FRIDAY - March 28, 2008-----------------------------------------------------News Archive/Return to Today's News Alerts

Male Contraception Hormone Combination Gaining Ground

Combining androgens and progestins appears to provide reliable and reversible contraception for most men, researchers are now saying.

But while "considerable progress" has been made in identifying the best combinations of androgens and progestins, the finding isn't quite ready for practical use, Dr. Wang reported online in the Journal of Clinical Endocrinology & Metabolism.

"Further optimization of androgen-progestin treatment regimens is still required," the researchers concluded.

Researchers - including many of the leaders in the field of male contraception - re-analyzed raw data from 30 studies including 1,756 men, about two-thirds of them Caucasian and the remainder Asian. "It's an outstanding study," said Dale McClure, M.D., of Virginia Mason Medical Center in Seattle, and the incoming president of the American Society for Reproductive Medicine. Dr. McClure was not involved in the research.

The results, he said, are "hopeful" although he, like the authors of the study, said more work is needed before a male hormonal contraceptive will be available for general use. In the 30 studies, the original researchers tested a range of hormones, including several formulations of testosterone, as well as androgen-progestin combinations. The current re-analysis looked at which men suppressed their sperm count to a million or less per milliliter of semen, as well as how quickly that happened.

Older age, higher baseline sperm level, and higher baseline blood testosterone were all associated with slower suppression of spermatogenesis. Oral and transdermal testosterone were also associated with slower suppression.

Only two factors stood out because of their large effect size, Dr. Wang said: concurrent use of a progestin and ethnicity. Men given a concurrent progestin were 60% more likely to suppress their sperm count, the researchers found. The finding implies, they said, that "a practical male hormonal method will require an androgen and progestin combination."

They cautioned that the study treated all progestins as equivalent in order to get an average effect, but "in reality, progestins are likely to differ in their effects on the rate of suppression." Compared with Asian men, the Caucasians were significantly more likely to suppress their sperm count to a million or less per milliliter of semen.

Interestingly, when the researchers looked at the time course of suppression, they found that Caucasian men suppressed their sperm more rapidly during the first three months of treatment, but more slowly thereafter.

Published February 26, 2008 in the Journal of Clinical Endocrinology & Metabolism

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Are Genomes Identical In A Stem Cell?

Stem cell researchers from UCLA used a high resolution technique to examine the genome - or total DNA content - of a pair of human embryonic stem cell lines and found that while both lines could form neurons, there were differences in the numbers of certain genes that control such things as individual traits and disease susceptibility.

The technique used to study the genome, which contains all the genes on 46 chromosomes, is called Array CGH. The use of higher resolution techniques, such as Array CGH and, soon, whole genome sequencing, will enhance the ability of researchers to examine stem cell lines to determine which are best – least likely to result in diseases and other problems – to use in creating therapies for use in humans.

Array CGH provided a much better look at the gene content on the chromosomes of human embryonic stem cells, with a resolution about 100 times better than standard clinical methods. Clinical specialists commonly generate a karyotype to examine the chromosomes of cancer cells or for amniocentesis in prenatal diagnosis, which has a much lower resolution than Array CGH, said Michael Teitell, a researcher with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research and the senior author of the study. Small defects that could result in big problems later on could be missed using karyotyping for stem cells.

“Basically, this study shows that the genetic makeup of individual human embryonic stem cell lines is unique in the numbers of copies of certain genes that may control traits and things like disease susceptibility,” said Teitell, who also is an associate professor of pathology and laboratory medicine and a researcher at UCLA’s Jonsson Comprehensive Cancer Center. “So, in choosing stem cell lines to use for therapeutic
applications, you want to know about these differences so you don’t pick a line likely to cause problems for a patient receiving these cells.”

Differences between individual DNA sequences provide the basis for human genetic variability. Forms of variation include single DNA base pair alterations, duplications or deletions of genes or sets of genes, and translocations, a chromosomal rearrangement in which a segment of genetic material from one chromosome becomes heritably linked to another chromosome. These changes can be benign, but they can also promote diseases such as certain cancers, or confer increased risk to other diseases, such as HIV infection or certain types of kidney ailments.

In this study, Teitell and his team sought to determine copy number variants
(CNVs), or differences in the numbers of certain genes, in two embryonic stem cell lines. The CNVs provide a unique genetic fingerprint for each line, which can also indicate relatedness between any two stem cell lines. Teitell used embryonic stem cell lines that made different types of neurons and studied them with array CGH for comparison. His team found CNV differences between the two lines in at least seven different chromosome locations below the level of detection using standard karyotype studies. Such differences could impact the therapeutic utility of the lines and could have implications in disease development. More studies will be required to determine the effect of specific CNVs in controlling stem cell function and disease susceptibility, he said.

“In studying embryonic stem cell lines in the future, if we find differences in
regions of the genome that we know are associated with certain undesirable traits or
diseases, we would choose against using such stem cells, provided safer alternative lines are available,” Teitell said.

Large genome-wide association studies are underway in a variety of diseases to
determine what genetic abnormalities might be at play. When the genetic fingerprint or predisposing genes for a certain disease is discovered, it could be used as key information in screening embryonic stem cell lines.

Published March 27, 2008 in the journal Stem Cells
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Genetic Test Improves Artificial Fertilization

Polar body diagnosis can make artificial fertilization more successful, according to Katrin and Hans van der Ven and Markus Montag of Bonn University Clinic, writing in the current edition of Deutsches Ärzteblatt International.

