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Panel Finds Exercise May Lower Cancer Risk, Improve Outcomes

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Mature woman doing moderate exercise
Credit: gettyimages/vgajic

Exercise can work wonders for your health, including strengthening muscles and bones, and boosting metabolism, mood, and memory skills. Now comes word that staying active may also help to lower your odds of developing cancer. 

After reviewing the scientific evidence, a panel of experts recently concluded that physical activity is associated with reduced risks for seven common types of cancer: colon, breast, kidney, endometrial, bladder, stomach, and esophageal adenocarcinoma. What’s more, the experts found that exercise—both before and after a cancer diagnosis—was linked to improved survival among people with breast, colorectal, or prostate cancers.

About a decade ago, the American College of Sports Medicine (ACSM) convened its first panel of experts to review the evidence on the role of exercise in cancer. At the time, there was limited evidence to suggest a connection between exercise and a reduced risk for breast, colon, and perhaps a few other cancer types. There also were some hints that exercise might help to improve survival among people with a diagnosis of cancer.

Today, the evidence linking exercise and cancer has grown considerably. That’s why the ACSM last year convened a group of 40 experts to perform a comprehensive review of the research literature and summarize the level of the evidence. The team, including Charles Matthews and Frank Perna with the NIH’s National Cancer Institute, reported its findings and associated guidelines and recommendations in three papers just published in Medicine & Science in Sports & Exercise and CA: A Cancer Journal for Clinicians [1,2,3].

Here are some additional highlights from the papers:

Ÿ There’s moderate evidence to support an association between exercise and reduced risk for some other cancer types, including cancers of the lung and liver.

Ÿ While the optimal amount of exercise needed to reduce cancer risk is still unclear, being physically active is clearly one of the most important steps in general that people of all ages and abilities can take.

Ÿ Is sitting the new smoking? Reducing the amount of time spent sitting also may help to lower the risk of some cancers, including endometrial, colon, and lung cancers. However, there’s not enough evidence to draw clear conclusions yet.

Ÿ Every cancer survivor should, within reason, “avoid inactivity.” There’s plenty of evidence to show that aerobic and resistance exercise training improves many cancer-related health outcomes, reducing anxiety, depression, and fatigue while improving physical functioning and quality of life.

Ÿ Physical activity before and after a diagnosis of cancer also may help to improve survival in some cancers, with perhaps the greatest benefits coming from exercise during and/or after cancer treatment.

Based on the evidence, the panel recommends that cancer survivors engage in moderate-intensity exercise, including aerobic and resistance training, at least two to three times a week. They should exercise for about 30 minutes per session.

The recommendation is based on added confirmation that exercise is generally safe for cancer survivors. The data indicate exercise can lead to improvements in anxiety, depression, fatigue, overall quality of life, and in some cases survival.

The panel also recommends that treatment teams and fitness professionals more systematically incorporate “exercise prescriptions” into cancer care. They should develop the resources to design exercise prescriptions that deliver the right amount of exercise to meet the specific needs, preferences, and abilities of people with cancer.

The ACSM has launched the “Moving Through Cancer” initiative. This initiative will help raise awareness about the importance of exercise during cancer treatment and help support doctors in advising their patients on those benefits.

It’s worth noting that there are still many fascinating questions to explore. While exercise is known to support better health in a variety of ways, correlation is not the same as causation. Questions remain about the underlying mechanisms that may help to explain the observed associations between physical activity, lowered cancer risk, and improved cancer survival.

An intensive NIH research effort, called the Molecular Transducers of Physical Activity Consortium (MoTrPAC), is underway to identify molecular mechanisms that might explain the wide-ranging benefits of physical exercise. It might well shed light on cancer, too.

As that evidence continues to come in, the findings are yet another reminder of the importance of exercise to our health. Everybody—people who are healthy, those with cancer, and cancer survivors alike—should make an extra effort to remain as physically active as our ages, abilities, and current health will allow. If I needed any more motivation to keep up my program of vigorous exercise twice a week, guided by an experienced trainer, here it is!

