Genes Linked To Cancer May Be Better Detected By Liquid Lasers

Using a liquid laser, University of Michigan researchers have developed a better way to detect the slight genetic mutations that might predispose a person to a particular type of cancer or other diseases.

Their results are published in the current edition of the German journal Angewandte Chemie.

This work could advance understanding of the genetic basis of diseases. It also has applications in personalized medicine, which aims to target drugs and other therapies to individual patients based on a thorough knowledge of their genetic information.

The researchers say their technique works much better than the current approach, which uses fluorescent dye and other biological molecules to find and bind to mutated DNA strands. When a patrol molecule catches one of these rogues, it emits a fluorescent beacon. This might sound like a solid system, but it's not perfect. The patrol molecules tend to bind to healthy DNA as well, giving off a background glow that is only slightly dimmer than a positive signal.

"Sometimes, we can fail to see the difference," said Xudong Fan, an associate professor in the Department of Biomedical Engineering and principal investigator on the project. "If you cannot see the difference in signals, you could misdiagnose. The patient may have the mutated gene, but you wouldn't detect it."

In the conventional fluorescence technique, the signal from mutated DNA might be only a few tenths of a percent higher than the background noise. With Fan's new approach it's hundreds of times brighter.

"We found a clever way to amplify the intrinsic difference in the signals," Fan said.

He did it with a bit of backtracking.

Liquid lasers, discovered in the late '60s, amplify light by passing it through a dye, rather than a crystal, as solid-state lasers do. Fan, who works at the intersection of biomedical engineering and photonics, has been developing them for the past five years. In his unique set-up, the signal is amplified in a glass capillary called a "ring resonator cavity."

Last year, Fan and his research group found that they could employ DNA (the blueprints for life that reside in all cells) to modulate a liquid laser, or turn it on and off. His group is one of just a few in the world to accomplish this, Fan said. At the time, they didn't have a practical application in mind. Then they had an epiphany.

"We thought, 'Let's look at the laser output. Can we see what's causing the different outputs and use it to detect differences in the DNA?'" Fan said. "I had an intuition, and it turns out the output difference was huge."

Researchers Develop Novel Drug Delivery System

Long duration, controllable drug delivery is of wide interest to medical researchers and clinicians, particularly those seeking to improve treatment for patients with chronic pain or to prevent cancer recurrence after surgery. Now a team of researchers led by Boston University Biomedical Engineer and Chemist Mark Grinstaff has developed a unique material and drug delivery mechanism that could pave the way for implants that release a drug at a designated rate for months.

The system consists of a biocompatible, highly porous, three-dimensional polymer material containing a selected drug and a volume of air that slows infiltration from surrounding water. As water seeps into the material, it displaces the air, gradually releasing the drug.

"The idea was to create a 3D material that has polymer fibers throughout and air trapped within," said Grinstaff, who developed the material in conjunction with BU biomedical engineering PhD student Stefan Yohe and Dr. Yolanda Colson, a Brigham and Women's Hospital thoracic surgeon and lung cancer specialist. "If we can slow the penetration of water into the structure, it will slow the release of the drug."

To prevent water from flooding the structure and causing an immediate release of the drug, Grinstaff and his colleagues designed the air-filled, mesh-like material to be "superhydrophobic" - so water-resistant that droplets of water barely touch the surface, forming beads similar to those that appear on a freshly waxed car. They produced the porous polymer mesh using a process called electrospinning, which overlays micron-sized fibers upon one another.

To control the rate of drug release, they adjusted chemical and physical properties of the material so that the entrapped air is loosely or tightly held. The more tightly held the air is within the structure, the harder it is for water to displace it, the slower the release, and the longer the treatment duration.

Loaded with a widely used anti-cancer drug called SN-38 in in vitro experiments, the polymer mesh and internal air pocket proved to be robust and effective against lung cancer cells in solution for more than 60 days, indicating its suitability for long-term drug delivery. Grinstaff and his collaborators next plan to conduct a series of in vivo experiments to evaluate the system's efficiency and potential clinical effectiveness - a critical preliminary step before initiating clinical trials.

Supported by the National Institutes of Health, The Wallace H. Coulter Foundation, the Center for Integration of Medicine & Innovative Technology and Boston University, this research was originally sparked by the Grinstaff group's ongoing investigation of potential therapies for recurring lung cancer, and interest in the use of new materials and procedures to deliver drugs over the course of months.

"Many researchers are advancing new drug delivery systems, and several others are designing superhydrophobic materials, but we're combining these disciplines to see if we can open up new doors and enable more effective treatments for a wide range of diseases," said Grinstaff.

Cancer Patients' Health Benefits From Physical Activity

According to an investigation published on bmj.com, cancer patients who have completed their primary cancer-related treatment, who engage in physical activity, can enhance their health.

Earlier studies discovered that individuals with cancer anticipate to return to normal daily activities after completing their primary cancer-related treatment. However, these patients often find they experience lower physical activity, increased fatigue and a decrease in quality of life (QOL). Although, several health factors including QOL can be enhanced through engaging in exercise, according to studies.

Investigators from the University of Hong Kong examined the results of 34 human trials that evaluated how exercise effects adult individuals with cancer. Each trial consisted of an average of 93 participants who had either suffered from prostate, breast, lung, colorectal, gynecologic or gastric cancer. The average age of the participants was 55 years.

The trials included resistance, strength and aerobic training for a median duration of 13 weeks.

Health improvements, such as BMI and body weight, blood sugar control, lower limb strength, fatigue, depression and QOL, were observed among participant's who received breast cancer treatment who engaged in a period of physical activity.

Improvements, such as oxygen consumption, depression, BMI, body weight, handgrip strength and QOL, were also observed among patients who completed treatments for other types of cancer.

Furthermore, variations in intensity and type of physical activity influenced the physical health of cancer patients and played a vital role in the effects of the exercise. Individuals with breast cancer found that resistance and aerobic exercise was considerably more effective on emotional and physical fitness, as well as concerns regarding breast cancer and overall well-being, than aerobic activity alone.

In addition, the researchers found that the effect of exercise was greater on younger patients. However, this finding was not fully conclusive, as they were able to engage in physical activity for longer durations.

According to the researchers, additional trials are required, particularly on the intensity of activity needed and on individuals with cancer types other than breast cancer.

They conclude that:

"Quality of life was a clear significant benefit of physical activity and that clinically, there were important positive effects on physical functions and quality of life."

Chaos In The Cell's Command Center -- Bad

A defective operating system is never a good thing.

Like computers, our cells depend on operating systems to drive normal functions. Gene expression programs comprise the software code our cells rely on, with each cell type controlled by its own program. Corrupted programs can trigger disease.

Cellular operating systems can be corrupted by viruses, mutations, or malfunctions that occur as cells change from one type to another. Unlike computers that can use one operating system for their entire existence, differentiating cells need to switch operating systems as they mature - from stem cell to, for example, nerve or muscle cell. In simple terms, differentiation requires two key steps: the genes active in the initial operating system must be deactivated; and the genes of the new cellular operating system must be turned on. If the switch is not flawless, a transitioning cell may die or be driven by a disease-causing program.

New research from Whitehead Institute scientists reveals the critical role one enzyme, lysine-specific demethylase 1 (LSD1), plays as embryonic stem cells differentiate into other cell types. Their research is published online this week in the journal Nature.

LSD1 was known to be critical to development, but little was known about the key role it plays during differentiation, when operating systems are switched.

