Body

Researchers from Tokyo Medical and Dental University (TMDU) find that immune system signaling molecule TNF-α may trigger high blood pressure in patients with chronic kidney disease

Tokyo, Japan - Detecting threats, sending out response molecules, and altering gene expression--our immune system works tirelessly day and night to protect us from invading pathogens and maintain general health and wellbeing. But in a study published this month in peer-reviewed journal Kidney International, a group of researchers from Tokyo Medical and Dental University (TMDU) in Japan have found a link between the immune system and high blood pressure in patients with chronic kidney disease (CKD).

CKD affects almost 800 million people worldwide and is the underlying cause of over a million deaths each year. One of the major complications of CKD is high blood pressure, or hypertension, and studies have shown that controlling blood pressure is an important factor in preventing CKD progression. However, many CKD patients display increased salt-sensitivity, a condition where blood pressure is unduly influenced by dietary salt intake, making it much harder to control.

Inappropriate over-activation of a pathway called the WNK-SPAK-NCC phosphorylation cascade increases salt reabsorption in the kidney, leading to salt-sensitive hypertension. However, whether this pathway causes hypertension in CKD patients and what regulates the phosphorylation cascade had not been investigated.

Using a mouse model of disease, the researchers confirmed that mice with CKD had increased levels of the WNK1 protein in their kidneys, causing increased activation of the downstream proteins SPAK and NCC. When fed a high salt diet, the WNK-SPAK-NCC pathway remained activated in CKD mice, leading to salt-sensitive hypertension.

The researchers then looked to several recent studies suggesting that the immune system may play a role in salt sensitivity. Sure enough, levels of pro-inflammatory cytokine TNF-α were elevated in the kidneys of CKD mice, and provision of TNF-α resulted in increased levels of WNK1.

"Interestingly, TNF-α did not increase the transcription of WNK1, suggesting that it somehow prevented the degradation of mature WNK1 protein instead," says corresponding author of the study Dr Eisei Sohara. "Based on this hypothesis, we confirmed that TNF-α enhances WNK1 protein levels by preventing the transcription of NEDD4-2 E3-ligase, a protein that normally degrades mature WNK1." By inhibiting TNF-α, the researchers were able to reverse the salt sensitivity of CKD mice fed a high salt diet, confirming the link between the immune system and salt sensitivity.

Thiazide diuretics, NCC inhibitors, are widely used antihypertensive drugs, but their efficacy varies among patients with CKD. To achieve precision medicine, it is important to predict the efficacy of medication beforehand. Patients with enhanced activity of NCC are considered to respond well to thiazide diuretics. Therefore, finding of this study may contribute to better choice of antihypertensives in the future.

Opioid-containing painkillers are virtually indispensable in clinical practice and are typically used in postoperative patients and patients undergoing cancer treatment. In addition to having severe side effects, however, these drugs have also been associated with extensive misuse, particularly in the United States. Recent findings by a team of researchers from Charité - Universitätsmedizin Berlin represent a significant step towards the development of a new generation of painkillers. Published in Scientific Reports*, their findings show that tissue acidity - or tissue pH - at the source of the pain (i.e. injury) is a crucial determinant in the development of new drugs. This is because the fine-tuning of an opioid molecule's acid dissociation constant (pKa) will determine its risk profile, including its addiction potential.

Opioids have powerful pain-relieving effects but can quickly lead to dependence. For some time, these drugs have been prescribed too readily, particularly in the United States, where opioid addiction is so widespread that the situation is referred to as the 'opioid crisis'. Germany, too, is witnessing an increase in the prescription of opioid-containing drugs, which are now even used in patients with non-cancer-related chronic pain. What remains elusive to this day, is medication which offers powerful pain-relieving properties but is associated with fewer risks.

A group of researchers, led by Prof. Dr. Christoph Stein, Head of Charité's Experimental Anesthesiology Unit on Campus Benjamin Franklin, has been trying to track down an alternative type of painkiller with fewer side-effects. Previous efforts resulted in the development of three new opioid substances - known as FF6, FF3 and NFEPP - which were developed in collaboration with applied mathematics colleagues from the Zuse Institute Berlin (ZIB). Using an animal model of inflammatory pain for a more in-depth study of these three substances, the researchers have been able to explore their pain-relieving effects in greater detail, while also examining typical side effects such as tiredness and constipation and studying the risk of respiratory arrest and addiction. "When compared to the standard opioid - fentanyl - results of this new class of drugs speak for themselves," says Prof. Stein, who is also a member of the Einstein Center for Neurosciences. "The more closely the pKa value of the binding molecule matches the acidity level of the inflamed or injured tissue, the more selective is the activation of the opioid receptors at the source of pain and the lower the risk of addiction or side effects. In the case of fentanyl, the pKa value is higher than normal physiologic pH. This standard opioid also enters the brain more readily."

The researchers are exploring the option of alleviating inflammatory and postoperative pain by directly targeting the site of its origin - injured tissue. In contrast to conventional opioids, the new drugs will only activate opioid receptors (the docking stations for pain-relieving medication) under acidic conditions. This means they will only work in injured tissue; severe side effects will be prevented. "We used cultured cells to study the ways in which opioid receptors and opioid receptor-binding molecules interact at different pH levels. We did this to determine the chemical properties needed to optimize the effects of these new drugs. Some of the receptors were also genetically altered," explains study lead Prof. Stein, and adds: "We came to the conclusion that the acid dissociation constant - or pKa value - determines a particular opioid molecule's risk profile, i.e. its side effects, such as tiredness or respiratory arrest. Until now, nobody knew about the significance of pH and pKa values and their role in opioid safety." A ground-breaking finding in the field of receptor research.

