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Blame people for lowering their guard against Covid: Doctors

Mutant variants of the coronavirus are to be expected, but they cannot be held solely responsible for the current spike in Covid-19 cases nationwide, say top health experts and doctors.

Shalini Bhardwaj



We may have to learn to live with the novel coronavirus, because it can last a lot longer than predicted if people fail to follow Covid guidelines and get vaccinated, and the spread of the virus is not contained, emphasised Dr Neeraj Nischal, Associate Professor, Medicine, All India Institute of Medical Sciences (AIIMS), Dr Anjan Trikha, Chairman of Clinical Managerial Group, Covid Centre at AIIMS, and Dr Arunesh Kumar, HoD, Respiratory Medicine at Paras Hospital.

Dr Arunesh KumarDr Anjan TrikhaDr Neeraj Nischal

Q: A study that says that the second wave of Covid-19 is going to continue for 100 or 150 days. How would you comment on this?

Dr Trikha: Yes, I think it could go on for 100 or 150 days. It is all speculation. Studies like this have a lot of mathematical equations with which they make such predictions. But what is important is that we are having a second stage and unless we take care we don’t know what is going to happen. So let’s not try to predict how many days it’s going to last, let us try to see how we can shorten it. If I say it is going to last 200 days, would people start wearing masks? No. So, the idea is not to predict the number of days, but to see how we can stop it. We have already lowered our guards. Each one of us has attended weddings or religious ceremonies or parties. We have seen the cricket matches – there were about 20,000 to 50,000 people there.

Q: People are not ready to follow guidelines. Do you think this is one of the biggest reasons for the mutation of this virus?

Dr Nischal: First of all, I would like to echo Dr. Anjan’s comment. You can make a prediction, but we all know that how long this particular infection or wave continues for will entirely depend upon how we react to this situation. Even last year, many doomsday predictions were made. Some rosy pictures were painted. All were proven wrong because of the behaviour of the people. So, this 100-day prediction may not come true if we behave properly, and if we become irresponsible, it could last for 1000 days. We have been discussing this thing for almost a year now, so it all depends on our behaviour. If you ask who is responsible for the mutation of this virus: we all know this virus uses a human host for multiplication and if we are not going to rent out our body as an experiment lab for this virus, we are not going to see any mutant variants in our country. But if we keep on providing our bodies for this virus, if the population keeps getting infected, this virus will mutate. These mutations could be fatal too because the virus is trying to evolve so as to survive. Though most species try to coexist with its source – maybe this virus is trying that too – but since this mechanism is not foolproof, there could be a variant which could be fatal for humans. And till it achieves that, we are at risk of catching a dangerous strain which may cause complicated diseases. So it all depends on us and our behaviour. If we behave properly and responsibly, we can control it. Or else, we will keep seeing these mutant strains frequently.

Q: What is the double mutant variant?

Dr Kumar: We know about mutation, it is nothing new about this virus or any virus. All viruses are mutated now and mutations sometimes happen for good because the virus becomes less effective. But sometimes mutations can be bad because they become more virulent. That’s what this double mutation is. There are the South African and Brazilian variants, soon there will be an Indian variant as well because the virus will mutate. As we do genetic studies, we find out a new name for it. But even the mutated variants have the same mode of transmission as the native mutant. They are transmitted by secretions or droplets when you cough and don’t wear masks. So, whatever the virus, people should be tested and treated and we should contain the spread. The principle remains the same. I think let us treat it as any other virus. It is no different and it also behaves in the same way. The good thing is that we are not seeing many sick patients as we were a year back. Believe me, there are hardly 2%-3% of patients who are very sick. The rest are the same, so we are actually seeing a better trend. As the vaccinations are being rolled out, I appeal to people to come get themselves vaccinated. Let’s use the knowledge which we have and not be alarmists about double or triple mutations. Let this be for biologists to deal with. Let’s take the positives and move forward.

Q: Do you think this variant is the reason behind the increasing number of Covid-19 cases in India or the ‘second wave’?

