Publisher Health

A new type of CAR T-cell therapy more than triples the expected length of remission for multiple myeloma patients who have relapsed several times, according to an international clinical trial with UT Southwestern as the lead enrolling site.
Results of the trial, published recently in the New England Journal of Medicine, were significantly better than those seen with other therapies available to heavily relapsed and refractory myeloma patients who had already received the three main classes of treatment. Nearly three-quarters of the patients had at least a partial response to the therapy. About a third achieved a complete remission, with the disappearance of all traces of cancer.
Median time without the disease worsening was 8.8 months with this new treatment, but Larry D. Anderson Jr., M.D., Ph.D., associate professor of internal medicine and co-first author of the journal article, points out that patients who received the trial’s maximum dose of engineered T-cells experienced longer remissions, bringing the average to more than 12 months. Previously, similar patients treated with currently available therapies following multiple relapses have only had an average of three to four months of remission before their disease returned.
“We have patients that are over two years out from their single infusion of CAR T-cells and still in remission despite having no other treatment options when they were enrolled in this trial,” says Anderson, a member of the Harold C. Simmons Comprehensive Cancer Center who cares exclusively for patients with plasma cell disorders, mostly myeloma patients. “The results mark a true breakthrough with unprecedented depth and duration of remissions from what we hope will be the first cellular therapy option to become available for myeloma patients. Even though we don’t yet know if some of these patients may be cured, and many relapse within one to two years, it can at least buy many patients time until other treatment options become available. Most patients also have good quality of life with relatively low risk of severe CAR T-cell-related side effects.”
Multiple myeloma, the second most common blood cancer, is a cancer of plasma cells, a white blood cell important in the immune system. The disease’s attack on bone marrow puts patients at risk of life-threatening infections. It is diagnosed in more than 32,000 people a year, and African Americans are twice as likely as the general population to be diagnosed with this disease.
Three main classes of treatment are available now for multiple myeloma: drugs called proteasome inhibitors, drugs to modulate the immune system, and antibody treatments. Among more than a dozen new therapies for myeloma approved by the Food and Drug Administration over the past decade, most offer only a few months of remission for patients with multiple relapses. Until now, most treatments induce responses in only a third of patients, and complete remissions are rare.

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The phase 2 trial involved 128 patients, ages 18 and older, who previously had been given regimens from the three main classes of treatment. The patients received a median of six previous antimyeloma regimens; 120 formerly had undergone stem cell transplantation.
The clinical trial included nine sites in the U.S., one in Canada, and 10 sites in five European countries. Several patients traveled from as far away as Michigan and Minnesota to UT Southwestern’s Dallas campus to be part of the trial.
Study participants had their T-cells engineered to target a molecule called B-cell maturation antigen, or BCMA, which is only found in plasma cells and myeloma cells. This new T-cell therapy for myeloma patients is called idecabtagene vicleucel, or ide-cel. It is also known as bb2121.
The infusions of the engineered cells started a two-week hospitalization period during which doctors watched for possible side effects such as anemia; neutropenia, a drop in a type of white blood cells; and thrombocytopenia, a drop in blood platelets. Although low blood counts were common, they were manageable, and other severe side effects were uncommon.
“One of the nice things we saw in this study was that the rates of severe CAR T-cell-related toxicities — called neurotoxicity and cytokine release syndrome — were very low in multiple myeloma compared to what we have seen with lymphoma CAR T-cell infusions,” Anderson says. “The majority of people had some side effects, but most were low level and manageable, and I would say this therapy is often much better tolerated than a stem cell transplant, which most of these patients had already gone through.”
Pioneered in the late 1980s, CAR T-cell therapy is a promising and still emerging treatment for blood cancers. CAR, which stands for chimeric antigen receptor, takes part of its name from the chimera, the mythical animal with the tail of a serpent and head of a lion. In modern medicine’s version of the chimera, the head is an antibody, and the tail is a T-cell receptor. CAR T-cell therapy involves harvesting a patient’s own T-cells by withdrawing blood, reengineering them in a lab to have this cancer-fighting chimera, and then growing hundreds of millions of them to put back into the patient by infusion.
CAR T-cell therapy is currently approved for use only in lymphoma and leukemia. Several different CAR T-cell treatments for myeloma are in clinical trials, but this CAR T-cell treatment is the first to complete and publish data from an FDA registration trial. Based on these results, the pharmaceutical companies Bristol Myers Squibb and bluebird bio are seeking FDA approval of ide-cel as a standard therapy for relapsed myeloma with a decision expected by the end of March.
The trial was funded by bluebird bio and Celgene, a Bristol Myers Squibb company. Anderson is a consultant who serves on an advisory board for Celgene and has other consulting activities disclosed in the manuscript.