According to the researchers' findings, both the fine-tuning of the pKa value and the formation of specific chemical bonds to opioid receptors will be crucial factors in the development of new types of drugs. Should this new generation of painkillers become a reality, both dangerous side effects and addiction potential could become a thing of the past. "Our previous clinical studies have already shown that the selective activation of peripheral opioid receptors in injured tissue, for instance by injection of conventional opioids like morphine, can have powerful pain-relieving effects in humans. We are therefore confident that our new class of drugs, which are now available for intravenous use for the first time, will turn out to be a success," says Prof. Stein. The first clinical trials on these new drugs are expected to start in two to three years' time. In parallel, the team is also pursuing the study of other drugs derived from this new generation of substances. Funded via the SPARK program, this work is being conducted at the Berlin Institute of Health (BIH).

Researchers from the Lille Centre for Infection and Immunity (CNRS/INSERM/Institut Pasteur de Lille/University of Lille/CHU Lille), INRAE and from Brazilian (Belo Horizonte), Scottish (Glasgow) and Danish (Copenhagen) laboratories have shown for the first time in mice that perturbation of the gut microbiota caused by the influenza virus favours secondary bacterial superinfection. Published in Cell Reports on March 3, 2020, these results open up new prospects for the prevention and treatment of bacterial pneumonia, a major cause of death in elderly or vulnerable people infected with the influenza virus.

Influenza and its complications continue to be a significant public health concern as well as a major social and economic burden. Vaccination campaigns, together with the discovery of new antiviral therapies, provide preventive and therapeutic solutions. However, impairment of defence mechanisms against secondary bacterial infections, which considerably worsen the clinical picture of people with influenza, remains a major problem.

Specializing in the field of pulmonary immunity, a team led by François Trottein, a CNRS researcher at the Lille Centre for Infection and Immunity focused on the gut microbiota, well known for their key role in many physiological processes, including immune defence mechanisms. Scientists have shown that, in mice, influenza temporarily alters the composition and metabolic activity of the gut microbiota, probably due to reduced food consumption during illness. During influenza, the production of short-chain fatty acids by the bacteria of the microbiota is also diminished. The team has now shown that these fatty acids remotely favour the bactericidal activity of macrophages present in the lungs. Perturbation of the intestinal microbiota by influenza thus compromises lung defences, particularly against Streptococcus pneumoniae, the leading cause of bacterial pneumonia in humans.

The researchers also showed that this sensitivity to bacterial superinfection can be corrected by treatment with acetate, one of the main short-chain fatty acids produced by the microbiota. Their work could have practical applications for the well-being of infected patients, who would be better protected against influenza-related complications. This work was made in collaboration with scientists from the Micalis Institute (INRAE/AgroParistech/Université Saclay), the Lille Inflammation Research International Center (INSERM/Université de Lille/CHU Lille), the Laboratory of Design and Application of Bioactive Molecules (CNRS/University of Strasbourg), the Molecular Virology and Immunology Unit (INRAE) and GenoScreen (Lille), the Universidade Federal de Minas Gerais (Belo Horizonte, Brazil), the Institute of Molecular, Cell and Systems Biology (Glasgow, Scotland) and the Department of Pharmacology (University of Copenhagen, Denmark). This discovery represents a major breakthrough in the understanding of the mechanisms behind bacterial superinfections in influenza patients. It could lead to the development of new nutritional and/or therapeutic strategies to better control bacterial infections.

Results from 46 patients given treatments that target specific molecular changes in tumour cells suggest that these therapies could help patients with pancreatic cancer whose tumours harbour those changes survive an extra year.

Patients with molecular changes in their tumours who received a targeted therapy alongside other treatment survived for an average of one year longer after being diagnosed with advanced disease compared with patients who received standard chemotherapy (survival of 31 vs 18 months), according to an observational study published in The Lancet Oncology journal.

Pancreatic cancer is often diagnosed late and there are few treatment options available. Previous studies have shown that up to a quarter of patients [1] have molecular alterations in their tumours that could potentially be treated with targeted therapies. The new study is the first to show that this approach could be a successful treatment option for people with a pancreatic tumour that has molecular alterations.

One limitation to the study is that many of the patients who received a targeted therapy were also treated with other therapies at the same time, making it difficult to definitively determine the precise benefits of this approach over standard care. However, because both groups received chemotherapy, the only variable was whether or not the patients also received the molecularly targeted therapy.

Dr Michael Pishvaian, of The University of Texas MD Anderson Cancer Centre, USA, said: "Although only a small number of patients in this study received a targeted therapy, the results are promising. No other type of therapy has offered a survival benefit of this magnitude to patients with pancreatic cancer. Our findings suggest that adopting a precision medicine approach, where patients are given a therapy targeted to the specific conditions of their tumour, could have a substantial effect on survival prospects for these patients."[2]

Targeted therapies work by targeting the specific molecular changes inside tumour cells that contribute to cancer growth and survival, unlike chemotherapy that works more generally against cancer cells. [3] Targeted therapy has already helped improve survival for many forms of cancer, such as PARP inhibitors for ovarian cancer and Herceptin for breast cancer.

