Body

The technology, developed by researchers at Imperial College London and The University of Hong Kong, can be used to measure hormones that affect fertility, sexual development and menstruation more quickly and cheaply than current methods.

The work, published in Nature Communications, took place in the Chemistry Department at Imperial College London and the School of Biomedical Sciences at the University of Hong Kong. It was tested in patients at Hammersmith Hospital, part of Imperial College Healthcare NHS Trust.

A third of women in England suffer from severe reproductive health problems such as infertility and early menopause. Doctors usually diagnose these conditions by carrying out a blood test to measure the amount of luteinizing hormone (LH) in the sample. Current blood tests cannot easily measure the rise and fall of LH levels which is vital for normal fertility - so-called LH pulse patterns that are linked to reproductive disorders. It is not currently feasible to measure LH pulse patterns in a clinical setting as doctors need to take a blood sample from patients every 10 minutes for at least eight hours. In addition, the analysis of these samples is time consuming as the blood needs to be sent to a laboratory and testing is expensive.

The researchers behind the trial have used a novel biosensor linked to a robotic system, which they call Robotic APTamer-enabled Electrochemical Reader (RAPTER). It has the potential to transform the clinical care of patients with reproductive disorders by monitoring the hormone patterns of patients in real-time. In the study, the prototype RAPTER device was used to measure LH in the blood of patients taken every ten minutes to yield an immediate result.

The team believe that it could pave the way for more personalised medicine. They hope that the technology can be developed to give clinicians a clearer picture of LH pulsatility and suggest more effective treatments based on an individual's needs.

Professor Waljit Dhillo, one of the lead authors and NIHR Research Professor in Endocrinology and Metabolism at Imperial College London, said:

"Reproductive health issues are common amongst women in the UK and around the world. Diagnosis of some of these conditions can be lengthy resulting in delays to treatment. Reproductive health issues can also impact on women's mental and physical wellbeing. There is a clear need for new and better ways to diagnose these conditions more quickly. Our technology will be able to give clinicians a faster and more accurate diagnosis of hormone pulsatility that affects reproductive health, which could lead to better and more targeted treatments for women."

In the study, which took place between 2015 and 2019, researchers used the RAPTER to measure LH pulse patterns from 441 blood samples of women who either had normal reproductive function, were menopausal, or had hypothalamic amenorrhea, a condition where a woman's period stops. The large-scale device then gave an immediate reading.

Working with researchers from the Universities of Bristol and Exeter, the team then used a mathematical method called the Bayesian Spectrum Analysis (BSA) to give an overall score of LH pulse levels. The results were compared with current tests to measure LH levels.

The RAPTER platform was able to detect changes in LH pulse patterns in patients with reproductive disorders. It was also able to distinguish between different patient cohorts for the first time using this new technology. For example, women with menopause have high LH levels compared to healthy fertile women with normal LH levels, or women with hypothalamic amenorrhoea who have low LH levels. Unlike current methods, the test is low-cost and can provide results instantly.

The team will now work on refining the technology to create a smaller sensor similar to a glucose monitoring device that can be used to continuously track changes to LH levels of patients in the clinic or remotely and could be available in the next three to five years.

Professor Tony Cass, a senior author on the study from the Chemistry Department at Imperial College London, said:

"We have developed technology that is able to measure LH pulsatility in patients more quickly and cheaply than current methods. We will now work towards making the technology more accessible for the clinic by reducing the size of the device, which could revolutionise the clinical care of patients with reproductive or other disorders."

Dr Julian Tanner, a senior author on the study from the LKS Faculty of Medicine at The University of Hong Kong, added that the technology could also be developed to monitor other hormones such as cortisol. He added: "The detection methodology that we have developed for LH sensing is widely applicable for real-time monitoring of all kinds of biomolecules that relate to health and wellbeing. Excitingly, with further research this technology could be adapted for implanted sensors that could transform health monitoring in all kinds of contexts."

(COLUMBUS, Ohio) - In recent years, kratom has become popular as a treatment for chronic or acute pain as well as mood conditions such as depression and anxiety. It is also often used to help with opioid withdrawal. While there is a perception that kratom is safe because it is classified as an herbal supplement, a variety of serious medical outcomes as well as 11 deaths have occurred following kratom use. A new study conducted by the Center for Injury Research and Policy and the Central Ohio Poison Center at Nationwide Children's Hospital found that there were more than 1,800 calls to U.S. Poison Control Centers regarding exposures to kratom from January 2011 through December 2017. The annual number of calls increased dramatically, going from 13 calls in 2011 to 682 calls in 2017. That is the equivalent of going from about one call a month to two calls a day. Almost two-thirds (65%) of these exposures occurred from 2016 through 2017- the two most recent years of the study.

