Even a Little Physical Activity May Prevent Depression.


Even low levels of physical activity may reduce the risk of developing depression in individuals of all ages, new research suggests.

In 25 of 30 large studies examined in the systematic review, which included participants between the ages of 11 and 100 years, a “negative risk” was found between baseline physical activity (PA) and the future development of depression.

In addition, this inverse association was found in all levels of PA ― including less than 2.5 hours of walking per week.

“It was a little surprising that 25 of the studies found this protective effect, and that’s really promising,” lead author George Mammen, PhD candidate from the Faculty of Kinesiology and Physical Education Department at the University of Toronto in Ontario, Canada, told Medscape Medical News.

“We also did quality assessments on each study, and the majority were of high methodologic quality, which adds weight to the findings,” said Mammen.

He noted that the take-home message is that being active is important for more than just physical health.

“From a population health perspective, promoting PA may serve as a valuable mental health…strategy in reducing the risk of developing depression,” write the investigators.

The study was published in the November issue of the American Journal of Preventive Medicine.

Prevention Strategy Needed

Previous studies have shown a link between exercise and decreasing symptoms in patients with depression,including several reported by Medscape Medical News.

“However, with the high prevalence of depression worldwide and its burden on well-being and the healthcare system, intuitively, it would make more sense…to shift focus toward preventing the onset of depression,” the investigators write.

We need a prevention strategy now more than ever. Our health system is taxed. We need to…look for ways to fend off depression from the start,” added Mammen in a release.

After searching 6 of the top databases, including MEDLINE and PubMed, the researchers found 6263 worldwide citations of PA and depression. For this analysis, they selected 30 English-language studies that were published between January 1976 and December 2012.

All were prospective, longitudinal, and “examined relationships between PA and depression over at least two time intervals.” They had follow-up periods ranging from 1 to 27 years.

Results showed that 25 of the studies revealed a significant inverse effect between any PA reported at baseline and subsequent depression development.

Interestingly, 4 of these studies showed that women who reported baseline PA were less likely than men to develop depression.

“These studies postulate that psychological factors may explain these findings because women may benefit more from the social aspects of PA than men,” note the investigators.

Of the 5 studies that did not find a significant association between PA and depression, “only 1 was considered to be of high quality,” and 2 focused only on older adults.

Get Moving

Using data from the 7 studies that measured amounts of weekly PA participation, the researchers found that exercising more than 150 minutes per week was associated with a 19% to 27% decreased risk of developing depression.

Surprisingly, participating in less than 150 minutes per week of PA was associated with a 8% to 63% decreased depression risk compared with individuals who were sedentary. Still, the 63% decreased risk was found in one study of patients participating in 120 minutes of weekly PA.

Maternal, congenital hypothyroidism affects brain development and cognitive ability.


Maternal hypothyroidism and congenital hypothyroidism affected the development of the child’s corpus callosum, resulting in different changes to the size and shape of regions such as the genu and affecting cognitive ability, a presenter said here.

 “The size of specific corpus callosum regions was associated with performance in different cognitive abilities,” said Joanne F. Rovet, MD,of the Hospital for Sick Children and the University of Toronto. “We observed in congenital hypothyroidism, a flat corpus callosum, a smaller and narrower genu and a normal splenium that was unaffected. In the maternal hypothyroidism group, instead, we found a normal shape corpus callosum, a smaller and wider genu and a larger, longer, skinnier splenium.”

In both studies, Rovet and colleagues instituted a quantitative and a qualitative approach, looking at the size and shape of the genu and splenium.

In the maternal hypothyroidism study, Rovet and colleagues looked at 20 children, aged 9 to 12 years (mean age, 10.3 years), born between 1996 and 2001 to women with hypothyroidism. They were age-matched to 22 controls. The researchers conducted a 4-hour neuropsychology exam and performed an MRI on each child.

Children born to mothers who had hypothyroidism during pregnancy showed smaller genus (P=.06) and larger splenium (P=.045) in both an area comparison and proportion comparison. Groups did not differ in overall corpus callosum shape, but they did differ in shape of genu and splenium.