However, the new study is the first to assess the benefits of targeted therapies for patients with pancreatic cancer, by analysing information from patients who had been prescribed targeted therapy by their own doctors.

The number of patients with pancreatic cancer carrying a particular molecular alteration are too low to carry out a clinical trial. However, as there are often no other treatment options for pancreatic cancer, in some countries doctors are permitted to prescribe therapies that have been approved for use in other types of cancer, a practice known as using a drug off-label. In this case, the use of targeted therapies off-label can be justified if the patient's tumour carries the same molecular alteration as the type of cancer the drug was approved for [4].

In this study, the authors carried out a retrospective analysis of data from the Pancreatic Cancer Action Network's Know Your Tumour® programme, a registry of patients with pancreatic cancer from across the USA who had undergone molecular testing of their tumours.

Around a quarter of pancreatic cancer patients registered in the programme who received molecular testing (282 of 1,082) were found to have tumours that harboured molecular changes that were potentially susceptible to targeted therapies. Treatment outcomes were only available for 189 of these patients because some had died before the report could be delivered and others had no documented information about their treatment.

Of those, 46 patients had received a targeted therapy matched to the specific molecular change associated with their tumour.

The researchers found the average survival for those who received a targeted therapy was a little over two and a half years (31 months). Average survival for patients who did not have one of the molecular changes for which a targeted therapy exists, and had been treated with standard chemotherapy, was 16 months.

143 patients were eligible for a targeted therapy, because they had tumours carrying one of the relevant molecular changes, but had been given standard chemotherapy alone. Their average survival was 18 months.

Lynn Matrisian, co-author of the study and Chief Scientific Officer of The Pancreatic Cancer Action Network, USA, said: "Access to high-quality molecular testing is variable. Future efforts should focus on addressing barriers to molecular testing so that more people can benefit from this personalised approach to cancer treatment. We will continue to work to close that gap through our Know Your Tumour programme and through patient and healthcare professional outreach and education." [2]

In addition, some 351 patients who had received molecular testing were not included in the final analysis owing to missing data on their initial treatment before they entered the study. This could affect the overall survival results but the researchers expect findings would be similar in this group.

Writing in a linked Comment, lead author Professor Jörg Kleeff (who was not involved in the study) from the Martin-Luther-University Halle-Wittenberg, in Germany, said: "There will be a number of important questions to be addressed. These will comprise technical details regarding sequencing of tumour tissues and of germline material but also clinical questions such as timing of treatment, choosing the right chemotherapy (backbone), as well as combination treatment regimens."

Pancreatic cancer is one of the hardest cancers to treat. It is often diagnosed late and survival rates are low, with fewer than one in ten patients surviving for five years or more after diagnosis. Globally, there were 458,918 new cases reported in 2018. [5] This study is publishing at the same time as a cross journal series from The Lancet Oncology, The Lancet Gastroenterology & Hepatology, and EBioMedicine on pancreatic cancer, tackling these challenges and highlighting the progress being made in all areas of pancreatic cancer research (series available under embargo via links below).

New direct-acting antiviral therapies are highly effective at eliminating the Hepatitis C virus infection, according to a systematic evidence review by researchers at Oregon Health & Science University.

The review, published today in the Journal of the American Medical Association, informed a new recommendation by the U.S. Preventive Health Task Force for universal screening of Hepatitis C. Until now, screening has been recommended for people born between 1945 and 1965 with risk factors such as injection drug use.

The evidence review found that new direct-acting antiviral therapies effectively target the virus with few side effects.

"This has really been a remarkable advance in treatment," said corresponding author Roger Chou, M.D., director of the Pacific Northwest Evidence-based Practice Center at OHSU and a professor of medicine (general internal medicine and geriatrics) in the OHSU School of Medicine.

"Historically, Hepatitis C has been very difficult to treat, and the treatments were longer and difficult to tolerate," Chou added. "The new treatments are more effective but also have few side effects and therapy is usually completed in 8 to 12 weeks, compared with around a year previously."

Hepatitis C is the most common blood-borne virus in the United States with an estimated 2.4 million people affected. Left untreated, Hepatitis C can lead to severe complications including liver failure and liver cancer.

The new study updates a previous review conducted in 2013.

At that time, direct-acting antiviral therapies were just beginning to be used in combination with injections of interferon. Interferons ramp up the body's overall immune response to suppress the virus, however the year-long treatment caused flu-like side effects. In the 2013 review, the first direct-acting antiviral medications had just been introduced. In combination with interferon, the first-generation antiviral drugs were between 68% and 78% effective in driving the virus to undetectable levels in the blood following treatment.

New all-direct-acting antiviral regimens without interferon are more than 95% effective in eliminating the virus even in young people, the review found.

The review covered eight randomized controlled trials comparing direct-acting antiviral therapies to placebo or an outdated antiviral regimen, 48 other treatment studies, and 33 cohort studies with a total of almost 180,000 patients.

The research was funded under contract HHSA290201500009i, Task Order 7, from the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services, under a contract to support the U.S. Preventive Services Task Force.