The study, published online today in the journal Clinical Toxicology, found that most exposures occurred among males (71%), age 20 years and older (89%), at a residence (86%), and were intentional abuse or misuse (60%), suspected suicide (9%), or adverse reaction (8%). Exposure rates were highest in Idaho and Oregon and lowest in Delaware and Wisconsin.

Overall, nearly one third (32%) of the calls resulted in admission to a healthcare facility and more than half (52%) resulted in serious medical outcomes, especially among teenagers and adults. Taking kratom with another substance increased the odds of admission to a health care facility (OR 2.80) and of having a serious medical outcome (OR 2.25). The medical effects noted in this study ranged from tachycardia (rapid heartbeat), agitation/irritability, and hypertension (high blood pressure) to seizures, coma (loss of consciousness), increased bilirubin, renal (kidney) failure, and death.

"Kratom use has been associated with a variety of serious medical outcomes, from seizures and coma in adults to severe withdrawal syndrome in newborns," said Henry Spiller, MS, DABAT, co-author of this study and director of the Central Ohio Poison Center at Nationwide Children's Hospital. "Individuals who choose to use kratom need to be aware of the potential risks. Just because it is currently classified as an herbal supplement does not mean it is regulated or that it is safe."

Kratom is listed by the Drug Enforcement Administration (DEA) as a "drug of concern" and has not been approved for any medical use by the Food and Drug Administration (FDA). Because it is not currently regulated, product quality, purity, and concentration varies dramatically. The researchers are calling for FDA regulation to ensure product uniformity.

Among the 48 kratom exposures that involved children age 12 years and younger, 69% were children younger than two years, including seven newborns, five of whom were experiencing withdrawal.

"As physicians, we need to educate pregnant women on the risks of kratom use during pregnancy and while breastfeeding," said Spiller.

Data for this study were obtained from the National Poison Data System, which is maintained by the American Association of Poison Control Centers (AAPCC). The AAPCC receives data about calls to poison control centers that serve the U.S. and its territories. Poison control centers receive phone calls through the Poison Help Line and document information about the product, route of exposure, individual exposed, exposure scenario, and other data.

Worsening epidemics could spread beyond Venezuelan borders, potentially causing a public health emergency of 'hemispheric concern'.

Many solutions are possible, even with scarce resources, and national, regional, and global health authorities must act.

The ongoing humanitarian crisis in Venezuela is accelerating the re-emergence of vector-borne diseases such as malaria, Chagas disease, dengue, and Zika virus, and threatens to jeopardise public health gains in the country over the past two decades, warn leading public health experts. The conclusion comes from a Review paper that provides the most comprehensive assessment of the impact of the crisis in Venezuela, published in The Lancet Infectious Diseases journal.

With the collapse of the health care system and the dramatic decline in public health programmes and disease surveillance, vector-borne diseases (which are transmitted by insects such as mosquitoes and ticks) are on the rise and have spread into new territories across Venezuela--once a regional leader in public health and vector control, and the first WHO-certified country to eradicate malaria in 1961.

This is the first time so much information has been brought together to assess the impact of Venezuela's health crisis on vector-borne diseases. However, the authors caution that given the lack of disease surveillance and public health infrastructure available for diagnosis, the true burden of disease remains unknown.

Worryingly, the authors say that this might be just the tip of the iceberg. "As well as the return of measles and other vaccine-preventable infectious diseases, the continued upsurge in malaria could soon become uncontrollable. The stark reality is that in the absence of surveillance, diagnostic, and preventive measures, these figures most likely represent an underestimate of the true situation", says Dr Martin Llewellyn from the University of Glasgow, UK, who led the research with Venezuelan, Colombian, Brazilian, and Ecuadorian colleagues. [1]

Analysis of published and unpublished data (see panel) indicate that between 2010 (29,736 cases) and 2015 (136,402 cases), Venezuela experienced an estimated 359% increase in malaria cases, followed by a 71% increase between 2016 (240,613 cases) and 2017 (411,586 cases) because of a decline in mosquito-control activities and shortages in medication. This is potentially the largest malaria increase reported worldwide. Worse still, say the authors, endemic malaria transmission is beginning to spread across the whole country (figure 1).

Findings from the review suggest that the ongoing crisis has also had dramatic effects on other vector-borne diseases. For example, Chagas disease, one of the leading causes of heart failure in Latin America, may be resurging, with active Chagas disease transmission the highest seen in 20 years. Based on samples collected between 2008 and 2018 seroprevalence among children younger than 10 years was estimated at 12.5% in some communities, compared to an all-time low of 0.5% in 1998 (figure 3).

The incidence of dengue has risen more than five-fold, with an average incidence of 211 cases per 100,000 people between 2010 and 2016, and six increasingly large epidemics recorded nationally between 2007 and 2016, compared with four in the previous 16 years (figure 5).

Similarly, the frequency of chikungunya and Zika outbreaks with epidemic potential appear to be increasing, with an estimated 2 million suspected chikungunya cases in 2014 (incidence 6,975 per 100,000)--more than 12 times higher than official national estimates.

