Body

Lugano, Switzerland, 2 July 2021 - Doctors and patients are being advised to reduce unnecessary antibiotic use following new data suggesting that these medicines may increase the risk of cancer of the large intestine (colon), especially in people under 50 years. (1) The results, presented at the ESMO World Congress on Gastrointestinal Cancer (30 June-3 July) raise fresh concerns about the impact of the estimated 65% increase in global antibiotic consumption reported between 2000 and 2015, despite not showing a direct cause and effect. (2)

"To our knowledge, this is the first study to link antibiotic use with the growing risk of early onset colon cancer - a disease which has been increasing at a rate of at least 3% per year over the last two decades. (3) Junk food, sugary drinks, obesity and alcohol are likely to have played a part in that rise, but our data stress the importance of avoiding unnecessary antibiotics, especially in children and young adults," said Ms Sarah Perrott, from the University of Aberdeen, Aberdeen, UK, presenting the data.

Using a large Scottish primary care database of up to 2 million people, the study looked at nearly 8000 people with bowel cancer (colon and rectum) matched with people without bowel cancer. It found antibiotic use was associated with an increased risk of colon cancer across all ages, but the risk was increased by almost 50% in the under-50s compared to 9% in the over-50s. In the younger age group, antibiotic use was linked to cancers in the first part of the colon (the right side). Quinolones and sulfonamides/trimethoprim, which are used to treat a wide range of infections, were associated with these right-side cancers.

Dr Leslie Samuel, Aberdeen Royal Infirmary, UK, senior author of the study, explained that the contents of the right side of the colon are more liquid and that the natural bacteria living there, called the microbiome, may be different from further along the colon.

"We now want to find out if there is a link between antibiotic use and changes in the microbiome which can make the colon more susceptible to cancer especially in younger people. It's a complex situation as we know that the microbiome can quickly revert to its previous state even when the bowel has been cleared out for a diagnostic procedure such as an endoscopy. We don't yet know if antibiotics can induce any effects on the microbiome that could directly or indirectly contribute to development of colon cancer," said Samuel.

Commenting on the new research, Professor Alberto Sobrero, Ospedale San Martino, Genoa, Italy, explained that, of the 2 million people diagnosed with colon cancer worldwide each year, (4) younger people aged 20-40 with colon cancer generally have a worse prognosis than older people because they are often diagnosed later.

"Physicians are less likely to investigate a patient with abdominal discomfort for colon cancer if they are in their 30s than if they are in their 70s, and younger patients are not eligible for bowel cancer screening. As a result, their cancer is usually diagnosed at a later stage, when it is more difficult to treat," he said.

Like Perrott and Samuel, he believes that physicians should now think of bowel cancer in younger patients with abdominal symptoms, and he supports more research into the multiple possible causes of the rising incidence of colon cancer in this age group.

"It is too early to say if excessive use of antibiotics could be a causative factor, and we need to understand more about the possible role of the microbiome in bowel cancer before we consider the impact of antibiotics on the intestinal flora. However, the new research does remind us that antibiotics should not be given unless they are really needed, and we cannot exclude the possibility that unnecessary use of antibiotics may be exposing people to an increased risk of cancer," Sobrero concluded.

Several cancer tumors grow through immunosuppression; that is, they manipulate biological systems in their microenvironments and signal to a specific set of immune cells--those that clear out aberrant cells--to stop acting. It is no wonder that immunotherapy designed to re-establish anti-tumor immunity is rapidly becoming the treatment of choice for these cancers.

One natural immunosuppressive molecule that falls prey to helping cancer tumors is indoleamine-2,3-dioxygenase 1 (henceforth, IDO1). Because it is found in a broad range of cancer tumors, including those of the skin, breast, colon, lung, and blood, scientists have begun to see it as a promising therapeutic target: Suppress its activity and anti-tumor immunity should be back. But all endeavors so far have failed in phase 3 clinical trials--the stage at which a large number of people with the disease try out the optimal dose to test its true efficacy. Why is something so promising in theory and in the lab fizzling out in late phase clinical trials?

To find out, a team of researchers, led by Dr. Ming-Rong Zhang, Director of the Department of Advanced Nuclear Medicine Sciences at the National Institutes for Quantum and Radiological Science and Technology, Japan, tried positron emission tomography (PET) imaging to track IDO1 activity after a possible treatment has been administered. What they found is a breakthrough now published in BMJ's Journal for ImmunoTherapy of Cancer.

"In our paper, we highlight the development cycle of our PET imaging method, starting from tracer synthesis and biomarker identification to biomarker validation in a mouse model of melanoma treated with different immunotherapy regimens," says Dr. Zhang.

The team of scientists began with a radiotracer--chemicals that emit radiation which can then be detected by machines--that is known to bind to IDO1. After establishing that this radiotracer can reliably reflect levels of IDO1 expression at specific sites in the body, they proceeded to find out whether it can also reflect the varied treatment outcomes of three combinatory immunotherapy strategies, each involving an IDO1 inhibitor.