When scientists try to predict the spread of something across populations--anything from a coronavirus to misinformation--they use complex mathematical models to do so. Typically, they'll study the first few steps in which the subject spreads, and use that rate to project how far and wide the spread will go.

But what happens if a pathogen mutates, or information becomes modified, changing the speed at which it spreads? In a new study appearing in this week's issue of Proceedings of the National Academy of Sciences (PNAS), a team of Carnegie Mellon University researchers show for the first time how important these considerations are.

"These evolutionary changes have a huge impact," says CyLab faculty member Osman Yagan, an associate research professor in Electrical and Computer Engineering (ECE) and corresponding author of the study. "If you don't consider the potential changes over time, you will be wrong in predicting the number of people that will get sick or the number of people who are exposed to a piece of information."

Most people are familiar with epidemics of disease, but information itself--nowadays traveling at lightning speeds over social media--can experience its own kind of epidemic and "go viral." Whether a piece of information goes viral or not can depend on how the original message is tweaked.

"Some pieces of misinformation are intentional, but some may develop organically when many people sequentially make small changes like a game of 'telephone,'" says Yagan. "A seemingly boring piece of information can evolve into a viral Tweet, and we need to be able to predict how these things spread."

In their study, the researchers developed a mathematical theory that takes these evolutionary changes into consideration. They then tested their theory against thousands of computer-simulated epidemics in real-world networks, such as Twitter for the spread of information or a hospital for the spread of disease.

In the context of spreading of infectious disease, the team ran thousands of simulations using data from two real-world networks: a contact network among students, teachers, and staff at a US high school, and a contact network among staff and patients in a hospital in Lyon, France.

These simulations served as a test bed: the theory that matches what is observed in the simulations would prove to be the more accurate one.

"We showed that our theory works over real-world networks," says the study's first author, Rashad Eletreby, who was a Carnegie Mellon Ph.D. student when he wrote the paper. "Traditional models that don't consider evolutionary adaptations fail at predicting the probability of the emergence of an epidemic."

While the study isn't a silver bullet for predicting the spread of today's coronavirus or the spread of fake news in today's volatile political environment with 100% accuracy - one would need real-time data tracking the evolution of the pathogen or information to do that - the authors say it's a big step.

"We're one step closer to reality," says Eletreby.

Researchers and the participants who enroll in their clinical trials do not always speak the same language, making it difficult to share trial results with study participants.

As a result, most clinical trial participants are not told the results of the study in which they were involved, though most would like to know, and most researchers would like to tell them, report Medical University of South Carolina (MUSC) researchers in an article published in the Journal of Clinical and Translational Science.

Helping researchers to learn how to translate their findings for a lay public could make participants feel like respected partners in research and potentially increase the number of patients willing to enroll in trials.

Study participants deserve the right to hear those results and know their efforts made a difference, said the two National Institutes of Health-funded MUSC translational researchers who led the study: senior author Teresa J. Kelechi, R.N., Ph.D., associate dean for research in the MUSC College of Nursing, and lead author Cathy L. Melvin, Ph.D., a professor in the Department of Public Health in the MUSC College of Medicine. The study was funded by a special commission pilot project grant from the South Carolina Clinical & Translational Research (SCTR) Institute, the Clinical and Translational Science Awards hub headquartered at MUSC.

Translational research is about "translating" research breakthroughs into clinical practice, but it is also about translating research results into meaningful messages for members of the community, particularly those who made the research possible.

"So part of translation is not only translating from bench to bedside but also translating your findings back to the participants who made it work," said Kelechi. "At the end of the day, it's because of them that we're doing science."

Kelechi and Melvin interviewed and ran focus groups for past study participants to find out whether and how they would like to receive study results. The study also canvassed researchers to determine whether they were willing to share results and identify any barriers to doing so.

Of the 48 past study participants surveyed, almost 70% never received the results from the study in which they participated, though 75% would have liked to. The vast majority of researchers surveyed - 95% - thought it was important, and even an ethical duty, to report findings to study participants.

If informed of findings, many study participants also expressed a willingness to share them with friends, health care providers and others with the same condition. As such, participants could become champions for research in the community, helping to disseminate findings while encouraging others to participate through their example.

Study participants expressed different preferences for how to receive study findings, based on their ages. Two groups of study participants were surveyed: teens/young adults and adults older than 50. The top preference for both groups was email, but older adults greatly preferred mailed letters, postcards, newsletters or calls to texts or social media, while teens/young adults expressed a strong preference against mailed correspondence or newsletters.

The researchers surveyed said they had received little training in communicating to a lay public through age-appropriate channels. Several of the surveyed researchers expressed a desire for more training through workshops as well as templates for a variety of communication documents.

"For me, this was an eye-opening experience," said Kelechi. "I've been doing research for 20 years but was unaware how much the research community feels unequipped to report their findings to study participants. They want to give back, but that is not a skill set that they have, but it is one they want to develop."

To meet that need, Kelechi and Melvin have already developed a number of communication templates and are currently working to refine them further. They also would like to develop lunch and learns and an online module on the topic. At MUSC, researchers can also request recruitment consults and marketing assistance from SCTR via the electronic tool SPARCRequest.

Researchers were also unsure if they should communicate preliminary, partial or equivocal findings to participants. Melvin thinks they should. "Whatever the results are, researchers have a responsibility to share that information back to the participants," she said.

