Body

KRAS was one of the first oncogenes to be identified, a few decades ago. It is among the most common drivers of cancer and its mutations can be detected in around 25 per cent of human tumours. The development of KRAS inhibitors is, thus, an extremely active line of research. Effective results have been elusive so far, though - no KRAS inhibitor had been available until a month ago, when the FDA granted approval to Sotorasib.

KRAS encodes two gene products, KRAS4A and KRAS4B, whose levels can vary across organs and embryonic stages. When KRAS mutates, both variants, or isoforms, are activated. Though, some studies have focussed on approaches to target only KRAS4B, since it usually found to be expressed at higher levels in tumours.

In this study, Matthias Drosten, Marina Salmón and Guillem Paniagua of the Experimental Oncology Programme, headed by Mariano Barbacid at the CNIO, had a more fundamental goal: to understand how the isoforms work separately. As they state in the paper to be published in PNAS, "The biological relevance of the expression of two isoforms has puzzled researchers for decades."

Lung cancer and metastasis

A basic research project in principle, Drosten and Salmón's study produced results that came as "a surprise." Even though KRAS4B is the dominant form in cancer, the KRAS4A mutant is also oncogenic, and it is even more active.

In the words of the authors, "KRAS4AG12V alone, in the absence of KRAS4B, can induce lung cancer and metastasis in 20 percent of individuals. Our results suggest that for therapies to be effective, the two KRAS isoforms should be targeted."

KRAS genes in embryonic development

The researchers at the CNIO created two genetically engineered mouse models that lacked KRAS4B and expressed the KRAS4A variant only, both with and without the G12V mutation (KRAS4AG12V).

In addition, the study explored the role of the two isoforms in embryonic development. One of them, KRAS4B, "is key after birth, since in the absence of this variant, mice cannot grow as a result of heart disease".

The CNIO Experimental Oncology Group is a global reference studying KRAS-related cancers, with notable examples such as the elimination of lung tumors and advanced pancreatic tumors by inactivating the RAF1 kinase in animal models.

ROCHESTER, Minn. -- Did you know multiple sclerosis (MS) means multiple scars? New research shows that the brain and spinal cord scars in people with MS may offer clues to why they developprogressive disability but those with related diseases where the immune system attacks the central nervous system do not.

In a study published in Neurology, Mayo Clinic researchers and colleagues assessed if inflammation leads to permanent scarring in these three diseases:

MS.
Aquaporin-4 antibody positive neuromyelitis optica spectrum disorder (AQP4-NMOSD).
Myelin oligodendrocyte glycoprotein antibody associated disorder (MOGAD).

They also studied whether scarring may be a reason for the absence of slow progressive disability in AQP4-NMOSD and MOGAD, compared with MS.

"The differences in scarring that we found will help physicians distinguish these three diseases more easily to aid in diagnosis," says Eoin Flanagan, M.B., B.Ch., a Mayo Clinic neurologist and senior author of the study. "More importantly, our findings improve our understanding of the mechanisms of nerve damage in these three diseases and may suggest an important role of such scars in the development of long-term disability in MS."

In all three of these diseases, the body's immune system targets the myelin, the insulation around nerves. This causes inflammation and leads to removal of myelin, called demyelination, within the brain and spinal cord. Visual problems, numbness, weakness, or bowel or bladder dysfunction are common symptoms. Areas of demyelination, known as lesions, appear as white spots on an MRI. The repair mechanisms within the body try to reinsulate the nerves and repair the lesions, but this may be incomplete, leading to a scar that remains visible on future MRIs. Just like an electrical cable without its insulation, this scar may leave nerve fibers vulnerable to further damage and to degenerate over time.

The study included 156 patients, consisting of 67 patients with MS; AQP4-NMOSD, 51; and MOGAD, 38. These patients had172 attacks, or relapses, combined.

With MS, the researchers found that areas of inflammation reduced only modestly in size and led to a moderately sized scar. When scars are in regions of the brain and spinal cord that control arm and leg muscles, nerve fibers can degenerate and lead to slow worsening of disability in the secondary progressive course of MS.

"Our study highlights the importance of the currently available MS medications that very effectively can prevent attacks, new lesions and subsequent scar formation" says Elia Sechi, M.D., a former Mayo Clinic fellow and first author of the study. Dr. Sechi is now at the University of Sassari in Sardinia, Italy.

But AQP4-NMOSD and MOGAD are different from MS in that they do not have the same slow worsening of disability typical of the progressive course in MS.

With AQP4-NMOSD, large areas of inflammation occur during attacks, which often results in severe symptoms. Scars are common, but they tend to be smaller and in less important locations than in MS. Thus, less long-term problems result from those scars.

With MOGAD, despite having large areas of inflammation during an attack, the researchers found lesions tended to disappear completely over time and not leave any scar. This fits well with the excellent recovery from episodes and overall good long-term prognosis without the slow worsening disability seen in MS.

