SPOTLIGHT

Discovery may lead to lower doses of chemotherapy

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Scientists at Brigham Young University discovered the two proteins that pair up and switch on this process — known as autophagy.

“This gives us a therapeutic avenue to target autophagy in tumors,” said Josh Andersen, a BYU chemistry professor. “The idea would be to make tumors more chemo-sensitive. You could target these proteins and the mechanism of this switch to block autophagy, which would allow for lower doses of chemotherapy while hopefully improving patient outcomes.”

Lower doses would mean milder side effects. The prospect spurred an international hunt for this switch. For good reason, several other labs started with a protein called ATG9 as their prime suspect and then looked for its accomplice among thousands of other proteins.

But the BYU team, comprised mainly of undergraduate students, stumbled into the race unexpectedly, coming at it from a different direction. They wanted to know why cancer cells made a surplus of protein called 14-3-3 zeta.

Using breast cancer tissue in the lab, they forced tumor cells to undergo autophagy by depriving them of oxygen and glucose. A comparison with a control group let them see that the two proteins hook up only when under attack. That’s because stress makes Atg9 undergo a modification that enables 14-3-3 zeta to bind with it and switch the cancer cells to survival mode.

“This unique approach we used, partially by luck, gave us an advantage,” Andersen said. “I don’t think we would have discovered this through more conventional approaches.”

The study results appear in the journal Molecular and Cellular Biology.

Andersen notes that several medicines already exist that could block autophagy and make chemotherapy more effective. One of them is called chloroquine, an anti-malarial drug invented in 1934. In the event that this and other existing inhibitors don’t cross-over safely or effectively, the study offers a blueprint for development of a drug specific to the task.

source : http://www.sciencedaily.com/releases/2014/10/141009091949.htm

Drinking decaf or regular coffee maybe good for the liver

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Coffee consumption is highly prevalent with more than half of all Americans over 18 drinking on average three cups each day according to a 2010 report from the National Coffee Association. Moreover, the International Coffee Association reports that coffee consumption has increased one percent each year since the 1980s, increasing to two percent in recent years. Previous studies found that coffee consumption may help lower the risk of developing diabetes, cardiovascular disease, non-alcoholic fatty liver disease, cirrhosis, and liver cancer.

“Prior research found that drinking coffee may have a possible protective effect on the liver. However, the evidence is not clear if that benefit may extend to decaffeinated coffee,” explains lead researcher Dr. Qian Xiao from the National Cancer Institute in Bethesda, Maryland.

For the present study researchers used data from the U.S. National Health and Nutrition Examination Survey (NHANES, 1999-2010). The study population included 27,793 participants, 20 years of age or older, who provided coffee intake in a 24-hour period. The team measured blood levels of several markers of liver function, including aminotransferase (ALT), aminotransferase (AST), alkaline phosphatase (ALP) and gamma glutamyl transaminase (GGT) to determine liver health.

Participants who reported drinking three or more cups of coffee per day had lower levels of ALT, AST, ALP and GGT compared to those not consuming any coffee. Researchers also found low levels of these liver enzymes in participants drinking only decaffeinated coffee.

Dr. Xiao concludes, “Our findings link total and decaffeinated coffee intake to lower liver enzyme levels. These data suggest that ingredients in coffee, other than caffeine, may promote liver health. Further studies are needed to identify these components.”

source : http://www.sciencedaily.com/releases/2014/10/141009112642.htm

Access to minimally invasive colon cancer surgery varies by location

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A new study by researchers at the University of Michigan Comprehensive Cancer Center finds that in some parts of the country, about two-thirds of colon cancer patients will receive laparoscopic colectomy, a minimally invasive procedure to remove part of the colon. In other parts of the country, the rate was zero.

Colectomy is recommended for most patients with non-metastatic colon cancer. Laparoscopic colectomy, in which the surgeon makes multiple small incisions and inserts thin instruments to perform the operation, has been shown to be equally effective for treating colon cancer. But patients undergoing laparoscopic surgery have less pain, shorter hospital stays and faster recovery.