Researchers also found that the children’s corpus callosum size and shape did not correlate with any specific trimester of maternal hypothyroidism, but their size of anterior and posterior segments correlated with duration of hypothyroidism in pregnancy. Anterior segments were smaller for children born to women with two (P=.01) or three (P=.017) trimesters of hypothyroidism vs. the controls. Posterior segments were larger for children born to women with two (P=.032) and three (P=.016) trimesters of hypothyroidism vs. controls. 

Rovet showed that larger anterior corpus callosum was associated with better reading ability, and larger genus was associated with better cognitive flexibility. Smaller isthmus correlated with better nonverbal memory while smaller splenium correlated with better verbal ability, Rovet said.

“Inadequately treated hypothyroidism in pregnancy disturbs corpus callosum development by disrupting the patterning of axonal growth and pruning,” she said.

In the congenital hypothyroidism study, researchers looked at 41 children aged 9 to 16 years (mean age, 12.4 years) whose median onset of congenital hypothyroidism was 13 days, median thyroid-stimulating hormone at diagnosis was 31.1 mU/L and mean thyroxine at diagnosis was 53.9 ± 36.2 nmol/L. They were matched with 42 controls for age (mean age, 12 years), sex and socioeconomic status. They underwent the same testing as in the maternal hypothyroidism group.

Children with congenital hypothyroidism had smaller (P<.01) and narrower (P<.05) genus with an abnormal shape to their overall corpus callosum due to their angle of curvature (P<.001) and less droop of the splenium (P=.017) as well as more “more bulbous” genus than controls.

Researchers found an association of the genu size with matrix reasoning (P=.009), abstract visual memory (P=.005) and visual reasoning (P=.017).

“Youth with [congenital hypothyroidism] show reduced size and width of corpus callosum genu, less curvature, abnormal orientation of splenium and more bulbous genus,” Rovet said. “More severe [congenital hypothyroidism] at diagnosis was associated with reduced size of genu.” – by Katrina Altersitz

 

 

PERSPECTIVE

 

 

R. Michael Tuttle

·         These findings further verify the critical importance of having normal thyroid functions in the mother and the fetus during pregnancy.  Rather than simply relying on cognitive function testing to prove an effect of hypothyroidism on the fetal brain, the finding of structural differences in specific regions of the corpus callosum clearly document the impact of hypothyroidism on the developing brain.

o    R. Michael Tuttle, MD

o    Professor of medicine 
Attending physician 
Memorial Sloan-Kettering Center

·          

What Will Stem Cells Become?


Scientists at the University of Toronto say they have developed a technique that can rapidly screen human stem cells and better control what they will turn into. The technology could have potential use in regenerative medicine and drug development, according to the researchers, who published their findings (“High-throughput fingerprinting of human pluripotent stem cell fate responses and lineage bias”) in this week’s issue of the journal Nature Methods.

“The work allows for a better understanding of how to turn stem cells into clinically useful cell types more efficiently,” explained Emanuel Nazareth, a Ph.D. student at the Institute of Biomaterials & Biomedical Engineering at the University of Toronto. The research comes out of the lab of Peter Zandstra, Ph.D., Canada Research Chair in Bioengineering at U of T.

The researchers used human pluripotent stem cells (hPSC), cells which have the potential to differentiate and eventually become any type of cell in the body. But the key to getting stem cells to grow into specific types of cells, such as skin cells or heart tissue, is to grow them in the right environment in culture, and there have been challenges in getting those environments (which vary for different types of stem cells) just right, Nazareth said.

The researchers developed a high-throughput platform, which uses robotics and automation to test many compounds or drugs at once, with controllable environments to screen hPSCs in. With it, they can control the size of the stem cell colony, the density of cells, and other parameters in order to better study characteristics of the cells as they differentiate or turn into other cell types. Studies were done using stem cells in micro-environments optimized for screening and observing how they behaved when chemical changes were introduced.

