SUNDAY - September 23, 2007-------------------------------------------News Archive/Return to Today's News Alerts

Gene Assigns ID Tags to Help Organize the Developing Brain.
A single gene capable of producing more than 38,000 cell surface proteins is an essential tool in assuring the assembly of precise neural circuits in the fruit fly, Drosophila melanogaster. Now, two teams of researchers from the Howard Hughes Medical Institute (HHMI) have demonstrated how these closely related proteins establish the specificity that allows them to serve as identification tags for individual neurons. Published September 21, 2007 in the journal Cell.

New Understanding of Basic Units of Memory.
A molecular "recycling plant" permits nerve cells in the brain to carry out two seemingly contradictory functions – changeable enough to record new experiences, yet permanent enough to maintain these memories over time.

The discovery of this molecular recycling plant, detailed in a study appearing early online Sept. 19 in the journal Neuron, provides new insights into how the basic units of learning and memory function. Individual memories are "burned onto" hundreds of receptors that are constantly in motion around nerve synapses – gaps between individual nerve cells crucial for signals to travel throughout the brain.

According to the study's leader, Duke University Medical Center neurobiologist Michael Ehlers, M.D., Ph.D., these receptors are constantly moving around the synapse and often times they disappear or escape. Ehlers discovered that a specific set of molecules catch these elusive receptors, take them to the recycling plant where they are reprocessed and returned to the synapse intact. Published September 19, 2007 in the journal Neuron.

Our Brain is Listening, Even When We Don't Realize It.
Robert T. Knight, M.D., Department of Psychology and Helen Wills Neuroscience Institute, University of California, Berkeley, and colleagues at the Interdisciplinary Center for Neural Computation, The Hebrew University of Jerusalem, and the Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel have captured through MRIs evidence that our minds are paying attention to sound even though we are unaware of the process. Spatial variation to an unattended stream of sounds elicits a response in a region of the brain called the planum temporale - previously shown to be active during attentive listening. The results of the three experiments suggest that neurons in this region represen the location of sound sources in the environment. Space representation in this region may be the focal point for an orientation response to critical auditory events and for linking auditory information with information acquired. Published September 20, 2007 in the journal Neuron.

Customized Virus Kills Brain Tumor Stem Cells of Lethal Cancer.
A tailored virus destroys brain tumor stem cells that resist other therapies and cause lethal re-growth of cancer after surgery, a research team led by scientists at The University of Texas M. D. Anderson Cancer Center report. "We have shown first in lab experiments and then in stem cell-derived human brain cancer in mice, that we have a tool that can target and eliminate the cells that drive brain tumors," says co-senior author Juan Fueyo, M.D., associate professor in M. D. Anderson's Department of Neuro-Oncology. A request to launch a clinical trial of the virus, called Delta-24-RGD, is expected to go to federal regulators this month.

The virus was tested against the most aggressive brain tumor - glioblastoma multiforme, which originates in the glial cells that surround and support neurons. It is highly resistant to radiation and chemotherapy and so invasive that surgery almost never eliminates it. Patients suffering from this malignant glioma live on average for about 14 months with treatment. Fueyo and colleagues developed Delta-24-RGD to prey on a molecular weakness in tumors and altered the virus so it could not replicate in normal tissue. They showed in a JNCI paper in 2003 that the virus eliminated brain tumors in 60 percent of mice who received injections directly into their tumors. The virus spreads in a wave through the tumors until there are no cancer cells left, then it dies. Published September 18, 2007 in the Journal of the National Cancer Institute.

Merck Abandons HIV Vaccine Trials of Most Promising Drug.
International drug company Merck has halted trials on an HIV vaccine that was regarded as one of the most promising in the fight against Aids. Merck stopped testing the vaccine after it was judged to be ineffective.

In trials, the vaccine failed to prevent HIV infections among volunteers who were at risk of catching the virus, including gay men and sex workers. Merck had previously expressed high hopes for the drug, which it spent 10 years developing. The international trial, called Step, began in 2004 and involved 3,000 HIV-negative volunteers from diverse backgrounds, between the ages of 18 and 45; 24 of 741 volunteers who got the vaccine became infected with HIV, the virus that causes Aids. Out of a group of 762 volunteers who were given a dummy version of the jab, 21 became infected with HIV.

An independent monitoring panel recommended discontinuing the vaccination of volunteers, saying the trial was headed for failure. Most of the volunteers were at high risk of HIV infection, although they were repeatedly given advice about how to practise safe sex, according to Merck.

The vaccine contained a common cold virus loaded with copies of three HIV genes. The hope was that exposure to the genes would prompt an immune response in the body so that cells containing HIV virus would be recognised and destroyed. "Today is a very sad day for the industry because Merck's vaccine had shown an ability to turn on the immune system, which gave many people optimism it would work," said Sarah Alexander, from the HIV Vaccine Trials Network. Doctors have said a preventative vaccine would be the best way to control the spread of HIV. Published September 21, 2007 in BBC News.


SATURDAY - September 22, 2007-------------------------------------------News Archive/Return to Today's News Alerts

UK to Reimburse Egg Donors for Costs of In Vitro Fertilisation.
Women in the UK will be reimbursed about half the cost of their in vitro fertilisation in return for donating "surplus" eggs for stem cell research, in the first study funded by the UK Medical Research Council (MRC) that will pay participants.

