The research is significant in helping determine why tamoxifen and other synthetic estrogens are linked to increased rates of endometriosis and uterine cancer, and identifies a pathway that could be targeted in drug therapies for those diseases, researchers say.

Findings are published in the July 1, 2009 issue of “Cancer Research,” the journal of the American Association for Cancer Research. The paper also can be found online at http://cancerres.aacrjournals.org/current.shtml.

The research found that when activated by estrogens, endometrial cells obtained from patients suffering from endometriosis or human uterine cancer cells initiate a previously unknown cascade of signals that leads to cellular replication and further estrogen production, the paper says.

The ensuing cycle leads to abnormal growth of the cells lining the uterus, or endometrium, which occurs in endometriosis and uterine cancer, according to senior author Holly A. Ingraham, PhD, a professor in the UCSF School of Medicine’s Department of Cellular and Molecular Pharmacology.

“It turns out that displaced endometrial cells, such as those used in this study, are estrogen factories,” said Ingraham, who also is affiliated with the UCSF Helen Diller Family Comprehensive Cancer Center and the UCSF Center for Reproductive Sciences. “They pump out estrogen in a feed-forward pathway, so the more estrogen they produce, the more estrogen they’re capable of producing.”

While this pathway was previously unknown, Ingraham said a June 2009 paper led by researchers at the University of New Mexico and published in the journal “Nature Chemical Biology” showed that blocking the GPR30 receptor in this pathway decreases uterine proliferation in a mouse. The two together, she said, validate what researchers now think may be a key area in addressing both uterine cancer and endometriosis.

Uterine cancer is the fourth most common cancer in women, with more than 37,000 women being diagnosed each year in the United States alone, according to data from the Centers for Disease Control.

Endometriosis, in which endometrial cells grow in areas other than the uterus, is the most common gynecological disease and affects more than 5.5 million women in North America, according to the National Institutes of Health. The disease often causes severe pain and can lead to infertility.

Working in collaboration with clinicians at Northwestern University in Chicago, the UCSF team analyzed cells from women with ectopic endometriosis. By studying those patients’ endometrial cells, the team was able to identify an unusual, circular pathway involving these cells, the transmembrane estrogen receptor GPR30 and the nuclear receptor SF-1.

The researchers propose that this pathway increases local concentrations of estrogen and, together with classic estrogen-receptor signaling, control the proliferative effects of these estrogens in promoting endometriosis and endometrial cancers.

The UCSF team used a unique chemical biology approach, making use of a tamoxifen-like compound developed in the laboratory of co-author Thomas Scanlan, PhD, who is affiliated with both the UCSF Department of Pharmaceutical Chemistry and the Department of Chemical Biology at the Oregon Health Sciences University in Portland.

“Tamoxifen and other synthetic estrogens have been known to increase the risk of uterine cancer, but until now, we didn’t know why that was on a cellular level,” Ingraham said. “We think this pathway is going to be an important one in solving that mystery.”

The lead investigator on the paper was Benjamin C. Lin. Lin and co-author Sandra C. Tobias are affiliated with the Department of Pharmaceutical Chemistry at UCSF. Other co-authors are Miyuki Suzawa, in the UCSF Department of Cellular and Molecular Pharmacology; Raymond D. Blind in the UCSF Department of Pharmaceutical Chemistry and Department of Cellular and Molecular Pharmacology; and Serdar E. Bulun, in the Department of Obstetrics and Gynecology, Feinberg School of Medicine at Northwestern University.

The authors report no potential conflicts of interest in this research.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. For further information, visit http://www.ucsf.edu.

ChattahBox News

AML is a cancer of the white blood cells that has an extremely poor prognosis and does not respond well to conventional chemotherapy. “The cellular and molecular basis for this dismal picture is unclear,” offers senior study author Associate Professor Richard Lock from the Children’s Cancer Institute Australia and the University of New South Wales. “However, previous research has suggested that leukemia stem cells (LSCs) may lie at the heart of post-treatment relapse and chemoresistance.” LSCs are cells that can initiate AML and are critical for its long-term growth.

Associate Professor Lock and colleagues exploited the fact that the molecule CD123 is expressed at very high levels on LSCs but not on normal blood cells. CD123 is part of the interleukin-3 receptor, a protein that interacts with a growth factor (called a cytokine) that influences cell survival and proliferation. The researchers created a therapeutic antibody that recognized and bound to CD123 with the hope that this antibody would selectively interfere with AML-LSC survival.

