Day: 11/11/2011

Hereditary Mutations in BAP1 Gene Raise Risk of Mesothelioma

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In two independent studies, researchers have shown that people with hereditary mutations in a gene known as BAP1 are predisposed to develop malignant mesothelioma and melanoma of the eye (uveal or intraocular melanoma), and a distinctive type of benign skin tumor. The findings, published online August 28 in Nature Genetics, suggest that inherited BAP1 mutations may also be linked to some other forms of cancer, including melanoma of the skin.

In one study, supported by NCI, a team of investigators led by Dr. Joseph Testa of the Fox Chase Cancer Center and Dr. Michele Carbone of the University of Hawaii Cancer Center focused on two U.S. families with a high incidence of mesothelioma. The study is the first to show that inherited gene mutations can influence a person’s risk of mesothelioma—one of the least curable forms of cancer. Mesothelioma is typically associated with exposure to asbestos or to a similar mineral fiber, erionite.

The second study, led by Drs. Thomas Wiesner of the Medical University of Graz, Austria, and Memorial Sloan-Kettering Cancer Center (MSKCC); Boris Bastian of MSKCC; and Michael Speicher, also of the Medical University of Graz, focused on two families, one from Germany and one from Austria, in which members developed numerous small, benign skin growths starting at an early age. These raised growths occurred in pigment-producing cells called melanocytes but were skin-colored, unlike typical moles.

In both studies, researchers zeroed in on the BAP1 gene after finding genetic changes in or near the region of human chromosome 3 where BAP1 is located. The BAP1 gene encodes a protein known as BRCA1-associated protein-1, which is found in the cell nucleus and is thought to suppress tumors. The BAP1 protein has been implicated in a range of cellular processes, including regulation of cell growth and division and response to DNA damage.

In the two families with mesothelioma, Drs. Testa, Carbone, and their colleagues found BAP1 mutations in two individuals with uveal melanoma, one of whom subsequently developed mesothelioma. The research team also found hereditary alterations in BAP1 in 2 of 26 patients with sporadic mesothelioma. Both individuals had previously been diagnosed with uveal melanoma, although none of the other 24 patients had. Some of the patients with sporadic mesothelioma were found to have noninherited BAP1 alterations in their tumors.

Their findings, Drs. Testa and Carbone wrote, “suggest that individuals with uveal melanoma who carry [hereditary] BAP1 mutations are at high risk of developing mesothelioma and should be closely monitored.”

In each family that Dr. Wiesner and his colleagues studied, one individual with benign skin tumors also had melanoma of the eye. In addition, three members of one family were diagnosed with skin melanoma. These investigators also found noninherited BAP1 mutations in randomly selected tumors from an independent group of patients with melanoma of the eye and skin.

In two other recent studies , noninherited mutations in BAP1 were found in tumor tissue of sporadic cases of mesothelioma and melanoma of the eye.

source: NCI

Smokers at Greater Risk of Bladder Cancer than Previously Estimated

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Current cigarette smokers have a higher risk of bladder cancer than previously reported, and the proportion of bladder cancers due to smoking in women is now comparable to that in men, according to a study by researchers in NCI’s Division of Cancer Epidemiology and Genetics (DCEG). Their findings were published August 17 in JAMA.

This latest study included data from more than 450,000 participants in the NIH-AARP Diet and Health Study, a questionnaire-based study that began in 1995, with follow-up through the end of 2006.

“Current smokers in our study had a fourfold excess risk of developing bladder cancer, compared to a threefold excess risk observed in previous studies,” said study co-author Dr. Neal Freedman. “The stronger association between smoking and bladder cancer is possibly due to changes in cigarette composition or smoking habits over the years.”

In the current study, former smokers were twice as likely to develop bladder cancer than those who never smoked. As with many other smoking-related cancers, the risk of bladder cancer fell after people quit smoking.

Previous studies had indicated that only 20 to 30 percent of bladder cancer cases in women were caused by smoking, but the new data indicate that smoking is responsible for about half of bladder cancer cases among women, a proportion similar to that found in men in this and previous studies.

