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Week Ending FRIDAY February 18, 2011---------News Archive

How Male Skeleton Regulates Male Fertility

Study provides first evidence that bone plays a role in reproduction

Researchers at Columbia University Medical Center have discovered that the skeleton acts as a regulator of fertility in male mice through a hormone released by bone, known as osteocalcin.

Until now, interactions between bone and the reproductive system have focused only on the influence of gonads on the build-up of bone mass.

"Since communication between two organs in the body is rarely one-way, the fact that the gonads regulate bone really begs the question: Does bone regulate the gonads?" said Dr. Karsenty.

Dr. Karsenty and his team found their first clue to an answer in the reproductive success of their lab mice. Previously, the researchers had observed that males whose skeletons did not secrete a hormone called osteocalcin were poor breeders.

The investigators then did several experiments that show that osteocalcin enhances the production of testosterone, a sex steroid hormone controlling male fertility.

As they added osteocalcin to cells that, when in our body produce testosterone, its synthesis increased. Similarly, when they injected osteocalcin into male mice, circulating levels of testosterone also went up.

Conversely, when osteocalcin is not present, testosterone levels drop, which causes a decline in sperm count, the researchers found. When osteocalcin-deficient male mice were bred with normal female mice, the pairs only produced half the number of litters as did pairs with normal males, along with a decrease in the number of pups per litter.

Though the findings have not yet been confirmed in humans, Dr. Karsenty expects to find similar characteristics in humans, based on other similarities between mouse and human hormones.

If osteocalcin also promotes testosterone production in men, low osteocalcin levels may be the reason why some infertile men have unexplained low levels of testosterone.

Skeleton Regulates Male Fertility, But Not Female

Remarkably, although the new findings stemmed from an observation about estrogen and bone mass, the researchers could not find any evidence that the skeleton influences female reproduction.

Estrogen is considered one of the most powerful hormones that control bone; when ovaries stop producing estrogen in women after menopause, bone mass rapidly declines and can lead to osteoporosis.

Sex hormones, namely estrogen in women and testosterone in men, have been known to affect skeletal growth, but until now, studies of the interaction between bone and the reproductive system have focused only on how sex hormones affect the skeleton.

"We do not know why the skeleton regulates male fertility, and not female. However, if you want to propagate the species, it's probably easier to do this by facilitating the reproductive ability of males," said Dr. Karsenty. "This is the only rationale I can think of to explain why osteocalcin regulates reproduction in male and not in female mice."

The unexpected connection between the skeleton and male fertility is one of a string of surprising findings in the past few years regarding the skeleton. In previous papers, Dr. Karsenty has found that osteocalcin helps control insulin secretion, glucose metabolism and body weight.

"What this work shows is that we know so little physiology, that by asking apparently naïve questions, we can make important discoveries," Dr. Karsenty says. "It also shows that bone exerts an important array of functions all affected during the aging process. As such, these findings suggest that bone is not just a victim of the aging process, but that it may be an active determinant of aging as well."

Next, the researchers plan to determine the signaling pathways used by osteocalcin to enhance testosterone production.

And as for potential drug development, since the researchers have also identified a receptor of osteocalcin, more flexibility in designing a drug that mimics the effect of osteocalcin is expected.

Whether it's for glucose metabolism or fertility, says Dr. Karsenty, knowing the receptor will make it easier for chemists to develop a compound that will bind to it.

"This study expands the physiological repertoire of osteocalcin, and provides the first evidence that the skeleton is a regulator of reproduction," said Dr. Karsenty.

The research is slated to appear online February 17 in Cell, ahead of the journal's print edition, scheduled for March 4.

Authors of the Cell study are: Franck Oury, Ph.D. (CUMC); Grzegorz Sumara, Ph.D. (CUMC); Olga Sumara, Ph.D. (CUMC); Mathieu Ferron, Ph.D. (CUMC); Haixin Chang, Ph.D. (Cornell University); Charles E. Smith, Ph.D. (McGill University); Louis Hermo, Ph.D. (McGill University); Susan Suarez, Ph.D. (Cornell University); Bryan L Roth, Ph.D.(UNC-Chapel Hill); Patricia Ducy, Ph.D. (CUMC); and Gerard Karsenty, M.D., Ph.D. (CUMC).

The research was led by Gerard Karsenty, M.D., Ph.D., chair of the Department of Genetics and Development at Columbia University Medical Center.

This study was supported in part by the National Institute of Child Health Research (NICHR) and the National Institutes of Health (NIH).

The authors declare no financial or other conflicts of interest.

Columbia University has filed for patents relating to osteocalcin and its use to treat a variety of conditions, including male reproductive disorders.

How Eggs' Manage Quality Control

To protect the health of future generations, your body keeps a careful watch on its precious and limited supply of eggs.

Human egg surrounded by sperm
That's done through a key quality control process in oocytes ( immature eggs), which ensures damaged cells are eliminated before they reach maturity.

In a new report in the February 18th Cell, researchers have made progress in unraveling how a protein called p63 initiates the deathblow.

In fact, p63 is a close relative of the infamous tumor suppressor p53 - both proteins recognize DNA damage.

Because of this, it was initially assumed that p63 would also function as a tumor suppressor, but various forms of the protein are now known to be important in development.