If the two polar bodies in an egg cell are examined, it can be seen whether the chromosomes are damaged or whether the positions of the chromosomes are abnormal.

This should help to prevent pregnancies and births of severely ill children and lead to higher implantation and birth rates.

Preimplantation diagnosis (PID) on the individual cells of a developing embryo allows the hereditary material to be examined directly.

In Germany, PID is thought to be incompatible with the German Embryo Protection Act. This is why polar body diagnosis has become established in parallel to the debate on ethical and legal issues.

In an accompanying editorial, the human geneticist Peter Propping asks whether it is honest that German doctors continue to draw on PID results obtained abroad to compare the reliability of polar body diagnosis.

Published March 25, 2008 in the journal Deutsches Arzteblatt International
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THURSDAY - March 27, 2008-------------------------------------------------News Archive/Return to Today's News Alerts

The Genes that Put the "Stem" in Cell

Embryonic stem cells are the ultimate in indecision. Precursors of all the specialized cells of the body, embryonic stem cells exist in an undefined form until the time comes to head down the path toward nerve, organ, or muscle. They are distinct from other cells in two ways: First, they are pluripotent - they have the ability to develop into any cell type; Second, they are perpetually self-renewing, meaning that unlike other cells they do not die after a set number of divisions.

Led by Stuart Orkin, a team of Howard Hughes Medical Institute (HHMI) researchers has identified a network of hundreds of genes that keep embryonic stem cells in their characteristic malleable state, able to develop into any cell type when the time comes. The finding, based on studies of mouse cells, provides valuable insight into the way stem cells function, and could help researchers find ways to reprogram adult cells for therapeutic use.

For years, researchers have sought to decipher the genetics behind these unique characteristics. In 2006, Orkin's team reported in the journal Nature that a set proteins that physically associate with one another regulates gene activity critical for maintaining cells in the embryonic stem-like state. These proteins, called transcription factors, bind to regulatory regions of DNA associated with specific genes and influence the genes' activity by encouraging or restricting their transcription (the first step in making a protein).

According to Orkin, the new study is a sequel to that Nature paper. “We're asking: `Well, we've got all these proteins - what are the genes they likely regulate?'”

To find out, the team tagged a set of nine critical proteins with "molecular hooks" that made it possible to fish out the proteins attached to their target genes. Together, the proteins bound to roughly 6,500 genes that fell into two groups: those that the proteins kept switched OFF in the stem cells, and those that they switched ON. However, it wasn't a simple matter of each gene being turned ON or OFF by one transcription factor.

Instead, Orkin explained, “one class is genes that are targeted by many of the nine proteins we tested - even as many as six, seven, or eight. These genes tend to be ON in embryonic stem cells, and OFF when the cells differentiate.” Genes that were turned OFF in the embryonic stem cells, on the other hand, were bound by only one or two of the transcription factors.

According to Orkin, “This is the first time we've had a sense that one could distinguish these classes.” And, he said, the identity of the genes fit with the scientists' expectations of functions that need to be regulated to maintain the stem cell state. “They have to promote self renewal,” he said, “but at the same time they have to block differentiation. The two classes we see seem to more or less fit into those functions.”

Orkin said that the findings represent a “catalog of the genes bound by these factors,” which he hopes will be useful in future studies. According to Orkin, there has been a recent explosion of interest in reprogramming skin or other developed cells to act like stem cells, with the ultimate goal of treating disease. But currently, he said, the process is still essentially a “black box.” “You add genes, and the cells reprogram,” he said. “What happens in between?

“This kind of work provides the materials to get a better understanding of that process,” said Orkin. “The goal is to be able to manipulate cells in a very directed way.”

Published March 21, 2008 in the journal Cell
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UK Physician Dramatically Revolutionizes Gene Research

A dramatic new study published in the most recent issue of Nature questions some of the mechanisms underlying a new class of drugs based on Nobel Prize-winning work designed to fight diseases ranging from macular degeneration to diabetes.

Dr. Jayakrishna Ambati, a University of Kentucky researcher and the paper's senior author, has for years been investigating gene silencing, a 1998 discovery that won a Nobel Prize in Physiology or Medicine in unusually quick fashion in 2006.

While the prize-winning discovery remains important, the findings made by Ambati's lab show the mechanisms behind it are not as scientists once believed. In fact, Ambati's work imparts the need for caution in current clinical trials using the technology, as it may have potentially harmful effects on subjects.

Gene Silencing Leads to New Class of Drugs

In short, researchers in 1998 discovered a class of double-stranded RNA (dsRNA) that possessed powerful gene-silencing capabilities, or the ability to "turn off" disease-causing genes in the body.

The technique of targeting these dsRNA for single genes was refined with synthetic molecules called small-interfering RNA (siRNA). siRNA were thought to have the capability to interfere with specific disease-causing genes and prevent them from being expressed.

Because gene-targeted silencing with siRNA does not involve permanent DNA mutations, this approach rapidly gained popularity throughout biomedical research. The breakthrough, with the powerful ability to turn off genes, has become a standard research tool for genetic studies and has resulted in a new class of 21st century drugs designed to silence disease-causing genes in the body or disarm an invading virus by knocking out its genes.

Many diseases including age-related macular degeneration, diabetes, kidney disease, cancer, Lou Gehrig's and Parkinson's have been heralded as candidates for siRNA therapy, creating a wave of on-going clinical trials.

