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Agent orange chemical, dioxin, attacks the mitochondria to cause cancer, says Penn research team

Contact: Jordan Reese
jreese@upenn.edu
215-573-6604
University of Pennsylvania

PHILADELPHIA— Researchers with the University of Pennsylvania School of Veterinary Medicine have demonstrated the process by which the cancer-causing chemical dioxin attacks the cellular machinery, disrupts normal cellular function and ultimately promotes tumor progression.

The team identified for the first time that mitochondria, the cellular sub-units that convert oxygen and nutrients into cellular fuel, are the target of tetrachlorodibenzodioxin, or TCDD. The study showed that TCDD induces mitochondria-to-nucleus stress signaling, which in turn induces the expression of cell nucleus genes associated with tumor promotion and metastasis.

The mechanism the research team has described is directly relevant to understanding incidences of breast and other cancers in human populations exposed to these chemicals. With a better understanding of this underlying cellular mechanism, researchers hope to improve their understanding of tumor growth and promotion.

“Now that we have identified this signaling mechanism we can look at ways to disrupt this complex chain of events,” said Narayah Avadhani, chair of the Department of Animal Biology at Penn’s School of Veterinary Medicine and the study’s lead investigator. “Our ultimate goal is to block the propagation of this mitochondrial stress signaling and inhibit the expression of the proteins that combine to assist cancer growth.”

A well-characterized mechanism of TCDD action occurs through activation of arylhydrocarbon receptors, AhR, by directly binding to the protein subunits. Activated AhR mediates the transcriptional activation of many genes including those involved in fatty acid metabolism, cell cycle regulation and immune response. The present study, however, shows that TCDD starts the chain of events that promote tumor progression in vivo by directly targeting mitochondrial transcription and induction of mitochondrial stress signaling. A unique feature of this TCDD-induced signaling is that it does not involve the action of AhR but occurs through increased calcium levels in cells and activation of calcium responsive factors. A net result of signaling cascade is slowing down of cellular apoptosis, increased cell proliferation and tumor cell metastasis. Taken together, this study describes a novel mechanism of TCDD-induced tumor progression and emergence of metastatic cancer cells.

TCDD is the most toxic compound in the dioxin family. Formed as a by-product during waste incineration, paper, chemical and pesticide manufacturing, it was the toxic ingredient in Agent Orange and closed the Love Canal in Niagara Falls. The public health impact of dioxin, according to the Environmental Protection Agency, compares to that of the pesticide DDT.

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The study appears online and in the Dec. 17 issue of the Proceedings of the National Academy of Sciences and was performed by Avadhani, Gopa Biswas, Satish Srinivasan and Hindupur Anandatheerthavarada of the Penn School of Veterinary Medicine.

The research was supported by a grant from the National Cancer Institute and the National Institutes of Health.

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December 18, 2007 Posted by | Cancer, Cancer Biology, FMS Global News, Global, Global News, London, London UK Feed, National Cancer Institute, NIH, Ottawa, Ottawa City Feed, PTSD, RSS Feed, Toronto, Toronto City Feed, Washington DC, Washington DC City Feed, World News | , , , , | Leave a comment

USC researcher identifies stem cells in tendons that regenerate tissue in animal model

Finding promise new treatments for tendon injury and disease

Los Angeles, Sept. 7, 2007—Athletes know that damage to a tendon can signal an end to their professional careers. But a consortium of scientists, led in part by University of Southern California (USC) School of Dentistry researcher Songtao Shi, has identified unique cells within the adult tendon that have stem-cell characteristics—including the ability to proliferate and self-renew. The research team was able to isolate these cells and regenerate tendon-like tissue in the animal model. Their findings hold tremendous promise for the treatment of tendon injuries caused by overuse and trauma.

The results of their research will be published in the October 2007 issue of the journal Nature Medicine and will be available online at http://www.nature.com/nm on Sunday, September 9, 2007.

Tendons, the tough band of specialized tissues that connect bone to muscle, are comprised of strong collagen fibrils that transmit force allowing the body to move. Tendon injuries are a common clinical problem as damaged tendon tissue heals slowly and rarely regains the integrity or strength of a normal, undamaged tendon.

“Clinically, tendon injury is a difficult one to treat, not only for athletes but for patients who suffer from tendinopathy such as tendon rupture or ectopic ossification,” Shi says. “This research demonstrates that we can use stem cells to repair tendons. We now know how to collect them from tissue and how to control their formation into tendon cells.”