"We knew that cells express a new set of genes when the operating switch occurs," says Steve Bilodeau, one of the Nature paper's authors and a postdoctoral researcher in the lab of Whitehead Member Richard Young. "But this study shows it is also essential to shut off genes that were active in the prior cell state. If you don't, the new cell is corrupted."

By investigating gene silencing during cell state transitions, Bilodeau and Warren Whyte, a Young lab graduate student and co-author of the Nature paper, redefined LSD1's role and described a previously unknown mechanism for silencing genes.

When they looked at the embryonic stem cell operating system genes that must be turned off during differentiation, Whyte and Bilodeau found LSD1 poised on the stem cell genes' enhancers, short bits of DNA that act as a landing pad for the proteins that enhance a gene's transcription and ultimately its protein production. When LSD1 receives the signal that the stem cell is transitioning into a more differentiated state, the enzyme pops into action and silences the ESC genes' enhancers. With their enhancers no longer operational, transcription of the stem cell genes is silenced, shutting down the stem cell operating system. As this occurs, other mechanisms switch on the cell's new operating system.

"This reveals the critical function of LSD1 in cell differentiation," says Whyte. "The enzyme decommissions the stem cell enhancers, thus allowing the new cell to function entirely within the parameters of the new operating system."

Although the work focuses on one enzyme's job in normal cells, Young sees broader implications. LSD1 is a member of a class of molecules that regulate both gene activity and chromosome structure, so the findings about LSD1 could give insight into how related regulators function. Also, knowing how a mechanism operates in normal cells provides a solid foundation for teasing apart what is going wrong in abnormal cells.

"This new knowledge brings us one important step closer to understanding defective operating systems in diseases such as cancer," says Young. "And this may give us a new angle on drug development for these diseases."

NIH Study Revealed Probable Mechanism Underlying Resveratrol Activity

National Institutes of Health researchers and their colleagues have identified how resveratrol, a naturally occurring chemical found in red wine and other plant products, may confer its health benefits. The authors present evidence that resveratrol does not directly activate sirtuin 1, a protein associated with aging. Rather, the authors found that resveratrol inhibits certain types of proteins known as phosphodiesterases (PDEs), enzymes that help regulate cell energy.

These findings may help settle the debate regarding resveratrol's biochemistry and pave the way for resveratrol-based medicines. The chemical has received significant interest from pharmaceutical companies for its potential to combat diabetes, inflammation, and cancer. The study appears in Cell.

"Resveratrol has potential as a therapy for diverse diseases such as type 2 diabetes, Alzheimer's disease, and heart disease," said lead study author Jay H. Chung, M.D., Ph.D., chief of the Laboratory of Obesity and Aging Research at the NIH's National Heart, Lung, and Blood Institute. "However, before researchers can transform resveratrol into a safe and effective medicine, they need to know exactly what it targets in cells."

Several previous studies suggested that resveratrol's primary target is sirtuin 1. Chung and colleagues suspected otherwise when they found that resveratrol activity required another protein called AMPK. This would not be the case if resveratrol directly interacted with sirtuin 1.

In this study, the researchers methodically traced out the metabolic activity in cells treated with resveratrol and identified PDE4 in the skeletal muscle as the principal target for the health benefits of resveratrol. By inhibiting PDE4, resveratrol triggers a series of events in a cell, one of which indirectly activates sirtuin 1.

To confirm that resveratrol attaches to and inhibits PDE proteins, Chung's group gave mice rolipram, a drug known to inhibit PDE4. Rolipram reproduced all of the biochemical effects and health benefits of resveratrol, such as preventing diet-induced obesity, improving glucose tolerance, and increasing physical endurance.

Chung noted that because resveratrol in its natural form interacts with many proteins, not just PDEs, it may cause not-yet-known toxicities as a medicine, particularly with long-term use. He added that the levels of resveratrol found in wine or foods are likely not high enough to produce significant health benefits or problems. Convincing clinical studies in humans have used about 1 gm of resveratrol per day, roughly equal to the amount found in 667 bottles of red wine.

The study results also suggest that inhibitors of PDE4 may offer the benefits of resveratrol without the potential toxicities arising from resveratrol's interactions with other proteins. One PDE4 inhibitor called roflumilast has already been approved by the FDA for the treatment of COPD (chronic obstructive pulmonary disease).

"This result underscores the need for careful, well-controlled studies to illuminate how these natural products operate," said Robert Balaban, Ph.D., director of the NHLBI Division of Intramural Research. "As Dr. Chung's work suggests, the effects of resveratrol seem to be more complicated than originally thought. However, this new insight into the phosphodiesterases might prove an interesting avenue to pursue."

A New Hope For Patients With Deadly Brain Tumor

Jim Black is fighting the meanest, most aggressive, most common kind of brain tumor in the United States: recurrent glioblastoma multiforme (GBM). In the United States, each year, approximately 10,000 patients are affected by GBM. Now, a novel investigational device - available only at clinical trial sites - is offering new hope to these patients.

The non-invasive procedure - called Tumor Treating Fields (TTF) - is delivered using a portable device - called the NovoTTF-100A System made by Novocure. The TTF procedure uses alternating electrical fields to disrupt the rapid cell division exhibited by cancer cells.

"Patients with recurrent GBM present a significant treatment challenge," said Santosh Kesari, MD, PhD, director of Neuro-Oncology at UC San Diego Moores Cancer Center. "The initial clinical research for the approval trial demonstrated that, compared to patients who were treated with chemotherapy, patients treated with NovoTTF achieved comparable survival times, had fewer side effects, and reported improved quality of life."

On average, a patient with GBM survives less than 15 months with optimal treatment and only three to five months without additional effective treatment. The TTF procedure may provide physicians with a fourth treatment option in addition to surgery, radiation therapy and chemotherapy.

TTFs inhibit tumor growth by causing cancerous cells to die. The TTF procedure is delivered using non-invasive, insulated transducer arrays (electrodes) that are placed directly on the skin in the region of the tumor. The hat-like collection of electrodes connects to a portable device which is slightly thicker than a laptop and weighs about six pounds. The device sends a low intensity, alternating electric field into the tumor which prevents the cells from dividing and spreading and causes cancer cells to die.

The most commonly reported side effect from NovoTTF is a mild-to-moderate scalp rash, beneath the electrodes. The FDA-approved device is intended as an alternative to standard medical therapy for GBM after surgical and radiation options have been exhausted.

"When all other options have been exhausted, patients are willing to do just about anything to keep the tumor at bay," said Kesari. "This device gives them an opportunity to fight back, to feel like they are taking an active, hands-on role in their own treatment, and provides tremendous hope."

Scientists Prove Multiple DNA Repair Defect In Monocytes

Scientists working with Professor Bernd Kaina of the Institute of Toxicology at the Medical Center of Johannes Gutenberg University Mainz have demonstrated for the first time that certain cells circulating in human blood - so-called monocytes - are extremely sensitive to reactive oxygen species (ROS). They were also able to clarify the reason for this: ROS are aggressive forms of oxygen that are generated during states of "oxidative stress" and play a significant role in various diseases. However, ROS are also naturally produced by cells of the immune system, in particular by macrophages, in response to exposure to pathogens. Macrophages are, similar to dendritic cells, generated by monocytes, which happens when monocytes leave the blood stream and enter the tissue. The scientists show that both macrophages and dendritic cells are resistant to ROS, as opposed to their precursor cells, the monocytes. The Mainz team attributes this hypersensitivity of monocytes to multiple defects in DNA repair that are apparent in these cells. They assume that a sophisticated mechanism for regulating the immune response and preventing excessive ROS production is behind this phenomenon, which was observed for the very first time. Their work has been published in the leading scientific journal Proceedings of the National Academy of Sciences.