The increase in the proportion of smoking-induced bladder cancer cases among women may be because smoking rates in men and women are now similar. The majority of the earlier studies were conducted at times or in places where smoking was much less common among women than men.

“Our findings provide additional evidence of the importance of preventing smoking initiation and promoting cessation for both men and women,” said senior author Dr. Christian Abnet.

source:NCI

Bacterium Associated with Stomach Cancer Directly Damages DNA

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A new study helps explain how infection with the stomach bacterium Helicobacter pylori, the strongest known risk factor for gastric (stomach) cancer, may lead to cancer. Researchers have found that H. pylori infection triggers breaks in both strands of the DNA double helix in the nucleus of gastric epithelial cells. These DNA double-strand breaks activate the cells’ machinery for repairing DNA damage, but prolonged H. pylori infection overloads this machinery, which could lead to mutations involved in gastric cancer development.

Drs. Anne Müller and Massimo Lopes of the University of Zurich and their colleagues reported the findings online September 6 in Proceedings of the National Academy of Sciences.

“Human biopsies from infected individuals reveal higher mutation rates of gastric mucosal cells, and results from animal models suggested the same,” Dr. Müller wrote in an e-mail. “But very little is known regarding the mechanism” that causes these mutations.

Using techniques that analyze DNA integrity, the researchers showed that exposing laboratory-grown cells to H. pylori caused DNA double-strand breaks in human gastric cancer cells and in normal mouse gastric epithelial cells. The frequency of double-strand breaks—the most harmful lesions a cell can encounter, according to the authors—depended on the intensity and duration of exposure.

The researchers also showed that DNA damage depends on direct contact of live H. pylori bacteria with their host cells and is not caused by factors such as toxins that these bacteria secrete.

“Our study is one of the few suggesting direct DNA damage as the cause for mutations,” Dr. Müller noted. Other studies have suggested that chronic H. pylori infection and resulting inflammation lead indirectly to DNA damage by triggering the production of chemicals known as reactive oxygen species, which cause oxidation of DNA, but this study ruled out a role for oxidation.

Although most DNA breaks were repaired efficiently by the cell when H. pylori was eliminated by antibiotics, continuous exposure of human gastric cancer cells for 48 hours or longer appeared to flood the DNA-repair machinery. “DNA damage followed by potentially imprecise repair…may contribute to the genetic instability and frequent chromosomal aberrations that are a hallmark of gastric cancer,” the study authors wrote.

Dr. Richard Peek of Vanderbilt University Medical Center, whose research focuses on the role of H. pylori in gastric cancer, commented, “These findings suggest that therapies directed at reducing inflammation, without concomitant elimination of H. pylori, may not be effective in preventing DNA damage that develops in response to this pathogen.”

source: NCI

Study Suggests How the BRCA1 Protein May Help Suppress Tumors

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Mutations in the BRCA1 gene are known to increase a woman’s lifetime risk of developing breast and ovarian cancers, but researchers are still investigating how the protein encoded by this gene helps suppress the formation of tumors. A study by Dr. Inder Verma and his colleagues at the Salk Institute for Biological Studies in the September 8 Nature offers some clues.

Using mice and human breast cancer cells, the researchers identified a series of abnormalities in cells lacking the BRCA1 protein. Taken together, the findings suggest that BRCA1 helps to preserve the integrity of a cell’s genome by “silencing” stretches of repetitive DNA that might harm the cell if “awakened,” or transcribed.

When BRCA1 is missing, the researchers found, certain chromosome regions are no longer maintained in a condensed state. Normally, these regions (known as constitutive heterochromatin) are bound tightly; as a result, certain stretches of repetitive DNA are silent. In the absence of BRCA1, however, cells may produce relatively large amounts of RNA from the repetitive regions.

This activity, in turn, may make the genome less stable and set the stage for cancer. “When cells make a lot of this noncoding RNA, it can lead to DNA damage,” said co-author Dr. Quan Zhu. “This kind of damage is thought to cause cancer.”

The maintenance of distinct chromosomal regions in a condensed state may underlie the tumor-suppressive effect of the protein, wrote Dr. Ashok Venkitaraman of the Hutchison/Medical Research Council Research Centre, Cambridge, UK, in an accompanying editorial. The finding, he added, “might herald a breakthrough” for the field.