New Discovery Shows Therapies Could Have Harmful Side Effects

Ambati, professor and vice chair of ophthalmology and visual sciences at the University of Kentucky College of Medicine, and his colleagues have made a critical discovery that challenges the view that siRNAs therapeutic effects are imparted solely through RNA interference.

Ambati and collaborators argue that siRNA functions generically rather than specifically, thus the new class of drugs being formulated may actually adversely affect blood vessel growth in a variety of organs.

"siRNAs are used in every area of biomedical research and are thought to be exquisitely specific in targeting a single gene," Ambati said. "My lab made the surprising discovery that siRNAs, including those in clinical trials, do not enter cells or trigger RNAi. Rather, we found that they generically, regardless of their sequence or target, bind a receptor known as TLR3 on cell surfaces and block blood vessel growth in the eye, skin and a variety of other organs."

Blocking blood vessel growth is beneficial in a variety of diseases. Prime examples include wet AMD, an eye disease hallmarked by the abnormal growth of blood vessels beneath the retina, as well as cancer. However, blocking blood vessel growth by administering siRNA intravenously could be detrimental if it impacts other organs, according to Ambati's study.

Ambati, however, quickly notes the Nobel Prize-winning discovery is still valid.

"RNA interference does, of course, exist," said Ambati, a University Research Professor and the Dr. E. Vernon Smith & Eloise C. Smith Endowed Chair in Macular Degeneration Research. "It is just that siRNA functions differently than commonly believed not via RNA interference."

Ambati said the main implications of his research are two fold: (1) for researchers to understand how siRNAs actually work and (2) for clinical trials of siRNA to be approached with great caution.

Ambatis lab also showed that people with a mutation in the TLR3 receptor would be resistant to the generic effects of siRNAs, thereby providing hope for personalized medicine in this population.

The next steps, Ambati said, are to better understand the generic mechanism of siRNA that inhibits blood vessel growth and to discover how to render it useful in creating treatments for the many conditions that would benefit from such effects. His lab also will work to refine siRNAs to potentially achieve their promise of precise gene targeting.”"

Published March 20, 2008 in the journal Nature
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Human Umbilical Cord Blood May Improve Alzheimer’s Disease

Targeted immune suppression using human umbilical cord blood cells may improve the outcomes associated with Alzheimer’s disease, reports a new study based on a mouse model.

Following a series of low-dose infusions of human umbilical cord blood cells into mice with Alzheimer’s-like disease, the amount of amyloid-ß and ß-amyloid plaques — hallmarks of Alzheimer’s pathology in the brain — was reduced 62%. Amyloid-ß induces an inflammatory response in the brain from interaction of CD40 and CD40L, two pro-inflammatory molecules. Researchers also reported an astonishing 86% improvement in cerebral amyloid angiopathy (CAA), another hallmark of Alzheimer’s disease. CAA compromises the integrity of the blood-brain barrier, disrupting normal trafficking of various molecules and cells from and to the brain and is believed to be the main culprit for the brain inflammation observed in Alzheimer’s.

Human umbilical cord blood cell therapy appeared to suppress CD40-CD40L activity, suggesting that this approach potentially targets the inflammatory response that contributes to Alzheimer’s disease and other degenerative conditions.

Jun Tan, PhD, MD, and colleagues from USF (Tampa), Yale University (New Haven, CT), Cedars-Sinai Medical Center (Los Angeles, CA), Saneron CCEL Therapeutics (Tampa, FL), and Saitama Medical School (Japan), concluded that human umbilical cord blood cell-induced disruption of the CD40-CD40L interaction may alleviate the key pathologic changes in the brain associated with Alzheimer’s disease.

“It has been well documented that altered immune functioning, characterized by the presence of molecules and cells that promote inflammation, can accelerate the progression of Alzheimer’s disease,” said senior study author Dr. Tan, Robert A. Silver Chair, Rashid Laboratory for Developmental Neurobiology at Silver Child Development Center, USF Department of Psychiatry. Said co-author Paul R. Sanberg, PhD, DSc, director of the USF Center for Aging and Brain Repair: “This study may open a door to a new field focusing on studying these molecular mechanisms in detail, and hopefully use them in the future not just for Alzheimer’s disease, but for other neurological or systemic chronic diseases.”

“Previously, challenging observations have reported phenomena suggesting the non-hematologic therapeutic potential of blood stem cells,” said Graham C. Parker, Ph.D., editor-in-chief of Stem Cells and Development, and a research professor in at Wayne State University School of Medicine, Children’s Hospital of Michigan. “What is novel about this paper is its application to Alzheimer’s disease, and a significant advance in characterizing the ameliorative mechanism of action.”The study was supported by the National Institutes of Health Small Business Technology Transfer program, the Florida Hi-Tech Corridor, the Johnnie B. Byrd Sr. Alzheimer’s Center & Research Institute, and Saneron CCEL Therapeutics, Inc.

Published March 25, 2008 in the journal Stem Cells and Development
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WEDNESDAY - March 26, 2008----------------------------------------------News Archive/Return to Today's News Alerts

Mounting Evidence Shows Red Wine Antioxidant Kills Cancer

For the first time, researchers have shown that a natural antioxidant found in grape skins and red wine can help destroy pancreatic cancer cells by reaching to the cell's core energy source, or mitochondria, and crippling its function. When the pancreatic cancer cells were pre-treated with resveratrol, and irradiated - the combination induced cell death - apoptosis - an important goal of cancer therapy.

