Plaing In Nature Boosts Children's Immune Systems Says New Study

Plaing In Nature Boosts Children’s Immune Systems Says New Study

  • October 23, 2020
Kids Microbiome Study

Photo: Stock Photos from PURINO/Shutterstock

Playing outside is an important and healthy part of childhood. Away from screens, children need time to breathe fresh air and get dirty as they explore the world around them. Many parents and teachers believe that getting a bit messy in nature is beneficial to children’s immune systems. A recent study by the University of Helsinki has proved this parental folk wisdom to be true. Focused on pre-school aged children, the study found that playing on a forest floor drastically boosted children’s immune systems and microbiomes—both critical for overall health.

Published in the journal Science Advances, the study focused on daycare centers serving children ages three to five in the Finnish cities of Lahti and Tampere. Three of the daycare centers had playgrounds with natural, forest earth. Three had gravel yards, which they maintained as a control throughout the study. The experimental cohorts of children attended another four centers which had previously had gravel playgrounds but were converted to forest earth for research. Scientists collected biological samples from each child before the study, then again after 28 days of sustained play in their respective environments.

The researchers were shocked by the results seen in their post-study biological samples. The children with the newly forested playgrounds showed results close to those of children who had played on forest floor before the study. Their gut and skin microbiomes were improved, and their blood showed more anti-inflammatory proteins—suggesting a stronger immune system. These results offer a hopeful path for children and adults in city environments—which suffer from pollutants and a lack of (helpful) bacterial diversity in the environment—to improve their microbiomes. Urban children with less outdoor access may especially benefit from changes in schoolyards such as those used in the study.

You can visit Science Advances to learn more about the study and its findings. And if you’re interested in why microbiomes are so important to your and your children’s health, The Guardian has a thoroughly fascinating article all about the human microbiome.

A recent study of young children in Finland found that changing a playground from gravel to forest earth distinctly improved the immune systems and microbiomes of the preschool subjects.

Immun System Benefits of Nature

Photo: Stock Photos from RAWPIXEL.COM/Shutterstock

Researchers found that after 28 days, children who had just began playing in their newly forested yards had greatly improved biological samples, closer to those of children who had long had natural space.

Children Play Outside In Forest

Photo: Stock Photos from VAGENGEIM/Shutterstock

These findings spur hope that more forested recreational space can help boost the (often weaker) microbiomes, immune systems, and general health of urban children, perhaps even to the level of their more rural peers.

Kids Playing Outside in the Dirt

Photo: Stock Photos from ESB PROFESSIONAL/Shutterstock

h/t: [IFL Science]

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Chinese COVID-19 vaccine candidate shows promise in human trial: Study

  • October 16, 2020
Beijing, Oct 16 (PTI) One of China”s leading COVID-19 vaccine candidates, called BBIBP-CorV, was shown to be safe and elicited immune response in a small early-phase human trial, researchers said on Friday.

A previous clinical trial reported similar results for a different vaccine that is also based on inactivated whole SARS-CoV-2 virus, but in that study the vaccine was only tested in people aged under 60 years.

The latest study, published in The Lancet Infectious Diseases journal, included participants aged between 18 and 80 years, and found that antibody responses were induced in all recipients.

Participants aged 60 and over were slower to respond, taking 42 days before antibodies were detected in all recipients compared with 28 days for participants aged 18-59, the researchers said.

Antibody levels were also lower in those aged 60-80 years compared with those aged 18-59, they said.

The BBIBP-CorV vaccine used in the study is based on a sample of the virus that was isolated from a patient in China.

Stocks of the virus were grown in the lab using cell lines and then inactivated using a chemical called beta-proprionolactone.

BBIBP-CorV includes the killed virus mixed with another component, aluminium hydroxide, which is called an adjuvant because it is known to boost immune responses.

The trial was not designed to assess efficacy of the vaccine, so it is not possible to say whether the antibody responses induced by the vaccine, called BBIBP-CorV, are sufficient to protect from SARS-CoV-2 infection, according to the researchers.

“Protecting older people is a key aim of a successful COVID-19 vaccine as this age group is at greater risk of severe illness from the disease,” said Professor Xiaoming Yang, one of the authors of the study, from the Beijing Institute of Biological Products Company Limited.

“However, vaccines are sometimes less effective in this group because the immune system weakens with age. It is therefore encouraging to see that BBIBP-CorV induces antibody responses in people aged 60 and older, and we believe this justifies further investigation,” said Yang.

There are currently 42 vaccines for COVID-19 in clinical trials, the researchers noted.

These vary in type and include DNA plasmid vaccines, inactivated virus vaccines, adenovirus-vectored vaccines, RNA vaccines, protein subunit vaccines and virus-like particle vaccines, they said.

Some of these have already been shown to be safe and to elicit immune responses in early phase clinical trials.

The first phase of the study involved 96 healthy volunteers aged between 18 and 59 years and a second group of 96 participants aged between 60 years and 80 years.

Within each group, the vaccine was tested at three different dose levels, with two vaccinations administered on day 0 and 28.

A fourth group within each age group were given two doses of a placebo vaccine.

In the second phase of the study, 448 participants aged between 18 and 59 years were randomly assigned to receive either one 8 microgramme shot of vaccine or placebo, or two shots of 4 microgramme vaccine or placebo.

No serious adverse events were reported within 28 days of the final vaccination, and the most common side effect was pain at the injection site, the researchers said.

There were no instances of clinically significant changes in organ functions detected in laboratory tests in any of the groups, they said.

