Compound preventing growth of prostate cancer cells


Researchers from VTT Technical Research Centre of Finland and the University of Turku have demonstrated that an antibiotic called ‘monensin’, currently used in the meat and dairy industry, prevents the growth of prostate cancer cells. Evidence pointing to the effects of monensin emerged in a project investigating the effects of nearly 5,000 drugs and micromolecules on the growth of prostate cancer cells. The project involved most of the drugs on the market today. Researchers found that small amounts of compounds – disulfiram (Antabus), thiram, tricostatin A, and monensin – can prevent the growth of prostate cancer cells without significant effects on the growth of the normal human prostate epithelial cells.

Further studies revealed that monensin caused prostate cancer cell death by reducing the amount of testosterone receptor and by increasing production of reactive oxygen species and inducing DNA damage. In addition, monensin was shown to have combined effects with antiandrogens – the drugs suppressing the effects of androgens – in preventing prostate cancer cell growth.

The original research findings concerning the effects of drugs and micromolecules were published in the Clinical Cancer Research journal in 2009. The effects of monensin on preventing the growth of prostate cancer, was published in the Molecular Cancer Therapeutics journal in December 2010.



High level of tumour protein signals cancer spread

Researchers at the National Institutes of Health and the University of Hong Kong have discovered that high levels of a particular protein in cancer cells are a reliable indicator that a cancer will spread. By measuring the protein's genetic material in tumours that had been surgically removed from patients, along with measuring the genetic material from surrounding tissue, the researchers could predict at least 90% of the time whether a cancer would spread within two years.

The findings appear in the Journal of Clinical Investigation and details the research that examined cells from liver, breast, colon, and head and neck, tumours and found that those known to spread most aggressively had the highest levels of CPE-delta N RNA. This protein is a form of carboxypeptidase E (CPE). Ordinarily, CPE is involved in processing insulin and other hormones.

“Testing for CPE-delta N, if combined with existing diagnostic methods, offers the possibility of more accurately estimating the chances that a cancer will spread,” said Alan E. Guttmacher, M.D., director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, which supported the study. “Conceivably, a patient's CPEdelta N levels could be a key guide in individualising their cancer care to improve outcome.”

Tests indicating high levels of the protein predicted the spread of a cancerous tumour even when conventional staging-diagnostic techniques to gauge the extent and seriousness of a cancer-indicated that spread was unlikely. The finding raises the possibility that testing for CPE-delta N might be used in combination with conventional staging to further refine treatment. For example, if conventional staging indicated that a cancer was unlikely to spread, but a patient's tumour had high CPE-delta N levels, that patient might be referred for more intensive therapies normally reserved for higher stage cancers.

The findings raise the long term possibilities of new tests to gauge the likelihood that a cancer will spread and, ultimately, of a treatment that could prevent cancer from spreading. The researchers tested a potential strategy for preventing the spread of cancer by halting the production of CPE-delta N in two different mouse models. The strategy involved treating metastatic tumours with antisense RNA, which binds to RNA, preventing it from making a protein, therefore preventing the cancer from spreading.



Key protein suppresses prostate cancer growth in lab tests

Cancer researchers have discovered an important protein, produced naturally inside cells, that appears to suppress the growth of prostate cancer cells in the laboratory. The findings, published in the February issue of the journal Cancer Research, offer promising leads for research towards new treatments. Prostate cancer is the most common cancer among men in the UK, with 37,500 men diagnosed with the disease every year. Many prostate cancers are slow growing, but in some cases the cancer is aggressive and spreads to other parts of the body, such as the bone. These cases are much more likely to be fatal.

In the new study, scientists at Imperial College London found that a protein called FUS inhibits the growth of prostate cancer cells in the laboratory, and activates pathways that lead to cell suicide. The researchers found that in patients with high levels of FUS, the cancer was less aggressive and was less likely to spread to the bone. Higher levels of FUS also correlated with longer survival. The results suggest that FUS might be a useful marker that can give doctors an indication of how aggressive a tumour will be.