Dr Kumar: There is no such evidence. We need to wait further. You know there was a dip 2-3 months back because people were a bit more disciplined and started putting on masks and observing all the Covid-appropriate behaviours. So, I don’t think this surge is because of a particular strain and that’s why I want to downplay the mutations. Let virologists think about that. For the public, let us treat this virus the same as it was a year ago. Even for us general physicians and practitioners, we don’t treat anybody differently according to whether it is a variant from the UK or Hong Kong or Africa. They just have Covid-19. I’m saying it again, emphatically, that there is no evidence that this increase is related to the new mutant variants. In the coming days, we’ll have more information. More genotyping and molecular studies will be done. But the treatment remains the same, the precautions remain the same, and the mask remains of the utmost importance. To reduce the chain of spread, we have to contain it. If you are sick, you stay home, quarantine yourself for 17 days, and you’ll be alright. If you are breathless or have a bit of fever, you need to seek early help. If you have co-morbidities, you should be extra careful. That’s what we have been saying for the last one year and we are still saying the same. Do not take it for granted because we don’t have a treatment for this condition. All we are doing is symptom control. There is no accurate antiviral. The onus is on the people to follow Covid guidelines. Vaccine skepticism also has to go down. This is the only way out.

Q: Do you think it is high time to start mass vaccinations in India?

Dr Trikha: That is easier said than done. We must not forget that we are a 1.4 billion strong country. I think the vaccination program of the government is doing excellently. It is seamless. I have seen it in Delhi – you can go anywhere, there is no rush, and they are doing an excellent job of it. The government is doing its job. But the government cannot come to my house and put a mask on my face or stop me from going out. This is what you and I have to do. Sarojini Nagar, Lajpat Nagar, Chandni Chowk, Karol Bagh – the markets are all overflowing because people think Holi will never come back again. Chances are, if they get a virus and become very sick and land with a ventilator, Holi might never come back. Meanwhile, there is such a big discussion about the vaccines going on in our country. People who are not even graduates are trying to discuss whether they should take Covishield or Covaxin. Let the government decide that. There are knowledgeable people sitting in the planning commissions at various hospitals. Let them decide what is good or bad for the country. There will always be grey areas in a pandemic, especially with a disease which is evolving like this. The virus will mutate but that’s not a problem. Hopefully, it will mutate and become non-infected, which we are already seeing. But that doesn’t mean people are not dying.

Q: Do you think we need more vaccines?

Dr Nischal: As sir said, it’s a pandemic and we cannot be choosy. They may be more than sufficient to save your life. We don’t know who is going to land up on a ventilator. Many people over 90 years have come out without any problems, while we have also not been able to save somebody in their 20s. The blame ultimately lands on healthcare workers but there is nothing we can do about this virus, apart from providing support and care. For the two vaccines which are available, even if the efficacy is between 60% and 80%, as long as they are safe, one should not hesitate and come forward and take it as soon as possible. You cannot generate a vaccine overnight. These vaccines have come very fast but they have taken at least one year. Of course, there are a number of other vaccines in the pipeline. One of the most promising is the nasal vaccine, and once it is launched the immunization program will be easier to carry forward. But till the time we have other vaccines, we have to rely on what we have and I think these two are perfect and one should not delay or hesitate about taking them.

Dr Trikha: I would just like to add that Neeraj and I work at the same place and he is totally right in saying that, from 1 April 2020 to this year, we have had about four people above the age of 90 who have gone back home, while some of the most powerful or rich or youngest people have died. So, this can happen to each one of us. That kind of feeling should be there – you can call it fear. It is something like thinking “I won’t get cancer”. Anybody can get cancer. So, precaution and treatment and prevention is the thumb rule.

Q: Do you think a time will come when this particular virus will become like the common flu?