Deep learning is a potential tool for scientists to glean more detail from low-resolution images in microscopy, but it’s often difficult to gather enough baseline data to train computers in the process. Now, a new method developed by scientists at the Salk Institute could make the technology more accessible — by taking high-resolution images, and artificially degrading them.
The new tool, which the researchers call a “crappifier,” could make it significantly easier for scientists to get detailed images of cells or cellular structures that have previously been difficult to observe because they require low-light conditions, such as mitochondria, which can divide when stressed by the lasers used to illuminate them. It could also help democratize microscopy, allowing scientists to capture high-resolution images even if they don’t have access to powerful microscopes. The findings were published March 8, 2021, in the journal Nature Methods.
“We invest millions of dollars in these microscopes, and we’re still struggling to push the limits of what they can do,” says Uri Manor, director of the Waitt Advanced Biophotonics Core Facility at Salk. “That’s the problem we were trying to solve with deep learning.”
Deep learning is a type of artificial intelligence (AI) in which computer algorithms learn and improve by studying examples. To use deep learning to improve microscope images — either by improving the resolution (sharpness) or reducing background “noise” — the system would need to be shown many examples of both high- and low-resolution images. That’s a problem, because capturing perfectly identical microscopy images in two separate exposures can be difficult and expensive. It’s especially challenging when imaging living cells that might be moving around during the process.
That’s where the crappifier comes in. According to Manor, the method takes high-quality images and computationally degrades them, so that they look something like the lowest low-resolution images the team would acquire.
Manor’s team showed high-resolution images and their degraded counterparts to the deep learning software, called Point-Scanning Super-Resolution, or PSSR. After studying the degraded images, the system was able to learn how to improve images that were naturally poor quality.
That’s significant because, in the past, computer systems that learned on artificially-degraded data still struggled when presented with raw data from the real world.
“We tried a bunch of different degradation methods, and we found one that actually works,” Manor says. “You can train a model on your artificially-generated data, and it actually works on real-world data.”
“Using our method, people can benefit from this powerful, deep learning technology without investing a lot of time or resources,” says Linjing Fang, image analysis specialist at the Waitt Advanced Biophotonics Core Facility, and lead author on the paper. “You can use pre-existing high-quality data, degrade it, and train a model to improve the quality of a lower-resolution image.”
The team showed that PSSR works in both electron microscopy and with fluorescence live cell images — two situations where it can be extraordinarily difficult or impossible to obtain the duplicate high- and low-resolution images needed to train AI systems. While the study demonstrated the method on images of brain tissue, Manor hopes it could be applied to other systems of the body in the future.
He also hopes it could someday be used to make high-resolution microscopic imaging more widely accessible. Currently, the most powerful microscopes in the world can cost upwards of a million dollars, because of the precision engineering required to create high-resolution images. “One of our visions for the future is to be able to start replacing some of those expensive components with deep learning,” Manor says, “So we could start making microscopes cheaper and more accessible.”

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Many parents know the struggle of having to make children with pneumonia finish the usual 10-day course in antibiotics despite the child feeling better after a few days of medication.
New research from McMaster University has proven that a five-day course of high-dose amoxicillin will do just as well for children six months to 10 years old with common pneumonia.
“Several studies have proven that adults with pneumonia do fine with short courses of antibiotics, and now we have proved a short course of antibiotics also works for children,” said Dr. Jeffrey Pernica, lead study author, associate professor of pediatrics of McMaster’s Michael G. DeGroote School of Medicine and an infectious disease pediatrician for Hamilton Health Sciences.
The study, involving 281 Ontario children, found that 85.7% of those who received the short course of antibiotics and 84.1% of those who received the longer course of medication were cured two to three weeks later.
The paper was published online by the journal JAMA Pediatrics today.
“The dramatic increase in antimicrobial resistance in the world today is driven by overuse of antibiotics — which has only worsened during the COVID-19 pandemic,” Pernica said. “This is why we need these clinical studies — to figure out how short we can make antibiotic treatment courses for common infections.”
He said there are other reasons to use the least amount of antibiotics needed to effectively treat bacterial infections, including minimizing the costs of medicine.
As well, he noted, a number of conditions including obesity, asthma, and arthritis, have been associated with changes in the human microbiome that can be caused by the use of antibiotics.
The research team is recommending that clinical practice guidelines prepared for health professionals consider recommending five days of amoxicillin for pediatric pneumonia.
This study was supported by the PSI Foundation, Pediatric Emergency Research Canada and Hamilton Health Sciences.
The research is part of Canada’s Global Nexus for Pandemics and Biological Threats, an international network based at McMaster, with scientists, clinicians, engineers, social scientists and other experts working collaboratively to prevent future pandemics and mitigate global health threats.

