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Lifestyle choices for brain health

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Living a brain healthy lifestyle is particularly important once you reach middle age, as this is the time when changes in the brain start to occur. They may start decades before symptoms appear. This means that it is important to look after the brain throughout your life. It is never too late or too early to bring lifestyle changes as brain function can be improved at any age.

Exercise your brain: Any activity that involves thinking, learning and active networking regularly challenges your brain. These stimulating activities can improve your brain health. The best activities are those that you enjoy. Hobbies like painting, woodwork , sewing, knitting and writing provide stimulus to the brain.  Doing jigsaw puzzles, crossword , suduko, chess , card games learning to dance , playing an instrument, learning a new language challenge the brain.

Regular and enjoyable interaction with friends like travelling , volunteering with a local charity, walking with friends and family, joining a book club, catching up with friends and talking to your neighbours is active networking which is beneficial to the brain. Passive networking such as Whattsapp or Facebook do not give such benefits.

Physical exercise is neuro-protective: Regular physical exercise can reduce the risk of Dementia. It can also slow down further deterioration in those who are showing early symptoms of Dementia. Exercise for 30 mins, walk, jog, cycle,hike,swim or join a dance group….. not gyming !! To avoid risk of fall balance and coordination exercises can help you stay agile. Exercises like Yoga , Pilates, Tai chi go a long way to improve balance and coordination and avoid fall or head injury.

You can also introduce exercise in your daily routine by taking some simple steps. Walk while you are on your mobile phone, take stairs instead of lift. If you have to work for long hours while sitting on a desk, take frequent breaks and walk around or stand up for a couple of minutes.  Some of the offices are providing standing work stations in the place of work and conference rooms. Opt for that option if available , or request for that healthy change in your work place.

The human brain is an organ which improves through mental stimulation. It continues to adapt, grow and rewire itself through the growth of new neurons. Using your non-dominant hand to write, use is to control computer mouse, television remote, brushing your teeth, opening doors etc will strengthen neural connections. Exercise also improves body posture . Walking with a hunch slows down your gait is associated with increase risk of Dementia. There is clear evidence that physical exercise helps in sprouting of neurons to prevent neuro-generative disease like Alzheimer’s.

Healthy Diet: The foods we eat can have a big impact on the structure and health of our brains. Eating a brain-boosting diet can support both short- and long-term brain functions. Indian home cooked diet of Roti ,dal ,legumes vegetables , salads ( washed well) is good for brain health. Red meats, beef , pork and chicken should be limited in your daily intake.  Fish could be included in your diet but make sure it is not bred in toxic waters with high content of mercury. All Vegetables and fruits of different colours like capsicum, green, yellow and red, cabbage , green leafy vegetables , zucchini , cauliflower, kale, carrots , brocolli ( it has glutathione a very powerful antioxidant, which prevents memory decline) and fruits like apples guava, mangoes, pears, grapes bananas etc should be included in our diet regularly.

Antioxidant-rich berries that can boost brain health: Include strawberries, blackberries, blueberries, blackcurrants and mulberries in your diet. Eating more nuts and seeds may be good for the brain, as these foods contain omega-3 fatty acids and antioxidants and healthful unsaturated fats .  Walnuts and Brazil nuts, cashews, almonds and peanuts can give you protection against chronic diseases.
Sunflower seeds,flaxseed and chia seeds also reduces the risk of Alzheimer’s disease. Eggs are a source of  vitamin B-6, vitamin B-12 and folic acid. Recent research suggests that these vitamins may prevent brain shrinkage and delay cognitive decline.

Yoghurt :  Yoghurt contain beneficial bacteria known as probiotics. These bacteria stimulates the Vagus nerve, and that, in turn stimulates the production of various neurotransmitters , which get depleted under stress.

Turmeric: Turmeric is a super spice. It contains Curcumin a natural anti- inflammatory compound and a potent antioxidant. It keeps the memory sharp, boosts the brain and helps it to heal.