“Although every patient makes his or her own unique decision, most patients offered a laparoscopic colectomy will strongly consider this approach, given the benefits of minimally invasive surgery. Our study shows that these are benefits may not be available to patients who live in certain regions,” says lead author Bradley N. Reames, M.D., M.S., a surgical resident at the University of Michigan.

The researchers looked at Medicare claims data and tied it to hospital referral regions. They assessed 93,786 patients who underwent colectomy for colon cancer at nearly 3,500 hospitals across the country. Overall, about a third of the procedures were laparoscopic. Rates ranged from a low of 0 percent to a high of 67 percent. Results appear in the Journal of Clinical Oncology.

The equipment to perform laparoscopic surgery was available at nearly every hospital, the researchers found, suggesting that it’s not an infrastructure or equipment issue. Not all patients are eligible for laparoscopic surgery; however, it is likely that a surgeon’s comfort with the procedure influences which patients that surgeon will recommend for it.

“We believe the key issue is surgeon training or experience. Many surgeons offering this approach complete additional fellowship training in colorectal surgery or seek out opportunities to learn this approach while in practice. Those who don’t are not likely to offer the approach to their patients, or they do so only to a highly specialized group of ideal, straightforward candidates,” says senior study author Scott E. Regenbogen, M.D., assistant professor of surgery at the University of Michigan.

The researchers suggest that better patient education and surgeon training are both needed to reduce the geographic variation in laparoscopic colectomy.

They urge patients who are referred for colon cancer surgery to research the qualifications and training of surgeons, and understand what types of procedures the surgeon offers. Patients should inquire about a laparoscopic approach and whether they are eligible.

source : http://www.sciencedaily.com/releases/2014/10/141006174140.htm

Socioeconomic factors, fashion trends linked to increase in melanoma

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Their findings are the subject of a report, “More Skin, More Sun, More Tan, More Melanoma,” in the October 6, 2014 issue of the American Journal of Public Health.

The authors surmised that early diagnosis and improved reporting practices do not fully account for the steady rise in cases of melanoma. They set out to explore extenuating factors that may also have contributed to the increase in reported cases in the U.S.

Led by David Polsky, MD, PhD, Alfred W. Kopf, MD Professor of Dermatologic Oncology in the Ronald O. Perelman Department of Dermatology at NYU Langone, they looked into the transformative effect of socioeconomic trends dating from the1900’s. They analyzed clothing styles, social norms, medical paradigms, perceptions of tanned skin, economic trends and travel patterns.

For comparisons between periods, they estimated percentage of exposed areas of the body. For example, early in the 20th century people donned clothing that almost totally concealed the body from head to toe. “Porcelain” skin was favored over the “tanned” skin, which was associated with a lower class of people who worked outdoors.

Changes in medical practice also would pave the way for a shift.

“In the early 20th century, sunshine became widely accepted as treatment for rickets and tuberculosis, and was considered to be good for overall general health,” Dr. Polsky said. In lay circles, this medical prescriptive translated into a growing belief in the benefit of tanning.People also began to enjoy more leisure time and to favor swimwear and sportswear that progressively covered less skin. Voices that raised concern about the dangers of UV exposure were largely ignored.

Another contributing factor, the researchers concluded, has been the reversal in attitude about tanned skin, which became a sign of the leisurely upper class quality of life and good health. Graphs tracking the incidence by year and percentage of estimated skin exposure show that these developments rose in parallel with the rise in melanoma cases in the U.S.

The increased incidence of melanoma over the years has been a particular concern, especially with the average age of diagnosis and death from melanoma trending younger than for most of the other major cancers. “Years-of-life lost to melanoma is nearly as high as breast cancer,” Dr. Polsky said.

The study, however, did cite one positive trend — down under. Australia, widely considered the “skin cancer capital of the world” according to Dr. Polsky, has managed to turn things around, possibly with the help of a public education campaign and a change of view about tanning — thus giving other places still basking in the sun a glimmer of hope.