Prior to this research, little existed on the cellular makeup of tendons and their precursors. By looking at tendons at the molecular level, the research team identified a unique cell population—termed tendon stem/progenitor cells (TSPCs) in both mice and adult humans—that when guided by a certain molecular environment, form into tendon cells. The team included leading scientists from the National Institute of Dental and Craniofacial Research at the National Institutes of Health, Johns Hopkins University and the University of Maryland School of Medicine.

Songtao Shi, a researcher for USC’s Center for Craniofacial Molecular Biology, a Division within the USC School of Dentistry, has published numerous studies on the role of stem cells in regeneration. He was part of an international research team that successfully generated tooth root and supporting periodontal ligaments to restore tooth function in the animal model. Earlier this year, his research was published in the journal Stem Cells after he and his team discovered that mesenchymal stem cells are capable of regenerating facial bone and skin tissue in the mouse and swine models.

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Funding for the study came from the USC School of Dentistry and the National Institutes of Health.

Yanming Bi, Driss Ehirchiou, Tina M Kilts, Colette A Inkson, Mildred C Embree, Wataru Sonoyama, Li Li, Arabella I Leet, Byoung-Moo Seo, Li Zhang, Songtao Shi & Marian F Young. “Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche.” Nature Medicine, http://www.nature.com/nm

USC’s Center for Craniofacial Molecular Biology

USC’s Center for Craniofacial Molecular Biology is a research laboratory located on the Health Sciences Campus of the University of Southern California in Los Angeles. Administratively, CCMB is part of the USC School of Dentistry. The laboratory is funded through multiple research grants, including several from the National Institutes of Health, under which research is conducted into development, biochemical and molecular biological aspects of human development, with a special emphasis on craniofacial structures in both health and disease. Current investigations include the molecular etiology of cleft palate, the molecular genetics of tooth development and lung development in the premature infant.

Contact: Angelica Urquijo
urquijo@usc.edu
213-740-6568
University of Southern California

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September 9, 2007 Posted by | Global Health Vision, Global News, Health, News, NIH, Science, Tendons, USC | 1 Comment

Multicenter study nets new lung tumor-suppressor gene

BOSTON–Collaborating scientists in Boston and North Carolina have found that a particular gene can block key steps of the lung cancer process in mice. The researchers report in the journal Nature that LKB1 is not only a “tumor-suppressor” gene for non-small cell lung cancer in mice, it also may be more powerful than other, better-known suppressors. The study will be published on the journal’s Web site on Aug. 5 and later in a print version.

If further research shows LKB1 has a similar effect in human lung cells, it could influence the way non-small cell lung cancer is diagnosed and treated, says the study’s senior author, Kwok-Kin Wong, MD, PhD, of Dana-Farber, one of three institutions, along with Massachusetts General Hospital and the University of North Carolina School of Medicine, leading the work. If tumors with LKB1 mutations are found to be especially fast-growing, for example, patients with such tumors might be candidates for more aggressive therapy.

People born with defective versions of LKB1 often develop Peutz-Jeghers syndrome, which is marked by intestinal growths and an increased risk for certain cancers. Non-inherited mutations of the gene have been found in some lung cancers. This suggested that LKB1 normally thwarts tumors from forming. Mutated versions may be unable to act as a brake on cancer.

To find out, the investigators ran a series of experiments in mice with a defective form of a gene called Kras, which drives the formation and growth of lung cancer. They tracked the development of lung cancer in animals with mutated LKB1 and compared it to the experience of animals with abnormalities in either of two well-known tumor-suppressor genes.

They found that while Kras “cooperated” with the mutated tumor-suppressor genes to produce lung cancer, it cooperated even more strongly with mutated LKB1. “The LKB1-deficient tumors grew more rapidly and spread more frequently than the others, and comprised all three types of non-small cell lung cancer — squamous cell carcinoma, large-cell carcinoma, and adenocarcinoma — rather than just one or two,” Wong says. “This suggests that LKB1 plays a role at major stages of the tumors’ development: initiation, differentiation of normal lung cells into cancer cells, and metastasis.”

An examination of human non-small-cell lung tissue suggests LKB1 mutations play a role there as well. Of 144 samples analyzed, 34 percent of the lung adenocarcinomas and 19 percent of the squamous cell carcinomas contained abnormal versions of the gene, researchers report.