The MRC announced last week that it is funding a research proposal from the North East England Stem Cell Institute (NESCI), based in Newcastle, to find ways of improving the efficiency of therapeutic cloning. This technique is designed to create stem cells specific to a patient that might eventually be used to treat conditions in which new cells could be therapeutic—such as diabetes, heart disease, and Parkinson's disease.

Out of the funding of £470 000 (680 000; $950 000) for the research, the MRC will provide £150 000 to reimburse part of the cost of treatment for women undergoing in vitro fertilisation at the Newcastle Fertility Centre and who donate Published September 22, 2007 in the British Medical Journal (BMJ).

Gene Chip Data Can Boost Cancer Outcomes.
Dr. Eric P. Lester, president of Oncology Care Associates in St. Joseph, Michigan, had seven patients with advanced, incurable cancer. To determine which drugs might offer them the most benefit, Lester used DNA microarray chips to analyze the patients' tumors for expression of certain genes associated with a good response to various anti-cancer drugs. He then used the results from the gene chip analyses to determine an individualized treatment plan for each patient.

Four of the seven patients had a better outcome than expected, said Lester, who was to present the findings this week at an American Association for Cancer Research conference in Atlanta. The findings show that "a personalized molecular oncology approach, basing chemotherapy on relative gene expression in tumors, holds promise even at the relatively crude level employed here," Lester said in a prepared statement.

"Much of clinical medicine is an educated guess, and this was an attempt to come up with a better approach by using the technology of a gene chip to make multiple, highly educated guesses simultaneously," he said. Presented September 19, 2007 at American Academy of Family Physicians.

Our Skin Is A Living Coloring Book.
The pigment melanin, which is responsible for skin and hair color in mammals, is produced in specialized cells called melanocytes and then distributed to other cells. But not every cell in the complex layers of skin becomes pigmented. "Pigment recipient cells essentially tell melanocytes where to deposit melanin, and the pattern of those recipient [cells] determines pigment patterns," says Janice Brissette, PhD, who led the study at the Massachusetts General Hospital (MGH) Cutaneous Biology Research Center (CBRC). "Recipient cells act like the outlines in a child's coloring book; as recipient cells develop, they form a 'picture' that is initially colorless but is then 'colored in' by the melanocytes."

In humans, melanin is deposited in both the skin and the hair; but in some other mammals such as mice, melanin is primarily deposited in the coat, leaving the skin beneath the coat unpigmented. Melanocytes deposit melanin via cellular extensions called dendrites that reach out to other cells in the epidermis (the outer layer of skin) or the hair follicles. But the mechanism determining whether melanin is delivered to a particular cell has been unknown.

The MGH-CBRC researchers theorized that a mouse gene known as Foxn1 might play a role as a lack of Foxn1 is responsible for so-called 'nude mice,' with hair so brittle it breaks off, resulting in baldness, and defects in their skin. A similar phenomenon exists in humans with inactivation of the corresponding gene. Examination of human skin samples showed that the human version of Foxn1 was also expressed in cells known to be pigment recipients. Further experiments revealed that Foxn1 signals melanocytes through a protein called Fgf2, levels of which rise as Foxn1 espression increases. "Foxn1 makes epithelial cells into pigment recipients, which attract melanocytes and stimulate pigment transfer, engineering their own pigmentation," says Brissette, an associate professor of Dermatology at Harvard Medical School.

"We know that Foxn1 and Fgf2 act in concert with other factors and function within a larger network of genes. Our next step will be to identify other genes that can confer the pigment recipient phenotype or control the targeting of pigment," Brissette adds. Her research may eventually be relevant to disorders such as vitiligo - in which pigment disappears from patches of skin - age spots, the greying of hair and even the deadly melanocyte-based skin cancer melanoma. Published September 7, 2007 in Cell.

The Evolution of Imprinting - Not From Sex Chromosomes.
The evolution of genomic imprinting, the specific expression of parental genes, is the subject of much debate. There are several theories to account for how the mechanism evolved including the hypothesis that it was driven by the evolution of X-inactivation, or that it arose from ancestrally imprinted chromosomes.

Dr. Malcolm A Ferguson-Smith and colleagues present their findings to demonstrate that mammalian orthologues of imprinted genes are dispersed among autosomes, or non-sex linked chromosomes, in both monotremes and marsupials. A similar distribution seen in birds, suggests that imprinted genes were not located on an ancestrally imprinted chromosome or associated with a sex chromosome. "Our results suggest imprinting evolution was a stepwise, adaptive process, with each gene/cluster independently becoming imprinted as the need arose." Published September 6, 2007 in BMC.

Toward Growing Heart Valves For Children.
Infants and children receiving artificial heart-valve replacements face several repeat operations as they grow, since the replacements become too small and must be traded for bigger ones. Researchers at Children's Hospital Boston have now developed a solution: living, growing valves created in the lab from a patient's own cells.