Funding can be another barrier for researchers. Most monies dedicated to communication in a grant are used to recruit patients, leaving little at the end of the study to cover the costs of disseminating the findings. Kelechi suggests that researchers buy postage and other supplies ahead of time to ensure that they have the necessary resources at the end of the study.

Kelechi and Melvin are confident that the gap in communication between researchers and study participants can be bridged.

"We have two groups of people who want the same thing, which is to share information with each other," said Melvin. "So, given the good will on both sides, I'm very optimistic and feel that there is a real opportunity for us to make a difference in this area."

A research team funded by the National Institutes of Health has updated an online tool to provide information for clinicians and parents on outcomes for extremely preterm infants. The key change in the update was the incorporation of data from the hospital where the infant was born, which the researchers found was as important as gestational age in determining infant outcome. The original web-based outcome tool was developed in 2008 by the Neonatal Research Network, a group of clinical sites supported by NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).

The revised tool, developed using data from the Neonatal Research Network and later validated using data from hospitals in the Vermont Oxford Network (VON), is based on outcomes for extremely preterm births in the United States. The researchers also used VON data to describe differences in survival across U.S. hospitals. The researchers describe the basis for the revision in an article appearing in JAMA Pediatrics.

The extremely preterm infants in this study were born from weeks 22 through 25 of pregnancy; a full-term pregnancy is 40 weeks. Many of these infants die soon after birth, despite receiving the best treatment available. Although some survive and reach adulthood largely unaffected, others will experience disability, ranging from correctable hearing loss to profound physical or intellectual impairment. Physicians and family members often must choose between aggressive treatment to save an infant's life or comfort care, which meets the infant's basic needs but forgoes painful medical procedures unlikely to benefit the infant.

Like its predecessor, the new tool provides information on infant survival and neurological impairment on the basis of five factors: gestational age (the week of pregnancy the infant was born), whether the baby is male or female, birth weight, whether the baby was a single baby or from a multiple pregnancy, and whether the baby's mother was given antenatal steroids during labor to accelerate the baby's maturation and overall development. Hospital-specific estimates of survival for each participating hospital in VON are now available to that hospital through the VON website.

The developers of the tool stress that while it provides information useful for families and clinicians considering treatment options, it cannot substitute for a physician's careful assessment or predict with certainty the outcome for any infant.

A study led by the University of Southampton, funded by Cancer Research UK, has shown a new drug - originally developed to tackle the scarring of organ tissue - could help to significantly improve the success rate of cancer immunotherapy treatment.

Scientists have shown in mouse cancers, that GKT137831 (Setanaxib) can help break down the 'barrier' which makes many cancerous tumours resistant to immunotherapy drugs. GKT137831 is a drug currently undergoing clinical trials for treatment of organ fibrosis.

The team's findings are published in the journal Cancer Research, a journal of the American Association for Cancer Research.

Immunotherapy treatment harnesses the power of the body's own immune system to fight cancer. Its success depends on 'killer' lymphocytes penetrating into a tumour to combat malignant cells. However, most patients fail to respond, often because the lymphocytes are blocked at the edge of the tumour, preventing their attack. The scientists behind this latest study believe they have found why this happens and identified a way to overcome it - potentially improving immunotherapy treatment for many patients with different types of cancer.

The team found that normal cells called cancer-associated fibroblasts (CAF) are hijacked by cancer cells to protect them from immune attack. Fibroblasts are healthy cells that normally maintain the structure of tissues, but when they are corrupted by cancer cells, they become CAFs and shield tumours from lymphocyte attack and stop immunotherapy from working effectively. A significant proportion of many solid cancers are CAF-rich and associated with poor survival, including more than 50 percent of cases of head and neck, esophageal, colorectal and pancreatic cancers.

Previously, the group had identified that CAF formation depends on an enzyme called NOX4. In this study, they found that blocking NOX4 in mouse cancers, either genetically or with the drug GKT137831, could prevent and reverse CAF formation, allowing lymphocytes to infiltrate tumours and kill cancer cells*. Combining immunotherapies with GKT137831 was effective in treating tumours that were previously resistant, significantly improving survival**.

The findings could form the basis for making cancers respond better to existing immunotherapy drugs and demonstrate the potential for greatly improved clinical outcomes in a significant number of cancers. Cancer Research UK is currently funding the Southampton scientists to see if this approach improves immunotherapy in breast cancer.

Study author Professor Gareth Thomas, of the University of Southampton's Centre for Cancer Immunology, comments: "Immunotherapy for cancer has been a very exciting development, but still doesn't work in most patients. Our results suggest that in many cases, treatment resistance is caused by CAF, and we think this can be overcome by targeting NOX4. GKT137831 hasn't yet been tested on cancer patients, but we hope may give immunotherapy drugs a much better chance of fighting cancer cells effectively; this technique could hugely improve the success rate of cancer immunotherapy."

Liz Allaway, from Cancer Research UK says: "Immunotherapy is a promising cancer treatment that boosts the power of the body's immune system against cancer, but unfortunately it doesn't work for everyone. This exciting study showed that a drug, currently being tested for the treatment of another disease could make tumours in the lab more sensitive to immunotherapy. The next step would be to see if the drug has the same effect in people, which would open up immunotherapy as a treatment option for more people with cancer."