It is generally known that one of the undesirable effects of ionizing radiation and drugs used to treat cancer is an impairment of the immune system, which ceases to function properly. However, it is still unclear which immune system cells respond most sensitively following radio- and chemotherapy, and which cells are resistant. "This is the question we addressed in our current research project," explains Professor Dr. Bernd Kaina, Director of the Institute of Toxicology at the University Medical Center in Mainz. "We were able to demonstrate that human monocytes are hypersensitive to reactive oxygen species (ROS), while macrophages and dendritic cells derived from monocytes by cytokine maturation are resistant." The scientists observed this extreme sensitivity of monocytes after exposure to radiation, chemicals, and even oxidized low-density lipoprotein (oxLDL), which plays a role in atherosclerosis. All of the above resulted in the formation of intracellular ROS, which damages the DNA and leads to cell death or even malignant transformation. Specific immune system cells, particularly the macrophages, produce ROS in response to an invasion of the body by pathogens. Ideally, production of ROS should cease once the pathogens have been eliminated. There also need to be limitations on the quantity of ROS produced, as these can damage healthy cells in inflamed tissue as well. In fact, chronic infections, in which ROS are continuously being produced, are frequently linked to an increased susceptibility to cancer.

Why do monocytes react so sensitively to ROS? Kaina's team has successfully determined the cause of the hypersensitivity of monocytes to oxidative stress: The monocytes were unable to repair DNA following ROS-induced damage to their genetic substance. This is because these cells produce very low levels of certain important repair proteins called XRCC1, ligase III, PARP-1, and DNA-PK in medical jargon. "Monocytes are in fact defective as far as two important DNA repair systems are concerned, i.e. base excision repair and DNA double-strand break repair," explains Kaina. "Thus far, a general repair defect of this nature has been observed neither in the cells of the human body nor in experimental in vitro systems."

Professor Kaina assumes that the repair defect in monocytes plays an important role in the regulation of the immune response: To prevent excessive production of ROS by macrophages in the inflamed tissue and an overactivation of the immune response, monocytes, as precursor cells of the ROS-producing macrophages, undergo increased and selective destruction due to their extreme sensitivity to ROS. In turn, fewer monocytes mean fewer macrophages and consequently lower levels of ROS - all in all a sophisticated way of regulating the monocyte/macrophage/dendritic cell system. It is clear that this has potential clinical implications: In the case of chronic inflammatory diseases in particular, the body is in a state of imbalance and excessive amounts of ROS are produced, which results in damage to the genetic substance of the healthy cells and is a contributing factor to the onset of cancer. It is possible that this vicious circle could be interrupted by the selective elimination of monocytes in the inflamed tissue.

Brain Tumor Eradication And Prolonged Survival

Tocagen Inc. has announced the publication of data showing the company's investigational treatment for high grade glioma eradicates brain tumors and provides a dramatic survival benefit in mouse models of glioblastoma. Almost all mice receiving the top dose of Toca 511 followed by 5-FC were still alive at 180 days, which was the termination date for the experiment, whereas all control mice died by day 43. The article was published in the February issue of the Neuro-Oncology journal.

"After administration of Toca 511, the efficiency and specificity of viral spread through the tumor in an immune-competent animal model was impressive," said John Coffin, Ph.D., American Cancer Society Professor at the Sackler School of Biomedical Sciences at Tufts University and Special Advisor to the Director, HIV Drug Resistance Program, Center for Cancer Research, National Cancer Institute. "As a career retrovirologist and advisor to the scientists at Tocagen, I am pleased to see the progress they have achieved with their retroviral replicating vector technology, and I look forward to seeing how this approach translates in humans with advanced cancer."

The results published in Neuro-Oncology showed that Toca 511 delivers a pro-drug activating gene to tumor cells where it converts the pro-drug 5-FC (flucytosine) into the anti-cancer drug 5-fluorouracil. Treatment with the high doses of Toca 511 resulted in elimination of tumors in most animals after dosing with 5-FC. The combination treatment of Toca 511 and 5-FC was well tolerated and did not cause toxicity over the course of the six month treatment protocol.

"Because of the invasive nature of glioblastoma, cancer cells are typically left behind after surgery, even with a 'complete' resection, making tumor re-growth almost inevitable," said Santosh Kesari, M.D., Ph.D., director of Neuro-Oncology in the Moores Cancer Center and in the Department of Neurosciences at the University of California, San Diego, one of the investigators in the Toca 511 clinical study. "There is an urgent need for new treatments that can eliminate residual cancer cells in patients with glioblastoma and other invasive gliomas. These preclinical results are very promising and provided the support for initiating human clinical trials of Toca 511."

About Toca 511 & Toca FC: The combination of Toca 511 (vocimagene amiretrorepvec), for injection & Toca FC (flucytosine), extended-release tablets is being investigated at leading centers across the US in clinical studies in patients with recurrent high grade glioma, including glioblastoma multiforme (GBM). Toca 511 is a retroviral replicating vector (RRV) that is designed to deliver a prodrug activator gene called cytosine deaminase (CD) selectively to cancer cells. After allowing time for Toca 511 to spread through the tumor, those cancer cells expressing the CD gene can convert the anti-biotic drug flucytosine into the anti-cancer drug 5-fluorouracil (5-FU). In these studies, patients receive a single administration of Toca 511 at the time of surgery (craniotomy or biopsy) followed by multiple cycles of oral Toca FC.

Vaccine prolongs life of patients with pancreatic cancer

A professor at the University of Oslo has developed a cancer vaccine that can prolong the life expectancy of patients with pancreatic cancer. Now he is testing a new vaccine that hopefully is able to kill all types of cancer cells.

For the last 20 years, Gustav Gaudernack, the Emeritus Professor at the Institute of Cancer Research at the University of Oslo, Norway, has researched into various vaccines against pancreatic cancer. This is one of the cancers with the highest mortality rate and lowest survival rate. The average life-time after surgery is only 18 months.

Gaudernack's research team trialled the first tailored treatment against pancreatic cancer in 1993. A specific gene in the cancer cells had mutated in 9 out of 10 patients. There were seven different mutations. Therefore, Gaudernack produced a cancer vaccine that was to stimulate the immune system to attack those cancer cells containing these mutations.

Last year saw the study on long-term survival, in which 130 patients were followed over 10 years. All had undergone surgery. 23 received the cancer vaccine. A fifth of the vaccinated patients survived seven to ten years. None of the non-vaccinated patients survived for any length of time.

"These figures are highly reliable. On average, patients receiving the vaccine survived twice as long as those who had not been vaccinated," comments Gaudernack to the research magazine Apollon at University of Oslo.

Through the company Targovax, his research group has now received funds of NOK 9 million from Innovation Norway to test out the cancer vaccine in a larger group of operated patients.

For those who cannot undergo surgery

Only 15% of patients can be operated for pancreatic cancer. If it is not possible to operate, the average life-time is less than six months. In 2000, Gaudernack had a new vaccine ready for those patients who could not undergo surgery.

"Treatment options for this group of patients have practically been at a standstill for the past 30 years, in spite of a new form of chemotherapy that has increased the life-time by a few months."

The British Cancer Society has now tested this cancer vaccine on 1100 patients at 50 English hospitals.