In a special issue of Circulation, they describe making pulmonary valves through tissue engineering. These valves, which provide one-way blood flow from the heart's right ventricle into the pulmonary artery, are often malformed in congenital heart disease, putting an extra burden on the heart. "The heart valve is a complex organ," says Virna Sales, MD, a researcher in Children's Department of Cardiac Surgery and the study's first author. "It must open and close synchronously, withstand pressure, and be pliable and elastic. We are one of the few labs in the U.S. that's attempting to make heart valves through tissue engineering. We hope these could just be implanted in a child just once, instead of the many heart operations most children have to go through as they get older."

The researchers, led by Sales and senior investigator John Mayer, MD, in Children's Department of Cardiac Surgery, first isolated endothelial progenitor cells (precursors of the cells that line blood vessel walls) from the blood of laboratory animals. They then "seeded" the cells onto tiny, valve-shaped biodegradable molds and pre-coated with proteins found in the natural "matrix" that surrounds and supports cells. Experimenting with different matrix proteins and growth factors, they were able to make pulmonary valve leaflets that had the right mechanical properties - sturdy yet pliable. Tests showed the original cells had differentiated to form both endothelial cells and smooth-muscle-like cells and added to the surrounding matrix to hold them together. "I would like to mimic what really happens in the embryo -- what Mother Nature does," says Sales. The next step would be to implant the living valves into animals. Published September 11, 2007 in Circulation.


FRIDAY - September 21, 2007-------------------------------------------News Archive/Return to Today's News Alerts

Day Care Safer Thanks to Vaccines.
Vaccines used to prevent a range of childhood infections - enteric and pneumococcal illnesses, as well as flu and varicella - "have been extraordinarily effective in preventing disease and particularly effective for children in child-care," Larry Pickering, M.D., an infectious disease specialist at the CDC, told attendees at the Interscience Conference on Antimicrobial Agents and Chemotherapy.

Dr. Pickering cautioned, however, that day care centers are still more dangerous places than homes, simply because there are more kids and more chances to pass pathogens on. "But now that we have these vaccines, I feel a lot more confident having kids in day care centers," he said.

Dr. Pickering, who was moderating a symposium on the topic, said he's particularly interested in seeing if the success of the Hepatitis A vaccine can be matched by the recently licensed rotavirus vaccine. Currently, Dr. Pickering said, the nationwide rate of Hepatitis A is about 1.5 per 100,000 people (of all ages) every year. In 1996, the year the vaccine was licensed, a survey of 11 western states showed a rate of 20 cases per 100,000. Overall, said Janet Englund, M.D., of the University of Washington in Seattle, "day care centers now are safer than they were even five years ago." Presented September 20, 2007 at the ICAAC: Day-Care Safer Thanks To Vaccines.

Cancer Cells Chill Out to Survive.
When cells are under stress, heat shock proteins (HSPs) get busy by preventing other proteins from folding incorrectly or congregating into potentially hazardous clumps. HSPs are molecular guardians in fact, and may help stave off neurodegenerative disorders such as Parkinson's disease. A take-charge protein called heat shock factor 1 (HSF1) orchestrates how the HSPs respond.

Like other cells, cancer cells boost their production of HSPs in response to stress, but whether they use HSF1 to call the shots wasn't certain until molecular biologist Susan Lindquist of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, and colleagues dabbed mice with cancer-inducing chemicals. More and larger skin tumors sprouted in animals lacking HSF1 than in control animals. The researchers also tested how the loss of HSF1 affected mouse cells carrying either of two cancer-inducing mutant genes. If the cells could make HSF1, they divided rapidly and piled up on the culture dish. HSF1-deficient cells, by contrast, rarely formed these mounds. Those results suggest that HSF1 is necessary for cells to become cancerous.

HSF1 isn't a cause of cancer, it's an enabler, mobilizing defenses that permit the cells to survive under harsh conditions. Co-author Luke Whitesell, a pediatric oncologist at the Whitehead Institute, says that the protein puts organisms in a bind: "HSF1 enhances survival and stress tolerance, but there appears to be a flip side in cancer." That duality could complicate the use of HSF1 inhibitors--which the researchers are now hunting for - to combat tumors. However, Whitesell says, short, intense treatments with such drugs might stall cancer without leaving patients vulnerable to neurodegeneration and other disorders caused by cell stress. Published September 21, 2007 in Cell magazine..

Putting the Brakes on Cell Death by Necrosis.
There are several ways a cell can die. One, apoptosis, is a form of controlled cellular suicide, usually for the benefit of the whole organism. The gaps between our fingers and toes are one mark of this process. Necrosis is the opposite: The cell isn't trying to die, but factors such as blood loss or oxygen deprivation make it swell and explode. Necrosis has gotten much less attention than apoptosis, and although some scientists have found ways to accelerate it, it's never been clear that it can be halted.

Neonatologist and molecular biologist Gary Silverman of the University of Pittsburgh in Pennsylvania and his colleagues came to necrosis in a roundabout fashion. The team was interested in proteins called serpins, some of which help control blood clotting and inflammation. So they knocked out the gene for a serpin called SRP-6 in worms. To their disappointment, the animals seemed unbothered.