References:

[1] Exercise Is Medicine in Oncology: Engaging Clinicians to Help Patients Move Through Cancer. Schmitz KH, Campbell AM, Stuiver MM, Pinto BM, Schwartz AL, Morris GS, Ligibel JA, Cheville A, Galvão, DA, Alfano CM, Patel AV, Hue T, Gerber LH, Sallis R, Gusani NJ, Stout NL, Chan L, Flowers F, Doyle C, Helmrich S, Bain W, Sokolof J, Winters-Stone KM, Campbell KL, Matthews CE.  CA Cancer J Clin. 2019 Oct 16 [Epub ahead of publication]

[2] American College of Sports Medicine Roundtable Report on Physical Activity, Sedentary Behavior, and Cancer Prevention and Control. Patel AV, Friedenreich CM, Moore SC, Hayes SC, Silver JK, Campbell KL, Gerber LH, George SM, Fulton JE, Denlinger C, Morris GS, Hue T, Schmitz KH, Matthews CE. Med Sci Sports Exerc. 2019 Oct 16. [Epub ahead of publication]

[3] Exercise Guidelines for Cancer Survivors: Consensus Statement from International Multidisciplinary Roundtable. Campbell KL, Winters-Stone KM, Wiskemann J, May AM, Schwartz AL, Courneya KS, Zucker DS, Matthews CE, Ligibel JA, Gerber LH, Morris GS, Patel AV, Hue TF, Perna FM, Schmitz KH. Med Sci Sports Exerc. 2019 Oct 16. [Epub ahead of publication]

Links:

Physical Activity and Cancer (National Cancer Institute/NIH)

Moving Through Cancer (American College of Sports Medicine, Indianapolis, IN)

American College of Sports Medicine

Charles Matthews (NCI)

Frank Perna (NCI)

NIH Support: National Cancer Institute


Multiplex Rainbow Technology Offers New View of the Brain

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Proteins imaged with this new approach
Caption: Confocal LNA-PRISM imaging of neuronal synapses. Conventional images of cell nuclei and two proteins (top row, three images on the left), along with 11 PRISM images of proteins and one composite, multiplexed image (bottom row, right). Credit: Adapted from Guo SM, Nature Communications, 2019

The NIH-led Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative is revolutionizing our understanding of how the brain works through its creation of new imaging tools. One of the latest advances—used to produce this rainbow of images—makes it possible to view dozens of proteins in rapid succession in a single tissue sample containing thousands of neural connections, or synapses.

Apart from their colors, most of these images look nearly identical at first glance. But, upon closer inspection, you’ll see some subtle differences among them in both intensity and pattern. That’s because the images capture different proteins within the complex network of synapses—and those proteins may be present in that network in different amounts and locations. Such findings may shed light on key differences among synapses, as well as provide new clues into the roles that synaptic proteins may play in schizophrenia and various other neurological disorders.

Synapses contain hundreds of proteins that regulate the release of chemicals called neurotransmitters, which allow neurons to communicate. Each synaptic protein has its own specific job in the process. But there have been longstanding technical difficulties in observing synaptic proteins at work. Conventional fluorescence microscopy can visualize at most four proteins in a synapse.

As described in Nature Communications [1], researchers led by Mark Bathe, Massachusetts Institute of Technology (MIT), Cambridge, and Jeffrey Cottrell, Broad Institute of MIT and Harvard, Cambridge, have just upped this number considerably while delivering high quality images. They did it by adapting an existing imaging method called DNA PAINT [2]. The researchers call their adapted method PRISM. It is short for: Probe-based Imaging for Sequential Multiplexing.

Here’s how it works: First, researchers label proteins or other molecules of interest using antibodies that recognize those proteins. Those antibodies include a unique DNA probe that helps with the next important step: making the proteins visible under a microscope.