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Mental health issues such as burnout and psychological distress are matters for concern among young adults, and are even more pertinent in today’s uncertain global climate. A recent paper by Yale-NUS College alumna Ms Joanna Chue (Class of 2019) and Assistant Professor of Social Sciences (Psychology) Cheung Hoi Shan identified five components of resilience that are applicable in Singapore’s cultural context, and demonstrated that college students possessing a higher degree of resilience were less susceptible to burnout and psychological distress. By identifying learnable components of resilience, the paper points to concrete, actionable ways that young adults can learn this vital characteristic, resulting in better mental health outcomes.
Published in Current Psychology in February 2021, the paper reported the results of two interrelated studies. The first established the validity of the Connor-Davidson Resilience Scale (CD-RISC), an internationally recognised measure of resilience, in the Singaporean context, and identified the five factors that constitute resilience among Singaporean students. While there are other measures of resilience, such as the local Singapore Youth Resilience Scale (SYRESS), the CD-RISC is more widely used internationally. Establishing the CD-RISC’s validity in the Singaporean context is a valuable result that enables its use by future researchers to make meaningful comparisons between resilience in Singapore and elsewhere.
“It was important to ascertain the validity of the CD-RISC to ensure that when administered to college students, it could accurately measure the construct of resilience in context,” said Ms Chue, first author of the study. “Validating the scale would then allow for its use, for example, in quantifying the impact of relevant programmes and interventions in strengthening mental resilience.”
The study also identified five factors that make up resilience in the Singaporean context: approach coping in adversity (a desire to actively seek ways to solve a problem, rather than avoiding it); self-belief and trust in one’s abilities; effort and purpose (being motivated by a sense of purpose and a desire to work hard to attain one’s goals); having good interpersonal and internal resources (including secure relationships, knowing where to find help in difficult times, and traits such as a sense of humour and a disposition to recognise one’s past successes and achievements); and spirituality (attributing happenings in life, including adversity, to a higher force such as God or fate).
“The five factors of resilience affirmed that mental resilience comprises both character traits and skills, the latter of which are learnt and honed over time. It’s heartening to know that we are all still works-in-progress, and can be equipped with skills to grow and adapt to the stressful situations we face,” Ms Chue added.
The second study linked resilience to lower levels of academic burnout in Singaporean college students, which was subsequently linked to lower psychological distress. By helping to regulate burnout, resilience contributed to better mental health overall. This insight points to an actionable way forward for professionals who work with young adults: instead of attempting to change the environment to lower the incidence of burnout — which, while important, is a daunting task — they can focus instead on cultivating resilience through training programmes and interventions. Not only is this a more practical way forward, it would also serve young adults well by equipping them with useful skills to deal with other stressful situations that they may face later on in life.
Asst Prof Cheung noted, “As resilience is a broad term, it was important for us to identify specific traits or skills that constitute resilience, so that we can develop in-house training programmes to enhance those skills among our students. After a discussion with colleagues from the Yale-NUS Wellness and Counselling Centres, we found that the skills related to resilience as identified in this study were indeed very trainable. These skills include increasing students’ confidence in harnessing their strengths to overcome challenges, teaching students active problem-solving skills, and the effective use of external support sources (such as peer support) that would enhance their resilience in the face of adversity.”
Ms Chue and Asst Prof Cheung pursued these new studies as a continuation of the findings in Ms Chue’s capstone project, where final-year Yale-NUS students embark on a year-long in-depth research study in their chosen major and field of study. At Yale-NUS, students have extraordinary opportunities to work closely with faculty to conduct original research, enabling them to increase their competitive edge as they consider graduate studies or other professional opportunities.