Ongoing work with Cancer Research UK will now investigate how best to progress these findings.

A new research from the University of Helsinki showed for the first time how the pre-immunization acquired through common childhood vaccines can be used to enhance therapeutic cancer treatment.

Professor Vincenzo Cerullo's research team at the University of Helsinki discovered that when animals were pre-immunized with ordinary vaccine, e.g. anti-tetanus, engrafted with tumor and then treated with the new hybrid viral platform called PeptiCRAd, they showed a dramatic improvement in tumor-specific immune response and, consequently, a significantly improved anti-tumor efficacy. According to Cerullo this approach can be very easily translated into clinical trials as it relies on pre-existing immunity of vaccines included in the national vaccination programs worldwide.

"This method has potential to have a significant impact on current immunotherapy protocols," says
Vincenzo Cerullo, professor at University of Helsinki, director of the Drug Research Program and a founder at VALO therapeutics.

Due to the high coverage of international vaccination programs, majority of the worldwide population has been vaccinated against common pathogens, leading to a pathogen specific immunological memory. This is able to deploy a much faster and more effective immune response when we re-encounter the pathogens; this is called secondary response and it is stronger and faster than the first time we encounter a pathogen (primary response). Generally speaking, the therapeutic cancer vaccines generate an anti-tumor response more similar to a primary than a secondary immune response.

"To overcome this limitation, and convert the anti-tumor response into a secondary response we developed a hybrid tumor-pathogen therapeutic cancer vaccine," explains Cerullo. "Since their introduction, the vaccines have made one of the greatest contribution to public health, with the eradication of common deadly infections such as smallpox and rinderpest. We thought that they could do even more and help our fight with the cancer."

Tapping immunological memory and viral platform

Cerullo and his research team are developing therapeutic cancer vaccines based on viral platform. One of these is called PeptiCRAd, basically a virus dressed as tumors. Cerullo's team generated PeptiCRAd by attaching small tumor pieces (peptides) to the surface of the virus to direct the immune response against the tumor.

"We decided to modify the well-established PeptiCRAd platform in our lab by adding another set of peptides derived from pathogens, which patients have been vaccinated for e.g. tetanus or diphtheria," says Cerullo.

"The main idea behind this new hybrid PeptiCRAd is taking advantage of the pre-existing pathogen-specific immunological memory present in the worldwide population of vaccinated individuals. This is to boost the anti-tumor response directing the pre-existing memory T cells towards the tumor" summarizes Sara Feola, postdoctoral researcher in Cerullo´s lab and one of the co-authors of the study.

University of Helsinki has filed a patent application on these findings.

CHICAGO (March 2, 2020): Opioid prescriptions have been a known driver of the opioid epidemic, and it's now known that opioid prescriptions that last longer than five days are a risk factor for longer-term opioid use.1 As some surgeons' prescribing patterns have been found to be part of the problem, the surgical community is now working hard to address it. A recent solution has been enacted by a large health-care system in central Texas, where surgeons implemented a pain management program that reduced longer-term prescriptions by two-thirds, according to a study published as an "article in press" on the Journal of the American College of Surgeons website ahead of print.

The program reduced postsurgery opioid prescriptions at Baylor Scott &White (BSW) hospitals of more than five days by 64 percent, from 1,228 in the three months before the program started to 432 in the first three months of 2019. Prescriptions of less than five days duration increased 15 percent, from 5,133 to 5,923. Baylor Scott & White in central Texas consists of 15 hospitals, 104 clinics, and 1,543 physicians. Overall, BSW encompasses 50 hospitals, more than 7,800 physicians, and 5,100 patient beds.

"Opioid prescriptions of over five days have been shown to dramatically increase addiction to opioids," said lead study author Richard Frazee, MD, FACS, a general surgeon at Baylor Scott & White Healthcare in Temple, Texas. "We established a standard of opioid prescriptions of five days or less after elective surgery."

The program consisted of using the monthly surgical grand rounds--a conference of a hospital's physicians, residents and medical students--to educate surgeons and anesthesiologists about the opioid epidemic and how postsurgery opioid prescriptions contributed to it. At these meetings, the rationale for limiting opioid prescriptions to five days or less was introduced. The program also used the electronic health record (EHR) to monitor each physician's opioid prescribing practices and, after six months, tied this measure to the quality component of their compensation.

Overall, the study included 31,814 patients who had elective surgery at the hospitals from January 2018, when the program began, through March 2019. Over the five quarters the study observed, a greater proportion of opioid prescriptions shifted from more than five days to fewer than five days.

Changing the way surgeons prescribe pain medication after surgery was not easy, Dr. Frazee acknowledged. The researchers noted that surgeons' prescribing patterns have been slow to respond nationally to the opioid crisis, citing a Kaiser Health News-Johns Hopkins analysis2 that found that surgeons frequently wrote prescriptions of 100 pills or more from 2011 to 2016. "As always, to change surgeons' behavior you have to convince them that it is a benefit to their patients," he said. "We had to overcome many years of misinformation on the 'safety' of liberal use of opioids after surgery."

The program is one that can easily be used in other hospitals and health systems, Dr. Frazee said. "This is an issue that health-care providers and the public are increasingly aware of," he said. "The Baylor Scott & White Healthcare System has adopted and emphasized a culture of safety. This program offers a model for other health-care systems and individual surgeons to adopt in the care of their patients."

