Body

NHS-approved PARP inhibitor therapy found to boost the body's immune response

Drugs could be used to increase number of patients who respond to immunotherapies

Treatment developed for ovarian and breast cancers could also work in some lung cancers

Precision cancer drugs called PARP inhibitors have a previously unknown ability to boost the immune system, and could help many more patients benefit from immunotherapy, a new study reveals.

Scientists found that PARP inhibitors sparked a powerful immune response when used against cancer cells with weaknesses in repairing their DNA.

The study changes our understanding of how PARP inhibitors work - and suggests they could be used alongside immunotherapies to boost their effectiveness. Clinical trials have already started to assess this combination.

Some patients have benefited dramatically from a new generation of immunotherapies - but often only between 10 and 20 per cent of patients will respond, with many others' cancers able to hide from the immune system.

Scientists at The Institute of Cancer Research, London, and the Institut Gustave Roussy, France, led by Professor Chris Lord and Dr Sophie Postal-Vinay, found that PARP inhibitors could unmask some of these cancers that can currently evade detection by immune cells.

Their study is published in the Journal of Clinical Investigation and was funded by Breast Cancer Now and Cancer Research UK.

PARP inhibitors such as olaparib block one of the systems which cells use to repair their DNA. They are designed to attack tumours that are already defective at DNA repair, especially ovarian and breast cancers in women with inherited BRCA mutations.

The researchers looked at lung tumours taken from patients, and found those with deficiencies in their DNA repair contained significantly more immune cells within the tumours, compared with tumours in patients with a functioning DNA repair system. This suggested that the DNA repair mutations were stimulating an immune response against the tumours.

They also studied cancer cells from non-small cell lung cancers and triple-negative breast cancers with mutations in DNA repair genes such as ERCC1 or BRCA, to assess whether PARP inhibitors could increase this immune response.

When cancer cells with defective repair systems are treated with PARP inhibitors to block their remaining system of DNA repair, they can no longer repair any DNA damage so accumulate more and more DNA mutations until they die.

The researchers found that the accumulation of DNA damage in cancer cells treated with PARP inhibitors triggered the release of various molecular signals that have the potential to attract immune cells to the tumour, suggesting that treatment with PARP inhibitors could enhance the immune response against these cancer cells.

In one ERCC1-deficient cancer cell line, 24 out of the 50 signalling pathways that were activated after exposure to PARP inhibitors were related to the immune system.

The scientists found that PARP inhibitors could potentially be used to treat lung cancers with faults in their DNA repair genes, in part because of these newly discovered effects on the immune system. By using PARP inhibitors alongside immunotherapy, this immune response could be further enhanced to kill the cancer cells more effectively.

As 30 to 50 per cent of patients with non-small cell lung cancer have a deficiency in the ERCC1 DNA repair system, this could open up a new, more effective ways of treating a large proportion of non-small cell lung cancer patients.

Study leader Professor Chris Lord, Professor of Cancer Genomics at The Institute of Cancer Research, London, said:

"The findings of this study substantially change our understanding of how PARP inhibitors work. We now know that they not only kill tumours by damaging their DNA, but also by attracting immune cells to attack them - acting as a sort of double-pronged attack.

"Immunotherapy is a genuinely brilliant cancer treatment but generally only for the 10 to 20 per cent of people who respond to it. Finding the tumour is half of the battle in immunotherapy so by attracting the immune cells to the tumour, PARP inhibitors could enable the immunotherapy drug to target their attack."

Study co-leader Dr Sophie Postel-Vinay, Clinician Scientist and Medical Oncologist at Gustave Roussy, France, and The Institute of Cancer Research, London, said:

"Our study found that PARP inhibitors enlist immune cells to aid in the killing of cancer cells. This provides a rationale for using PARP inhibitors alongside immunotherapies to further stimulate the immune response to cancer cells with DNA repair defects and enhance the therapeutic benefit of the treatment."

"This will be evaluated in a clinical trial of lung, prostate and bladder cancers, which is starting later this year."

Dr Ian Walker, Director of Clinical Research at Cancer Research UK, said:

"This study highlights the important role that research in the lab plays in helping us devise new clinical trials. Identifying new combinations that make cancer drugs more effective could open up many new treatment options for patients with cancers that are hard-to-treat, like lung cancer. This is an exciting development and we look forward to seeing if PARP inhibitors can improve survival for these patients."

Dr Kotryna Temcinaite, Research Communications Manager at Breast Cancer Now, said:

"These are really promising findings that show once more just how important PARP inhibitors could be in treating a number of cancers. Not only do these drugs interfere with tumour cells' ability to repair DNA but this study suggests they may have additional effects in initiating an immune response, which could then be exploited using other treatments.

"Activating the immune system to attack tumours is an exciting approach that is beginning to show promise in breast cancer. We now look forward to seeing how the combination of PARP inhibitors and checkpoint inhibitors may work in clinical trials for breast cancer patients."

WASHINGTON--Researchers will explore the link between unhealthy snack intake and screen time, long-term opioid use and its impact on men's testosterone levels, and other emerging science during news conferences at ENDO 2019, the Endocrine Society's annual meeting taking place March 23-26 in New Orleans, La.

The Society is debuting two new Clinical Practice Guidelines at the news conferences, which will be webcast at endowebcasting.com.