Healthy oils: Include healthy oils in your diets such as mustard oil , peanut oil,sunflower oil , soyabean oil, olive oil and a small amount of Ghee. Palm oil is unhealthy and is used mostly in bakery products like cakes, biscuits , sweets etc. Also these processed food have high sugar and salt content which is unhealthy as it promotes obesity , diabetes and high cholesterol which is toxic to brain and body .
Avoid snacking on junk food, sugary drinks, sweets and inculcate this habit in children as it will provide many benefits to them in their mid life and beyond in protecting their brain health.

Sleep Deprivation:
Sleep is absolutely essential for good mental health. Sleep is not a passive but active function of the brain.
In the daytime we all make Beta amyloid proteins in the brain. During sleep the brain cells known as glymphatics enlarge and pulsate to remove toxins from the brain. Due to lack of sleep the brain does not have enough time to drain beta amyloids and other neuro toxic waste . These substances continue to accumulate day after day in form of plaques and tangles in the brain, which is the main cause of Alzheimer’s disease . Harmful effects of inadequate sleep can start at the age of 50 if not earlier. It is essential to have 6-8 hours of sleep. Avoid sleeping pills as it does not give you the deep sleep required for memory consolidation in the permanent memory centres of brain.

Quit Smoking: Smoking or inhaling of tobacco smoke or passive smoking has been linked to oxidative stress. Due to this the risk of Alzheimer’s/ Dementia becomes significantly higher. Brain uses 20% of body oxygen supply from the blood. Smoking damages the structures of blood vessels making it harder for the blood to flow freely around body and brain. Due to this the brain is deprived of oxygen rich blood supply and the brain cells do not get adequate nutrients to survive, thrive and resist damage.

Alcohol in moderation: Long term exposure to excessive alcohol can shrink the brain. It can change a person’s typical behaviour without mental clarity , interfere with his or her long term memory and may cause hallucinations. All these factors can substantially increase the risk of developing Alzheimer’s/ Dementia.

Laughter is the best medicine: Laughter triggers the release of endorphins, the body’s natural feel good chemicals. Endorphins promote overall sense of well-being and de-stress the brain. So how do we bring more laughter in our lives? Practice smiling at someone like your coworkers or someone you meet regularly in the lift or bus. You will notice that smile like laughter is contagious. When you hear laughter move towards it. Spend time with playful friends. Join a laughter club.  Learn to laugh at yourself to make an embarrassing moment funny. Put up a funny poster in your home or office. Choose a computer screen saver which makes you laugh. You may think of countless other ways of humour to improve the brain health. Laughter is also as effective as antipsychotic medications for reducing anxiety in the elderly people with Dementia.

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Medically Speaking

RESEARCH: INTERMITTENT FASTING WORKS FOR WEIGHT LOSS, HEALTH CHANGES

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According to a new study review led by University of Illinois Chicago researchers, intermittent fasting can produce clinically significant weight loss as well as improve metabolic health in individuals with obesity.

The findings of the study were published in the journal Annual Review of Nutrition. “We noted that intermittent fasting is not better than regular dieting; both produce the same amount of weight loss and similar changes in blood pressure, cholesterol and inflammation,” said Krista Varady, professor of nutrition at the UIC College of Applied Health Sciences and author of “Cardiometabolic Benefits of Intermittent Fasting.”

According to the analysis published in the Annual Review of Nutrition, all forms of fasting reviewed produced mild to moderate weight loss, 1 to 8 percent from baseline weight, which represents results that are similar to that of more traditional, calorie-restrictive diets.

Intermittent fasting regimens may also benefit health by decreasing blood pressure and insulin resistance, and in some cases, cholesterol and triglyceride levels are also lowered. Other health benefits, such as improved appetite regulation and positive changes in the gut microbiome, have also been demonstrated.

The review looked at over 25 research studies involving three types of intermittent fasting: alternate-day fasting, which typically involves a feast day alternated with a fast day where 500 calories are consumed in one meal, 5:2 diet—a modified version of alternate-day fasting that involves five feast days and two fast days per week, time-restricted eating—which confines eating to a specified number of hours per day usually four to 10 hours with no calorie restrictions during the eating period.

Various studies of time-restricted eating show participants with obesity losing an average of 3 percent of their body weight, regardless of the time of the eating window.