The findings also sit in the context of mass emigration. With an average of 5,500 people leaving the country every day in 2018 [2], neighbouring countries are also facing major challenges. For instance, regions of Brazil neighbouring Venezuela have reported an escalating trend in malaria cases (eg. Roraima saw the number of imported cases of malaria rise from 1,538 cases in 2014 to 3,129 in 2017 (figure 2)), but rates in other neighbouring countries remain unclear. The authors highlight that many solutions are possible, even with limited resources. For example, in recent years, malaria has been successfully controlled on the Ecuador-Peru border through bi-national collaboration that involved strengthening surveillance and treatment strategies, and sharing of resources (eg, information, personnel, medication, and insecticides) [3].

Reaching and testing those at risk of infection across Venezuela is a major challenge, say the authors, so it is especially important that communities most at-risk from disease are made aware of the growing threat. Additionally, more needs to be done to improve surveillance and data sharing. The authors point out that surveillance is crucial and must be used to raise awareness among Venezuelan and regional authorities, and encourage them to recognise the growing crisis, cooperate, and accept international medical interventions. Relevant international health authorities must also take action to maintain accurate disease surveillance and response systems in the region.

Successful control of the emerging health crisis will require regional coordination and powerful national and international political commitment, and the authors urge regional health-care authorities to recognise and act on a public health emergency of hemispheric concern.

"We call on the members of the Organization of American States and other international political bodies to apply more pressure to the Venezuelan government to accept the humanitarian assistance offered by the international community in order to strengthen the buckling health system. Without such efforts, the public health gains achieved over the past 18 years could soon be reversed", warns Llewellyn. [1]

Must cook dinner. Need to pick the kids up from school. Have to catch up on my favourite TV series. Live too far from the gym. Any of these sound familiar? With growing time demands, many middle-aged adults are finding time to engage in exercise increasingly difficult. For many, even the thought of fitting exercise in after a busy day at work can be as tiring as it is unappetising. The standing belief that high-intensity exercise should be avoided in the early evening due to its effect on sleep only serves to act as another barrier to exercise at this time.

However, encouraging new research published in Experimental Physiology has suggested that 30 minutes of high-intensity exercise performed in the early evening does not negatively affect subsequent sleep, and may also reduce feelings of hunger.

Researchers at Charles Sturt University in Australia recruited eleven middle-aged men to complete three experimental trials to investigate sleep and appetite responses to exercise performed in the morning (6 - 7 am), afternoon (2 - 4 pm) and evening (7 - 9 pm). Participants were required to perform high-intensity cycling involving six one-minute, maximal intensity sprints interspersed by four minutes of rest. Blood collections were taken prior to exercise and following exercise to examine appetite-related hormones, and multiple tests were performed during sleep to assess sleep stages.

The results not only showed that evening exercise did not have a detrimental impact on subsequent sleep, but also that afternoon and evening high-intensity exercise were associated with greater reductions of the hunger stimulating hormone, ghrelin. It is important to note that a single bout of exercise was not linked to reduced hunger, but nevertheless, the observations from this study support high-intensity exercise early in the evening as a viable time-of day for exercise.

As this study's sample size was relatively small, the findings extrapolated to other population groups beyond middle-aged men may be limited, given that sleep and appetite regulation are influenced by sex and age.

Penelope Larsen, lead author of the study, commented said:

"In the future, we hope to conduct similar studies recruiting women, to determine whether sleep and appetite responses may be different depending on sex. Also, this study only considered a single bout of exercise; therefore, it would be beneficial to investigate long-term sleep and appetite adaptations to high-intensity exercise training performed either in the morning, afternoon or evening."

Interestingly, power output during the sprint efforts was higher for the afternoon and evening trials compared to the morning trial, indicating that participants were able to perform better during latter parts of the day. Therefore, time-of-day may also need to be considered when planning training schedules."

PITTSBURGH-- Physicians will be able to predict which of their patients with severe asthma are likely to benefit from treatment with systemic corticosteroids -- and which might only suffer their side effects -- with help from a dozen clinical variables researchers have identified using machine learning techniques.

Physicians already have some clues about which patients are most helped by corticosteroid injections or pills. But the newly identified set of variables -- when processed by computer software -- will yield more precise predictions of a patient's response, said Wei Wu, a faculty member in Carnegie Mellon University's Computational Biology Department.

"Systemic corticosteroids are the most effective therapy we have for asthma, but not all patients respond in the same way," Wu said. "Unfortunately, when clinicians don't see a big improvement after initial treatment, they might give patients even higher doses. If a patient is one of those who can't be helped by corticosteroids, the higher dose just means worse side effects."

The study, led by Wu and Dr. Sally E. Wenzel, director of the University of Pittsburgh Asthma Institute at UPMC, was recently published online by the American Journal of Respiratory and Critical Care Medicine.

