Cholesterol-lowering drugs and the risk of hemorrhagic stroke

Contact: Angela Babb
ababb@aan.com
651-695-2789
American Academy of Neurology

ST. PAUL, Minn. – People taking cholesterol-lowering drugs such as atorvastatin after a stroke may be at an increased risk of hemorrhagic stroke, or bleeding in the brain, a risk not found in patients taking statins who have never had a stroke. But researchers caution the risk must be balanced against the much larger overall benefit of the statin in reducing the total risk of a second stroke and other cardiovascular events when making treatment decisions. The research is published in the December 12, 2007, online issue of Neurology®, the medical journal of the American Academy of Neurology.

For the study, researchers conducted a secondary analysis of the results of the Stroke Prevention with Aggressive Reduction in Cholesterol Levels (SPARCL) clinical trial. The trial enrolled 4,731 people who were within one to six months of having had a stroke or transient ischemic attack, or mini-stroke, and with no history of heart disease. Half of the participants received atorvastatin and half received a placebo. The participants were then followed for an average of four and a half years.

Overall, treatment was associated with a 16-percent reduction in total stroke, the study’s primary endpoint, as well as significant reductions in coronary heart events. However, secondary analysis found that the overall reduction in stroke included an increase in the risk of brain hemorrhage. Of those people randomized to atorvastatin, the study found 2.3 percent experienced a hemorrhagic stroke during the study compared to 1.4 percent of those taking placebo. The study also found there was a 21-percent reduction in ischemic stroke, a more common type of stroke involving a block in the blood supply to the brain, among people taking atorvastatin.

Other factors were also found to increase the risk of brain hemorrhage. For example, those who had experienced a hemorrhagic stroke prior to the study were more than five times as likely to suffer a second stroke of this kind. Men were also nearly twice as likely as women to suffer a hemorrhagic stroke. People with severe high blood pressure at their last doctor’s visit prior to the hemorrhagic stroke had over six times the risk of those with normal blood pressure.

“Although treatment of patients with a stroke or transient ischemic attack was clearly associated with an overall reduction in a second stroke, hemorrhagic stroke was more frequent in people treated with atorvastatin, in those with a prior hemorrhagic stroke, in men and in those with uncontrolled hypertension,” according to study author Larry B. Goldstein, MD, with Duke University Medical Center in Durham, North Carolina, and Fellow of the American Academy of Neurology. “This risk of hemorrhagic stroke also increased with age.”

“Treatment with atorvastatin did not disproportionately increase the frequency of brain hemorrhage associated with these other factors. The risk of hemorrhage in patients who have had a transient ischemic attack or stroke must be balanced against the benefits of cholesterol-lowering drugs in reducing the overall risk of a second stroke, as well as other cardiovascular events,” said Goldstein.

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The SPARCL trial was funded by Pfizer, the maker of atorvastatin.

The American Academy of Neurology, an association of more than 20,000 neurologists and neuroscience professionals, is dedicated to improving patient care through education and research. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as stroke, Alzheimer’s disease, epilepsy, Parkinson disease, and multiple sclerosis.

For more information about the American Academy of Neurology, visit http://www.aan.com.

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New study highlights link between unemployment and hospital trauma admissions

Press Releases

Heidelberg, 8 August 2007

Unemployment cuts

Socioeconomic status, and unemployment rates in particular, predict both the type of trauma seen in emergency rooms and the population groups more likely to be victims of trauma, according to Atul Madan (1) from the University of Tennessee Health Science Center and his team. Their findings have just been published online in Springer’s World Journal of Surgery.

The researchers looked at the link between unemployment rates and the types of trauma admissions in New Orleans over six years. Unemployment rates were obtained from the Bureau of Labor Statistics. The trauma registry of the Medical Center of Louisiana at New Orleans (Charity Hospital) provided data on the trauma emergency room admissions, including patient demographics.

Between January 1994 and November 1999, there were over 24,000 trauma admissions. During that period, the higher the unemployment rate, the higher the number of admissions for penetrating trauma – injuries that occur primarily by an object piercing the skin or entering a tissue of the body, such as bullets and knives.