They administered the radiotracer and the therapies to mice with a cancerous tumor and watched what happened over time through whole-body PET imaging. To their surprise, despite one of the treatment strategies clearly having greater efficacy than the others--wherein, IDO1 was inhibited much more than in the others--the radiotracer uptake in the tumors seemed to be the same across all treatments. However, in the case of this standout treatment strategy, the radiotracer signal beamed in an off-tumor organ called the mesenteric lymph node. This was not the case for the other two treatment strategies. Further probing confirmed that in these lymph nodes as well, the radiotracer bound to IDO1. But why this organ? That is research for another study.

In this study, the scientists went on to explore one more checkpoint: did the peak and trough of this radiotracer in the lymph nodes mirror those of maximum tumor inhibition and decline of treatment effect? Turns out the radiotracer uptake increased from a few days before the peak, peaked with peak treatment efficacy, plateaued until a few days before treatment decline began, and fizzled out when the tumor relapsed.

So, the scientists had stumbled upon an unprecedented new biomarker with which IDO1 activity could be monitored non-invasively, a really promising alternative to the invasive biopsy.

Further explaining the results of the study, Dr. Lin Xie, co-author of the paper says, "Our findings imply that the IDO1 status in the mesenteric lymph node is an unprecedented surrogate marker of the cancer-immune set point, which is an equilibrium state from tumor tolerance to elimination, in response to immunotherapeutic intervention."

Dr. Kuan Hu, another researcher involved in the study, says, "Our study holds great potential as a robust method for visualizing personalized antitumor responses in patients, to address the possible causes for the failure of the existing clinical trials, thereby improving the therapeutic outcome of IDO1 regimens. Our research also illustrates a potential precision medicine paradigm for noninvasive visualization of each patient's individual response in combinatorial cancer immunotherapy and opens up new avenues for future clinical trials for precision anti-cancer immunotherapies."

In an Australian world-first, researchers have successfully repurposed two existing medications to reduce the severity of sleep apnoea in people by at least 30 per cent.

Affecting millions around the world, sleep apnoea is a condition where the upper airway from the back of the nose to the throat closes repetitively during sleep, restricting oxygen intake and causing people to wake as often as 100 times or more per hour.

Those with untreated sleep apnoea are more likely to develop cardiovascular disease, dementia and depression, and are two to four times more likely to crash a car than the general population.

Despite almost thirty years of research, there are no approved drug therapies to treat the condition.

Professor Danny Eckert, Principal Research Scientist at NeuRA and Professor and Director of Adelaide Institute for Sleep Health at Flinders University, has brought scientists one step closer by repurposing two existing medications to test their efficacy in people in sleep apnoea.

Previous research showed two classes of medication, reboxetine and butylbromide, were able to keep muscles active during sleep in people without sleep apnoea, and assist their ability to breathe.

By repurposing the medications, researchers used a multitude of recording instruments to measure whether reboxetine and butylbromide could successfully target the main causes of sleep apnoea.

This included balancing the electrical activity of muscles around the airway, preventing the throat from collapsing while people were sleeping, and improving the regulation of carbon dioxide and breathing during sleep.

Results from the study showed these medications did in fact increase the muscle activity around participants' airways, with the drugs reducing the severity of participants' sleep apnoea by up to one-third.

"Almost everyone we studied had some improvement in sleep apnoea," said Professor Eckert.

"People's oxygen intake improved, their number of breathing stoppages was a third or more less. We were thrilled because the current treatment options for people with sleep apnoea are limited and can be a painful journey for many," he said.

These new findings allow researchers to further refine these types of medications so that they have even greater benefit than what has currently been found.

"Next, we will look at the effects of these and similar medications over the longer term. We will assess whether we can harness the benefits of one drug without needing to use them both.

"Equally, we will test whether these treatments can be combined with other existing medications to see if we can improve their efficacy even more," said Professor Eckert.

Until now, the main therapy for sleep apnoea involves wearing a mask to bed, or Continuous Positive Airway Pressure Therapy (CPAP), which benefits millions.

However, many people find it uncomfortable and half the people that try it find it hard to tolerate. Plus, the efficacy of second line therapies, such as mouthguards fitted by dentists, can be unpredictable and expensive.

Researchers at the Francis Crick Institute and University of Dundee have screened thousands of drug and chemical molecules and identified a range of potential antivirals that could be developed into new treatments for COVID-19 or in preparation for future coronavirus outbreaks.

While COVID-19 vaccines are being rolled out, there are still few drug options that can be used to treat patients with the virus, to reduce symptoms and speed up recovery time. These treatments are especially important for groups where the vaccines are less effective, such as some patients with blood cancers.