But postdoc Cliff Luke noticed that the worms died rapidly when he washed them in room-temperature water. The death was necrotic, the team found, and appeared to be a stress response gone awry; the animals couldn't adjust the volume of fluid in their cells as normal worms do when exposed to water. Looking more closely, the scientists saw that lysosomes, sacs in cells that help break down cellular garbage, had burst. The worms without SRP-6 were also more likely to die than normal worms when subjected to other stressors, including heat and oxygen deprivation. Finally, the researchers found that, when they injured the worms' lysosomes, worms lacking SRP-6 could not repair their lysosomes, whereas normal worms could. Taken together, this suggests that SRP-6 protects worm cells against lysosome rupture and necrosis.

"I'm quite amazed," says Wei-Xing Zong, a molecular biologist who studies cell death at Stony Brook University in New York. "When people look at necrosis, ... they kind of never think that this can be controlled." Published September 21, 2007 in Cell.

Steinman's Dendritic Cells Bask in the Lasker Award Limelight.
This year's Albert Lasker Award for Basic Medical Research is to be given to Ralph M. Steinman, a Henry G. Kunkel Professor and Senior Physician at New York's Rockefeller University, for his discovery of dendritic cells (DCs) and for demonstrating that they are the key determinant of the type of immune response the body should mount.

Steinman revealed a previously unrecognized population of stellate cells found in virtually every organ of the body that continuously sample the local environment, process antigens, and then present them to other immune cells. He further discovered that the state of activation and differentiation of these cells determines the magnitude and nature of the immune response mounted by the body. Dendritic cells maintain peripheral tolerance to self-antigen cells and initiate immunity to foreign substances. It can be said that DCs are the sentinel cells that ensure an immune response is appropriate in specificity, intensity, and type to the nature of the threat posed by the antigen-bearing entity.

Steinman's unique discovery is of immense importance to understanding the organization and regulation of immune response - and for manipulating the immune system to either enhance response or, under the right circumstances, achieve tolerance. Steinman's achievement is particularly noteworthy because he began as a lonely voice, championing an idea that was not popular. But he continued and through the sheer weight of his growing body of evidence, he turned the study of DCs from a one-lab operation to one of the dominant themes of modern immunology. Published December 16, 2002 in PubMed.


THURSDAY - September 20, 2007-------------------------------------------News Archive/Return to Today's News Alerts

Corticosteroids Safe in Pregnancy?
Treating moms with repeat prenatal corticosteroids is commonly used to speed up fetal lung development if there's risk of premature delivery. The corticosteroids appear not to hinder mental or physical development based on two large trials that provided the original evidence. The benefit of early lung function and other outcomes with repeat dosing showed no excess impairment in infant growth, neurocognitive development, blood pressure, respiratory morbidity, or behavior through age two.

Now, a follow-up analysis offers some reason for caution. Children exposed to repeat corticosteroid doses tended to have higher risk for cerebral palsy in one trial (relative risk 5.7, P=0.12) and more attention problems in the other (P=0.04). Overall, both studies offered reassurance, but further follow-up of the children through school age is needed, commented Alan D. Stiles, M.D., of the University of North Carolina at Chapel Hill, in an accompanying editorial. Meanwhile, "if a decision is made to give repeat courses of corticosteroids, it may be prudent to consider the use of lower doses," he said. Published September 20, 2007 in the New England Journal of Medicine.

One Patient's Cancer-fighting Cells Appear to Help Another's.
There are some people who are more "cancer-resistant" than others. Now scientists at Wake Forrest University in North Carolina are harvesting those mmune cells from one cancer survivor to join the battle against cancer in another. Scientist Dr Zheng Cui wants to transplant "granulocytes" into patients, a finding which surprises some experts, who had thought granulocytes played a fairly minor role in fighting cancer.

Tooling up the body's immune system for the destruction of cancer cells is not a new idea. But granulocytes are normally associated with bacterial infections - not cancer. Dr Cui found that after taking blood samples from 100 volunteers, and mixing just their granulocytes with cervical cancer cells in the laboratory, 97% of the cancer cells appeared to be killed in just two days, while at the other end of the scale, after 48 hours, one sample had destroyed just 2% of the cancer cells.

Patients with cancer provided granulocytes with a lower than average cancer-killing ability, as did people who reported being stressed, or those over the age of 50. Remarkably, even the time of year seemed to have an effect on the potency of granulocytes. "Nobody seems to have any cancer-killing ability during the winter months from November to April," said Dr Cui. In other research, granulocytes from a strain of mice completely resistant to cancer cured the disease when those cells were transplanted into other mice.

Dr Cui now plans human trials next summer to see if donor granulocytes - which are plentiful and easily harvested as granulocyte transfusions are already given to some patients with depleted immune systems after being irradiated to make sure that no immune cells given could cause "graft-versus-host" disease - can have a similar beneficial effect. Published September 20, 2007 in the New Scientist magazine.

Gene Therapy Might Not Have Caused Patient's Death.
A patient with arthritis who died in July during a gene-therapy trial may have succumbed to an infection she had before the viral vector was administered, experts said on Monday at a meeting of an advisory panel in Bethesda, Maryland, investigating the incident. Little of the evidence presented to the panel seemed to indicate that the injected viral vector had a key role in 36-year-old Jolee Mohr's death. Although DNA sequences from the vector were found in her liver and spleen, "the detection of the sample is very low and below the limit of quantification in these assays", said Jeffrey Bartlett, a member of the National Institutes of Health (NIH) Recombinant DNA Advisory Committee (RAC). "It really indicates the absence of ongoing replication of the vector in these tissues."