Asthma affects about one in every 12 Americans and the rate continues to rise. The lifelong disease causes wheezing, breathlessness, chest tightness and coughing. Predicting how people will respond to corticosteroid therapy could significantly reduce the suffering of many patients, Wenzel said.

"I see so many patients in my clinic who have been ravaged by the side effects of corticosteroids," said Wenzel, also chair of the Department of Environmental and Occupational Health at Pitt's Graduate School of Public Health. Weight gain, extreme emotions, inability to sleep, glaucoma and thinning of the skin are among the possible side effects of corticosteroid pills and injections, so physicians would like to prescribe them only to patients they know will benefit from them, she added.

She emphasized that the study addresses corticosteroid pills and injections, not the widely used corticosteroid inhalers, although there is likely to be some overlap in patient response to the medications in either form.

To better understand how different subgroups of patients respond to systemic corticosteroid therapy, the researchers used a machine learning algorithm to sift through 100 variables for each of 346 adult patients in the federally funded Severe Asthma Research Program (SARP).

The algorithm, developed by Wu and Seojin Bang, a Ph.D. student in CMU's Computational Biology Department, recognizes patterns in massive volumes of complex clinical data. It clustered patients into four subgroups, including two for severe asthmatics -- one that responded to systemic corticosteroids and one that didn't.

Of the original 100 variables, they identified 12 -- including age of onset, weight, race and scores on a quality-of-life questionnaire -- that could correctly categorize patients with high confidence if processed by a computer app. To test this process, they used the 12 variables (or their equivalents) to categorize a group of 182 SARP participants not included in the original analysis. The variables proved effective in successfully categorizing these additional patients.

The benefits of systemic corticosteroids can be substantial, so physicians likely will continue to try them initially in the treatment of severe asthma, Wenzel said. But once software becomes available for practitioners to predict patient response, she said they will likely switch to alternative therapies, rather than increase corticosteroid dosages, if patients haven't responded and fall into the subgroup of patients that don't usually benefit from the drugs.

"We believe we've made progress toward making precision medicine a reality," Wei said. "Five years ago, we were only able to categorize patients clinically. Now, using incredibly complex data, we're able to predict how these subgroups will respond to a critical drug treatment."

Scientists find new drugs compound for treating cancer

Cancer is less likely to become resistant to the compound than standard chemotherapy

The compound could be particularly effective against ovarian cancer

Scientists from the University of Sheffield have discovered a compound that could be more effective in treating certain cancers than standard chemotherapy.

Chemotherapy is still the first line of defence for most cancer tumours and is often highly effective. However, many cancers are naturally resistant, or develop resistance, to commonly used first-line chemotherapy drugs like cisplatin.

Researchers from the University of Sheffield's Departments of Biomedical Science and Chemistry collaborated to identify new drug-candidates that would work against these types of treatment resistant cancers.

In the paper, published in the Journal of the American Chemical Society, scientists screened new compounds made in the lab against a "panel" of cancers that were sensitive and resistant to standard cancer therapy.

The researchers also tested the compounds with non-malignant cells to see how toxic they were to normal cells. They found two lead compounds that had low toxicity to non-malignant cells but were highly active against cancer cells sensitive or resistant to standard treatment.

Professor Jim Thomas, from the University's Department of Chemistry, said: "Many cancer cells - about 20 per cent - become resistant to common treatments by learning to ignore the internal signals that tell them to undergo programmed cell death, known as apoptosis.

"We have identified a compound that kills cancer cells that avoids the need for apoptosis, and so the usual resistance mechanism doesn't work against our compound.

"The compound is as potent as common current chemotherapeutics, but crucially retains its potency against treatment-resistant cancers. By looking at the cellular response from the cancers we found the new drug lead works by two different mechanisms simultaneously, making it much more difficult for cancers to develop resistance toward them during treatment.

"We think this compound could be particularly effective against ovarian cancer."

The team used a technique called "proteomics" to determine how thousands of proteins in the cells responded to exposure to the drug lead.

Professor Carl Smythe, from the University's Department of Biomedical Science, said: "Proteomics is a remarkably powerful approach we have in Sheffield to identify how living things respond to new drug candidates. The multiple mechanisms of action of the new molecules was an unexpected and exciting result."

Researchers now want to carry out further studies to find out if the compound can be used in combination with current treatments to improve their performance.

Professor Thomas added: "We also want to discover if we can identify derivatives that further enhance the effectiveness of the drugs without being harmful to 'normal' non-malignant cells and discover against what types of cancers the compounds are most effective."