Over the past decade and a half, many studies have proposed potential functions for the normal BRCA1 protein, such as repairing damaged DNA or helping with transcription. Dr. Verma and his colleagues believe their findings could provide a framework for understanding the role this protein plays in a number of cellular functions.

By and large, the researchers note, their observations in mice and in human cells are consistent with previous studies of BRCA1. “We observed all of the cellular problems that people have reported over the years related to the loss of BRCA1,” said co-author Dr. Gerald Pao.

The activation of repetitive DNA observed in this study was seen in mouse and human tumors. “Whether, and how, this event promotes cancer development in carriers of germline BRCA1 mutations is not yet evident,” Dr. Venkitaraman wrote. Nonetheless, the study “reveals an intriguing new pathway for tumor suppression,” he added.

source: NCI

Fluorescent Probe Helps Surgeons Find Ovarian Cancer Cells

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In a proof-of-concept study, a fluorescent probe designed to bind to epithelial ovarian cancer cells was used safely to visualize small deposits of cancer in the abdominal cavity during surgery, thus helping the surgeon remove the cells. The target of the probe, called folate receptor-alpha, is found in 90 to 95 percent of ovarian cancers but not in normal tissue. The study, the first in of its kind in humans, was led by Dr. Gooitzen M. van Dam of the University of Groningen in the Netherlands and published online September 18 in Nature Medicine.

Ovarian cancer often spreads widely throughout the abdominal cavity, and small deposits of cancer can be difficult to see with the naked eye or detect during surgery. To improve the visualization of tumor cells and allow surgeons to remove more tumor tissue, the researchers tested the imaging agent, which consists of folate linked to a compound (fluorescein isothiocyanate) that glows green under fluorescent light.

The researchers injected 10 women with the probe before surgery. During surgery, the surgeon performed a standard inspection of the abdominal cavity for tumor tissue; the researchers then captured and examined fluorescent images with a three-camera system that did not interfere with the surgical procedure. After the surgeon removed all suspected tumor tissue identified by eye and by the fluorescent probe, the researchers captured a second set of fluorescent images to look for remaining tumor cells. The surgeon then took biopsy specimens of remaining fluorescent tissue to make sure the probe did not give false-positive results (that is, did not mark normal tissue as tumor tissue).

Nine of the patients had tumors that expressed folate receptor-alpha, and the researchers detected fluorescence in tumor tissue in all of these patients during surgery. No fluorescence was seen in adjacent normal tissue. “Real-time image-guided excision of fluorescent tumor deposits [less than 1 mm in diameter] was feasible, and all fluorescent tissue was confirmed to be malignant,” wrote the authors. One woman’s tumor did not express folate receptor-alpha, and the camera system could not detect the tumor cells in her abdomen.

“The use of targeted fluorescent agents could provide a paradigm shift in surgical imaging,” stated the authors, potentially improving the outcomes for patients after surgery by allowing for more thorough removal of tumor tissue. Large studies are needed to confirm these results and determine whether use of the probe can improve diagnosis and surgical treatment, Dr. van Dam and his colleagues concluded.

source: NCI

HPV Vaccine Study in Costa Rica Yields Insights on Cancer Prevention

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Diagram of an HPV virus-like particle and neutralizing antibodies
The HPV vaccine contains virus-like particles (blue) that are noninfectious and stimulate the immune system to produce antibodies (red) that can prevent HPV infections.

A flurry of new research findings on a vaccine that prevents persistent infections by cancer-causing types of the human papillomavirus (HPV) has confirmed the vaccine’s efficacy and opened new avenues for research. The results, published in three separate reports, suggest that the vaccine could be simpler to administer and more affordable than researchers had previously thought—and that the vaccine may also have unexpected benefits.

All three studies originate from an ongoing clinical trial of Cervarix in Costa Rica. The new findings could help inform efforts to develop vaccination programs to prevent cervical cancer in countries around the world, the researchers said.