The lower the unemployment rates, the higher the number of admissions for blunt trauma – physical trauma caused to a body part, either by impact, injury of physical attack which can result in contusions, abrasions, lacerations and bone fractures. In this instance, the majority of blunt trauma was the result of motor vehicle collisions. The authors suggest that a possible explanation for this surprising finding could be the fact that with higher incomes, more travel is likely, which in turn increases the likelihood of motor vehicle collisions. Alternatively, more tourism to the area may have reduced unemployment but caused more road accidents.

The study also shows that as the socioeconomic status, measured here by unemployment rates, of the community changes, so do the demographics and mortality rates of the trauma population. There were more male patients, African American patients and deaths at times of high unemployment. These results suggest that during times of economic hardship, certain population groups are at higher risk of life-threatening injuries.

The authors recommend that “injury prevention efforts targeted at economically disadvantaged populations and high-risk groups should be stressed when designing community trauma outreach programs, especially during times of economic hardships.”

Reference
(1) Madan A et al (2007). Unemployment rates and trauma admissions. World Journal of Surgery (DOI 10.1007/s00268-007-9190-4)

Contact:
Renate Bayaz
tel +49-6221-487-8531

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A pioneering study opens roads for tailor-made antidepressants

In spite that the causes of depression have not still been fully identified, scientists acknowledge that genetic and environmental factors play a common role in the onset of this disorder. One of the environmental risk factors more often related to depression is exposure to threatening life events. On the other side, from a genetic point of view, the serotonin transporter gene, with a crucial role in communication between neurons, could predispose to depression.

An international group of scientists, headed by professors Jorge Cervilla Ballesteros and Blanca Gutiérrez Martínez, from the department of Legal Medicine, Toxicology and Psychiatry of the University of Granada, has recently published in the prestigious journal Molecular Psychiatry the pioneering study PREDICT-gene, confirming the relation between allele s in the serotonin transporter gene and exposure to threatening life events in the onset of depression. The study proves, for a population sample accounting for gender, age and family history of psychiatric disorders, that 24% of the Spanish population, comprising people with the s/s genotype, need minimal exposure to threatening life events, unlike individuals with s/l or l/l genotypes, thus confirming the relation between genetic and environmental factors in this mental disorder.

Tailor-made antidepressants

The most important consequence of research on interaction between genetic and environmental factors is that, in a foreseeable future, scientists will be able to produce measures to predict response to antidepressants taking into account each individual’s genotype, i. e. they will be able to design tailor-made drugs according to each person’s genetic configuration and their exposure to environmental factors.

The research group headed by professor Cervilla Ballesteros and Gutiérrez Martínez is currently working at the University of Granada to open roads for psycho-pharmaco-genetics, a field that will allow for individual treatments, tailor-made drugs, for each patient with depression, a disorder affecting one in every five Spaniards visiting the doctor’s.

This study is framed in the international project PREDICT and is funded by the European Union and the Spanish Ministry of Education and Science. One of its most important novelties is that it has been carried out through a very representative sample: a total of 737 people agreed to participate in the genetic tests, with ages ranging from 18 to 75, patients of nine primary care centres in the South of Spain. That is why this is the first representative population-based replication of earlier research, as until now research had been done into restricted population samples, comprising only women, adolescents, twins or people with affective disorders.

Contact: Professor Jorge Cervilla Ballesteros
jacb@ugr.es
34-663-075-835
Universidad de Granada

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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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European heat waves double in length since 1880

The most accurate measures of European daily temperatures ever indicate that the length of heat waves on the continent has doubled and the frequency of extremely hot days has nearly tripled in the past century. The new data shows that many previous assessments of daily summer temperature change underestimated heat wave events in western Europe by approximately 30 percent.

Paul Della-Marta and a team of researchers at the University of Bern in Switzerland compiled evidence from 54 high-quality recording locations from Sweden to Croatia and report that heat waves last an average of 3 days now—with some lasting up to 4.5 days—compared to an average of around 1.5 days in 1880. The results are published 3 August in the Journal of Geophysical Research-Atmospheres, a publication of the American Geophysical Union. The researchers suggest that their conclusions contribute to growing evidence that western Europe’s climate has become more extreme and confirm a previously hypothesized increase in the variance of daily summer temperatures since the 19th century.