Dr Trikha: I am telling you today that we’ll have to live with this virus like we live with so many viruses. The last pandemic took about two to three decades to go. I know science has improved, but this pandemic is just one year old. A time will come when we will live with it and we will get used to it. It will be like getting our jabs every year. There is already a jab by Johnson & Johnson who have brought out a single short vaccine in the USA, where it has been given to homeless people because they can’t be traced for the second shot. So there will be many options available. Neeraj has talked about a nasal drop that will also come. Maybe every one year or 14 months, we will get a shot like you do for influenza. Not many people in India take an influenza shot, but if you go to an office in Europe or America, they advise you to take an influenza shot because that is what prevention is. Even if you get influenza after that, the severity will be less. The same is true with vaccines. Let’s not talk about efficacy in terms of 74% or 82%. These are numbers that pharmaceuticals will push. Let us be honest. If you have had the jab and have the antibodies – and it takes some time after the second jab – and you contract the disease, it is likely to be less severe.

Q: Are you getting Covid-19 patients with any different symptoms?

Dr Nischal: I will carry forward the discussion about mutations. One has to understand that you can’t just blame mutations for the rise in cases. If there had been an increase in cases of re-infection among patients who already had the infection in the past, we could have blamed the mutant variants as a cause. But we believe it’s the mutation in the behaviour of people which is the prime reason for this increase in the number of cases. What we had been seeing in the past, it has been almost the same. Luckily, to be very frank, we are not seeing much sicker patients. Many people are also opting for home isolation which is why the rise in cases is not reflecting in hospitals.  But it may increase because if we are not careful and do not monitor our disease progression, we might get sicker patients. The rise in cases and the number of patients in hospitals takes some time to reflect. So if we don’t follow Covid-appropriate behaviour then more cases will start coming after two to three weeks. If we start behaving properly now, the effect will start somewhere in April. This is the only way we can fight this pandemic.

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Medically Speaking




Patients with metastatic hormone receptor-positive breast cancer who have low activity levels of the enzyme sTK1 in their blood serum at the start of anti-estrogen treatment live longer and go longer without their disease progressing than patients with high levels, according to a recent study by SWOG (the Southwest Oncology Group) Cancer Research Network.

The findings of the study were published in the journal ‘Clinical Cancer Research’. The results suggest that patients with low sTK1 activity levels have a slow-growing disease that can be controlled initially with single-drug endocrine therapy for a prolonged period.

It remains to be determined whether these patients gain further benefit from adding a CDK4/6 inhibitor to their endocrine therapy. The findings come from an analysis of serum samples from 432 women with breast cancer who took part in the S0226 clinical trial, which was conducted by the SWOG Cancer Research Network, a cancer clinical trials group funded by the National Cancer Institute (NCI), part of the National Institutes of Health (NIH).

“SWOG researchers have demonstrated that a blood serum test can identify which of these patients have a slow-growing disease that might be controlled with a simple aromatase inhibitor pill alone,” said Dr Lajos Pusztai, MD, DPhil, professor of medicine (medical oncology) at Yale Cancer Center, who is a co-author on the paper.

Study S0226 found that most women with metastatic hormone-receptor-positive breast cancer who have not had previous treatment for their metastatic breast cancer live longer when they get a combination of the endocrine therapy drugs anastrozole and fulvestrant than when they get just anastrozole.

However, not all patients see extra benefit from the combination; some do just as well on a single drug. Having a way to identify which patients would not derive added benefit from the combination could save these patients the additional side effects and extra costs associated with taking two drugs instead of one.

The work was led by Costanza Paoletti, MD, who was then with the University of Michigan Rogel Cancer Center. She and her colleagues measured the level of serum thymidine kinase 1, or sTK1, considered a marker of cellular proliferation, in 1,726 samples taken from S0226 patients before the start of their treatment and at four-time points during treatment.

The samples were evaluated using a commercially available test known as the DiviTum assay, produced by Biovica International of Uppsala, Sweden, which measures levels of the enzymatic activity of sTK1. The researchers found what was considered high levels of the enzyme in samples from 171, or 40 per cent, of the patients.

Patients with high sTK1 levels, either before treatment or at any time during treatment, tended to have a significantly shorter period of time before their disease advanced (progression-free survival time, or PFS). Those with high levels at the start of treatment, or baseline, had a median PFS of only 11.2 months compared to 17.3 months for patients with low levels at baseline.