The patients were allocated to three groups. One group only received chemotherapy. The second group received either chemotherapy or the cancer vaccine. The third group received chemotherapy and the cancer vaccine at the same time.

The results are now being analysed by an independent group and will be published in the autumn of 2011. Gaudernack has so far not been informed, but his expectations are high.

"If the results had been clearly negative, the study would have been stopped early. If the results are positive, the cancer vaccine will be commercialised. It will also be possible to use the vaccine on other types of cancer such as lung cancer."

Prolongs life expectancy

Now Gaudernack's research group is working on in an entirely new cancer vaccine that is intended to prolong the lives of patients with other types of serious, highly advanced cancer.

The new vaccine has three components which the immune system of long-term survivors will react to.

In order to commercialise the vaccine, the innovation company Invent2 has established the company Ultimovacs. Investor Bjørn Rune Gjelstad has already invested NOK 15 million. The vaccine is manufactured in Switzerland and during the coming year will be tested on patients with prostate cancer or lung cancer.

"In the first part of the study we will investigate possible side effects and determine the optimum dose. We can only do this by measuring the immune response. An indicator of whether the vaccine is working is that the immune response is greater in those who survive longer than those who do not survive for very long. However, this is not enough to get the vaccine approved. Just as with all medical developments, the vaccine must also be tested in studies in which the patients are randomly given either the vaccine or standard of care treatment."

Kills immortal cells

The vaccine ensures that the immune system kills all cells that divide infinitely. Most cancer cells divide infinitely. This is due to the enzyme telomerase.

Healthy cells can only divide a limited number of times. This is to do with the way the chromosomes are structured. A chromosome contains all the gene material in a cell. Telomeres are regions at the tips of the chromosome that contain repeating sections. Each time the cell divides, one piece falls off. This causes the cell to age. When the cell has divided many times and there are no more sections left, the cell dies.

"You can compare this with a "pay-as-you-go" card. Healthy cells can only divide a certain number of times. Therefore it is important that you are born with as many units as possible.

If the cancer cells divided only a limited number of times like the healthy cells it would be easier to fight cancer. But unfortunately, the enzyme telomerase makes sure that the telomere bit is always re-attached to the chromosome so that the length of the chromosome remains constant. This means that cancer cells have an unlimited "pay-as-you-go card" with an infinite number of units."

"Cancer cells can therefore divide an unlimited number of times."

The vaccine destroys this possibility.

This special enzyme is also found in stem cells and sex cells. However, the vaccine does not kill the stem cells. Researchers still do not know why.

All types of cancer?

This special telomerase enzyme is found in nine out of ten cancer cells. Gaudernack hopes therefore that the vaccine can be used against all types of cancer.

"In far-advanced cancer, where other treatment is unsuccessful, we hope to delay the development of the disease. If there is a danger of recurrence we hope to be able to delay or prevent this recurrence. And if the cancer is discovered early we hope that the vaccine will enable complete recovery," states Gustav Gaudernack.

Subfertile men have 50 percent lower risk of having prostate cancer

Involuntary childlessness owing to reduced fertility is a concern for many men. However, these men do have one advantage -- they run a significantly lower risk of suffering from prostate cancer. Researchers are interested in whether this phenomenon could be used in the fight against cancer.

There is a clear link between male subfertility and a lower risk of prostate cancer. According to a new thesis from Lund University in Sweden, involuntarily childless men have around a 50 per cent lower risk of suffering from prostate cancer than men who have fathered at least one child.

Yasir Ruhayel, a doctoral student at Lund University and doctor at Skåne University Hospital, has based his research on the Malmö Diet and Cancer population study, where he has compared around 450 men with prostate cancer with an equal number of men in a control group who had not been diagnosed with the disease.

The thesis reinforces the findings of previous register-based studies, which have shown a connection, but this is the first time the issue has been studied in greater detail. An important conclusion is that the connection between reduced prostate cancer risk and subfertility is stronger than the connection between prostate cancer and other factors previously studied, for example diet, smoking, alcohol consumption and a number of different diseases.

Are there genetic explanations? Yasir Ruhayel has also investigated whether variation in certain genes may be linked to the reduction in prostate cancer risk observed in the subfertile men.

"We have found certain genetic associations, but the results are preliminary and more extensive studies involving a larger number of men are needed before the significance of the genetics can be verified," says Yasir Ruhayel.

One of the identified candidate genes is the AHR gene, which interacts with the male and female sex hormone signalling systems. AHR is also known as the 'dioxin receptor' because it mediates the harmful effects of the environmental toxicant dioxin, which can affect fertility.

If future research is able to more accurately determine which genes reduce the risk of prostate cancer, then this may open up new opportunities to develop drugs. However, before this can happen the genes with the desirable properties must be considered in a broader context, because reduced fertility is usually caused by a number of factors. The cancer-blocking properties must also be separated out and isolated from the properties that reduce fertility.

The researchers at Lund University are also interested in the reverse situation -- whether it is possible to find ways of helping men with reduced fertility by studying the genes of men with prostate cancer.

Yasir Ruhayel defended his thesis, Male Subfertility and Prostate Cancer Risk: Epidemiological and Genetic Studies, on 27 January.

Molecules and cell in action, shown in a new technology

A photograph of a polar bear in captivity, no matter how sharp the resolution, can never reveal as much about behavior as footage of that polar bear in its natural habitat. The behavior of cells and molecules can prove even more elusive. Limitations in biomedical imaging technologies have hampered attempts to understand cellular and molecular behavior, with biologists trying to envision dynamic processes through static snapshots.

Deborah Kelly, an assistant professor in the Virginia Tech Carilion Research Institute, has now developed a novel technology platform to peer closely into the world of cells and molecules within a native, liquid environment.

Kelly and colleagues have developed a way to isolate biological specimens in a flowing, liquid environment while enclosing those specimens in the high-vacuum system of a transmission electron microscope (TEM). The TEM liquid-flow holder, developed by Protochips Inc. of Raleigh, N.C., accommodates biological samples between two semiconductor microchips that are tightly sealed together. These chips form a microfluidic device smaller than a Tic Tac. This device, positioned at the tip of an EM specimen holder, permits liquid flow in and out of the holder. When these chips are coated with a special affinity biofilm that Kelly developed, they have the ability to capture cells and molecules rapidly and with high specificity. This system allows researchers to watch -- at unprecedented resolution -- biological processes as they occur, such as the interaction of a molecule with a receptor on a cell that triggers normal development or cancer.

"With this new technology, we can capture and view the native architecture of cells and their surface protein receptors while learning about their dynamic interactions, such as what happens when cells interact with pathogens or drugs," said Kelly. "We can now isolate cancer cells, for example, and view the early events of chemotherapy in action."

Kelly had previously worked with colleagues at Harvard Medical School to develop a way to capture protein machinery in a frozen environment. "But life moves," said Kelly. "It's better if biological processes don't have to be paused or frozen in order to be studied, but can be viewed in dynamic and life-sustaining liquid environments."

Kelly's affinity capture device, in combination with high-resolution TEM, helps bridge the gap between cellular and molecular imaging, allowing researchers to achieve spatial resolution as high as two nanometers. "This device allows us to see new features on the surface of live cancer cells, providing new targets for drug therapy," Kelly said. "With this resolution, scientists may even be able to visualize disease processes as they unfold."