The panel is still awaiting the results of tests on Mohr's tissue samples, expected by December, and the results of blood studies looking for the vector and protein produced by the transgene.The uncertainty surrounding Mr.s Mohr's death is due to her immunocompromised state. In the design of the trial, some patients were taking immunosuppressant drugs, while Mrs. Mohr was also taking a TNF-alpha-inhibitor drug for her arthritis, which suppresses the immune system. Carol Kauffman, an infectious-disease specialist at the University of Michigan, Ann Arbor, told the panel that overwhelming histoplasmosis infection has killed several patients taking such TNF-inhibitory drugs. Published September 18, 2007 in Nature.

Stem Cells from Testes Produce Wide Range of Tissue Types.
After a decade of research, Howard Hughes Medical Institute scientist Shahin Rafii and his colleagues have succeeded in reprogramming adult stem cells from the testes of male mice into functional blood vessels and contractile cardiac tissue. The research offers a promising new source of stem cells for use in organ regeneration studies.

Rafii and colleagues at Weill Cornell Medical College and Memorial Sloan-Kettering Cancer Center report that they have identified a novel cell surface marker that is expressed on a unique set of cells within adult testes known as the spermatogonial stem and progenitor cells (SPCs). The marker, GPR125, enabled the scientists to identify and harvest a large number of SPCs from adult mouse testes, then propagate and reprogram them in the lab to become stem cells that could differentiate into many cell types.

The researchers demonstrated that these multipotent adult spermatogonial-derived stem cells (MASCs) could develop in vivo into working blood vessel (endothelial) cells and tissue, as well as contractile cardiac tissue, brain cells, and a host of other cell types. They also injected MASCs from culture into mouse blastocysts—embryonic cells—that they implanted in mature female mice. When the blastocysts developed into mice, the researchers could see that the MASCs had differentiated into many kinds of tissue. This suggests that the MASCs are truly multipotent: reprogrammable to differentiate into functional tissues.

Ten years ago, Rafii observed that human testicular cancer cells share many characteristics with adult stem cells. As an oncologist, he also noticed that a large number of patients with testicular cancer develop tumors called teratomas, which contain different types of tissue. Based on these observations, he reasoned that spermatogonia, whose sole function is to generate the precursors to sperm, have the potential to readily give rise to pluripotent cells. As such, he thought, they might prove more amenable to reprogramming than other adult stem cells. Published September 20, 2007 in the journal Nature.


WEDNESDAY - September 19, 2007------------------------------------------News Archive/Return to Today's News Alerts

Contraceptive Pill May Reduce the Risk of Developing Cancer.
Researchers from the University of Aberdeen analysed data spanning a 36 year period from the Royal College of General Practitioners (RCGP) Oral Contraception Study which began in 1968. The study recruited 46,000 women, with an average age of 29. Approximately half using oral contraceptives; the other half never having taken it. Every six months their General Practitioner (GP) provided the study with information on the women's health. In addition, three quarters of the women were 'flagged' at the National Health Service (NHS) central registries so that deaths and cancers were notified to the study even if women had left their recruitment GP.

Professor Philip Hannaford and colleagues from the University of Aberdeen's Department of General Practice and Primary Care used the data to calculate the risk of developing any type of cancer and the main gynaecological cancers combined. They also considered the effects of variables such as age, smoking and social class. They calculated the cancer risks using two sets of data. One of cancers reported while the women remained registered with their doctor. The second or "main", a larger data set, included cancers notified by the central NHS registries after women had left their recruiting doctor.

In both data sets there was no overall increased risk of cancer among pill users. When the first dataset was used, women who had taken the pill at some time during their lives had a 3% reduced risk of developing any cancer. When the second and larger dataset was used, the reduction was 12%. A 12% reduction equates to approximately one fewer case of cancer for every 2,200 women who have used the pill for a year and 3% equates to one fewer case of cancer for every 10,000 women. In the main dataset women on the pill had statistically significant lower rates of large bowel/rectal, uterine body and ovarian cancer. They also had a 29% reduced risk of developing one of the main gynaecological cancers.  The data in the first or "doctor/GP" data set also showed a reduced risk of uterine and ovarian cancer. Issued on September 12, 2007 by the Communications Team, Office of External Affairs, University of Aberdeen, King's College, Aberdeen. Tel: (01224) 273174.

National Effort to Restore Fertility In Women With Cancer.
The Oregon National Primate Research Center (ONPRC) and the Oregon Health & Science University School of Medicine (OHSU) have been named to a national team of institutions hoping to preserve or restore fertility in women battling cancer. "Biomedical research has helped save the lives of many women battling cancer,” explaines Richard Stouffer, Ph.D., director of ONPRC’s reproductive sciences division and is a professor of obstetrics and gynecology in the OHSU. “However, the powerful chemotherapy drugs and radiation used to beat cancer can also result in a loss of reproductive function, which is a tremendous blow to young cancer patients who hope to have children.”

In 2004 Lee and colleagues published results in the journal Nature demonstrating great strides in re-establishing fertility in a rhesus macaque monkey after ovarian tissue transplantation that resulted in a successful birth. Current research aims to build upon these earlier findings. “Because this is a relatively new field, OHSU is home to one of the only fertility preservation programs in the country,” explained David Lee, M.D., an assistant professor of obstetrics and gynecology, reproductive endocrinology and infertility in the OHSU School of Medicine.