The greatest antibody responses were elicited by two 4 microgramme doses of the vaccine at either days 0 and 21 or 0 and 28, according to the resaerchers.

“Our findings indicate that a booster shot is necessary to achieve the greatest antibody responses against SARS-CoV-2 and could be important for protection. This provides useful information for a phase 3 trial,” Yang said.

The researchers noted some limitations with the study, including the short duration of follow up at just 42 days.

They also highlighted that the study did not include children and adolescents aged under 18.

” More studies are needed to establish whether the inactivated SARS-CoV-2 vaccines are capable of inducing and maintaining virus-specific T-cell responses,” said Professor Larisa Rudenko from the Institute of Experimental Medicine, Russia, who was not involved in the study.

This is because CD4-positive T-cell help is important for optimal antibody responses, as well as for cytotoxic CD8-positive T-cell activation, which, in turn, are crucial for viral clearance if neutralising antibody-mediated protection is incomplete, Rudenko said. PTI SAR
SAR



Disclaimer :- This story has not been edited by Outlook staff and is auto-generated from news agency feeds. Source: PTI


More from Outlook Magazine

Playing among forests (as pictured) and parklands — rather in than concrete and gravel yards — helps children to foster a stronger immune system, a study has concluded

Nature: Children who play in forests and parklands have stronger immune systems, study suggests

  • October 15, 2020

Playing among forests and parklands — rather in than concrete and gravel yards — helps children to foster a stronger immune system, a study has concluded.

Previous studies have proposed that city-dwellers may be at a greater risk of immune-mediated diseases thanks to a lack of exposure to diverse microbiota.

This fails to challenge the immune system and paves the way for conditions like asthma, eczema, inflammatory bowel disease, multiple sclerosis and type 1 diabetes.

Researchers from Finland renovated the outdoor play areas of four nurseries with plants, grasses and soil — finding that it had a positive impact in just one month.

The children who played in the greener spaces maintained more diverse skin and gut microbiota, the team said — along with signs of a better-regulated immune system. 

The findings suggest that the bodily defences of city-dwelling children could be boosted by providing daily access to green spaces and soil to play in.

Playing among forests (as pictured) and parklands — rather in than concrete and gravel yards — helps children to foster a stronger immune system, a study has concluded

Playing among forests (as pictured) and parklands — rather in than concrete and gravel yards — helps children to foster a stronger immune system, a study has concluded

Researchers from Finland renovated the outdoor play areas of four nurseries with planting boxes (pictured), grasses and soil — finding that it had a positive impact in just one month

Researchers from Finland renovated the outdoor play areas of four nurseries with planting boxes (pictured), grasses and soil — finding that it had a positive impact in just one month

In their study, environmental researcher Aki Sinkkonen of the University of Helsinki and colleagues altering the outdoor play spaces of four nurseries in Finland.

They overhauled the previously ‘bare’ concrete-, sand- and gravel-covered yards with the introduction of wood-like elements including grass, mosses, small shrubs, planting boxes, and natural forest floor.

Over the course of 28 days, the children attending the nurseries — each aged between 3–5 — spent 1.5 hours each day in the green renovated spaces playing games, planting vegetation and crafting with natural materials.

The renovations cost less than €5,000 (£4,524 / $5,860) to implement — less than each yard’s annual maintenance budget.

Skin swabs for microorganisms were taken from each of the children both before and after the study period — along with blood and stool samples — and the researchers also analysed soil or sand samples from the yards before and after.

The team compared these nurseries with three ‘standard’ childcare centres whose yards were left bare, as well as three ‘nature-orientated’ establishments where children were taken to nearby forests on a daily basis.

In total, the study included 75 children across the 10 nursery centres.

The team found that the children attending the four renovated nurseries maintained a high diversity in their skin microbiota across the length of the study.

The kids also developed a higher ration of anti-inflammatory cytokine IL-10 to the pro-inflammatory cytokine IL-17A — suggesting that exposure to the more natural environment and dirt had stimulated their immunoregulatory pathways.

While similar results were observed from the three centres where children were routinely taken out to play in nature, those attending the three centres whose yards were left more bare got no immune boost — and their microbiota declined.

‘When we saw the results, we were very surprised because they were so strong,” Dr Sinkkonen told the Guardian.

‘Our study can pave the way for new preventive practices to cut the global epidemic of immune-mediated diseases.’

In their study, environmental researcher Aki Sinkkonen of the University of Helsinki and colleagues altering the outdoor play spaces of four nurseries in Finland. Pictured: one of the nurseries' concrete- and gravel-covered yards prior to its renovation

In their study, environmental researcher Aki Sinkkonen of the University of Helsinki and colleagues altering the outdoor play spaces of four nurseries in Finland. Pictured: one of the nurseries’ concrete- and gravel-covered yards prior to its renovation

They overhauled the previously 'bare' concrete-, sand- and gravel-covered yards with the introduction of wood-like elements including grass, mosses, small shrubs, planting boxes, and natural forest floor. Pictured, the same yard from the previous picture after the renovation

They overhauled the previously ‘bare’ concrete-, sand- and gravel-covered yards with the introduction of wood-like elements including grass, mosses, small shrubs, planting boxes, and natural forest floor. Pictured, the same yard from the previous picture after the renovation

‘It is wonderful forward-looking work, immunologist Graham Rook of the University College London told the Guardian.

‘Many of the disorders that are increasing in western urbanised populations are due to failure of the mechanisms that supervise the immune system,’ he added.

‘This study shows that exposing children to a biodiverse natural environment boosts several biomarkers of the essential control mechanisms.’