“The results from our trial and from other trials are extremely promising for this vaccine,” said Dr. Allan Hildesheim of NCI’s Division of Cancer Epidemiology and Genetics (DCEG), a leader of the trial. “And they suggest that the impact of the vaccine may go beyond cervical disease.”

HPV infections can lead to cancers of the anus, vagina, vulva, penis, and some oropharyngeal cancers, in addition to cervical cancer. Cervarix is one of two HPV vaccines currently approved by the Food and Drug Administration to prevent these infections; the other is Gardasil.

One of the studies found that fewer than the prescribed three doses of Cervarix may offer the same protection as the full course. If confirmed, this could make vaccination easier to administer and more affordable, factors that are especially important in developing countries that have high rates of cervical cancer.

A second study from the Costa Rica HPV Vaccine Trial found that the vaccine may protect against anal HPV infections that could eventually lead to anal cancer. (See “Clinical Trial Shows Potential Benefit of HPV Vaccine for Anal Cancer.”)

Vaccine May Protect against Additional HPV Types

The third study confirmed that the vaccine is highly effective in preventing persistent infections with HPV types 16 and 18—the types targeted by Cervarix. The researchers also found evidence of “cross-protection” against other cancer-causing HPV types not targeted by the original formulation—HPV types 31, 33, and 45.

Testing an HPV Vaccine in the “Real World”The safety and effectiveness of Cervarix and the other FDA-approved HPV vaccine, Gardasil, were established in clinical trials sponsored by the vaccine makers. Nonetheless, NCI researchers and their long-time collaborators in Costa Rica decided to conduct an independent study of a vaccine in a real-world setting.

A goal of the community-based trial was to collect data that could help with the implementation of cervical cancer prevention programs, said Dr. Herrero. “Our results could help the people who are planning vaccination programs to use this expensive vaccine in the most effective way possible.”

Launched in 2004, the randomized trial includes 7,466 women between the ages of 18 and 25 from two Costa Rican communities (approximately one-third of the women in the region). Participants initially received Cervarix or a vaccine against hepatitis A. At the end of 4 years, the researchers offered the HPV vaccine to women in the control group.

The researchers will continue to follow the participants. “This community-based trial provides avenues to study not just the theoretical efficacy of the vaccine but the impact of vaccination on a well-defined population,” said Dr. Hildesheim.

“This is a potential additional benefit from vaccination that we had not considered initially,” said Dr. Hildesheim, noting that suggestive evidence for cross-protection has been reported previously.

The third study, published online September 9 in Cancer Discovery, also provided further evidence that the benefit of vaccination is greatest when the vaccine is given to young women before they have initiated sexual activity.

“Exposure to HPV occurs as soon as sexual activity begins, so if you start vaccination after that point, you will miss an opportunity to prevent infections,” said the study’s lead author, Dr. Rolando Herrero, formerly the study director in Costa Rica and now with the International Agency for Research on Cancer.

The findings on age are consistent with previous studies, noted Dr. Kevin Ault of Emory University’s School of Medicine, who studies HPV but was not involved in the study. “As you age, you accumulate exposures to HPV, and, if the vaccine is given after you’ve been exposed to the virus, then it’s not going to be effective.”

Fewer Doses May Offer Protection

The discovery that two doses—and possibly even one—of Cervarix may protect against infection was possible because the study was done in a “real world” community setting. Many women in the trial (approximately 20 percent) received only one or two doses, often because of pregnancy or an unrelated health problem.

The researchers found, however, that all of the women who received the vaccine were protected equally—at least for the first 4 years after vaccination. Those results appeared online in the Journal of the National Cancer Institute on September 9.

“This study is terrific proof of concept,” said Dr. Eduardo Franco of McGill University’s Faculty of Medicine, who also studies HPV and was not involved in the research. “It suggests that countries could adopt the suboptimal dose regimens and still receive the same protection as the full course, assuming that the protection against lesions will also hold.”

At the end of 4 years, the researchers offered the HPV vaccine to women in the control group. The researchers will follow the trial participants to determine how long the protection lasts.