Although red wine consumption during chemotherapy or radiation treatment has not been well studied, it is not "contraindicated," said lead author Paul Okunieff, M.D., chief of Radiation Oncology at the James P. Wilmot Cancer Center at the University of Rochester Medical Center. In other words, if a patient already drinks red wine moderately, most physicians would not tell the patient to give it up during treatment. Perhaps a better choice, Okunieff said, would be to drink as much red or purple grape juice as desired. Some physicians are concerned antioxidants might end up protecting tumors, but Okunieff's study showed there is little evidence to support that fear. In fact, the research suggests resveratrol not only reaches its intended target, injuring the nexus of malignant cells, at the same time it protects normal tissue from the harmful effects of radiation.

Resveratrol is known for its ability to protect plants from bacteria and fungi. Purified versions have been described in scientific journals as potential anti-cancer, anti-inflammatory and anti-atherogenic agents, and for their ability to modulate cell growth. Other well-known antioxidants derived from natural sources include caffeine, melatonin, flavonoids, polyphenols, and vitamins C and E.

At the suggestion of a young scientist in his lab, Okunieff began studying resveratrol as a tumor sensitizer, and discovered its link to mitochondria. Like the cell nucleus, mitochondria contains its own DNA and continuously supply the cell with energy when functioning properly. Stopping the energy flow theoretically stops the cancer.

Their experiments showed that resveratrol:

-- Reduced the function of proteins in the pancreatic cancer cell membranes that are responsible for pumping chemotherapy out of the cell, making the cells chemo-sensitive.
-- Triggered the production of reactive oxygen species (ROS), which are substances circulating in the human body that have been implicated in a number of diseases: when ROS is increased, cells burn out and die.
-- Caused apoptosis, which is likely the result of increased ROS.
-- Depolarized the mitochondrial membranes, which indicates a decrease in the cell's potential to function. Radiation alone does not injure the mitochondrial membrane as much.

The team also wanted to know why pancreatic cancer cells seem particularly resistant to chemotherapy. The pancreas, a gland located deep in the abdomen, produces insulin and regulates sugar, and pumps powerful digestive enzymes into the duodenum. This natural pumping process, however, ends up pumping out needed chemotherapy from cells in the pancreas. But just as reseveratrol interferes with the cancer cells' mitochondria energy source, it decreases the power available to pump chemotherapy out of the cell.

Published March 20, 2008 in the journal Advances in Experimental Medicine and Biology
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Spit Tests May Soon Replace Many Blood Tests

One day soon patients may spit in a cup, instead of bracing for a needle prick, when being tested for cancer, heart disease or diabetes. A major step in that direction is the cataloguing of the “complete” salivary proteome, a set of proteins in human ductal saliva, identified by a consortium of three research teams, according to an article published today in the Journal of Proteome Research. Replacing blood draws with saliva tests promises to make disease diagnosis, as well as the tracking of treatment efficacy, less invasive and costly.

Saliva proteomics and diagnostics is part of a nationwide effort to create the first map of every human protein and every protein interaction, as they contribute to health and disease and as they act as markers for disease states. Following instructions encoded by genes, protein “machines” make up the body’s organs and regulate its cellular processes. Defining exact protein pathways on a comprehensive scale enables the development of early diagnostic testing and precise drug design. In the current study, researchers sought to determine the “complete” set of proteins secreted by the major salivary glands (parotid, submandibular (SM) and sublingual (SL)). Recent, parallel efforts that mapped the blood (plasma) and tear proteomes allows for useful comparisons of how proteins and potential disease markers are common or unique to different body fluids.

“Past studies established that salivary proteins heal the mouth, amplify the voice, develop the taste buds and kill bacteria and viruses,” said James E. Melvin, D.D.S., Ph.D., director of the Center for Oral Biology at the University of Rochester Medical Center, and an author on the paper. “Our work, and the work of our partners, has shown that salivary proteins may represent new tools for tracking disease throughout the body - tools that are potentially easier to monitor in saliva than in blood,” said Melvin, who collaborates with the research labs of Mark Sullivan, Ph.D., and Fred K. Hagen, Ph.D.

The National Institute of Dental and Craniofacial Research (NIDCR), part of the National Institutes of Health, funded the current study. The saliva proteome study represents a consortium effort with research teams at The Scripps Research Institute (John R. Yates III), University of Rochester, University of Southern California (Paul Denny), The University of California at San Francisco (Susan J. Fisher) and UC Los Angeles (David T. Wong, Joseph A. Loo).

Not Your Parent’s Saliva

To describe the results of the current study, it is important to note that the definition of saliva is evolving. Saliva once referred to everything in oral fluid, including: bacterial waste products, dead cells that had shed from mucous membranes and substances oozing from gum crevices. Among researchers today, however, the term saliva is increasingly reserved for just the salivary gland secretions (ductal saliva). The new definition is significant because of the emerging theory that the mix of proteins in ductal saliva tracks closely with that of blood, making saliva a potential diagnostic stand-in for blood.