‘These Finnish research groups have been leading the way in applying this understanding in a practical way.’

The full findings of the study were published in the journal Science Advances.

The findings suggest that the bodily defences of city-dwelling children could be boosted by providing daily access to green spaces to play in. Pictured, one of the green yards

The findings suggest that the bodily defences of city-dwelling children could be boosted by providing daily access to green spaces to play in. Pictured, one of the green yards

THE IMPORTANCE OF OUR MICROBIOMES TO OUR HEALTH

Researchers now estimate that a typical human body is made up of about 30 trillion human cells and 39 trillion bacteria.

These are key in harvesting energy from our food, regulating our immune function, and keeping the lining of our gut healthy.

Interest in, and knowledge about, the microbiota has recently exploded as we now recognise just how essential they are to our health.

A healthy, balanced microbiome helps us break down foods, protects us from infection, trains our immune system and manufactures vitamins, such as K and B12.

It also sends signals to our brain that can affect mood, anxiety and appetite.

Imbalances in the gut are increasingly being linked to a range of conditions. Last year, scientists at California Institute of Technology found the first ever link between the gut and Parkinson’s symptoms.

The composition of our gut microbiota is partly determined by our genes but can also be influenced by lifestyle factors such as our diet, alcohol intake and exercise, as well as medications.

UK study tests if BCG vaccine protects against COVID

UK study tests if BCG vaccine protects against COVID

  • October 11, 2020

LONDON (Reuters) – The widely used BCG tuberculosis vaccine will be tested on frontline care workers in Britain for its effectiveness against COVID-19, researchers running the UK arm of a global trial said.

Bacillus Calmette-Guérin (BCG) vaccine, used to protect against tuberculosis, induces a broad innate immune-system response and has been shown to protect against infection or severe illness with other respiratory pathogens.

“BCG has been shown to boost immunity in a generalised way, which may offer some protection against COVID-19,” Professor John Campbell, of the University of Exeter Medical School, said.

“We are seeking to establish whether the BCG vaccine could help protect people who are at risk of COVID-19. If it does, we could save lives by administering or topping up this readily available and cost-effective vaccination.”

The UK study is part of an existing Australian-led trial, which launched in April and also has arms in the Netherlands, Spain and Brazil. The BCG vaccine is also being tested as a protection against COVID-19 in South Africa.

The British trial is recruiting volunteers ahead of winter months that officials have warned may be tough as the country grapples with a second wave of infections.

UK Prime Minister Boris Johnson has indicated that restrictions to curb the pandemic could be in place until spring.

The trial’s UK arm, which is being run from Exeter, southwest England, is seeking to recruit 1,000 people who work in care homes and community healthcare nearby.

Globally, more than 10,000 healthcare staff will be recruited.

(Reporting by Alistair Smout; Editing by Christina Fincher)

Study finds a common nutritional supplement might boost cancer immunotherapy

Study finds a common nutritional supplement might boost cancer immunotherapy

  • October 5, 2020
mitochondria
Credit: CC0 Public Domain

A Ludwig Cancer Research study has uncovered a mechanism by which the tumor’s harsh internal environment sabotages T lymphocytes, leading cellular agents of the anticancer immune response. Reported in Nature Immunology, the study describes how a variety of stressors prevalent in the tumor microenvironment disrupt the power generators, or mitochondria, of tumor-infiltrating T lymphocytes (TILs), pushing them into a permanently sluggish state known as terminal exhaustion.

The study, led by Ludwig Lausanne Associate Member Ping-Chih Ho, also found that a widely available nutritional supplement— (NR)—helps TILs overcome the and preserves their ability to attack tumors in mouse models of melanoma and colon cancer.

“TILs often have a high affinity for antigens expressed by cancer cells,” says Ho. “This means that, in principle, they should attack vigorously. But we often don’t see that. People have always wondered why because it suggests that the best soldiers of the immune system are vulnerable when they enter the battlefield of the tumor. Our study provides a mechanistic understanding of why this happens and suggests a possible strategy for preventing the effect that can be quickly evaluated in clinical trials.”

The inner recesses of tumors are often starved of oxygen and essential nutrients, such as the sugar glucose. Cells in these stressful conditions adjust their to compensate—for example, by making more mitochondria and burning their fat reserves for energy.

In tumors, prolonged stimulation by cancer antigens is known to push TILs into an exhausted state marked by the expression of PD-1—a signaling protein that suppresses T cell responses and is targeted by existing “checkpoint blockade” immunotherapies. If sustained, such exhaustion can become permanent, persisting even when the stimulus of cancer antigens is removed.

Ho and his colleagues found that exhausted TILs are packed with damaged—or ‘depolarized’—mitochondria. Like old batteries, depolarized mitochondria essentially lack the voltage the organelles require to generate energy.

“Our revealed that those T cells with the most depolarized mitochondria behaved most like terminally exhausted T cells,” said Ho.

Ho and colleagues show that the accumulation of depolarized mitochondria is caused primarily by the TIL’s inability to remove and digest damaged ones through a process known as mitophagy. “The TILs can still make new mitochondria but, because they don’t remove the old ones, they lack the space to accommodate the new ones,” said Ho.

The genomes of these TILs are also reprogrammed by —chemical groups added to DNA and its protein packaging—to induce patterns of gene expression associated with terminal exhaustion.

The researchers found that the breakdown in mitophagy stems from a convergence of factors: chronic stimulation by cancer antigens, PD-1 signaling and the metabolic stress of nutrient and oxygen deprivation. They also show that the epigenetic reprograming that fixes TILs in a terminally exhausted state is a consequence, not a cause, of the mitochondrial dysfunction.