The high-sTK1 patients also died sooner, on average, than patients with low levels of the biomarker, with median overall survival times of just 30 months versus 58 months.

Importantly, patients with low sTK1 levels did just as well on the single drug anastrozole as on the combination. This means a measurement of pretreatment sTK1 level could potentially be used to determine whether a patient should start treatment with two-drug endocrine therapy (high sTK1) or single-drug endocrine therapy (low sTK1).

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A new study has claimed that much of the blame for the current obesity epidemic lies on modern dietary patterns characterised by excessive consumption of foods with a high glycemic load: in particular, processed, rapidly digestible carbohydrates.

These foods cause hormonal responses that fundamentally change our metabolism, driving fat storage, weight gain, and obesity. The findings of the study were published in ‘The American Journal of Clinical Nutrition’.

Statistics from the Centers for Disease Control and Prevention (CDC) show that obesity affects more than 40 per cent of American adults, placing them at higher risk for heart disease, stroke, type 2 diabetes, and certain types of cancer.

The USDA’s Dietary Guidelines for Americans 2020 – 2025 further says that losing weight “requires adults to reduce the number of calories they get from foods and beverages and increase the amount expended through physical activity.”

This approach to weight management is based on the century-old energy balance model which states that weight gain is caused by consuming more energy than we expend. In today’s world, surrounded by highly palatable, heavily marketed, cheap processed foods, it’s easy for people to eat more calories than they need, an imbalance that is further exacerbated by today’s sedentary lifestyles.

Overeating, coupled with insufficient physical activity, is driving the obesity epidemic. On the other hand, despite decades of public health messaging exhorting people to eat less and exercise more, rates of obesity and obesity-related diseases have steadily risen.

The study points to fundamental flaws in the energy balance model, arguing that an alternate model, the carbohydrate-insulin model, better explains obesity and weight gain. Moreover, the carbohydrate-insulin model points the way to more effective, long-lasting weight management strategies.

According to lead author Dr David Ludwig, Endocrinologist at Boston Children’s Hospital and Professor at Harvard Medical School, the energy balance model doesn’t help us understand the biological causes of weight gain: “During a growth spurt, for instance, adolescents may increase food intake by 1,000 calories a day. But does their overeating cause the growth spurt or does the growth spurt cause the adolescent to get hungry and overeat?”

In contrast to the energy balance model, the carbohydrate-insulin model makes a bold claim: overeating isn’t the main cause of obesity.

Instead, the carbohydrate-insulin model lays much of the blame for the current obesity epidemic on modern dietary patterns characterised by excessive consumption of foods with a high glycemic load: in particular, processed, rapidly digestible carbohydrates.

When we eat highly processed carbohydrates, the body increases insulin secretion and suppresses glucagon secretion. This, in turn, signals fat cells to store more calories, leaving fewer calories available to fuel muscles and other metabolically active tissues.

The brain perceives that the body isn’t getting enough energy, which, in turn, leads to feelings of hunger. In addition, metabolism may slow down in the body’s attempt to conserve fuel. Thus, we tend to remain hungry, even as we continue to gain excess fat.

To understand the obesity epidemic, we need to consider not only how much we’re eating, but also how the foods we eat affect our hormones and metabolism. With its assertion that all calories are alike to the body, the energy balance model misses this critical piece of the puzzle.

While the carbohydrate-insulin model is not new–its origins date to the early 1900s–The American Journal of Clinical Nutrition perspective is the most comprehensive formulation of this model to date, authored by a team of 17 internationally recognised scientists, clinical researchers, and public health experts.

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New research uncovers link between inflammation and pancreatic cancer development



A new discovery from researchers at The University of Texas MD Anderson Cancer Center has clarified the long-established connection between inflammation and pancreatic cancer development.

The findings of the study were published in the journal ‘Science’. According to the study, pancreatic cells display an adaptive response to repeated inflammatory episodes that initially protects against tissue damage but can promote tumour formation in the presence of mutant KRAS.