The reasons behind this recovery are not clear, the researchers note. It may suggest an enhanced ability to put the covering back onto nerves, or remyelination.

"We hope that the improved understanding on the ways MOGAD repairs its lesions so well may lead to novel treatment avenues to prevent scar formation in MS," Dr. Flanagan says.

Evidence shows that early detection and treatment of cancer can significantly improve health outcomes, however women in Mississippi, particularly in underserved populations, experience the worst health outcomes for cervical, breast, and oropharyngeal cancer.

A new publication from Michelle Williams, associate professor at George Mason University's College of Health and Human Services Department of Global and Community Health, published in the Journal of Cancer Education evaluates the feasibility of offering free, same-day cancer screening and health education to reduce disparities of "preventable cancers." Williams evaluated the effects of providing access to free mammograms, Pap tests and pelvic exams, and oral cancer exams on participants' knowledge about cancer, self-efficacy for obtaining healthcare, and intentions to change their health behaviors.

Williams and colleagues evaluated an implementation of the See, Test, & Treat Program, an evidence-based program developed by the College of American Pathologists (CAP) Foundation which they adapted for use with uninsured and underserved women in the Jacksonville Metropolitan Area. See, Test, & Treat participants were educated about cancer screenings during their consultation with providers. Important features of the See, Test, & Treat program were that participants received screening results within 2 hours and participants who received abnormal results were able to schedule a follow-up appointment at a Federally Qualified Health Center (FQHC) before leaving. In addition, upon arriving at the screening site waiting room, participants could choose from a variety of health activities, including demonstrations of healthy cooking, yoga, and Zumba.

"Cancer screenings are a valuable tool for the early detection of cancer - however uninsured and underserved women may lack access to life-saving routine screenings. Evaluating the implementation of this program helps show that it is feasible to provide access to free cancer screenings to vulnerable populations and to provide screening results in the same day," said Williams.

The majority of participants reported that they attended the See, Test, & Treat Program because they wanted free cancer screening and they could get the test results back the same day. The majority of participants reported that the program had a positive effect on their knowledge of cancer screenings and their self-efficacy for seeking regular check-ups. In addition, participants reported that the health education activities had a significant effect on their understanding of the cancers for which they screened as well as health, nutrition, and exercise.

Follow-up appointments were made for all participants who received abnormal test results, including 18 women who received abnormal mammogram results. 15 of the 18 women obtained a diagnostic mammogram, three of whom required biopsies. All the biopsy results were benign. Two of the women who received the oral cancer exams had abnormal results and both were referred for treatment. None of the 44 Pap tested were abnormal, however 14 women were diagnosed with trichomonas and referred for treatment.

Overall, the program was positively received by the participants and successfully provided uninsured and under-served women with free cancer screening and health education. When asked about what they enjoyed most about the program, participants identified the convenience of same day screening results and that the staff treated them with respect. One participant reported that the staff "didn't make me feel like someone who didn't have health insurance." Limitations of the evaluation approach include the lack of long-term follow-up because the evaluation survey was completed anonymously. William seeks to include an interview and follow-up survey of all participants in future iterations of the program.

Participants learned of the program through advertising disseminated through channels such as churches, healthcare centers, and social media. Childcare was made available for participants with young children. The American Cancer Society guidelines were used to determine eligibility for the breast and cancer screening. 72 women met the eligibility requirements, 53 women were screened, and 52 participants completed the evaluation survey.

From the onset of the COVID-19 pandemic there have been countless comparisons to the 1918 influenza pandemic in terms of overall medical impact. Many of the comparisons addressed overall cases which, given the lack of a confirmatory lab test in 1918 and no meaningful case definitions for both pandemics, make such comparisons patently invalid. Overall mortality comparisons, although methodologically flawed as well, do offer a reasonably comparative outcome measure and offers a greater degree of validity. This measure is further enhanced when adjusted for population and average life years lost (see accompanying table for mortality comparisons presented 3 ways). The resulting value(s) can also be used to assess and better quantify the cumulative health impacts of our interventions and give a more objective base for our decision-making. A concluding observation is presented on the impact of a rapidly developed vaccine on a 1918 type event.

Researchers at Michigan Medicine have discovered yet another functional autoantibody in COVID-19 patients that contributes to the disease's development and the "firestorm" of blood clots and inflammation it induces.

A growing body of studies suggests COVID-19 emulates many aspects of systemic autoimmune disorders, including the release of a flurry of overactive immune cells that produce toxic webs of proteins and DNA called neutrophil extracellular traps, or NETs.

For this study, the team analyzed serum from over 300 hospitalized COVID patients, searching for a novel autoantibody that shields the toxic NETs from being destroyed and produces a lasting noxious effect in a patient's body.

The results, published in JCI Insight, reveal markedly elevated levels of the anti-NET antibodies in many of the participants. Those with higher levels of the autoantibodies were more likely to develop severe COVID-19 symptoms.