Atopic dermatitis, a common inflammatory skin condition also known as allergic eczema, affects nearly 20 percent of children, 30 percent of whom also have food allergies. Scientists have now found that children with both atopic dermatitis and food allergy have structural and molecular differences in the top layers of healthy-looking skin near the eczema lesions, whereas children with atopic dermatitis alone do not. Defining these differences may help identify children at elevated risk for developing food allergies, according to research published online today in Science Translational Medicine. The research was supported by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

"Children and families affected by food allergies must constantly guard against an accidental exposure to foods that could cause life-threatening allergic reactions," said NIAID Director Anthony S. Fauci, M.D. "Eczema is a risk factor for developing food allergies, and thus early intervention to protect the skin may be one key to preventing food allergy."

Children with atopic dermatitis develop patches of dry, itchy, scaly skin caused by allergic inflammation. Atopic dermatitis symptoms range from minor itchiness to extreme discomfort that can disrupt a child's sleep and can lead to recurrent infections in scratched, broken skin.

The study, led by Donald Y.M. Leung, M.D., Ph.D., of National Jewish Health in Denver, examined the top layers of the skin, known as the stratum corneum, in areas with eczema lesions and in adjacent normal-looking skin. The study enrolled 62 children aged 4 to 17 who either had atopic dermatitis and peanut allergy, atopic dermatitis and no evidence of any food allergy, or neither condition. Investigators collected skin samples by applying and removing small, sterile strips of tape to the same area of skin. With each removal, a microscopic sublayer of the first layer of skin tissue was collected and preserved for analysis. This technique allowed researchers to determine the skin's composition of cells, proteins and fats, as well as its microbial communities, gene expression within skin cells and water loss through the skin barrier.

Researchers found that the skin rash of children with both atopic dermatitis and food allergy was indistinguishable from the skin rash of children with atopic dermatitis alone. However, they found significant differences in the structure and molecular composition of the top layer of non-lesional, healthy-appearing skin between children with atopic dermatitis and food allergy compared with children with atopic dermatitis alone. Non-lesional skin from children with atopic dermatitis and food allergy was more prone to water loss, had an abundance of the bacteria Staphylococcus aureus, and had gene expression typical of an immature skin barrier. These abnormalities also were seen in skin with active atopic dermatitis lesions, suggesting that skin abnormalities extend beyond the visible lesions in children with atopic dermatitis and food allergy but not in those with atopic dermatitis alone.

"Our team sought to understand how healthy-looking skin might be different in children who develop both atopic dermatitis and food allergy compared to children with atopic dermatitis alone," said Dr. Leung. "Interestingly, we found those differences not within the skin rash but in samples of seemingly unaffected skin inches away. These insights may help us not only better understand atopic dermatitis, but also identify children most at risk for developing food allergies before they develop overt skin rash and, eventually, fine tune prevention strategies so fewer children are affected."

Allergy experts consider atopic dermatitis to be an early step in the so-called "atopic march," a common clinical progression found in some children in which atopic dermatitis progresses to food allergies and, sometimes, to respiratory allergies and allergic asthma. Many immunologists hypothesize that food allergens may reach immune cells more easily through a dysfunctional skin barrier affected by atopic dermatitis, thereby setting off biological processes that result in food allergies.

Exercise can shift the human body clock, with the direction and amount of this effect depending on the time of day or night in which people exercise. That's according to new research in published in The Journal of Physiology. These findings suggest exercise could counter the effects of jet lag, shift work, and other disruptions to the body's internal clock (e.g. military deployments) helping individuals adjust to shifted schedules.

The circadian "body"' clock is the 24 hour cycle that regulates many physiological processes including sleeping and eating. Many factors affect this internal body clock including light and time cues. Exercise has been known to cause shifts in the circadian clock however very little is known about this effect.

This study found that exercising at 7 am or between 1 and 4 pm advanced the body clock to an earlier time, and exercising between 7 and10 pm delayed the body clock to a later time. Exercising between 1 and 4 am and at 10 am, however, had little effect on the body clock, and the phase-shifting effects of exercise did not differ based on age nor gender.

The researchers at University of California, San Diego and Arizona State University examined body clocks following exercise in 101 participants for up to five and a half days. The baseline timing of each participant's body clock was determined from urine samples collected every 90 minutes to measure the time of the evening rise in melatonin and the peak of melatonin several hours later. Participants then walked or ran on a treadmill at a moderate intensity for one hour per day for three consecutive days. They exercised at one of eight different times of day or night, but each individual exercised at the same time on all three days or nights. The timing of the body clock was re-assessed following the third exercise session.

Given that the subjects tested were more physically active than average, the results might not translate to the average person. Further research will look at combining exercise with bright lights and melatonin to see what impact this has on body clocks, as well as examining the effect of changes in exercise duration and intensity on the body clock.

Shawn Youngstedt, first author on the paper, said:

"Exercise has been known to cause changes to our body clock. We were able to clearly show in this study when exercise delays the body clock and when it advances it. This is the first study to compare exercise's effects on the body clock, and could open up the possibility of using exercise to help counter the negative effects of jet lag and shift work."