In a series of seven papers, published today (2 July) in the Biochemical Journal, the scientists identified 15 molecules which inhibit the growth of SARS-CoV-2 by blocking different enzymes involved in its replication.

The researchers developed and ran tests for around 5,000 molecules provided by the Crick's High Throughput Screening team to see if any of these effectively blocked the functioning of any of seven SARS-CoV-2 enzymes. The tests were based on fluorescent changes with a special imaging tool detecting if enzymes had been affected.

They then validated and tested the potential inhibitors against SARS-CoV-2 in the lab, to determine if they effectively slowed viral growth. The team found at least one inhibitor for all seven enzymes.

Three of the molecules identified are existing drugs, used to treat other diseases. Lomeguatrib is used in melanoma and has few side-effects, suramin is a treatment for African sleeping sickness and river blindness and trifluperidol is used in cases of mania and schizophrenia. As there is existing safety data on these drugs, it may be possible to more quickly develop these into SARS-CoV-2 antivirals.

John Diffley, lead author of the papers and associate research director and head of the Chromosome Replication Laboratory at the Crick, said: "We've developed a chemical toolbox of information about potential new COVID-19 drugs. We hope this attracts attention from scientists with the drug development and clinical expertise needed to test these further, and ultimately see if any could become safe and effective treatments for COVID-19 patients."

The 15 molecules were also tested in combination with remdesivir, an antiviral being used to treat patients with COVID-19. Four of these, all which target the SARS-CoV-2 enzyme Nsp14 mRNA Cap methyltransferase, were found to improve the effectiveness of this antiviral in lab tests.

The scientists now plan to run tests to see if any pairing of the 15 molecules they identified decrease the virus' growth more than if they are used alone. Targeting enzymes involved in virus replication could also help prepare for future viral pandemics.

"Proteins on the outside of viruses evolve rapidly but within different classes of viruses are well conserved proteins that change very little with time," adds John.

"If we can develop drugs that inhibit these proteins, in the situation of a future pandemic, they could provide a valuable first line of defence, before vaccines become available."

Hitherto, the development of valvular heart disease in patients with chronic heart failure has been underestimated and rarely treated. This is the finding of a study conducted at the Division of Cardiology within the Department of Medicine II at Vienna General Hospital and MedUni Vienna and published in the prestigious British Medical Journal (BMJ). Mitral regurgitation was often previously interpreted as part of the progression of heart failure rather than a treatable disease in its own right.

Mitral regurgitation is a disease, in which the valve between the left atrium and left ventricle starts to leak, so that blood refluxes with each heartbeat. Typical symptoms of mitral regurgitation are increasing fatigue, increased shortness of breath on physical exertion and water retention in the lungs and legs. Mitral regurgitation is frequently also associated with cardiac arrhythmias such as atrial fibrillation. The disease is associated with a significant reduction in life expectancy and frequent hospital referrals.

The condition is particularly dangerous and particularly common in patients with chronic heart failure. This is indicated by the recent findings of a working group led by Philipp Bartko and Georg Goliasch from the Division of Cardiology of the Department of Medicine II. The working group analysed data from more than 13,000 patients who meet the criteria for heart failure and who had had a cardiac ultrasound scan at the Division of Cardiology at MedUni Vienna and Vienna General Hospital between 2010 and 2020. Mitral regurgitation can easily be identified by cardiac ultrasound. The working group established a correlation between patient mortality and mitral regurgitation.

"Mitral regurgitation has hitherto often been interpreted as the progression of heart failure rather than as a treatable disease in its own right. The results of the study show that mitral regurgitation is much more prevalent in patients with chronic heart failure than was previously thought and that it has a particularly negative impact on the long-term prognosis of the patient," explains Georg Goliasch.

The results of the study were published in the prestigious British Medical Journal (BMJ) and provide an impetus to make changes in the approach to diagnosis and treatment.

"The results clearly indicate that, even in patients with chronic heart failure, mitral regurgitation should not be interpreted as the progression of heart failure but as a disease in its own right, that can be treated," says Philipp Bartko.

New treatment options allow high-risk patients to be treated

The fact that mitral regurgitation was hitherto rarely treated as a separate disease in patients with chronic heart failure, is related to the treatment options. "Until a few years ago, the only option for treating mitral regurgitation was open-heart surgery. This procedure involves opening up the chest and connecting the patient to a heart-lung machine. This type of intervention is much riskier in patients with chronic heart failure," explains Bartko.

There has been increased focus on heart valve disease in the last few years. New, minimally invasive treatment options have been developed, so that it is now possible to treat patients with heart valve disease who could not have been treated previously or for whom treatment would have carried a higher risk. So-called transcatheter techniques can be carried out with much less risk. In the minimally invasive procedures, the heart valve is repaired via a femoral vein, and, in most cases, patients are able to go home the following day.