To do it, they deliver short snippets of complementary fluorescent DNA, which bind the DNA-antibody probes. While each protein of interest is imaged separately, researchers can easily wash the probes from a sample to allow a series of images to be generated, each capturing a different protein of interest.

In the original DNA PAINT, the DNA strands bind and unbind periodically to create a blinking fluorescence that can be captured using super-resolution microscopy. But that makes the process slow, requiring about half an hour for each protein.

To speed things up with PRISM, Bathe and his colleagues altered the fluorescent DNA probes. They used synthetic DNA that’s specially designed to bind more tightly or “lock” to the DNA-antibody. This gives a much brighter signal without the blinking effect. As a result, the imaging can be done faster, though at slightly lower resolution.

Though the team now captures images of 12 proteins within a sample in about an hour, this is just a start. As more DNA-antibody probes are developed for synaptic proteins, the team can readily ramp up this number to 30 protein targets.

Thanks to the BRAIN Initiative, researchers now possess a powerful new tool to study neurons. PRISM will help them learn more mechanistically about the inner workings of synapses and how they contribute to a range of neurological conditions.

References:

[1] Multiplexed and high-throughput neuronal fluorescence imaging with diffusible probes. Guo SM, Veneziano R, Gordonov S, Li L, Danielson E, Perez de Arce K, Park D, Kulesa AB, Wamhoff EC, Blainey PC, Boyden ES, Cottrell JR, Bathe M. Nat Commun. 2019 Sep 26;10(1):4377.

[2] Super-resolution microscopy with DNA-PAINT. Schnitzbauer J, Strauss MT, Schlichthaerle T, Schueder F, Jungmann R. Nat Protoc. 2017 Jun;12(6):1198-1228.

Links:

Schizophrenia (National Institute of Mental Health)

Mark Bathe (Massachusetts Institute of Technology, Cambridge)

Jeffrey Cottrell (Broad Institute of MIT and Harvard, Cambridge)

Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative (NIH)

NIH Support: National Institute of Mental Health; National Human Genome Research Institute; National Institute of Neurological Disorders and Stroke; National Institute of Environmental Health Sciences


Americans Are Still Eating Too Much Added Sugar, Fat

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Foods with refined grains and sugar
Credit: iStock/happy_lark

Most of us know one of the best health moves we can make is to skip the junk food and eat a nutritious, well-balanced diet. But how are we doing at putting that knowledge into action? Not so great, according to a new analysis that reveals Americans continue to get more than 50 percent of their calories from low-quality carbohydrates and artery-clogging saturated fat.

In their analysis of the eating habits of nearly 44,000 adults over 16 years, NIH-funded researchers attributed much of our nation’s poor dietary showing to its ongoing love affair with heavily processed fast foods and snacks. But there were a few bright spots. The analysis also found that, compared to just a few decades ago, Americans are eating more foods with less added sugar, as well as more whole grains (e.g., brown rice, quinoa, rolled oats), plant proteins (e.g., nuts, beans), and sources of healthy fats (e.g., olive oil).

Over the last 20-plus years, research has generated new ideas about eating a proper diet. In the United States, the revised thinking led to the 2015-2020 Dietary Guidelines for Americans. They recommend eating more fruits, vegetables, whole grains, and other nutrient-dense foods, while limiting foods containing added sugars, saturated fats, and salt.

In the report published in JAMA, a team of researchers wanted to see how Americans are doing at following the new guidelines. The team was led by Shilpa Bhupathiraju, Harvard T. H. Chan School of Public Health, Boston, and Fang Fang Zhang, Tufts University, Boston.

To get the answer, the researchers looked to the National Health and Nutrition Examination Survey (NHANES). The survey includes a nationally representative sample of U.S. adults, age 20 or older, who had answered questions about their food and beverage intake over a 24-hour period at least once during nine annual survey cycles between 1999-2000 and 2015-2016.