One form in particular, called TAp63a, is responsible for killing off damaged oocytes.

But it seems that plenty of TAp63a is always around, whether oocytes are damaged or not, suggesting that there must be a very special way that the protein is kept under wraps lest it kill off perfectly good cells. A team lead by Volker Dötsch of Goethe University has figured out how that works.

The quality control factor normally exists in oocytes in inactive pairs called dimers, he explained.

When double strand breaks in the DNA occur, those dimers are chemically modified by an unidentified enzyme, allowing them to open up and join forces with another double strand break. The result is an tetramer that can bind DNA and lead to the death of the damaged cells.

Activation of TAp63a cannot be undone, even if you reverse the chemical modification that enabled the tetramer formation in the first place. This irreversibility relies on an extra helix structure that keeps the tetramer stable.

"It's all or nothing," Dötsch said. "Once activated, the path to cell death is decided."

Dötsch believes that this quality control mechanism keeps the genetic integrity of eggs (oocytes), and likely represents the original function of the p53 family. Cell cycle arrest and tumor suppression arise in late evolutionary development as p53-like genes are found in invertebrates, including tiny nematode worms.

"Worms live for two weeks," Dötsch said. "They don't need a tumor suppressor, but they do need to worry about the genetic stability of their germ (sex) cells."

It turns out the worm version of the gene also resembles p63 more closely than it does p53.

The finding helps explain what happens in young women who undergo chemotherapy - which often leads them to become infertile, Dötsch noted.

It may even be possible to devise strategies to counteract the players responsible for activating TAp63a once it is found or others in the pathway, he said. Unfortunately, that might not be such a good idea.

"If oocytes are damaged, there is probably good reason for them to be destroyed," he said.

THURSDAY February 17, 2011---------News Archive

Dwarfism Gene Linked to Protection From Cancer and Diabetes

Long-term study of remote community finds almost no cancer or diabetes in individuals with genetically low growth hormone activity

A 22-year study of abnormally short individuals suggests that growth-stunting mutations also may stunt two of humanity's worst diseases.

Published in Science Translational Medicine, part of the Science family of journals, the study raises the prospect of achieving similar protection in full-grown adults by other means, such as pharmaceuticals or controlled diets.

The international study team, led by cell biologist Valter Longo of the University of Southern California and Ecuadorian endocrinologist Jaime Guevara-Aguirre, followed a remote community on the slopes of the Andes mountains.

The community includes many members with Laron syndrome, a deficiency in a gene that prevents the body from using growth hormone. The study team followed about 100 such individuals and 1,600 relatives of normal stature.

Over 22 years, the team documented no cases of diabetes and one non-lethal case of cancer in Laron's subjects.

Among relatives living in the same towns during the same time period, 5 percent were diagnosed with diabetes and 17 percent with cancer.

Because other environmental and genetic risk factors are assumed to be the same for both groups, Longo and his team concluded that -- at least for adults past their growing years -- growth hormone activity has many downsides.

"The growth hormone receptor-deficient people don't get two of the major diseases of aging. They also have a very low incidence of stroke, but the number of deaths from stroke is too small to determine whether it's significant," Longo said.

Overall lifespan for both groups was about the same, with the abnormally short subjects dying more often from substance abuse and accidents. The study did not include psychological assessments that could have helped explain the difference.

"Although all the growth hormone deficient subjects we met appear to be relatively happy and normal and are known to have normal cognitive function, there are a lot of strange causes of death, including many that are alcohol-related," Longo said.

Longo noted that any treatment for preventive reduction of growth hormone would have to show fewer and milder side effects than drugs used against a confirmed disease.

But he added that any preventive treatment would target adults with high growth hormone activity in order to bring it down to average, and not to the extremely low and potentially riskier state observed in Laron's subjects.

If high growth factor levels "become a risk factor for cancer as cholesterol is a risk factor for cardiovascular diseases," drugs that reduce the growth factor could become the new statins, Longo said.

Such drugs would be used at first only for families with a very high incidence of cancer or diabetes.

And because growth hormone activity decreases naturally with age, any preventive treatment would be appropriate only until the effects of advanced age took over, Longo explained.

Animal studies provide evidence for the health benefits of blocking growth hormone. Groups led by John Kopchick of Ohio University and Andrzej Bartke of Southern Illinois University achieved a record 40 percent lifespan extension with growth factor deficient mice in studies published in 2000 and 1996, respectively.

Later, the researchers linked growth factor deficiency to reduced tumor risk.

The Food and Drug Administration has already approved drugs that block growth hormone activity in humans. These are used to treat acromegaly, a condition related to gigantism.

Because studies have shown that growth hormone deficiency protects mouse and human cells against some chemical damage, Longo said his team would initially seek approval for a clinical trial to test such drugs for the protection of patients undergoing chemotherapy.

Growth hormone-blocking drugs such as pegvisomant appear to be well tolerated, Longo said. But even if chronic growth hormone blocking should come with a minor side effect, Longo predicted that societies and governments would make the trade in exchange for less chronic disease.

He called it the "square survival curve," where most of one's life is lived without major illness.

"It's the dream of every administration, anywhere in the world. You live a long healthy life, and then you drop dead," Longo said.