"We see a slew of different antibodies produced in COVID-19 patients, and now we discovered another clinically significant one that is likely contributing to severe COVID," said Yu (Ray) Zuo, M.D., lead author and a rheumatologist at Michigan Medicine. "They feed into the inflammatory storm that we're seeing in the most serious cases of viral infection."

Researchers generated NETs in the lab and incubated them with COVID patient serum. They found the serum from patients with higher levels of anti-NET antibodies struggled to degrade the toxic traps.

The team also spiked healthy serum with anti-NETs purified from the infected patients. While a healthy person's serum should completely disintegrate the extracellular traps, the purified anti-NET antibodies significantly hindered the process.

"We knew that people with severe forms of COVID have higher amounts of these neutrophil extracellular traps, which amplify inflammation and promote blood clot formation," said Jason Knight, M.D., corresponding author of the paper and an associate professor of rheumatology at Michigan Medicine. "We've now found that this process is exacerbated by the anti-NET antibodies, which disrupt our body's immune homeostasis during COVID-19 infection."

Similarities to another autoimmune disease

Zuo and the Michigan Medicine team previously reported the presence of anti-NETs in patients with antiphospholipid syndrome, a systemic autoimmune condition characterized by severe blood clots and recurring pregnancy loss.

The anti-NET antibodies, which are likely associated with the development of recurrent blood clots and more severe disease in antiphospholipid syndrome, showed remarkably similar function in this study of COVID-19 patients, said corresponding author Yogen Kanthi, M.D., a cardiologist and vascular medicine specialist at the National Heart, Lung, and Blood Institute and Lasker Investigator at the National Institutes of Health.

"In both diseases, the anti-NET antibodies coat the surface of the neutrophil extracellular traps, making it much harder for the body to clear out this web that causes inflammation and clotting," Kanthi said. "Knowing their function is likely to help physicians design more targeted COVID-19 treatments and also for other inflammatory diseases."

How COVID-19 manages to trigger the production of a variety of autoantibodies, including anti-NETs, remains unknown. Further study of the virus' autoimmune aspects, Zuo noted, will not only lead to better understanding of the disease, but will also likely shed light onto the origins of autoimmune diseases.

Future research and "long COVID"

The paper's findings may also unlock other COVID mysteries, including the persistence of symptoms in some people months after clearing the virus, a phenomenon known as long COVID, Zuo said.

The team is currently conducting a follow-up study, calling back patients who were previously hospitalized to repeat testing for the anti-NETs and other autoantibodies that formed during their hospitalizations.

Previously, they found durable anti-NET antibodies that persisted in antiphospholipid syndrome patients for up to four years. The team will investigate if and how the autoantibodies influence long COVID, the post-acute sequalae of the virus marked by symptoms like brain fog, fatigue and shortness of breath.

While vaccination is doing its job to limit severe infections and hospitalizations, millions still feel the effects of long COVID, which is why this research is so important, Zuo said.

"The better we understand these COVID-induced autoantibodies such as anti-NET antibodies, the more equipped we will be to fight COVID-19 at every stage of viral infection," Zuo said. "Studying these antibodies will also teach us about the mechanisms of autoimmunity in general, especially in the field of rheumatology."

EAST LANSING, Mich. - Tens of millions of patients around the world suffer from persistent and potentially life-threatening wounds. These chronic wounds, which are also a leading cause of amputation, have treatments, but the cost of existing wound dressings can prevent them from reaching people in need.

Now, a Michigan State University researcher is leading an international team of scientists to develop a low-cost, practical biopolymer dressing that helps heal these wounds.

"The existing efficient technologies are far too expensive for most health care systems, greatly limiting their use in a timely manner," said Morteza Mahmoudi, an assistant professor in the Michigan State University College of Human Medicine and the Precision Health Program. "An economically accessible, practical and effective technology is needed."

To develop that new technology, Mahmoudi tapped into years of experience and expertise, having studied advanced materials to heal heart tissue, fight infections and support immune systems. But the team also kept an eye on cost, working to develop a product that could be made available to as many patients as possible, even in resource constrained markets.

"My goal is always to make something that works and is practical," Mahmoudi said. "I want to see my research become clinical products that help patients."

With his latest work, published July 19 in the journal Molecular Pharmaceutics, Mahmoudi is getting closer to that goal. He's working with partners in the United Kingdom who have started a company to oversee the development and approval of the new technology.

"We are building an experienced and expert team in the U.K. who will be able to efficiently commercialize the dressing," Mahmoudi said. "The company has just won a very competitive Eurostar grant to accelerate product development."

Working with his collaborators, Mahmoudi conducted a small pilot trial of the wound dressing with 13 patients with chronic wounds, all of whom were cured, he said.

Patients with advanced chronic wounds -- those which do not respond to traditional therapies -- are estimated to number over 45 million globally, making this one of the world's most pressing and urgent health care needs, Mahmoudi said.

The United States is home to about 5% of this population, yet more than 90% of the sales of "active" wound care technologies happen in the U.S. That essentially means that the rest of the world is left out, Mahmoudi said.