News Conference Schedule:

Saturday, March 23

Diabetes (8:30 a.m. CDT): The Society is unveiling its new Clinical Practice Guideline on treating older adults with diabetes. Researchers will also discuss how many older adults with type 1 diabetes are unaware of when they have low blood sugar, the technical challenges with implementing a new hybrid closed loop insulin pump (the precursor to the artificial pancreas), and how the hemoglobin A1c (HbA1c) test misses many cases of diabetes.

Reproductive Health (11 a.m. CDT): Studies will highlight the correlation between improved PCOS symptoms and healthy gut bacteria, long-term opioid use and hormone deficiencies, and how repeat miscarriages may be caused by sperm DNA damage.

Sunday, March 24

Obesity (10 a.m. CDT): This press conference will examine the hormone oxytocin and its ability to weaken the brain's reward signals for food, a hormone released from fat tissue and how it may play a role in obesity-related asthma, exposure to HIV before birth and its link to obesity later in life, and why teens who sit for hours in front of the TV while eating unhealthy snacks are at increased risk for heart disease and diabetes.

EDCs (11:30 a.m. CDT): The EDC experts in this news conference will present research on chemicals in household dust and fat cell development, and how exposure to the widely used chemical bisphenol A (BPA) during pregnancy can alter circadian rhythms.

Monday, March 25

Aging (8 a.m. CDT): The Society is debuting a new Clinical Practice Guideline for treating osteoporosis in postmenopausal women. Researchers will also cover older men with higher levels of sex hormones and why they have a lower biological age, how changing when you eat may prevent postmenopausal breast cancer, and why walking downhill after meals may have a positive effect on bone health in postmenopausal women.

Reporters may register for the meeting at: https://www.xpressreg.net/media/start.php?sc=ENDO0319.

Reporters also may register to view live news conference webcasts at: endowebcasting.com.

More information about media resources at ENDO 2019 is available at http://www.endocrine.org/news-room/endo-annual-meeting.

Registered news media receive a badge that provides access to all meeting sessions, as well as to the newsroom and news conferences. No one will be admitted without a valid ENDO badge.

New research suggests two-thirds (67%) of pregnant women in London aged between 16 and 24 years have mental health problems including depression, anxiety disorders, post-traumatic stress disorder and obsessive compulsive disorder, according to new research funded by the National Institute for Health Research (NIHR). Anxiety disorders, in particular social phobia, are especially high.

By comparison, the research suggests roughly one in five (21%) pregnant women in London aged 25 years and over have mental health problems.

Researchers from Institute of Psychiatry, Psychology & Neuroscience at King's College London recruited 575 women through their first antenatal appointment with an inner-city London maternity service. Of this group, 57 women were aged between 16 and 24.

All women were interviewed using a psychiatric gold standard diagnostic interview to determine if they met the criteria for one or more mental health condition. The researchers also recorded information about their socio-demographic background, such as ethnicity, educational level and employment status.

According to the research, published today in BJPsych Open, pregnant women under 25 were also more likely to be non-white, single, living in poverty, homeless or living in emergency accommodation, unemployed, or have an unplanned pregnancy.

The rate of lifetime abuse was high (38.9%), with rates of sexual abuse at 20.6% and partner abuse at 19.5%. The researchers note that this is probably an under-estimate, as abuse is often under-reported. Experience of abuse and living alone were both risk factors for mental health problems in this group.

Lead author Dr Georgia Lockwood Estrin, Senior Research Associate at King's College London, said: "We've shown a shockingly high prevalence of mental disorders in young pregnant women aged 16 to 24 years in London compared with women aged 25 years or older. We found that, in comparison to previous research has focused primarily on postnatal depression, young women experience a broad range of mental disorders during early pregnancy, with anxiety disorders being particularly prevalent."

The researchers particularly highlight that the high risk for mental disorders is not limited to pregnant teenagers, as may have been suggested by previous research, but remains high for women in their early 20s.

The research suggests that more could be done to target perinatal mental health services at women aged under 25. This aligns with the recent NHS Long Term Plan and NHS Five Year Plan* to ensure that by 2023/24 at least 54,000 more women each year can access evidence-based specialist mental health care during the perinatal period.

Prof Louise Howard, senior author on the paper and NIHR Research Professor in maternal mental health at King's College London, said: "We were alarmed to see such high rates of mental illness in pregnant women under 25. The recent National Well-Being Survey and other studies have highlighted that around one in four women under 25 have self-harmed and/or have mental illness, higher than in previous surveys, but our study suggests that pregnant women under 25 are at even higher risk of mental disorders.

"This study needs to be repeated as it is based on relatively small numbers of women in a particular area of London, but our findings highlight the need for maternity services to ensure pregnant women under 25 are comprehensively assessed for mental health problems and domestic or sexual abuse so they can receive appropriate treatment and help."

An estimated 15 to 20 percent of all breast cancer patients are "triple negative." These unfortunate women lack three crucial treatment targets--the estrogen receptor, the progesterone receptor and human epidermal growth factor receptor 2. Because they lack these targets, most triple negative patients are treated with standard chemotherapy, rather than the preferred targeted drugs. Triple negative breast cancer (TNBC) also disproportionately affects younger women, women of African descent and women with mutations in the BRCA1 gene.

The lack of better medicines for TNBC prompted a team of researchers to look for novel drug targets and new ways to disrupt disease-causing pathways. In the process, they found a pair of new weapons, two seasoned drugs that--when tested in mice--produced encouraging results.