“Past fertility research milestones at OHSU include our research in monkeys who underwent ovarian tissue transplantation and also human studies such as the first human pregnancy from frozen-thawed eggs. Other institutions involved include the University of California, San Diego; the University of Pennsylvania, the University of Missouri-Columbia and the lead institution: Northwestern University. These institutions will study preserving reproductive tissues for future transplantation, studying human follicles, and global and social studies of the oncofertility issue; and invite people interested in educational opportunities to contact them. Additional information on this consortium can be located at the research team’s Web site.

Sperm Development Involves Cell Death - New Pathway Found.
Heavy, bulky sperm would not be good swimmers. To trim down, sperm rely on cell death proteins called caspases, which facilitate removal of unwanted cell material, radically remodelling them into their sleek, light shape. New research from scientists at the Howard Hughes Medical Institute and Rockefeller University has now uncovered a new pathway that regulates these killer proteins, yielding new knowledge about caspase function as well as insights into the causes of human infertility.

The team tracked down this new pathway by studying the activation of important immune defense cells in psoriasis. Plasmacytoid dendritic cells (pDCs) are highly specialized to recognize viral and other microbial infections. They engulf a virus and set off an immune system cascade to fight the infection by producing interferons. Michel Gilliet, M.D., assistant professor in M. D. Anderson’s Departments of Immunology and Melanoma Medical Oncology, and colleagues previously showed that pDC activation in psoriatic skin drives the development of human psoriasis.

In a series of lab experiments, they identified LL37 as the key ingredient in psoriatic tissue that activates the dendritic cells. The peptide is a member of a family of antimicrobial peptides long known to defend against infection through their ability to directly destroy bacteria and viruses. The team then demonstrated that LL37 activates the dendritic cells by binding to the self-DNA to form a structure that allows it into the dendritic cells, as if it were an invading microbe. The complex is taken up inside a walled-off chamber in the pDCs called an endosome, where it connects to a sensitive internal receptor that launches production of interferon-alpha, setting off the immune response.

“We think LL37’s normal job is to alert the immune system to tissue damage and stimulate a temporary inflammatory response that enhances resistance to infection and initiates wound healing,” Gilliet says. “When tissue is injured, cells are destroyed and they spill DNA into the areas surrounding the cells. LL37, released by epithelial cells, binds this extracellular DNA, which is then taken up by the pDCs to launch the protective inflammatory immune response,” Gilliet says. But in the case of autoimmune disease, LL-37 remains persistently produced, well beyond the temporary jolt needed to dampen infection and promote healing. Gilliet says follow-up research to better understand the pathway and to exploit it to treat autoimmune disease and cancer is under way. Published in this week in PLoS Biology.

UNICEF Reports Child Deaths Fall Below 10 Million Per Year.
For the first time in modern history, the number of children dying before the age of five has fallen below 10 million. New survey figures reported by UNICEF today show solid progress, with worldwide child deaths at a record low of 9.7 million per year – down from almost 13 million in 1990.

Much of the progress reflected in the new child mortality figures is the result of widespread adoption of basic health interventions such as early and exclusive breastfeeding, measles immunization, vitamin A supplementation to boost children’s immune systems, and the use of insecticide-treated bednets to prevent malaria. Proper treatment of pneumonia, diarrhoeal diseases and severe malnutrition, and treatment of paediatric HIV/AIDS, are also important for child survival—as are hygiene promotion and access to safe drinking water and sanitation.. Published September 10, 2007 in Science.


TUESDAY - September 18, 2007------------------------------------------News Archive/Return to Today's News Alerts

Drugs Linked to Birth Defects Still Given to Pregnant Women.
Half of pregnancies in the United States are unintended, according to national estimates. While regular use of contraception can prevent unplanned pregnancies, women filling prescriptions that can increase the risk of birth defects are no more likely to use contraception than other women, a study finds.

For this investigation, Eleanor Bimla Schwarz, M.D., assistant professor in the departments of medicine and obstetrics, gynecology and reproductive medicine at the University of Pittsburgh School of Medicine and colleagues studied patient data related to all prescriptions filled by 488,175 reproductive-aged women enrolled with a large managed health care plan during 2001. Prescriptions involved drugs considered safe for use in pregnancy and those labeled as posing a fetal risk. “We found that over the course of a year, one in six women of reproductive age filled a prescription for a medication labeled by the Food and Drug Administration as increasing the risk of fetal abnormalities.”

The researchers found that internists and family practitioners prescribed the largest proportion (48 percent) of riskier medications to women of childbearing age. Psychiatrists prescribed 15 percent of these drugs; dermatologists, 12 percent; obstetrician/gynecologists, 6 percent; and pediatricians, 3 percent, according to the study.

“Women should not avoid using prescription medications, but clinicians need to remember that sometimes birth control is needed until a woman is ready to have a healthy pregnancy and a healthy baby,” Dr. Schwarz added. Published September 18, 2007 online in Annals of Internal Medicine.