Probable mechanism underlying resveratrol activity uncovered

National Institutes of Health researchers and their colleagues have identified how resveratrol, a naturally occurring chemical found in red wine and other plant products, may confer its health benefits. The authors present evidence that resveratrol does not directly activate sirtuin 1, a protein associated with aging. Rather, the authors found that resveratrol inhibits certain types of proteins known as phosphodiesterases (PDEs), enzymes that help regulate cell energy.
 
These findings may help settle the debate regarding resveratrol's biochemistry and pave the way for resveratrol-based medicines. The chemical has received significant interest from pharmaceutical companies for its potential to combat diabetes, inflammation, and cancer. The study appears in the Feb. 3 issue of Cell.

"Resveratrol has potential as a therapy for diverse diseases such as type 2 diabetes, Alzheimer's disease, and heart disease," said lead study author Jay H. Chung, M.D., Ph.D., chief of the Laboratory of Obesity and Aging Research at the NIH's National Heart, Lung, and Blood Institute. "However, before researchers can transform resveratrol into a safe and effective medicine, they need to know exactly what it targets in cells."

Several previous studies suggested that resveratrol's primary target is sirtuin 1. Chung and colleagues suspected otherwise when they found that resveratrol activity required another protein called AMPK. This would not be the case if resveratrol directly interacted with sirtuin 1.

In this study, the researchers methodically traced out the metabolic activity in cells treated with resveratrol and identified PDE4 in the skeletal muscle as the principal target for the health benefits of resveratrol. By inhibiting PDE4, resveratrol triggers a series of events in a cell, one of which indirectly activates sirtuin 1.

To confirm that resveratrol attaches to and inhibits PDE proteins, Chung's group gave mice rolipram, a drug known to inhibit PDE4. Rolipram reproduced all of the biochemical effects and health benefits of resveratrol, such as preventing diet-induced obesity, improving glucose tolerance, and increasing physical endurance.

Chung noted that because resveratrol in its natural form interacts with many proteins, not just PDEs, it may cause not-yet-known toxicities as a medicine, particularly with long-term use.

He added that the levels of resveratrol found in wine or foods are likely not high enough to produce significant health benefits or problems. Convincing clinical studies in humans have used about 1 gm of resveratrol per day, roughly equal to the amount found in 667 bottles of red wine.

The study results also suggest that inhibitors of PDE4 may offer the benefits of resveratrol without the potential toxicities arising from resveratrol's interactions with other proteins. One PDE4 inhibitor called roflumilast has already been approved by the FDA for the treatment of COPD (chronic obstructive pulmonary disease).

"This result underscores the need for careful, well-controlled studies to illuminate how these natural products operate," said Robert Balaban, Ph.D., director of the NHLBI Division of Intramural Research. "As Dr. Chung's work suggests, the effects of resveratrol seem to be more complicated than originally thought. However, this new insight into the phosphodiesterases might prove an interesting avenue to pursue."

In addition to Dr. Chung's lab at the NHLBI, other contributors to this study included collaborators in the Cardiovascular Pulmonary Branch of the NHLBI; the University of California, Davis; the University of North Carolina, Chapel Hill; University of Texas Southwestern Medical Center, Dallas; Sun Yat-sen University, Guangzhou, China; University Medical Center, Utrecht, The Netherlands; and Emerald BioStructures, Bainbridge Island, Wash.

New Drug Release Mechanism Developed That Utilizes 3D Superhydrophobic Materials

According to a recent study, there is a new mechanism of drug release using 3D superhydrophobic materials that utilizes air as a removable barrier to control the rate at which drug is released.
The study was electronically published in the Journal of the American Chemical Society.

Boston University (BU) graduate student Stefan Yohe, under the mentorship of Mark Grinstaff , PhD, BU professor of biomedical engineering and chemistry, and Yolonda Colson, MD, PhD, director of the Dana-Farber Cancer Institute/Brigham and Women's Hospital (BWH) Cancer Center, prepared drug-loaded superhydrophobic meshes from biocompatible polymers using an electrospinning fabrication method.

By monitoring drug release in aqueous solution and mesh performance in cytotoxicity assays, the team demonstrated that the rate of drug release correlates with the removal of the air pocket within the material, and that the rate of drug release can be maintained over an extended period.

"The ability to control drug release over a 2-3 month period is of significant clinical interest in thoracic surgery with applications in pain management and in the prevention of tumor recurrence after surgical resection," said Colson. Colson is also a thoracic surgeon at BWH with an active practice focused on the treatment of lung cancer patients.

This approach along with the design requirements for creating 3D superhydrophobic drug-loaded materials, the authors write, should facilitate further exploration and evaluation of these drug delivery materials in a variety of cancer and non-cancer applications.

Solving The Mystery Of Membrane Fusion

The many factors that contribute to how cells communicate and function at the most basic level are still not fully understood, but researchers at Baylor College of Medicine have uncovered a mechanism that helps explain how intracellular membranes fuse, and in the process, created a new physiological membrane fusion model.

The findings appear in the current edition of the journal PLoS Biology.

"Within our cells, we have communicating compartments called vesicles (a bubble-like membrane structure that stores and transports cellular products)," said Dr. Christopher Peters, assistant professor of biochemistry and molecular biology at BCM and lead author on the study. "These vesicles migrate through the cell, meet other vesicles and fuse. That fusion process is, in part, mediated through SNARE proteins that bring the vesicles together. How this happens has been in question for years."

The classic model for this process has been studied using artificial liposome models created in a lab. Peters and his colleagues knew a more physiological fusion model had to be studied in order to see a more accurate account of exactly what acts on this process. Using purified yeast organelles they were able to see that more factors come into play than had been originally believed.

In the classic model, it was believed SNARE proteins originating from two opposing membranes are somehow activated and separated into single proteins. Accepter SNARE proteins then form, allowing fusion with another vesicle membrane. How this mechanistically happens has been unknown.

"What we found with our physiological model is that a tethering complex (termed HOPS) is interacting with the SNARE proteins, activating them to begin this process. Also, the SNARE proteins do not completely separate into single proteins as first believed. Only one protein is detached, leaving behind the acceptor complex," Peters said. "This new acceptor SNARE-complex incorporates the single SNARE that has separated from another vesicle and the two vesicles are in position to fuse."

Researchers found that when this tethering factor was removed, the SNARE proteins were unstable and there was no fusion.

"This finding deals with one of the most fundamental reactions in a cell, how membranes fuse with each other. It is important to understand how this works, because when these events go wrong, either accelerating or slowing down, then it can affect certain disorders such as tumor formation," Peters said. "By using our physiological yeast fusion model, the impact of these tethering factors on the SNARE topology can be investigated, along with the many other factors that come into play. This was not the case in the artificial liposome models used in the past."

Engineered Bacteria Effectively Target Tumors, Enabling Tumor Imaging Potential In Mice

Tumor-targeted bioluminescent bacteria have been shown for the first time to provide accurate 3D images of tumors in mice, further advancing the potential for targeted cancer drug delivery, according to a study published in the Jan. 25 issue of the online journal PLoS ONE.

The specially engineered probiotic bacteria, like those found in many yoghurts, were intravenously injected into mice with tumors, after which the researchers took full body bioluminescent images. The 3D images revealed information about the number and location of the bacteria, to the level of precisely revealing where within the tumour the bacteria were living, providing much more information on the interaction of bacteria and tumors than was previously available using similar two-dimensional imaging methods.

According to the authors, led by Mark Tangney of University College Cork in Ireland, "before now, researchers used luminescence to provide an approximation of where a test organism was within the body, and would then follow up with multiple further experiments using different techniques to try to find a precise location". This new research suggests that such bacteria can be engineered to contain diagnostic or therapeutic agents that would be produced specifically within the tumor for targeted treatment.