“Attitudes and behaviors shape exposures. More skin, more sun and more tan lead to more melanoma,” Dr. Polsky concluded.

source : http://www.sciencedaily.com/releases/2014/10/141002123802.htm

New rules for anticancer vaccines

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As cancer cells divide, they accumulate random mistakes (mutations). This process creates new versions of proteins, some of which are recognized as foreign invaders by immune cells called T cells, prompting the cells to attack and eliminate the cancer cells. With our current ability to identify all of the mutations in a patient’s cancer and to understand which protein sequences can be recognized by T cells, scientists can now predict which mutations will result in new T cell targets (called “neoepitopes”). Some of these neoepitopes can then be used as vaccines to elicit a protective T cell response that destroys the cancer.

But here’s the catch. These prediction tools generate hundreds of possible neoepitopes, of which only a handful can actually elicit T cells capable of attacking the tumor. And so far, there has been no reliable common denominator to help pinpoint this useful handful.

Previous attempts to predict cancer neoepitopes have relied on how strongly the mutated protein is recognized by the immune system. But scientists at the University of Connecticut now show that the strength of this interaction is a poor predictor. A better (albeit still imperfect) measure turns out to be how different the mutation looks to the T cell when compared to its normal counterpart — the more distinct, the better. These results have the potential to completely change current approaches to generating anticancer vaccines.

source : http://www.sciencedaily.com/releases/2014/09/140922110145.htm

Fine line between breast cancer, normal tissues

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The study is published online the week of September 22, 2014 in the Proceedings of the National Academy of Sciences.

The tool, known as DESI mass spectrometry imaging (or Desorption ElectroSpray Ionization mass spectrometry imaging), works by turning molecules into electrically charged versions of themselves, called ions, so that they can be identified by their mass. By analyzing the mass of the ions, the contents of a tissue sample can then be identified. The tool sprays a microscopic stream of charged solvent onto the tissue surface to gather information about its molecular makeup and produces a color-coded image revealing the nature and concentration of tumor cells.

In this particular case, the researchers used DESI mass spectrometry imaging to look at the distribution and amounts of fatty acid substances, called lipids, within breast tissue and normal tissue from 61 samples obtained from 14 breast cancer patients that underwent mastectomy. A software program was used to characterize the breast cancer tumors and detect boundaries between healthy and cancerous tissue.

The researchers found that several fatty acids, such as oleic acid, were more abundant in breast cancer tissue compared to normal tissue. The results were also confirmed using traditional pathology methods to test for accuracy.

“Our findings demonstrate the feasibility of classifying cancerous and normal breast tissues using DESI mass spectrometry imaging,” said Nathalie Agar, PhD, director of the Surgical Molecular Imaging Laboratory, BWH Departments of Neurosurgery and Radiology, senior study author. “The results may help us to move forward in improving this method so that surgeons can use it to rapidly detect residual cancer tissue during breast cancer surgery, hopefully decreasing the need for multiple operations.”

source : http://www.sciencedaily.com/releases/2014/09/140922152842.htm

New approach aims to silence cancer ‘survival genes’

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The new method works by silencing cancer ‘survival genes’ and could potentially combat cancer through the selective killing of colorectal cancer cells without adverse effects on normal, non-cancer cells.

Funded by York’s Centre for Chronic Diseases and Disorders (C2D2), the project led by Professor Jo Milner from York’s Department of Biology involved preliminary studies to establish the suitability of an ex vivo model for the future development of anti-cancer therapies for colorectal cancer using a technique called RNA interference.

The new approach builds on ground-breaking research by Professor Milner and her team at York more than a decade ago. This early work, funded by Yorkshire Cancer Research (YCR), used the newly-developed technique of RNA interference to successfully kill human cervical cancer cells grown in culture without causing damage to healthy cells.

Professor Milner explained: “When a mammalian cell elects to die it does so with great precision and without harming its neighbours. This process of ‘programmed cell death’ enables the continuous replacement of aging cells and also the sculpting of tissues and neuronal pathways.

“However, when this normal process of programmed cell death fails the continued abnormal growth of affected cells can lead to cancer. Some cancers develop following infection with a virus, such as human papilloma virus which causes human cervical cancer. Here the virus expresses specific viral genes that disrupt normal cellular control mechanisms resulting in abnormal cell proliferation and survival.