Studies showed alternate day fasting resulted in weight loss of 3% to 8% of body weight over three to eight weeks, with results peaking at 12 weeks. Individuals on alternate day fasting typically do not overeat or binge on feast days, which results in mild to moderate weight loss, according to the review.

Studies for the 5:2 diet showed similar results to alternate-day fasting, which surprised the study’s reviewers. The subjects who participate in the 5:2 diet fast much less frequently than alternate-day fasting participants do, but the results of weight loss results are similar.

Weight loss in both the alternate day and 5:2 fasting are comparable to more traditional daily calorie-restrictive diets. And, both fasting diets showed individuals were able to maintain an average of 7% weight loss for a year.

“You’re fooling your body into eating a little bit less and that’s why people are losing weight,” Varady said.

Varady added the review set out to debunk some myths regarding intermittent fasting. Intermittent fasting does not negatively affect metabolism, nor does it cause disordered eating, according to the studies reviewed.

“Fasting people are worried about feeling lethargic and not being able to concentrate. Even though you are not eating, it won’t affect your energy,” Varady said. “A lot of people experience a boost of energy on fasting days. Don’t worry, you won’t feel crappy. You may even feel better.”

The study review includes a summary of practical considerations for those who may want to try intermittent fasting. Among the considerations are:

Adjustment time—side effects such as headaches, dizziness, and constipation subside after one to two weeks of fasting. Increased water intake can help alleviate headaches caused by dehydration during this time.

Exercise—moderate to high-intensity endurance or resistance training during food abstention can be done, and some study participants reported having more energy on fast days. However, studies recommend those following alternate day fasting eat their fasting day meal after exercise.

Diet during fasting—there are no specific recommendations for food consumption during intermittent fasting, but eating fruits, vegetables, and whole grains can help boost fibre intake and help relieve constipation that sometimes accompanies fasting.

Alcohol and caffeine—for those using an alternate day or 5:2 fasting plan, alcohol is not recommended on fast days as the limited calories should be used on healthy foods that provide nutrition.

There are several groups who should not intermittent fast, according to the studies. Those individuals include: those who are pregnant or lactating, children who are under 12, those with a history of disordered eating, those with a body mass index, or BMI, less than 18.5, shift workers—studies have shown they may struggle with fasting regimens because of shifting work schedules, and those who need to take the medication with food at regimented times.

“People love intermittent fasting because it’s easy. People need to find diets that they can stick to long term. It’s definitely effective for weight loss and it’s gained popularity because there are no special foods or apps necessary. You can also combine it with other diets, like Keto,” Varady said.

It’s definitely effective for weight loss and it has gained popularity because there are no special foods or apps necessary. You can also combine it with other diets, like Keto.

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Optimal blood pressure helps our brains age slower: Study

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People with elevated blood pressure that falls within the normal recommended range are at risk of accelerated brain ageing, according to new research from The Australian National University (ANU).

The research also found optimal blood pressure helps our brains stay at least six months younger than our actual age. The researchers are now calling for national health guidelines to be updated to reflect their important findings. The ANU study, published in Frontiers in Aging Neuroscience, found participants with high blood pressure had older and therefore less healthy brains, increasing their risk of heart disease, stroke, and dementia.

Participants with elevated blood pressure, but within the normal range, also had older-looking brains and were at risk of health problems. “This thinking that one’s brain becomes unhealthy because of high blood pressure later in life is not completely true,” Professor Nicolas Cherbuin, Head of the ANU Centre for Research on Ageing, Health, and Wellbeing, said.

“It starts earlier and it starts in people who have normal blood pressure.” Normal blood pressure is defined by pressure below 120/80, whereas an optimal and healthier blood pressure is closer to 110/70.

The new research comes after a large international study found the number of people over 30 with high blood pressure has doubled globally. Cardiologist and co-author of the study, Professor Walter Abhayaratna, said if we maintain optimal blood pressure our brains will remain younger and healthier as we age.

“It’s important we introduce lifestyle and diet changes early on in life to prevent our blood pressure from rising too much, rather than waiting for it to become a problem,” he said.