If the current results are confirmed, the costs of vaccination programs could drop. “Our results may have important implications for public health, although many questions remain unanswered,” said the study’s first author, Dr. Aimée Kreimer of DCEG.

For instance, how long one or two doses of the vaccine protect against HPV infection is not known. In addition, the findings may not apply to other vaccines or to other populations, such as people who are malnourished or lack strong immune responses, the study authors cautioned.

More Affordable and Sustainable Cervical Cancer Prevention

Costa Rica HPV Vaccine Trial team
The Costa Rica HPV Vaccine Trial team in Guanacaste, Costa Rica, at the start of the study in 2004.

“The importance of the current study is not so much for Costa Rica, which has cervical cancer screening programs, but for countries that have truly high incidences of cervical cancer and no screening,” Dr. Franco said. More follow-up is needed to show that the suboptimal doses translate into fewer cervical precancerous lesions for vaccinated women, he added.

This study “represents an important step on the road to more affordable and sustainable cervical cancer prevention programs,” wrote Dr. Cosette Marie Wheeler of the University of New Mexico in an accompanying editorial.

Few, if any, developing countries where cervical cancer is common can afford vaccination programs, said Dr. Herrero. But if countries can afford to vaccinate only certain groups, they need to know which ones would benefit most, he noted. As the current study shows, this group would likely be young women who are not yet sexually active.

“When we started more than 25 years ago, we were just discovering that HPV was the cause of cervical cancer,” said Dr. Herrero. “Today we have a tremendous amount of tools and knowledge, which make it possible to intervene in this disease.”

source: NCI

New Research Calls Salt Guidelines Into Question

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Study Suggests Reducing Sodium May Increase Unhealthy Blood Fats; Critics Say Study Is Flawed
salt on counter

Everyone knows that too much salt is bad for you, right? Well, according to new research, not everyone is convinced.

Reducing dietary sodium (salt) helps lower blood pressure a little, but it also may increase levels of some hormones and unhealthy blood fats, a new review of studies shows.

Researchers say that means cutting back on sodium may not have a substantial health benefit.

But critics say the review draws faulty conclusions because it relies on too many small, short-term studies. They say the weight of research evidence shows clear health benefits when people cut back on sodium.

The review is an analysis of data from more than 167 studies of people with normal or high blood pressure who were randomly assigned to eat either high- or low-sodium diets.

It found that eating less than 2,800 milligrams of sodium a day helped lower blood pressure. But the reductions were small — an average of 1% for people who had normal blood pressure to begin with and 3.5% for people with high blood pressure.

But cutting back on salt appeared to have other effects, too.

People on lower-sodium diets had an average 2.5% increase in cholesterol and a 7% increase in bad blood fats called triglycerides compared to people who were eating more than 3,450 milligrams of sodium — an amount that’s close to what the CDC says the average American eats every day.

Higher cholesterol and triglyceride levels are thought to be associated with an increased risk of heart disease, which can lead to heart attacks and strokes.

Researchers say it’s not clear why cutting back on sodium may affect blood fats.

Lower-sodium diets also boosted levels of the hormones renin and aldosterone, which can raise blood pressure. Researchers say that may be one reason that slashing salt from the diet has only modest effects on blood pressure.

“The theory that you can reduce the risk of cardiovascular disease by reducing salt intake and thereby blood pressure is tempting. But our study shows that the effect of reduced salt intake on blood pressure in healthy persons is only 1%,” says study researcher Niels A. Graudal, MD, DrMedSci, in an email to WebMD.

“Furthermore, reduced salt intake leads to an increase in lipids [blood fats], which is bigger than the reducing effect on blood pressure. Therefore it is likely that reduced salt intake does not have a beneficial effect. On the contrary the net effect may be harmful,” says Graudal, who is a senior consultant in the departments of rheumatology and internal medicine at Copenhagen University Hospital in Denmark.

source: American Journal of Hypertension.

Does Maya calendar predict 2012 apocalypse?

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With humanity coming up fast on 2012, publishers are helping readers gear up and count down to this mysterious — some even call it apocalyptic — date that ancient Mayan societies were anticipating thousands of years ago.