Related work done by other researchers—including co-authors in the current study, Ludwig Lausanne Investigator Nicola Vannini and Ludwig Lausanne Branch Director George Coukos—has shown that NR, a chemical analogue of vitamin B3, can boost mitophagy and improve mitochondrial fitness in a variety of other cell types.

With this in mind, the researchers explored whether NR might also prevent TILs from committing to terminal exhaustion. Their cell culture experiments showed that the supplement improved the mitochondrial fitness and function of T grown under stressors resembling those of the .

More notably, dietary supplementation with NR stimulated the anti-tumor activity of TILs in a mouse model of skin cancer and . When combined with anti-PD-1 and another type of checkpoint blockade, anti-CTLA-4 immunotherapy, it significantly inhibited the growth of tumors in the mice.

“We have shown that we may be able to use a nutritional approach to improve checkpoint blockade immunotherapy for cancer,” said Ho.

He and his colleagues are now exploring the signals from depolarized mitochondria that epigenetically reprogram TILs for terminal exhaustion—information that could be more generally applied to improve immunotherapy.


Virus-targeting white blood cells in tumors offer intriguing insights into responsiveness to immunotherapy


More information:
Yi-Ru Yu et al, Disturbed mitochondrial dynamics in CD8+ TILs reinforce T cell exhaustion, Nature Immunology (2020). DOI: 10.1038/s41590-020-0793-3

Citation:
Study finds a common nutritional supplement might boost cancer immunotherapy (2020, October 5)
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from https://medicalxpress.com/news/2020-10-common-nutritional-supplement-boost-cancer.html

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Ludwig study finds a common nutritional supplement might boost cancer immunotherapy

Ludwig study finds a common nutritional supplement might boost cancer immunotherapy

  • October 5, 2020

IMAGE

IMAGE: Ludwig Lausanne Associate Member Ping-Chih Ho
view more 

Credit: Ludwig Cancer Research

OCTOBER 5, 2020, NEW YORK – A Ludwig Cancer Research study has uncovered a mechanism by which the tumor’s harsh internal environment sabotages T lymphocytes, leading cellular agents of the anticancer immune response. Reported in Nature Immunology, the study describes how a variety of stressors prevalent in the tumor microenvironment disrupt the power generators, or mitochondria, of tumor-infiltrating T lymphocytes (TILs), pushing them into a permanently sluggish state known as terminal exhaustion.

The study, led by Ludwig Lausanne Associate Member Ping-Chih Ho, also found that a widely available nutritional supplement–nicotinamide riboside (NR)–helps TILs overcome the mitochondrial dysfunction and preserves their ability to attack tumors in mouse models of melanoma and colon cancer.

“TILs often have a high affinity for antigens expressed by cancer cells,” says Ho. “This means that, in principle, they should attack cancer cells vigorously. But we often don’t see that. People have always wondered why because it suggests that the best soldiers of the immune system are vulnerable when they enter the battlefield of the tumor. Our study provides a mechanistic understanding of why this happens and suggests a possible strategy for preventing the effect that can be quickly evaluated in clinical trials.”

The inner recesses of tumors are often starved of oxygen and essential nutrients, such as the sugar glucose. Cells in these stressful conditions adjust their metabolic processes to compensate–for example, by making more mitochondria and burning their fat reserves for energy.

In tumors, prolonged stimulation by cancer antigens is known to push TILs into an exhausted state marked by the expression of PD-1–a signaling protein that suppresses T cell responses and is targeted by existing “checkpoint blockade” immunotherapies. If sustained, such exhaustion can become permanent, persisting even when the stimulus of cancer antigens is removed.

Ho and his colleagues found that exhausted TILs are packed with damaged–or “depolarized”–mitochondria. Like old batteries, depolarized mitochondria essentially lack the voltage the organelles require to generate energy.

“Our functional analysis revealed that those T cells with the most depolarized mitochondria behaved most like terminally exhausted T cells,” said Ho.

Ho and colleagues show that the accumulation of depolarized mitochondria is caused primarily by the TIL’s inability to remove and digest damaged ones through a process known as mitophagy. “The TILs can still make new mitochondria but, because they don’t remove the old ones, they lack the space to accommodate the new ones,” said Ho.

The genomes of these TILs are also reprogrammed by epigenetic modifications–chemical groups added to DNA and its protein packaging–to induce patterns of gene expression associated with terminal exhaustion.

The researchers found that the breakdown in mitophagy stems from a convergence of factors: chronic stimulation by cancer antigens, PD-1 signaling and the metabolic stress of nutrient and oxygen deprivation. They also show that the epigenetic reprograming that fixes TILs in a terminally exhausted state is a consequence, not a cause, of the mitochondrial dysfunction.

Related work done by other researchers–including co-authors in the current study, Ludwig Lausanne Investigator Nicola Vannini and Ludwig Lausanne Branch Director George Coukos–has shown that NR, a chemical analogue of vitamin B3, can boost mitophagy and improve mitochondrial fitness in a variety of other cell types.

With this in mind, the researchers explored whether NR might also prevent TILs from committing to terminal exhaustion. Their cell culture experiments showed that the supplement improved the mitochondrial fitness and function of T cells grown under stressors resembling those of the tumor microenvironment.

More notably, dietary supplementation with NR stimulated the anti-tumor activity of TILs in a mouse model of skin cancer and colon cancer. When combined with anti-PD-1 and another type of checkpoint blockade, anti-CTLA-4 immunotherapy, it significantly inhibited the growth of tumors in the mice.