Birth After Cancer Treatment Is Enabled By Removal And Storage Of Ovarian Tissue

For the first time in Germany, a woman has given birth to a child after removal and preservation of tissue from one of her ovaries. This course of action was necessary to avoid infertility owing to chemo- and radiotherapy. Andreas Müller and his colleagues report the case in the current issue of Deutsches Arzteblatt International.
The majority of young female patients who need radio- or chemotherapy for treatment of a tumor express concerns about fertility. The retransplantation of frozen (cryopreserved) ovarian tissue is an experimental technique for restoration of fertility that has led to 15 live births worldwide.

The woman in question was diagnosed with Hodgkin's lymphoma in 2003, at the age of 25. She was treated with chemotherapy followed by radiotherapy, but in 2005 the disease recurred and further treatment was required. To protect her fertility, ovarian tissue was removed via laparoscopy and cryopreserved. She was then treated with high-dose chemotherapy and remained free of disease for 5 years.

Because she still wanted to have a child, the preserved ovarian tissue was retransplanted into her right abdominal wall in 2010. After hormone treatment to stimulate follicular maturation and ovulation, she conceived by natural means. On 10 October 2011 she was delivered of a healthy child by cesarean section.

Diagnosis Wait Time of Cancer Patients Reduced By Danish Health Care Fast Track Program

In Denmark, implementing a national fast track system for cancer patients reduced the waiting time between a patient's initial meeting with a health care provider and their first treatment by four weeks when comparing 2010 to 2002, according to a study presented at the Multidisciplinary Head and Neck Cancer Symposium, sponsored by AHNS, ASCO, ASTRO and SNM.

Denmark's health care system is state run, meaning health care services are funded by taxes with no out-of-pocket costs to patients. Many similar health care systems in western counties are plagued by long waiting times for surgery and radiation therapy, which can lead to significant tumor progression for head and neck cancer patients and as a result an increased risk of local recurrence and death.

In 2008, a new fast track program was implemented, where cancer patients and potential cancer patients were given the highest priority in the Danish health care system. Also, telephone hotlines, reserved slots in ENT and radiology, faster pathology reporting, and twice weekly multidisciplinary tumor boards and clinics were implemented and paper referrals eliminated to curb the increasing wait times.

Researchers from the Danish Head and Neck Cancer Group (DAHANCA) compared data from 474 patients treated in 2002 or 2010, before and after the fast track program, respectively. The median treatment time from first contact with health care provider to initial treatment was 41 days in 2010, reduced significantly from 69 days in 2002.

"Although it is still too early to tell if the shorter waiting period has a significant effect on tumor control or survival, our study shows that the treatment waiting period can be significantly reduced by prioritizing cancer patients and that most patient and health care professionals are satisfied with the fast track system," Cai Grau, MD, DMSc, lead author of the study and a professor of radiation oncology at Aarhus University Hospital in Aarhus, Denmark, said. "This reduced waiting period will more than likely lead to a decrease in tumor progression and lower a patient's risk of local recurrence and death, which ultimately will reduce the government's costs for treating a cancer patient."

Researchers at CIC Discover New Therapeutic Target To Combat Liver Cancer

Researchers at CIC Biogune, the Cooperative Centre for Research into Biosciences and led by Dr. Maria Luz Martinez Chantar, have found a strong relationship between high levels of Hu antigen R (HuR) protein and the malignancy of Hepatocellular Carcinoma, through a novel molecular process in the investigation of this pathology and known as neddylation. The project provides new opportunities for making advances in the quest for personalised therapeutic applications in the treatment for Hepatocarcinoma.

Hepatocellular Carcinoma (HCC) is the cause of most liver cancers, the fifth most frequent cancer worldwide and the third after lung and gastric cancers. HCC is a tumour with a poor prognosis, even in developed countries; its incidence is similar to its death rate, most patients dying within months of diagnosis, despite diagnostic and therapeutic advances. It is a highly heterogeneous tumour and so the scientific community is redoubling its efforts to establish personalised and highly specific therapeutic targets.

Researchers from the Metabolomic Unit at CIC bioGUNE and led by Dr. Martinez, have gone one step further with this type of tumour and have revealed a hitherto unknown molecular mechanism that is involved in the development of CHC, showing that the malignancy of this illness may be linked to the overexpression of the HuR protein, published in the Hepatology journal. It has also obtained a mention in the Cancer section of the prestigious Nature Reviews Gastroenterology & Hepatology journal. It shows the relationship between high levels of HuR protein and the malignancy of Hepatocellular Carcinoma by means of a molecular mechanism - neddylation - totally novel in these kinds of tumour and effectively opens up new opportunities for the future development of potential therapeutic applications for patients with this pathology. The route also proved to have an application in cancer of the colon, given the high correlation between both types of tumour.

"Neddylation is an enzymatic reaction which, in the biological context, avoids the degradation of the protein modified with the NEDD8 molecule. Just as the ubiquitination marks the proteins to order them to be degraded, neddylation marks them in order to stabilise them and, in theory, these proteins are important for the tumour to proliferate and develop", explained Dr Martínez, lead researcher in the project.

In this way, the strategy followed has been to maintain the HuR protein at high levels of expression through its modification by neddylation, thus encouraging its proliferation and the malignancy of the HCC, in such a way that, "when we block the neddylation action or regulate the levels of HuR protein in liver tumours and in in vitro and in vivo hepatoma lines, cell death is induced and tumour regression takes place", stated Dr Martínez.

The options of conventional oncological treatment for Hepatocellular Carcinoma are limited, given that it is a highly chemoresistant tumour, usually arising from a cirrhotic liver. Approximately 40% of the patients diagnosed with HCC are in at an advanced stage and their short-term prognosis produces a survival rate of 1 year in 29% of cases and of 2 years in 16%. This neoplasia is a unique situation in oncology and, despite its high incidence and poor prognosis, has not had an effective therapeutic option to date. A possible explanation for this is the wide-ranging heterogeneity in the molecular mechanisms involved in the development of this tumour.

The next step in this long and complex process of research is to find a potential therapeutic application for the formula found. This is why Dr Martínez has come to an agreement with the pharmaceutical Millenium: the Takeda Oncology Company, to apply new neddylation inhibitors, marketed by this company and currently being tested in other types of tumours, to in vivo Hepatocellular Carcinoma models (mice), in order to explore this new therapeutic solution.

"Now that we have discovered that neddylation can play an important role in the development and progress of HCC, the next step is to undertake an in-depth study of possible therapeutic applications", concluded Dr Martínez.

Head And Neck Cancer Cells Destroyed By Grape Seed Extract, But Healthy Cells Are Unharmed

Nearly 12,000 people will die of head and neck cancer in the United States this year and worldwide cases will exceed half a million.
A study published in the journal Carcinogenesisshows that in both cell lines and mouse models, grape seed extract (GSE) kills head and neck squamous cell carcinoma cells, while leaving healthy cells unharmed.

"It's a rather dramatic effect," says Rajesh Agarwal, PhD, investigator at the University of Colorado Cancer Center and professor at the Skaggs School of Pharmaceutical Sciences.

It depends in large part, says Agarwal, on a healthy cell's ability to wait out damage.

"Cancer cells are fast-growing cells," Agarwal says. "Not only that, but they are necessarily fast growing. When conditions exist in which they can't grow, they die."