"We think we may have found a way to treat resistant breast cancers that currently have no targeted therapy by repurposing two older drugs, metformin and heme, that are already in the marketplace," said the study's senior author Marsha Rosner, PhD, the Charles B. Huggins Professor in the Ben May Department for Cancer Research at the University of Chicago.

Neither drug was designed to treat cancer. Metformin, discovered in 1922 and used clinically since 1957, was developed to treat type-2 diabetes. It decreases glucose production by the liver and increases insulin sensitivity. In 2016, it was the fourth most prescribed medication in the United States, with more than 81 million prescriptions.

Although cancer is more common in patients with diabetes than in healthy controls, patients who take metformin for diabetes are less likely to develop cancer. The drug has a direct anti-cancer effect that can repress the proliferation of tumor cells.

The other drug, heme, marketed as panhematin, is older still. It was first crystallized from blood in 1853. It is now used to treat defects of heme synthesis. These defects can cause porphyrias, a group of eight related ailments. Many of these patients are treated with injections of panhematin, derived from processed red blood cells.

"To our knowledge," Rosner added, "this is the first joint use of these two drugs. We think we have elucidated a new mechanism, something basic and fundamental, and found ways to use it."

The researchers found that the primary anti-cancer target for heme is a transcription factor known as BACH1 (BTB and CNC homology1). This protein is often highly expressed in triple negative breast cancers and is required for metastasis. High BACH1 levels often lead to poor outcomes. Fortunately, BACH1 "is not essential," the authors note, "and therefore may be inhibited with few side effects."

BACH1 targets mitochondrial metabolism. It controls the rate of transcription of genetic information from DNA to messenger RNA by binding to a specific DNA sequence. This can suppress transcription of mitochondrial electron transport chain genes, a key source of cellular energy. When BACH1 is high, this energy source is shut down.

"We found we could basically put a thumb on this trouble-making BACH1 protein," Rosner said. "We can get rid of it. We can do that with heme. It's part of a normal process."

"When cancer cells are treated with hemin, BACH1 is reduced, causing BACH1-depleted cancer cells to change metabolic pathways," said co-author Jiyoung Lee, PhD, an instructor affiliated with the Rosner laboratory. "This causes cancers that are vulnerable to metformin to suppress mitochondrial respiration. We found that this novel combination, hemin plus metformin, can suppress tumor growth, and we validated this in mouse tumor models."

"We think we can reach three distinct populations of patients with triple negative breast cancer," added Joseph Wynne, MD, PhD, a clinical fellow in the Rosner lab. "Patients with low BACH1 and high mitochondrial gene expression would likely respond to metformin alone. For patients with high BACH1 and low mitochondrial gene expression, we would predict metformin resistance. However, our work suggests that the addition of heme treatment would sensitize them to metformin. The third group is somewhere in between. We are not quite sure of their level of metformin resistance, but anticipate that they would also respond to combination treatment with metformin and heme."

"Our results highlight BACH1 as a key regulator of mitochondrial metabolism and a determinant of TNBC response to metformin treatment," the authors wrote. "The role of BACH1 as a novel regulator of metabolism has not previously been recognized or studied. This study," they add, "will open new avenues for future investigation."

The findings, the authors note, could extend beyond breast cancer. BACH1 expression is enriched not only in TNBC but is seen in many cancers, including lung, kidney, uterus, prostate and acute myeloid leukemia. BACH1 inhibition of mitochondrial electron transport chain genes appears to be a common mechanism.

"We started with something that gave us insights into how cells generate energy and metabolize foods. That led us to novel ideas about how to treat resistant cancers," Rosner added. "How cool," she mused, "is that?"

PHILADELPHIA - When cancer spreads to another organ, it most commonly moves to the liver, and now researchers at the Abramson Cancer Center of the University of Pennsylvania say they know why. A new study, published today in Nature, shows hepatocytes - the chief functional cells of the liver - are at the center of a chain reaction that makes it particularly susceptible to cancer cells. These hepatocytes respond to inflammation by activating a protein called STAT3, which in turn increases their production of other proteins called SAA, which then remodel the liver and create the "soil" needed for cancer cells to "seed." The researchers show that stopping this process by using antibodies that block IL-6 - the inflammatory signal that drives this chain reaction - can limit the potential of cancer to spread to the liver.

"The seed-and-soil hypothesis is well-recognized, but our research now shows that hepatocytes are the major orchestrators of this process," said senior author Gregory L. Beatty, MD, PhD, an assistant professor of Hematology-Oncology at Penn's Perelman School of Medicine. Jae W. Lee, an MD/PhD candidate in Beatty's laboratory, is the lead author.

For this study, the team first used mouse models of pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer and currently the third leading cause of cancer death in the United States. They found that nearly all hepatocytes showed STAT3 activation in mice with cancer, compared to less than two percent of hepatocytes in mice without tumors. They then partnered with investigators at the Mayo Clinic Arizona and other Penn colleagues to show that this same biology could be seen in patients with pancreatic cancer as well colon and lung cancer. Genetically deleting STAT3 only in hepatocytes effectively blocked the increased susceptibility of the liver to cancer seeding in mice. The team collaborated further with investigators at the University of Kentucky to show that IL-6 controls STAT3 signaling in these cells and instructs hepatocytes to make SAA, which acts as an alarm to attract inflammatory cells and initiate a fibrotic reaction that together establish the "soil."