“We have shown that we may be able to use a nutritional approach to improve checkpoint blockade immunotherapy for cancer,” said Ho.

He and his colleagues are now exploring the signals from depolarized mitochondria that epigenetically reprogram TILs for terminal exhaustion–information that could be more generally applied to improve cancer immunotherapy.

###

Ho is an Associate Member of the Lausanne Branch of the Ludwig Institute for Cancer Research and an Associate Professor at the University of Lausanne.

This study was supported by Ludwig Cancer Research, the Swiss National Science Foundation, the Swiss Institute for Experimental Cancer Research, European Research Council, the Kristian Gerhard Jebsen Foundation, the Austrian Science Fund, the Austrian Academy of Sciences, the European Research Council, the Swiss Ministry of Science and Technology, the National Health Research Institute in Taiwan and the Swiss Cancer League.

About Ludwig Cancer Research


Ludwig Cancer Research is an international collaborative network of acclaimed scientists that has pioneered cancer research and landmark discovery for nearly 50 years. Ludwig combines basic science with the ability to translate its discoveries and conduct clinical trials to accelerate the development of new cancer diagnostics and therapies. Since 1971, Ludwig has invested $2.7 billion in life-changing science through the not-for-profit Ludwig Institute for Cancer Research and the six U.S.-based Ludwig Centers. To learn more, visit http://www.ludwigcancerresearch.org.

For further information please contact Rachel Reinhardt, rreinhardt@lcr.org or +1-212-450-1582.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

Ludwig Study Finds a Common Nutritional Supplement Might Boost the Effects of Cancer Immunotherapy

Ludwig Study Finds a Common Nutritional Supplement Might Boost the Effects of Cancer Immunotherapy

  • October 5, 2020

Newswise — OCTOBER 5, 2020, NEW YORK – A Ludwig Cancer Research study has uncovered a mechanism by which the tumor’s harsh internal environment sabotages T lymphocytes, leading cellular agents of the anticancer immune response. Reported in Nature Immunology, the study describes how a variety of stressors prevalent in the tumor microenvironment disrupt the power generators, or mitochondria, of tumor-infiltrating T lymphocytes (TILs), pushing them into a permanently sluggish state known as terminal exhaustion.

 The study, led by Ludwig Lausanne Associate Member Ping-Chih Ho, also found that a widely available nutritional supplement—nicotinamide riboside (NR)—helps TILs overcome the mitochondrial dysfunction and preserves their ability to attack tumors in mouse models of melanoma and colon cancer. 

“TILs often have a high affinity for antigens expressed by cancer cells,” says Ho. “This means that, in principle, they should attack cancer cells vigorously. But we often don’t see that. People have always wondered why because it suggests that the best soldiers of the immune system are vulnerable when they enter the battlefield of the tumor. Our study provides a mechanistic understanding of why this happens and suggests a possible strategy for preventing the effect that can be quickly evaluated in clinical trials.”

The inner recesses of tumors are often starved of oxygen and essential nutrients, such as the sugar glucose. Cells in these stressful conditions adjust their metabolic processes to compensate—for example, by making more mitochondria and burning their fat reserves for energy.

In tumors, prolonged stimulation by cancer antigens is known to push TILs into an exhausted state marked by the expression of PD-1—a signaling protein that suppresses T cell responses and is targeted by existing “checkpoint blockade” immunotherapies. If sustained, such exhaustion can become permanent, persisting even when the stimulus of cancer antigens is removed.

Ho and his colleagues found that exhausted TILs are packed with damaged—or “depolarized”—mitochondria. Like old batteries, depolarized mitochondria essentially lack the voltage the organelles require to generate energy.

“Our functional analysis revealed that those T cells with the most depolarized mitochondria behaved most like terminally exhausted T cells,” said Ho.

Ho and colleagues show that the accumulation of depolarized mitochondria is caused primarily by the TIL’s inability to remove and digest damaged ones through a process known as mitophagy. “The TILs can still make new mitochondria but, because they don’t remove the old ones, they lack the space to accommodate the new ones,” said Ho.

The genomes of these TILs are also reprogrammed by epigenetic modifications—chemical groups added to DNA and its protein packaging—to induce patterns of gene expression associated with terminal exhaustion.

The researchers found that the breakdown in mitophagy stems from a convergence of factors: chronic stimulation by cancer antigens, PD-1 signaling and the metabolic stress of nutrient and oxygen deprivation. They also show that the epigenetic reprograming that fixes TILs in a terminally exhausted state is a consequence, not a cause, of the mitochondrial dysfunction.

Related work done by other researchers—including co-authors in the current study, Ludwig Lausanne Investigator Nicola Vannini and Ludwig Lausanne Branch Director George Coukos—has shown that NR, a chemical analogue of vitamin B3, can boost mitophagy and improve mitochondrial fitness in a variety of other cell types.

With this in mind, the researchers explored whether NR might also prevent TILs from committing to terminal exhaustion. Their cell culture experiments showed that the supplement improved the mitochondrial fitness and function of T cells grown under stressors resembling those of the tumor microenvironment.

More notably, dietary supplementation with NR stimulated the anti-tumor activity of TILs in a mouse model of skin cancer and colon cancer. When combined with anti-PD-1 and another type of checkpoint blockade, anti-CTLA-4 immunotherapy, it significantly inhibited the growth of tumors in the mice.

“We have shown that we may be able to use a nutritional approach to improve checkpoint blockade immunotherapy for cancer,” said Ho.

He and his colleagues are now exploring the signals from depolarized mitochondria that epigenetically reprogram TILs for terminal exhaustion—information that could be more generally applied to improve cancer immunotherapy.