When AML-LSCs from human patients were transplanted into mice treated with the antibody, called 7G3, cytokine signaling in the tumor cells was blocked. Further, 7G3 impaired migration of the AML-LSCs to bone marrow and activated the innate immune system of the host mouse to destroy the AML-LSCs. Overall, treatment with 7G3 substantially improved mouse survival when compared with control groups. The researchers go on to report that a CD123-targeting antibody is currently being used in phase 1 clinical trials of advanced AML and that there are no signs of treatment-related toxicity.

These results hold substantial promise for future cancer therapeutics. “The recent characterization of defined populations of cancer stem cells in a range of human malignancies, as well as their relative resistance to conventional chemotherapy and radiotherapy, supports the broad applicability of our approach and provides rationale for the progression of AML-LSC-targeted therapeutics from preclinical evaluation to clinical trials,” concludes Associate Professor Lock.

The researchers include Liqing Jin, University Health Network, Toronto, Canada; Erwin M. Lee, University of New South Wales, Sydney, Australia; Hayley S. Ramshaw, Centre for Cancer Biology, Adelaide, Australia; Samantha J. Busfield, CSL Limited, Melbourne, Australia; Armando G. Peoppl, University Health Network, Toronto, Canada; Lucy Wilkinson, Queensland Institute of Medical Research, Brisbane, Australia; Mark A. Guthridge, Centre for Cancer Biology, Adelaide, Australia; Daniel Thomas, Centre for Cancer Biology, Adelaide, Australia; Emma F. Barry, Centre for Cancer Biology, Adelaide, Australia; Andrew Boyd, Queensland Institute of Medical Research, Brisbane, Australia; David P. Gearing, CSL Limited, Melbourne, Australia; Gino Vairo, CSL Limited, Melbourne, Australia; Angel F. Lopez, Centre for Cancer Biology, Adelaide, Australia; John E. Dick, University Health Network, Toronto, Canada; and Richard B. Lock, University of New South Wales, Sydney, Australia.

Cell Press

The results of the Phase II trial are published today in Diabetes Care, a journal of the American Diabetes Association.

“It shows a strong trend in preserving insulin-producing beta cell function that is significantly better than placebo,” said Staley Brod, M.D., principal investigator of the trial, which includes the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). “It can extend the ‘honeymoon phase’ of the disease, allowing the body to still produce insulin from beta cells, which correlates with decreased complication rates.”

As many as 3 million Americans may have type I diabetes, formerly called juvenile diabetes, according to the Juvenile Diabetes Research Foundation International. Each year, 15,000 children are diagnosed with the autoimmune disease, in which the pancreas stops producing the insulin needed to transfer glucose from the blood to cells for energy. The result is too much glucose in the blood, which can lead to kidney failure, blindness, nerve damage, amputations, heart attack and stroke.

A honeymoon phase sometimes occurs just after diagnosis as the body tries to rebound. Many patients experience a period when their need for insulin becomes minimal, control of blood sugar improves and beta cells partially recover. If the pancreas is still able to function, the highs and lows experienced by taking manufactured insulin can be decreased.

The Phase II trial included 128 patients from the NIDDK’s Intramural Studies Office, The University of Texas Southwestern Medical Center in Dallas and Children’s Hospitals and Clinics in Minneapolis/St. Paul, Minn. Research was conducted at The University of Texas Clinical Research Center at Memorial Hermann-Texas Medical Center, which is part of the Center for Clinical and Translational Sciences at The University of Texas Health Science Center at Houston.

Research subjects ages 3 to 25 diagnosed with type 1 diabetes within six weeks of enrollment were randomized to receive 5,000 units of interferon alpha, 30,000 units of interferon alpha or placebo once daily for one year. Patients treated with 5,000 units lost only 29 percent of their beta cell function compared to 48 percent for patients receiving 30,000 units and 56 percent for patients receiving the placebo.

Austin resident Jarod Wallquist, 11, was 5 years old when he was diagnosed with type I diabetes and his mother Amy learned about Brod’s study. Jarod received the 5,000 units of interferon alpha, but neither she nor the researchers knew it at the time because of the double-blind nature of the study.

“My husband and I are both scientific-minded so we understood the importance of the research even if we didn’t know whether it would help Jarod,” said Wallquist, whose family made regular trips to Houston for the study. “Jarod is doing really well. He wears an insulin pump but he’s never had to go to the emergency room. To this day, according to his doctor, his amount of insulin needed is much lower than other kids his age and weight. He plays baseball and is on the swim team and he totally has a normal life.”

The research builds on Brod’s earlier studies on oral interferon alpha in animals and a Phase I safety trial. After the results of the safety trial, NIDDK researchers asked to join Brod’s research before the Phase II trial.