Grape seed extract creates these conditions that are unfavorable to growth. Specifically, the paper shows that grape seed extract both damages cancer cells' DNA (via increased reactive oxygen species) and stops the pathways that allow repair (as seen by decreased levels of the DNA repair molecules Brca1 and Rad51 and DNA repair foci).

"Yet we saw absolutely no toxicity to the mice, themselves," Agarwal says.Again, the grape seed extract killed the cancer cells but not the healthy cells.

"I think the whole point is that cancer cells have a lot of defective pathways and they are very vulnerable if you target those pathways. The same is not true of healthy cells," Agarwal says.

The Agarwal Lab hopes to move in the direction of clinical trials of grape seed extract, potentially as an addition to second-line therapies that target head and neck squamous cell carcinoma that has failed a first treatment.

Diagnostic Brain Tumor Test Could Revolutionize Patient Care

Researchers at UT Southwestern Medical Center have developed what they believe to be the first clinical application of a new imaging technique to diagnose brain tumors. The unique test could preclude the need for surgery in patients whose tumors are located in areas of the brain too dangerous to biopsy.
This new magnetic resonance spectroscopy (MRS) technique provides a definitive diagnosis of cancer based on imaging of a protein associated with a mutated gene found in 80 percent of low- and intermediate-grade gliomas. Presence of the mutation also means a better prognosis.

"To our knowledge, this is the only direct metabolic consequence of a genetic mutation in a cancer cell that can be identified through noninvasive imaging," said Dr. Elizabeth Maher, associate professor of internal medicine and neurology at UT Southwestern and senior author of the study, available online in Nature Medicine. "This is a major breakthrough for brain tumor patients."

UT Southwestern researchers developed the test by modifying the settings of a magnetic resonance imaging (MRI) scanner to track the protein's levels. The data acquisition and analysis procedure was developed by study lead author Dr. Changho Choi, associate professor of the Advanced Imaging Research Center (AIRC) and radiology. Previous research linked high levels of this protein to the mutation, and UT Southwestern researchers already had been working on MRS of gliomas to find tumor biomarkers.

"Our next step is to make this testing procedure widely available as part of routine MRIs for brain tumors. It doesn't require any injections or special equipment," said Dr. Maher, medical director of UT Southwestern's neuro-oncology program.

To substantiate the test as a diagnostic tool, biopsy samples from 30 glioma patients enrolled in the UT Southwestern clinical trial were analyzed; half had the mutation and expected high levels of the protein. MRS imaging of these patients had been done before surgery and predicted, with 100 percent accuracy, which patients had the mutation.

For Thomas Smith of Grand Prairie, the test helped determine the best time to begin chemotherapy. When an MRS scan showed a sharp rise in the 25-year-old's protein levels, this indicated to his health care team that his tumor was moving from dormancy to rapid growth.

"We treated him with chemotherapy and his protein levels came down," Dr. Maher said.

Before participating in the study, Mr. Smith had tumor removal surgery in 2007. Because part of the tumor could not be safely removed, however, he continued to suffer seizures and had other neurological problems. Since chemotherapy, his symptoms have diminished.

"I did six rounds of chemo, every six weeks," Mr. Smith said. "My seizures stopped and all my symptoms improved. I am only on anti-seizure medication now."

Genetic Variation Revealed That Raises A Risk Linked To Bisphosphonates

Researchers at the Columbia University College of Dental Medicine have identified a genetic variation that raises the risk of developing serious necrotic jaw bone lesions in patients who take bisphosphonates, a common class of osteoclastic inhibitors. The discovery paves the way for a genetic screening test to determine who can safely take these drugs. The study appears in the online version of the journal The Oncologist.
Oral bisphosphonates are currently taken by some 3 million women in the United States for the prevention or treatment of osteoporosis. In addition, intravenous bisphosphonates are given to thousands of cancer patients each year to control the spread of bone cancer and prevent excess calcium (hypercalcemia) from accumulating in the blood. Bisphosphonates work by binding to calcium in the bone and inhibiting osteoclasts, bone cells that break down the bone's mineral structure.

"These drugs have been widely used for years and are generally considered safe and effective," said study leader Athanasios I. Zavras, DMD, MS, DMSc, associate professor of Dentistry and Epidemiology and Director of the Division of Oral Epidemiology & Biostatistics at the Columbia University College of Dental Medicine. "But the popular literature and blogs are filled with stories of patients on prolonged bisphosphonate therapy who were trying to control osteoporosis or hypercalcemia only to develop osteonecrosis of the jaw."

Osteonecrosis of the jaw, or ONJ, often leads to painful and hard-to-treat bone lesions, which can eventually lead to loss of the entire jaw. Among people taking bisphosphonates, ONJ tends to occur in those with dental disease or those who undergo invasive dental procedures.

There are no reliable figures on the incidence of ONJ in patients taking oral bisphosphonates. Estimates range from 1 in 1,000 to 1 in 100,000 patients for each year of exposure to the medication, according to the American College of Rheumatology. ONJ is more common among cancer patients taking the intravenous form of the drug, affecting about 5 to 10 percent of these individuals, noted Dr. Zavras.

Studies have suggested that genetic factors play a major role in predisposing patients to ONJ. Delving deeper into this question, Dr. Zavras and his colleagues performed genome-wide analyses of 30 patients who were taking bisphosphonates and had developed ONJ and compared them with several bisphosphonate users who were disease free.

The researchers found that patients who had a small variation in the RBMS3 gene were 5.8 times more likely to develop ONJ than those without the variation. The study also identified small variations in two other genes, IGFBP7 and ABCC4, that may contribute to ONJ risk.

"Our ultimate goal is to develop a pharmacogenetic test that personalizes risk assessment for ONJ, a test that you could give to people before they start to use bisphosphonates," said Dr. Zavras. "Those who are positive for this genetic variation would select some other treatment, while those who are negative could take these medications with little fear of developing ONJ."

"At the moment, many women discontinue or avoid treatment for serious osteoporosis because they are afraid of losing their jaw bones," added Dr. Zavras. "There even are reports of dentists who have refused to perform certain invasive procedures in patients taking bisphosphonates. So there is a great need for a pharmacogenetic screening test to determine which patients are really at risk for ONJ."

The current study looked only at Caucasians. Further studies are needed to determine whether the RBMS3 gene variation is seen in other racial groups, according to the researchers.

Cancer Sequencing Initiative Revealed Mutations Tied To Aggressive Childhood Brain Tumors

Researchers studying a rare, lethal childhood tumor of the brainstem discovered that nearly 80 percent of the tumors have mutations in genes not previously tied to cancer. Early evidence suggests the alterations play a unique role in other aggressive pediatric brain tumors as well.

The findings from the St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project (PCGP) offer important insight into a poorly understood tumor that kills more than 90 percent of patients within two years. The tumor, diffuse intrinsic pontine glioma (DIPG), is found almost exclusively in children and accounts for 10 to 15 percent of pediatric tumors of the brain and central nervous system.

"We are hopeful that identifying these mutations will lead us to new selective therapeutic targets, which are particularly important since this tumor cannot be treated surgically and still lacks effective therapies," said Suzanne Baker, Ph.D., co-leader of the St. Jude Neurobiology and Brain Tumor Program and a member of the St. Jude Department of Developmental Neurobiology. She is a corresponding author of the study published in the January 29 online edition of the scientific journal Nature Genetics.

DIPG is an extremely invasive tumor that occurs in the brainstem, which is at the base of the skull and controls such vital functions as breathing and heart rate. DIPG cannot be cured by surgery and is accurately diagnosed by non-invasive imaging. As a result, DIPG is rarely biopsied in the U.S. and little is known about it.