Ho is an Associate Member of the Lausanne Branch of the Ludwig Institute for Cancer Research and an Associate Professor at the University of Lausanne.

This study was supported by Ludwig Cancer Research, the Swiss National Science Foundation, the Swiss Institute for Experimental Cancer Research, European Research Council, the Kristian Gerhard Jebsen Foundation, the Austrian Science Fund, the Austrian Academy of Sciences, the European Research Council, the Swiss Ministry of Science and Technology, the National Health Research Institute in Taiwan and the Swiss Cancer League.

# # #

About Ludwig Cancer Research

Ludwig Cancer Research is an international collaborative network of acclaimed scientists that has pioneered cancer research and landmark discovery for nearly 50 years. Ludwig combines basic science with the ability to translate its discoveries and conduct clinical trials to accelerate the development of new cancer diagnostics and therapies. Since 1971, Ludwig has invested $2.7 billion in life-changing science through the not-for-profit Ludwig Institute for Cancer Research and the six U.S.-based Ludwig Centers. To learn more, visit www.ludwigcancerresearch.org.

A Bit of Mom's Poop Might Boost Health of C-Section Babies: Study | Health News

A Bit of Mom’s Poop Might Boost Health of C-Section Babies: Study | Health News

  • October 1, 2020

By Amy Norton
HealthDay Reporter

(HealthDay)

THURSDAY, Oct. 1, 2020 (HealthDay News) — Delivering by cesarean section deprives babies from receiving mom’s beneficial bacteria during the journey through the birth canal. Now researchers are studying an innovative way to counter that: Feeding newborns breast milk fortified with their mother’s poop.

There is, indeed, a yuck factor, the scientists acknowledge. But they also stress that the tactic, still under study, is done through a carefully controlled, hygienic process. And mothers seem to be all for it.

The research, described in the Oct. 1 issue of Cell, is part of a growing interest in the microbiome — the vast collection of bacteria and other microbes that naturally dwell in and on the body.

Studies in recent years have been revealing just how important those bugs are to the body’s normal processes — from metabolism to immune defenses to brain function.

And there’s evidence that the way a baby is delivered could have critical effects on the composition of the early-life microbiome.

Vaginal childbirth exposes newborns to the beneficial microbes in the birth canal, but C-sections bypass that process. In turn, studies have found that babies born by cesarean tend to have different microbiomes than babies born vaginally.

Those differences can be seen out to one year of age, said Dr. Martin Blaser, a professor and chairman of the human microbiome at Rutgers Robert Wood Johnson Medical School in Piscataway, N.J.

“Things do normalize, but for a while the microbiome is abnormal,” said Blaser, who was not involved in the new study.

Children born by C-section tend to have higher risks for conditions like asthma, allergies, obesity and type 1 diabetes, Blaser said. And it’s thought that the early-life microbiome may play a role, by affecting immune system and metabolic development.

In a small 2016 study, Blaser’s colleague and wife, Maria Dominguez-Bello, tested a way to “restore” a more-normal microbiome to C-section babies: swabbing them with their mothers’ vaginal fluids right after birth.

It seemed to work. One month later, the swabbed infants had microbial communities that were more similar to vaginally delivered babies’ than to those of other C-section babies.

The new study took a different route to restoring the microbiome: diluting a mother’s fecal sample in breast milk, and feeding it to her infant shortly after birth.

Seven women provided the samples three weeks before undergoing a planned C-section. All were carefully screened for viruses like hepatitis and HIV, and the fecal samples were tested for a range of bacterial infections and parasites, according to co-senior researcher Dr. Sture Andersson.

The breast milk was the mother’s own, or retrieved from a donor-milk bank.

“This should only be performed under rigorously controlled conditions,” stressed Andersson, of the Pediatric Research Center at the University of Helsinki.

Similar to the swabbing study, this one found that internally delivering moms’ microbes seemed to affect development of the newborns’ microbiome. At the age of 3 months, the babies’ microbial makeup looked more like that of vaginally delivered babies than untreated C-section infants’.

But the “big question,” Blaser said, is whether that will translate into future health benefits, like lower risks of asthma, allergies or obesity.

“That will take some time to show,” he said.

As a next step, the Finnish researchers plan to study immune-system development in babies who receive the fortified breast milk. Unlike the current study, future ones will include a comparison group of C-section babies who will receive breast milk with no added fecal sample.

Breastfeeding, itself, helps in forming a healthy microbiome. It’s likely, Andersson said, that “some microbiome” was transferred by the breast milk, not only the fecal sample — and the two “may act in concert.”

Blaser called the approach “rather ingenious,” but said it remains to be seen whether it is any more effective than the vaginal swabbing tactic.

He noted that in the United States, about one-third of births are done by C-section. Worldwide, Blaser said, C-section rates vary hugely by country — from percentages in the single digits to more than 50%.

“How many of those C-sections are unnecessary?” Blaser questioned. “Because of the effects on the microbiome, there are consequences to it.”

For now, the Finnish researchers stressed that their approach to microbiome restoration is not a do-it-yourself technique. The samples “have to be tested for safety and suitability,” they said.

Copyright © 2020 HealthDay. All rights reserved.

New Preventative Nasal Spray Reduces Viral Replication by Up to 96% in COVID-19 Challenge Study - COVID-19

New Preventative Nasal Spray Reduces Viral Replication by Up to 96% in COVID-19 Challenge Study – COVID-19

  • September 29, 2020

A new preventative nasal spray treatment that has been shown to reduce viral replication by up to 96% in a COVID-19 challenge study could protect people from the SARS-CoV-2 virus and prevent its transmission.