The study adds evidence that heat waves, such as the devastating 2003 event in western Europe, are a likely sign of global warming; one that perhaps began as early as the 1950s, when their study showed some of the highest trends in summer mean temperature and summer temperature variance.

“These results add more evidence to the belief among climate scientists that western Europe will experience some of the highest environmental and social impacts of climate change and continue to experience devastating hot summers like the summer of 2003 more frequently in the future,” Della-Marta said.

The authors note that temperature records were likely overestimated in the past, when thermometers were not kept in modern Stevenson screens, which are instrument shelters used to protect temperature sensors from outside influences that could alter its readings. The researchers corrected for this warm bias and other biases in the variability of daily summer temperatures and show that nearly 40 percent of the changes in the frequency of hot days are likely to be caused by increases in summer temperatures’ variability. This finding demonstrates that even a small change in the variance of daily summer temperatures can radically enhance the number of extremely hot days.

“These findings provide observational support to climate modeling studies showing that European summer temperatures are particularly sensitive to global warming,” Della-Marta said. “Due to complex reactions between the summer atmosphere and the land, the variability of summer temperatures is expected to [continue to] increase substantially by 2100.”

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The research was supported by the European Environment and Sustainable Development Program, the Swiss National Science Foundation and the National Center for Excellence in Climate Research (NCCR Climate).

Contact: Jonathan Lifland
jlifland@agu.org
202-777-7535
American Geophysical Union

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Identifying the mechanism behind a genetic susceptibility to type 2 diabetes

Type 2 diabetes is reaching epidemic proportions in the developed world. Determining if and how certain genes predispose individuals to type 2 diabetes is likely to lead to the development of new treatment strategies for individuals with the disease.

In a study appearing in the August issue of the Journal of Clinical Investigation Valeriya Lyssenko and colleagues from Lund University in Sweden show that certain variants of the gene TCF7L2 make individuals more susceptible to type 2 diabetes. The susceptibility variants were associated with increased expression of TCF7L2 in pancreatic islet cells and decreased islet cell secretion of insulin. Consistent with this, ectopic overexpression of TCF7L2 in human islet cells decreased insulin secretion in response to exposure to glucose. This study identifies TCF7L2 type 2 diabetes susceptibility variants and provides a mechanism by which these genetic variants might cause susceptibility to the disease. As discussed by the authors and in the accompanying commentary by Andrew Hattersley from Peninsula Medical School in the United Kingdom, future studies are likely to investigate the potential for manipulating the signaling pathways controlled by TCF7L2 for the development of new therapeutics for type 2 diabetes.

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TITLE: Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes

AUTHOR CONTACT:
Valeriya Lyssenko
Lund University, University Hospital Malma, Malma, Sweden.
Phone: 46-40-391214; Fax: 46-40-391222; E-mail: Valeri.Lyssenko@med.lu.se.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30706

ACCOMPANYING COMMENTARY
TITLE: Prime suspect: the TCF7L2 gene and type 2 diabetes risk

AUTHOR CONTACT:
Andrew T. Hattersley
Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Exeter, United Kingdom.
Phone: 44-1392-406806; Fax: 44-1392-406767; E-mail: Andrew.Hattersley@pms.ac.uk.

View the PDF of this article at: https://www.the-jci.org/article.php?id=33077

Contact: Karen Honey
press_releases@the-jci.org
215-573-1850
Journal of Clinical Investigation

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U-M researchers find family of ‘on switches’ that cause prostate cancer

Gene fusions trigger cancer growth, could impact treatment choices

ANN ARBOR, Mich. — Researchers at the University of Michigan Comprehensive Cancer Center have discovered how genes turn on the switch that leads to prostate cancer.

The team discovered that pieces of two chromosomes can trade places with each other and cause two genes to fuse together. The fused genes then override the “off” switch that keeps cells from growing uncontrollably, causing prostate cancer to develop.