"The liver is an important sensor in the body," Lee said. "We show that hepatocytes sense inflammation and respond in a structured way that cancer uses to help it spread."

The study also found that IL-6 drives changes in the liver whether there's a tumor present or not, implying that any condition associated with increased IL-6 levels - such as obesity or cardiovascular disease, among others - could affect the liver's receptiveness to cancer. Researchers say this provides evidence that therapies which target hepatocytes may be able to prevent cancer from spreading to the liver, a major cause of cancer mortality.

Infants who are admitted to hospital with the common infection bronchiolitis are at increased risk of further emergency hospital admissions for asthma, wheezing and respiratory illness in the first five years of their life.

These are the findings of researchers from Imperial College London, who tracked 613,377 babies (almost all births in England between April 2007 - March 2008) up to the age of five years. Around 16, 000 babies were admitted to hospital with bronchiolitis before their first birthday.

Researchers found these children had up to a fivefold risk of emergency admissions to hospital with asthma, wheezing or a respiratory illness in the first five years of their life, compared with those who were not admitted for bronchiolitis.

The researchers found that one in five children admitted to hospital with bronchiolitis as a baby will have a subsequent emergency hospital admission for asthma, wheeze, or respiratory infections.

Dr Helen Skirrow, lead author of the research from the School of Public Health at Imperial, said: "We know that hospital admissions for bronchiolitis have been rising over recent years in England. Previous studies have suggested a link between the condition and an increased risk of conditions such as asthma, but this is the largest study to suggest a severe case of bronchiolitis can result in subsequent emergency admissions for asthma and other respiratory conditions. "

Dr Skirrow added: "An emergency hospital admission is incredibly stressful for children and their families, and also places a burden on hospitals. If we develop interventions to prevent the initial bout of bronchiolitis - we may also be able to reduce the number of subsequent emergency admissions."

Bronchiolitis is a common type of chest infection that affects around one in three children in their first year of life, most commonly babies between three and six months of age.

The condition causes the airways to become inflamed, triggering symptoms such as a fever, cough and wheezing. The majority of children get better on their own - however up to one in 20 (2-5%) will require hospital treatment if they develop more severe symptoms, such as breathing difficulties.

Most cases of bronchiolitis are caused by the respiratory syncytial virus (RSV) which is responsible for around 3.2 million hospital admissions every year worldwide. Although there is no treatment for bronchiolitis, children thought to be at risk of RSV infection, such as babies born prematurely, can be given a preventative treatment called palivizumab. There are also a number of RSV vaccines currently in development.

Many factors contribute to a baby's risk of being admitted to hospital for bronchiolitis and other respiratory illnesses. These include exposure to tobacco smoke inside the home, environmental factors (such as air quality) and whether a child was breastfed.

The team say this current finding, published in the journal Archives of Disease in Childhood, highlight the importance of preventing cases of bronchiolitis.

Professor Sonia Saxena, senior author and head of Imperial's Child Health Unit, added: "Having your baby admitted to hospital with a serious chest infection like bronchiolitis is a frightening experience for parents. Our study shows these children are at high risk of subsequent hospital admission for asthma and recurrent infections across the early years of life, so we should be doing all we can to prevent this happening. Health professionals should counsel parents about benefits of breastfeeding, avoid infant's exposure to tobacco smoke and raise parent's awareness of when and how to seek help for respiratory problems as their child develops during preschool years."

When analysing the findings the research team took into account infants with pre-existing conditions. The scientists say more work is still needed to investigate why bronchiolitis may be linked to subsequent respiratory problems such as asthma. One theory is the initial viral infection that caused bronchiolitis may alter the immune system's response, increasing the chance of subsequent asthma and wheezing. Or it may be that a baby remains exposed to the initial triggers of bronchiolitis, such as second-hand smoke or pollution, which subsequently triggers asthma or other respiratory conditions.

The team say the research also highlights the need to develop a vaccine against RSV, which would help prevent cases of bronchiolitis.

Dr Skirrow explained: "There are a number of trials underway at the moment developing an RSV vaccine that could either be given to new-borns or pregnant women. This work provides more evidence of the importance of investing in this research, and the effect it could have on children's long-term health."

Bundled payments have been touted as mechanisms to optimize quality and costs. A prior feasibility study evaluating bundled payments for screening mammography episodes predated widespread adoption of digital breast tomosynthesis (DBT). A new study, published online in the Journal of the American College of Radiology (JACR), explores an episodic bundled payment model for breast cancer screening that reflects the emerging widespread adoption of DBT.

"Bundled episodic payments are an important type of alternative payment model (APM) that incentivize cost savings within discrete episodes of care," said the new study's lead author Margaret Fleming, assistant professor of radiology and imaging sciences at Emory University. "More recent interest has been expressed in developing outpatient imaging-based cancer screening episodes."

In the earlier 2016 JACR study, Hughes and colleagues explored the feasibility of screening mammography as a potential bundle payment model. The claims data they used predated the implementation of Current Procedural Terminology (CPT) and Healthcare Common Procedure Coding System (HCPCS) codes to report digital breast tomosynthesis (DBT), and thus did not consider the potential impact of this emerging service on their proposed bundled prices. Since receiving approval from the US FDA in 2011, DBT has gained widespread acceptance.