“Using RNA interference (RNAi) we first identified the viral gene responsible for the continued survival of cervical cancer cells. Then we established the feasibility of RNAi-based therapeutics for the selective killing of human cervical cancer cells growing in vitro.”

Professor Milner and her team next studied cells from other cancer types, including colorectal cancer and breast cancer. Such cancers develop when the cell’s internal control system fails due to damage to one or more of the regulatory genes.

Professor Milner said “We discovered that other genes, belonging to a group called stress-response genes, acquire a new pro-survival function during the process of cancerous transformation. Importantly, this acquired cancer-specific survival function operates under normal, physiological conditions. Silencing these cancer-specific survival genes by RNA interference causes the cancer cells to die while the survival of non-cancerous cells appears normal. This is in contrast to treating cancer by radiotherapy and/or genotoxic drugs — these agents cause genotoxic stress and damage both cancer and normal cells and tissues in the body, resulting in unwanted adverse side effects for the patient.”

For the work on colorectal cancer therapies to progress towards the clinic, the team has had to meet the challenge of modifying the agent siRNA. siRNA is the synthetic RNA molecule which is designed to silence a chosen gene by inducing RNA interference and selectively suppressing expression of that gene. However, siRNA is very unstable and is rapidly degraded when in contact with human tissues.

As reported in the journal Molecular Therapy, the team has now successfully met this challenge and converted the unstable siRNA molecule into a stable form without losing its ability and very high efficacy for targeted gene silencing. A novel siRNA/DNA has been shown to be resistant to degradation while retaining high efficacy and selectivity for target gene silencing when tested on human cancer cells grown in culture.

The next step will involve testing this novel therapeutic agent for cancer-specific cell killing using human tissue maintained ex vivo, using an experimental model which was validated in the course of the C2D2-funded research.

Professor Paul Kaye, Director of C2D2, said: “Professor Milner’s team has now shown that ex vivo cultures of colorectal tumour material, derived from human patients, maintain cancer-related biochemistry over several days, and of sufficient time known to produce a killing effect with the novel siRNA/DNA in vitro. It is marvelous that C2D2 has been able to support this ground breaking research that has validated an ex vivo model that can be used to progress this novel therapeutic towards the clinic, and without the need for animal research.”

source : http://www.sciencedaily.com/releases/2014/09/140923085939.htm

Fine line between breast cancer, normal tissues — ScienceDaily

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The study is published online the week of September 22, 2014 in the Proceedings of the National Academy of Sciences.

The tool, known as DESI mass spectrometry imaging (or Desorption ElectroSpray Ionization mass spectrometry imaging), works by turning molecules into electrically charged versions of themselves, called ions, so that they can be identified by their mass. By analyzing the mass of the ions, the contents of a tissue sample can then be identified. The tool sprays a microscopic stream of charged solvent onto the tissue surface to gather information about its molecular makeup and produces a color-coded image revealing the nature and concentration of tumor cells.

In this particular case, the researchers used DESI mass spectrometry imaging to look at the distribution and amounts of fatty acid substances, called lipids, within breast tissue and normal tissue from 61 samples obtained from 14 breast cancer patients that underwent mastectomy. A software program was used to characterize the breast cancer tumors and detect boundaries between healthy and cancerous tissue.

The researchers found that several fatty acids, such as oleic acid, were more abundant in breast cancer tissue compared to normal tissue. The results were also confirmed using traditional pathology methods to test for accuracy.

“Our findings demonstrate the feasibility of classifying cancerous and normal breast tissues using DESI mass spectrometry imaging,” said Nathalie Agar, PhD, director of the Surgical Molecular Imaging Laboratory, BWH Departments of Neurosurgery and Radiology, senior study author. “The results may help us to move forward in improving this method so that surgeons can use it to rapidly detect residual cancer tissue during breast cancer surgery, hopefully decreasing the need for multiple operations.”

source : http://www.sciencedaily.com/releases/2014/09/140922152842.htm

Ovarian cancer oncogene found in ‘junk DNA’

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Most of those studies have focused on the portion of the human genome that encodes protein — a fraction that accounts for just 2 percent of human DNA overall. Yet the vast majority of genomic alterations associated with cancer lie outside protein-coding genes, in what traditionally has been derided as “junk DNA.” Researchers today know that “junk DNA” is anything but — much of it is transcribed into RNA, for instance — but finding meaning in those sequences remains a challenge.