Brod’s theory is that autoimmune diseases, which occur when the body is attacked by its own immune system, are actually an alpha interferon immunodeficiency syndrome. Interferons are a group of proteins produced by cells in response to an attack by a virus.

The research was supported in part by two grants from the National Institutes of Heathone to Brod from the NIDDK and one to the UT Health Science Center at Houston for the Center for Clinical and Translational Sciences. The research also was supported by grants from the Children’s Hospital of Minnesota Foundation and the Diabetes Action Research and Education Foundation.

Co-authors of the study from the UT Medical School at Houston are Philip Orlander, M.D., professor and director of the Division of Endocrinology, and Miriam Morales, B.S., consultant. Corresponding author from the NIDDK is Kristina Rother, M.D., M.H.Sc.

University of Texas Health Science Center at Houston

People with ankle injuries who do not respond successfully to initial treatment may have a second chance at recovery, thanks to two new procedures developed to restore the injured area, according to a study published in the July 2009 issue of the Journal of the American Academy of Orthopaedic Surgeons (JAAOS).

The study reviews emerging techniques that have proven successful in treating injuries to the talus, the small bone, which is located between the heel bone and the lower bones of the leg. The talus helps form the ankle joint.

Although most injuries to the talus can be successfully treated using traditional “first-line” therapies involving removal of dead tissue (called “debridement”) and drilling, about one-fifth to one-quarter of people with ankle injuries need additional “second-line” restorative treatment to heal successfully, said lead author Matthew Mitchell, MD, an orthopaedic surgeon in private practice in Casper, Wyoming.

The two new techniques rely on cells grown in a lab, and eliminate the need for ostetomy (cutting the bone of the tibia) in some cases, he said.

• Autologous chondorcyte implantation, or ACI, involves removing cartilage cells from the knee or the ankle and growing them in a lab. Once grown, the cartilage is transplanted to the talus. ACI usually involves an ostetomy in order to implant the cells.
• In matrix-induced autologous chondrocyte implantation, or MACI, cells are grown on a special backing material, or “matrix,” and then transplanted to the talus. In the authors’ experience, an osteotomy is not necessary to implant the cells.

Of these two techniques, the newer MACI technique may offer the most benefits to the patient, according to Dr. Mitchell.

“Both ACI and MACI show a lot of promise, but I think the advantage of MACI is that an osteotomy is not necessary in order to successfully implant the matrix,” he said. “You only need to make an incision to place the graft, which decreases the morbidity of the procedure quite a bit.”

“In my experience so far with this emerging technique in Australia, the results have been as good as, or better than, other restorative techniques,” he added. MACI is currently considered investigational by the FDA in the United States.

Traditional restorative techniques involve removing a cartilage donor plug from the knee and implanting it over the ankle injury, or “lesion.” This requires an operation on the knee and cutting the bone (osteotomy) of the tibia to accomodate the graft.

As a result, these traditional techniques involve potential problems, including:

• pain in the donor knee
• tissue damage in the donor knee
• tissue damage in the ankle as a result of osteotomy

“In most individuals, results are favorable with reparative techniques, such as debridement and drilling,” said Dr. Mitchell. “The lesions that are problematic and which don’t respond well to reparative treatments are lesions that are larger, and those which are fairly deep, as well as lesions which have a cyst-like structure. Whether or not an ankle “lesion” requires additional treatment after an initial reparative procedure often depends upon several factors, including: size, depth and structure of the legion.

“Once you’ve performed a reparative technique and the patient still doesn’t heal properly, then we would move on to a second-line restorative treatment,” he said.

American Academy of Orthopaedic Surgeons

Previous work in this area has looked at gene profiles in such tissues as the uterine lining, but Dr. Allen and her team chose to examine the gene expression patterns in RNA extracted from peripheral (circulating) blood, an easily accessible biological sample. Blood samples were taken at eight different stages during the period around conception and the early stages of the IVF cycle. Five of these samples came from women who achieved clinical pregnancies, three from those who had implantation failure, and three from subfertile women who conceived spontaneously. Analysis showed that 128 genes showed a more than two-fold difference in expression in early clinical pregnancy compared with a non-pregnant state.

The molecular pathways that were most over-represented in this expression were concerned with angiogenesis (the growth of new blood vessels), endothelin signalling (blood vessel constriction), inflammation, oxidative stress (damage to cell structures), vascular endothelial growth factor (signalling processes in blood vessel growth), and pyruvate metabolism (the supply of energy to cells). “All these processes are important in the achievement and maintenance of pregnancy,” said Dr. Allen.