Venous leg ulcers and pressure ulcers associated with immobility in older and paralyzed patients are also major causes of chronic wounds, but perhaps the best-known examples of this type of injury being diabetic foot ulcers. Worldwide, there are more than 400 million people living with diabetes, and some studies have estimated that up to a quarter of those patients will develop foot ulcers within their lifetime.

Even with the high level of care available in the U.S., more than 30% of patients who develop a diabetic foot ulcer will die within five years of its onset. For reference, that percentage is higher than breast cancer, prostate cancer and colon cancer.

Diabetic foot ulcers also illustrate many of the reasons why chronic wounds can be so challenging to treat.

Patients with diabetes can be dealing with restricted blood flow and other factors that slow their immune response, compromising the body's ability to heal the wound on its own. They can also have nerve damage that dulls the wound's pain and can delay patients from seeking treatment. When wounds heal more slowly and stay open longer, bacteria have more opportunities to cause infections and lead to serious complications. Put bluntly, there's a lot going wrong in a chronic wound.

"Chronic wounds are some of the most complicated things doctors have to treat," Mahmoudi said. "If you want to make a dressing that works, it has to address all those problems. And in order to be relevant to the majority of patients in the world, it has to be easy to use, practical and inexpensive as well."

There are many technologies available to support healing in chronic wounds, but those that can stimulate tissue regeneration are typically derived from harvested natural tissues. This is complex and expensive, resulting in products that cost upwards of $1,000, putting them out of reach for many patients and health care systems.

To attack those problems, Mahmoudi drew on a wealth of experience in developing new materials for biomedical applications. By designing a product that can be manufactured from readily available biopolymers, production costs can be kept low, and the team could add various other materials to lead to improved healing.

The team starts with a flexible framework of nanofibers -- exceedingly thin threads -- of natural polymers, including collagen, a structural-support protein found in our skin and cartilage. The framework provides a three-dimensional scaffold that fosters cell migration and the development of new blood vessels, essentially replicating the function of the extracellular matrix, the natural support system found in healthy, living tissue.

"It's important that the physical and mechanical properties of the dressing are really close to that of skin," Mahmoudi said. "In order to heal, the new cells have to feel like they're at home."

To that framework, the team can incorporate proteins, peptides and nanoparticles that not only spur the growth of new cells and blood vessels but also fight off bacteria by encouraging a patient's own immune system to join the charge. (The team's experiences on these elements were documented in earlier publications in Nature Nanotechnology and Trends in Biotechnology).

The dressing also degrades over time, meaning that nobody would have to change or remove it and potentially aggravate the wound site. And at roughly $20 apiece, Mahmoudi believes that the dressings -- if and when approved by regulatory agencies -- will be affordable to even resource-strapped health care systems faced with treating these serious wounds.

Although there are many existing wound care products, Mahmoudi is optimistic that the new dressing will stand out thanks to its low cost, high performance and another piece of research he did years ago.

For this previous project, though, he wasn't developing any new technology. He was interviewing hundreds of health care workers around the U.S., asking them what they wanted and needed in a wound dressing.

"We developed this dressing to solve the problems they were having. One of the clinicians told me, 'When you see too many products on the market, that means none of them works,'" said Mahmoudi, a Spartan driven to make things that work.

Russian scientists have synthesized chemical compounds that can stop the degeneration of neurons in Alzheimer's, Parkinson's, and other severe brain pathologies. These substances can provide a breakthrough in the treatment of neurodegenerative pathologies. New molecules of pyrrolyl- and indolylazine classes activate intracellular mechanisms to combat one of the main causes of "aged" brain diseases - an excess of so-called amyloid structures that accumulate in the human brain with age. The essence of the study was published in the European Journal of Medicinal Chemistry. Experts from the Institute of Cytology of the Russian Academy of Sciences, the Institute of Organic Synthesis of the Ural Branch of the Russian Academy of Sciences, and the Ural Federal University (UrFU) took part in the study.

"Our compounds activate the synthesis of specific heat shock proteins and cause their accumulation in the cell," said research co-author, professor of the Department of Organic and Biomolecular Chemistry at UrFU Irina Utepova. "Proteins of this type make it possible to protect neuronal tissue from an excess of toxic amyloids and to protect cells from various types of stress, including proteotoxic stress characteristic of neurodegenerative diseases."

Important advantages of compounds from the series of pyrrolyl- and indolylazine classes are a profitable synthesis technology and low toxicity.

The obtained compounds were tested in cellular models of Alzheimer's disease and secondary injuries after traumatic brain injury. In both cases, the new substances demonstrated a significant therapeutic effect, increasing the survival of neuronal cells. The most effective compound has been tested in living tissues of rats with secondary injuries after traumatic brain injury.

According to scientists, the use of pyrrolylazine in rehabilitation therapy allowed the animals to avoid the appearance of movement disorders and degeneration of hippocampal neurons. The research team has been continued to study the mechanism of action of new compounds and is preparing for their preclinical testing.