PHILADELPHIA - Specialized lung cells appear in the developing fetus much earlier than scientists previously thought. A new animal study published this week in the Proceedings of the National Academy of Sciences reports how cells that become alveoli, the tiny compartments in which gas exchange occurs in the lung, begin their specialized roles very early in prenatal life. The researchers from the Perelman School of Medicine at the University of Pennsylvania and the Children's Hospital of Philadelphia (CHOP) say that investigating the fetal signaling pathways active in this biological event may offer future opportunities to treat lung damage caused by prematurity and other lung injuries.

The research team focused on the basic function of respiration--the exchange of oxygen and carbon dioxide within key cells, called alveolar type 1 and type 2 cells. The same research team previously identified a new cell lineage in the lungs of mice and humans, which they called alveolar epithelial progenitor cells. The new research used single-cell RNA sequencing analysis, protein expression studies, and a new lineage-tracing tool to reveal details of early lung formation in a fetal mouse model.

Edward E. Morrisey, PhD, director of the Penn Center for Pulmonary Biology, Rajan Jain, MD, an assistant professor of Cardiovascular Medicine at Penn, and David B. Frank, MD, PhD, a pediatric cardiologist at CHOP, were co-authors on the study.

The investigators are interested in deciphering the basics of how cells form their identity - essentially, why a cell becomes a lung cell as opposed to a heart cell. In particular, understanding how the lung forms is critical because many babies born prematurely have poorly formed organs. "What we found is that lung cells take on their intended fate much earlier than expected, which is a critical step toward being able to develop new therapeutics," said Jain.

Alveolar cells share similar characteristics in mice and humans, both have similar underlying genes, proteins and signaling systems, so the biological mechanisms found in the current study of mice is relevant to how these cells function in humans. "This cell specification begins remarkably early in lung development, and it progressively seeds the premature lung alveolus throughout the fetus's gestation," said Frank.

The team found that the specification of alveolar cells begins simultaneously with early lung formation, as cells in the developing embryo begin to move apart and branch out into specialized structures such as airways and alveoli. Many lung cells commit themselves to "cell fates," their specialized roles, during branching morphogenesis, which occurs before the formation of the sac-shaped structure that becomes the lung alveolus.

"The early presence of these specialized alveolar cells may account for the fact that a minority of extremely premature human babies survive even with underdeveloped lungs," said Frank. He added that because many other organ systems in addition to the pulmonary system remain underdeveloped in extremely premature infants, morbidity and mortality remain high in such cases.

The research team plans to further explore how their findings could eventually contribute to future treatments. Better understanding of lung development could lead to potential tools in regenerative medicine, perhaps by manipulating key signaling pathways or novel progenitor cell targets to grow new lung tissue after injury from prematurity or from acquired lung disease.

Researchers at The University of Texas MD Anderson Cancer Center have discovered that a combination of immune checkpoint blockade and targeted therapies that block normal DNA damage repair (DDR) achieved significant tumor regression in mouse models of small cell lung cancer (SCLC), suggesting a promising new approach for treating patients with this aggressive cancer.

The preclinical research, published today in Cancer Discovery, suggest that the PARP inhibitor olaparib and other DDR inhibitors induce a rapid immune response and sensitize SCLC cells to immunotherapy, to which they were previously resistant.

Small cell lung cancer, one of the most aggressive types of cancer, makes up about 15 percent of all lung cancers diagnosed in the U.S., representing about 30,000 patients each year, explained Lauren Averett Byers, M.D., associate professor of Thoracic/Head & Neck Medical Oncology and corresponding author on the study.

Standard treatment for advanced SCLC is chemotherapy, but recurrence is common and the average survival is only about 12 months, according to Byers. For about 30 years, there were no changes to this approach, but recently the use of immunotherapy in combination with chemotherapy has become a new standard. However, the benefits are minimal for patients.

"While the use of immunotherapy has revolutionized the way we treat lung cancer, we find that small cell lung cancers can escape the immune system very effectively, so we see a much lower response rate," said Byers. "However, we want to do a lot better for our patients, and we think there's a lot of room for further improvement."

Previously, Byers discovered that DDR pathways were highly active in SCLC and blocking these pathways with drugs, such as PARP and CHK1 inhibitors, was effective in treating SCLC in the lab. Additionally, cancers with extensive amounts of DNA damage have been shown to respond better to immunotherapy.

"Therefore, we predicted that if we combined PARP inhibitors or other drugs that cause DNA damage with immune therapies, we might see a much greater response to the immune therapy," said Byers. "We found that if we added either PARP or CHK1 inhibitors to immunotherapy, we saw a dramatic shrinkage of tumors. In fact, in some cases, the tumors disappeared completely."