“Compared to a person with a high blood pressure of 135/85, someone with an optimal reading of 110/70 was found to have a brain age that appears more than six months younger by the time they reach middle age.”

The ANU team, in collaboration with colleagues in Australia, New Zealand, and Germany, examined more than 2,000 brain scans of 686 healthy individuals aged 44 to 76. The blood pressure of the participants was measured up to four times across a 12-year period. The brain scan and blood pressure data were used to determine a person’s brain age, which is a measure of brain health.

Lead author, Professor Cherbuin, said the findings highlight a particular concern for young people aged in their 20s and 30s because it takes time for the effects of increased blood pressure to impact the brain.

“By detecting the impact of increased blood pressure on the brain health of people in their 40s and older, we have to assume the effects of elevated blood pressure must build up over many years and could start in their 20s. This means that a young person’s brain is already vulnerable,” he said.

Professor Abhayaratna said the research findings show the need for everyone, including young people, to check their blood pressure regularly. “Australian adults should take the opportunity to check their blood pressure at least once a year when they see their GP, with an aim to ensure that their target blood pressure is closer to 110/70, particularly in younger and middle age groups,” he said.

“If your blood pressure levels are elevated, you should take the opportunity to speak with your GP about ways to reduce your blood pressure, including the modification of lifestyle factors such as diet and physical activity,” he added.

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HOW TO TACKLE ANTIMICROBIAL RESISTANCE IN INDIA

Dr Rahul Pandit

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A recent ICMR report has left healthcare providers, patients, and infection control experts worried about the rising Antimicrobial Resistance in India. The report says that more than 50 percent of ICU patients in recent times have been battling a type of Pneumonia caused by the bacteria ‘Klebsiella Pneumonia’, which will not respond to even powerful antibiotics like Carbapenem. Another antibiotic, Imipenem, will not affect a mutated form of E-coli in 3 out of 10 cases. This means mutations in microbes, be it bacteria, viruses, or fungi—are rendering medicines useless when the patients most need them.

Given the pandemic and the extensive use of antibiotics to fight Covid-19, antibiotic resistance has been accelerated. Many experts are of the opinion that our approach to treating Covid-19 in hospitals could be exacerbating the problem.

Having said that, India with its combination of a large population, rising incomes that facilitate the purchase of antibiotics, high burden of infectious diseases, and easy over-the-counter access to antibiotics —is an important locus for the generation of resistance genes. This was the state even before the pandemic hit us.

Antibiotic resistance leads to longer hospital stays, higher medical costs, and increased mortality. We have already seen the rise of secondary infections and rare fungal infections such as mucor mycosis or black fungus, white fungus, and yellow fungus, taking a toll on Covid-19 patients during the second wave. Several studies attribute this to the injudicious use of steroids and other antibiotics medicines.

Moreover, even before the pandemic, India experienced over 56,000 newborn deaths each year due to Sepsis that is caused by organisms that are resistant to first-line antibiotics. Also, an estimated 170,000 deaths from Pneumonia in children under five, can be averted with timely access to effective antibiotics. While rising rates of resistant infections are a threat, many deaths are attributable to the lack of access to basic antibiotics.

Another important aspect is the use of antibiotics in the poultry and animal industry. This is much larger than what we imagine and obviously contributes to the growing menace of resistance.

So, how do we control and tackle growing Antimicrobial Resistance (AMR) in India?

We need to balance excessive and inappropriate use, a key driver of antibiotic resistance while ensuring live-saving medicines are available to those who need them. There is also a need to improve vaccination coverage, access to clean water, adequate sanitation, and improved hygiene.

However, efforts must be made to bring about behavioral changes in terms of hygiene practices, self-medication efforts, and proper health education. Vaccination has been shown to reduce the transmission of AMR infections and the volume of antibiotics consumed due to both, appropriate treatment of bacterial infections and viral infections.