Exactly how growth hormone deficiency might protect a person is not fully understood.

In test tube studies, Longo's team found that serum from Laron's subjects had a double protective effect: it protected DNA against oxidative damage and mutations but it promoted the suicide of cells that became highly damaged.

Laron's subjects tend to have very low insulin levels and low insulin resistance, which may explain the absence of diabetes.

In joint experiments with a group led by Rafael de Cabo at the National Institute on Aging, human cells exposed to the Laron's serum also showed surprising changes in the activity of genes linked to life extension in yeast and other model organisms. Although Longo and colleagues had identified such genes 15 years ago, they had not been shown to be important for disease prevention in humans.

Artificial hormone blocking is not the only way to reduce these hormones in humans.

A natural method appears to achieve the same effect: restriction of calories or of specific components of the diet such as proteins.

Several studies are underway to assess the effect of dietary restriction in humans and other primates. The results are not yet known, but a recent study by Longo's group showed that fasting induces rapid changes in growth factors similar to those caused by the Laron mutation.

However, because fasting or restriction in particular nutrients for long periods can lead to dangerous conditions including anorexia, reduced blood pressure and immunosuppression -- and because individuals with rare genetic mutations can suffer life-threatening effects from even short periods of fasting -- Longo emphasized that additional studies are needed and that any changes in diet must be approved and monitored by a physician.

The study in Science Translational Medicine began as an attempt by Longo to test evidence from animal studies that longevity mutations prevent progressive DNA damage and/or cancer.

Co-author Guevara-Aguirre wanted to understand the reasons for the stunted growth of children in the remote community, centered in the Loja province of southern Ecuador.

Initially, Longo said, the children "were more looked at in search of problems than solutions."

But as the study wore on, Guevara-Aguirre began to notice that the adults in the community were not dying of the usual chronic diseases.

That was the clue Longo had been seeking. After hearing of the Ecuador study, he invited Guevara-Aguirre to present at a symposium on aging and cancer in 2006 at USC's Leonard Davis School of Gerontology, where Longo is associate professor.

Together, they obtained funding from the Center of Excellence in Genomic Science in the USC College of Letters, Arts and Sciences, which sponsored part of the initial field research in Ecuador, and from the National Institute on Aging, which sponsored the cellular studies.

Longo and Guevara-Aguirre's collaborators were co-lead author Priya Balasubramaniam, postdoctoral researcher in Longo's laboratory in the USC Leonard Davis School of Gerontology; Sue Ingles, associate professor in the Keck School of Medicine of USC; Min Wei, research assistant professor, Federica Madia, research associate, and Chia-Wei Cheng, graduate student, all in Longo's lab; Marco Guevara-Aguirre and Jannette Saavedra of the Institute of Endocrinology, Metabolism and Reproduction, in Quito, Ecuador; David Hwang and Pinchas Cohen of the David Geffen School of Medicine at UCLA; Rafael de Cabo of the National Institute on Aging; and Alejandro Martin-Montalvo of the National Institute on Aging and the Centre for Biomedical Research on Rare Diseases in Sevilla, Spain.

Balasubramaniam and Marco Guevara-Aguirre were responsible for major parts of the study in the laboratory and in the field, respectively.

Finally! Blood Test For Ectopic Pregnancy

A long last, an urgent search for proteins in the blood of pregnant women that could be used in early diagnosis of ectopic pregnancy (EP) is found.

A discovery of biomarkers that seem to be specific enough to begin testing in clinical trials, has been reported in a new study in ACS's Journal of Proteome Research.

David Speicher and colleagues explain that ectopic pregnancy happens when an embryo does not attach normally inside the mother's uterus, but instead attaches and begins growing elsewhere.

Most occur inside one of the Fallopian tubes, which link the ovaries to the uterus. Left undiagnosed, EP can burst the Fallopian tube and result in bleeding that is the second most common cause of maternal death early in the first trimester of pregnancy. EP is difficult for doctors to diagnose, and scientists long have searched for substances present in the blood of women with EP that could be the basis for a test.

The scientists describe discovery of such proteins in blood analyzed from women with ectopic pregnancies and compared it to blood of women with normal pregnancies.

They identified almost 70 proteins occurring in unusual levels in the blood in EPs. One of those proteins is called Adam12 and it might be a particularly good early warning sign for EP - it appears at levels that are 20 times lower than in normal pregnancies.

"The next step is clearly to test the candidate biomarkers on a larger, independent patient group, both individually and in multi-biomarker panels," the report states.

Systematic Discovery of Ectopic Pregnancy Serum Biomarkers Using 3-D Protein Profiling Coupled with Label-free Quantitation

Waking Up Is Hard To Do

Scientists identify a gene important for the daily rhythms of the sleep-wake cycle.

Northwestern University scientists have discovered a new mechanism in the core gears of the circadian clock. They found the loss of a certain gene, dubbed "twenty-four," messes up the rhythm of the common fruit fly's sleep-wake cycle, making it harder for the flies to awaken.

The circadian clock drives, among other things, when an organism wakes up and when it sleeps. While the Northwestern study was done using the fly Drosophila melanogaster, the findings have implications for humans.

The research will be published Feb. 17 in the journal Nature.