“We developed a high-throughput platform to screen hPSCs in configurable microenvironments in which we optimized colony size, cell density, and other parameters to achieve rapid and robust cell fate responses to exogenous cues,” wrote the investigators. “We used this platform to perform single-cell protein expression profiling, revealing that Oct4 and Sox2 costaining discriminates pluripotent, neuroectoderm, primitive streak, and extraembryonic cell fates.”

In essence, Oct4 and Sox2, two specific proteins found within stem cells, can be used to track the four major early cell fate types that stem cells can turn into, allowing four screens to be performed at once.

“One of the most frustrating challenges is that we have different research protocols for different cell types. But as it turns out, very often those protocols don’t work across many different cell lines,” added Nazareth.

The work also provides a way to study differences across cell lines that can be used to predict certain genetic information, such as abnormal chromosomes. What’s more, these predictions can be done in a fraction of the time compared to other existing techniques, and for a substantially lower cost compared to other testing and screening methods, pointed out Nazareth.

“We anticipate this technology will underpin new strategies to identify cell fate control molecules, or even drugs, for a number of different stem cell types,” said Dr. Zandstra said.

Vaccination Against Seasonal Influenza May Reduce the Risk of Cardiovascular Events.


For many people, getting a seasonal flu shot may help them avoid a week or more of misery. But for some individuals, especially those with heart disease, vaccination against influenza appears to help reduce the likelihood of major adverse cardiovascular events, such as heart attack and stroke.

Researchers, whose findings appear today in JAMA, found that receiving influenza vaccine was associated with a 36% lower risk of cardiovascular events compared with not being immunized against flu. For individuals with recent acute coronary syndrome, such as a heart attack or unstable angina, influenza vaccine was associated with a 55% lower risk of cardiovascular events within 12 months compared with those who had a recent acute coronary syndrome but did not receive the vaccine. The findings are based on a systematic review and meta-analysis involving 6 randomized clinical trials, 5 published and 1 unpublished. These trials collectively enrolled 6735 patients with a mean age of 67 years; 36% had a history of heart disease.

Lead author Jacob A. Udell, MD, MPH, of the University of Toronto in Canada, discusses his team’s findings.

news@JAMA: Why did you do the study?

Dr Udell: There have been reports suggesting that getting the flu shot was protective against heart attack and stroke, but most of these reports were observational. So we went back and systematically reviewed all clinical trials involving vaccine or placebo to see if this signal of cardioprotection was reproducible and consistent across the studies.

news@JAMA: What did you find?

Dr Udell: We found there was a 36% risk reduction overall for getting a cardiac event in those who were vaccinated compared with those who did not get the vaccine. We also found that those who had a heart attack had even more benefit. So in the higher-risk patients, the flu vaccine gave more benefit.

news@JAMA: Although your study cannot answer this question, can you speculate why influenza vaccination is associated with reduced heart risk?

Dr Udell: The flu may be a severe illness, causing a lot of inflammation, and that will have an effect on all your organs, including the heart and brain. This inflammation may also disrupt stable hardened arteries and free atherosclerotic plaque, causing a heart attack. Another theory is that the flu may push people over a tipping point, especially among the frail and elderly.

news@JAMA: So what would you tell others about the implications of your study findings for vaccination against influenza?

Dr Udell: For the skeptics out there, I’d note that we now have yet another reason why receiving influenza vaccine might be a beneficial thing to do. And those hospitalized with a heart attack should be vaccinated before they walk out the door so they don’t have care gaps that could be very dangerous.

Metformin May Lower Risk of Prostate Cancer Death.


Metformin, a widely used diabetes drug, may reduce the risk of dying from prostate cancer, according to new research.

A study of nearly 4,000 diabetic men found that those taking metformin when diagnosed with prostate cancer were less likely to die of the cancer or other causes compared to men using other diabetes drugs.

“We demonstrated that metformin is associated with improved survival among diabetic patients with prostate cancer,” said Dr. David Margel, a uro-oncologist at Rabin Medical Center in Petah Tikva, Israel, who conducted the research while at the University of Toronto.

“It’s associated in a dose-response manner,” he said. “The longer you were on metformin, the less likely you were to die of prostate cancer and of all causes.”