The authors demonstrated that mutant KRAS — which is found in roughly 95 per cent of all pancreatic cancers — supports this adaptive response, leading to selective pressure to maintain the cancer-causing mutation.

“We discovered that a single transient inflammatory event induced long-term transcriptomic and epigenetic reprogramming of epithelial cells that cooperated with oncogenic KRAS to promote pancreatic tumours long after the inflammation was resolved,” said corresponding author Andrea Viale, MD, assistant professor of Genomic Medicine.

“In the setting of repeated pancreatitis, KRAS mutations can be acquired early on to limit tissue damage, suggesting the existence of a strong evolutionary pressure to select mutated cells and providing a possible explanation for the nearly universal presence of mutant KRAS in pancreatic cancers,” Viale added.

Inflammation has long been linked to tumour development in several cancer types, but the specific reasons behind this connection were previously unclear.

The research team, led by co-first authors Edoardo Del Poggetto, PhD, postdoctoral fellow, and I-Lin Ho, a graduate student in the Viale Laboratory, sought to study the effect of pancreatitis — a condition of inflammation in the pancreas linked with a higher risk of pancreatic cancer — on pancreatic epithelial cells.

The researchers stimulated transient inflammation in a model system of inducible KRAS-driven pancreatic cancer. Inflammation caused immediate pathological changes in pancreatic cells, but they resolved within one week.

However, activation of KRAS even months following the resolution of inflammation resulted in accelerated tumour formation compared with controls, suggesting that inflammation drives long-term changes in epithelial cells that cooperate with mutant KRAS to promote cancer development.

Deep molecular analysis of epithelial cells following a single inflammatory event demonstrated substantial reprogramming of gene expression and epigenetic regulation that persisted long after recovery of the tissue damage, a process the researchers termed “epithelial memory.”

This cellular reprogramming activated pathways related to cell survival, proliferation and embryonic development, which are similar to pathways active during cancer development. The cellular reprogramming caused by inflammation also facilitated the acquisition of acinar-to-ductal metaplasia (ADM), a reversible process in which pancreatic acinar cells acquire features of ductal cells.

Acinar cells are responsible for producing and secreting digestive enzymes, while ductal cells are responsible for delivering those enzymes to the small intestine. ADM, a process that normally occurs in response to pancreatic damage, is thought to be a pancreatic cancer precursor.

In the context of epithelial memory, repeated inflammatory episodes resulted in the rapid and extensive appearance of ADM with minimal signs of cellular damage, suggesting that cellular reprogramming protects the pancreas against an accumulation of tissue damage. These findings also clarify that ADM is not a cancer precursor state, but rather an adaptive response to inflammation. Previous research has shown that KRAS mutations can induce and stabilise ADM.

Here, the authors demonstrated that induction of mutant KRAS during repeated inflammations resulted in more pronounced ADM and virtually no tissue damage. Thus, the authors predict that cells undergoing inflammation would have a strong positive selection for KRAS mutations or other alterations that stimulate ADM and limit damage accumulations.

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New study reveals nearly half of New York City mothers who had been trying to have another baby before the coronavirus pandemic began stopped in the first few months of the outbreak.

The findings of the study were published in the journal ‘JAMA Network Open’. Led by researchers at NYU Grossman School of Medicine, the survey of 1,179 mothers in New York City also found that one-third of women who had been thinking about becoming pregnant before the pandemic but had not yet begun trying said they were no longer considering it.

“Our findings show that the initial COVID-19 outbreak appears to have made women think twice about expanding their families and, in some cases, reduce the number of children they ultimately intend to have,” said study lead author and epidemiologist Linda Kahn, PhD, MPH.

“This is yet another example of the potential long-lasting consequences of the pandemic beyond the more obvious health and economic effects,” added Kahn.

Pregnancy becomes riskier and more difficult to achieve as women age, so the delays prompted by the pandemic may lead to increased health risks for both mother and child, as well as the need for costly fertility treatments, she added.

Kahn, an assistant professor in the Departments of Pediatrics and Population Health at NYU Langone Health, noted that all of the women in the study already had at least one child age 3 or younger.