To construct a credible protein list for saliva, the teams used competing techniques both to capture the greatest number of protein candidates for the list and to lend extra credibility to those found using different methodologies. Each team subjected saliva collected from patients to some form of mass spectrometry, which determines the identity of proteins based on measurements of their mass and charge. Saliva was collected from 23 adults of several races and both sexes. Although small, the set of study subjects was large enough to serve as a baseline list for near-future comparisons between healthy people and individuals with major diseases, researchers said.

Using mass spectrometry techniques, three teams at five institutions identified 1,166 proteins in parotid and submandibular/sublingual saliva. The results indicated that more than a third of saliva proteins were found in the blood proteome, as well. Comparison of these proteins against known protein pathways and other proteomes provided a first glimpse of the function of the core proteins. In addition, a number of the salivary proteins were found to match proteins with known roles in Alzheimer’s, Huntington’s and Parkinson’s diseases; breast, colorectal and pancreatic cancer; and type I and II diabetes. Specifically, a majority of the proteins were found to be part of signaling pathways, which is central to the body’s response to (and thus diagnosic of) system-wide diseases, researchers said.

Determining the salivary proteome is only the first step toward salivary-based diagnosis and treatment. These findings provide crucial protein information that is already being incorporated into microarray technology, a high-speed test that can determine the levels of multiple proteins, during disease progression. Related work is underway under within the NIH-funded Bioengineering Nanotechnology Initiative to design biochips, nano-scale computer chips packed with salivary protein chains. Protein probes on the chip react with proteins in a saliva sample, say from the mouth of someone with oral cancer, and inform a computer about which proteins are present.

“We believe these projects will dramatically accelerate diagnosis and improve prognosis by treating diseases at the earliest stages,” said Mireya González Begné, D.D.S., Ph.D., research assistant professor of Dentistry in the Center for Oral Biology at the Medical Center. “Researchers have already shown that saliva proteins can be used to detect oral cancer and HIV infection. We think this list will soon expand to include leading causes of death like cancer and heart disease, which, if caught early, are much more likely to be successfully treated.”

Published March 25, 2008 in the journal Proteome Research
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Cigarettes Leave Deadly Path by Purging Protective Genes

Turns out that the toxins in cigarette smoke wipe out a gene that plays a vital role in protecting the body from the effects of premature aging. Without this gene we not only lose a bit of youthfulness – but the lungs are left open to destructive inflammation and diseases such as chronic obstructive pulmonary disease (COPD) and lung cancer.

Irfan Rahman, Ph.D., associate professor of Environmental Medicine and an investigator in the University of Rochester’s Lung Biology and Disease Program, has identified the Sirtuin (SIRT1) gene’s role in pulmonary disease and begun testing the powerful antioxidant resveratrol, which is extracted from red grape skins, to develop a treatment to target SIRT1 and reverse lung damage, or at least enhance the way standard COPD therapies work.

“This novel protein will allow us to program our body’s immune-inflammatory system against lung damage and premature aging. The hallmark of this discovery is that we may be able to provide remedies to millions of smokers who would like to quit but cannot kick their addiction, and millions of former smokers who, despite quitting, remain at risk for illness as they age,” said Rahman.

The research was published in two separate studies, in the American Journal of Respiratory Critical Care Medicine, appearing online Jan. 3, 2008, and in the American Journal of Physiology, appearing Dec. 27, 2007.

Rahman has spent years studying how the 4,700 toxic chemical compounds in cigarettes assault lung tissue, also focusing on why some people seem genetically predisposed to develop lung diseases while others are more fortunate, despite being smokers. SIRT1 plays a pivotal role in the puzzle. It belongs to a class of genes that regulate chronic inflammation, cancer and aging. When SIRT1 is highly active, or over-expressed in mice, worms and fruit flies, their life spans are greatly increased. Recent studies also show that SIRT1 plays a positive role in stress resistance, metabolism, apoptosis and other processes involved in premature aging. However, environmental stress such as cigarette smoke or pollution can decrease production of SIRT1 in the lungs.

The next step was to investigate what pathways lead to the depletion of SIRT1. Researchers found that Sirtuin also plays a role in regulating the entire chemical signaling system that protects the lungs from smoke and pollution. They investigated and found how SIRT1 relates to another key protective molecule, Nrf2, a transcription factor. Just as in the case of SIRT1, an airway deficient in Nrf2 is weak and inflamed and more prone to conditions such as COPD.

Nrf2 is also important because it directly regulates several antioxidant genes such as gluthathione (GSH), the most abundant cellular antioxidant responsible for detoxifying the airways. Therefore, the pathway from SIRT1 to Nrf2 ultimately leads to the depletion of GSH, exacerbating the organ’s aging process. “You can be 45 years old and look great on the outside, but if you are a smoker or former smoker, your lungs can easily be 60 years old because of the chemical assault,” Rahman said.

Although he was not involved in the study, James D. Crapo, M.D., a leading expert in the field of lung disease and a professor of Medicine at the National Jewish Medical and Research Center, University of Colorado Health Sciences Center in Denver, said Rahman’s novel finding opens new doors. “This is certainly an important breakthrough in understanding the persistent lung damage and inflammation that occur in patients with COPD, and therapies can now be directed towards this protein.”"

Published March 20, 2008 in the journal American Journal of Respiratory Critical Care Medicine
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TUESDAY - March 25, 2008--------------------------------------------------News Archive/Return to Today's News Alerts

The Surprising Power of The Pill

Women who have tried to conceive using in vitro fertilization (IVF) methods are painfully aware that timing is of the essence. There are cancelled vacations, too many sick days taken from work, and the necessity to plan everything around “the treatment.”