Since November, at least three new books on 2012 have arrived in mainstream bookstores. A fourth is due this fall. Each arrives in the wake of the 2006 success of 2012: The Return of Quetzalcoatl, which has been selling thousands of copies a month since its release in May and counts more than 40,000 in print. The books also build on popular interest in the Maya, fueled in part by Mel Gibson’s December 2006 film about Mayan civilization, Apocalpyto.

Authors disagree about what humankind should expect on Dec. 21, 2012, when the Maya’s “Long Count” calendar marks the end of a 5,126-year era.

Journalist Lawrence Joseph forecasts widespread catastrophe in Apocalypse 2012: A Scientific Investigation Into Civilization’s End. Spiritual healer Andrew Smith predicts a restoration of a “true balance between Divine Feminine and Masculine” in The Revolution of 2012: Vol. 1, The Preparation. In 2012, Daniel Pinchbeck anticipates a “change in the nature of consciousness,” assisted by indigenous insights and psychedelic drug use.

The buildup to 2012 echoes excitement and fear expressed on the eve of the new millennium, popularly known as Y2K, though on a smaller scale, says Lynn Garrett, senior religion editor at Publishers Weekly. She says publishers seem to be courting readers who believe humanity is creating its own ecological disasters and desperately needs ancient indigenous wisdom.

“The convergence I see here is the apocalyptic expectations, if you will, along with the fact that the environment is in the front of many people’s minds these days,” Garrett says. “Part of the appeal of these earth religions is that notion that we need to reconnect with the Earth in order to save ourselves.”

But scholars are bristling at attempts to link the ancient Maya with trends in contemporary spirituality. Maya civilization, known for advanced writing, mathematics and astronomy, flourished for centuries in Mesoamerica, especially between A.D. 300 and 900. Its Long Count calendar, which was discontinued under Spanish colonization, tracks more than 5,000 years, then resets at year zero.

“For the ancient Maya, it was a huge celebration to make it to the end of a whole cycle,” says Sandra Noble, executive director of the Foundation for the Advancement of Mesoamerican Studies in Crystal River, Fla. To render Dec. 21, 2012, as a doomsday or moment of cosmic shifting, she says, is “a complete fabrication and a chance for a lot of people to cash in.”

Part of the 2012 mystique stems from the stars. On the winter solstice in 2012, the sun will be aligned with the center of the Milky Way for the first time in about 26,000 years. This means that “whatever energy typically streams to Earth from the center of the Milky Way will indeed be disrupted on 12/21/12 at 11:11 p.m. Universal Time,” Joseph writes.

But scholars doubt the ancient Maya extrapolated great meaning from anticipating the alignment — if they were even aware of what the configuration would be.

Astronomers generally agree that “it would be impossible the Maya themselves would have known that,” says Susan Milbrath, a Maya archaeoastronomer and a curator at the Florida Museum of Natural History. What’s more, she says, “we have no record or knowledge that they would think the world would come to an end at that point.”

University of Florida anthropologist Susan Gillespie says the 2012 phenomenon comes “from media and from other people making use of the Maya past to fulfill agendas that are really their own.”

G. Jeffrey MacDonald, Special to USA TODAY

source: USA today

http://www.usatoday.com/tech/science/2007-03-27-maya-2012_n.htm

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The neurogenesis hypothesis of depression posits  that neurogenesis in the subgranular zone of the dentate gyrus is regulated negatively by stressful experiences and positively by treatment with antidepressant drugs and  that alterations in the rate of neurogenesis play a fundamental role in the pathology and treatment of major depression. This hypothesis is supported by important experimental observations, but is challenged by equally compelling contradictory reports. This review summarizes the phenomenon of adult hippocampal neurogenesis, the initial and continued evidence leading to the development of the neurogenesis hypothesis of depression, and the recent studies that have disputed and/or qualified those findings, to conclude that it can be affected by stress and antidepressants under certain conditions, but that these effects do not appear in all cases of psychological stress, depression, and antidepressant treatment.

source Neuropsychopharmacology

Pulmonary CT Angiography

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http://medical.toshiba.com/products/ct/dynamic-volume/studies/clinical/pulmonary-angiography.php