The researchers assessed the overall quality of the American diet using the Healthy Eating Index-2015 (HEI-2015), which measures adherence to the 2015-2020 Dietary Guidelines. The HEI-2015 scores range from 0 to 100, with the latter number being a perfect, A-plus score. The analysis showed the American diet barely inching up over the last two decades from a final score of 55.7 to 57.7.

That, of course, is still far from a passing grade. Some of the common mistakes identified:

• Refined grains, starchy vegetables, and added sugars still account for 42 percent of the average American’s daily calories.
• Whole grains and fruits provide just 9 percent of daily calories.
• Saturated fat consumption remains above 10 percent of daily calories, as many Americans continue to eat more red and processed meat.

Looking on the bright side, the data do indicate more Americans are starting to lean toward the right choices. They are getting slightly more of their calories from healthier whole grains and a little less from added sugar. Americans are also now looking a little more to whole grains, nuts, and beans as a protein source. It’s important to note, though, these small gains weren’t seen in lower income groups or older adults.

The bottom line is most Americans still have an awfully long way to go to shape up their diets. The question is: how to get there? There are plenty of good choices that can help to turn things around, from reading food labels and limiting calories or portion sizes to exercising and finding healthy recipes that suit your palate.

Meanwhile, nutrition research is poised for a renaissance. Tremendous progress is being made in studying the microbial communities, or microbiomes, helping to digest our foods. The same is true for studies of energy metabolism, genetic variation influencing our dietary preferences, and the effects of aging.

This is an optimum time to enhance the science and evidence base for human nutrition. That may result in some updating of the scoring system for the nation’s dietary report card. But it will be up to all of us to figure out how to ace it.

References:

[1] Trends in Dietary Carbohydrate, Protein, and Fat Intake and Diet Quality Among US Adults, 1999-2016. Shan Z, Rehm CD, Rogers G, Ruan M, Wang DD, Hu FB, Mozaffarian D, Zhang FF, Bhupathiraju SN. JAMA. 2019 Sep 24;322(12):1178-1187.

Links:

Eat Right (National Heart, Lung, and Blood Institute/NIH)

Dietary Fats (MedlinePlus, National Library of Medicine/NIH)

ChooseMyPlate (U.S. Department of Agriculture)

Healthy Eating Index (Department of Agriculture)

NIH Nutrition Research Task Force (National Institute of Diabetes and Digestive and Kidney Disease/NIH)

Dietary Guidelines for Americans (U.S. Department of Health and Human Services)

Shilpa Bhupathiraju (Harvard T. H. Chan School of Public Health, Boston)

Fang Fang Zhang (Tufts University, Boston)

NIH Support: National Institute on Minority Health and Health Disparities; National Institute of Diabetes and Digestive and Kidney Diseases


Body-on-a-Chip Device Predicts Cancer Drug Responses

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Body-on-a-Chip
Credit: McAleer et al., Science Translational Medicine, 2019

Researchers continue to produce impressive miniature human tissues that resemble the structure of a range of human organs, including the livers, kidneys, hearts, and even the brain. In fact, some researchers are now building on this success to take the next big technological step: placing key components of several miniature organs on a chip at once.

These body-on-a-chip (BOC) devices place each tissue type in its own pea-sized chamber and connect them via fluid-filled microchannels into living, integrated biological systems on a laboratory plate. In the photo above, the BOC chip is filled with green fluid to make it easier to see the various chambers. For example, this easy-to-reconfigure system can make it possible to culture liver cells (chamber 1) along with two cancer cell lines (chambers 3, 5) and cardiac function chips (chambers 2, 4).

Researchers circulate blood-mimicking fluid through the chip, along with chemotherapy drugs. This allows them to test the agents’ potential to fight human cancer cells, while simultaneously gathering evidence for potential adverse effects on tissues placed in the other chambers.

This BOC comes from a team of NIH-supported researchers, including James Hickman and Christopher McAleer, Hesperos Inc., Orlando, FL. The two were challenged by their Swiss colleagues at Roche Pharmaceuticals to create a leukemia-on-a-chip model. The challenge was to see whether it was possible to reproduce on the chip the known effects and toxicities of diclofenac and imatinib in people.