Tokyo, Japan - Chronic obstructive pulmonary disease (COPD) causes illness and death worldwide. It is characterized by destruction of the walls of tiny air sacs in the lungs, known as emphysema, and a decline in lung function. Little has been known about the mechanisms by which it begins to develop. But now, researchers from Japan have found a protein that promotes the development of the early stages of emphysema, with the potential to be a therapeutic target.

COPD can be triggered by environmental factors such as cigarette smoking that result in lung inflammation. The development of inflammation involves the movement of molecules inside cells, and this "intracellular trafficking" is known to be associated with some diseases. The team searched for COPD-related proteins that are involved in trafficking and identified a protein called FCHSD1, which is associated with some diseases but with no currently known role in lung function.

It is possible to create a mouse model of emphysema by treating mice with an enzyme called elastase. The team developed a mouse line that was missing the FCHSD1 protein and studied the responses of these mice in comparison with normal mice when emphysema was induced. Normal mice showed a large increase in FCHSD1 after treatment, while mice lacking FCHSD1 were protected from the development of emphysema. These mice showed less airspace expansion owing to damage to the air sacs in the lungs, and had less inflammation and cell death, known as apoptosis.

The researchers went on to investigate the molecular mechanism by which FCHSD1 acts. A protein called NRF2 moves into the nucleus in response to stress and acts to defend against it. However, FCHSD1 binds to NRF2 and prevents it moving into the nucleus. "Mice with a FCHSD1 deficiency showed enhanced nuclear translocation of NRF2 and a smaller reduction in SIRT1 levels, which is seen to occur as emphysema develops," explains lead author Takahiro Kawasaki, "and this reduced inflammation and apoptosis of lung cells."

A potential therapy for COPD could therefore be to increase the activity of NRF2 to counteract FCHSD1. There are treatments currently available that target NRF2, and it may be that inhibiting FCHSD1 at the same time as targeting NRF2 could make these treatments more effective and prevent systemic complications. "Our findings may also lead to a specific therapeutic strategy to ameliorate, or even halt, the progression of emphysema by inhibiting FCHSD1," says Takashi Satoh, senior author of the paper.

COPD is a highly significant disease. The discovery of this mechanism by which FCHSD1 acts to promote the development of emphysema could lead to new treatments for many people.

Research led by the University of Southampton into the uptake of the COVID-19 vaccine in Ghana, West Africa has concluded that vaccine hesitancy has seen a small, but significant increase over the last three months. This research is in collaboration with youth-led not-for-profit organisation PACKS Africa.

In the latest survey of 1,295 unvaccinated people, in May/June 2021, willingness to be vaccinated remained relatively high at just over 71.4 percent. However, this figure is down 11 percent on results from March 2021 when an earlier version of the same survey was conducted.

The latest findings show 28.6 percent of respondents are still either undecided or unwilling to get the jab. Among this 28.6 percent group, a little over half said they didn't have enough information, with some believing the vaccine to be dangerous and others mistrusting the government. The odds of accepting the vaccine was 1.43 times higher for respondents who got their vaccine-related information from the Ghana Health Service.

Report author and Research Fellow at the University of Southampton, Dr Ken Brackstone said: "Proactive health promotion and public health messaging is vital to reassure the Ghanaian general public about vaccine safety. Vaccine supply to Ghana and the rest of sub-Saharan Africa is too slow and when supplies do arrive, they will undoubtedly be limited, so it's imperative that they end up in people's arms."

Just under a third of all those who took part in the survey reported that they had seen or heard stories about the indecision surrounding the rollout of the Oxford/AstraZeneca vaccine in Europe and North America, with many admitting this made them concerned about accepting a COVID-19 vaccine in the future.

Dr Michael Head, Senior Research Fellow in Global Health at Southampton who also worked on the report, commented: "The COVID-19 vaccines will be the key tools that underpin the global route out of the pandemic. Therefore, an observed increase in hesitancy gives some cause for concern. The actions of how we in Europe and North America handle these vaccines is seen all over the world, and we don't want the Oxford AstraZeneca vaccine to be widely viewed as ineffective or dangerous, when the evidence shows it is safe and effective."

The survey also found that education, religion and political alignment play a part in influencing vaccination acceptance. Interestingly, it revealed that people educated to University level are more likely to show vaccine hesitancy than those who aren't.

Kirchuffs Atengble, Executive Director of PACKS Africa said: "In recent times, the political terrain in Ghana has become very fluid and volatile, influencing policy response by a good number of citizens. Following positive vaccine response from the leadership of the two major political parties, the Ghana Health Service may want to pursue multidimensional strategies to increase COVID-19 vaccination uptake, including vaccine communication through political agents across the divides, community opinion leaders and repentant anti-vaccine campaigners."

The findings are presented in a report (not yet a peer-reviewed paper - journal papers are being prepared) Examining Drivers of COVID-19 Vaccine Hesitancy in Ghana. The team hopes the findings will be useful for stakeholders in Ghana, and that lessons can be learned, adapted and adopted by other African nations.