India has undertaken many activities like Mission Indradhanush — to address low vaccination coverage and strengthened micro-planning and additional mechanisms to improve monitoring & accountability. Yet, improvements in coverage are still needed. Moreover, antibiotic stewardship programs are very much needed, to help providers and clinicians make the best clinical decisions possible for an antibiotic prescription. Antibiotic stewardship is the systemic effort to ensure effective treatment of infections, and therefore combat AMR, by monitoring and advising on antibiotic prescription and use. Another aspect is the appropriate management of antibiotics throughout the supply chain—from manufacturing to consumption. Effluents from pharma manufacturing contain active antibiotics, resistant bacteria, and resistant genes; they contaminate rivers, streams, and wells, including waters that are used for drinking and bathing. This increases both the emergence of resistant bacteria in local populations and also its spread. In addition, even lower levels of contamination in wastewater can cause resistant bacteria. In the same light, researchers have noted that contamination in areas where there is an antibiotic manufacturing industry led to an increase in bacterium causing resistance to Carbapenems.

Another source of environmental contamination is contaminated hospital waste. Untreated hospital waste may contain antibiotics and resistant bacteria. Where disposal mechanisms are inadequate, such waste puts staff and patients at increased risk from AMR. Hence, a concerted approach that incorporates diverse stakeholders to tackle and control the spread of antibiotics is essential.

The author is Director of Critical Care at Fortis Hospital, Mumbai and a member of Maharashtra’s Covid-19 Taskforce

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STUDY EXPLORES ADVERSE COMPLICATIONS FOR COVID POSITIVE PREGNANT WOMEN, THEIR NEWBORNS

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A new study, which finds an increased risk of poorer outcomes for the newborns and symptomatic women with Covid-19, adds further weight to the argument for pregnant women to be vaccinated for the virus.

The peer-reviewed findings were published in The Journal of Maternal-Fetal and Neonatal Medicine. Assessing 2,471 women in the third trimester of their pregnancy, close to their delivery, researchers found “significant differences” for symptomatic Covid-positive patients including higher rates of gestational diabetes, lower white blood cell counts, and heavier bleeding during delivery, whilst respiratory complications were witnessed in their babies. Thankfully in the group of patients—which included 172 covid positive women (56 of whom were symptomatic)—monitored at the Mayanei Hayeshua Medical Center in Israel, only one person needed mechanical ventilation, and there were no maternal deaths.

They show, lead Dr Elior Eliasi stated that Covid-19 in the third trimester of pregnancy “has clinical implications, albeit at lower rates than expected once asymptomatic patients are taken into account.”

The analysis found that there was no significant increase in cesarean delivery in women, who were Covid-19 positive and the incidence of preterm deliveries was not significantly different among the three groups (healthy, covid positive asymptomatic, covid positive symptomatic). Most pregnancy and delivery outcomes were similar between Covid-positive and -negative parturients (a woman about to give birth; in labour).

Dr Eliasi said, “However, There were significant differences between the Covid-positive and healthy controls included higher rates of GDM (gestational diabetes), low lymphocyte counts (white blood cell count) which were significantly lower, postpartum hemorrhage (bleeding during birth), and neonatal respiratory complications.”

“Our findings support the importance of vaccinating all pregnant women at all stages of pregnancy,” he added.

The study looked at births at the hospital between 26 March and 30 September 2020. A total of 93 percent of women admitted to the labour ward during this period were negative for Covid-19. Of the Covid-positive patients, 67 percent were asymptomatic.

On average the increased risk of incidence of adverse outcomes was 13.8 percent higher for asymptomatic covid patients and 19.6 percent higher for those symptomatic.

“More data is now needed to better delineate the differences between pregnancy outcomes seen in certain populations, potentially related to different viral characteristics (subtypes, viral load), patient epigenetics, or other factors. Additionally, the effects of maternal infection on the fetus both in terms of symptomatic maternal illness and vertical viral transmission remain to be further investigated,” the authors stated.

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RESEARCHERS TAKE STEPS TOWARD MORE EFFECTIVE FITNESS TRACKERS, GREATER PHYSICAL ACTIVITY

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As the popularity of fitness trackers has increased, so have the opportunities to use such devices to not only track fitness goals but also increase the motivation to meet those goals.