Natural Chemical Thwarts Estrogen's Heart Protection.
In 2002, the National Institutes of Health stopped a large clinical trial when data revealed that women taking estrogen for symptoms of menopause had an increased risk of developing cardiovascular disease. New research suggests that higher risk may be partially explained by the presence of a naturally occurring chemical that blocks estrogen's protective effects on the heart.

The researchers theorize that women taking hormone replacement therapy may be at greater risk of developing heart disease because the chemical 27-hydroxycholesterol (27HC) inhibits the activity of estrogens circulating in the blood. 27-hydroxycholesterol is produced when the body breaks down cholesterol. Decreased estrogen, when combined with high cholesterol, atherosclerosis, or both, could lead to an increased risk of cardiovascular disease. Published September 16, 2007 online in Nature Medicine.

Possible Key to Autoimmune Disease Found.
A human peptide that acts as a natural antibiotic against invading microbes can also bind to the body’s own DNA and trigger an immune response in the absence of an infection, a research team led by scientists at The University of Texas M. D. Anderson Cancer Center reports. “This combination of the peptide and self-DNA activates the same immune response pathway as a virus does,” says senior author Michel Gilliet, M.D., assistant professor in M. D. Anderson’s Departments of Immunology and Melanoma Medical Oncology. Researchers believe this response is both a likely key driver of autoimmune disease and an integral part of an early warning system that flags tissue damage to launch a protective inflammatory response to injury. “We show that this pathway may drive autoimmunity in psoriasis, a chronic inflammatory skin disease,” Gilliet says. But the key peptide, called both LL37 and CAMP, is also heavily expressed in other autoimmune diseases such as inflammatory bowel disease and rheumatoid arthritis. Published in an early online publication in Nature.

A Gene Therapy Death.
An investigation into whether gene therapy killed a 36-year-old woman in an arthritis trial has so far come up empty. At a meeting today, the National Institutes of Health's (NIH's) Recombinant DNA Advisory Committee (RAC) ruled out some hypotheses but came to no firm conclusions about what role, if any, gene therapy played in the woman's death. The murky bottom line eased concerns of researchers who have worried that gene therapy, which has been blamed for two deaths in the past 8 years, would be linked to a third. Results presented at the meeting did not challenge the consensus that the popular vector used, adeno-associated virus (AAV), is relatively safe. However, questions about the design and ethics of the trial have cast a negative light on the field, particularly gene therapy for non-life-threatening diseases. Published September 10, 2007 in Science.

Salamander Hybrids Have a Leg Up on Mom and Dad.
As scientists probe deeper into the genetics of animals, time and again they've turned up evidence of hybridization between species. In most cases, hybrids are less fit than the original species, plagued by problems such as sterility or inviability - take the mule, for example. But a growing body of evidence shows that some hybrids are healthy enough to establish populations. That's a particularly important issue in the Salinas Valley, where the conservation of native, federally threatened California tiger salamanders has been a complex problem. The natives have been breeding with banded salamanders introduced from Texas for more than 50 years, and hybrid populations have existed for much of that time. But until now, nobody knew how the hybrids fared compared to the original species. Evolutionary biologist Benjamin Fitzpatrick of the University of Tennessee, Knoxville, and H. Bradley Shaffer of the University of California, Davis, observed hybrid, native, and introduced salamanders in several breeding ponds. Hybrid larvae, they discovered, were significantly more likely to survive than those of either parental species. A genetic phenomenon known as hybrid vigor may be at work. Published September 16, 2007, online in the Proceedings of the National Academy of Sciences (PNAS).

You Don't Know JAK - If You Think Cancer Genes Are Simple.
"Cancer-causing genes can work in more powerful and sneaky ways than have been realized. Scientists have shown that a gene named JAK that is closely related to a common cancer-causing gene in people tips the scales toward cancer in an unexpected manner. JAK disrupts the activity of an organism’s DNA on a broad scale, thwarting a critical molecular event very early on in an embryo’s development. A team from the University of Rochester Medical Center made the finding through research involving fruit flies, which share much of the same complex cellular signaling as humans. By manipulating the DNA of fruit flies and analyzing their body types as they develop – as maggots – the team made a surprising finding: The cancer-promoting effects of a mutation to the DNA sequence of a gene that normally suppresses cancer can be passed from parents to offspring, even if the mutation itself is not passed to the offspring. Under some circumstances, having one parent with the mutation is enough to ultimately affect the offspring, even when the mutation itself is not passed to the next generation. Published in the Sept. 7 issue of Public Library of Science (PLoS) Genetics.

MONDAY - September 17, 2007------------------------------------------News Archive/Return to Today's News Alerts

Single Gene Determines Smell of Male Body Odor.
Androstenone, found in higher concentrations in the urine and sweat of men than women, is used by some mammals to convey social and sexual information, and the ability to perceive androstenone’s scent may have far-reaching behavioral implications for humans. New research from Rockefeller University, performed in collaboration with scientists at Duke University in North Carolina, reveals for the first time that the extreme variability in people’s perception of the smell of androstenone is due in large part to genetic variations in a single odorant receptor called OR7D4. Many cannot smell androstenone at all. Although some participants with the RT/WM genotype can, they experience the smell very differently than those with two copies of the fully functional receptor: To them, androstenone doesn’t smell like urine; it has a vanilla scent. ”Since some mammals clearly use androstenone to communicate sexuality and dominance within a social hierarchy, it’s intriguing to think whether the same thing may happen in humans,“ Vosshall says. ”If so, what happens to humans who can’t get the signal because they have the nonfunctional copy of the gene? Or the hyperfunctional one? What could be the social and sexual implications of this on one’s perception of the smell of fellow humans?“ Published September 16, 2007, in the advance online journal Nature.