But thanks to a Tel Aviv University study, trying for a baby has just been made easier. In a surprising finding, researchers have discovered that the same pill used to prevent pregnancy can actually help a woman conceive.

Dr. Haim Pinkas MD, a senior physician at the Rabin Medical Center and an academic staff member of Tel Aviv University’s Sackler School of Medicine, and his colleagues at the infertility center where he practices, have found that a two-week intervention treatment using a standard low-dose birth control pill can help time egg harvesting, making the IVF process more convenient for both doctor and patient.

The study was done on 1,800 women at the Infertility and IVF Unit, Helen Schneider Hospital for Women, Rabin Medical Center, Petach Tikva and appeared in the Journal of Assisted Reproduction & Genetics in January of this year.

According to the American Fertility Association, more than 15% of American couples have difficulty conceiving a child. There are currently two types of therapy — natural methods and assisted reproductive techniques such as IVF. In many cases, IVF offers the last hope to conceive a child.

Convenience is a factor that contributes to a woman’s general peace of mind and health. But from a clinician’s point of view, the ability to time the IVF process is also crucial.

Dr. Pinkas explains, “One of the main drawbacks in treating infertility is timing a woman’s body with the clinic’s schedule, so we can get as many mature eggs as possible. IVF clinics can be extremely busy. With a proven and safe method for timing when a woman can undergo therapy, there is a lot less stress placed on the physicians’ shoulders too.”

Normally doctors start the IVF treatment from the moment a woman gets her period. But the use of birth control pills, for 10-14 days after a period, allows the treatment to be adjusted without compromising the “ovarian response to stimulation,” says Dr. Pinkas. This way, egg-harvesting can fall on a date mutually convenient to both the clinician and patient.

This study is not the first to investigate the use of the pill in IVF, but it is the largest one performed so far. It is also unique in that it placed an emphasis on the impact of a patient’s age, her ovarian response, the characteristics of her cycle, and the final outcome – a birth.

The bottom line is that the treatment gives a woman comfort without compromising her chances to conceive. Dr. Pinkas says, “The IVF process can be very stressful. Adding to that stress is the timing issue. Women need to be able to get on with their lives. This treatment makes it possible.”

And while old wives’ tales persist about days of the month when women can conceive, Dr. Pinkas says it is bunk. “The timing of ovulation for different women is spaced out evenly throughout the year. We can schedule a woman’s ovulation with contraceptive pills, but not with the moon.”

Published January, 2008 in the Journal of Assisted Reproduction & Genetics
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Wired for Language

Humans can do all sorts of things. Talking, is one. Long attributed to our big brains - a new study suggests that the brain's wiring played a key role in language evolution - and not just its size.

In the 1800's, neuroanatomists linked small regions of the brain - Broca's area in the frontal cortex and Wernicke's area in the temporal cortex - to language. Recently, scientists have found that language ability is not limited to discrete brain regions but requires close communication between different areas. In the arcuate fasciculus, multiple bundles of nerve fibers connect Broca's and Wernicke's areas. When the arcuate fasciculus is damaged, severe difficulty in speaking and comphrehension results.

At Yerkes National Primate Research Center, Emory University in Atlanta, Georgia, a team led by anthropologist James Rilling conducted the first study ever comparing brains in hominid species, using a relatively new technique called diffusion tensor imaging or DTI (a type of MRI). The scans allow the visualization of brain tissues by detecting the flow of water through them. Scientists can then trace the long nerve fibers that connect parts of the brain. Rilling and colleagues studied the arcuate fasciculus with DTI, comparing the size and trajectory of the arcuate fasciculus in humans, rhesus macaques and chimpanzees.

They have identified a language feature unique to the human brain that is shedding light on how human language evolved.

The scans showed dramatic differences between humans and the other primates. Although the arcuate fasciculus in all three species was hooked up to the frontal cortex - including to Broca's area in humans - only in humans did the arcuate fasciculus extend deeply into language-associated areas of the temporal cortex, such as Wernicke's area. In chimps, the arcuate fasciculus made only very limited connections with temporal cortex regions homologous to Wernicke's area, and there was little evidence of any connection in macaques.

According to Rilling, "The human arcuate fasiculus differed from that of the rhesus macaques and chimpanzees in having a much larger and more widespread projection to areas in the middle temporal lobe, outside of the classical Wernicke's area. We know from previous functional imaging studies that the middle temporal lobe is involved with analyzing the meanings of words. In humans, it seems the brain not only evolved larger language regions but also a network of fibers to connect those regions, which supports humans' superior language capabilities."

The authors conclude that the evolution of specialized language areas in the human brain was accompanied by the addition of major new wiring via the arcuate fasciculus. The net effect was that Wernicke's area, which is associated with understanding word meaning, became strongly connected with Broca's area, which plays an important role in the construction and understanding of sentences.

"This is a landmark," said Yerkes researcher Todd Preuss, PhD, one of the study's coauthors. "Until DTI was developed, scientists lacked non-invasive methods to study brain connectivity directly. We couldn't study the connections of the human brain, nor determine how humans resemble or differ from other animals. DTI now makes it possible to understand how evolution changed the wiring of the human brain to enable us to think, act and speak like humans."