“We were surprised at how significant a role LKB1 mutations play in non-small cell lung cancer development in mice,” say Wong, who is also an assistant professor of medicine at Harvard Medical School. “This suggests there may be additional lung tumor-suppressor genes yet to be discovered. We’re currently examining whether these results apply to human lung cancers as well and, if so, how such information can improve treatment.”

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The lead author of the study was Hongbin Ji, PhD, of Dana-Farber. Other Dana-Farber co-authors include Dongpo Cai, PhD, Liang Chen, PhD, Pasi Janne, MD, PhD, Bruce Johnson, MD, Jussi Koivunen, MD, PhD, Danan Li, Mei-Chih Liang, PhD, Kate McNamara, Matthew Meyerson, MD, PhD, Samanthi Perera, PhD, Geoffrey Shapiro, MD, PhD, and Takeshi Shimamura, PhD. Other authors were based at Children’s Hospital Boston, Brigham and Women’s Hospital, Broad Institute of Harvard University and Massachusetts Institute of Technology, University of Tennessee Health Science Center, and the University of Texas Southwestern Medical Center.

The research was supported by the National Institutes of Health, the Sidney Kimmel Foundation for Cancer Research, the American Federation of Aging, the Joan Scarangello Foundation to Conquer Lung Cancer, the Flight Attendant Medical Research Institute, the Waxman Foundation, the Harvard Stem Cell Institute, and the Linda Verville Foundation.

Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.

Contact: Bill Schaller
william_schaller@dfci.harvard.edu
617-632-5357
Dana-Farber Cancer Institute

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August 5, 2007 Posted by | Baltimore, Barcelona, Bethesda, Biological Sciences, Calgary, Canada, Cancer, Cancer Biology, France, Genes, Genetic, Genetic Link, Genetics, Genome, Genomic, Germany, Global, Global Health Vision, Global News, Health Canada, Human Genome, LKB1, Lung Cancer, Medical History, Medical Journals, Newfoundland, News, News Australia, News Canada, News Israel, News Italy, News Jerusalem, News Switzerland, News UK, News US, News USA, NIH, Peutz-Jeghers syndrome, University of North Carolina, World News | 2 Comments

Flip of genetic switch causes cancers in mice to self-destruct, Stanford researchers find

STANFORD, Calif. – Killing cancerous tumors isn’t easy, as anyone who has suffered through chemotherapy can attest. But a new study in mice shows that switching off a single malfunctioning gene can halt the limitless division of tumor cells and turn them back to the path of their own planned obsolescence.

The surprising possibility that a cell’s own natural mechanism for ensuring its mortality could be used to vanquish tumors opens the door to a new approach to developing drugs to treat cancer patients, according to Dean Felsher, MD, PhD, associate professor of medicine (oncology) and of pathology at the Stanford University School of Medicine. Felsher is the senior author of the study to be published July 30 in the advance online version of the Proceedings of the National Academy of Sciences.

“Our research implies that by shutting off a critical cancer gene, tumor cells can realize that they are broken and restore this physiologic fail-safe program,” said Felsher.

Cancer can be notoriously resistant to medical treatment. Not only do cancer cells proliferate uncontrollably, they somehow circumvent the mechanism that causes normal cells to die when they get old or malfunction. That makes cancer cells effectively immortal unless doctors manage to squelch them.

The gene Felsher’s team studied produces a protein called Myc (pronounced “mick”), which promotes cell division. A mutation of the gene causes cells to overproduce the protein, prompting perpetual cell division and tumor growth. By turning off the mutated gene, the researchers found that not only did uncontrolled cell division cease, but the cells also reactivated a normal physiological mechanism, called senescence, which makes it possible for a cell to eventually die.

“What was unexpected was just the fact that cancer cells had retained the ability to undergo senescence at all,” said Felsher. Cancer researchers had long thought the senescence process had to be irreversibly disrupted for a tumor to develop.

The researchers worked with a series of mice engineered to have Myc-triggered cancers of either the liver, blood or bones, along with a specially constructed version of the Myc gene that they could switch off by feeding the mice antibiotics. When the mice dined on doses of the drugs, invariably, the tumors ceased growing and then diminished, with some disappearing over the course of just a few days.

