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Could cancer immunotherapy success depend on gut bacteria?

Gut bacteria can penetrate tumor cells and boost the effectiveness of an experimental immunotherapy that targets the CD47 protein.

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Could the response to cancer immunotherapy depend on bacteria that originate in the gut and travel to the tumor?

A study by researchers at UT Southwestern Medical Center and the University of Chicago suggests exactly that, revealing that gut bacteria can penetrate tumor cells and boost the effectiveness of an experimental immunotherapy that targets the CD47 protein.

Using mouse models of malignancy, the scientists found that the intestinal microbe Bifidobacterium accumulates within tumors, transforming anti-CD47 unresponsive tumors into responsive ones.

The team’s study, published today in the Journal of Experimental Medicine, discovered that the response to treatment depends on the type of bacteria living in the animals’ guts. They then identified the mechanism, finding that the combination of antibodies against CD47 and gut bacteria works via the body’s STING pathway of innate immunity – the body’s first line of defense against infection.

Their experiments used mice from different resource facilities, antibiotic-fed mice, and mice raised in a germ-free environment.

In one experiment, they studied mice raised in two different facilities and that had distinct mixtures of bacteria in their intestines. One group was responsive to anti-CD47 and another was not. The second group became responsive, however, after being housed with the responders, indicating that oral transfer or contact transmission of gut bacteria occurred between groups, the researchers say.

The protein CD47 is expressed in high levels on the surface of many cancer cells, where it acts as a “don’t eat me” signal to the immune system’s macrophages, commonly known as white blood cells. As a result, anti-CD47, also known as CD47 blockade therapy, is currently under investigation in multiple clinical trials. However, the mouse studies that predated those trials had mixed results, with only some mice responding to the anti-CD47 therapy, explains corresponding author Yang-Xin Fu, M.D., Ph.D., professor of pathology, immunology, and radiation at UT Southwestern.

“We felt we needed to improve anti-CD47 therapy and understand the mechanisms,” he says, leading them to wonder about the gut microbiome, the bacteria that grow in the intestines and aid with digestion. That bacterial ecosystem, sometimes called the microbiota, is also known to affect the gut’s ability to resist pathogens and the host’s response to cancer immunotherapy.

“But how the microbiota does that has been unclear,” Fu says. “This study finds that some of the bacteria from the gut travel to the tumor and get into the cells, or microenvironment, where the bacteria facilitate CD47 blockade’s ability to attack the tumor. We found it does that via the immune signaling pathway called stimulator of interferon genes (STING).”

The findings suggest that a probiotic might someday be used to improve anti-CD47 therapy, says Fu, a Cancer Prevention and Research Institute (CPRIT) Scholar and holder of the Mary Nell and Ralph B. Rogers Professorship in Immunology at UT Southwestern.

The researchers also found that tumor-bearing mice that normally respond to anti-CD47 treatment failed to respond if their gut bacteria were killed off by antibiotics. In contrast, anti-CD47 treatment became effective in mice that are usually nonresponsive when these animals were supplemented with Bifidobacteria, a type of bacteria that is often found in the gastrointestinal tract of healthy mice and humans.

They further discovered that the bacteria migrate into tumors, activating the STING immune signaling pathway. This sets off production of immune signaling molecules such as type 1 interferons and activating immune cells that appear to attack and destroy the tumor once the anti-CD47 agent nullifies the CD47’s “don’t eat me” tag, the researchers report. The researchers found that mice genetically unable to activate type 1 interferon failed to respond to the bacteria-immunotherapy approach. Similarly, mice unable to access the STING pathway showed no benefit from the combined bacteria-immunotherapy approach, confirming that STING signaling is essential.

“It is very possible that more than one type of gut microbiota could enhance tumor immunity in a similar way and we would like to investigate that,” he adds.

Fu and Ralph R. Weichselbaum, M.D., at the University of Chicago led the study. Co-authors include lead authors Yaoyao Shi and Wenxin Zheng as well as Kaiting Yang, Katharine G. Harris, Kaiyuan Ni, Lai Xue, Wenbin Lin, and Eugene B. Chang, all of the University of Chicago.

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Fitness

Study finds moderate-vigorous physical activity is the most efficient at improving fitness

Dedicated exercise (moderate-vigorous physical activity) was the most efficient at improving fitness. Specifically, exercise was three times more efficient than walking alone and more than 14 times more efficient than reducing the time spent sedentary. Additionally, they found that the greater time spent exercising and higher steps/day could partially offset the negative effects of being sedentary in terms of physical fitness.

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In the largest study performed to date to understand the relationship between habitual physical activity and physical fitness, researchers from Boston University School of Medicine (BUSM) have found that higher amount of time spent performing exercise (moderate-vigorous physical activity) and low-moderate level activity (steps) and less time spent sedentary, translated to greater physical fitness.

“By establishing the relationship between different forms of habitual physical activity and detailed fitness measures, we hope that our study will provide important information that can ultimately be used to improve physical fitness and overall health across the life course,” explained corresponding author Matthew Nayor, MD, MPH, assistant professor of medicine at BUSM.

He and his team studied approximately 2,000 participants from the community-based Framingham Heart Study who underwent comprehensive cardiopulmonary exercise tests (CPET) for the “gold standard” measurement of physical fitness. Physical fitness measurements were associated with physical activity data obtained through accelerometers (device that measures frequency and intensity of human movement) that were worn for one week around the time of CPET and approximately eight years earlier.