Researchers in the College of Engineering and the College of Health and Human Development at Penn State have teamed up to use control systems engineering tools to tailor motivational messages sent to individual device users. The results of their study were published in Health Psychology. “One of the really exciting advances of the last 15 years has been the advent of wearable and portable consumer technology that can be used to help promote physical activity,” said David Conroy, professor of kinesiology and human development and family studies, and co-principal investigator on the paper.

David added, “You can get real-time feedback from these devices and monitor your goals, and you can even push people messages, depending on what their goals are and what their behaviour is. We know that those messages work well for improving behaviour on average. But nobody is average, and we don’t know how to make sure each individual consistently gets the greatest benefit from a limited number of messages.”

Conroy said that researchers have tried several strategies, including messages that are specific to certain population segments; messages based on recent behaviour—for example, sending one of two different messages depending on if a user did or did not meet their goals the previous day; and customising the messages by putting in a person’s name or something they might like. So far, none of these approaches has proven to be consistently effective in improving the messages’ effects.

The new messaging approach developed by Conroy and Constantino Lagoa, co-principal investigator and professor of electrical engineering, applies tools used regularly in controlled systems engineering to behaviour science.

“Essentially, we’re using the same mathematical tools that people in control engineering usually use to model behaviours as differential equations,” Lagoa said. “We’re using those models to design feedback controllers that take into account the current state of the person and together with the model decide what is the best time to send the messages.”

Conroy emphasised that establishing the correct dosing—meaning the type of message and its timing, frequency and context—is a critical part of this approach.

“We’re really prioritising understanding the dosing so that we only send the right message at the right time and in the right context so people get the benefits that they’re looking for,” he said. “We don’t want to disrupt them without them getting the payoff that they’re looking for.”

The researchers refer to this individualised approach as precision behavioural medicine. “This is one of the first studies that were able to leverage data collected from each individual and zoom in on his or her personal response,” Lagoa said.

One of the main examples of how the researchers personalised the messages was by considering the weather in the area of the user, noting that certain messages were more effective for certain individuals on rainy days, hot days and so on.

The researchers acknowledged the potential concern people may have about trading privacy for personalization but said that the automation means that the data can be used and then discarded, as opposed to stored, and the location settings only need to be approximate to know the weather and customise the messaging appropriately. They also said, if their approach is commercialised, users would be able to adjust their settings to select how much information to share, and they plan on conducting more research before applying their approach to a larger population.

“We’ve established here is there’s a new tool to use with an established problem,” Conroy said. “Our next project will focus on establishing efficacy: Does this work better than sending messages at random or not sending messages at all? But once we establish efficacy, I would imagine that it’d be very attractive to device manufacturers to consider this kind of approach.”

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Strategy for overcoming colorectal cancer’s immunotherapy resistance

Immune checkpoint inhibitors, which unleash the immune response against tumor cells, have revolutionised cancer treatment; however, the medications aren’t effective in a large number of patients, including those with colorectal cancer.

New research published in the journal PNAS that was led by investigators at Massachusetts General Hospital (MGH) and the University of Geneva (UNIGE) provides insights into why some types of colorectal cancer don’t respond to immune checkpoint inhibitors and offer a strategy to overcome their resistance. “Colorectal cancer is the second leading cause of cancer-related death in the United States and worldwide,” said senior and co-corresponding author Rakesh K. Jain, PhD, director of the E.L. Steele Laboratories for Tumor Biology at MGH. He added, “A major cause of mortality in patients with colorectal cancer is the development of liver metastases, which is the spread of cancer to the liver.”

Jain explains that most colorectal cancers that spread to the liver do not respond to immune checkpoint inhibitors. When the team injected these colorectal cancer cells under the skin in the hind flank of mice (the most commonly used method for studying cancer in these animals), the cells responded well to immune checkpoint inhibitors, unlike what happens in patients.

To address this discrepancy, the investigators decided to take an approach that is referred to as orthotopic (meaning “the normal place in the body”) by injecting the cancer cells in the relevant anatomical sites—for example, the colon, where primary colorectal cancer cells grow, and the liver, where these cells metastasize.