Heart valve diseases become more prevalent with age

The working group's study results indicate that the probability of developing a heart valve defect increases with age. Because of the increasing life expectancy of the general population, Goliasch therefore expects the number of cases of this disease to increase in the near future. He says that they are prepared for these challenges at Vienna General Hospital/MedUni Vienna: "Not only are we able to repair the mitral valve via a minimally invasive procedure but also most other heart valve leaks and constrictions, such as aortic stenosis or tricuspid valve failure, and replace defective valves with prostheses in a minimally invasive procedure." For a few years now, an ultramodern hybrid operating theatre has been available for such procedures and this is shared by the Division of Cardiology and the Department of Cardiac Surgery and operated in close collaboration with the Department of Anaesthesia, Intensive Care Medicine and Pain Medicine, the Division of Vascular Surgery and the Division of Cardiovascular and Interventional Radiology.

Early 2020 saw the world break into what has been described as a "war-like situation": a pandemic, caused by the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), the likes of which majority of the living generations across most of the planet have not ever seen. This pandemic has downed economies and resulted in hundreds of thousands of deaths. At the dawn of 2021, vaccines have been deployed, but before populations can be sufficiently vaccinated, effective treatments remain the need of the hour.

Thus, other than fast-tracking research into novel drugs, scientists have also been exploring their arsenals of existing medicines in a bid to find anything that could work against COVID-19. Some approved drugs, like hydroxychloroquine, lopinavir, and interferon, have already been put to clinical use against SARS-CoV-2 without well establishing their clinical efficacies, due to the severity of the pandemic. Subsequent randomized trials have not been able to yield a consensus on the efficacy of these drugs. Only remdesivir has been approved for clinical use against severe COVID-19, although its efficacy is still being debated.

In a breakthrough study, a team of scientists--comprising Dr. Koichi Watashi, Kaho Shionoya, Masako Yamasaki, Dr. Hirofumi Ohashi, Dr. Shin Aoki, Dr. Kouji Kuramochi, and Dr. Tomohiro Tanaka from Tokyo University of Science (along with scientists from the National Institute of Infectious Diseases, Kyushu University, The University of Tokyo, Kyoto University, Japanese Foundation for Cancer Research, and Science Groove Inc.)--have identified an anti-malarial drug, mefloquine (which is incidentally a derivative of hydrochloroquine), that is effective against SARS-CoV-2. Their findings are published in Frontiers in Microbiology.

Detailing their modus operandi, lead scientist in the team Dr. Watashi says, "To identify drugs with higher antiviral potency than existing antivirals, we first screened approved anti-parasitic/anti-protozoal drugs. We found that mefloquine had the highest anti-SARS-CoV-2 activity among the tested compounds. Upon testing it against other quinoline derivatives, such as hydrochloroquine, in a cell line mimicking the cell-based environments of human lung cells, we found it to be better."

The team further explored mefloquine's mechanism of action. Dr. Watashi explains the process, "In our cell assays, mefloquine readily reduced the viral RNA levels when applied at the viral entry phase but showed no activity during virus-cell attachment. This shows that mefloquine is effective on SARS-COV-2 entry into cells after attachment on cell surface."

Thus, to bolster mefloquine's anti-viral activity, the scientists looked into the possibility of combining it with a drug that inhibits the replication step of SARS-CoV-2: Nelfinavir. Interestingly, they observed that the two drugs acted in "synergy" and the drug combination showed greater anti-viral activity than either showed alone, without being toxic to the cells in the cell lines themselves.

The scientists also mathematically modelled the effectiveness of mefloquine to predict its potential real-world impact if applied to treat COVID-19. What they predicted was that mefloquine could reduce the overall viral load in affected patients to under 7% and shorten the 'time-till-virus-elimination' by 6.1 days.

This study must of course be succeeded by clinical trials, but the world can hope that mefloquine becomes a drug used to effectively treat patients with COVID-19.

Exercise training can help support management of overweight and obesity in adults, and can contribute to health benefits beyond "scale victories". The supplement published today in Obesity Reviews, based on the work of an expert group convened under the auspices of the European Association for the Study of Obesity (EASO), provides scientific evidence on health and wellbeing benefits of exercise training for people living with overweight and obesity. Supplement highlights include a summary of key recommendations; additional developed materials provide infographic tools for health care practitioners (HCPs) and people who are overweight or living with obesity, and a written interview with the senior scientist who coordinated development of these important new physical activity recommendations, Professor Jean-Michel Oppert.

ROCKVILLE, MD, USA - June 30, 2021 - Researchers from Sanaria® Inc. and the National Institutes of Health (NIH) are making progress in the development of highly protective malaria vaccines.

In an article published today in Nature, Sanaria's PfSPZ-CVac (CQ) vaccine is reported as being safe and protecting 100% of six subjects against a variant malaria parasite three months after their last dose in the company's Phase 1 safety and efficacy trial. This is the first time complete protection against a variant malaria parasite has ever been achieved that long after vaccine administration.