In Fleming's large academic health system, screening mammography is performed at outpatient sites affiliated with four separate hospitals, which have all now since adopted DBT as part of routine screening. For this analysis, Fleming and colleagues focused on the two large hospitals that had no DBT capabilities in 2013, but which subsequently performed DBT routinely as part of their screening examinations in 2015 (2014 was a transition year for both).

"Excluding DBT, Medicare-normalized bundled prices for traditional breast imaging 364 days downstream to screening mammography are extremely similar pre- and post-DBT implementation- $182.86 in 2013; $182.68 in 2015," stated study senior author Richard Duszak, MD, FACR, professor and vice chair for health policy and practice in the department of radiology and imaging sciences at Emory University and senior affiliate research fellow at the Neiman Institute. "The addition of DBT increased a DBT-inclusive bundled price by $53.16--an amount lower than the $56.13 Medicare allowable fee for screening DBT but was associated with significantly reduced recall rates 13.0% versus 9.4%." Without or with DBT, screening episode bundled prices remained sensitive to bundle-included services and varied little by patient age, race, or insurance status.

Based on their findings, the authors concluded that non-DBT approaches to bundled payment models for breast cancer screening remain viable as DBT becomes the standard of care, with bundle prices varying little by patient age, race, or insurance status. Higher DBT-inclusive bundled prices, however, highlight the need to explore societal costs more broadly (eg, reduced time away from work from fewer recalls) as bundled payment models evolve.

DURHAM, NC - Researchers today presented results from the HPTN 071 (PopART) study at the annual Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle. The study examined the impact of a package of HIV prevention interventions on community-level HIV incidence in urban and peri-urban communities in Zambia and South Africa. Findings from HPTN 071 (PopART) show delivery of an HIV prevention strategy that includes offering in-home HIV testing to everyone, with immediate referral to HIV care, and treatment for people living with HIV based on prevailing in-country guidelines, can substantially reduce new HIV infections.

"We saw a highly significant 30 percent decrease in new HIV infections with a prevention strategy where HIV treatment was started according to in-country guidelines," said Richard Hayes, DSc, HPTN 071 (PopART). protocol chair and professor of epidemiology and international health at the London School of Hygiene and Tropical Medicine. "We did not see a similar reduction in new HIV infections with another strategy where universal HIV treatment was offered from the beginning of the study. Additional analyses are underway to explore the reasons for this finding."

The HPTN 071 (PopART) study involved more than one million people living in 21 communities in Zambia and South Africa, making it the largest HIV prevention trial to date. The study measured the effects of two HIV combination prevention strategies offering HIV testing to people in their homes annually, with linkage to HIV care and treatment at the local health facility for those living with HIV.

"Overall, both strategies improved knowledge of HIV status and uptake of treatment," said Wafaa El-Sadr MD, MPH, MPA, HPTN co-principal investigator, and professor of epidemiology and medicine at Columbia University in New York. "These findings show that a combination prevention strategy similar to PopART may be an effective tool to slow the global HIV epidemic."

HPTN 071 (PopART) researchers are currently examining the effects of the interventions on other study outcomes including herpes simplex virus-2 incidence, tuberculosis and HIV-related stigma. Work is also in progress to estimate the cost-effectiveness of the interventions.

"While the findings from the study are very encouraging, testing and treatment coverage fall short among young people and men necessitating the need for further research on how to fill these important gaps," said Sarah Fidler, MBBS, PhD, HPTN 071 (PopART) protocol co-chair and professor of medicine at Imperial College, London

The research team in Zambia was led by Helen Ayles, MBBS, PhD, director of research, Zambart, Lusaka, Zambia. The research team in South Africa was led by Nulda Beyers, MD, PhD, and Peter Bock, MD, PhD, MPH, research clinicians, Desmond Tutu TB Centre at Stellenbosch University, Cape Town, South Africa.

"The study team is deeply grateful to the South African and Zambian study participants, the implementing and community partners, research teams, Ministries and Departments of Health, study funders and sponsor, without whom this research would not have been possible," said Myron Cohen, MD, HPTN co-principal investigator and director of the Institute for Global Health at the University of North Carolina in Chapel Hill.

Scientists have shown for the first time that the brain is involved in the development of a heart condition called Takotsubo syndrome (TTS). They found that regions of the brain responsible for processing emotions and controlling the unconscious workings of the body, such as heart beat, breathing and digestion, do not communicate with each other as well in TTS patients as in healthy people.

The study is published in the European Heart Journal [1] today (Tuesday) and the researchers say that although, at this stage, they cannot show that the reduced brain functions definitely cause TTS, their findings suggest that these alterations in the central nervous system may be part of the mechanism involved and they are linked with the onset of TTS in response to stressful or emotional triggers.

TTS is known as "broken heart" syndrome and is characterised by a sudden temporary weakening of the heart muscles that causes the left ventricle of the heart to balloon out at the bottom while the neck remains narrow, creating a shape resembling a Japanese octopus trap, from which it gets its name. Since this relatively rare condition was first described in 1990, evidence has suggested that it is typically triggered by episodes of severe emotional distress, such as grief, anger or fear, or reactions to happy or joyful events. Patients develop chest pains and breathlessness, and it can lead to heart attacks and death. TTS is more common in women with only 10% of cases occurring in men. [2]

In an unusual example of collaboration between neuroscientists and cardiologists, researchers carried out MRI brain scans in 15 TTS patients taken from the InterTAK Registry, established at the University Hospital Zurich, Switzerland, in 2011 [3]. They compared the scans with those from 39 healthy people. The scans were performed between July 2013 and July 2014 and the average time between TTS diagnosis and the MRI scans was about a year.

