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Usage of Testicular Cancer Markers Too Limited, Say Researchers

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A standard part of testicular cancer care isn’t used in more than half of all patients who have the condition, researchers have found.

Doctors generally rely on a series of three serum-based tumor markers for testicular cancer, since these are helpful with diagnosis, prognostication and surveillance for disease recurrence following treatment.

Reviewing 4,700 testicular cancer cases however, the researchers found that a combination of two of these tumor markers were used less than half of the time, while all three tumor markers were measured in just 16 percent of the cases.

The study authors also discovered that only 45% of cases used the tumor markers AFP (alpha fetoprotein) and HCG (human chiorionic gonadotrophin), with a third tumor marker, LDH or lactate dehydrogenates, used in combination with the other two, just 16% of the time. These results are reported in Urologic Oncology, Seminars and Original Investigations.

"Tumor markers play a central role in showing physicians how a patient is responding to treatment and whether the disease has recurred," says lead author Scott M. Gilbert, M.D., clinical lecturer in the University of Michigan Department of Urology. "We were extremely surprised by the low rates of usage."

Dr. Gilbert conduct regular checks on all three markers in their patients, because if the markers stay elevated after therapy, it shows the cancer remains; or if the markers begin to rise during the observation period following successful treatment, this too shows the cancer has returned.

One explanation for the low rates of marker usage could be poor documentation in medical records, since incidents of tumor marker use were not always recorded, says senior author Brent K. Hollenbeck, M.D., M.S., assistant professor in the U-M Department of Urology. "Even if it isn’t a problem related to the care of the patients, it is a quality problem at the medical centers that are not recording the data properly. Either way, major improvements need to occur," he says.

But other data in the study suggest that the reporting of tumor marker use may not be the problem. Using the data from the Surveillance, Epidemiology, and End Results (SEER) program, the researchers found substantially more documentation of PSA use in prostate cancer patients compared to the testicular cancer tumor markers. That information supports the notion that recording may not be the problem, but that the use of testicular cancer markers is in fact very low.

Source: University of Michigan

Are Optimists Healthier than Pessimists?

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According to a series of studies, optimists enjoy better health than pessimists. The May issue of Harvard Men’s Health Watch explores possible reasons for this connection.

Many studies have reported that optimism influences health. Among the findings:

  • Optimistic coronary bypass patients were only half as likely as pessimists to require re-hospitalization.
  • Highly pessimistic men were three times more likely to develop hypertension.
  • People with positive emotions had lower blood pressures.
  • In one study, the most pessimistic men were more than twice as likely to develop heart disease compared with the most optimistic.

These results argue persuasively that optimism is good for health. But people who are healthy are likely to have a brighter outlook than people who are ill, so perhaps optimism is actually the result of good health instead of the other way around.

To counter this argument, scientists have adjusted their analyses to account for pre-existing medical conditions. The studies that made these adjustments found that existing illnesses did not tarnish the benefits of optimism.

One explanation is behavioral. It is possible that optimists enjoy better health and longer lives because they lead healthier lifestyles, build stronger social support networks, and get better medical care. In addition, optimism itself may have biological benefits, such as lower levels of stress hormones and less inflammation.

Finally, heredity may explain some of the link. It is possible that genes predispose some people to optimism, and that the same genes affect health and longevity.

Source: Harvard Health Publications

Researchers Find that a Small Molecule Can Block Cancer Cell Division

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By activating a cancer suppressor gene, a small molecule called nutlin-3a can block cancer cell division, according to researchers at the National Cancer Institute (NCI), part of the National Institutes of Health.

This activation of the p53 gene leads to cellular senescence, a process by which cells lose their ability to grow and divide. An opportunity for new genetic mutations occurs each time a cell divides, so limiting the number of cell divisions in a cancer cell inhibits tumor progression.

Activation of p53 can suppress tumor growth through more than one mechanism. It can interfere with the cell cycle, prompting a cell with unrepaired DNA damage to commit suicide through a complex signaling pathway called apoptosis. Alternatively, p53 may trigger cellular senescence in response to DNA damage or cellular stress.

The expression of p53 is regulated by Mdm2, a protein that is overexpressed in several human cancers. ,are small-molecule inhibitors that prevent the p53 protein from forming a complex with Mdm2, resulting in activation of p53. Previous studies have shown that nutlin can induce apoptosis in human cancer cells.