“We found that the gene expression profiles in blood of patients at the time of pituitary down-regulation showed interesting patterns of gene clustering. Over 200 genes were differentially expressed in patients who went on to achieve an IVF pregnancy compared with those who did not,” she said.

The researchers found that the peripheral blood gene expression ’signature’ (also known as the transcriptome) before IVF was predictive of IVF outcome. This finding demonstrates the power of high-dimensional technology in biomarker discovery, and highlights the potential for developing clinically useful tools, they say.

One of the most difficult decisions for patients who have had unsuccessful IVF treatments is whether they should undergo further attempts at IVF, or if there are ways to optimise chances of success. The researchers hope that the results generated by this work will lead to the development of a test to aid in IVF decision-making. They say that their work will help to identity biomarkers that can identify events occurring at implantation, the maintenance of pregnancy and successful or unsuccessful pregnancy outcome.

“IVF technology has advanced tremendously over the past three decades, yet success after IVF remains an unpredictable outcome,” said Dr. Allen. “Our work will help understand whether the implantation of embryos is influenced by the constantly changing expression of human genes.”

Previous studies in the field of gene-expression have focused on single genes as opposed to genome-wide screening of all the human genes with high density DNA microarrays, as used by Dr. Allen and her team. The advent of tools like microarrays that can simultaneously probe for up to 29,000 genes has radically changed scientific approaches to this type of research. “It’s like looking at how a team of players perform together rather than focusing on the individual players,” said Dr. Allen.

“We intend to look further at the most significant genes we have identified as being important in this field in order to be able to understand their exact biological role in reproductive function. We hope that our work will lead to the development of a clinically useful tool to help doctors counsel their patients in the difficult decision-making involved in IVF,” she said.

Abstract no: O-269 Wednesday 14.15 hrs CEST (Elicium 1)

European Society for Human Reproduction and Embryology

ROCHESTER, Minn. — Celiac disease, (http://www.mayoclinic.org/celiac-disease/) an immune system reaction to gluten in the diet, is over four times more common today than it was 50 years ago, according to findings of a Mayo Clinic study published this month in the journal Gastroenterology (http://www.gastrojournal.org/).

The study also found that subjects who did not know they had celiac disease were nearly four times more likely than celiac-free subjects to have died during the 45 years of follow-up.

“Celiac disease has become much more common in the last 50 years, and we don’t know why,” says Joseph Murray, M.D., (http://www.mayoclinic.org/bio/13032852.html) the Mayo Clinic gastroenterologist who led the study. “It now affects about one in a hundred people. We also have shown that undiagnosed or ’silent’ celiac disease may have a significant impact on survival. The increasing prevalence, combined with the mortality impact, suggests celiac disease could be a significant public health issue.”

In patients with celiac disease, the presence of a protein called gluten from wheat, barley or rye triggers an immune system attack, damaging the villi in the small intestine. Villi are fingerlike projections that increase the intestine’s surface area for nutrient absorption. Celiac disease symptoms may include diarrhea, abdominal discomfort, weight loss, anemia, unexplained infertility, loss of teeth or even premature or severe osteoporosis.

The Mayo Clinic research team tested blood samples gathered at Warren Air Force Base (AFB) in Wyoming between 1948 and 1954 for the antibody that people with celiac disease produce in reaction to gluten. They compared those blood test results with those from two recently collected sets from Olmsted County, Minn. One matched the ages of those from the 1948 testing at the time of the blood draw, and the other matched their birth years. Researchers found that young people today are 4.5 times more likely to have celiac disease than young people were in the 1950s, while those whose birth years matched the Warren AFB participants were four times more likely to have celiac disease.

“Celiac disease is unusual, but it’s no longer rare,” says Dr. Murray. “Something has changed in our environment to make it much more common. Until recently, the standard approach to finding celiac disease has been to wait for people to complain of symptoms and to come to the doctor for investigation. This study suggests that we may need to consider looking for celiac disease in the general population, more like we do in testing for cholesterol or blood pressure.”

Dr. Murray says the study findings highlight the need for increased awareness of celiac disease, both among physicians and patients. “Part of the problem is that celiac disease symptoms are variable and can be mistaken for other diseases that are more common, such as irritable bowel syndrome,” he says. “Some studies have suggested that for every person who has been diagnosed with celiac disease, there are likely 30 who have it but are not diagnosed. And given the nearly quadrupled mortality risk for silent celiac disease we have shown in our study, getting more patients and health professionals to consider the possibility of celiac disease is important.”