Professor Christian Templin, principle investigator at the Registry and professor of cardiology at University Hospital Zurich, said: "We were interested in four specific brain regions that are spatially separate from one another but functionally connected, meaning they share information. We found that TTS patients had decreased communication between brain regions associated with emotional processing and the autonomic nervous system, which controls the unconscious workings of the body, compared to the healthy people.

"For the first time, we have identified a correlation between alterations to the functional activity of specific brain regions and TTS, which strongly supports the idea that the brain is involved in the underlying mechanism of TTS. Emotional and physical stress are strongly associated with TTS, and it has been hypothesised that the overstimulation of the autonomic nervous system may lead to TTS events."

The regions of the brain that the researchers looked at included the amygdala, hippocampus and cingulate gyrus, which control emotions, motivation, learning and memory. The amygdala and cingulate gyrus are also involved in the control of the autonomic nervous system and regulating heart function. In addition, the cingulate gyrus is involved in depression and other mood disorders that are common among TTS patients.

"Importantly, the regions we've identified as communicating less with one another in TTS patients are the same brain regions that are thought to control our response to stress. Therefore, this decrease in communication could negatively affect the way patients respond to stress and make them more susceptible to developing TTS," said Professor Templin.

A limitation of the study is that the researchers did not have MRI scans of patients' brains before or at the time they developed TTS, so cannot say for certain that the decreased communication between brain regions caused the TTS or vice versa.

Co-author, Dr Jelena Ghadri, a senior research associate at the University Hospital Zurich and co-principle investigator of the InterTAK Registry, said: "Our results suggest that additional studies should be conducted to determine whether this is a causal relationship. We hope this study offers new starting points for studying TTS in terms of understanding that it much more than 'broken heart' syndrome and clearly involves interactions between the brain and the heart, which are still not fully understood. We are at the beginning of learning more about this complex disorder. Hopefully, one day new findings can be translated into developments in preventive, therapeutic and diagnostic strategies to improve patient care.

"Of note, this study presents the results of a collaboration between neuroscientists and cardiologists. One problem in TTS research is that usually cardiologists only focus on the heart; we believe that approaching TTS in a multidisciplinary way might help to uncover the real nature and causes of this disease. The methods we used are mainly neuroscientific in nature, but the findings we uncovered are, in our view, of major importance for cardiologists in understanding TTS."

American smokers mistakenly think that using snus, a type of moist snuff smokeless tobacco product, is as dangerous as smoking tobacco, according to a Rutgers study.

The study, published in the April 2019 issue of the journal Addictive Behaviors, provides new research on what smokers think about snus, a Swedish style product that is popular in Scandinavia, but newer to the United States. Snus -- a Swedish word for "snuff" -- is a moist powder tobacco that can be sold in a loose form or in small prepacked pouches that users place under the top lip for about 30 minutes. It is typically spit free. About seven in 100 men use some form of smokeless tobacco in the United States, a figure the Centers for Disease Control and Prevention report is on the rise.

While smokeless tobacco products are addictive, contain cancer-causing chemicals and are linked with cardiovascular and certain cancer risks, products such as snus have comparatively fewer health risks than smoking when used exclusively -- not in tandem with smoking -- and may serve as harm-reduction alternatives for smokers unable or unwilling to completely quit tobacco. In Sweden, snus use has been linked to a decrease in tobacco smoking and smoking-related diseases.

The researchers reviewed how 256 smokers responded to questions about their perceived risk of developing lung cancer, heart disease and oral cancer from using snus versus cigarettes, and whether there were subgroups of smokers with similar patterns of beliefs. More than 75 percent of the participants smoked daily and about 20 percent had tried smokeless tobacco.

The researchers found that smokers fell into three subgroups based on their beliefs. About 45 percent perceived snus to be as harmful as smoking overall and for all three risks: lung cancer, heart disease and oral cancer. About 38 percent perceived that snus poses less risk for lung cancer and heart disease than cigarettes but had the same oral cancer risk as cigarettes, and another 17 percent accurately perceived snus to have lower risks for lung cancer but perceived risks for oral cancer and heart disease to be about the same as that from smoking. Almost 40 percent incorrectly perceived the risk of oral cancer to be higher from snus use than smoking.

"These findings continue to suggest that the public does not understand that combustion escalates the health risks in tobacco products that are smoked, making them more harmful than non-combusted smokeless tobacco on a continuum of risk," said lead researcher Olivia Wackowski, assistant professor of Health Behavior, Society and Policy at Rutgers School of Public Health and a member of the Rutgers Center for Tobacco Studies and Rutgers Cancer Institute of New Jersey. "They are also significant given that use of Scandinavian snus has not been clearly associated with oral cancer, unlike smoking, which poses a significant risk for oral cancer."

Quitting all tobacco is the best course of action. However, smokers who have not been successful in quitting or who do not want to quit tobacco entirely may be able to reduce their risks by learning about and switching to a product like snus, Wackowski said. However, this information can be challenging to communicate and is a key area for research work. It’s important for smokers to know that the reduced risks may come from completely switching over from smoking to snus use, and not using both products, she said. It’s also important that such messaging does not unintentionally encourage product initiation among non-users, especially youth.