"Although p53 is mutated or deleted in about half of all cancers, it is still potentially functional in the other 50 percent," said Curtis C. Harris, M.D., chief of the Laboratory of Human Carcinogenesis at NCI’s Center for Cancer Research and an author of the study. "A better understanding of molecules, such as nutlin-3a, that can activate p53 may lead to the development of new treatment options for certain cancers."

To examine the effects of nutlin-3a on cellular senescence, the Harris team exposed human skin cells and cancer cells to two different forms of nutlin-3: forms a and b. (Nutlin-3a has a 150-fold greater affinity for Mdm2 than nutlin-3b.) After a seven-day exposure period, the scientists found that almost 100 percent of the cells treated with nutlin-3a had stopped proliferating. These cells did not regain the ability to proliferate even after being removed from nutlin-3a, indicating that they had undergone permanent senescence. By contrast, nutlin-3b had little effect on the cells.

Next, the researchers investigated whether the senescence induced by nutlin-3a is dependent on the presence of p53 protein. After exposure to nutlin-3a for seven or 14 days, more than 80 percent of the human cells containing a functional p53 gene exhibited signs of senescence. The researchers also found that nutlin-3 treatment increased the expression of p53. However, the researchers did not observe any changes in p53-deficient cells.

Previous research by this team showed that the genes affected by p53 activation differed depending on the type of activator. To gain a better understanding of nutlin-3a-induced senescence, the researchers used microarray analysis to determine the effect of p53 activation on gene expression after cancer cells were treated with nutlin-3a. Microarray analysis is a technique that allows researchers to examine the expression of thousand of genes simultaneously. Almost 3,000 genes were differentially expressed when cells with normal p53, cells with mutant p53, and p53-deficient cells were compared. Among the genes with increased expression after nutlin-3a-activation of p53 were several genes that play a role in cellular senescence and cell death.

The researchers also found that the inhibitor of growth 2 gene (ING2) was among those with decreased expression in response to nutlin-3a treatment. ING2 regulates gene activation or expression, and it may play a role in tumor development, cell proliferation, and senescence. The researchers found that p53 seemed to suppress ING2 expression by binding directly to two sites on the ING2 promoter.

"This study further characterizes the actions of nutlin-3a on genes that can play a role in the development of cancer," said Harris. "Our study reinforces the idea that using Mdm2 inhibitors, such as nutlin-3a, to promote the growth suppressive and cell-killing activity of p53 is a potentially valuable strategy to pursue in cancer treatment."

Source: Cancer Research, May 1, 2008 and National Institutes of Health (NIH)

FDA Approves Amitiza to Treat Irritable Bowel Syndrome (IBS-C)

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The U.S. Food and Drug Administration has approved Amitiza (lubiprostone) for the treatment of Irritable Bowel Syndrome with Constipation (IBS-C) in adult women aged 18 and over. There is currently no prescription drug therapy for IBS-C. With this approval, Amitiza becomes the only FDA-approved medical treatment for IBS-C available in the United States.

Irritable bowel syndrome is a disorder characterized by cramping, abdominal pain, bloating, constipation, and diarrhea. IBS causes a great deal of discomfort and distress to its sufferers. It affects at least twice as many women as men.

"For some people IBS can be quite disabling, making it difficult for them to fully participate in everyday activities," said Julie Beitz, M.D., director of the Office of Drug Evaluation III, Center for Drug Evaluation and Research, FDA. "This drug represents an important step in helping to provide medical relief from their symptoms."

The safety and efficacy of Amitiza was established in two major studies involving 1,154 patients diagnosed with IBS-C. The majority of the patients studied were women (approximately 8 percent were men). Patients enrolled in the studies were experiencing at least mild abdominal discomfort or pain that was associated with at least two of the following additional symptoms: 1) fewer than 3 spontaneous bowel movements per week (that did not result from laxative use); 2) hard stools; or 3) moderate or severe straining with bowel movements. In the studies some patients received Amitiza and others were given a placebo. More patients treated with Amitiza reported that their IBS symptoms were moderately or significantly relieved over a 12 week treatment period than patients who received placebo. The safety of long term treatment was assessed in a study in which all patients were treated with Amitiza for a duration that ranged 9 to 13 months.