Combining the CHK1 inhibitor, prexasertib, or the PARP inhibitor, olaparib, together with an immune checkpoint inhibitor against PD-L1 resulted in significant tumor regression in SCLC mouse models, whereas immunotherapy alone had no effect.

The combination of PARP inhibitor and immunotherapy resulted in complete regression in all treated mice in as little as one week, leaving no tumors available for further analysis. The CHK1 combination treatment led to complete regression in 60 percent of treated mice.

The researchers discovered that DDR inhibitors activated an immune response in the mice, leading to an increase in cancer-killing immune cells in the tumors. This process was controlled by the STING pathway, which normally works to detect signals of a viral or bacterial infection. In this case, the STING pathway responded to DNA damage to activate the immune system, thus making SCLC cells susceptible to immunotherapy treatment.

"I think the results from this study are really compelling because of the dramatic activity that we saw with the combination of adding a targeted therapy to immune therapy," said Byers. "I think our findings can be rapidly translated into the clinic for our patients and also to other cancer types."

Clinical trials testing PARP inhibitors or immunotherapies for patients with SCLC are ongoing. Byers and colleagues hope to launch clinical trials to investigate the combination approach later this year, and expect this may also be effective in other cancer types defined by increased DNA damage, such as BRCA-mutant breast and ovarian cancers.

This study was supported by the Lung Cancer Moon Shot™, part of MD Anderson's Moon Shots Program™, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients' lives.

"The support of the Moon Shot really helped us to jumpstart the work in the lab and generate a great deal of the preliminary data that showed us this was a promising approach," said Byers. "That allowed us then to pursue additional funding to expand this work and advance it toward the clinic."

Physicists at McMaster University have for the first time identified a simple mechanism used by potentially deadly bacteria to fend off antibiotics, a discovery which is providing new insights into how germs adapt and behave at a level of detail never seen before.

The findings, published today in the journal Nature Communications Biology, could have implications in the global battle against antibiotic resistance, enabling the design of better, more effective drugs to fight infection.

"There are many, many bacteria out there, and so many antibiotics, but by proposing a basic model that applies to many of them, we can have a much better understanding on how to tackle and predict resistance better," says Maikel Rheinstädter, a professor in the Department of Physics and Astronomy at McMaster and lead author of the study.

Researchers examined how the membranes of bacteria interacted with the antibiotic polymyxin B (PmB), which is commonly used to treat urinary tract infections, meningitis, blood and eye infections.

They concentrated on PmB because it was once considered the strongest drug of its kind, a last line of defense for physicians when nothing else worked. That failsafe status came into question in 2016, when Chinese scientists discovered a gene that allowed bacteria to become resistant even to polymyxins.

"We wanted to find out how this bacteria, specifically, was stopping this drug in this particular case," says Adree Khondker, a health sciences undergraduate student and first author on the study. "If we can understand that, we can design better antibiotics."

Employing techniques typically used by physicists for materials research, the team used highly specialized equipment to peer deep into the bacterial membrane, capturing images with a resolution so fine they could view individual molecules at approximately 1/1,000,000th the width of a strand of human hair.

"If you take the bacterial cell and add this drug, holes will form in the wall, acting like a hole-puncher, and killing the cell. But there was much debate on how these holes were formed in the first place." explains Khondker.

When these antibiotics are working properly, researchers know the basic laws of physics apply: because the drug is positively charged it is attracted to the negatively charged bacteria. At the same time, the bacterial membrane is employing a repulsive force as it attempts to repel the drug.

Through imaging and simulations, researchers pinpointed which part of the antibiotic enters the membrane, where it enters and how deeply it penetrates. They simulated these processes on microsecond timescales with high-end gaming computers in their lab.

They determined that when a bacterium has become resistant, its membrane is more rigid and the charge is weaker, making it much less attractive to the drug and harder to penetrate. "For the drug, it's like going from cutting Jello to cutting through rock." Khondker says.

"There has been a lot of speculation about this mechanism," says Rheinstädter. "But for the first time we can prove the membrane is more rigid and the process is slowed."

The World Health Organization (WHO) considers the issue of antibacterial resistance a top global threat to public health, threatening our ability to treat common infectious illnesses, resulting in prolonged illness, disability and death. An estimated 70,000 people worldwide die every year from drug-resistant strains of bacterial infections, HIV/AIDS, tuberculosis and malaria.

Experts have warned that by 2050, the annual death toll will soar to 10 million worldwide.

Melanoma patients with a history of smoking cigarettes are 40 per cent less likely to survive their skin cancer than people who have never smoked, according to a new report funded by Cancer Research UK.

The study of more than 700 melanoma patients mainly from the north of England - and published today in Cancer Research - provides evidence to suggest that smoking may blight the immune response against melanoma and reduce survival.

These new findings from researchers at the University of Leeds provide another reason why people should try to give up smoking, particularly those who have been diagnosed with malignant melanoma - the most dangerous form of skin cancer.