CLEMSON, South Carolina -- By loading a chelation drug into a nano-sized homing device, researchers at Clemson University have reversed in an animal model the deadliest effects of chronic kidney disease, which kills more people in the United States each year than breast or prostate cancer.

When kidneys stop working properly, calcium builds up in artery tissue, leading to heart disease. Although nearly half a million Americans receive kidney dialysis, heart disease is the leading cause of death for people with chronic kidney disease.

"The findings are very exciting scientifically, but also for the thousands of patients who could potentially benefit from this technology one day," said Naren Vyavahare, the Hunter Endowed Chair and professor of bioengineering at Clemson and the principal investigator of the research.

Chelation, a method of removing metals such as iron and lead from the body, has been used experimentally for some people with heart disease. The therapy is not approved by the Food and Drug Administration, but the National Institutes of Health has sponsored two large-scale, multi-center studies using ethylene diamine tetra-acetic acid, or EDTA, as chelation therapy for people with heart disease.

In clinical studies, EDTA is included in an infusion that circulates through the body; it's systemic and non-specific. This method of chelation has shown good results in improving heart function, especially in diabetic patients, Vyavahare said. But EDTA infusion therapy is arduous (it requires 40 infusions over a period of a year), and it can cause side effects, including a depletion of calcium from the blood and from bone.

In 2014, Vyavahare's team proved a targeted approach is effective. In animals without kidney disease, they loaded nanoparticles with EDTA and special antibodies that recognize and latch onto damaged elastin to deliver the therapy directly to arterial sites damaged by calcification.

Now, in a paper published Feb. 22, 2019, in Scientific Reports, a Nature publication, Vyavahare's team members describe how they developed an animal model that mimics a human's chronic kidney disease. Animals were treated with EDTA infusions like in the NIH human trials and with EDTA enclosed in a nanoparticle coupled with an antibody that seeks out damaged elastin. In animals that received the targeted therapy, calcium buildup was destroyed without causing side effects. Moreover, the calcification did not come back up to four weeks after the last injection, even though other signs of chronic kidney disease were present.

"Dr. Vyavahare's work is extremely important for those of us who believe that calcium is not just a passive indicator of coronary disease, but also an active participant," said Gervasio Lamas, chairman of medicine and chief of cardiology at Mount Sinai Medical Center in Miami Beach, Florida. Lamas, principal investigator of the NIH-funded Trial to Assess Chelation Therapy 2, was not involved in the Clemson study.

"The potential with a targeted drug is enormous, and the methodology for targeting that Dr. Vyavahare has developed is unique," Lamas said.

Vyavahare and his co-authors wrote that in a previous study they showed that polyphenols, when delivered with nanoparticles, "regenerate degraded aortic elastin. Thus, there is an exciting opportunity of dual nanoparticle therapy to first remove calcium deposits using EDTA and then restore medial elastin layers with (polyphenols)."

Vyavahare has been studying elastin degradation and damages caused by calcification for nearly 20 years. He's director of the South Carolina Center of Biomaterials for Tissue Regeneration.

The nanoparticle delivery technology has been licensed by Elastrin Therapeutics, a startup company Vyavahare helped found. He serves as chief science officer of the company.

"With recent funding we received from NIH to carry out more studies on understanding how reversal of calcification works, and Elastrin Therapeutics Inc. licensing this technology from Clemson University, we believe we would be able to translate this approach for use in clinical trials within the next few years," Vyavahare said.

Each year in the United States, more than 600,000 children are seen in emergency rooms due to traumatic brain injury, a disruption to the normal function of the brain caused by a bump, blow or jolt to the head. Severe TBI results in approximately 7,000 childhood deaths annually, while survivors of the condition may suffer from long-term health conditions such as seizures, learning difficulty and communication disorders.

To help promote the highest standards of care, and improve the overall rates of survival and recovery following TBI, a panel of pediatric critical care, neurosurgery and other pediatric experts today issued the 3rd edition of the Brain Trauma Foundation Guidelines for the Management of Pediatric Severe TBI.

The updated guidelines reflect the addition of nearly 50 research studies, and include eight new, or revised, treatment recommendations for health care providers that range from the use of intracranial monitoring to the use of hypertonic saline to reduce acute brain swelling.

An executive summary of the guidelines published in the journals Pediatric Critical Care Medicine and Neurosurgery; the full guidelines are available via Pediatric Critical Care Medicine, an official journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.

"These guidelines are vital to the proper care and treatment of children with serious brain injury," said co-author and clinical investigator Nathan Selden, M.D., Ph.D., Campagna Professor and Chair of the Department of Neurological Surgery at the OHSU School of Medicine in Portland, Oregon. "Now, health care providers around the world will have access to the best medical evidence and recommendations to help save and improve countless lives."

An associated manuscript, also published in Pediatric Critical Care Medicine, describes an algorithm designed to guide first and second tier therapies for infants and children with severe TBI. The tool for bedside use by caregivers, which supplements evidence-based recommendations in the updated guidelines, was created using a validated, consensus-based expert opinion process.

"We believe a combination of research findings and real-life experience will further advance the bedside care of infants and children with severe TBI, especially in treatment scenarios where scientific and clinical research is lacking," said first author Patrick Kochanek, M.D., Grenvik Professor and Vice Chairman of Critical Care Medicine and Director of the Safar Center for Resuscitation Research at the University of Pittsburgh. "This algorithm will also help to identify key research priorities to help ensure the ongoing momentum of consistent, high-quality care for patients across the globe."