By testing these gene fusions in mice and in cell cultures, the researchers showed that the fusions are what cause prostate cancer to develop. But it’s not just one set of genes that fuse. The researchers found that any one of several in a family of genes can become scrambled and fuse. Results of the study appear in the Aug. 2 issue of Nature.

“Each of these switches, or gene fusions, represent different molecular subtypes. This tells us there’s not just one type of prostate cancer. It’s a more complex disease and potentially needs to be treated differently in each patient,” says lead study author Arul Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology, a new U-M center whose goal is to translate research into real world practice.

The gene fusion research is the centerpiece project of the new center. In the current study, researchers found one of several abnormal gene fusions in the prostate cancer tissue samples they tested. In 2005, the researchers identified a prostate-specific gene called TMPRSS2, which fuses with either ERG or ETV1, two genes known to be involved in several types of cancer.

The Nature paper reports on five additional genes that fuse with ERG or ETV1 to cause prostate cancer. Gene fusions were involved in 60 percent to 70 percent of the prostate cancer cell lines the researchers looked at. The genes involved are all controlled by a different mechanism. For example, four of the genes are regulated by androgen, a male sex hormone known to fuel prostate cancer. Androgen deprivation is a common therapy for prostate cancer.

Knowing which gene fusion is involved in an individual patient’s tumor could impact treatment options. If an androgen-regulated gene is involved, androgen therapy would be appropriate. But if the gene fusion involves a gene that represses androgen, the anti-androgen therapy could encourage the cancer’s growth. This may also explain why androgen treatment is not effective for some prostate cancers.

“Typing someone’s prostate cancer by gene fusion can affect the treatment given. We would not want to give androgen to someone whose prostate cancer gene fusion is not regulated by androgen,” says Chinnaiyan, who is the S.P. Hicks Collegiate Professor of Pathology at the U-M Medical School.

Rearrangements in chromosomes and fused genes are known to play a role in blood cell cancers like leukemia and lymphoma, and in Ewing’s sarcoma. A fused gene combination that plays a role in chronic myelogenous leukemia led researchers to develop the drug Gleevec, which has dramatically improved survival rates for that disease.

Chinnaiyan believes the prostate gene fusions will eventually lead to similar treatments for prostate cancer.

“More immediately, we hope to develop tests for diagnosis or prognosis. But long-term, we hope this will lead to better therapies to treat prostate cancer. The key challenge is to find a drug that would go after this gene fusion,” Chinnaiyan says.

The gene fusion technology has been licensed to San Diego-based Gen-Probe Inc., which is working on a screening tool to detect gene fusions in urine. The tool could one day supplement or replace the prostate specific antigen, or PSA, test currently used to screen for prostate cancer.

The idea of translating laboratory research findings into a test or treatment that will impact patients is central to the new Michigan Center for Translational Pathology. The center brings together experts in genomics, proteomics and bioinformatics to look at common patterns and potential targets in cancer and other diseases. This is the first center of its kind in the nation in that it is associated with one of 39 National Cancer Institute-designated “comprehensive” cancer centers, a premier medical school and a large health system with both clinicians and patients.

The center’s goal is to study the genes, proteins and other markers on cells to develop new diagnostic tests or screening tools as well as targeted treatments for cancer and other diseases, with the key being to translate these laboratory discoveries into clinical applications.

Chinnaiyan and his team have received numerous awards and honors, including the American Association for Cancer Research Team Science Award for their previously published work on gene fusions, and the Specialized Program of Research Excellence Outstanding Investigator award. The new Center for Translational Pathology supported in part by the Prostate Cancer Foundation, which has offered to match up to $1 million dollars in donations to support work related to developing therapies against prostate cancer gene fusions at the university.

“Mapping of the human genome was only the beginning. Equipped with the comprehensive analysis of the human genome, we can now systematically examine the blueprint of disease at the molecular level. This essential knowledge may lead to better diagnostic tests and promising new treatments for cancer, cardiovascular disease, diabetes and other illnesses,” Chinnaiyan says.