In addition to Dr. Murray, authors of the study, which was conducted in collaboration with the University of Minnesota Medical School and the Medical Follow-Up Agency, Washington, D.C., include Alberto Rubio Tapia, M.D.; Robert Kyle, M.D.; Edward Kaplan, M.D.; Dwight Johnson; William Page, Ph.D.; Frederick Erdtmann, M.D.; Tricia Brantner; W. Ray Kim, M.D.; Tara Phelps; Brian Lahr; Alan Zinsmeister, Ph.D.; and L. Joseph Melton III, M.D.

VIDEO ALERT: Additional audio and video resources, including excerpts from an interview with Dr. Dr. Joseph Murray describing the research, are available on the Mayo Clinic News Blog (http://newsblog.mayoclinic.org/2009/06/29/celiac-disease-prevalence-and-mortality/). These materials are also subject to embargo, but may be accessed in advance by journalists for incorporation into stories. The password for this post is 0701Murray.

About Mayo Clinic

Mayo Clinic is the first and largest integrated, not-for-profit group practice in the world. Doctors from every medical specialty work together to care for patients, joined by common systems and a philosophy of “the needs of the patient come first.” More than 3,300 physicians, scientists and researchers and 46,000 allied health staff work at Mayo Clinic, which has sites in Rochester, Minn., Jacksonville, Fla., and Scottsdale/Phoenix, Ariz. Collectively, the three locations treat more than half a million people each year. To obtain the latest news releases from Mayo Clinic, go to www.mayoclinic.org/news. For information about research and education, visit www.mayo.edu. MayoClinic.com (www.mayoclinic.com) is available as a resource for your health stories.

When muscles are stretched during exercise, they produce a specific substance known as mechano growth factor (MGF) that activates stem cells already present in the tissue. Once activated, these progenitor cells begin to divide, creating additional muscle fibres and increasing the size and strength of the muscle. In addition to intensive exercise, muscles need to be stimulated by growth hormone (GH) in order to release MGF. Since there is a natural decrease in the levels of this hormone as we age, this may combine with the lack of intensive physical activity to cause muscle wasting in elderly people. “The downside”, warns Dr. Goldspink, “is that MGF has great potential for doping in sports. A synthetic version is already available over the internet, and although it is still very expensive, it is expected that new technologies will bring down the price to make it comparable to that of human insulin”.

Society for Experimental Biology

Cystic fibrosis is an inherited chronic disease that affects the lungs and digestive system of about 30,000 children and adults in the United States (70,000 worldwide). A defective gene and its protein product cause the body to produce unusually thick, sticky mucus that clogs the lungs and leads to life-threatening lung infections; and obstructs the pancreas and stops natural enzymes from helping the body break down and absorb food.

Researchers reviewed the medical records of cystic fibrosis (CF) patients at Children’s Hospital Boston over a 13 year period, and found that seven of 50 CF patients (14%) suffered from sensorineural hearing loss. Of that group, 43 percent of those that had received aminoglycosides intravenously had received more than 10 courses of the treatment; patients who were treated more than five times with nasal irrigation of aminoglycosides were also at risk of sensorineural hearing loss.

Because CF patients are prone to suffer from infections of the pulmonary and sinonasal systems, aminoglycosides are commonly administered to CF patients because of the potent effect they have on bacteria. The treatment is considered so effective that it outweighs the well-known side-effects, which include hair cell loss, and thus hearing loss.

The authors contend that CF patients should have routine hearing evaluations that specifically target the detection of sensorineural hearing loss, especially when repeated courses of systemic or intranasal aminoglycosides have be used in treatment. They also note that further investigation through a prospective study is warranted in order to replicate these results.

Otolaryngology Head and Neck Surgery is the official scientific journal of the American Academy of Otolaryngology Head and Neck Surgery Foundation (AAO-HNSF) and the American Academy of Otolaryngic Allergy (AAOA). The study’s authors are Alan G. Cheng, MD; Patrick R. Johnston, MMath; Jeniffer Luz, BS; Ahmet Uluer, DO; Brian Fligor, ScD; Greg R. Licameli, MD, MHCM; Margaret A. Kenna, MD, MPH; and Dwight T. Jones, MD.

The American Academy of Otolaryngology Head and Neck Surgery (www.entnet.org), one of the oldest medical associations in the nation, represents nearly 12,000 physicians and allied health professionals who specialize in the diagnosis and treatment of disorders of the ears, nose, throat, and related structures of the head and neck. The Academy serves its members by facilitating the advancement of the science and art of medicine related to otolaryngology and by representing the specialty in governmental and socioeconomic issues. The organization’s vision: “Empowering otolaryngologist-head and neck surgeons to deliver the best patient care.”