They found dedicated exercise (moderate-vigorous physical activity) was the most efficient at improving fitness. Specifically, exercise was three times more efficient than walking alone and more than 14 times more efficient than reducing the time spent sedentary. Additionally, they found that the greater time spent exercising and higher steps/day could partially offset the negative effects of being sedentary in terms of physical fitness.

According to the researchers, while the study was focused on the relationship of physical activity and fitness specifically (rather than any health-related outcomes), fitness has a powerful influence on health and is associated with lower risk of cardiovascular disease, diabetes, cancer and premature death. “Therefore, improved understanding of methods to improve fitness would be expected to have broad implications for improved health,” said Nayor, a cardiologist at Boston Medical Center.

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Fitness

Tips to avoid common running injuries

Injuries are very common among runners. Recent research estimates that 82% of runners will become injured during their running career and up to 90% will experience injury while training for a marathon. Some of the most common include a stress fracture, plantar fasciitis, hamstring tendinitis, ankle sprain, runners’ knee, and Achilles’ tendonitis.

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Whether training for a marathon or preparing for your first community race, being knocked off course with pain can be hard to handle mentally and physically.

Injuries are very common among runners. Recent research estimates that 82% of runners will become injured during their running career and up to 90% will experience injury while training for a marathon. Some of the most common include a stress fracture, plantar fasciitis, hamstring tendinitis, ankle sprain, runners’ knee, and Achilles’ tendonitis.

Injury prevention is critical. Here are some safety tips from Dr. Joshua Blomgren, a 15-time Chicago Marathon team physician and sports medicine physician, Midwest Orthopaedics at Rush:

Don’t over-train

Don’t increase weekly mileage or intensity by more than 10 percent each week. Build up slowly and let a good training schedule determine how much you run.

Invest in good shoes

Go to a specialty running shop to be properly fitted for running shoes and/or orthotics. Replace them every 350-500 miles. Incorrect shoes can affect your gait, leading to injuries in your feet, legs, knees, or hips.

Choose the best running surface

Look for running surfaces that absorb shock. Opt for asphalt over concrete. Find grass or dirt trails, especially for higher mileage. Avoid uneven surfaces and seek paths with slow curves.

Stretch!

Training causes tight muscles, leading to strain and changes in your gait. Commit to a stretching program. Just 5 -10 minutes after each workout can make a big difference.

Strengthen muscles

Runners have tight hip flexors because their quads are overtrained. Strengthen your hamstrings and glutes to reduce chance of injury and abductors, adductors, and core to create stability.

Watch out for heel striking

Heel striking occurs when your feet land in front of you and your heel hits the ground first. This is common among new runners but can lead to injuries such as shin splints, stress fractures, and joint pain. Land mid-sole with your foot directly underneath your body.

Prioritize posture

Good form means staying upright and keeping your shoulders back and relaxed. Work core exercises into your training and do posture checks every so often. Hold your head right above your shoulders and hips.

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Fitness

Postmenopausal women can dance their way to better health

After menopause, women are more likely to experience weight gain, overall/central body adiposity increases, and metabolic disturbances, such as increases in triglycerides and bad cholesterol. Together, these changes ultimately increase cardiovascular risk. Around this same time, women often are less physically active, which translates into reductions in lean mass and an increased risk of falls and fractures.

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Women often struggle with managing their weight and other health risk factors, such as high cholesterol, once they transition through menopause. A new study suggests that dancing may effectively lower cholesterol levels, improve fitness and body composition and in the process, improve self-esteem. Study results are published online today in Menopause, the journal of The North American Menopause Society (NAMS).

After menopause, women are more likely to experience weight gain, overall/central body adiposity increases, and metabolic disturbances, such as increases in triglycerides and bad cholesterol. Together, these changes ultimately increase cardiovascular risk. Around this same time, women often are less physically active, which translates into reductions in lean mass and an increased risk of falls and fractures. As a result of all these changes, postmenopausal women often suffer from decreased self-image and self-esteem, which are directly related to overall mental health.

Physical activity has been shown to minimize some of the many health problems associated with menopause. The effect of dancing, specifically, has already been investigated with regard to how it improves body composition and functional fitness. Few studies, however, have investigated the effects of dance on body image, self-esteem, and physical fitness together in postmenopausal women.

This new study was designed to analyze the effects of dance practice on body composition, metabolic profile, functional fitness, and self-image/self-esteem in postmenopausal women. Although the sample size was small, the study suggested some credible benefits of a three-times-weekly dance regimen in improving not only the lipid profile and functional fitness of postmenopausal women but also self-image and self-esteem.

Dance therapy is seen as an attractive option because it is a pleasant activity with low associated costs and low risk of injury for its practitioners. Additional confirmed benefits of regular dancing include improvement in balance, postural control, gait, strength, and overall physical performance. All of these benefits may contribute to a woman’s ability to maintain an independent, high-quality lifestyle throughout her lifespan.

Study results are published in the article “Dance practice modifies functional fitness, lipid profile, and self-image in postmenopausal women.”

“This study highlights the feasibility of a simple intervention, such as a dance class three times weekly, for improving not only fitness and metabolic profile but also self-image and self-esteem in postmenopausal women. In addition to these benefits, women also probably enjoyed a sense of camaraderie from the shared experience of learning something new,” says Dr. Stephanie Faubion, NAMS medical director.

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