Now a team led by Lin Zhang, PhD, research associate professor in the Department of Obstetrics and Gynecology at the Perelman School of Medicine at the University of Pennsylvania, has mined those sequences to identify a non-protein-coding RNA whose expression is linked to ovarian cancer. The study is published online in Cancer Cell.

Supported by the Basser Research Center for BRCA in Penn’s Abramson Cancer Center, Zhang and his team built a DNA copy number profile for nearly 14,000 long non-coding RNA, or lncRNAs, across 12 cancer types, including ovarian and breast cancers — the two major BRCA-related cancers. They found that the number of copies of lncRNA genes on a chromosome consistently change in 12 different cancer types and lncRNA genes are widely expressed in cancer cells.

What these non-protein-coding RNAs do is still relatively unknown. However, given their vast numbers in the human genome, researchers believe that they likely play important roles in normal human development and response to disease.

Using clinical, genetic, and gene expression data as filters to distinguish genes whose copy number alteration causes cancer from those for whom copy number changes are incidental, the team whittled down their list from 14,000 to a more manageable number, each of which they systematically tested using genetic experiments in animals.

Of the 37 lncRNAs the team fully tested, one, which they called focally amplified lncRNA on chromosome 1, or FAL1, had all the makings of an RNA oncogene. FAL1 is one of only a handful of lncRNAs to be linked to cancer to date. This knowledge is being applied for clinical applications. For example, FAL1 expression may be a biomarker of BRCA-related cancer prognosis and the basis of new anti-cancer therapeutics. As proof-of-principle of the potential efficacy, Zhang’s team grew human ovarian tumors in immunocompromised mice, then injected short-interfering RNAs to block the tumors’ growth using RNA interference against FAL1. The tumors in treated animals shrank over the course of the experiment, while tumors in control animals continued to grow.

Personalized Diagnostics

FAL1 is overexpressed in ovarian and breast cancer samples. Blocking the activity of the gene via RNA interference reduces cancer cells’ growth, while overexpressing it in normal cells increases their growth. When the team assessed FAL1 expression in human ovarian cancer samples, they found that high FAL1 expression tended to correlate with poor clinical prognosis.

“This is the first genome-wide study to use bioinformatics and clinical information to systematically identify one lncRNA, which we found to be oncogenic,” Zhang says.

Finally, the team investigated what FAL1 does. They looked for proteins that associate with the FAL1 RNA and identified a protein called BMI1, a member of a gene regulatory complex called PRC1. In the absence of FAL1, the BMI1 protein is unstable. FAL1 RNA stabilizes BMI1, which in turn acts to turn down the expression of several hundred other genes. One of those downregulated genes encodes a tumor suppressor protein called p21.

These data, Zhang explains, suggest a molecular mechanism in which amplification of the FAL1 gene in ovarian cancer causes a surfeit of FAL1 RNA. That leads to enhanced stability of the BMI1 protein and downregulation of p21 and ultimately, unrestrained cell growth.

FAL1 expression may be able to serve as a biomarker of BRCA-related cancer prognosis, assuming these findings can be validated in other populations. But there also is the potential for new anti-cancer therapeutics, he says, whether those are therapeutics specifically targeting FAL1 RNA or small molecules that block the interaction between FAL1 and BMI1.

source : http://www.sciencedaily.com/releases/2014/09/140906093056.htm

Rates of heart disease, stroke continue to decline in Europe

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The research, which provides an update for 2014 on the burden of cardiovascular disease (CVD) in Europe, shows that death rates from CVD (diseases of the heart and blood vessels) vary enormously. For some eastern European countries, including Russia and Ukraine, the death rate from coronary heart disease for 55-60 year olds is greater than the equivalent rate in France for people 20 years older.