The variant parasite used in the trial is a Brazilian malaria parasite genetically more variant from the African parasites in the vaccine than 700 malaria parasites from Africa. Protection was achieved at a dose that is 20% of the company's first-generation malaria vaccine dosage.

"These results represent extremely important progress, unanticipated by most malaria experts," said Professor Martin Grobusch, Head of the Center of Tropical Medicine and Travel Medicine, Amsterdam University Medical Centers. "Until recently, malaria vaccine developers sought to achieve high-level protection against non-variant malaria parasites, often only two to three weeks after vaccination, with immunity waning thereafter. The finding of 100% protection against variant parasites that are so divergent from the vaccine parasites at three months is unprecedented. This vaccine approach should be advanced now as a potential tool to protect travelers to Africa and further developed for the prevention of malaria in African populations."

The Nature paper also includes results of a second study using PfSPZ-CVac (PYR), which combines Sanaria's PfSPZ with pyrimethine (PYR), a drug used for seasonal malaria prevention in African preschoolers. This vaccine was well tolerated and protected 82% of the 17 subjects to whom it was administered from the Brazilian variant parasites or the African vaccine parasites three months after their last dose.

"We are encouraged by the significant findings reported in this seminal paper, which justify our investment in Sanaria and its systematic, scientifically sound approach to developing the highly protective, cost effective vaccines required to eliminate malaria, a scourge of humanity, particularly for the most underserved on our planet," said Holm Keller, Co-Managing Director, the EU Malaria Fund.

"Sanaria's vaccine development program is designed to produce safe, cost-effective vaccines that provide high-level protection against malaria parasites that cause more than 400,000 deaths annually, primarily in Africa," said Stephen L. Hoffman, Sanaria's CEO. "With this goal in mind, Sanaria and our partners in the International PfSPZ Consortium have pursued a step-by-step approach to maintaining safety, increasing efficacy toward 100% against variant parasites, increasing the durability of efficacy, and decreasing the required vaccine dosage. This study reports huge progress in all four areas."

Sanaria® PfSPZ-CVac is a chemo-attenuated, live whole parasite vaccine in which an anti-malarial drug is co-administered with parasite cells (PfSPZ) to kill them before a clinical infection develops. In the trial reported in Nature, the anti-malarial was either chloroquine (CQ) or PYR and efficacy was measured by controlled human malaria infection (CHMI). In addition to exposure in natural settings in Africa, the company has relied on CHMI of vaccinated and unvaccinated adults to assess vaccine efficacy. This is a rigorous test of malaria vaccines that can be conducted with small numbers of trial participants since 100% of unvaccinated subjects develop malaria.

MINNEAPOLIS - Finding treatments for advanced multiple sclerosis (MS) has been difficult. But new research may help neurologists identify which drugs are best for people with the advanced form of MS called secondary progressive MS. The new study, published in the June 30, 2021, online issue of Neurology®, the medical journal of the American Academy of Neurology, found that the more potent disease-modifying drugs are more effective in reducing flare-ups in secondary progressive MS than the less potent drugs that tend to be safer to take. However, the researchers found no difference in how fast the disease progressed between these two types of drugs.

Most people with MS are initially diagnosed with relapsing-remitting MS, marked by symptom flare-ups called relapses followed by quiet periods called remission. More than half of these people eventually transition to secondary progressive MS, which is a slow, steady, worsening of the disease that may or may not include relapses.

"Multiple sclerosis is a complicated disease to treat and must be closely monitored as it is managed with various medications, some of which can have serious side effects," said study author Tomas Kalincik, MD, PhD, of the University of Melbourne in Australia. "High-efficacy medications are prescribed in early multiple sclerosis to more aggressively treat the disease and have been found to more effectively prevent flare-ups and modify progression, but less is known about how effective these therapies may be later when relapsing-remitting MS transitions to secondary progressive MS."

The study involved 1,000 people with secondary progressive MS. Participants were followed for 10 years to see whether they had relapses and if they became more disabled over time.

Researchers divided participants into two groups, those treated with one of the more potent drugs, or high-efficacy drugs (natalizumab, alemtuzumab, mitoxantrone, ocrelizumab, rituximab, cladribine and fingolimod) and those treated with one of the less potent drugs, or low-efficacy drugs (interferon β, glatiramer acetate and teriflunomide). People in each group were matched for factors like disability level and how long they had secondary progressive MS.

After accounting for the lag time before a person starts to experience the benefit of a medication, researchers found that in people with active disease, or those experiencing relapses within the past two years, people who were treated with high-efficacy medications experienced 30% fewer relapses than people treated with low-efficacy medications. People in the high-efficacy group experienced an average of 0.17 relapses per year compared 0.27 relapses per year in the low-efficacy group.