As published in Science Translational Medicine, they more than met the challenge. The researchers showed as expected that imatinib did not harm liver cells [1]. But, when treated with diclofenac, liver cells on the chip were reduced in number by about 30 percent, an observation consistent with the drug’s known liver toxicity profile.

As a second and more challenging test, the researchers reconfigured the BOC by placing a multi-drug resistant vulva cancer cell line in one chamber and, in another, a breast cancer cell line that responded to drug treatment. To explore side effects, the system also incorporated a chamber with human liver cells and two others containing beating human heart cells, along with devices to measure the cells’ electrical and mechanical activity separately.

These studies showed that tamoxifen, commonly used to treat breast cancer, indeed killed a significant number of the breast cancer cells on the BOC. But, it only did so after liver cells on the chip processed the tamoxifen to produce its more active metabolite!

Meanwhile, tamoxifen alone didn’t affect the drug-resistant vulva cancer cells on the chip, whether or not liver cells were present. This type of cancer cell has previously been shown to pump the drug out through a specific channel. Studies on the chip showed that this form of drug resistance could be overcome by adding a second drug called verapamil, which blocks the channel.

Both tamoxifen alone and the combination treatment showed some off-target effects on heart cells. While the heart cells survived the treatment, they contracted more slowly and with less force. The encouraging news was that the heart cells bounced back from the tamoxifen-only treatment within three days. But when the drug-drug combination was tested, the cardiac cells did not recover their function during the same time period.

What makes advances like this especially important is that only 1 in 10 drug candidates entering human clinical trials ultimately receives approval from the Food and Drug Administration (FDA) [2]. Often, drug candidates fail because they prove toxic to the human brain, liver, kidneys, or other organs in ways that preclinical studies in animals didn’t predict.

As BOCs are put to work in testing new drug candidates and especially treatment combinations, the hope is that we can do a better job of predicting early on which chemical compounds will prove safe and effective in humans. For those drug candidates that are ultimately doomed, “failing early” is key to reducing drug development costs. By culturing an individual patient’s cells in the chambers, BOCs also may be used to help doctors select the best treatment option for that particular patient. The ultimate goal is to accelerate the translation of basic discoveries into clinical breakthroughs. For more information about tissue chips, take a look at NIH’s Tissue Chip for Drug Screening program.

References:

[1] Multi-organ system for the evaluation of efficacy and off-target toxicity of anticancer therapeutics. McAleer CW, Long CJ, Elbrecht D, Sasserath T, Bridges LR, Rumsey JW, Martin C, Schnepper M, Wang Y, Schuler F, Roth AB, Funk C, Shuler ML, Hickman JJ. Sci Transl Med. 2019 Jun 19;11(497).

[2] Clinical development success rates for investigational drugs. Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J. Nat Biotechnol. 2014 Jan;32(1):40-51.

Links:

Tissue Chip for Drug Screening (National Center for Advancing Translational Sciences/NIH)

James Hickman (Hesperos, Inc., Orlando, FL)

Hesperos, Inc.

NIH Support: National Center for Advancing Translational Sciences


Gene Therapy Shows Promise Repairing Brain Tissue Damaged by Stroke

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Glial Gene Therapy
Caption: Neurons (red) converted from glial cells using a new NeuroD1-based gene therapy in mice. Credit: Chen Laboratory, Penn State, University Park

It’s a race against time when someone suffers a stroke caused by a blockage of a blood vessel supplying the brain. Unless clot-busting treatment is given within a few hours after symptoms appear, vast numbers of the brain’s neurons die, often leading to paralysis or other disabilities. It would be great to have a way to replace those lost neurons. Thanks to gene therapy, some encouraging strides are now being made.

In a recent study in Molecular Therapy, researchers reported that, in their mouse and rat models of ischemic stroke, gene therapy could actually convert the brain’s support cells into new, fully functional neurons [1]. Even better, after gaining the new neurons, the animals had improved motor and memory skills.