But whether metformin can prevent prostate cancer progression in people without diabetes remains to be seen, experts say.

Diabetes and prostate cancer are common in the United States. This year, about 239,000 new cases of prostate cancer will be diagnosed, and more than 29,000 men will die from it, according to the American Cancer Society.

Type 2 diabetes is rampant, and metformin is the drug most commonly prescribed to treat it. More than 61 million metformin prescriptions were filled in the United States last year. Brand names includeGlucophage and Glumetza. The drug, in its generic forms and certain brand names, is relatively inexpensive.

Previous research has focused on whether metformin might reduce the risk of getting prostate cancer, but most studies were negative. Some experts believe the drug instead works to improve survival once the cancer occurs.

In the new study, published online Aug. 5 in the Journal of Clinical Oncology, Margel looked at more than 3,800 diabetic men aged 67 or older who lived in Ontario. About one-third were taking metformin at the study’s start. Others were using different diabetes drugs.

The men took the metformin for a median of 19 months (half longer than that, half shorter) before the cancer was diagnosed and nearly nine months after.

During roughly four years of follow-up, Margel found those who took metformin had a 24 percent reduction in risk from prostate cancer death for every additional six months of use after their cancer diagnosis. The risk reduction of death from other causes was initially the same but declined over time.

In both instances, although an association was found between metformin and survival, a direct cause-and-effect relationship was not established.

No reduction in death risk was seen for patients taking any other diabetes drug.

Although other diabetes drugs work by increasing the body’s insulin production, metformin is an “insulin sensitizer” that works by making the body more sensitive to the insulin already produced. Insulin is needed to move glucose into cells for energy.

Some research suggests that high insulin levels can influence cancer growth. Metformin, by not increasing the body’s insulin production, may decrease cancer cells’ growth, some experts say.

Typical side effects of the drug are mild diarrhea and stomach problems, Margel said. “Usually they subside after one or two weeks,” he said.

In their next study, the researchers plan to test metformin in patients with prostate cancer but not diabetes. “Metformin is very safe to use among nondiabetic patients,” Margel said.

The findings point to a need for a large study in which men with early stage prostate cancer are assigned to a metformin group or placebo group, one expert said. Writing in an accompanying journal editorial, Kathryn Penney, an instructor in medicine at Brigham and Women’s Hospital in Boston, said at least nine ongoing trials are looking at metformin in men with recurrent or advanced prostate cancer.

But these current trials might be starting too late, she said. Instead, a trial should look at metformin’s effect at the time of diagnosis, when the disease is typically in early stages.

“If this trial showed a benefit, then yes, men without diabetes could be put on metformin at the time of prostate cancer diagnosis,” she said.

Source: Drugs.com

2.6 Billion-Year-Old Water Found in Deep Mine.


ancient-water-660

One and a half miles beneath the surface of Earth in a Canadian mine, researchers have found pockets of water in rocks that have been isolated from the surface for some two billion years.

The chemistry of the water could support life, the team reports today in the journal Nature — a tantalizing discovery that raises the possibility that life-supporting water might also lie in similar kinds of rocks deep beneath the surface of Mars.

Because the water was trapped at a time when Earth was very different than it is today, the new findings also lend insight into the evolution of the early atmosphere and the habitability of the deep Earth. Until now, the oldest known reservoirs of underground water dated back just tens of millions of years.

“For the first time, we found that waters of this age can be preserved on our planet,” said Barbara Sherwood Lollar, an isotope geochemist at the University of Toronto. “Really, it’s a whole new world, a whole new hydrosphere on our planet. We didn’t know it was possible to trap this amount of fluid and gas for this kind of time scale.”

Miners have long known that water sometimes flows out of fractures in rocks deep underground, Sherwood Lollar said. As scientists have more recently become interested in the phenomenon, they have discovered that these fluids are often very salty, with salinity levels 10 times higher than seawater.

Deep isolated waters also contain large amounts of dissolved hydrogen, making it possible that they might sustain microorganisms like the ones that live around hydrothermal vents. In 2006, in fact, Sherwood Lollar and colleagues found a community of microbes living deep below South Africa in isolated waters that were tens of millions of years old.