Although Felsher’s lab had previously shown that mouse tumors diminished and disappeared when Myc was switched off, they hadn’t been sure how the process actually worked. Historically, most research involving genetic methods of battling cancer cells has focused on reactivating genes called tumor-suppressor genes, which are generally overcome by a proliferating cancer. No one had explored the idea that senescence might play a key role in diminishing tumors.

Felsher described senescence as acting like a fail-safe mechanism to stop cancer. When a cell detects a deleterious mutation, it launches the senescence process, resulting in the permanent loss of the cell’s ability to proliferate, thus halting any cancer.

“In order to become tumor cells, those cells have to overcome senescence,” said Chi-Hwa Wu, PhD, postdoctoral researcher in Felsher’s lab and first author of the study. Wu had the inspiration to explore whether the sudden diminishment they had observed in the tumors might be due to the reactivation of some latent remnant of the trigger for senescence.

Through a series of experiments looking at enzymes associated with the senescence process, as well as some molecular markers, Wu confirmed her suspicion. And not only was senescence occurring in cells that had been thought to be incapable of it, the process was reactivated in all the different tumors they studied.

Consider it a cell version of the Jekyll-and-Hyde transformation. “It’s sort of like Mr. Hyde realizing that there’s something wrong with him and then being able to put himself back into his normal state as Dr. Jekyll,” Felsher said.

In addition to the deepened understanding of how the process of senescence works, Felsher and Wu see a lot of potential for new approaches to treating cancer, beyond the traditional tactic of trying to kill cancer cells directly. “This work implies that maybe part of the strategy should involve figuring out how to get the cancer cells to just be allowed to do what they originally wanted to do anyway, which is to not be proliferating endlessly and growing uncontrolled,” said Felsher.

The next step for the team is to see how well the approach works in human cancer cells. “And we’re also trying to figure out what the mechanism is,” Felsher said. “What are the molecular mechanisms of this, so that we can figure out how to better treat cancer””

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Other authors on the research paper are Jan van Riggelen, PhD, postdoctoral researcher; Alper Yetil, graduate student in cancer biology; Alice Fan, MD, instructor in medicine (oncology), and medical student Pavan Bachireddy.

The study was funded by the National Cancer Institute, the National Institutes of Health, the Leukemia and Lymphoma Society, the Burroughs Wellcome Fund, the Damon Runyon Lilly Clinical Investigator Award, the Lymphoma Research Foundation and the Howard Hughes Medical Institute.

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 at Stanford. For more information, please visit the Web site of the medical center’s Office of Communication & Public Affairs at http://mednews.stanford.edu.

Contact: Lou Bergeron
louisb3@stanford.edu
650-723-3900
Stanford University Medical Center

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July 31, 2007 Posted by | acute lymphoblastic leukemia, Alberta, Baltimore, Barcelona, Bethesda, Biological Sciences, Calgary, Canada, Cancer, Cancer Biology, Cancer Biology and Therapy, Childhood Lukemia, France, Genes, Genetic, Genetic Link, Genetics, Genome, Genomic, Germany, Global, Global Health Vision, Global News, Health Canada, Howard Hughes Medical Institute, Human Genome, Italy, Japan, Leukemia, Medical Journals, Molecular Biology, National Cancer Institute, National Institutes of Health, Newfoundland, News, News Australia, News Canada, News Israel, News Italy, News Jerusalem, News Switzerland, News UK, News US, News USA, NIH, non-Hodgkin's lymphoma, Nova Scotia, Nunavut, Osaka, Ottawa, Prince Edward Island, Public Health, Quebec, Research, RSS, RSS Feed, Toronto, UK, US, Virginia, Washington DC, Washington DC City Feed, Wellcome Trust, World News | Leave a comment

New studies on goat milk show it is more beneficial to health than cow milk

-It helps to prevent diseases such as anaemia and bone demineralisation
-UGR researchers have carried out a comparative study on the properties of goat milk compared to those of cow milk. Rats with induced nutritional ferropenic anaemia have been used in the study
-Goat milk helps digestive and metabolic utilisation of minerals such as iron, calcium, phosphorus and magnesium
-Part of the results of this research have been published in the prestigious scientific journals International Dairy Journal and Journal Dairy Science

C@MPUS DIGITAL Research carried out at the Department of Physiology of the University of Granada has revealed that goat milk has more beneficial properties to health than cow milk. Among these properties it helps to prevent ferropenic anaemia (iron deficiency) and bone demineralisation (softening of the bones).