"Our study finding that high-efficacy therapies are superior to low-efficacy therapies only in reducing relapses in people with active secondary progressive MS provides valuable guidance for neurologists when choosing the most effective therapies for people with this form of MS," said Kalincik. "When the goal is to alleviate ongoing relapse activity, more potent therapy is justified. But when the goal is to limit disability progression in secondary progressive MS, both types of drugs show comparable effectiveness."

A limitation of the study was that participants were grouped by those taking high-efficacy or low-efficacy therapies. However, therapies were not studied individually. Kalincik said it is possible that individual therapies may have different effects on symptoms and disability and recommend that they be examined separately in future research.

Many neurodevelopmental disorders share similar symptoms, such as learning disabilities or attention deficits. A new study from MIT has uncovered a common neural mechanism for a type of cognitive impairment seen in some people with autism and schizophrenia, even though the genetic variations that produce the impairments are different for each condition.

In a study of mice, the researchers found that certain genes that are mutated or missing in some people with those disorders cause similar dysfunctions in a neural circuit in the thalamus. If scientists could develop drugs that target this circuit, they could be used to treat people who have different disorders with common behavioral symptoms, the researchers say.

"This study reveals a new circuit mechanism for cognitive impairment and points to a future direction for developing new therapeutics, by dividing patients into specific groups not by their behavioral profile, but by the underlying neurobiological mechanisms," says Guoping Feng, the James W. and Patricia T. Poitras Professor in Brain and Cognitive Sciences at MIT, a member of the Broad Institute of Harvard and MIT, the associate director of the McGovern Institute for Brain Research at MIT, and the senior author of the new study.

Dheeraj Roy, a Warren Alpert Distinguished Scholar and a McGovern Fellow at the Broad Institute, and Ying Zhang, a postdoc at the McGovern Institute, are the lead authors of the paper, which appears in Neuron.

Thalamic connections

The thalamus plays a key role in cognitive tasks such as memory formation and learning. Previous studies have shown that many of the gene variants linked to brain disorders such as autism and schizophrenia are highly expressed in the thalamus, suggesting that it may play a role in those disorders.

One such gene is called Ptchd1, which Feng has studied extensively. In boys, loss of this gene, which is carried on the X chromosome, can lead to attention deficits, hyperactivity, aggression, intellectual disability, and autism spectrum disorders.

In a study published in 2016, Feng and his colleagues showed that Ptchd1 exerts many of its effects in a part of the thalamus called the thalamic reticular nucleus (TRN). When the gene is knocked out in the TRN of mice, the mice show attention deficits and hyperactivity. However, that study did not find any role for the TRN in the learning disabilities also seen in people with mutations in Ptchd1.

In the new study, the researchers decided to look elsewhere in the thalamus to try to figure out how Ptchd1 loss might affect learning and memory. Another area they identified that highly expresses Ptchd1 is called the anterodorsal (AD) thalamus, a tiny region that is involved in spatial learning and communicates closely with the hippocampus.

Using novel techniques that allowed them to trace the connections between the AD thalamus and another brain region called the retrosplenial cortex (RSC), the researchers determined a key function of this circuit. They found that in mice, the AD-to-RSC circuit is essential for encoding fearful memories of a chamber in which they received a mild foot shock. It is also necessary for working memory, such as creating mental maps of physical spaces to help in decision-making.

The researchers found that a nearby part of the thalamus called the anteroventral (AV) thalamus also plays a role in this memory formation process: AV-to-RSC communication regulates the specificity of the encoded memory, which helps us distinguish this memory from others of similar nature.

"These experiments showed that two neighboring subdivisions in the thalamus contribute differentially to memory formation, which is not what we expected," Roy says.

Circuit malfunction

Once the researchers discovered the roles of the AV and AD thalamic regions in memory formation, they began to investigate how this circuit is affected by loss of Ptchd1. When they knocked down expression of Ptchd1 in neurons of the AD thalamus, they found a striking deficit in memory encoding, for both fearful memories and working memory.

The researchers then did the same experiments with a series of four other genes -- one that is linked with autism and three linked with schizophrenia. In all of these mice, they found that knocking down gene expression produced the same memory impairments. They also found that each of these knockdowns produced hyperexcitability in neurons of the AD thalamus.

These results are consistent with existing theories that learning occurs through the strengthening of synapses that occurs as a memory is formed, the researchers say.

"The dominant theory in the field is that when an animal is learning, these neurons have to fire more, and that increase correlates with how well you learn," Zhang says. "Our simple idea was if a neuron fires too high at baseline, you may lack a learning-induced increase."

The researchers demonstrated that each of the genes they studied affects different ion channels that influence neurons' firing rates. The overall effect of each mutation is an increase in neuron excitability, which leads to the same circuit-level dysfunction and behavioral symptoms.