But tackling opioid addiction requires a multipronged approach. "The opioid crisis is ongoing; this study is one step in the process to addressing it," Dr. Frazee said. "A continued multipronged approach is needed that incorporates education, pharmaceutical reform, rehabilitation programs, and easy disposal of unneeded prescriptions."

Ultrafast, multidimensional spectroscopy unlocks macroscopic-scale effects of quantum electronic correlations.

Researchers found that low-energy and high energy states are correlated in a layered, superconducting material LSCO (lanthanum, strontium, copper, oxygen).

Exciting the material with an ultrafast (

The strong correlation between the energy of this coherence and the optical energy of the emitted signal indicates a coherent interaction between the states at low and high energy.

This kind of coherent interaction, reported here for the first time, is the root of many intriguing and poorly-understood phenomena displayed by quantum materials.

It is one of the first applications of multidimensional spectroscopy to study of correlated electron systems such as high-temperature superconductors.

PROBING QUANTUM MATERIALS

The intriguing magnetic and electronic properties of quantum materials hold significant promise for future technologies.

However, controlling these properties requires an improved understanding of the ways in which macroscopic behaviour emerges in complex materials with strong electronic correlations.

Potentially useful electric and magnetic properties of quantum materials with strong electronic correlations include: Mott transition, colossal magnetoresistance, topological insulators, and high-temperature superconductivity.

Such macroscopic properties emerge out of microscopic complexity, rooted in the competing interactions between the degrees of freedom (charge, lattice, spin, orbital, and topology) of electronic states.

While measurements of the dynamics of excited electronic populations have been able to give some insight, they have largely neglected the intricate dynamics of quantum coherence.

In this new study, researchers applied multidimensional coherent spectroscopy to the challenge for the first time, utilising the technique's unique capability to differentiate between competing signal pathways, selectively exciting and probing low-energy excitations.

Researchers analysed the quantum coherence of excitations produced by hitting LSCO (lanthanum, strontium, copper and oxygen) crystals with a sequence of tailored, ultrafast beams of near-infrared light lasting less than 100 femtoseconds

This coherence has unusual properties, lasts a surprisingly 'long' time of around 500 femtoseconds, and originates from a quantum superposition of excited states within the crystal.

2D spectrum showing energy difference between the states in the quantum superposition, shown before, during and after pulse overlap

"We found a strong correlation between the energy of this coherence and the optical energy of the emitted signal, which indicates a special coherent interaction between the states at low and high energy in these complex systems," says study author Jeff Davis (Swinburne University of Technology).

Because the number of available excitations affects the band structure of a crystal, the effective energy structure changes transiently during measurement, which links low-energy excitations and optically excited electronic states.

The study demonstrates that multidimensional coherent spectroscopy can interrogate complex quantum materials in unprecedented ways.

As well as representing a major advancement in ultrafast spectroscopy of correlated materials, the work has wider significance in optics/photonics, chemistry, nanoscience, and condensed-matter science.

THE STUDY

Persistent coherence of quantum superpositions in an optimally doped cuprate revealed by 2D spectroscopy was published in Science Advances in February 2020.

The authors acknowledge funding by the Australian Research Council (Future Fellowship and Centres of Excellence programs). Work was conducted at the Centre for Quantum and Optical Science (Swinburne University of Technology), Ruhr University (Germany) and University of Oxford (UK).

ULTRAFAST SPECTROSCOPY AT FLEET

Within FLEET, Jeff Davis uses ultrafast spectroscopy to study and control the microscopic interactions in 2D materials and how they lead to macroscopic behaviour.

In FLEET's third research theme, light-transformed materials, systems are temporarily driven out of thermal equilibrium to investigate the qualitatively different physics displayed and new capabilities for dynamically controlling their behaviour.

FLEET is an Australian Research Council-funded research centre bringing together over a hundred Australian and international experts to develop a new generation of ultra-low energy electronics.

A team of researchers has developed an online platform of tried and true resources to help people living with spinal cord injury (SCI) lead a more active life.

Professor Kathleen Martin Ginis is the director of the Centre for Chronic Disease Prevention and Management based at UBC Okanagan. She says a major barrier to physical activity for people with a spinal cord injury is a lack of knowledge or resources about the amount and type of activity needed to achieve health and fitness benefits.

"It's really hard for people to be active, let alone people living with a spinal cord injury," she says.

To complicate matters, an international consortium of experts created two international guidelines for people with SCI. One provides recommendations for using exercise to increase cardiorespiratory fitness and muscle strength while the other is a recommendation for using exercise to improve cardiometabolic health.

Both guidelines stipulate the minimum amount of aerobic exercise and strengthening exercises needed weekly.

"These are scientific guidelines, that are great for scientists," says Martin Ginis, who led the international consortium of experts. "But for Canadians with a spinal cord injury, we didn't provide a really clear path and clear information on how to implement those guidelines into a daily routine."

Martin Ginis's team, including staff from Spinal Cord Injury BC and researchers with the International Collaboration on Repair Discoveries, spent the past two years reviewing, analyzing and testing the guidelines. More than a hundred people from the SCI community provided feedback.

"We sat down with experts, scientists, clinicians, people living with spinal cord injury, and key organizations and asked how can we take this scientific information and put it into something that people can use," she explains.