“At the moment, there’s no way to say whether a prostate tumour will kill you or be fairly harmless,” said Dr Charlotte Bevan, senior author of the study, from the Department of Surgery and Cancer at Imperial College London. “Current hormonal therapies only work for a limited time, and chemotherapy is often ineffective against prostate cancer, so there’s a real need for new treatments.” Greg Brooke, first author of the study, from the Department of Surgery and Cancer at Imperial College London said: “Our study suggests that FUS is a crucial link that connects male hormones with cell division. The next step is to investigate whether FUS could be a useful test of how aggressive prostate cancer is. Then we might look for ways to boost FUS levels in patients to see if that would slow tumour growth or improve response to hormone therapy.” He adds, “If FUS really is a tumour suppressor, it might also be involved in other cancers, such as breast cancer, which has significant similarities with prostate cancer.”



Medication errors on the curriculum

Medical students should have basic knowledge of common medication errors before they begin seeing patients at the hospital, and researchers from the Johns Hopkins Children’s Center report that allowing them to play detective by watching, spotting and analysing medical errors as they occur can go a long way toward helping prevent potentially fatal mistakes in their future practices.

The nine-week observational course, now taught as part of the Johns Hopkins School of Medicine curriculum, was piloted in the 2008-2009 academic year, and an analysis of its impact was published online on Januaray 12, 2011 in the journal BMJ Quality and Safety in Healthcare. Students began the course by watching a video of a child receiving the wrong medication. They were then asked to reconstruct the events leading up to the error, answering questions such as “What happened and why?” and “What can be done to prevent future errors?” The students then applied the same watchspot- analyse approach to their daily rotation in the hospital. Each day’s rotation ended with students discussing any nearmisses or errors they witnessed and ways to prevent them from happening. Students were also encouraged to speak up about errors and report them to attending physicians and senior doctors before they reached the patient, as well as log the errors in the hospital’s electronic system that keeps track of such events. On several occasions, the drills led to the reporting of patient-safety concerns by students and were dealt with promptly.

After the course, 89% students reported a better understanding that in their future practice they will witness colleagues and other hospital staff making errors, compared with 57% before taking it. And after completing the course, 79% of students acknowledged they themselves will likely make mistakes that could harm patients, compared with 64% before the course. Being aware of one’s own fallibility is critical in preventing errors, the investigators say. Also, after the course, more students (94%) reported a better understanding that disruptions in the flow of care – such as transferring a patient from one unit to another – are high-risk periods for medication and other errors, compared with 81% before taking the course. More students (75%) reported feeling comfortable reporting medication errors to authorities after taking the course, than before (50%).

Research by Johns Hopkins and other institutions indicates that most errors stem from the complexity of the medical system, a system that involves a multiplestep process of calculating dosages, prescribing, dispensing and giving drugs, with the most common causes of medication errors attributed to misinterpretation of the patient's weight, mathematical errors of computation, misinterpretation of orders, and giving extra doses or missing doses.



Mortality rates higher for diabetic breast cancer patients

Breast cancer patients are nearly 50% more likely to die of any cause if they also have diabetes, according to a comprehensive review of research conducted by Johns Hopkins physicians. The findings, published in the January issue of the Journal of Clinical Oncology, suggest future research could focus on whether high levels of insulin in patients with type 2 diabetes could play a role in promoting tumour growth.

The researchers who conducted the review also found that diabetics tend to be diagnosed with later-stage breast cancers and to receive altered, potentially less effective treatment regimens. “When patients are faced with a diagnosis of breast cancer, which they see as an imminent threat to their lives, diabetes care often goes on the back burner,” says study leader Kimberly S. Peairs, M.D., an assistant professor of medicine at the Johns Hopkins University School of Medicine. “This research suggests we may need to proactively treat the diabetes as well as the cancer,” she adds.

Peairs and her team conducted a systematic review and meta-analysis of previously published research on breast cancer and diabetes, ultimately looking in depth at eight studies. In six of seven studies of breast cancer patients, preexisting diabetes was associated with significantly higher long-term, all-cause mortality. Peairs says her research suggests that diabetics diagnosed with breast cancer may get less effective treatment because practitioners may be concerned about these patients suffering more side effects from chemotherapy or radiation treatments as a result of the metabolic condition. Patients also may be more likely to be hospitalised, get infections, and/or become anaemic - complicating their care. Peairs says the higher death rate may also be linked to the fact that they come to breast cancer treatment less healthier than their counterparts without diabetes, which is associated with obesity, high cholesterol and high blood pressure.