The efficacy of Amitiza in men was not conclusively demonstrated for IBS-C.
Amitiza, like most prescription medications, is accompanied by some side effects. Common side effects of Amitiza include nausea, diarrhea, and abdominal pain. Other rare side effects include urinary tract infections, dry mouth, syncope (fainting), peripheral edema (swelling of the extremities), dyspnea (difficulty breathing), and heart palpitations.

Amitiza should be taken twice-a-day in 8 microgram doses with food and water. Patients and their health care professionals should periodically assess the need for continued therapy.

Amitiza is not approved for use in children and men. It is not to be administered to patients suffering from severe diarrhea or patients with known or suspected bowel obstructions. Its safety and efficacy has not been established in patients with renal or hepatic impairment, pregnant, or nursing mothers.

Amitiza is also approved for the treatment of chronic idiopathic constipation (CIC), but the dose for that indication is higher, 24 micrograms twice a day.

Amitiza is manufactured by Sucampo Pharmaceuticals, Bethesda, MD, and will be jointly marketed by Sucampo and Takeda Pharmaceuticals America, Inc., Deerfield, IL. As with all FDA-approved products, the agency will monitor Amitiza throughout its life cycle. Consumers and health care professionals are encouraged to report adverse events to the FDA.

Source: FDA, April 29, 2008

Higher Fracture Risk for Diabetes Drugs Such as Pioglitazone and Rosiglitazone, Says Study

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Insulin-sensitizing thiazolidinediones, such as pioglitazone and rosiglitazone, appear to be associated with an increased risk of fractures, according to a recent report. These two drugs account for about 21% of oral diabetes medications prescribed in the United States, and 5% of those prescribed in Europe.

The class of drugs is a relatively new and effective class of oral antidiabetic agents that have gained wide use in clinical conditions characterized by insulin resistance, the study authors note. Other recent studies have suggested that these therapies may have unfavorable effects on bone, resulting in slower bone formation and faster bone loss.

According to the study, individuals who were currently taking rosiglitazone and pioglitazone had approximately 2x or 3x the likelihood of hip and other non-spine fractures than those who did not take these drugs. The odds for fracture were increased among patients who took the drugs for approximately 12 to 18 months and the risk was highest for those with two or more years of therapy.

Source: Archives of Internal Medicine, April 28, 2008

Exercise Habits Strongly Influenced by Neighborhood

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The quality of a neighborhood can encourage—or discourage—people to stay physically active and exercise regularly, says a Chicago study led by Christopher Browning, associate professor of sociology at Ohio State University. Such factors as levels of poverty, lower education, and more families headed up by women can actively discourage exercise habits. The study found that individual income was less important in determining exercise levels as the type of neighborhood involved.

"We can’t encourage people to exercise more without looking at the neighborhood environment in which they live," said says Christopher Browning, co-author of the study and associate professor of sociology at Ohio State University.. "Some people may have the personal resources and desire to exercise, but don’t live in a neighborhood in which they feel comfortable to go outside for activities."

The study found that neighborhood context was more important for women than for men in determining how much they exercised. Additional factors brought out by the study were that levels of trust among neighbors, perceived violence in the community, and beliefs that neighbors help each other, all contributed to how much people exercised in a specific community.

Ming Wen, assistant professor of sociology at the University of Utah, and Kathleen Cagney, associate professor of health studies at the University of Chicago, collaborated with Browning on the study, the results of which appeared in a recent issue of Urban Studies.

The study examined levels of exercise among 8,782 residents of 373 neighborhoods in Chicago, and combined statistics from three data sources from the 1990s: the Metropolitan Chicago Information Center Metro Survey, the 1990 U.S. Census, and the Project on Human Development in Chicago Neighborhoods Survey. Social and economic factors, and the level of poverty were found to be the most important factors affecting levels of physical activity, although neighborhood characteristics were judged to be more important in determining a person’s exercise level than income.

"The result is surprising enough that it needs to be confirmed by other studies," said Browning. "But if the finding is substantiated, it would show just how important neighborhoods are, and would have important implications for any new initiatives aimed at enhancing health and well-being." Women’s exercise habits were affected more by the neighborhood than men, which could also explain why African-American women have much higher obesity rates than other groups, said Browning.

