinant viruses, to
deliver the Par-4 gene to cancer cells, and it significantly expands the potential
applications of Par-4 to selectively kill cancer cells." Funded by several grants
from the National Institutes of Health, Rangnekar's study found that when the Par-4
molecule binds to its receptor GRP78 on the surface of a tumor cell, it triggers a
biological process called apoptosis or "cell suicide." Consistent with previous
research by Rangnekar's laboratory with intracellular Par-4, the newly discovered secreted
Par-4 acts selectively against cancer cells, leaving healthy cells unharmed. Few other
molecules are known to exhibit such selectivity.
Sticky protein helps reinforce
fragile muscle membranes
A new study by scientists at the University of Iowa shows why muscle membranes don't
rupture when healthy people exercise. The findings shed light on a mechanism that appears
to protect cells from mechanical stress. The study, which appears online July 20-24 in
Proceedings of the National Academy of Sciences (PNAS) Early Edition, also helps explain
why muscle damage is so severe when this mechanism is disrupted, which occurs in certain
congenital and limb-girdle muscular dystrophies. Specifically, the team identified a
protein called alpha dystroglycan as the "glue" that binds muscle membranes to a
tough layer of extracellular proteins called the basal lamina. Just as a piece of sticky
tape can prevent a pin from bursting a balloon, the sturdy basal lamina reinforces muscle
cell membranes and keeps small tears from bursting open -- but only if the dystroglycan
"glue" affixing the basal lamina to the membrane is working. "This study
helps us understand how membrane structure is designed to protect cells, which is a
universally important process," said senior study author Kevin Campbell, Ph.D.,
professor and head of molecular physiology and biophysics at the UI Roy J. and Lucille A.
Carver College of Medicine and a Howard Hughes Medical Institute investigator. "The
findings may also have clinical implications for muscular dystrophies that are caused by
abnormal dystroglycan." These congenital muscular dystrophies include Fukuyama
Congenital Muscular Dystrophy, Walker-Warburg Syndrome and Muscle-Eye-Brain disease and
limb-girdle muscular dystrophy 2I. In these so-called dystroglycanopathies, too few sugar
groups are added to alpha dystroglycan, leading to a version of the protein that does not
attach properly to the basal lamina. Detachment of the basal lamina from the muscle
membrane appears to be a common feature of these conditions, and patients develop a very
severe muscular dystrophy. Working with a mouse model of these diseases, the researchers,
including Renzhi Han, Ph.D., a UI research scientist and the first author of the study,
found that injecting functional dystroglycan into muscle that lacks this component
restored muscle membrane integrity and protected the muscles from damage.
Scientists discover gene mutation
responsible for hereditary neuroendocrine tumor
University of Utah researchers and their colleagues have identified the gene that is
mutated in a hereditary form of a rare neuroendocrine tumor called paraganglioma (PGL).
The gene, called hSDH5, is required for activation of an enzyme complex that plays a
critical role in the chemical reactions that take place within cells to convert
biochemical energy into usable energy. This study will be published in the journal
Science, to be released online in Science Express on July 23, 2009. Paragangliomas are
rare, generally benign tumors that arise from cells called glomus cells, which are located
along blood vessels and play a role in regulating blood pressure and blood flow.
Approximately 25 percent of paragangliomas are hereditary. Of the four familial PGL
syndromes, three forms have previously been associated with mutations in genes of the
succinate dehydrogenase (SDH) complex, an enzyme complex involved in the ability of cells
to extract energy from nutrients.
Newly Discovered Gene Fusion May
Lead to Improved Prostate Cancer Diagnosis
Researchers from NewYork-Presbyterian Hospital/Weill Cornell Medical Center have
discovered a new gene fusion that is highly expressed in a subset of prostate cancers. The
results may lead to more accurate prostate cancer testing and new targets for potential
treatments. Experts believe that gene fusions — a hybrid gene formed from two
previously separated genes — may be at the root of what causes cancer cells to grow
more quickly than normal cells. The new findings, published in the August issue of the
journal Neoplasia, are exciting, because unlike two previous fusions co-discovered by the
same Weill Cornell Medical College laboratory group, this fusion, called NDRG1-ERG,
produces a protein that may be a potential target for drug therapies. "The prostate
cancer gene fusions, and proteins they produce, are important because they serve as a
cancer-specific marker," says Dr. Mark A. Rubin, the Homer T. Hirst Professor of
Oncology in Pathology, professor of pathology and laboratory medicine, and vice chair for
experimental pathology at Weill Cornell Medical College. "Currently, PSA testing is
the standard of care, yet it is not accurate enough to predict prostate cancer, because
many men may have an elevated PSA level, but have benign conditions such as inflammation
of the prostate." It is important to distinguish harmful cancer from non-lethal
diseases, such as benign prostatic hyperplasia, or enlarged prostate disease that exhibits
similar symptoms to prostate cancer, in order to provide effective care, explains Dr.
Rubin. Gen-Probe, a biotechnology diagnostics company, has licensed this technology and is
currently working with Dr. Rubin, and his collaborator Dr. Arul Chinnaiyan at the
University of Michigan, to develop urine tests to screen for gene fusions as a means of
improving upon the current standard PSA test.