"The function of a clock is to tell your system to be prepared, that the sun is rising, and it's time to get up," said Ravi Allada, M.D., who led the research at Northwestern. "The flies without the twenty-four gene did not become much more active before dawn. The equivalent in humans would be someone who has trouble getting out of bed in the morning."

Allada is professor of neurobiology and physiology in the Weinberg College of Arts and Sciences and associate director for the Center for Sleep and Circadian Biology.

Period (per) is a gene in fruit flies that encodes a protein, called PER, which regulates circadian rhythm. Allada and his colleagues found that twenty-four is critically important to producing this key clock protein. When twenty-four is not present very little PER protein is found in the neurons of the brain, and the fly's sleep-wake rhythm is disturbed.

It seems it was fate that the gene Allada and his team pinpointed would be important in regulating the 24-hour sleep-wake cycle. The gene's generic name is CG4857, and the numbers add up to 24, earning it the twenty-four nickname. (The fruit fly's genome was sequenced in 2000, but until now the function of this gene was unknown.)

The known core mechanisms of the circadian clock, both in flies and humans, involve the process of transcription, where RNA is produced from DNA. A portion of the control system called a transcriptional feedback loop also is important. (The word circadian comes from the Latin phrase "circa diem," meaning "about a day.")

In trying to identify new clock components, the researchers identified a new player in the system, the gene twenty-four. Instead of operating in the process of transcription, they found twenty-four operates in the process of translation: translating proteins from RNA.

Twenty-four appears to be a protein that promotes translation of period RNA to protein. "This really defines a new mechanism by which circadian clocks are functioning," Allada said. "We found that twenty-four has a really strong and critical role in translating a key clock protein. Translation really wasn't appreciated before as having such an important role in the process."

The researchers believe it is likely that a mechanism similar to that described for the fly gene twenty-four will be evolutionarily conserved and found in humans.

Allada and his Northwestern team worked with scientists at the Korea Advanced Institute of Science and Technology (KAIST). Using a Drosophila library at KAIST, the researchers first screened the behavior of 4,000 different flies looking for flies whose sleep-wake cycles were awry. (Each fly had a different overexpressed gene and thus different behavior.) The fly with the most dramatic change was one with a longer cycle than normal, 26 hours instead of 24.

The overexpressed gene in this fly was CG4857. The researchers next removed, or knocked out, this gene in the flies. These flies had very poor sleep-wake rhythm and would sleep and wake at all times of day. The researchers found very little of the critical PER protein in the brain neurons despite the fact that per RNA is likely produced in the neurons. Without twenty-four the RNA was not translated into the PER protein, leading to dysfunction.

The paper is titled "The Novel Gene Twenty-four Defines a Critical Translational Step in the Drosophila Clock." In addition to Allada, other authors of the paper Chunghun Lim and Valerie L. Kilman, from Northwestern; Jongbin Lee, Changtaek Choi, Juwon Kim and Joonho Choe, from Korea Advanced Institute of Science and Technology, Korea; and Sung Mi Park and Sung Key Jang, from Pohang University of Science and Technology, Korea.

WEDNESDAY February 16, 2011---------News Archive

Whole Genome Used to Help Cancer Therapy

Whole genome sequencing — spelling out a person's entire DNA genetic code — has moved one step closer to being a medical option for direct patient care.

Physicians and researchers at Mayo Clinic in Arizona and the Translational Genomics Research Institute (TGen) successfully completed sequencing both a single patients normal and cancer cells – a tour de force of more than 6 billion DNA chemical bases.

While the whole genomes of several individuals or their cancers have been sequenced in recent years, this is believed to be among the first successful application of whole genome sequencing performed in support of the medical care of a specific cancer patient.

A male patient with pancreatic cancer was the first patient at Mayo Clinic to have whole genome sequencing performed on both his tumor and non-cancerous cells as part of a clinical research project. By comparing the tumor DNA to the patient's normal DNA, researchers found genetic changes (mutations) that were important in helping inform doctors about how best to plan the patient's next treatment. This was a case of using a definable genetic change that could be linked to specific treatment, something believed to be a glimpse into the almost certain future of individualizing cancer care.

Mayo Clinic administered all the clinical aspects of the research. TGen performed the genetic sequencing.

While the Mayo-TGen sequencing was done as part of ongoing research, it signals a major step toward implementation of whole genome sequencing to support clinic treatment options.

"This is a demonstration of the clinical utility of whole genome sequencing," said Keith Stewart, M.B., Dean of Research at Mayo Clinic. "As we do more and more of this, we will move closer and closer to personalized genetic medicine, which means using genetic information to minimize or prevent disease."

Details of this research, its results and implications for the future, will be included in an upcoming scientific paper.

In 2003, after 13 years and nearly $2.7 billion, the government-funded international Human Genome Project deciphered the first entire human genome sequence. Continuing technological advances now allow scientists to evaluate the entire human genome at a fraction of the time and cost.

"No one thought that this would be possible this soon, and the key now is to combine all medical and scientific information together," said Mitesh J. Borad, M.D., Assistant Professor of Medicine and oncology specialist at Mayo Clinic. "However, we are still very early in the process. A lot of questions will come out of this. But in the long run, this will only help."