The scientists found that overall, smokers were 40 per cent less likely to survive their disease than people who have never smoked within a decade after their diagnosis. In a subset of 156 patients who had the most genetic indicators for immune cells, smokers were around four and a half times less likely to survive from the cancer than people who had never smoked.

Given that reduced survival was found to be greatest for smokers in the group with most indicators of immune cells, the researchers think that smoking could directly affect how smokers' bodies deal with the melanoma cancer cells.

This study found an association between smoking and a patient's chance of survival from melanoma. But it could not determine for sure that smoking caused the drop in survival.

Smoking has been reported by other scientists to have adverse effects on the immune system, but it's not yet known which chemicals are responsible for this effect.

Lead author Julia Newton-Bishop, professor of dermatology at the University of Leeds, said: "The immune system is like an orchestra, with multiple pieces. This research suggests that smoking might disrupt how it works together in tune, allowing the musicians to continue playing but possibly in a more disorganised way.

"The result is that smokers could still mount an immune response to try and destroy the melanoma, but it appears to have been less effective than in never-smokers, and smokers were less likely to survive their cancer.

"Based on these findings, stopping smoking should be strongly recommended for people diagnosed with melanoma."

Researchers believe that smoking may have had an impact on patients' immune systems and this may have altered their ability to fight their skin cancer, as well as increasing their risk of other health issues relating to smoking.

Dr Julie Sharp, head of health information at Cancer Research UK, said: "Overall, these results show that smoking could limit the chances of melanoma patients' survival so it's especially important that they are given all the support possible to give up smoking for good."

In the current issue of Cardiovascular Innovations and Applications (Special Issue on Stable Ischemic Heart Disease, Volume 3, Number 3, 2019, pp. 269-278(10); DOI https://doi.org/10.15212/CVIA.2017.0071, Radmila Lyubarova, Joshua Schulman-Marcus and William E. Boden from the Division of Cardiology, Department of Medicine, Albany Medical Center, Albany, NY, USA and VA New England Healthcare System, Boston, MA, USA consider contemporary management of patients with stable ischemic heart disease.

Angina persists for many patients despite medical therapy and/or revascularization. In all patients with angina, aggressive risk factor modification and optimized medical management must be instituted. Revascularization should be performed for high-risk patients or patients with persistent symptoms. A beta-blocker is likely a first-line agent; how-ever, most patients require multiple medications for symptom control. Novel agents with new mechanisms improve treatment options, including ivabradine (sinus node inhibitor), and late Na+blockade (with a mechanism of action complementary to traditional agents) is beneficial in a broad range of patients unresponsive to current treatment options. Ongoing trials may help better define the role of aggressive medical therapy with or without revascularization.

In the current issue of Cardiovascular Innovations and Applications (Special Issue on Stable Ischemic Heart Disease, Volume 3, Number 3, 2019, pp. 279-283(5); DOI: https://doi.org/10.15212/CVIA.2017.0074 C. Richard Conti from the University of Florida Medical School, Gainesville, FL, USA considers epidemiology, pathophysiology, and therapeutic targets in stable ischemic heart disease.

Chronic stable angina affects approximately 10 million Americans, of whom more than 50% are older than 65 years. Angina is a more common manifestation of coronary heart disease in women than in men. The growing prevalence of recurring ischemia is probably due to residual coronary artery disease after percutaneous coronary intervention or coronary artery bypass grafting. Those with angina have a high socioeconomic burden that significantly limits functional capacity and impairs quality of life, and includes the high cost of care. The presence of common comorbidities, including diabetes, is associated with poorer outcomes adjust rates for this subgroup.

In the current issue of Cardiovascular Innovations and Applications (Special Issue on Stable Ischemic Heart Disease, Volume 3, Number 3, 2019, pp. 285-290(6); DOI: https://doi.org/10.15212/CVIA.2017.0073 Cody Schwartz and David Winchester from the Malcom Randall VAMC, Gainesville, FL, USA consider diabetes mellitus and stable ischemic heart disease.

More than 30 million Americans have diabetes mellitus (DM), and heart disease is the cause of death in 68% of them. Patients with DM are at increased risk of developing stable ischemic heart disease (SIHD) by several mechanisms. While noninvasive testing for ischemia is an intuitive strategy to reduce cardiovascular events, trial data do not show a clear benefit. For the DM patient with no symptoms and no evidence of SIHD, two randomized trials found no benefit for either nuclear stress or cardiac computed tomography. While silent ischemia is associated with increased cardiovascular risk, on a population level, reducing ischemia does not appear to improve outcomes. Another important consideration in the management of SIHD in DM patients is that recent randomized trial data show no benefit from coronary revascularization for this population. In conclusion, the decision to test for ischemia may be a reasonable option in some DM patient groups; however, in many cases, revascularization for SIHD does not reduce mortality or the rate of myocardial infarction.