The age adjusted CVD death rates for men and women of all ages were six-fold higher in Russia than in France. In 2010 in Russia 915 men and 517 women died per 100,000 of the population, whereas the equivalent rates in France were 150 and 87 per 100,000 respectively.

In the UK the CVD death rates for 2010 were 205 and 129 per 100,000 men and women respectively.

Overall, CVD remains the single, greatest cause of death among Europeans than any other disease, and, in many countries causes twice as many deaths as cancer. However, the researchers, led by Dr Melanie Nichols, a Research Associate from the British Heart Foundation Centre on Population Approaches for Non-Communicable Disease Prevention at the University of Oxford (UK) and senior research fellow at Deakin University, Australia, found there were some countries where cancer was now causing more deaths than heart disease in men (Belgium, Denmark, France, Israel, Luxembourg, The Netherlands, Portugal, Slovenia, Spain and San Marino). For the first time, cancer has also overtaken CVD as the main cause of death among women in a European country: Denmark.

Co-author, Dr Nick Townsend, senior researcher at the BHF Centre on Population Approaches for Non-Communicable Disease Prevention, said: “The reason why cancer has overtaken cardiovascular disease as the main cause of death in these countries is due to the fact that fewer people develop cardiovascular disease and, in those who do, fewer die from it. This is probably due to improvements in the behavioural risk factors associated with CVD, such as decreases in the number of people smoking tobacco, along with better treatments, including preventive ones, such as the increasing use of statins. However, increases in some risk factors, such as rising levels of obesity, suggest that these decreasing trends may be in danger of reversing.”

Dr Nichols and her colleagues in the Oxford research group looked at trends in deaths from CVD over a period of ten years to the most recent year available, (2010 to 2012 for most countries), for 52 out of 53 European countries (there were no data for Andorra). They looked at the total number of deaths for all ages, and also at those that could be classified as “premature”: those before the age of 65 and those before the age of 75.

Data from the latest available year showed that there were just over four million deaths (1.9 million men and 2.2 million women) from CVD, close to half of all deaths in Europe. This was made up of 1.8 million deaths from coronary heart disease, one million from cerebrovascular disease (stroke) and 1.2 million from other cardiovascular diseases.

Just under a million men died before the age of 75 and half a million before the age of 65. Half a million women died before the age of 75 and just over 200,000 before the age of 65. Three in every ten deaths of Europeans aged under 65 were caused by CVD, as were 37% of all deaths occurring before the age of 75

Dr Townsend said: “The proportion of women who die from cardiovascular disease is much greater than men: 51% of women died compared to 42% of men. This difference is driven mainly by a higher rate of stroke and other cardiovascular diseases among women. There was very little difference in the rates of coronary heart disease between men and women: 20% versus 21% respectively.”

Overall, the researchers say that CVD death rates are declining in most, but not all European countries. Trends have also been downwards for what are known as “case fatality rates” — the percentage of people who are diagnosed with a condition and die from the illness within a given period. In the 25 countries for which there were data, there was an average annual reduction in people dying after being admitted to hospital with a heart attack of five per cent in the past five years. On the other hand, the rates of people hospitalised for CVD have increased, probably reflecting the impact of increasing numbers of elderly people in the population.

In their paper, the authors conclude: “Worldwide, there have been few moments in history during which NCDs [non-communicable diseases] have enjoyed such a prominent place in the world’s attention, with cardiovascular disease at the forefront of the activity. Despite this, there has been little commitment at the national or regional level to greater monitoring and reporting of risk factors and outcomes for cardiovascular disease. It is clear that in many countries of Europe, CVD mortality has continued to decrease substantially in recent years, and will make a large contribution to achieving this goal. In these (predominantly high income) countries, a ‘tipping point’ is rapidly approaching, when cancer deaths will outnumber cardiovascular disease deaths, particularly among men. In many other countries, however, the CVD burden dwarfs that of cancer, and a large proportion of the populations will lose their lives prematurely to heart disease and stroke.”

source : http://www.sciencedaily.com/releases/2014/08/140819200107.htm