“I refer to hydrogen as the jelly donuts of the microbe world,” Sherwood Lollar said. “If it’s there, they want to eat it.”

For the new study, the researchers lowered a tube-shaped device into pre-drilled boreholes in a mine in Ontario. Water flowed through the device, which separated the gas from the fluid and collected both.

In laboratories in Canada and the United Kingdom, scientists then measured levels of hydrogen, carbon, nitrogen and other stable elements as well as noble gasses such as helium, xenon and krypton. Knowing how quickly chemical reactions proceed over time between rocks and water, the team could then use the levels of those components to determine how long the fluid had been trapped in the deep crust.

Results showed that the water was between one billion and 2.6 billion years old — orders of magnitude older than the South African samples.

The water dates back to a time before the Great Oxygenation Event that filled Earth’s atmosphere with oxygen, making it possible for higher life forms to evolve, said planetary scientist Michael Mumma, director of the Goddard Center for Astrobiology at the NASA Goddard Space Flight Center.

Now, the search is on for signs of life in the ancient Canadian waters. If microbes turn up there and they are as old as the water is, the discovery could offer new places to look for life on Mars, which has rocks of similar age to those looked at in the new study.

“I think this is quite a profound finding,” Mumma said. “In a similar environment, a tectonically quiet environment on Mars, such reservoirs of these trapped gasses could in fact host a population of microbes of similar nature. And we could still find evidence that they were there at one time or in fact still do exist.”

Source: Discovery channel

Researchers Look to Single Cells for Cancer Insights


When asked about the biggest challenges to better understanding cancer, one word practically leaps from the mouths of many researchers: heterogeneity.

A tumor, the researchers stress, is not a uniform mass of identical cells with identical behaviors. Cells can act quite differently in one part of a tumor than in another. Genes critical to cell proliferation, for instance, may be active in one area but not another, or a subpopulation of cancer cells may be dormant, practically hiding from any drug that may try to enter their lair.

This heterogeneity has been blamed, for example, for the limited success of targeted therapies and of efforts to identify better diagnostic and prognostic markers of disease.

Researchers are now discovering what many have long suspected: much of what makes tumors heterogeneous overall is the substantial heterogeneity among individual cancer cells.

Until recently, the meticulous scrutiny of individual cells has been nearly impossible, particularly because of the relative scarcity in each cell of the key components that need to be measured, such as DNA and RNA. But thanks to technological advances that can help overcome some of those limitations, a growing number of investigators are beginning to delve deeper into the biology of the single cell.

The studies conducted to date “show us how much diversity there is among cancer cells in a given tumor,” said Dr. Garry Nolan, an immunologist at Stanford University whose lab is focused on mapping communication networks in individual cancer cells.

Even with improved technology, however, conducting studies at the single-cell level is difficult and can be time-consuming and expensive. But with growing interest—and $90 million over 5 years from the NIH Common Fund initiative (see the sidebar)—there is cautious optimism that over the next decade single-cell research may begin to pay dividends for patients with cancer and other diseases.

Moving beyond the Average

Most research on the molecular biology of tumors requires the use of mixtures of tens or hundreds of thousands of cells. Those samples “have immune cells, endothelial cells, and other infiltrating cells that make up the milieu of what a tumor actually is,” explained Dr. Dan Gallahan of NCI’s Division of Cancer Biology. “That really makes it difficult to get a grasp on what defines or, more importantly, how to treat a tumor.”

Results from studies that involve a bulk population of cells, Dr. Gallahan continued, essentially represent an average measurement.

Studying single cells is a way to “defy the average,” Dr. Marc Unger, chief scientific officer of Fluidigm Corporation, said earlier this year at a stem cell conference in Japan. (Fludigm, which develops tools for single-cell analysis, and the Broad Institute recently announced plans to establish a single-cell genomics research center.)

Single-cell analysis may be able to provide important clinical insights, said Dr. Nicholas Navin of the University of Texas MD Anderson Cancer Center, who has used next-generation sequencing to study variations in the number of genes (copy number variation) in single cancer cells.