The findings demonstrate "the uniqueness of the human brain, because it has been widely assumed that the basic brain structures are essentially similar between humans and apes," says Kuniyoshi Sakai, a language researcher at the University of Tokyo in Japan.

Thomas Schoenemann, an anthropologist at James Madison University in Harrisonburg, Virginia, says diffusion tensor imaging is a promising approach to understanding how our brains are wired, but he cautions that the approach should be repeated with more samples before drawing firm conclusions.

Published March 23, 2008 in the journal Nature - Neuroscience
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Biology Cited for Racial Disparities in Uterine Cancer Outcomes

Blacks with uterine cancers have an increased risk for death and recurrence, even when they receive the same level of care as white women, suggested two studies reported here.

Review of a government database revealed a 54% increased mortality risk for blacks after adjustment for all known prognostic factors, Jason D. Wright, M.D., of Columbia University, said at the Society of Gynecologic Oncologists meeting. "There tends to be a difference in the type of tumors that African-American women have compared to Caucasian women," said Dr. Wright. "But even when adjusting for that, it doesn't completely explain the survival difference we're seeing. That suggests to us that there is probably some intrinsic difference in the tumors in African-American women that is causing this worse survival."

In the other study, there was an 11-fold higher risk of recurrence in black versus white women with stage I endometrial cancer, despite enrollment in a clinical trial that employed uniform standards of care, reported by George Maxwell, M.D., of Walter Reed Army Medical Center in Washington. Black women with endometrial cancer have poorer outcomes compared with other racial and ethnic groups, a difference often attributed to disparities in access to healthcare services and in process of care. Whether biologic factors contribute to the outcome differences has remained unclear, said Dr. Wright.

Continuing the examination of outcome differences, investigators reviewed data from the Surveillance, Epidemiology, and End Results (SEER) program. The review identified 76,953 new cases of invasive uterine cancer from 1988 to 2004. The total included 66,829 white women, 4,940 black women, and 5,184 women of other racial and ethnic groups.

A comparison of histologic findings showed that 89% of white women had endometroid tumors, 9% had sarcomas, and 2% had serous/clear cell cancer.

Among black women, endometrioid tumors accounted for 70% all the cancers, whereas sarcomas made up 26% of the total and serous/clear cell 4% (P<0.0001).

Black women also had a higher proportion of advanced-stage (III-IV) tumors at diagnosis, 26% versus 15% for white patients, Dr. Wright reported.

Examination of the care patients received showed that 22% of white women and 23% of black women had adjuvant radiation therapy, and 40% of both racial groups had lymphadenectomy.

In a multivariate analysis, after adjusting for all other known prognostic factors including stage and histology, black women had a relative risk of mortality of 1.54 compared with white women (95% CI 1.4 to 1.6)."

Published March 20, 2008 in the journal Gynecologic Oncology

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MONDAY - March 24, 2008--------------------------------------------------News Archive/Return to Today's News Alerts

Therapeutic Cloning Treats Parkinson's Disease in Mice

Research led by investigators at Memorial Sloan-Kettering Cancer Center (MSKCC) has shown that therapeutic cloning, also known as somatic-cell nuclear transfer (SCNT), can be used to treat Parkinson's disease in mice. The study's results are published in the March 23 online edition of the journal Nature Medicine.

For the first time, researchers showed that therapeutic cloning or SCNT has been successfully used to treat disease in the same subjects from whom the initial cells were derived. While this current work is in animals, it could have future implications as this method may be an effective way to reduce transplant rejection and enhance recovery in other diseases and in other organ systems.

In therapeutic cloning or SCNT, the nucleus of a somatic cell from a donor subject is inserted into an egg from which the nucleus has been removed. This cell then develops into a blastocyst from which embryonic stem cells can be harvested and differentiated for therapeutic purposes. As the genetic information in the resulting stem cells comes from the donor subject, therapeutic cloning or SCNT would yield subject-specific cells that are spared by the immune system after transplantation.

The new study shows that therapeutic cloning can treat Parkinson's disease in a mouse model. The scientists used skin cells from the tail of the animal to generate customized or autologous dopamine neurons—the missing neurons in Parkinson's disease. The mice that received neurons derived from individually matched stem cell lines exhibited neurological improvement. But when these neurons were grafted into mice that did not genetically match the transplanted cells, the cells did not survive well and the mice did not recover.

The work was led by senior author Lorenz Studer, MD, Head of the Stem Cell and Tumor Biology Laboratory within the Sloan-Kettering Institute at MSKCC, and lead author Viviane Tabar, MD, Neurosurgeon and stem cell scientist at MSKCC. The work was performed in collaboration with scientists at the Riken Institute in Kobe, Japan.

Presented March 23, 2008 in the journal Nature Medicine
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The Switch That Controls Cell Division

Investigators at the Duke Institute for Genome Sciences and Policy have revealed the hidden properties of an on-off switch that governs cell growth.

The Duke team proved that if the switch is on, then a cell will divide, even if it's damaged or the signal to grow disappears. Showing how the switch works may provide clues to novel drug targets for cancer and other diseases in which cell growth goes awry.

The switch is part of a critical pathway that controls cell division, the process by which the body makes new cells. Before a cell starts to divide, it goes through a checklist to make sure everything is in order, much like preparing for a long trip. If a cell senses something is wrong early on, it can halt the process. But once a cell passes a milestone called the restriction point, there's no turning back, no matter the consequences. The switch controls this milestone and is key to cell growth.