The end result is a concise combination of the two scientific exercise guidelines into one clear and understandable online physical activity guideline.

"After two years of research, we've provided an online tool that people with a spinal cord injury can use with confidence to become more physically active."

Along with suggested amounts of cardio required each week, the research also provides strength training ideas and tips. Users will find links to community resources, suggestions on how to get started with a physical activity program and advice from people living with an SCI.

One such end-user is Vernon's Josh Dueck, retired Paralympic athlete and current executive director for Freestyle BC. Injured in a skiing accident in 2004, Dueck has continued with an active lifestyle winning numerous accolades in the sport of para-alpine ski racing. He has worked with UBCO's research team providing insight to the activity guidelines, which he says are easy to follow and should help promote an active lifestyle for the SCI community.

"There is a beauty in simplicity and the simple approach is often the most attainable," Dueck adds. "The SCI physical activity guidelines take the mystery out of what is needed to keep your body and mind thriving. It brings great joy to know the base parameters to maintain a healthy life are accessible and achievable."

Users will find beginner and advanced levels along with additional tips and suggestions to avoid chronic ailments like Type 2 diabetes and heart disease.

As Canada's population grows and ages, the cancer burden will remain high and even increase in 2020, according to a study on projected cancer rates published in CMAJ (Canadian Medical Association Journal).

Nearly 1 in 2 Canadians are expected to receive a diagnosis of cancer in their lifetime, and cancer is the leading cause of death in the country. With an aging population, deaths from cancer and the numbers of new cases are increasing, as are cancer-related costs. For example, cancer care costs rose from Can$2.9 billion in 2005 to Can$7.5 billion in 2012.

"The overall burden of cancer remains high in Canada and, owing to the growing and aging population, the number of cases and deaths will likely continue to increase," writes Dr. Leah Smith, Canadian Cancer Society, St. John's, Newfoundland, with coauthors.

The researchers estimate there will be 225 800 new diagnoses of cancer in 2020 in Canada -- with cases of lung cancer (29 800), breast cancer (27 700), colorectal cancer (26 900) and prostate cancer (23 300) accounting for almost half (48%) of new cancer diagnoses.

Highlights:

Lung cancer will be the leading cause of death, responsible for about 1 in 4 of the estimated 83 300 deaths from cancer expected in 2020.

The number of new cancer cases is expected to be about 5% higher in men than in women.

More men than women are expected to die from all forms of cancer except for breast and thyroid.

In men, prostate cancer will be the most commonly diagnosed cancer, accounting for about 1 in every 5 diagnoses.

Breast cancer is expected to be the most commonly diagnosed cancer in women, accounting for about 1 in 4 new cases.

Deaths from breast cancer have decreased by nearly half since the mid-1980s, largely owing to improved treatment.

Colorectal cancer deaths are also declining, which may be partly because of decreasing tobacco use and improvements in detection and treatment. Between 2007 and 2016, the Yukon territory and all provinces except Quebec introduced organized screening programs.

While the death rates for lung, breast, prostate and colorectal cancers have declined, deaths from pancreatic cancer have remained stable; this means pancreatic cancer is expected to surpass breast cancer as the third leading cause of cancer death in Canada.

"Although estimates for the number of cancer diagnoses and deaths in 2020 are higher than in 2019, the declining rates indicate progress is being made," says Dr. Smith. "This is largely due to prevention programs like smoking cessation and improvements in screening and early detection practices."

"Additional efforts to improve uptake of existing programs, as well as to advance research, prevention, screening and treatment, are needed," the authors conclude.

ROCHESTER, Minn. -- The density of immune cells, called tumor infiltrating lymphocytes, when combined with analysis of tumor budding may serve as a method to more accurately predict survival in patients with stage III colon cancer. The findings, by a team of researchers led by Mayo Clinic gastroenterologist and oncologist, Frank Sinicrope, M.D., were published today in Annals of Oncology.

Using colon cancer tissues from a completed clinical trial, Dr. Sinicrope and his colleagues were able to demonstrate that the extent or density of tumor infiltrating lymphocytes (TILs), reflecting the patient's anti-tumor immune response, is a robust predictor of survival in patients with stage III colon cancer. TILs are a type of immune cell that has moved from the blood into a tumor that can recognize and kill cancer cells.

"Our ability to predict patient outcome using TILs is strengthened when we combine it with tumor budding," says Dr. Sinicrope. Tumor budding is the presence of single cells or small clusters of tumor cells at the invasive margin, or front edge of a cancer, which can be scored by pathologists and may predict the potential for the cancer to spread or metastasize. .

"Determining the density of tumor infiltrating lymphocytes and analysis of tumor budding can be performed on resected tumor specimens," says Dr. Sinicrope. "We found that the combination of these tumor features were second only to number of tumor-containing lymph nodes for predicting patient survival. Furthermore, these features provided important data on patient survival in patients categorized into low-risk and high-riskT and N stage groups which guide the recommendation to receive 3 or 6 months of chemotherapy after surgery."

Dr. Sinicrope and his colleagues are working to automate the scoring of TILs and tumor budding in tumors from patients with stage III colon cancer. "We hope to provide important prognostic information on individual patient tumors using routine tissue sections without the need for the special stains typically used to identify specific immune cell types," he says.