Single-cell analysis might, for example, help identify “pre-existing [cell populations] that are resistant to chemotherapy or rare subpopulations that are capable of invasion and metastasis,” he said. “We may also be able to quantify the extent of heterogeneity in a patient’s tumor using single-cell data and use this index to predict how a patient will respond to treatment,” Dr. Navin continued.

Results from several recent studies have highlighted the challenges posed by tumor heterogeneity.

For example, researchers at BGI (formerly Beijing Genomics Institute) sequenced the protein-coding regions of DNA (the exome) of 20 cancer cells and 5 normal cells from a man with metastatic kidney cancer. The researchers found a tremendous amount of genetic diversity across the cancer cells, with very few sharing any common genetic mutations.

Much of the work in the analysis of single cells is still quite preliminary, and any potential clinical impact is still some years away, researchers agree.

“The problem with the single-cell data is that we don’t really know yet what they mean,” Dr. Sangeeta Bhatia of the Massachusetts Institute of Technology commented recently in Nature Biotechnology.

And studies involving bulk populations of cells will not be going away any time soon, noted Dr. Betsy Wilder, director of the NIH Office of Strategic Coordination, which oversees the NIH Common Fund.

“Single-cell analysis isn’t warranted for every question that’s out there,” Dr .Wilder stressed. “Studies using populations of cells will continue to be done, because it makes a lot of sense to do them.”

Technology, a Driving Force

Beyond just an interest in learning more about single cells—what Dr. Gallahan called “the operational units in biology”—technology has been the driving force behind the growth of this field.

Dr. Stephen Quake, also of Stanford, has pioneered the use of microfluidics, which typically uses small chips with microscopic channels and valves—often called lab-on-a-chip devices—that allow researchers to single out and study individual cells. Dr. Quake, who co-founded Fluidigm, and others are increasingly using these devices for gene-expression profiling and for sequencing RNA and DNA of individual cells.

Dr. Nolan’s research involves a hybrid approach that combines two technologies: a souped-up method of flow cytometry, which has been used for several decades to sort cells and to perform limited analyses of single cells, and mass spectrometry, which is often used to identify and quantify proteins in biological samples.

Dr. Nolan’s lab is using this “mass cytometry” approach—developed by Dr. Scott Tanner of the University of Toronto—to characterize the response of individual cells to different stimuli, such as cytokines, growth factors, and a variety of drugs. Much of the group’s work has focused on analyzing normal blood-forming cells.

They published an influential study last year in Science that revealed some of the subtle biochemical changes that occur during cell differentiation. The study also described how dasatinib (Sprycel), a drug used to treat chronic myelogenous leukemia, affects certain intracellular activities. The research, Dr. Nolan said, is a prelude to studying individual cells from patients with blood cancers. The approach, he believes, may prove particularly useful for identifying new drugs and for testing them in the lab.

A tumor is not a uniform mass of identical cells with identical behaviors. Cells can act quite differently in one part of a tumor than in another.

The Microscale Life Sciences Center (MLSC), an NIH Center of Excellence in Genomic Science that is housed at Arizona State University, develops and applies the latest technology to single-cell research.

The center—a collaboration of investigators from Arizona State, the University of Washington, Brandeis University, and the Fred Hutchinson Cancer Research Center—includes researchers from numerous disciplines, including microfluidics, computer science, physics, engineering, and biochemistry, explained principal investigator Dr. Deirdre Meldrum.

“All of these disciplines are needed to develop the new technologies we’re working on,” said Dr. Meldrum, an electrical engineer by training.

In its initial work, the MLSC has measured metabolic processes in single living cells, including cellular respiration—the process by which cells acquire energy—as it relates to an individual cell’s ability to resist or succumb to cell death. The workhorse of this effort is a platform called the Cellarium, developed by Dr. Meldrum’s team. Individual cells are isolated in controlled chambers, Dr. Meldrum explained, “where we perturb them and measure how they change over time.”