“We found that these colorectal cancer mouse models were profoundly resistant to immune checkpoint inhibitors, similar to what is seen in patients,” said co-corresponding author Dai Fukumura. He added, “Our results highlight how the environment in which cancer cells grow can influence the effectiveness of immunotherapy. Also, and most important, they indicate that these orthotopic cancer models should be used to study resistance to immune checkpoint blockade as observed in patients with colorectal cancer.”

To determine how liver metastases are resistant to immune checkpoint blockade, Jain and his colleagues investigated the composition of immune cells present in liver metastases in mice and compared it with that of colorectal cancer cells injected under the skin. “We found that liver metastases lacked certain immune cells–called dendritic cells—that are required for the activation of other immune cells known as cytotoxic T lymphocytes, which can kill cancer cells,” said lead author William W. Ho. “We saw a similar situation in patients–their liver metastases showed a lack of dendritic cells and activated T lymphocytes.”

When the team augmented the number of dendritic cells within liver metastases (by giving mice a growth factor called Flt3L), the treatment led to an increase in cytotoxic T lymphocytes within the tumors and caused the tumors to become sensitive to immune checkpoint inhibitors.

He added, “Our study highlights the importance of orthotopic tumor models in immunotherapy studies and underscores the relevance of dendritic cells for effective immune checkpoint blockade,” says co-corresponding author Mikael J. Pittet.

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Immune checkpoint inhibitors, which unleash the immune response against tumor cells, have revolutionised cancer treatment; however, the medications aren’t effective in a large number of patients, including those with colorectal cancer.

New research published in the journal PNAS that was led by investigators at Massachusetts General Hospital (MGH) and the University of Geneva (UNIGE) provides insights into why some types of colorectal cancer don’t respond to immune checkpoint inhibitors and offer a strategy to overcome their resistance. “Colorectal cancer is the second leading cause of cancer-related death in the United States and worldwide,” said senior and co-corresponding author Rakesh K. Jain, PhD, director of the E.L. Steele Laboratories for Tumor Biology at MGH. He added, “A major cause of mortality in patients with colorectal cancer is the development of liver metastases, which is the spread of cancer to the liver.”

Jain explains that most colorectal cancers that spread to the liver do not respond to immune checkpoint inhibitors. When the team injected these colorectal cancer cells under the skin in the hind flank of mice (the most commonly used method for studying cancer in these animals), the cells responded well to immune checkpoint inhibitors, unlike what happens in patients.

To address this discrepancy, the investigators decided to take an approach that is referred to as orthotopic (meaning “the normal place in the body”) by injecting the cancer cells in the relevant anatomical sites—for example, the colon, where primary colorectal cancer cells grow, and the liver, where these cells metastasize.

“We found that these colorectal cancer mouse models were profoundly resistant to immune checkpoint inhibitors, similar to what is seen in patients,” said co-corresponding author Dai Fukumura. He added, “Our results highlight how the environment in which cancer cells grow can influence the effectiveness of immunotherapy. Also, and most important, they indicate that these orthotopic cancer models should be used to study resistance to immune checkpoint blockade as observed in patients with colorectal cancer.”

To determine how liver metastases are resistant to immune checkpoint blockade, Jain and his colleagues investigated the composition of immune cells present in liver metastases in mice and compared it with that of colorectal cancer cells injected under the skin. “We found that liver metastases lacked certain immune cells–called dendritic cells—that are required for the activation of other immune cells known as cytotoxic T lymphocytes, which can kill cancer cells,” said lead author William W. Ho. “We saw a similar situation in patients–their liver metastases showed a lack of dendritic cells and activated T lymphocytes.”

When the team augmented the number of dendritic cells within liver metastases (by giving mice a growth factor called Flt3L), the treatment led to an increase in cytotoxic T lymphocytes within the tumors and caused the tumors to become sensitive to immune checkpoint inhibitors.

He added, “Our study highlights the importance of orthotopic tumor models in immunotherapy studies and underscores the relevance of dendritic cells for effective immune checkpoint blockade,” says co-corresponding author Mikael J. Pittet.

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