Other sequencing techniques — such as genome-wide association studies — are less expensive tests, but examine only selected portions of DNA. Whole genome sequencing (WGS) looks at the entire genome, giving scientists the most comprehensive view of the potential genetic origins of disease.

"Increasingly we will use information from an individuals DNA sequence to expand from today's attempts to define disease risk to actual disease management," said Jeffrey Trent, Ph.D., President and Research Director at TGen and the former Scientific Director of the federal government's National Human Genome Research Institute. "We recognize our lack of complete knowledge of many of the genetic changes we observe, and how exactly they will align with drugs for treatment. However, the use of new compounds for some leukemias and gastrointestinal tumors with defined genetic alterations is the prototype example of a genetic change matched to a targeted therapy providing profound clinical benefit. Our study is one of a handful now underway that is attempting to identify and then match a gene alteration to a targeted agents."

Performing genomic sequencing on cancerous tumors may provide clinicians with information to treat cancer more precisely, especially for patients who are resistant to traditional treatments. Cancer is a disease often rooted in genetic mutations and can change a person's DNA. Essentially, WGS distills all the molecular ingredients that make up a person's genetics so physicians can pinpoint the root cause of a disease. The knowledge gained from this research should allow clinicians to design treatments to address many specific diseases.

"Every step we take in research gets us closer to making this routine for cancer patients," said Rafael Fonseca, M.D., Deputy Director, Mayo Clinic Cancer Center in Arizona. "If we look in the not too distant future, this is a possibility for every cancer patient."

At this point, start-up costs for WGS are still significant. Genetic sequencing of tumors requires immense technological and human resources. Once processes are developed and regularly implemented, the long-term costs of sequencing are expected to further drop.

"Whole genome sequencing allows us to dig deeper into the genome than ever before by providing more information and increasing our probability of identifying an 'Achilles heel' not previously recognized by more conventional approaches," said John Carpten, Ph.D., Director of TGen's Integrated Cancer Genomics Division. "The long-term hope is that doctors will leverage this information to inform decisions about patient care in cancer, and beyond.''

Mayo Clinic is a non-profit worldwide leader in medical care, research, and education for people from all walks of life. For more information, visit www.mayoclinic.org/about/ and www.mayoclinic.org/news. To request an appointment at Mayo Clinic, please call 480-422-1490 for the Arizona campus; 904-494-6484 for the Florida campus; or 507-216-4573 for the Minnesota campus.

The Translational Genomics Research Institute (TGen) is a Phoenix, Arizona-based non-profit organization dedicated to conducting groundbreaking research with life changing results. Research at TGen is focused on helping patients with diseases such as cancer, neurological disorders and diabetes. TGen is on the cutting edge of translational research where investigators are able to unravel the genetic components of common and complex diseases. Working with collaborators in the scientific and medical communities, TGen believes it can make a substantial contribution to the efficiency and effectiveness of the translational process. TGen is affiliated with the Van Andel Research Institute in Grand Rapids, Michigan. For more information, visit: www.tgen.org.

Native American Kids At Greater Risk of Leukemia Relapse

New research from St. Jude Children’s Research Hospital and the Children’s Oncology Group ties the genetic variation characteristic of Native American ancestry to higher odds cancer will return and highlights a strategy to ease the racial disparities in survival

The first genome-wide study to demonstrate an inherited genetic basis for racial and ethnic disparities in cancer survival linked Native American ancestry with an increased risk of relapse in young leukemia patients. The work was done by investigators at St. Jude Children’s Research Hospital and the Children’s Oncology Group (COG).

Along with identifying Native American ancestry as a potential new marker of poor treatment outcome, researchers reported evidence the added risk could be eliminated by administering an extra phase of chemotherapy. The study involved 2,534 children and adolescents battling acute lymphoblastic leukemia (ALL), the most common childhood cancer. The work appears in the February 6 advance online edition of the scientific journal Nature Genetics.

The children were all treated in protocols conducted by St. Jude or COG. Although the overall cure rate for childhood ALL now tops 80 percent, and is close to 90 percent at St. Jude, racial and ethnic disparities have persisted. Based on self-declared status, African-American and Hispanic children with the disease have often fared worse than their white and Asian counterparts. This is the first study to use genomics to define ancestry, rather than relying on self-declared racial or ethnic categories.

“To overcome racial disparity you have to understand the reasons behind it,” said Jun Yang, Ph.D., St. Jude Department of Pharmaceutical Sciences assistant member and the study’s first author. “While genetic ancestry may not completely explain the racial differences in relapse risk or response to treatment, this study clearly shows for the first time that it is a very important contributing factor.”

This study identified a possible mechanism linking ancestry and relapse. Hispanic patients, who have a high percentage of Native American ancestry, were more likely than other patients to carry a version of the PDE4B gene that was also strongly associated with relapse. The PDE4B variants were also linked with reduced sensitivity to glucocorticoids, medications that play a key role in ALL treatment.

“This is just one example of how ancestry could affect relapse risk,” said the study’s senior author Mary Relling, Pharm.D., St. Jude Pharmaceutical Sciences chair. “It is likely that many other genes are involved.”