Investigators at the MLSC and elsewhere have also developed technologies to image single cells. MLSC scientists are using a device developed by VisionGate, called the Cell-CT, “that enables accurate measurement of cellular features in true 3D,” Dr. Meldrum said.

MLSC researchers have studied abnormal esophageal cells from people with Barrett esophagus, a condition that increases the risk of esophageal adenocarcinoma. In particular, they’ve looked at how these cells respond to very low oxygen levels, or hypoxia.

Acid reflux, which can cause Barrett esophagus, can damage the esophagus “and lead to transient hypoxia in the epithelial lining of the esophagus,” explained Dr. Thomas Paulson, an investigator at Fred Hutchinson. In effect, he continued, the Cellarium system provides a snapshot of how this hypoxic environment selects for variants of cells that are able to survive and grow in it, providing insights into the factors that influence the evolution of cells from normal to cancerous.

Although Dr. Paulson’s work at MLSC is focused on Barrett esophagus, he believes the approach represents an excellent model system for studying cancer risk in general.

“I think our understanding of what constitutes risk is probably going to change as we understand the types of changes that occur at the single-cell level” that can transform a healthy cell into a cancerous cell, he said.

Deeper Dives Ahead

There’s a general acknowledgement in the field that single-cell analysis still has important limitations. Technological improvements are needed that can allow for the same type of molecular and structural “deep dives” that can be achieved by studying batches of cells. And powerful computer programs will be needed to help interpret the data from single-cell studies.

In addition, the research will eventually have to move beyond the confines of the mostly artificial environments in which single cells are now being tested, Dr. Gallahan noted. “As the technology gets better, we should be able to do more of this work in an in vivo setting.”

Although much more work is needed, the potential for what can be learned from studying single cells is quite large, Dr. Nolan believes.

“The fact that we’ve been able to make good decisions and learn as much as we have, even at the level of resolution [of cell populations], means that there’s something of even greater value to mine when you get to the level of the single cell,” he said.

Transforming the Field of Single-Cell Research

This month, the National Institutes of Health will announce grant recipients for the NIH Common Fund’s single-cell analysis program.

The program, which includes three funding opportunities, “is largely a technology building program,” explained Dr. Wilder. The NIH Common Fund launched this program now because “there’s a sense that the technologies exist that can enable us to do the sort of analysis required to look at single cells in their native environment,” such as in a piece of excised tissue.

Although the focus is on technology, an important goal of the initiative is to support research that will “identify a few general principles of how single cells behave in a complex environment,” added Dr. Ravi Basavappa, the program director for the single-cell analysis program.

From the planning discussions, it was clear that the program should not limit the types of technology under consideration, Dr. Wilder commented. “Our analysis indicated that there are a lot of possibilities, so we left it up to the imaginations of the investigators to determine what technologies would be most transformative for the field as a whole.”

Source: NCI

Compounds activate key cancer enzyme to interfere with tumor formation.


NIH-supported research may provide tool to study cancer metabolism

Scientists have known for decades that cancer cells use more glucose than healthy cells, feeding the growth of some types of tumors. Now, a team that includes researchers from the National Institutes of Health’s new National Center for Advancing Translational Sciences (NCATS) has identified compounds that delay the formation of tumors in mice, by targeting a key enzyme that governs how cancer cells use glucose and its metabolites.

The study, published August 26 in the advance online publication of Nature Chemical Biology, was led by researchers from the Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology (MIT), Cambridge. Researchers from the Structural Genomics Consortium at the University of Toronto and Harvard Medical School, Boston, also joined NCATS scientists to author the paper.

All cells use an enzyme called pyruvate kinase to derive energy from glucose. Recent studies have shown that cancer cells preferentially use one form of pyruvate kinase, called PKM2, which uses glucose to make additional cancer cells instead of energy. This altered metabolic state appears to be a fundamental aspect of many cancers, and reversing the process represents a new opportunity for cancer treatment.