This project, conducted by Doctor Javier Díaz Castro and directed by professors Margarita Sánchez Campos, Mª Inmaculada López Aliaga and Mª José Muñoz Alférez, focuses on the comparison between the nutritional properties of goat milk and cow milk, both with normal calcium content and calcium enriched, against the bioavailability of iron, calcium, phosphorus and magnesium. To carry out this study, the metabolic balance technique has been used both in rats with experimentally induced nutritional ferropenic anaemia and in a control group of rats.

In order to know how the nutritive utilisation of these minerals may affect their metabolic distribution and destination, the UGR researcher has determined the concentration of these minerals in the different organs involved in their homeostatic regulation and different haematological parameters in relation to the metabolism of the minerals.

Better results with goat milk
Results obtained in the study reveal that ferropenic anaemia and bone demineralisation caused by this pathology have a better recovery with goat milk. Due to the higher bioavailability of iron, calcium, phosphorus and magnesium, the restoration of altered haematological parameters and the better levels of parathyroid hormone (PTH), a hormone that regulates the calcium balance in the organism was found in the rats that consumed this food.

Javier Díaz Castro points out that the inclusion of goat milk with normal or double calcium content in the diet “favours digestive and metabolic utilisation of iron, calcium and phosphorus and their deposit in target organs – parts of the organism to which these minerals are preferably sent – involved in their homeostatic regulation”.

According to this researcher, all these conclusions reveal that regular consumption of goat milk – a natural food with highly beneficial nutritional characteristics – “has positive effects on mineral metabolism, recovery from ferropenic anaemia and bone mineralisation in rats. In addition, and unlike observations in cow milk, its calcium enrichment does not interfere in the bioavailability of the minerals studied”.

Although there is no doubt that these findings may be a base for further in depth study of the multiple health benefits of goat milk, the UGR researcher warns that “studies in humans are still required in order to confirm the findings obtained in rats and to promote goat milk consumption both in the general population and in the population affected by nutritional ferropenic anaemia and pathologies related to bone demineralisation”. Part of the results of this research has been published in the prestigious scientific journals International Dairy Journal and Journal Dairy Science.

Reference: Dr Javier Díaz Castro. Department of Physiology of the University of Granada.
Tel.: +34 958248319. Mobile: +34 654574434. Email: javierdc@ugr.es

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July 30, 2007 Posted by | Alberta, Baltimore, Barcelona, Bethesda, Biological Sciences, Bone Demineralisation, Bone Diseases, Calgary, Canada, France, Germany, Global, Global Health Vision, Global News, Italy, Japan, Medical History, Medical Journals, Molecular Biology, Newfoundland, News, News Australia, News Canada, News Israel, News Italy, News Jerusalem, News Switzerland, News UK, News US, News USA, NIH, Nova Scotia, Nunavut, Nutritional Anthropology, Ottawa, Pennsylvania, Prince Edward Island, Quebec, Research, RSS, RSS Feed, Slovakia, Toronto, UK, University of Granada, US, Virginia, Vitamin D, Washington DC, Washington DC City Feed, World News | Leave a comment

Research links genetic mutations to lupus

WINSTON-SALEM, N.C. – A gene discovered by scientists at Wake Forest University School of Medicine has been linked to lupus and related autoimmune diseases. The finding, reported in the current issue of Nature Genetics, is the latest in a series of revelations that shed new light on what goes wrong in human cells to cause the diseases.

“This research is a huge leap toward understanding the cause of lupus and related autoimmune diseases,” said Fred Perrino, Ph.D., a co-author on the paper and a professor of biochemistry at Wake Forest. “There had been few clues before now.”

Perrino, who discovered the gene in 1998, said he suspected it was involved in human disease, but it took a group of researchers from around the world collaborating to put the puzzle together.

“We’ve known that lupus was a complex disease, but now we have a specific protein and a particular cellular process that appears to be one of the causes,” said Perrino. “We’re connecting the dots to understand the biology of what’s going on with the disease.”

In Nature Genetics, lead author Min Ae Lee-Kirsch, M.D., from the Technische Universität Dresden in Dresden, Germany, and colleagues report finding variations of the TREX1 gene discovered by Perrino in patients with systemic lupus erythematosus. The study involved 417 lupus patients from the United Kingdom and Germany. Mutations were found in nine patients with lupus and were absent in 1,712 people without lupus.