The results appear in the April issue of the journal Nature Cell Biology. The study was funded by the National Institutes of Health, the National Science Foundation and a David and Lucile Packard Fellowship.

The switch is part of the Rb-E2F signaling pathway. Rb, or retinoblastoma, is a key tumor suppressor gene, and E2F is a transcription factor that governs the expression of all the genes important for cells to grow.

"The wiring diagram is fundamentally the same. It's very likely that different organisms have evolved a very conserved design principle to regulate their growth," said Guang Yao, Ph.D., lead study author and a postdoctoral fellow in Duke's department of molecular genetics and microbiology.

The cellular pathway that includes the switch is found in all multi-cellular life, from plants to people. A cell decides to trigger the pathway when it receives an external chemical signal to grow.

During the project, the researchers discovered the switch has an unexpected property: it is bistable. Once turned on by an external signal, the switch can maintain its on state, even if the signal disappears.

It was an engineer, Lingchong You, Ph.D., who recognized that the switch might represent a bistable condition. You, an assistant professor of biomedical engineering in Duke's Pratt School of Engineering and an Institute for Genome Sciences & Policy (IGSP) investigator, works next door to Yao and his postdoctoral advisor Joseph Nevins, Ph.D., a professor of molecular genetics at the IGSP.

During conversations with Nevins and Yao about the restriction point phenomenon, You realized that the process could be described as a bistable switch.

The collaboration continued as the scientists broke down the pathway into individual chemical reactions that could be described by mathematical equations. Graduate student Tae Jun Lee worked with Yao to develop and analyze a mathematical model that predicted the switch could be bistable and identified the critical decision maker at the restriction point. Yao verified the results in laboratory experiments on single cells.

Nevins, who has studied the Rb-E2F pathway for 20 years, sees an opportunity to extend this approach to other critical aspects of cell behavior, such as the decisions involved in cell death.

"This pathway, and this decision whether it is time to proliferate, is very tightly coupled to decisions of cell fate," Nevins said. "There's a decision as to whether the proliferation process is normal, and if answer is not, then the result is that the cell dies. We don't know critical dynamics of that process."

"The simple and efficient tug-of-war mechanism could be used for the transport in micro-laboratories on chips," relates Melanie Müller. In the same way as with the biological model, teams of motors can transport certain molecules to specific reaction locations on the chip and then also bring back the reaction product. "Our quantitative tug-of-war theory allows motor properties to be optimized for this purpose," according to Müller.

To be published April, 2008 in the journal Nature - Cell Biology
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Insights From Genes Unique to Humans

Among the approximately 23,000 genes found in human DNA, scientists currently estimate that there may be as few as 50 to 100 that have no counterparts in other species.

Expand that comparison to include the primate family known as hominoids, and there may be several hundred unique genes.
Despite the distinctive contributions these genes likely make to our species, little is known about the roles they play. Now scientists at Washington University School of Medicine in St. Louis have produced the first detailed analysis of the cellular functions of a hominoid-only gene, TBC1D3; affirmming earlier evidence linking the gene to cancer, and showing that TBC1D3's protein can keep cellular growth factors active and helps turn on RAS, a protein that is active in a third of all human cancers.

TBC1D3 was originally identified by other scientists as a likely contributor to breast cancer. At the time of its discovery, researchers linked its protein to endocytosis, a process cells use to take in material from their surface. Stahl's laboratory studies how growth factor receptors, proteins important for both normal and cancerous growth, are turned on and off. Found on the surfaces of cells, growth factor receptors turn on when they bind to a growth factor protein. To turn them off, cells take in the combined receptor-protein through endocytosis and put it through a number of different processes before finally breaking down the growth factor receptor.

When senior author Philip D. Stahl, Ph.D., the Edward Mallinckrodt Jr. Professor and head of Cell Biology and Physiology, and colleagues determined in 2006 that the TBC1D3 gene is only found in hominoids, their curiosity was piqued. Evolution, Stahl notes, naturally tends to retain genes involved in the most important components of metabolism. Therefore, if the genome is compared to an automobile, human-only genes are unlikely to be adding new wheels. But they could, for example, be contributing a new anti-lock braking system: a regulatory function that fine-tunes essential processes originally established millennia ago in other species. Stahl found evidence that this is the case in TBC1D3. Human DNA has eight copies or paralogs of the TBC1D3 gene. His lab showed that the increased levels of the protein made by one of the paralogs makes human cells grow more rapidly. When they transplanted the gene for the protein into mouse cells, it had the same effect. A closer look showed that the protein from the TBC1D3 paralog delays a process that labels growth factor receptors for breakdown, prolonging the time that their signal is active. He also found evidence that the protein was helping to activate RAS, another gene whose protein is commonly found in human cancers.

There may be human diseases where these genes are mutated or missing, Stahl speculates. The effects of such conditions could provide important clues to what the humans-only genes do. "It's also going to be very interesting for evolutionary biologists to try to develop a sense for where these humans-only genes come from," Stahl says. "The building blocks of these genes may be present but not active in earlier species.""Imagine taking the ability to do something like that and applying it to drama and dance," Boghosian mused. "Imagine taking the ability to do something like that and trying to use it for facial recognition or occupational therapy or many other fields. We haven't really even begun to explore those kinds of things yet.". "Big pharmaceutical companies have devoted lots of resou²²"

Published March 20, 2008 in the Journal of Biological Chemistry
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