Investigators also found ALL patients with greater Native American ancestry who received additional chemotherapy as part of a COG clinical trial benefited more from the extra treatment than other children. “These are important steps on the way to personalized cancer care, whereby treatment can be tailored to provide maximal benefit to patient subgroups, and someday, individual patients,” said co-author Stephen Hunger, M.D., University of Colorado professor of pediatrics and chair of COG’s ALL committee.

For this study, scientists used a library of 444,044 common genetic variations known as single nucleotide polymorphisms, or SNPs, to search each patient’s DNA for evidence linking ancestry and relapse. The study found that cancer was 59 percent more likely to return in patients whose genetic makeup reflected at least 10 percent Native American ancestry.

About 25 percent of patients in this study met the 10 percent threshold. The percentage was highest among the self-reported Hispanic and Native American patients, who have been reported to be at higher risk of relapse.

Native American ancestry identified patients at high risk of relapse missed by current clinical tools, including testing for minimal residual disease (MRD), which measures the cancer cells that survive the initial round of therapy. Relling said additional research is needed to confirm the findings before screening becomes part of clinical care.

This study used advances in high throughput genomic technologies to better understand why cancer treatment sometimes fails and how the failure is related to genetic ancestry. Unlike previous research that relied on patient self-reports of race and ethnicity and focused on specific populations, this study focused on a group of patients as diverse as the U.S. and representative of the nation’s entire ALL population.

The other authors on this paper are Cheng Cheng, Xueyuan Cao, Yiping Fan, Dario Campana, Wenjian Yang, Geoff Neale, Ching-Hon Pui and William E. Evans, all of St. Jude; Meenakshi Devidas, University of Florida; Nancy Cox, University of Chicago; Paul Scheet, University of Texas M.D. Anderson Cancer Center; Michael Borowitz, Johns Hopkins Medical Institute; Naomi Winick, University of Texas Southwestern Medical Center; Paul Martin, Duke University; Cheryl Willman, University of New Mexico Cancer Center; W. Paul Bowman, Cook Children’s Medical Center; Bruce Camitta, Medical College of Wisconsin; Andrew Carroll, University of Alabama at Birmingham; Gregory Reaman, Children’s National Medical Center; William Carroll, New York University Cancer Institute and Mignon Loh, University of California at San Francisco.

Yang is supported by the American Society of Clinical Pharmacology and Therapeutics Young Investigator Award and Alex Lemonade Stand Foundation for Childhood Cancer Young Investigator Grant. The work was supported in part by National Institutes of Health’s National Cancer Institute, National Institute of General Medical Sciences and National Institute of Child Health and Human Development as well as the Jeffrey Pride Foundation, National Childhood Cancer Foundation, CureSearch and ALSAC.

St. Jude Children’s Research Hospital is internationally recognized for its pioneering research and treatment of children with cancer and other catastrophic diseases. Ranked the No. 1 pediatric cancer hospital by Parents magazine and the No. 1 children’s cancer hospital by U.S. News & World Report, St. Jude is the first and only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children.

TUESDAY February 15, 2011---------News Archive

New Program for Placental Disorders at Stanford


The placenta is probably the most-ignored human organ — in most pregnancies, it does its job without fanfare until the baby arrives, then ends up in a bucket.

Deirdre Lyell is directing a new program at Lucile Packard Children’s Hospital for treatment of placental disorders. While such conditions are rare, they can have dire consequences if not addressed. Photo by Steve Fisch

But for a small group of pregnant women who develop placental disorders, the organ is dangerous to ignore. In these rare cases, the placenta grows across the cervix, blocking the uterine opening, or attaches too deeply to the uterine wall. The consequences can include bleeding during pregnancy, restricted fetal growth, preterm labor and life-threatening maternal hemorrhage at delivery.

To address the problems faced by women with these types of pregnancies, Packard Children’s high-risk obstetrics team has inaugurated a new program for placental disorders in the hospital’s Johnson Center for Pregnancy and Newborn Services.

Assisting one patient safely through pregnancy and delivery can require input from practitioners in maternal-fetal medicine, gynecologic oncology, interventional radiology, vascular surgery, obstetric anesthesia, the blood bank, pediatric radiology and neonatal intensive care. The new program provides a streamlined process that ensures women and their babies will receive all the care they need, said Lyell, who is also an associate professor of obstetrics and gynecology at the School of Medicine said.

Lyell’s team treats the full range of placental abnormalities, including:

placenta previa in which the placenta partly or completely covers the cervix
placenta accreta and placenta increta in which the placenta grows too deeply into the uterine muscle
placenta percreta when the placenta grows all the way through the uterine wall, sometimes invading nearby organs such as the bladder

Center physicians also have ongoing research projects to investigate the causes of abnormal placental growth.

The new program accepts patients with known or suspected placental disorders, including those with no diagnosis but with risk factors such as a history of uterine surgery. (The placenta is more likely to attach deeply in scar tissue.)

All patients are scheduled for a confirmatory ultrasound and assessments with the multidisciplinary care team, followed by communication of the team’s findings back to the referring physician.

The program’s offerings range from consulting on patients who will deliver at their home hospitals to assuming all care if necessary. “We focus on keeping women in their own communities for as long as is safe,” Lyell said.