Contrary to other research, this study found that once neighborhood factors were taken into account, African Americans in general exercised as much as white residents did. Browning said this finding suggests African Americans will exercise more if they live in neighborhoods where they feel comfortable doing so.

Source: Ohio State University

Epileptic Seizures May Lead to Reduced Medication Entry to the Brain, Say Researchers

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Researchers have found that one of the body’s own neurotransmitters released during epileptic seizures, glutamate, could lead to reduced medication entry into the brain. This may explain why approximately 30% of patients with epilepsy do not respond to anti-epileptic medications.

The study was conducted by researchers at the National Institute of Environmental Health Sciences (NIEHS) using a rodent model of epilepsy.

"Our work identifies the mechanism by which seizures increase production of a drug transport protein in the blood brain barrier, known as P-glycoprotein, and suggests new therapeutic targets that could reduce resistance," said David Miller, Ph.D., a principal investigator in the NIEHS Laboratory of Pharmacology and co-author on the paper.

The blood-brain barrier (BBB), which resides in brain capillaries, is a limiting factor in treatment of many central nervous system disorders. It is altered in epilepsy so that it no longer permits free passage of administered antiepileptic drugs into the brain. Miller explained that P-glycoprotein forms a functional barrier in the BBB that protects the brain by limiting access of foreign chemicals.

"The problem is that the protein does not distinguish well between neurotoxicants and therapeutic drugs, so it can often be an obstacle to the treatment of a number of diseases, including brain cancer," Miller said. Increased levels of P-glycoprotein in the BBB has been suggested as one probable cause of drug resistance in epilepsy.

Using isolated brain capillaries from mice and rats and an animal model of epilepsy, the researchers found that glutamate, a neurotransmitter released when neurons fire during seizures, turns on a signaling pathway that activates cyclooxygenase-2 (COX-2), causing increased synthesis of P-glycoprotein in these experiments. Increased transporter expression was abolished in COX-2 knockout mice or by COX-2 inhibitors. It has yet to be shown in animals or patients that targeting COX-2 will reduce seizure frequency or increase the effectiveness of anti-epileptic drugs.

"These findings provide insight into one mechanism that underlies drug resistance in epilepsy and possibly other central nervous system disorders," said Bjoern Bauer, Ph.D., lead author on the publication. "Targeting blood-brain barrier signals that increase P-glycoprotein expression rather than the transporter itself suggests a promising way to improve the effectiveness of drugs that are used to treat epilepsy, though more research is needed before new therapies can be developed."

The study appears in the May, 2008 issue of Molecular Pharmacology.

Malaria Protection Provided By Inherited Blood Disorder

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An inherited childrens’ blood disorder called alpha thalassemia can protect children against malaria, according to a new study.

"We made the surprising finding that packaging your hemoglobin in smaller amounts in more cells is an advantage against malaria," says Karen Day, Ph.D., Professor and Chairman of the Department of Medical Parasitology at NYU School of Medicine, who led the research with colleagues at the University of Oxford. Hemoglobin is the oxygen-carrying protein in red blood cells.The study, published in the March issue of the journal PLoS Medicine, proposes an answer to a biological puzzle that first emerged more than 50 years ago.

The study was conducted in Papua, New Guinea, where malaria is endemic, with 800 children participating. 68% of children there have alpha thalassemia. Dr. Day and her then-Ph D. student Freya J.I. Fowkes, and colleagues from the University of Oxford, Papua New Guinea Institute of Medical Research, and Swansea University showed that a severe attack of malaria caused the loss of one third to one half of the total number of red blood cells. However, children with mild thalassemia started with 10% –20% more red blood cells than unaffected children, and could therefore withstand this huge loss.

"It is really remarkable and so simple. Children with alpha thalassemia have adapted to the loss of red blood cells associated with malarial disease by making more of these cells with less hemoglobin," says Dr. Day. "So, these children do better because they end up with more hemoglobin overall when they have a malaria attack compared to normal children," says Dr. Day.
Malaria afflicts hundreds of millions of people, causing up to 2 million deaths every year in Africa and Asia. Many of its victims are young children. In regions of the world where malaria is endemic, mutations have arisen in human populations that allow people to survive. Sickle cell trait, for example, protects against malaria.