“Our data identify a stronger risk for developing lupus in patients that carry variants of the gene,” said Lee-Kirsch.

In recent years, the gene was also linked to Aicardi-Goutieres syndrome, a rare neurological disease that causes death in infants, and to chilblain lupus, an inherited disease associated with painful bluish-red skin lesions that occur during cold weather and usually improve in summer. The current research also links it to Sjogren’s syndrome, a form of lupus.

The diseases are all autoimmuine diseases, which means that the body makes antibodies against itself. In lupus, these antibodies cause pain and inflammation in various parts of the body, including the skin, joints, heart, lungs, blood, kidneys and brain. The disease is characterized by pain, heat, redness, swelling and loss of function.

Perrino began studying the protein made by the gene more than 14 years ago.

“We basically cracked open cells to locate the protein and find the gene,” said Perrino. “In the 14 years since, we’ve learned a lot about the protein and how it functions.”

The gene manufactures a protein, also known as TREX1, whose function is to “disassemble” or “unravel” DNA, the strand of genetic material that controls processes within cells. The “unraveling” occurs during the natural process of cells dying and being replaced by new cells. If a cell’s DNA isn’t degraded or unraveled during cell death, the body develops antibodies against it.

“If the TREX1 protein isn’t working to disassemble the DNA, you make antibodies to your own DNA and can end up with a disease like lupus,” said Perrino.

Perrino and colleagues at Wake Forest have been studying the gene and its protein since 1993. Thomas Hollis, Ph.D., an assistant professor of biochemistry at Wake Forest, is credited with solving the structure of both TREX1 and a similar protein, TREX2. Perrino has also developed a way to measure the function of the proteins.

In a study reported in April in the Journal of Biological Chemistry, Hollis and Perrino found that three variations of the gene reduced the activity of the protein by four- to 35,000-fold.

“Now that we have the structure, we can understand how it disassembles DNA and how mutations in the gene may affect that process,” said Hollis.

The researchers hope that understanding more about the gene’s mutations and the structure of the protein may lead to drug treatments to help ensure that mutant copies of the gene are inactive.

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Media Contacts: Karen Richardson, krchrdsn@wfubmc.edu; Shannon Koontz, shkoontz@wfubmc.edu; at 336-716-4587.

Wake Forest University Baptist Medical Center is an academic health system comprised of North Carolina Baptist Hospital and Wake Forest University Health Sciences, which operates the university’s School of Medicine. U.S. News & World Report ranks Wake Forest University School of Medicine 18th in primary care and 44th in research among the nation’s medical schools. It ranks 35th in research funding by the National Institutes of Health. Almost 150 members of the medical school faculty are listed in Best Doctors in America.

Contact: Karen Richardson
krchrdsn@wfubmc.edu
336-716-4453
Wake Forest University Baptist Medical Center

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July 29, 2007 Posted by | Alberta, Baltimore, Barcelona, Bethesda, Biological Sciences, Calgary, Canada, Clinical Trials, France, Genes, Genetic, Genetic Link, Genetic Marker C allele of rs10505477, Genetics, Genome, Genomic, Global, Global Health Vision, Global News, Health Canada, Human Genome, Italy, Japan, Lupus, Nature Genetics, Newfoundland, News, News Australia, News Canada, News Israel, News Italy, News Jerusalem, News Switzerland, News UK, News US, News USA, NIH, Nova Scotia, Nunavut, Osaka, Ottawa, Prince Edward Island, Public Health, Quebec, Research, RSS, RSS Feed, Slovakia, Spain, Toronto, UK, US, Virginia, Wake Forest University Baptist Medical Center, WASHINGTON, Washington DC, Washington DC City Feed, World Health Organisation, World News | 1 Comment

One man’s junk may be a genomic treasure

Scientists have only recently begun to speculate that what’s referred to as “junk” DNA – the 96 percent of the human genome that doesn’t encode for proteins and previously seemed to have no useful purpose – is present in the genome for an important reason. But it wasn’t clear what the reason was. Now, researchers at the University of California, San Diego (UCSD) School of Medicine have discovered one important function of so-called junk DNA.

Genes, which make up about four percent of the genome, encode for proteins, “the building blocks of life.” An international collaboration of scientists led by Michael G. Rosenfeld, M.D., Howard Hughes Medical Investigator and UCSD professor of medicine, found that some of the remaining 96 percent of genomic material might be important in the formation of boundaries that help properly organize these building blocks. Their work will be published in the July 13 issue of the journal Science.