As a result, it is possible that the challenges of caring for a young child during the peak of New York City’s outbreak and subsequent lockdown may have played a role in their hesitancy to have another baby.

Early evidence has already identified a birthrate decline in the United States during the coronavirus pandemic. Recent data showed that the country saw roughly 300,000 fewer births in 2020 than experts had expected based on annual fertility trends, with a particular drop in the last two months of the year, which corresponds with fewer conceptions at the beginning of the outbreak in March.

However, until now, few investigations have explored the root causes behind individual parents’ decisions to delay pregnancy. The new study is the first to examine pregnancy plans among mothers during the first wave of COVID-19 in New York City. For the investigation, the researchers analysed data from an ongoing pregnancy and child health study. In the survey, which collected data beginning in mid-April 2020, the mothers were asked to recall their pregnancy plans before the pandemic as well as whether they were still going forward with their plans at the time of the survey.

Among the findings, the study revealed that fewer than half of mothers who had stopped trying to become pregnant were certain they would resume trying to become pregnant once the pandemic ended, suggesting that they may abandon rather than just delay their plans to expand their families, Kahn said.

In addition, those with higher stress levels and greater financial insecurity were especially likely to postpone or end their plans for an additional child.

According to the study authors, this finding highlights the importance of financial health in parents’ decisions around pregnancy and suggests that additional financial support for families may be needed to address the nation’s ongoing fertility decline, which began in 2008.

“These results emphasise the toll the coronavirus has taken not only on individual parents but perhaps on fertility rates overall,” said study senior author epidemiologist Melanie Jacobson, PhD, MPH.

Jacobson, a research scientist in the Division of Environmental Pediatrics at NYU Langone, cautions that the investigation only included women who were planning to have children and did not account for unplanned pregnancies.

She said the study authors next plan to repeat the survey with the same group of mothers and explore the potential impact of vaccination, an option not available at the time of the survey.

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Research finds breastfeeding is being overtly discouraged by infant formula websites



Despite public health efforts to support breastfeeding and informed choice, during a news study, an analysis of websites for baby formula manufacturers found that their messages and images discourage breastfeeding while touting the benefits of the formula.

The study, led by researchers at the NYU School of Global Public Health and published in the journal Public Health Nutrition, is the first to compare information and portrayals of breastfeeding with infant formula feeding on manufacturer websites directed at U.S. consumers. “Many factors influence parents’ decision to breastfeed or use formula, including breastfeeding support and work schedules. But we also know that marketing and advertising play a critical role,” said Jennifer Pomeranz, assistant professor of public health policy and management at NYU School of Global Public Health and the study’s lead author. “It is important to understand the messages caregivers are receiving directly from formula companies, whose websites are targeting pregnant women and new parents with marketing claims disguised as feeding advice and support.”

Breastfeeding has many well-documented benefits for infants and mothers. Because breast milk is a complete source of nutrition for babies and can protect them from infections and certain diseases later in life, the U.S. and global health authorities recommend breast milk as the sole source of nutrition during a child’s first six months and encourage continued breastfeeding.

Previous research shows that marketing from formula companies can influence norms and attitudes around infant feeding and may use unsubstantiated health claims to promote formula and diminish confidence in breast milk. To prevent this, the World Health Organization urges countries to ban the marketing of formula to consumers; while the U.S. still allows it, the Surgeon General recommended that infant formula be marketed in a way that does not discourage breastfeeding.

Pomeranz and her colleagues analyzed the websites of three major formula brands that make up 98 per cent of the U.S. market, as well as two organic brands, to compare messages and images about breastfeeding and breast milk with those about infant formula feeding.

The researchers found that substantial messaging on the five formula manufacturers’ websites focused on discouraging breastfeeding. The websites actually contained more messages about breastfeeding or breast milk than formula, but much of the breastfeeding content (40 per cent) focused on challenges, such as having a low supply of breast milk or difficulty latching.

The websites were significantly more likely to mention the benefits of formula (44 per cent)–for instance, statements that formula provides brain and gastrointestinal benefits–than benefits of breastfeeding or breast milk (26 per cent).