Some COVID-19 patients who experience acute respiratory failure respond by significantly increasing their respiratory effort - breathing faster and more deeply

There is concern among some doctors that this level of respiratory effort can lead to further damage to these patients' lungs.

Working with an international team of leading intensive care clinicians, engineering researchers at the University of Warwick have used computational modelling to provide new evidence that high respiratory efforts in COVID-19 patients can produce pressures and strains inside the lung that can result in injury.

The impact of high breathing efforts on the lungs of patients suffering with acute respiratory failure due to COVID-19 has been investigated by researchers at the University of Warwick, who assessed the likelihood of resulting lung injury.

Although mechanical ventilation is a life-saving intervention, the potential for mechanical ventilators to further damage already diseased lungs by applying excessive pressures and forces is now well recognised among intensive care clinicians, who implement specific protocols to minimise the risk of so-called ventilator-induced-lung-injury.

Since the start of the current pandemic, some clinicians have argued that similar injuries could potentially be produced by heightened respiratory efforts in spontaneously breathing COVID-19 patients.

So-called patient self-inflicted lung injury is a controversial concept in the intensive care community, with some clinicians insisting there is no evidence for its existence, while others argue that patients should, if necessary, be placed on mechanical ventilators to avoid it.

There is an ongoing debate about the potential for increased respiratory efforts to generate patient self-inflicted lung injury in spontaneously breathing patients with COVID-19 acute hypoxaemic respiratory failure, however direct clinical evidence linking increased inspiratory effort to lung injury is scarce.

In the paper, 'High risk of patient self-inflicted lung injury in COVID-19 with frequently encountered spontaneous breathing patterns: a computational modelling study', published in the journal Annals of Intensive Care, researchers from the University of Warwick have adapted a computational simulator of cardiopulmonary pathophysiology to quantify the mechanical forces that could lead to patient self-inflicted lung injury, at different levels of respiratory effort.

The simulator was set up to represent a population of 10 COVID-19 patients, being treated with supplemental oxygen.

For each of these patients, simulations across a range of tidal volumes (depth of breathing) and respiratory rates were tested, from a tidal volume of 7 ml/kg and respiratory rate of 14 breaths per minute (representing normal breathing), up to a tidal volume of 10 ml/kg and respiratory rate of 30 breaths per minute (representing high respiratory effort).

The results of the simulations indicated that potentially injurious pressures and strains could be generated at levels of respiratory effort that clinicians are frequently seeing in COVID-19 patients.

Professor Declan Bates, from the School of Engineering at the University of Warwick comments:

"Our modelling has found that patients who experience COVID-19 acute hypoxaemic respiratory failure may be at significant risk of patient self-inflicted lung injury due to increased respiratory efforts. These efforts need to be carefully monitored and controlled during their care."

"Patients should always follow the advice of their clinicians regarding timing of initiation of oxygen support, non-invasive ventilation, or mechanical ventilation".

Oncotarget published "Caspase-11 and AIM2 inflammasome are involved in smoking-induced COPD and lung adenocarcinoma" which reported that cigarette smoking is the leading risk factor for COPD and lung cancer establishment.

Epidemiologically, COPD patients are 6.35 times more likely to develop lung cancer.

To mimic COPD, the authors exposed mice to nose-only cigarette smoke and used human samples of lung adenocarcinoma patients according to the smoking and COPD status.

Interestingly, higher expression of AIM2 in non-cancerous tissue of smoking COPD adenocarcinoma patients was correlated to a higher hazard ratio of poor survival rate than in patients who presented lower levels of AIM2.

The Oncotarget authors found that AIM2 inflammasome is at the crossroad between COPD and lung cancer in that its higher presence is correlated to lower survival rate of smoking COPD adenocarcinoma patients.

The Oncotarget authors found that AIM2 inflammasome is at the crossroad between COPD and lung cancer in that its higher presence is correlated to lower survival rate of smoking COPD adenocarcinoma patients.

Dr. Rosalinda Sorrentino from The University of Salerno said, "Chronic Obstructive Pulmonary Disease (COPD) is characterized by chronic lung and systemic inflammation, associated with decline of lung function, airway remodelling and alveolar dysfunction."

Inhalation of cigarette smoke is the main risk factor for the development of COPD, but it is also the main risk factor for the development of lung cancer.

Epidemiological studies reveal that almost 40% of COPD patients develop lung cancer, whereas cigarette smoke is at the basis of almost 90% of lung cancer establishment.

Therefore, in the attempt to understand the crosstalk between smoking, COPD and lung cancer, which have been demonstrated as associated with inflammation, they focused our attention on an inflammatory pathway, the inflammasome.

Therefore, in the attempt to understand the role of the AIM2 inflammasome in smoking-induced COPD and COPD-induced lung cancer, they took advantage of a cigarette smoking model that could mimic COPD in mice, as already demonstrated by Beckett et al.,.