Cancer occurs when normal gene activity is disrupted, allowing for the unchecked cell growth and spread that makes cancer so lethal. In this study, investigators found 78 percent of the DIPG tumors had alterations in one of two genes that carry instructions for making proteins that play similar roles in packaging DNA inside cells. Both belong to the histone H3 family of proteins. DNA must be wrapped around histones so that it is compact enough to fit into the nucleus. The packaging of DNA by histones influences which genes are switched on or off, as well as the repair of mutations in DNA and the stability of DNA. Disruption of any of these processes can contribute to cancer.

Researchers said that the mutations seem unique to aggressive childhood brain tumors.

"It is amazing to see that this particular tumor type appears to be characterized by a molecular 'smoking gun' and that these mutations are unique to fast-growing pediatric cancers in the brain," said Richard K. Wilson, Ph.D., director of The Genome Institute at Washington University School of Medicine in St. Louis and one of the study's corresponding authors. "This is exactly the type of result one hopes to find when studying the genomes of cancer patients."

The results are the latest from the PCGP, an ambitious three-year effort to sequence the complete normal and cancer genomes of 600 children with some of the most poorly understood and aggressive pediatric cancers. The human genome includes the complete set of instructions needed to assemble and sustain human life. The goal is to identify differences that explain why cancer develops, spreads and kills. Researchers believe the findings will provide the foundation for new tools to diagnose, treat or prevent the disease.

For this study, researchers sequenced the complete normal and cancer genomes of seven patients with DIPG. "The mutations were found at such high frequency in the cancer genomes of those seven patients that we immediately checked for the same alterations in a larger group of DIPGs," Baker said. When researchers sequenced all 16 of the related genes that make closely related variants of histone H3 proteins in an additional 43 DIPGs, they found many of the tumors contained the same mistakes in only two of these genes.

Of the 50 DIPG tumors included in this study, 60 percent had a single alteration in the makeup of the H3F3A gene. When the mutated gene was translated into a protein, the point mutation led to the substitution of methionine for lysine as the 27th amino acid in this variant of histone H3 protein. Another 18 percent of the DIPG patients carried the same mistake in a different gene, HIST1H3B.

Researchers are now working to understand how mutations in H3F3A and HIST1H3B impact cell function and contribute to cancer. Earlier research provides some clues. The lysine that is mutated is normally targeted by enzymes that attach other molecules to histone H3, influencing how it interacts with other proteins that regulate gene expression, Baker said. Mutations in the enzymes that target histone H3 have been identified in other cancers, but this is the first report showing a specific alteration of histones in cancer.

H3F3A and HIST1H3B were also mutated in other aggressive childhood brain tumors, glioblastoma, that develop outside the brain stem. Of 36 such tumors included in this study, 36 percent carried one of three distinct point mutations in the genes. The alterations included another single change in the makeup of H3F3A not found in DIPGs.

The histone H3 genes, however, were not mutated in any of the 252 other childhood tumors researchers checked for this study. The list included the brain tumors known as low-grade gliomas, medulloblastomas and ependymomas plus other cancers outside the brain and nervous system. The H3 changes have not been reported in any other cancers, including adult glioblastoma. "This suggests these particular mutations give a very important selective advantage, particularly in the developing brainstem and to a lesser degree in the developing brain, which leads to a terribly aggressive brain tumor in children, but not in adults," Baker said.

"This discovery would not have been possible without the unbiased approach taken by the Pediatric Cancer Genome Project," Baker said. "The mutations had not been reported in any other tumor, so we would not have searched for them in DIPGs. Yet the alterations clearly play an important role in generating this particular tumor."

Processes leading to acute myeloid leukemia discovered

Researchers at UC Santa Barbara have discovered a molecular pathway that may explain how a particularly deadly form of cancer develops. The discovery may lead to new cancer therapies that reprogram cells instead of killing them. The findings are published in a recent paper in the Journal of Biological Chemistry.

The UCSB research team described how a certain mutation in DNA disrupts cellular function in patients with acute myeloid leukemia (AML). The researchers were prompted to study this process by another research team's discovery that AML patients have a mutation in a certain enzyme, which was reported in the New England Journal of Medicine. The enzyme is a protein called DNMT3A, which leads to changes in how the DNA of AML patients is methylated, or "tagged." Norbert Reich, professor in the Department of Chemistry and Biochemistry at UCSB, was already studying that particular enzyme with his research group, so they began to study the disease process of AML at the cellular level.

Reich explained that tagging is a way of reading DNA at the cellular level. This falls within an area of study called epigenetics, a process that occurs "on top" of genetics. Each person has approximately 200 types of cells, all with the same DNA, and these must be controlled in different ways. "There is an enzyme -- a protein -- that tags DNA and controls which of the genes in your cells, your DNA, gets turned on and off," said Reich. "So you have 20,000 genes, and you have to control them differently in your brain than in your liver."

Reich explained that there is current interest in this broader field of epigenetics as a direction for the treatment of cancer. "There's definitely the idea that this may be a new way of developing therapeutics, because you don't have to kill the cancer cell," said Reich. "Almost every cancer therapy that's out there works on the principle that a cancer cell needs to be killed."

With epigenetics, instead of only having DNA sequence coding for certain genes, there is an epigenetic process, with another layer of information on top of the genetic process. In this case, that information is the tagging by the methyl groups.

"If you really think about it, this is part of the answer as to how your cells can be so different and yet they all have the same DNA," said Reich. "You have the same genome in every one of your cells, but you do not have the same epigenome, which is basically the methylation pattern, the tagging pattern. That is different in every type of your cells. And the way this relates back to cancer, with leukemia, in those patients, the tagging is messed up. The patterns are not correct. Our big contribution to that is we've explained how the mutations in the enzyme could lead to that disruption of the tagging pattern."

The UCSB group developed a test to demonstrate that the mutant enzymes in AML can only work on DNA for short distances. As a result, the precise methylation patterns of a healthy cell are disturbed, resulting in genes being turned on at the wrong place and time, which in turn can initiate the growth of cancerous cells.

The team found that the mutation AML patients have causes a certain complex of four proteins to be disrupted. "The surprise was that the disruption doesn't stop the enzyme from being active; it doesn't stop the enzyme from tagging the DNA," said Reich. "Instead, it stops the way it can do it. Instead of going to your DNA and tagging an entire region of chromosome, it goes there, does one thing, and leaves. That process, that change, is what we see in the AML patients. So we think we have a molecular explanation for this disease."

Reich said that the currently prescribed drug Vidaza works by affecting the same enzyme that is mutated in AML. There is interest in the pharmaceutical industry in developing other therapeutics to target the enzymes responsible for tagging the DNA. These epigenetic inhibitors would reprogram rather than kill the cell.

Traditional cancer therapies use radiation and chemotherapy to remove or kill cancer cells. "The problem with that is that cancer cells are often very subtly different from normal cells," said Reich. "So you have one of the most difficult therapeutic challenges known to man, which is to distinguish between two human cells -- one that's cancerous and one that's not. Instead of killing the cell, the notion is that if you could just reprogram the cell, then it goes back to being normal. You intercept the cancer development. This is still an aspiration; it hasn't been achieved really, but that's what attracts people to the field of epigenetic-based therapies, because of the prospect of not having to kill cells."

Celeste Holz-Schietinger and Douglas Matje, both graduate students working in the Reich lab, are the first and second authors of the paper.