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A new substance could improve the treatment of persistent cancers. Researchers at Martin Luther University Halle-Wittenberg (MLU) and the University of Greifswald have developed a new inhibitor that makes drug-resistant tumour cells respond again to chemotherapy. The new substance blocks a protein in the cancer cells that normally transports the cancer drugs back out of the cells. The results were published in the scientific journal Molecules.
In addition to radiation therapy, cytotoxic agents, also known as chemotherapy, are frequently used to treat cancer. They prevent cells from dividing and thus cancer cells are unable to multiply unchecked. “Cytotoxic agents remain a very important form of treatment because they have a general effect, in other words, they work on different types of cancer,” explains Dr Andreas Hilgeroth, a professor of pharmacy at MLU. However, some tumours are resistant to chemotherapy. They possess certain proteins that transport the drugs back out of the cancer cell.
Hilgeroth’s research group has now developed a new class of substances that inhibits one of these transport proteins: the multi-drug resistant protein 4 (MRP4). “It plays a particular role in leukemia,” says Professor Christoph Ritter from the Institute of Pharmacy at the University of Greifswald. The protein transports chemical messengers that appear to contribute to the development of that type of cancer. Ritter supported the team in the efficacy studies on special, drug-resistant cancer cell lines. The researchers were able to show that the cells treated with the new inhibitor transported fewer of the dye-labelled messengers and that the cytotoxic agents began having an effect again. “One of the substances showed particularly promising results,” says Ritter, adding, it inhibited the protein much better than the best inhibitor known to date.
The new substances could have two simultaneously positive effects: “preventing the transport of cancer-promoting messengers and ensuring that the chemotherapy starts working again,” explains Hilgeroth. If they prove to be successful in further tests, however, they will only be administrable in patients who have tumours containing the MRP4 transport protein. However, a pre-screening that uses markers to identify the type and characteristics of a specific cancer is already part of standard treatment. “There is an increasing focus on individualised medicine, especially in cancer therapy,” says Hilgeroth. Drugs are used that are tailored to the type and characteristics of the cancer. A different inhibitor would then be used on a different transport protein.
The efficacy must now be confirmed in further preclinical trials. Researchers will try to establish how well the newly developed drugs specifically inhibit MRP4 in order to reduce side effects. If the substances are a success, several years of clinical trials will follow to confirm their efficacy in patients.

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Professor Rosalind Gill, from City, University of London’s Gender and Sexualities Research Centre, has today published a new report to mark International Women’s Day.
The report — Changing the Perfect Picture: Smartphones, Social Media and Appearance Pressures — is based on research with 175 young women and nonbinary people in the UK.
Covering a range of issues — experiences of lockdown, feelings about ‘body positivity’, how to show support for Black Lives Matter — the research documents young people’s persistent anger with a mass media that they deem ‘too white’, ‘too heterosexual’ and too focused on very narrow definitions of beauty.
Professor Gill said: “A critique of perfection ran through the research like a bass track, with young people telling me that they feel overwhelmed by images that are ‘too perfect’.
“Women of colour, disabled women and gender nonconforming folk told me they rarely see anyone like them in the media.”
The report raises particular issues about how appearance standards are narrowing and how the affordances of smartphones (e.g., magnification and screenshotting), together with editing and filtering apps like Facetune, are contributing towards a society in which young people feel under constant forensic scrutiny by their peers.

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Ninety per cent of women report using a filter or editing their photos before posting to even out their skin tone, reshape their jaw or nose, shave off weight, brighten or bronze their skin or whiten their teeth.
Young women in the study also described regularly seeing advertisements or push notifications for cosmetic procedures — particularly for teeth whitening, lip fillers, and surgery to enhance bottom, breasts or nose.
Social media algorithms mean that, as one 21-year-old put it: “Once you look, you will never be allowed to forget.”
Professor Gill said: “With nearly 100 million photos posted every single day on Instagram alone, we have never been such a visually dominated society.
“Posting on social media can produce the intense pleasure of ‘getting likes’ and appreciative attention, but it is also a source of huge anxiety for most young women.

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“I was struck by young women saying to me again and again: ‘I feel judged’.”
Professor Gill noted that, while the research would have been important at any time, the unique context of the Covid-19 pandemic and lockdown gave it a particular urgency.
She said: “Day after day, reports were published highlighting the devastating mental health impacts of the pandemic on young people: their education suddenly halted, their freedoms curtailed, with many experiencing financial hardship, emotional difficulties or bereavement.
“This research helps to shed light on how a diverse sample of young people navigated this challenging time, as well as offering more general insights into their lives.
“In some ways, young people’s familiarity with online tools and platforms better prepared them (relative to older groups) for the lockdown period in which so many aspects of life moved online — including work, education, psychological and health services, and social lives.
“In other ways, as this report shows, they experienced heightened pressure and distress.”
The research was funded by City, University of London, and carried out at the Gender and Sexualities Research Centre (GSRC) during 2020.
The GSRC analyses how gender and sexuality intersect with other social divisions and identities in a rapidly changing world, fostering interdisciplinary dialogue, collaboration and research.
A summary report was submitted to the Government Equalities Office’s Inquiry into Body Image.