The authors found that AIM2 inflammasome and caspase-11 underlie lung inflammation typical of smoking COPD patients who have a higher hazard ratio in terms of AIM2-related expression, implying lower survival rate than non-smoker, non-COPD adenocarcinoma patients.

The Sorrentino Research Team concluded in their Oncotarget Research Output, "we demonstrated that the exposure to first-hand smoking leads to emphysematous changes typical of human COPD and an inflammatory lung microenvironment which is associated to the non-canonical, caspase-11-dependent inflammasome pathway. Although a direct correlation between AIM2 and caspase-11 was not proved in this manuscript, we found that according to the role of caspase-11 (caspase-4 in humans) [11, 16, 17, 27], AIM2 inflammasome and IL-1α are at the crossroad between COPD and lung cancer in that their expression are increased in our experimental model of COPD and human lung cancer samples [11]. Therefore, although some questions are still open on the role of AIM2 and caspase-11/IL-1α in COPD, the data obtained so far pave the way for a novel scientific approach for COPD patients that develop lung cancer, focusing on the biology of the AIM2 inflammasome as a potential pharmacological target."

Researchers are using computer models to simulate COVID-19 infections on a cellular level - the basic structural level of the human body.

The models allow for virtual trials of drugs and vaccines, opening the possibility of pre-assessment for drug and vaccine efficacy against the virus.

The research team at the University of Waterloo includes Anita Layton, professor of applied mathematics and Canada 150 Research Chair in mathematical biology and medicine, and Mehrshad Sadria, an applied mathematics PhD student.

The team uses "in silico" experiments to replicate how the human immune system deals with the COVID-19 virus. In silico refers to trials situated in the silicon of computer chips, as opposed to "in vitro" or "in vivo" experiments, situated in test tubes or directly in living organisms.

"It's not that in-silico trials should replace clinical trials," Layton said. "A model is a simplification, but it can help us whittle down the drugs for clinical trials. Clinical trials are expensive and can cost human lives. Using models helps narrow the drug candidates to the ones that are best for safety and efficacy."

The researchers, one of the first groups to be working on these models, were able to capture the results of different treatments that were used on COVID-19 patients in clinical trials. Their results are remarkably consistent with live data on COVID infections and treatments.

One example of a treatment used in the model was Remdesivir, a drug that was used in the World Health Organization's global "solidarity" trials. The simulated model and the live trial both showed the drug to be biologically effective but clinically questionable, unless administered shortly after viral infection.

The model might also work for current and future variants of concern. The researchers anticipate the virus will continue to undergo mutation, which could precipitate new waves of infection.

"As we learn more about different variants of concern, we can change the model's structure or parameters to simulate the interaction between the immune system and the variants," Sadria said. "And we can then predict if we should apply the same treatments or even how the vaccines might work as well."

Layton and Sadria are part of a new team, led by researchers at the University Health Network (UHN), which recently received a rapid response grant from the Canadian Institute of Health Research on COVID variants.

The UHN team will conduct experimental studies and modeling simulations to understand the spread of COVID variants in Canada.

The research team led by Prof. WEI Haiming and Prof. TIAN Zhigang from Division of Life Sciences and Medicine, University of Science and Technology of China (USTC) of the Chinese Academy of Sciences (CAS), collaborating with the research group led by Prof. SUN Zimin from the First Affiliated Hospital of USTC revealed the pathological mechanism of severe pre-engraftment syndrome (PES) after umbilical cord blood transplantation, not only providing a treatment strategy for patients with PES, but significantly guiding for further improvement in the curative effect of unrelated cord blood transplantation (UCBT). This study was published in Nature Communications.

UCBT is an important means to cure hematological malignancies, hematopoietic failure, congenital immunodeficiency and some genetic metabolic diseases. The incidence of chronic graft-versus-host disease (GVHD) after transplantation is low and mild, so that the quality of life of patients is high. The First Affiliated Hospital of USTC has so far completed 1519 cases of UCBT since the first successful case using this method in the treatment of children's malignant hematological diseases in 2000, which makes it an internationally recognized umbilical cord blood transplantation treatment center, encouraging the emergence of more and more relevant clinical and scientific research achievements

Unfortunately, however, in the early stage after UCBT, 70-80% of recipients will suffer PES, which is characterized by high fever, rash, diarrhea, and other clinical findings. Severe PES increases the transplant-related mortality, but its mechanism is still unclear. Further study and revelation of the pathogenesis of PES after UCBT is of great clinical significance for the treatment of PES patients and the reduction of transplantation related mortality.

Faced with this problem, the research group analyzed the peripheral blood of recipients after UCBT and found significantly increasing number of monocytes in patients with PES. These monocytes derived from cord blood had inflammatory characteristics and produced proinflammatory cytokines such as GM-CSF and IL-6. After UCBT, monocytes expanded rapidly in the recipient body, increasing the levels of GM-CSF and IL-6 in serum, which led to the occurrence of PES.