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For information about the Michigan Center for Translational Pathology, go to http://www.med.umich.edu/mctp.

About 218,890 men will be diagnosed with prostate cancer this year, and 27,050 will die from the disease, according to the American Cancer Society. The gene fusion work is not currently available for treatment or diagnosis, and no clinical trials are currently recruiting. For information about prostate cancer and currently available treatments, go to http://www.mcancer.org or call the U-M Cancer AnswerLine at 800-865-1125.

In addition to Chinnaiyan, U-M study authors were Scott Tomlins; Saravana Dhanasekaran, Ph.D.; Bharathi Laxman; Qi Cao; Beth Helgeson; Xuhong Cao; David Morris, M.D.; Anjana Menon; Xiaojun Jing; Bo Han; James Montie, M.D.; Kenneth Pienta, M.D.; Diane Roulston; Rajal Shah, M.D.; Sooryanarayana Varambally, Ph.D.; and Rohit Mehra, M.D. Mark Rubin, M.D., from Brigham and Women’s Hospital, Dana-Farber Cancer Institute and Harvard Medical School is also a study author.

Funding for the study came from the U.S. Department of Defense, the National Institutes of Health, the Early Detection Research Network, the Prostate Cancer Foundation and Gen-Probe Inc.

The University of Michigan has filed for a patent on the detection of gene fusions in prostate cancer, on which Tomlins, Mehra, Rubin and Chinnaiyan are co-inventors. The diagnostic field of use has been licensed to Gen-Probe Inc. Chinnaiyan also has a sponsored research agreement with Gen-Probe; however, GenProbe has had no role in the design or experimentation of this study, nor has it participated in the writing of the manuscript.

Reference: Nature, Vol. 448, No. 7153, Aug. 2, 2007

Contact: Nicole Fawcett
nfawcett@umich.edu
734-764-2220
University of Michigan Health System

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Huntington’s disease study shows animal models on target

This release is available in French.

An international team of researchers has published a benchmark study showing that gene expression in several animal models of Huntington’s Disease (HD) closely resembles that of human HD patients.

The results, published August 1, 2007, in the , validate the applicability of using animal models to study human disease and will have important consequences for the pertinence of these models in preclinical drug testing.

Huntington’s disease is an incurable and fatal hereditary neurodegenerative disorder caused by a mutation in the gene that encodes the huntingtin protein. Neurons in certain regions of the brain succumb to the effects of the altered protein, leading to severe motor, psychiatric, and cognitive decline. Several recent studies have shown that the mutant huntingtin protein modifies the transcriptional activity of genes in affected neurons. This disease mechanism is a promising new avenue for research into the causes of neuronal death and a novel potential approach for treatment.

Led by EPFL professor Ruth Luthi-Carter, and involving collaborators from six countries, the current study found a marked resemblance between the molecular etiology of neurons in animal models and neurons in patients with HD. This implies that animal models are relevant for studying human HD and testing potential treatments.

To come to this conclusion, the scientists measured the gene expression profile of seven different transgenic mouse models of HD, representing different conditions and disease stages. These profiles clarified the role of different forms and dosages of the protein hungtintin in the transcriptional activity of neurons. They then designed and implemented novel computational methods for quantifying similarities between RNA profiles that would allow for comparisons between the gene expression in mice and in human patients. “Interestingly, results of different testing strategies converged to show that several available models accurately recapitulate the molecular changes observed in human HD,” explains Luthi-Carter. “It underlines the suitability of these animal models for preclinical testing of drugs that affect gene transcription in Huntington’s Disease.”

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More Information:

EPFL Laboratory of functional neurogenomics, http://lngf.epfl.ch/

Alexandre Kuhn ; +41 21 693 1731
alexandre.kuhn@epfl.ch

Professor Ruth Luthi-Carter; +41 21 693 9533
ruth.luthi-carter@epfl.ch

Contact: Alexandre Kuhn
alexandre.kuhn@epfl.ch
41-216-931-731
Ecole Polytechnique Fédérale de Lausanne

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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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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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