“Some of the ‘junk’ DNA might be considered ‘punctuation marks’ – commas and periods that help make sense of the coding portion of the genome,” said first author Victoria Lunyak, Ph.D., assistant research scientist at UCSD.

In mice, as in humans, only about 4 percent of the genome encodes for protein function; the remainder, or “junk” DNA, represents repetitive and non-coding sequences. The research team studied a repeated genomic sequence called SINE B2, which is located on the growth hormone gene locus, the gene related to the aging process and longevity. The scientists were surprised to find that SINE B2 sequence is critical to formation of the functional domain boundaries for this locus.

Functional domains are stretches of DNA within the genome that contain all the regulatory signals and other information necessary to activate or repress a particular gene. Each domain is an entity unto itself that is defined, or bracketed, by a boundary, much as words in a sentence are bracketed by punctuation marks. The researchers’ data suggest that repeated genomic sequences might be a widely used strategy used in mammals to organize functional domains.

“Without boundary elements, the coding portion of the genome is like a long, run-on sequence of words without punctuation,” said Rosenfeld.

Decoding the information written in “junk” DNA could open new areas of medical research, particularly in the area of gene therapy. Scientists may find that transferring encoding genes into a patient, without also transferring the surrounding genomic sequences which give structure or meaning to these genes, would render gene therapy ineffective.

Contributors to the paper include Lluis Montoliu, Rosa Roy and Angel Garcia-Díaz of the Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología in Madrid, Spain; Christopher K. Glass, M.D., Ph.D., UCSD Department of Cellular and Molecular Medicine; Esperanza Núñez, Gratien G. Prefontaine, Bong-Gun Ju, Kenneth A. Ohgi, Kasey Hutt, Xiaoyan Zhu and Yun Yung, Howard Hughes Medical Institute, Department of Molecular Medicine, UCSD School of Medicine; and Thorsten Cramer, Division of Endocrinology, UCSD Department of Medicine.

The research was funded in part by the Howard Hughes Medical Institute and the National Institutes of Health.

Contact: Debra Kain
ddkain@ucsd.edu
619-543-6163
University of California – San Diego

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July 13, 2007 Posted by | Alberta, Baltimore, Barcelona, Bethesda, Biological Sciences, Calgary, Chile, DNA, Genes, Genetic, Genetics, Genome, Genomic, Global, Global Health Vision, Global News, Howard Hughes Medical Institute, Human Genome, Irvine, Italy, Japan, National Institutes of Health, Newfoundland, News, News Australia, News Canada, News Israel, News Italy, News Jerusalem, News Switzerland, News UK, News US, News USA, NIH, Nova Scotia, Osaka, Ottawa, Pennsylvania, Prince Edward Island, Proteins, Quebec, Research, Research Australia, RSS, RSS Feed, Slovakia, Spain, Toronto, UCSD, University of California, Virginia, WASHINGTON, Washington DC, Washington DC City Feed, World News | Leave a comment

Low vitamin D levels may be common in otherwise healthy children

Many otherwise healthy children and adolescents have low vitamin D levels, which may put them at risk for bone diseases such as rickets. African American children, children above age nine and with low dietary vitamin D intake were the most likely to have low levels of vitamin D in their blood, according to researchers from The Children’s Hospital of Philadelphia.

A study in the current issue of the American Journal of Clinical Nutrition measured blood levels of vitamin D in 382 healthy children between six years and 21 years of age living in the northeastern U.S. Researchers assessed dietary and supplemental vitamin D intake, as well as body mass, and found that more than half of the children had low blood levels of vitamin D. Of the subjects, 55 percent of the children had inadequate vitamin D blood levels and 68 percent overall had low blood levels of the vitamin in the wintertime.

“The best indicator of a person’s vitamin D status is the blood level of a vitamin D compound called 25-hydroxyvitamin D,” said Babette Zemel, Ph.D., a nutritional anthropologist at Children’s Hospital and primary investigator of this study. “Vitamin D deficiency remains an under-recognized problem overall, and is not well studied in children.”