Moreover, manufacturers compared formula feeding to breastfeeding, rather than comparing their brands positively to other brands.

Images on the websites also illustrated the benefits of formula–including the ease of feeding, with babies holding their own bottles–while making breastfeeding look difficult and labour intensive.

“Infant formula manufacturers’ repeated communication about breastfeeding problems such as reduced breast milk supply or sore nipples, coupled with images of women holding their breasts to breastfeed, implies that breastfeeding is hard, painful work. These recurring messages may ultimately discourage breastfeeding,” said Pomeranz.

“Even if websites frame their ‘advice’ as providing solutions to the problems identified, it is completely inappropriate for a formula company to disseminate information–let alone negative information–about breastfeeding to new parents and mothers in particular,” added Pomeranz.

The researchers identified other marketing tactics on formula websites, including the use of discounts or coupons, contact information for sales representatives, and claims of health and nutritional benefits of infant formula over breast milk.

“These marketing practices directed towards U.S. consumers would be legally suspect in other countries, many of which follow W.H.O. recommendations and prohibit direct-to-consumer marketing of infant formula,” added Pomeranz.

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New research led by the University of Birmingham suggests that skin cancer patients could have a better prognosis if their T cells send messages from five specific genes in their immune response to drugs given to treat the disease.

The research, carried out in mice, cells in the laboratory, and using publicly available data from patients with advanced melanoma before and after treatment with Nivolumab therapy, was published in the journal Immunity. T cells are white blood cells that protect the body from harm from viruses, bacteria, and cancer cells and explore their environments by using their T cell receptor (TCR) to recognise fragments – called antigens – of microbes or damaged cancer cells.

The TCR controls the behaviour of the T cell and can send messages to the T cells’ command centre to kick-start an immune response. This process is important for vaccine research and treatment of autoimmune conditions but is particularly of interest for cancer treatments to improve the anti-tumour function of T cells.

The researchers carried out the study to better understand how the amount of antigen controls how the TCR sends messages to the T cells’ command centre, and how this affects the type of immune response. They wanted to explore how antigen amounts control the expression of so-called ‘immune checkpoints’ that act as brakes on immune responses. It is these immune brakes, such as one called PD1, that are the target of drugs that seek to increase the immune response in cancer immunotherapy.

Lead author Dr David Bending, of the University of Birmingham’s Institute of Immunology and Immunotherapy, explained: “Through our research, we discovered that the amount of antigen determined how many immune checkpoints or immune brakes a T cell had on its cell surface.

“When we exposed T cells to the highest amounts of antigen, they stopped sending signals to their command centre, and this was because they had increased the number of immune brakes, which shut down the messengers. This made these T cells unable to respond to antigens for a period.”

By blocking one of the immune brakes, called PD1, the researchers were able to re-awaken some of these ‘unresponsive’ T cells. They found that these re-awakened T cells not only started sending messages to their command centres, but the messages they sent were louder and clearer.

“The response from the command centre was that the T cells started to increase the number of messages from five specific genes,” added Dr Bending. “By looking for the messages from these five genes, we were able to show that these stronger and louder messages were increased in melanoma patients who survived for longer on drugs that block the immune brake PD1. We think that this means that those cancer patients whose immune cells can send messages from these five genes in response to drugs that target PD1, a good outcome is far more likely.”

The researchers said their finding shows that the immune system likely requires an optimal level of stimulation to mount the most effective immune response in skin cancer patients. Dr Bending added: “Our research gives us an interesting insight into fundamental workings of the immune system. It suggests that both the amount of antigen around a T cell and also the number of immune brakes the T cells have at their surface are very important in controlling immune responses. Furthermore, we have shown that we can alter the balance of the immune response through stopping some of these immune brakes, which results in a stronger T cell response.”

The study has generated a new potential readout to monitor patients on drugs targeting PD1 in cancer. It also may be useful for exploring the potential of combinations of drugs that target multiple immune checkpoints to try to further re-awaken T cells in cancer patients.

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