Standard care for patients includes pelvic rest, regular non-stress tests to check for contractions and administration of steroids to help mature the fetal lungs since placental disorders often require early delivery. Women can be hospitalized in the Packard Children’s antepartum unit if they show signs of trouble, such as repeated bleeding or preterm labor, or if they lack transportation to get to the hospital quickly as they near term.

For cases in which the probability of hemorrhage at delivery is high, the team schedules a combined cesarean-hysterectomy performed at Stanford Hospital by an obstetrician and a gynecologic oncologist experienced in complex uterine surgery. This option is often the best route to prevent significant blood loss. Both mother and baby benefit from the team’s coordinated care, since Packard Children’s neonatologists are present at the birth to receive the baby and move him or her to the NICU if needed.

“Streamlining care for these patients was really important and necessary,” Lyell said. “We’re excited about our new offerings.”

Stanford University Medical Center integrates research, medical education and patient care at its three institutions - Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital. For more information, please visit the Office of Communication & Public Affairs site at http://mednews.stanford.edu/.

Immune System Gene Linked to Preeclampsia

Researchers at North Carolina State University have discovered that the placentas of women who suffer preeclampsia during pregnancy have an overabundance of a gene associated with the regulation of the body’s immune system.

Their discovery may lead to improved screening and prenatal care for these patients and their babies.

Preeclampsia occurs in up to 10 percent of all pregnancies, and is responsible for about 15 percent of pre-term births. The disorder is usually marked by a rapid rise in blood pressure that can lead to stroke, seizures or organ failures in the mother.

Researchers have recently begun looking at preeclampsia as an autoimmune disorder, in which the mother’s body treats the placenta like an invader, but they weren’t sure of the genetic mechanisms involved.

Dr. Jorge Piedrahita, professor of genomics, along with colleagues from NC State and the Duke University School of Medicine, examined the genetic makeup of placentas from women with preeclampsia and compared the results to those from normal pregnancies. Their results are published in the February issue of the journal Placenta.

“When we looked at the preeclampsic placentas, we found that several genes associated with a particular autoimmune pathway were ‘upregulated’ – basically, that there were more of them in placentas of preeclampsic women than in normal placentas,” Piedrahita says.

“More specifically, we found the upregulation of a particular enzyme involved in sialic acid modification called SIAE. Sialic acid coats every cell in our body, making it possible for our immune system to distinguish ‘self’ from ‘not-self.’ If this process is disrupted, the body can end up attacking itself.”

The researchers were excited by this finding because SIAE has recently been linked to autoimmune diseases like rheumatoid arthritis and type I diabetes.

“Prior to this research, we knew that there was an autoimmune cascade effect with preeclampsia, but we didn’t know where it originated,” Piedrahita adds.

“Now we know that disregulation of SIAE helps start the cascade. We’ve been able to fill in the blanks, and hopefully pregnant women and their babies will benefit as a result.”

The research was funded by a grant from the National Institutes of Health. The Department of Molecular Biomedical Sciences and the Center for Comparative Medicine and Translational Research are part of NC State’s College of Veterinary Medicine.

MONDAY February 14, 2011---------News Archive

Two Genes Affecting Brain Development

Nerve cells are able to find and contact their partner cells thanks to the interaction of two genes.

3D-rotation through the optic lobe of a fly larva's brain.

The human brain consists of approximately one hundred billion nerve cells.

Each of these cells needs to connect to very specific cells during brain development in order to form a fully functional organism. Yet how does a nerve cell know where it should grow and which cells to contact?

Scientists of the Max Planck Institute of Neurobiology in Martinsried have now shown that growing nerve cells realise when they've reached their target area in the fly brain thanks to the interaction of two genes. Similar mechanisms are also likely to play a role in the development of the vertebrate brain and be important in understanding particular developmental disorders.

The nervous system is incredibly complex. Millions and even many billion nerve cells are created during development.

Each of these cells sets up connections to their neighbouring cells and then sends out a long connecting cable, the axon, to a different brain region.

Once the axon has reached its target area it connects to the local nerve cells. In this way a chain is established which allows us to see an object, recognize its' function, and determine how to interact with it. Misconnections between the nerve cells along the way between can confuse our perception and misdirect our response to visual cues.

It is thus essential for nerve cells to connect to the correct partner cells.

Based on this fact, scientists of the Max Planck Institute of Neurobiology in Martinsried and colleagues from Kyoto investigated how an axon knows where it should stop growing and start setting up connections with surrounding cells.

For their investigation, the neurobiologists analyzed the function of genes that play a role in the development of the visual system of the fruit fly.

Photoreceptor nerve cells (green) in fly's compound eye send their axons to the brain's optic ganglia. Axons are able to recognize their target area in the brain thanks to the interaction of two genes. Credit: Max Planck Institute of Neurobiology / Suzuki

Scientists now report in the journal Nature Neuroscience that the visual system of the fruit fly is only able to develop correctly, when two genes work together to produce the proteins "Golden Goal" and "Flamingo".

These two proteins are located at the tip of a growing axon, where they gather information about the environment from the surrounding tissue. They then enable nerve cells to find their way in the brain and recognize their target. The study showed that chaos results if only one of the genes is active, or if there is a mismatch in the genes: the axons cease to grow somewhere along the way and never reach their target area.