For the team led by Gong Chen, Penn State, University Park, the quest to replace lost neurons in the brain began about a decade ago. While searching for the right approach, Chen noticed other groups had learned to reprogram fibroblasts into stem cells and make replacement neural cells.

As innovative as this work was at the time, it was performed mostly in lab Petri dishes. Chen and his colleagues thought, why not reprogram cells already in the brain?

They turned their attention to the brain’s billions of supportive glial cells. Unlike neurons, glial cells divide and replicate. They also are known to survive and activate following a brain injury, remaining at the wound and ultimately forming a scar. This same process had also been observed in the brain following many types of injury, including stroke and neurodegenerative conditions such as Alzheimer’s disease.

To Chen’s NIH-supported team, it looked like glial cells might be a perfect target for gene therapies to replace lost neurons. As reported about five years ago, the researchers were on the right track [2].

The Chen team showed it was possible to reprogram glial cells in the brain into functional neurons. They succeeded using a genetically engineered retrovirus that delivered a single protein called NeuroD1. It’s a neural transcription factor that switches genes on and off in neural cells and helps to determine their cell fate. The newly generated neurons were also capable of integrating into brain circuits to repair damaged tissue.

There was one major hitch: the NeuroD1 retroviral vector only reprogrammed actively dividing glial cells. That suggested their strategy likely couldn’t generate the large numbers of new cells needed to repair damaged brain tissue following a stroke.

Fast-forward a couple of years, and improved adeno-associated viral vectors (AAV) have emerged as a major alternative to retroviruses for gene therapy applications. This was exactly the breakthrough that the Chen team needed. The AAVs can reprogram glial cells whether they are dividing or not.

In the new study, Chen’s team, led by post-doc Yu-Chen Chen, put this new gene therapy system to work, and the results are quite remarkable. In a mouse model of ischemic stroke, the researchers showed the treatment could regenerate about a third of the total lost neurons by preferentially targeting reactive, scar-forming glial cells. The conversion of those reactive glial cells into neurons also protected another third of the neurons from injury.

Studies in brain slices showed that the replacement neurons were fully functional and appeared to have made the needed neural connections in the brain. Importantly, their studies also showed that the NeuroD1 gene therapy led to marked improvements in the functional recovery of the mice after a stroke.

In fact, several tests of their ability to make fine movements with their forelimbs showed about a 60 percent improvement within 20 to 60 days of receiving the NeuroD1 therapy. Together with study collaborator and NIH grantee Gregory Quirk, University of Puerto Rico, San Juan, they went on to show similar improvements in the ability of rats to recover from stroke-related deficits in memory.

While further study is needed, the findings in rodents offer encouraging evidence that treatments to repair the brain after a stroke or other injury may be on the horizon. In the meantime, the best strategy for limiting the number of neurons lost due to stroke is to recognize the signs and get to a well-equipped hospital or call 911 right away if you or a loved one experience them. Those signs include: sudden numbness or weakness of one side of the body; confusion; difficulty speaking, seeing, or walking; and a sudden, severe headache with unknown causes. Getting treatment for this kind of “brain attack” within four hours of the onset of symptoms can make all the difference in recovery.

References:

[1] A NeuroD1 AAV-Based gene therapy for functional brain repair after ischemic injury through in vivo astrocyte-to-neuron conversion. Chen Y-C et al. Molecular Therapy. Published online September 6, 2019.

[2] In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer’s disease model. Guo Z, Zhang L, Wu Z, Chen Y, Wang F, Chen G. Cell Stem Cell. 2014 Feb 6;14(2):188-202.

Links:

Stroke (National Heart, Lung, and Blood Institute/NIH)

Gene Therapy (National Human Genome Research Institute/NIH)

Chen Lab (Penn State, University Park)

NIH Support: National Institute on Aging; National Institute of Mental Health


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