The novel product, INNA-051, has been developed by Ena Therapeutics (Melbourne, Australia) to boost the natural human immune system to fight common colds and flu. INNA-051 has proved remarkably successful in tests by reducing COVID-19 viral replication by up to 96% in a gold-standard animal study. The INNA-051 compound works by stimulating the innate immune system, the first line of defense against the invasion of pathogens into the body. By boosting the immune response in this way with INNA-051 prior to infection, the ability of the COVID-19 virus to infect the animals and replicate was dramatically reduced the study showed. The study provides evidence that INNA-051 can be used as a stand-alone method of antiviral preventative therapy, complementary to vaccine programs.

INNA-051, a synthetic small molecule, would be self-administered via an easy-to-use nasal spray, taken once or twice a week, with the treatment taking almost immediate effect. If human trials are successful and, given the unprecedented need for drugs to combat COVID-19, the prophylactic immune modulation therapy could be rapidly manufactured at scale and be available for use soon.

“We’ve been amazed with just how effective our treatment has been. By boosting the natural immune response of the ferrets with our treatment, we’ve seen a rapid eradication of the virus,” said Ena Respiratory Managing Director, Dr Christophe Demaison. “If humans respond in a similar way, the benefits of treatment are two-fold. Individuals exposed to the virus would most likely rapidly eliminate it, with the treatment ensuring that the disease does not progress beyond mild symptoms. This is particularly relevant to vulnerable members of the community. In addition, the rapidity of this response means that the infected individuals are unlikely to pass it on, meaning a swift halt to community transmission.”

“This is a significant development as the world races to find a solution to halt COVID-19 transmission and infection of at risk-populations,” said Professor Roberto Solari a respiratory specialist, advisor to Ena Respiratory and visiting Professor at Imperial College London. “Most exciting is the ability of INNA-051 to significantly reduce virus levels in the nose and throat, giving hope that this therapy could reduce COVID-19 transmission by infected people, especially those who may be pre-symptomatic or asymptomatic and thus unaware they are infectious.”

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Preventative nasal spray shown to reduce viral replication by up to 96% in COVID-19 challenge study | Coronavirus

  • September 29, 2020

New preventative nasal spray treatment that could protect people from COVID-19 infection and prevent transmission announcedNovel therapy developed by Australian biotech company, Ena Respiratory, shown to significantly reduce COVID-19 virus levels in the nose and throat, in a gold-standard animal studyReduced COVID-19 replication by up to 96%, study performed by Public Health England (PHE) scientistsMode of action complementary to COVID-19 vaccines, with easy nasal administration, delivered once or twice a weekPotential to be used to prevent infection in at-risk populations, including healthcare workers and the elderlyReady to progress to human clinical trials within four monthsCompany has raised AU$11.7m and is seeking additional investment

MELBOURNE, Australia, Sept. 28, 2020 /PRNewswire/ — A novel nasal treatment developed to boost the natural human immune system to fight common colds and flu, has proved remarkably successful in reducing COVID-19 viral replication test results, released today, reveal.

The novel product, INNA-051, being developed by Australian biotech company, Ena Respiratory, reduced viral replication by up to 96 percent in a gold-standard animal study led by Public Health England’s (PHE) Deputy Director, Professor Miles Carroll and published today on biomedical pre-publication research site, medRxiv.

The INNA-051 compound works by stimulating the innate immune system, the first line of defence against the invasion of pathogens into the body. By boosting the immune response in this way with INNA-051 prior to infection, the ability of the COVID-19 virus to infect the animals and replicate was dramatically reduced the PHE study showed. The study provides evidence that INNA-051 can be used as a stand-alone method of antiviral preventative therapy, complementary to vaccine programs.

“We’ve been amazed with just how effective our treatment has been,” says Ena Respiratory Managing Director, Dr Christophe Demaison. “By boosting the natural immune response of the ferrets with our treatment, we’ve seen a rapid eradication of the virus.”

“If humans respond in a similar way, the benefits of treatment are two-fold. Individuals exposed to the virus would most likely rapidly eliminate it, with the treatment ensuring that the disease does not progress beyond mild symptoms. This is particularly relevant to vulnerable members of the community. In addition, the rapidity of this response means that the infected individuals are unlikely to pass it on, meaning a swift halt to community transmission.”

Ena Respiratory has raised AU$11.7m from Australian investors and, subject to successful toxicity studies and regulatory approval, the company could be ready to test INNA-051 in human trials in less than four months.

Investment and support in developing the novel therapy has been led from the Australian Medical Research Commercialisation Fund (MRCF), Australia’s largest life science investment fund managed by Brandon Capital, with co-investment from university commercialisation fund Uniseed. The company is urgently seeking additional funding to accelerate the nasal spray’s clinical development and global distribution.

Dr Chris Nave, CEO of the MRCF and co-founder of Brandon Capital, says these extremely promising results means INNA-051 is an exciting frontrunner in the battle to beat COVID-19. “We are doing all we can to support Ena Respiratory and its quest to secure additional investment to accelerate the development and testing of the therapy in humans. While a vaccine is ultimately the key solution to combatting COVID-19, governments need to be developing different treatment approaches to ensure they have a range of options, in the event that a vaccine proves elusive or takes longer to develop.”

INNA-051 is a synthetic small molecule and would be self-administered via an easy-to-use nasal spray, taken once or twice a week, with the treatment taking almost immediate effect. If human trials are successful and, given the unprecedented need for drugs to combat COVID-19, this prophylactic immune modulation therapy could be rapidly manufactured at scale and be available for use soon.