Short Stressful Events May Improve
Working Memory
Experiencing chronic stress day after day can produce wear and tear on the body physically
and mentally, and can have a detrimental effect on learning and emotion. However, acute
stress -- a short stressful incident -- may enhance learning and memory.Researchers at the
University at Buffalo have shown, in trials using rodents as an animal model, that acute
stress can produce a beneficial effect on learning and memory, through the effect of the
stress hormone corticosterone (cortisol in humans) on the brain's prefrontal cortex, a key
region that controls learning and emotion. Specifically, they demonstrated that acute
stress increases transmission of the neurotransmitter glutamate and improves working
memory.
Injection reverses heart-attack
damage
Injured heart tissue normally can't regrow, but researchers at Children's Hospital Boston
have now laid the groundwork for regenerating heart tissue after a heart attack, in
patients with heart failure, or in children with congenital heart defects. In the July 24
issue of Cell, they show that a growth factor called neuregulin1 (NRG1), which is involved
in the initial development of the heart and nervous system, can spur heart-muscle growth
and recovery of cardiac function when injected systemically into animals after a heart
attack. After birth, heart-muscle cells (cardiomyocytes) normally withdraw from the cell
cycle – meaning they stop dividing and proliferating. But the researchers, led by
Bernhard Kühn, MD, and Kevin Bersell of the Department of Cardiology at Children's, were
able to restart the cell cycle with NRG1, stimulating cardiomyocytes to divide and make
copies of themselves -- even though they are not stem cells. "Although many efforts
have focused on stem-cell based strategies, our work suggests that stem cells aren't
required and that stimulating differentiated cardiomyocytes to proliferate may be a viable
alternative," says Kühn, the study's senior investigator and a practicing pediatric
cardiologist at Children's since 2007. When the team injected NRG1 into the peritoneal
cavity of live mice after a heart attack, once daily for 12 weeks, heart regeneration was
increased and pumping function (ejection fraction, assessed on echocardiograms) improved
as compared with untreated controls. The NRG1-injected mice also lacked the
left-ventricular dilation and cardiac hypertrophy that typify heart failure; both were
seen in the controls. When the researchers also stimulated production of a cellular
receptor for NRG1, known as ErbB4, cardiomyocyte proliferation was further enhanced,
demonstrating that NRG1 works by stimulating this receptor. They also identified the
specific kinds of cardiomyocytes (mononucleated) that are most likely to respond to
treatment.
The 'see food' diet
Current research suggests that a diet high in omega-3 fatty acids may help prevent one of
the leading causes of legal blindness among the elderly. The related report by Tuo et al,
"A high omega-3 fatty acid diet reduces retinal lesions in a murine model of macular
degeneration," appears in the August 2009 issue of the American Journal of
Pathology.Age-related macular degeneration (AMD), loss of vision in the center of the
visual field (macula) due to retinal damage, is one of the leading causes of legal
blindness among the elderly. Approximately 10% of people from 66 to 74 years of age will
develop some level of macular degeneration, making it difficult for them to read or even
recognize faces.A diet high in omega-3 fatty acids has been found to protect against a
variety of diseases including atherosclerosis and Alzheimer's disease. Retrospective
studies have suggested that diets high in fish oil or omega-3 fatty acids may also
contribute to protection against AMD. A group led by Dr. Chi-Chao Chan at the National Eye
Institute in Bethesda, MD examined the direct effect of omega-3 fatty acids on a mouse
model of AMD. A diet with high levels of omega-3 fatty acids resulted in slower lesion
progression, with improvement in some lesions. These mice had lower levels of inflammatory
molecules and higher levels of anti-inflammatory molecules, which may explain this
protective effect.
Some blood pressure drugs may help
protect against dementia, study shows
A particular class of medication used to treat high blood pressure could protect older
adults against memory decline and other impairments in cognitive function, according to a
newly published study from Wake Forest University School of Medicine. Research suggests
that some of the drugs classified as angiotensin-converting enzyme (ACE) inhibitors,
specifically those types of ACE inhibitors that affect the brain by crossing the
blood-brain barrier, may reduce inflammation that could contribute to the development of
Alzheimer's disease, a major cause of dementia. The study appears in the current issue of
Archives of Internal Medicine. "High blood pressure is an important risk factor for
Alzheimer's disease and vascular dementia," said Kaycee Sink, M.D., M.A.S., lead
author of the study, geriatrician and an assistant professor of internal medicine –
gerontology. "Our study found that all blood pressure medications may not be equal
when it comes to reducing the risk of dementia in patients with hypertension."
Dementia is the broad term used to describe conditions in the brain that cause loss of
brain function. There are several different causes of dementia, but Alzheimer's disease
and strokes are two of the most common. People with dementia begin to lose their memory
and may not be able to think well enough to do normal activities, such as getting dressed
or eating, may lose their ability to solve problems or control their emotions, may
experience personality changes and/or may become agitated or see things that are not
there. While memory loss is the hallmark of dementia, it does not, by itself, mean an
individual has dementia. People with dementia have serious problems with two or more brain
functions, such as memory and problem solving. Someone is diagnosed with dementia every 70
seconds. It is estimated that the number of people in the United States living with
dementia will increase to about 13 million by the year 2050. Therefore, delaying the onset
of dementia, even by one year, would have a substantial impact on public health.
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