Women with diabetes may also be at greater risk of chemotherapy-related toxicity, which may explain – and even justify – some of the less aggressive treatment, she says.

Peairs adds that more research should reveal whether increased insulin production in type 2 (adult onset) diabetics contributes to worse outcomes among diabetic breast cancer patients. Small studies suggest that some diabetes drugs may be associated with worse outcomes for cancer patients while other medications may actually improve survival. She noted that the popular drug Metformin, which makes diabetes patients more insulinsensitive thereby lowering the amount of unused insulin in the body, may be associated with better survival outcomes.
http://www.hopkinsmedicine.org/gim/faculty/peairs.html



Online dementia test

A quick online assessment tool developed by Johns Hopkins researchers can help worried seniors find out if they are at risk of developing dementia and determine whether they should seek a comprehensive, face-to-face diagnosis from a physician, according to a new study.

The tool, which is being refined and validated, is not meant to replace a full evaluation from a doctor that includes a physical exam, blood work, imaging studies and more. Instead, this assessment provides a scientific way to help a person educate herself about a disease that doctors now believe is best managed if caught early.

“As the population ages and dementia becomes more prevalent, it’s important to get people diagnosed early,” says Jason Brandt, Ph.D., a professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine and the leader of the study appearing online in the journal Alzheimer’s & Dementia. “Alzheimer’s disease and other types of dementia don’t just creep up on you. They’re incubating for decades in the brain. This tool is potentially very useful in determining who is at risk.”

Among the questions asked on the Dementia Risk Assessment are about whether a person has a history of high blood pressure, depression, diabetes, high cholesterol or head injury, all of which are considered well-documented risk factors for dementia. The assessment also includes a simple memory test that could point to a subtle cognitive decline, Brandt says.

The study analysed responses from 357 people over the age of 50 who took the assessment at www.alzcast.org. Those who scored lowest on the memory test were significantly older, and were more likely to be men, have hypertension and report severe memory problems. And while only 9% of respondents reported they had severe memory problems, more than one-third said they had a first-degree relative with dementia or severe memory loss – a major risk factor for the condition.

The assessment takes just five to 10 minutes to complete online, and the questions have been borrowed from other scientifically valid assessments. “Our goal is really to educate people about what some of the risk factors are and, often, to put people’s minds at ease,” Brandt says. “We somehow expect our memories to be as good at 50 as they were at 30. We can't run as fast as we could 20 years ago. Why should our memory be as good?”
“Screening procedures that have demonstrated validity and predictive value and are noninvasive, brief and do not require any special expertise to administer may have the greatest potential to be accepted and actually used by the greatest number of people,” Brandt says. “This tool, which this study preliminarily validates, is the first step toward developing such a procedure.”



Safety checklist yields 10% drop in hospital deaths

In 2009, U.S. Health and Human Services Secretary Kathleen Sebelius called for a 50% reduction in catheterrelated infections nationwide by 2012. The Keystone ICU Project, developed at Johns Hopkins, includes a muchheralded safety checklist programme that virtually eliminated bloodstream infections in hospital intensive-care units throughout Michigan, and it appears to have also reduced deaths by 10%, a new study suggests. Although prior research showed a major reduction in central-line related bloodstream infections at hospitals using the checklist, the new study is the first to show its use directly lowered mortality.

The checklist for doctors and nurses to follow when placing a central-line catheter highlights five cautionary and basic steps from hand-washing to avoiding placement in the groin area where infection rates are higher. Along with the checklist, the program promotes a ‘culture of safety’ that comprises safety science education, training in ways to identify potential safety problems, development of evidence-based solutions, and measurement of improvements. The programme also empowers all caregivers, no matter how senior or junior, to question each other and stop procedures if safety is compromised.

“We knew that when we applied safety science principles to the delivery of health care, we would dramatically reduce infections in intensive care units, and now we know we are also saving lives,” says Peter J. Pronovost, M.D., Ph.D., a professor of anesthesiology and critical care medicine at the Johns Hopkins University School of Medicine and leader of the study published in BMJ, the British Medical Journal. “Thousands of people are believed to have survived because of this effort to reduce bloodstream infections.”

Experts say an estimated 80,000 patients a year with central lines get infected, some 31,000 die – nearly as many as die from breast cancer annually – and the cost of treating them may be as high as $3 billion nationally.