“This is a significant development as the world races to find a solution to halt COVID-19 transmission and infection of at risk-populations,” says Professor Roberto Solari a respiratory specialist, advisor to Ena Respiratory and visiting Professor at Imperial College London. “Most exciting is the ability of INNA-051 to significantly reduce virus levels in the nose and throat, giving hope that this therapy could reduce COVID-19 transmission by infected people, especially those who may be presymptomatic or asymptomatic and thus unaware they are infectious,” Professor Solari says.

INNA-051 offers real hope to those in the frontline fight against COVID-19, says Dr Chris Smith, Ena Respiratory Board Director, and Senior Investment Manager at Brandon Capital. “The treatment offers significant potential to protect the most vulnerable, including those with pre-existing respiratory conditions and the elderly, where vaccines can be less effective.”

INNA-051 was in development before the outbreak of COVID-19 to promote resistance towards broader respiratory viral epidemics. Unlike vaccines which are targeted to a specific strain, INNA-051, is designed to be effective for all types of respiratory infections.

“Our nasal treatment has amazing potential for combatting COVID-19 and future pandemics,” continues Dr Smith. We know that vaccinations are often the most attractive approach in combating respiratory virus epidemics, but this method often comes with challenges as vaccines trigger a specific response in the adaptive immune system which might not be effective against future mutations of a virus. INNA-051 utilises the non-specific innate immune response meaning it is effective against a broad spectrum of viruses.”

“As an original investor alongside Uniseed, the MRCF saw great potential in INNA-051, before the COVID-19 era, to manage respiratory viral outbreaks, exactly like we are currently experiencing, although our initial focus was against influenza,” Dr Nave continues. “We are now thrilled to be able to redirect the effort toward the fight against COVID-19. The treatment has significant potential, not only against this pandemic but also to play a key role in future viral respiratory outbreaks.”

The authors of the study include scientists from Public Health England (PHE), Ena Respiratory, and leading Australian research organisations, the Hunter Medical Research Institute, Newcastle and the University of Melbourne.

Uniseed CEO Dr Peter Devine added, “These are very exciting results and demonstrate the potential clinical utility of the Ena drug in the treatment of COVID-19 which will likely require multiple treatment approaches. It also underlines the value of facilitating early-stage commercialisation of research, which can go on to create a global impact.”

About Ena Respiratory

Ena Respiratory is a wholly owned subsidiary company of Ena Therapeutics, aiming to transform the treatment and prevention of respiratory infections in at-risk populations.

Ena Respiratory is developing novel, synthetic innate immunomodulators for the prevention of respiratory viral and bacterial infections. The company is based in Melbourne and Sydney, Australia. Ena Therapeutics has secured a Series A investment from the Brandon Capital managed Medical Research Commercialisation Fund (MRCF) and Uniseed.

https://enarespiratory.com

About INNA-051

Ena Respiratory’s lead candidate, INNA-051 is a synthetic, pegylated TLR2/6 agonist. INNA-051 is developed for topical delivery to the airways (via nasal spray once/twice a week) in order to target the primary site of most respiratory virus infections, including COVID-19, influenza and rhinovirus. Topical respiratory administration of Ena Respiratory’s pegylated TLR2/6 agonists result in the activation of several key, innate immune defence mechanisms involved in antiviral prophylaxis. INNA-051 is based on discoveries made by Professorial Fellow David Jackson and his team. Professor Jackson heads the laboratory at the Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne.

The broad antiviral effectiveness of Ena Respiratory’s pegylated TLR2/6 agonists has been demonstrated in animal preclinical models of respiratory viruses, including influenza and rhinovirus (common cold) and secondary bacterial infection models.

INNA-051 efficacy against COVID-19 has been confirmed in a ferret challenge model by the team led by Professor Miles Carroll at Public Health England. In this study INNA-051 was administrated as prophylaxis. In the optimal dose regimen, after 5 days post-exposure to COVID-19, INNA-051 treated animals had statistically significant reduction of virus in throat swabs (96% reduction) and nasal washes (93% reduction) compared to untreated animals, despite very high levels of virus exposure (about 5 million virus particles were administrated in these studies).

About the Medical Research Commercialisation Fund (MRCF) and Brandon Capital Partners

Brandon Capital Partners is a venture capital firm that manages the Medical Research Commercialisation Fund (MRCF), Australia and New Zealand’s largest life science investment fund. The MRCF is a unique collaboration between major Australian superannuation funds, the Australian and New Zealand governments, Australian state governments and more than 50 leading medical research institutes and research hospitals. The MRCF supports the development and commercialisation of early-stage biomedical discoveries originating from member research organisations, providing both capital and expertise to guide the successful development of new therapies. The MRCF has supported more than 45 start-up companies to date, most of which were founded by the MRCF.

For more information about the MRCF visit: https://www.mrcf.com.au/

For more information about Brandon Capital Partners visit: www.brandoncapital.com.au

About Uniseed

Uniseed is Australia’s longest running early stage commercialisation fund that makes investments in research emanating from five of Australia’s leading research organisations – The University of Queensland, The University of Sydney, The University of New South Wales, The University of Melbourne and the CSIRO. Uniseed is a mutual fund, owned by research organisations, for research organisations. The fund facilitates the commercialisation of its research partners’ most promising intellectual property and secures targeted investment in resulting products and technologies. Uniseed has supported 57 start-up companies to date, being the seed investor in most of these.

For more information, visit: www.uniseed.com

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