"We assume that very similar mechanisms play a role also in other organisms – including humans", explains Takashi Suzuki, lead author of the study. "We are now a good way into understanding how to manipulate the cells in such a way that they are certain to reach their target area."

This knowledge would be an important foundation for eventual therapies of developmental disorders based upon a misguided growth of nerve cells. The knowledge may also help in the guidance of regenerating nerve cells back to their old connection sites.

Original publication: Hakeda-Suzuki S*, Berger-Mueller S*, Tomasi T, Usui T, Horiuchi S, Uemura T, Suzuki T (*equal contribution)

Golden Goal Collaborates with Flamingo in Conferring Synaptic-Layer Specificity in the Visual System Nature Neuroscience,February 14 2011

News From the Annual Meeting of the Society for Maternal-Fetal Medicine

Fetal Heart Monitor Greatly Reduces Infant Mortality

In a study to be presented at the Society for Maternal-Fetal Medicine's (SMFM) annual meeting, The Pregnancy Meeting ™, in San Francisco, researchers will present findings that prove that the use of fetal heart rate monitors lowers the rate of infant mortality.

There have been a handful of small studies conducted in the past that looked at the effectiveness of fetal heart rate monitors, but none of them were large enough to be conclusive.

"There was some criticism within the obstetric community that fetal heart rate monitoring was quickly accepted technology without proof that it was effective," said Suneet P. Chauhan, M.D., one of the study's authors. "We thought we could use data from the National Birth Cohort to get a large enough sample to gauge its effectiveness."

Chauhan and his colleagues (Han-Yang Chen, Cande Ananth, Anthony Vintzileos and Alfred Abuhamad) used a sample of 1,945,789 singleton infant birth and death records from the 2004 National Birth Cohort. Multivariable log-binomial regression models were fitted to estimate risk ratio to evaluate the association between electronic fetal heart rate monitoring (EFM) and mortality, while adjusting for age, race, marital status, education, smoking, and the infant's gender.

The results showed that in 2004, 89% of singleton pregnancies had EFM. EFM was associated with significantly lower infant mortality (adjusted RR 0.75; 95% CI 0.69, 0.81); this was mainly driven by the lower risk of early neonatal mortality (adjusted RR 0.50; 95% CI 0.44, 0.57) associated with EFM. In low-risk pregnancies, EFM was associated with decreased risk for low (< 4) 5 min Apgar scores (RR 0.54; 95% CI 0.49, 0.51), whereas in high risk pregnancies EFM was also associated with decreased risk of neonatal seizures (adjusted RR 0.65; 95% CI 0.46, 0.94).

The study demonstrates that the use of EFM decreased early neonatal mortality by 53%.

Babies Delivered Prior to 39 Weeks Are At Risk

In a study to be presented today at the Society for Maternal-Fetal Medicine's (SMFM) annual meeting, The Pregnancy Meeting ™, in San Francisco, researchers will present findings that show that despite fetal pulmonary maturity, babies delivered at between 36 to 38 weeks, still have a significantly increased risk of neonatal morbidities.

The American College of Obstetricians and Gynecologists recommends that fetal pulmonary maturity be documented for scheduled deliveries occurring prior to 39 weeks of gestation in order to prevent neonatal respiratory problems.

"We wanted to do the study because recent evidence suggests that deliveries prior to 39 weeks may result in increased neonatal morbidity," said Yu Ming Victor Fang, M.D., one of the study's authors. "We wanted to examine whether neonates who were delivered at between 36 to 38 completed weeks with confirmed fetal pulmonary maturity would be at increased risk for neonatal morbidities when compared to those that were delivered at 39 weeks or greater."

To compare neonatal outcomes, the team looked at mothers who had positive fetal lung maturity tests at between 36 to 38 completed weeks. They compared the neonatal outcomes from these scheduled deliveries prior to 39 weeks with known fetal lung maturity to the outcomes from scheduled deliveries at 39 weeks to 41 completed weeks.

The study was a retrospective cohort study from a single institution over a 12 year period. Neonatal outcomes of women who were delivered following documented fetal pulmonary maturity at 36, 37, and 38 weeks were compared to women undergoing a scheduled delivery at 39, 40, and 41 weeks. A lamellar body count of ≥36,000, lecitin/sphingomyelin (L/S) ratio >2.0, or a phosphotidyglycerol (PG) of 0.3 were considered mature. Neonatal outcomes examined included: neonatal intensive care unit (NICU) admission, length of stay (LOS) in the NICU, total neonatal respiratory morbidity (Tot resp morbid), cases of respiratory distress syndrome (RDS), transient tachypnea of the newborn (TTN), other respiratory morbidity (other resp morbid), neonates requiring mechanical ventilation (Vent), proven sepsis (Sepsis), hypoglycemia, and neonatal deaths. Fetuses with major congenital anomalies were excluded. Neonatal outcomes between the two groups were compared using the chi square test.

The study concluded that despite fetal pulmonary maturity, deliveries between 36 0/7 to 38 6/7 weeks are associated with significantly increased neonatal morbidity.

"Patients need to be counseled carefully if they choose to have a scheduled delivery prior to 39 weeks," said Dr. Fang. "Even if tests indicate that their baby's lungs are mature, delivery prior to 39 weeks is not without risks."


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