For the new study, Pronovost and his team, using Medicare claims data, studied hospital mortality of patients admitted to ICUs in Michigan before, during and after what is known as the Keystone ICU Project. They compared the Michigan information to similar data from 11 surrounding states. While data from both Michigan and the other states showed a reduction in hospital deaths of elderly patients admitted to ICUs over the fiveyear period from October 2001 to December 2006, the patients in Michigan were significantly more likely to survive a hospital stay during and after the Keystone project.

A branch of the American Hospital Association and the Michigan Hospital Association are now committed to rolling out the Johns Hopkins model state-by-state across the country. Forty states have launched the programme, and preliminary data from some of the early adopters is very encouraging, Pronovost says.



Study looks deep into the brain

Changes within deep regions of the brain can now be visualised at the cellular level, based on research on mice, which was funded by the National Institutes of Health. Published in Nature Medicine, the study used a groundbreaking technique to explore cellular-level changes over a period of weeks within deep brain regions, providing a level of detail not possible with previously available methods. The study was supported by the National Institute on Drug Abuse (NIDA), the National Cancer Institute, and the National Institute of Neurological Disorders and Stroke.

Researchers at Stanford University used time-lapse fluorescence microendoscopy, a technique that uses miniature probes to directly visualise specific cells over a period of time, to explore structural changes that occur in neurons as a result of tumour formation and increased stimulation in the mouse brain. This could lead to greater information on how the brain adapts to changing situations, including repeated drug exposure.

“Continued drug use leads to changes in neuronal circuits that are evident well after a person stops taking an addictive substance,” said Dr. Nora D. Volkow, director of NIDA. “This study demonstrates an innovative technique that allows for a glimpse of these cellular changes within the brain regions implicated in drug reward, providing an important tool in our understanding and treatment of addiction.”

Investigators focused on two brain regions within the study, the hippocampus and striatum. The striatum, a brain region important for motor function and habit formation, is also a major target for abused drugs. Some researchers believe that a shift in activity within the striatum is at least partly responsible for the progression from voluntary drug-taking to addiction. This new technique could allow a better understanding of how these processes occur at the cellular level, leading to insights into mechanisms underlying addictive behaviors.

“The results should now allow neuroscientists to track longitudinally in the living brain the effects of drugs of abuse at the levels of neural circuitry, the individual neuron, and neuronal dendrites,” said Dr. Mark Schnitzer, corresponding author for the article. “For example, our imaging methods work well in the dorsal striatum, which we have followed with microscopic resolution over weeks in the live brain. This should permit researchers interested in the reward system to address a range of issues that were previously out of reach.”

The study can be found online at http://dx.doi.org/10.1038/nm.2292




UV induced melanoma

Scientists have made an unanticipated discovery in mice that interferon-gamma, a type of protein primarily used by the immune system for intercellular communication, acts as a promoter for the deadly form of skin cancer known as melanoma. This finding resulted from a series of experiments designed to understand how solar ultraviolet (UV) radiation causes melanoma. The results of this study suggest that interferon-gamma, which has been thought to contribute to an innate defense system against cancer, under some circumstances may promote melanoma and incite the development of tumours. The work, led by researchers from the National Cancer Institute (NCI), part of the National Institutes of Health, appeared online in Nature, Jan. 19, 2011.

Cutaneous melanoma is a highly aggressive and frequently drug-resistant cancer with rising incidence rates. The major environmental risk factor for melanoma is UV radiation exposure, usually from the sun, with the highest risk associated with intermittent burning doses, especially during childhood. Over the past 10 years, the researchers used genetically engineered mice first to prove, and then to try to understand, the connection between exposure to UV radiation and the initiation of melanoma. The current work was the latest attempt to define the molecular mechanisms of this cause and effect relationship. The results of this study offer the possibility that the inhibition of interferon- gamma immediately after sunburn might block the carcinogenic activation of the skin’s pigment-producing cells, known as melanocytes, making it a potentially effective preventive strategy against UV radiation-induced melanoma, according to the scientists.

“We anticipate that this discovery may change how interferons are used in the clinic as anticancer agents,” said Merlino. “Our findings raise the possibility that targeting the interferon-gamma pathway may represent a novel, less toxic therapeutic alternative for effective treatment of malignant melanoma patients, who currently have poor cure rates.”

                                  
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