HIV Affected Women May Cut AIDS Risk Via Pregnancy.
Women with HIV infection who become pregnant have a lower risk of progression to AIDS and death, researchers at Vanderbilt University Medical Center report. Their findings suggest that a " complex set of immunologic changes" occur during pregnancy which are interacting in a beneficial way with combination drug therapy. Some previous studies in the developing world had reported higher levels of complications and deaths from AIDS among pregnant women. But those studies were conducted before the advent of highly active anti-retroviral therapy (HAART), drug "cocktails" that over the past decade have dramatically reduced death and complication rates among people infected with the AIDS-causing human immunodeficiency virus (HIV). The Vanderbilt study included 759 women treated between 1997 and 2004 at Nashville's Comprehensive Care Center, one of the nation's largest outpatient AIDS treatment programs. More than 500 of these women received HAART, including 119 of the 139 women who had at least one pregnancy during the study period. After using statistical modeling methods to adjust for differences between women, including their age, health and response to therapy, the researchers found that "pregnant women did better," said Timothy Sterling, MD, the study's senior author and associate professor of medicine. In addition, women who became pregnant more than once during the study tended to have a lower risk of disease progression than did women who became pregnant only once. That also supports the conclusion that something about pregnancy is beneficial to HIV patients. But more study is needed, Sterling cautioned. Published September 10, 2007 in Journal of Infectious Diseases.

Regeneration for Repair's Sake.
"We knew this protein, called Wnt, helped flies develop, but its role in vertebrate models was completely unknown," says Randall T. Moon, Ph.D., a Howard Hughes Medical Institute (HHMI) investigator at the University of Washington - heads the university's Institute for Stem Cell and Regenerative Medicine. In an early experiment, tadpoles with higher than normal amounts of Wnt, loudly hinted that the protein's signals regulate early embryo development. Today, Moon's long-term goal is to use Wnt signaling to coax stem cells into heart, brain, and other organs to replace, or regenerate, diseased cells. Rather than trying to grow whole limbs or sci-fi animals, Moon and a growing group of scientists focus on repairing existing tissue and organs.

"In the past, developmental biologists concentrated on the question of how you make an animal," says Douglas A. Melton, an HHMI investigator at Harvard University, who began in developmental biology before shifting his energies to stem cell medicine. "Now, researchers are returning to a question asked decades earlier: How do you maintain that animal?" He compares this shift in focus to working at a car repair shop, as opposed to a car factory. "We're beginning to appreciate the importance of maintenance, replenishment, and repair."

Humans share share an ability to regrow lost tissue with other organisms, whether from injury or natural biological cycles: every day, the human body replaces an estimated 10 billion cells, including those in the liver, skin, and blood. But why do some species regenerate body parts handily, while others do not? Why can humans regrow a liver but not a pancreas? Can we borrow from nature's regeneration toolkit to treat human disease? Moon and his colleagues have been documenting Wnt's mechanisms. Their studies show that zebrafish, tadpoles, mice, and potentially many other organisms respond to injury by turning on Wnt, a major signaling molecule. Wnt activates a cellular pathway, Wnt/ß-catenin, which launches the biochemistry of regeneration. Conversely, Moon's lab has found that another Wnt protein, Wnt5b, inhibits regeneration by launching a pathway that puts the brakes on regrowth signals.

Some proteins act as cellular brakes, regularly shutting down Wnt signaling and other cell-regeneration pathways. This "stop" mechanism keeps cell populations in check. For instance, scientists have documented that, in colorectal cancer and melanoma, mutations disrupt proteins that normally turn off Wnt. Through their investigations, the researchers discovered the potential involvement of WTX, a protein that normally acts as a tumor suppressor by degrading a protein network that activates the Wnt pathway. Working in zebrafish, frogs, and cultured cells, the team found that Wilms' tumor mutates the gene that encodes WTX, thus disabling the protein. Without WTX as a brake, the Wnt pathway is activated more than usual, triggering harmful cell growth that becomes a tumor.

There may be a safer and more practical application of regeneration research—the familiar human condition of degeneration, which, according to Melton, is the flip side of regeneration. On that note, Moon and colleagues published a study in the Proceedings of the National Academy of Sciences (May, 2007) demonstrating that a single amino acid change in a protein that works with Wnt is associated with late-onset Alzheimer's disease. Moon concludes that Wnt biochemistry is all about balance. Too much—or too little—Wnt affects both regeneration and degeneration.

"We increasingly suffer from diseases of degeneration," Melton notes. "Diabetes, neurodegenerative disorders, cardiovascular disease. All have features in common: an unknown environmental stimulus, many genes, and a long time between cause and effect. If we're interested in slowing degeneration, we should be focusing on how the body maintains and repairs itself.". Published online September 17, 2007 in Howard Hughes Medical Institute Bulletin Vol. 20, #3.