Vitamin D is crucial for musculoskeletal health. The primary dietary source of the vitamin is fortified milk, but the best way to increase vitamin D levels is from exposure to sunshine. Severe deficits in vitamin D may lead to muscle weakness, defective bone mineralization and rickets. In addition to musculoskeletal effects, vitamin D is important for immune function, and low blood levels of the vitamin may contribute to diseases such as hypertension, cancer, multiple sclerosis and type 1 diabetes. Decreased blood levels of vitamin D have also been linked to obesity.

Further study is needed to determine the appropriate blood levels of vitamin D in children, said Dr. Zemel, who added that a review of the current recommendations for vitamin D intake is needed.

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Grants from the National Institutes of Health and several private sources supported this study.

Dr. Zemel’s co-authors were Mary B. Leonard, M.D. and Virginia A. Stallings, M.D., of The Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine, as well as Francis L. Weng and Justine Shults, also of the University of Pennsylvania School of Medicine.

About The Children’s Hospital of Philadelphia: The Children’s Hospital of Philadelphia was founded in 1855 as the nation’s first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children’s Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country, ranking third in National Institutes of Health funding. In addition, its unique family-centered care and public service programs have brought the 430-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu.

Contact: Joey Marie McCool
McCool@email.chop.edu
267-426-6070
Children’s Hospital of Philadelphia

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Place of death shifting for children with complex chronic conditions

Contact: Rachel Salis-Silverman
267-426-6063
JAMA and Archives Journals

It is becoming more common for children with complex chronic conditions to die in their home than in a hospital, although black and Hispanic children with these conditions are less likely to die in their home, according to a study in the June 27 issue of JAMA, a theme issue on chronic diseases of children.

Chris Feudtner, M.D., Ph.D., M.P.H., of Children’s Hospital of Philadelphia, presented the findings of the study at a JAMA media briefing in New York.

Many pediatric palliative care clinicians suggest that the preferred place of death, by the family, of an infant, child, or adolescent with a medically complex chronic condition is the home. Advances in home-based medical technology and changes in attitudes about pediatric palliative care and hospice services may be making this a more viable option, according to background information in the article.

Dr. Feudtner and colleagues conducted a study to determine if the proportion of complex chronic condition-related deaths occurring at home among children and adolescents increased between 1989 and 2003, and to assess if there were any race and ethnicity disparities in the location of death. The researchers analyzed data from the National Center for Health Statistics’ Multiple Cause of Death Files.

Among the 22.1 percent of deaths (198,160 of 896,509 total deaths) attributed to a complex chronic condition between 1989 and 2003, the percentage of deaths occurring at home increased significantly for all age groups (overall, from 10.1 percent in 1989 to 18.2 percent in 2003), but with larger increases for deaths beyond infancy. The odds of death occurring at home increased by 3.8 percent annually.

The percentage of individuals dying at home increased significantly over time for infants (4.9 percent home deaths in 1989 to 7.3 percent in 2003); 1 to 9-year-olds (17.9 percent to 30.7 percent), and 10 to 19-year-olds (18.4 percent to 32.2 percent). During this same period, there was a significant decline in the percentage of deaths occurring in the hospital for each of these three age categories.

The authors suggest that this gradual change in place of death may be occurring because of advances in medical technology in the home setting and broad shifts in attitudes and decision-making processes regarding palliative and end-of-life care in U.S. culture.

The child’s race, ethnicity, and region of home residence were significantly associated with death occurring at home. The odds of dying at home were reduced by 50 percent among black individuals, and reduced by 48 percent among Hispanic individuals, when compared with whites.

Concerning possible reasons for the observed racial and ethnic differences, “ … differential access to health care services or medical technology, divergent cultural attitudes or approaches to palliative and end-of-life care decision making, or differing levels of financial or other support within the patient’s or family’s social network may make dying at home more or less likely.”

“… as efforts to improve understanding of the sources and remedies of racial and ethnic disparities in pediatric end-of-life care are completed, medical and other concerned professionals need to ensure that all patients have access to necessary care and that all dialogue and interactions regarding decisions about care—whether curative, life-extending, or palliative—are built on mutual understanding, trust, and respect,” the authors conclude.

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(JAMA. 2007;297:2725-2732. Available pre-embargo to the media at http://www.jamamedia.org)

Editor’s Note: The conduct of this study was supported in part by grants from the Agency for Healthcare Research and Quality and the National Institute of Nursing Research of the National Institutes of Health. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

For More Information: Contact the JAMA/Archives Media Relations Department at 312-464-JAMA or email: mediarelations@jama-archives.org.

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