In the study report, the researchers describe the identification of molecular compounds that activate PKM2, correct the way human cancer cells use glucose, and delay tumor development and decrease tumor size in mice. The results support PKM2 activation as a potential therapeutic strategy for cancer. However, the researchers emphasized there is much more work needed to understand the implications of their findings for humans, such as determining what types of tumors might be sensitive to PKM2 activation.

“The last several years have brought an avalanche of new discoveries that have begun to explain a phenomenon of altered cancer cell metabolism first described almost 90 years ago,” said Christopher P. Austin, M.D., NCATS Division of Pre-Clinical Innovation director and one of the paper’s authors. “This work provides a wonderful example of how molecular compounds can be used as tools to probe and understand biological processes, and at the same time explore new drug targets in the fight against cancer.”

NIH Common Fund’s Molecular Libraries Program supported this research, as well as the prior development of the PKM2 activators. Additional support was provided by NCATS.

“It is gratifying to see such important scientific discoveries made possible in part by the Molecular Libraries Program,” said James M. Anderson, M.D., Ph.D., director of the Division of Program Coordination, Planning, and Strategic Initiatives that guides the NIH Common Fund’s programs. “This collaboration paired experts from two different scientific disciplines and transformed our understanding of cancer cell metabolism.”

The study of cancer cell metabolism, pioneered by Nobel Laureate Otto Warburg in the early part of the 20th century, has witnessed a resurgence in research activity in recent years. New compound tools will be critical to dissecting the complex pathways that govern how cancer cells utilize nutrients such as glucose that provide the molecular building blocks to support rampant cell growth. The PKM2 activators detailed in the paper are among the first pharmacological compounds identified that will enable researchers to dig deeper into this key problem.

MIT researcher Matthew Vander Heiden, M.D., Ph.D., senior author of the paper and a medical oncologist whose lab studies cancer metabolism, has been a leading advocate of the idea that metabolic reprogramming provides cancer cells with an ability to prosper and grow. Previous work pioneered by Vander Heiden with Dimitrios Anastasiou and Lewis Cantley, both of Harvard Medical School, suggested that activating PKM2 might restore cancer cell metabolism to a normal state.

To test that theory, MIT researchers and the NIH formed a collaboration in 2008 to identify PKM2 activators, laying the foundation for the current study. NCATS researchers discovered the compounds, using a high-throughput screening robotic system. Researchers optimized the compounds in order to yield molecules with the needed pharmacological activity and the required physical properties for experimentation.

In the new study, the researchers focused their attention on how the compounds activate PKM2 and the effect this activation has on the formation of tumors. Hints as to the consequences of PKM2 activation were derived from experiments involving PKM1, a highly related enzyme of PKM2 that is found in healthy cells in an active state.

The unique mechanism of PKM2 activators prompted the research team to dig deeper into the metabolic consequences of activating PKM2. The researchers looked at the ability of the activators to mimic the results associating PKM1 expression with delayed tumor development. Aided by researchers at Agios Pharmaceuticals, Cambridge, Mass., they determined that one PKM2 activator, TEPP-46, could be used in a mouse study. The mice were given the compound, and it hindered tumor development and reduced tumor size.

“All cancers have PKM2, and learning about the basics of cancer cell metabolism and proliferation is essential to targeting human tumors,” Vander Heiden said. “I am cautiously optimistic that as we learn more about cancer cell metabolism, we may be able to identify drugs that act on PKM2 or other metabolic enzymes that could be tested against human cancers.”

The National Center for Advancing Translational Sciences (NCATS) aims to catalyze the generation of innovative methods and technologies that will enhance the development, testing and implementation of diagnostics and therapeutics across a wide range of human diseases and conditions. For more information about NCATS, visit http://www.ncats.nih.gov.

The NIH Common Fund supports a series of exceptionally high-impact research programs that are broadly relevant to health and disease. Common Fund programs are designed to overcome major research barriers and pursue emerging opportunities for the benefit of the biomedical research community at large. The research products of Common Fund programs are expected to catalyze disease-specific research supported by the NIH Institutes and Centers. Additional information about the NIH Common Fund can be found at http://commonfund.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases.

For more information about NIH and its programs, visit www.nih.gov.

Source: NIH.gov