The researchers also showed that they could restore normal cognitive function in mice with these genetic mutations by artificially turning down hyperactivity in neurons of the AD thalamus. The approach they used, chemogenetics, is not yet approved for use in humans. However, it may be possible to target this circuit in other ways, the researchers say.

The findings lend support to the idea that grouping diseases by the circuit malfunctions that underlie them may help to identify potential drug targets that could help many patients, Feng says.

"There are so many genetic factors and environmental factors that can contribute to a particular disease, but in the end, it has to cause some type of neuronal change that affects a circuit or a few circuits involved in this behavior," he says. "From a therapeutic point of view, in such cases you may not want to go after individual molecules because they may be unique to a very small percentage of patients, but at a higher level, at the cellular or circuit level, patients may have more commonalities."

WHAT:
Two U.S. Phase 1 clinical trials of a novel candidate malaria vaccine have found that the regimen conferred unprecedentedly high levels of durable protection when volunteers were later exposed to disease-causing malaria parasites. The vaccine combines live parasites with either of two widely used antimalarial drugs--an approach termed chemoprophylaxis vaccination. A Phase 2 clinical trial of the vaccine is now underway in Mali, a malaria-endemic country. If the approach proves successful there, chemoprophylaxis vaccination, or CVac, potentially could help reverse the stalled decline of global malaria. Currently, there is no vaccine in widespread use for the mosquito-transmitted disease.

The trials were conducted at the National Institutes of Health (NIH) Clinical Center in Bethesda, Maryland. They were led by Patrick E. Duffy, M.D., of the NIH National Institute of Allergy and Infectious Diseases (NIAID), and Stephen L. Hoffman, M.D., CEO of Sanaria Inc., Rockville, Maryland.

The Sanaria vaccine, called PfSPZ, is composed of sporozoites, the form of the malaria parasite transmitted to people by mosquito bites. Sporozoites travel through blood to the liver to initiate infection. In the CVac trials, healthy adult volunteers received PfSPZ along with either pyrimethamine, a drug that kills liver-stage parasites, or chloroquine, which kills blood-stage parasites. Three months later, under carefully controlled conditions, the volunteers were exposed to either an African malaria parasite strain that was the same as that in the vaccine (homologous challenge) or a variant South American parasite (heterologous challenge) that was more genetically distant from the vaccine strain than hundreds of African parasites. Exposure in both cases was via inoculation into venous blood, which infects all unvaccinated individuals.

At the lowest PfSPZ dosage, the CVac approach conferred modest protection: only two of nine volunteers (22.2%) who received the pyrimethamine combination were protected from homologous challenge. In contrast, seven out of eight volunteers (87.5%) who received the highest PfSPZ dosage combined with pyrimethamine were protected from homologous challenge, and seven out of nine volunteers (77.8%) were protected from heterologous challenge. In the case of the chloroquine combination, all six volunteers (100%) who received the higher PfSPZ dosage were completely protected from heterologous challenge. The high levels of cross-strain protection lasted at least three months (the time elapsed between vaccination and challenge) for both higher-dose regimens. One hundred percent protection for three months against heterologous variant parasites is unprecedented for any malaria vaccine in development, the authors note. These data suggest that CVac could be a promising approach for vaccination of travelers to and people living in malaria-endemic areas.

What The Study Did: This crossover trial found that perceived breathing resistance at peak exercise is uniquely and significantly elevated when exercise stress testing (EST) is performed while wearing a mask. Performing EST with a mask yielded lower peak exercise oxygen uptake and heart rates as compared with no mask. However, each experimental condition resulted in peak exercise values that generally remained within normal limits, and no EST required termination due to clinically indicated safety concerns. Thus, although it is possible that wearing a mask exerted a physical limitation on exercise capacity, the clinical relevance of such a possibility is not supported by these data.

Authors: Matthew Kampert, D.O., M.S., of the Cleveland Clinic, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamanetworkopen.2021.15219)

Editor's Note: The article includes funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

What The Study Did: Researchers in this randomized clinical trial found that a large proportion of patients who canceled visits and procedures early in the COVID-19 pandemic didn't reschedule once reopening occurred. A single message targeted directly to these patients didn't affect the return to in-person visits within a month but it resulted in a small increase in re-engagement through telemedicine and rescheduling of future visits.

Authors: Anne R. Cappola, M.D., Sc.M., of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamanetworkopen.2021.15211)

Editor's Note: The article includes funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

Japanese and Zambian scientists have shown that environmental lead poisoning in children affects not only their own health and wellbeing, but the vitality and mental health of their mothers, as well.

Lead poisoning is a common pediatric problem caused by the environment, and is easily preventable. Due to their smaller size and mass, infants and children are at a higher risk of negative effects compared to adults. Chronic lead poisoning leads to fatigue, sleeping problems, headaches, stupor, and anemia. The population of Kabwe, Zambia, is exposed to extremely high levels of lead. This is a direct result of the Broken Hill mine, which operated until 1994, contaminating the surrounding area; a large number of citizens in Kabwe make a living working the mine tailings, further exposing themselves to heavy metal poisoning.