Nearly sixty years ago the renowned evolutionary biologist J.B.S.Haldane postulated that the thalassemias were common in human populations because they protected against malaria. Alpha thalassemia is common in Asia, the Mediterranean and Melanesia where malaria is or was prevalent. In the mid 1990s researchers working on the north coast of Papua New Guinea proved that children with mild alpha thalassemia, who inherit mutations in the "alpha" part of hemoglobin genes from each parent, were protected against malaria. These children were 60 percent less likely to get severe malarial anemia than normal children, however the mechanism of such protection was unclear.

Dr. Day and colleagues based their new study on this same population of children. "We are proposing an unexpected mechanism of protection against severe malarial anemia" says Dr. Day. "We show that alpha thalassemia is giving the child a hematological advantage by making more red blood cells.

Source: New York University Medical Center

Research Shows Promise for Cystic Fibrosis and HIV Therapies

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Innovative therapies against cystic fibrosis have shown promise for increasing the effectiveness of antibiotics in the treatment of chronic and acute bacterial respiratory infections in cystic fibrosis patients, and may also provide a model for potential HIV therapies in the future.

A number of compounds that block a key protein (exoenzymeS or ExoS) have been identified by Professor Igor Stagljar of the University of Toronto, with one—exosin—inhibiting infections in mammalian cells.

Past studies have shown it is possible to prevent or delay the onset of certain chronic or deadly infections in cystic fibrosis patients with early antibiotic treatment. But the current availability of antibiotics against Pseudomonas aeruginosa, a pathogen that can cause urinary tract infections, respiratory system infections, dermatitis, soft tissue infections, bacteremia, bone and joint infections, gastrointestinal infections and a variety of systemic infections, is limited and the pathogen shows signs of drug resistance.

In an article published in the journal PLoS Genetics, a team of investigators identified several drugs that block a Pseudomonas aeruginosa toxin called ExoS.

"These studies created a road map to the rational design of more potent, highly selective inhibitors against other similar toxins using a totally novel yeast-based approach," says lead author Stagljar. "This innovative approach is an important advance, not only for the value it may have in cystic fibrosis treatment, but also because this technique could be used to design novel therapies for any bacterial pathogen as well as the HIV virus."

Staglar’s next step is to test the action of their inhibitors in an animal model of cystic fibrosis, which if successful may provide a way for the treatment ofthis debilitating disease.
In the next phase of their research, Stagljar and his colleagues plan to test the action of their inhibitors in an animal model of cystic fibrosis. If successful, the therapeutics may provide an avenue for the treatment of this debilitating disease.

Source: University of Toronto

TV in Teens’ Bedrooms Promotes Poor Diet and Exercise Routines

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University of Minnesota School of Public Health researchers have found that a television in the bedroom promotes poor dietary, study and exercise habits among teenagers. 62% of a sample of 781 teenagers aged 15 to 18 in the Minneapolis area had a television in their bedroom, and spent 4 to 5 hours per week watching television. Bedroom TV owners ranked as heavy watchers, at least 5 hours a day—twice the amount of teenagers without one.

Boys among the television owners achieved a lower grade point average, had less fruit and ate fewer meals with the family than boys without one. Girls owning television sets spent only 1.8 hours per week exercising (versus 2.5 hours for girls without one), consumer less vegetables, ate fewer family meals and drank more sweetened soft drinks.

Daheia Barr-Anderson, one of the research team, was quoted as saying that these results showed that there were clear advantages to banning a TV from a teenager’s bedroom. This view was supported by the American Academy of Pediatrics, which encouraged the removal of TV sets by parents from their childrens’ bedrooms. The findings of the study were published in the Academy’s journal, Pediatrics.

Statistically, the study showed that 68% of boys, compared with 58% of girls, would probably have a bedroom TV, while children from the highest income families were less likely to have one. 82% of black teenagers had a television in their bedroom, while only 66% of Hispanic teens and 60% of whites had one. 39% of Asian American teens reported ownership.

In this study, body mass index was not found to influence teenage obesity, although Barr-Andersen quoted previous studies that showed that ownership of a bedroom TV was a strong predictor of obesity. Both boys and girls with bedroom TV’s admitted to devoting less time to reading and homework, although the differences were not statistically significant, said the researchers.