Based on the pathogenesis study of PES, the team applied for a clinical trial using tocilizumab to block the IL-6 receptor at http://www.chictr.org.cn (Reference: ChiCTR1800015472) among patients with severe PES. The results showed that the use of tobuzumab for intervention treatment significantly controlled the clinical symptoms of PES and reduce the mortality of patients.

This study, lasting nearly 8 years, provides practical guidance for USTC to propose and implement treatment plan (tobuzumab) for patients with severe COVID-19 pneumonia. This treatment plan (tobuzumab) has been currently approved by U.S. Food & Drug Administration (FDA) and National Health Service (NHS) in clinical application.

Highlights

The sodium-glucose co-transporter 2 inhibitor dapagliflozin reduced kidney, cardiovascular, and mortality risks in patients with advanced chronic kidney disease, similar to benefits seen in individuals with normal or moderately impaired kidney function.

Rates of serious side effects were similar in patients with advanced chronic kidney disease who received dapagliflozin or placebo.

Washington, DC (July 16, 2021) -- Studies have shown that diabetes drugs called sodium-glucose co-transporter 2 (SGLT2) inhibitors can provide kidney- and cardiovascular-related benefits to individuals with or without diabetes and with or without impaired kidney function. An analysis appearing in an upcoming issue of JASN now provides insights about the efficacy and safety of SGLT2 inhibitors in people with advanced chronic kidney disease (CKD), an especially vulnerable population.

For the analysis, Glenn M. Chertow, MD, MPH (Stanford University School of Medicine) and his colleagues examined data from the Dapagliflozin And Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial, which enrolled patients with and without type 2 diabetes and with mildly decreased to severely decreased kidney function (stage 4 CKD).

In DAPA-CKD, 624 of 4,304 (14%) patients had stage 4 CKD--with an estimated glomerular filtration rate (eGFR), a measure of kidney function, as low as 25 mL/min/1.73m2--at the start of the study. Patients were randomized to receive daily treatments of the SGLT2 inhibitor dapagliflozin or placebo. Among patients with stage 4 CKD, those randomized to dapagliflozin experienced a 27% reduction in the primary endpoint (a composite of a sustained and large decline in kidney function, kidney failure, or death) and 29%, 17%, and 32% reductions in the kidney, cardiovascular, and mortality endpoints, respectively, compared with those randomized to placebo. Rates of serious side effects were similar in the two groups.

"This analysis shows that the effects of dapagliflozin in patients with stage 4 CKD are similar to effects in patients with mild to moderate CKD," said Dr. Chertow. "While patients with screening eGFR as low as 25 mL/min/1.73m2 were enrolled, it is noteworthy that neither dapagliflozin nor placebo were discontinued when eGFR declined, even to below 15 mL/min/1.73m2. Therefore, a drug initially developed for the treatment of diabetes can benefit patients with CKD with and without diabetes, including patients with moderate to advanced CKD."

All cancers fall into just two categories, according to new research from scientists at Sinai Health, in findings that could provide a new strategy for treating the most aggressive and untreatable forms of the disease.

In new research out this month in Cancer Cell, scientists at the Lunenfeld-Tanenbaum Research Institute (LTRI), part of Sinai Health, divide all cancers into two groups, based on the presence or absence of a protein called the Yes-associated protein, or YAP.

Rod Bremner, senior scientist at the LTRI, said they have determined that all cancers are present with YAP either on or off, and each classification exhibits different drug sensitivities or resistance. YAP plays an important role in the formation of malignant tumours because it is an important regulator and effector of the Hippo signaling pathway.

"Not only is YAP either off or on, but it has opposite pro- or anti-cancer effects in either context," Bremner said. "Thus, YAPon cancers need YAP to grow and survive. In contrast, YAPoff cancers stop growing when we switch on YAP."

Many YAPoff cancers are highly lethal. In their new research, Bremner and fellow researchers from the Roswell Park Comprehensive Cancer Center in Buffalo, NY, show that some cancers like prostate and lung can jump from a YAPon state to a YAPoff state to resist therapeutics.

When cancer cells are grown in a dish in a lab setting, they either float or stick down. The team of researchers found that YAP is the master regulator of a cell's buoyancy, where all the floating cells are YAPoff, and all the sticky cells are YAPon. Changes in adhesive behavior are well known to be associated with drug resistance, so their findings implicates YAP at the hub of this switch, explained Bremner.

Joel Pearson, co-lead author and a post-doctoral fellow in the Bremner Lab at the LTRI, said therapies that tackle these cancers could have a profound effect on patient survival.

"The simple binary rule we uncovered may expose strategies to treat many cancer types that fall into either the YAPoff or YAPon superclasses," Pearson said. "Moreover, since cancers jump states to evade therapy, having ways to treat either the YAPoff and YAPon state could become a general approach to stop this cancer from switching types to resist drug treatments."

The researchers hope by deducing common vulnerabilities of these types of cancer, it may be possible to develop new therapeutic approaches and improve patient outcomes.