Recently, a team of scientists from Japan and Zambia, including Hokkaido University's Professor Harukazu Tohyama and Dr. Hokuto Nakata, have established a significant negative correlation between chronic lead poisoning in children and health-related quality of life of their mothers. Their findings were published in the journal Chemosphere.

The health-related quality of life (HRQoL) comprehensively assesses the health and well-being of an individual. Children's health and well-being strongly influences the HRQoL of their mothers, with both positive and negative outcomes having been documented. The effects of chronic lead poisoning of children on maternal HRQoL were assumed to be negative; however, it had not been investigated and the exact extent of the interrelation was unknown.

The study was carried out on 40 randomly selected areas in Kabwe, with 25 households tested in each area. The scientists combined data from tests on blood samples, a health survey (SF-36) and an economic survey (KHSS 2017), and carried out statistical analyses to find significant relationships between these three factors.

The scientists demonstrated significant negative associations between the blood lead levels (BLLs) of the children in Kabwe and the HRQoL scores of their mothers, irrespective of the blood lead levels in the mothers. Mental health and vitality were particularly impacted. Previous studies reported that lead exposure may cause behavioral problems in children, which could be the cause of the adverse effects on the vitality of their mothers that was found in this study. Socio-economic factors and maternal age did affect the HRQoL scores, but only in some areas, unlike children's BLLs. In addition, the BLLs of children were significantly higher than that of their parents.

The biggest limitation of the study was that not all of the 1000 selected households were able to provide data for all parameters examined; in fact, just 404 households provided data of sufficient quality to be analysed. Future work must focus on examining the relations between HRQoL scores, household incomes, and BLLs at a larger scale.

"Urgent medical intervention for the children with high BLL combined in parallel with environmental remediation in Kabwe would not just improve the health status of children in Kabwe, but could also improve the HRQoL of mothers," says Hokuto Nakata.

Reactive oxygen species (ROS) are highly reactive chemicals which contain oxygen radicals. Hypochlorous acid, peroxides, superoxide, singlet oxygen, alpha-oxygen and hydroxyl radicals are the major examples of ROS, which are familiar to persons from many walks of life as they are used in many domestic and industrial processes. ROS are naturally produced during a variety of biochemical reactions within the cell organelles such as the endoplasmic reticulum, mitochondria and peroxisomes. ROS are also formed as a byproduct of the normal metabolism of oxygen. The production of ROS can be induced by various factors such as heavy metals, tobacco, smoke, drugs, xenobiotics, pollutants and radiation. From various experimental studies, it is reported that ROS acts as either tumor suppressing or tumor promoting agent. The elevated level of ROS can arrest the growth of tumor through the persistent increase in cell cycle inhibition. The increased level of ROS can induce apoptosis by both intrinsic and extrinsic pathways. ROS is considered to be tumor suppressing agent as the production of ROS is due to use of most of the chemotherapeutic agents in order to activate the cell death. The cytotoxic effect of ROS provides impetus towards apoptosis but in higher levels, ROS can cause initiation of malignancy that leads to uncontrolled cell death in cancer cells. Whereas, some species of ROS can influence various activities at cellular level that include cell proliferation. This recent review, published in Anti-Cancer Agents in Medicinal Chemistry explains the significance of ROS in cancer therapy.

Scientific reports suggest that ROS may promote either cell proliferation or cell death depending on the intensity or location of the oxidative burst and the activity of the antioxidant system. The ability of ROS to stimulate cell growth or cell death mainly depends on the intensity or duration of redox signals and defense mechanisms of antioxidants. The existing anti-cancer drugs exert harmful effects on normal cells which are partially activated by ROS. These species exert reverse cellular effects by promoting either cell proliferation and tumor progression or cell death. ROS act as "double edged sword" by acting not only as disease inducers or sustainers but also act as therapeutic weapons in cancer cells. The increased level of ROS in mitochondria is found to induce cell proliferation, cell survival, cell migration, and epithelial-mesenchymal transition through mitogen-activated protein kinase (MAPK) and Ras-ERK activation.

With these intracellular effects in view, various reactive oxygen species can be applied therapeutically for the treatment of different types of cancer cells. Novel therapeutic approaches of anti-cancer drugs are based on formation ROS or modulation of antioxidant mechanisms. By being able to differentiate between normal and cancer cells through the use of molecular signals researchers can target cancer cells for destruction in vivo. In spite of the current techniques of ROS signaling in cancer biology, the dual nature of ROS is still a great challenge in cancer therapies that target to ROS. The understanding of properties of ROS as major factor in signaling pathways may offer hope in the clinic for safer and effective pharmacological anti-cancer interventions in the future.