Research from the University of Kent predicts an end to deregulated competitive pubic transport in the UK as a consequence of Covid-19 social distancing measures leading to drastically reduced ridership, requiring a major rethinking of the provision of public transport.
This paper, published in Transport Policy, argues that the situation will require a fundamental approach to long-term policy for transport as a whole. This is an opportunity to reconstruct the system whilst addressing such problems as the environmental impact of transport, congestion and questions of transport justice such as accessibility to transport for disadvantaged groups in society.
Covid-19 has been a major disruptor on all aspects of the transport system, local, national and international. This has been significant for both the UK’s public sector and private sector operators and has thrown most business models into disarray, demonstrating the system’s fragility to crisis. Whilst the UK Government provides funding for services to continue amid the pandemic, the length of the emergency and the slow recovery threaten this ability to maintain support until demand returns to pre-pandemic levels.
In the UK central government borrowing in fiscal year 2020/21 is expected to reach almost £400 billion as the economy shrinks by an expected 11.3 per cent and unemployment rises to 7.5 per cent. Continued government funding for the public transport system is not sustainable for current pandemic levels of use, in which ridership is down across the system.
In addition to this, the increasing inequality in accessibility to transport according to income, age, disability and other individual and social characteristics was a pre-pandemic issue of major disparity, whilst the environmental crisis continues with transport accounting for a significant share of global emissions. These older issues continue and require immediate addressing.
The paper argues that returning to the old normal is unlikely and that public transport must adjust to increased home working and a fear of crowded spaces. This potentially spells the end of the prevailing model of a deregulated competitive public transport in the UK.
Roger Vickerman, Emeritus Professor of European Economics at Kent and author of the paper said: ‘Public transport’s flaws required urgent addressing prior to the pandemic and now much remains to be done in designing an inclusive transport system. In the light of the pandemic, we are presented with this opportunity now and may use it to establish a system that is efficient, environmentally considerate, and to the benefit of its users that currently suffer its disadvantages.’

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Over 10,000 people in Europe use an assistance dog; think of guide dogs for people with a visual impairment, hearing dogs for people with a hearing impairment, medical response service dogs and psychiatric service dogs.
According to a UN-agreement and the Dutch law, these dogs are welcome in stores, hospitals and other public places. However, in practice, many assistance dog users and their dogs are regularly refused entry. In the Netherlands, four out of five assistance dog users indicate that they regularly experience problems with this.
Often, hygiene reasons are given as the main argument for refusing entry to assistance dogs. Research by Utrecht University now shows that the paws of assistance dogs are cleaner than the shoe soles of their users, and thus, paw hygiene is no reason to ban assistance dogs from hospitals.
To investigate this, Jasmijn Vos, Joris Wijnker and Paul Overgaauw of Utrecht University’s Faculty of Veterinary Medicine took samples from the paws of 25 assistance dogs and the shoe soles of their users. For comparison, they also investigated an equally large group of pet dogs and their owners. Vos and her colleagues examined the samples for poop bacteria (Enterobacteriaceae), which are very common outdoors, and for an important diarrheal bacteria (Clostridium difficile).
“The dogs’ paws turned out to be cleaner than the soles of their shoes,” says Jasmijn Vos, Masters student at Utrecht University. “This makes the hygiene argument that is often used to ban assistance dogs from public locations invalid.” Moreover, the diarrheal bacteria did not occur on the dogs’ paws whatsoever, and only once on a shoe sole.
81% of assistance dogs are refused
Dutch assistance dog users were also surveyed about their experiences. 81% are still regularly refused entry to public places with their dog, even though this is prohibited by law. This is mainly down to lack of knowledge on the part of the person refusing entry: lack of knowledge on what an assistance dog is, how it can be recognised, and about the rules of law.
The study also shows that assistance dog users constitute only a small fraction of the total number of patients in Dutch hospitals. Should they decide to bring their assistance dog to the hospital, or elsewhere, this should be made possible; assistance dogs are usually well trained and are no more of a hygiene hazard than people!

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