The original Brain Trauma Foundation Guidelines published in 2003 and were last updated in 2012. The 3rd edition was developed as part of the Brain Trauma Evidence-based Consortium based at the Stanford University School of Medicine. The Pacific Northwest Evidence-based Practice Center at OHSU managed the effort, which included experts from OHSU, the University of Pittsburgh, Boston Children's Hospital, Phoenix Children's Hospital, Children's National Medical Center, Seattle Children's Hospital, the University of Utah, the University of British Columbia, and Duke University.

A team of University of Central Florida researchers has overcome a long-standing problem in laser science, and the findings could have applications in surgery, drilling and 3D laser mapping.

Using the principle of supersymmetry, they have developed the first supersymmetric laser array. Their findings were published recently in the journal Science.

Supersymmetry is a conjecture in physics that says every particle of matter, such as an electron, has one or more superpartners that is the same except for a precise difference in their momentum.

"This is the first demonstration of a supersymmetric laser array that is promising to meet the needs for high power integrated laser arrays with a high-quality beam emission," said study co-author Mercedeh Khajavikhan, an associate professor of optics and photonics in UCF's College of Optics and Photonics.

Khajavikhan lead the team that developed the laser array, which is comprised of rows of lasers and is able to produce large output power and high beam quality.

This is a first array that consistently generates high radiance, as previous designs have resulted in degraded beam quality.

Khajavikhan said that earlier work by Demetrios Christodoulides, a Pegasus professor of optics and photonics, Cobb Family Endowed Chair in the college and study co-author, suggested the use of supersymmetry in optics and her team has explored it further in its studies.

"However, it is only recently that my group managed to bring these ideas in actual laser settings, where such notions can be fruitfully used to address real problems in photonics," she said.

The trick in her team's laser arrays is spacing lasers beside each other using calculations that take into account supersymmetry.

She said this development is very important in many areas that a high-power integrated laser is needed.

"We foresee many applications of supersymmetric laser arrays in medicine, military, industry and communications, wherever there is a need for high power integrated laser arrays having a high beam quality," Khajavikhan said.

One exciting application could be in the use of LIDAR, which uses lasers to survey and map 3D terrain and is used in fields such as self-driving cars, archaeology, forestry, atmospheric physics and more.

"LIDAR requires a high-power and high-beam quality laser," Khajavikhan said. "Currently, because of the lack of this type of lasers in integrated form, they use other kinds of lasers. The supersymmetric laser provides an integrated high-power laser solution that also shows high beam quality."

Researchers at American University have developed a new, highly sensitive rapid genetic test that can determine whether bacteria carries a gene that causes resistance to two common antibiotics used to treat strep throat and other respiratory illnesses. The scientists show that the new method works as accurately as culture-based methods but gives results in minutes, not hours or days. The research has been published in BMC Infectious Diseases.

The new rapid test developed by the AU team determines if a person harbors bacteria carrying the Macrolide efflux gene A, or mef(A), which causes resistance to two antibiotics: erythromycin and azithromycin. Azithromycin (also known as Zithromycin or a Z-Pak) is among those commonly used to treat strep throat and is one of the most highly prescribed antibiotics in the United States.

"The test is able to detect the gene within 10 minutes of assay run-time," said John R. Bracht, assistant professor of biology at American University and corresponding author on the study. "Standard antibiotic testing requires at least an overnight culture and often isn't performed in routine diagnostic work. Instead, physicians guess which antibiotic to prescribe based on past experience and recommendations, and patients have to return if the treatment fails. We simplified the process of detecting antimicrobial resistance so a physician can determine whether or not a patient will be resistant to a prescribed drug while that patient is still in the waiting room. We think this is a game-changer for treating common illnesses."

It's common knowledge in the medical community that there's widespread resistance in people to azithromycin and erythromycin, but in spite of that, the antibiotics are still used a lot in the treatment of strep throat and other respiratory illnesses, said the paper's lead author Megan M. Nelson, a graduate of AU's biotechnology master's program.

"Our rapid genetic test can help doctors better assign medication on site, and improve point-of-care diagnostics, potentially leading to better outcomes without having prescribed a patient a useless antibiotic," she added. "There's a lot of trial and error with antibiotic use, so this is trying to take out some of the error."

The rise of antibiotic-resistant bacteria is a growing problem in the United States and the world. In the U.S. annually, more than 2 million people get infections that are resistant to antibiotics and at least 23,000 people die as a result, according to the Centers for Disease Control and Prevention. The U.S. National Institutes of Health, CDC, World Health Organization, and United Nations have prioritized the issue. However, tracking antimicrobial resistance is a significant challenge, the researchers write in the paper, precisely because the available culture-based methods are so slow and expensive.

The new rapid test addresses this challenge, making tracking antibiotic resistance quick, easy, and routine. It offers scientific researchers a way to monitor the prevalence and movement of antimicrobial drug resistance. The next step for the AU team to getting the test into doctors' offices is to seek approval of the test from the U.S. Food and Drug Administration.

A U.S.-funded initiative to improve quality of care and referrals during pregnancy and childbirth in Indonesia resulted in significant reductions in maternal and newborn mortality at participating hospitals, according to a new study led by scientists at the Johns Hopkins Bloomberg School of Public Health.

The $55-million initiative, known as Expanding Maternal and Neonatal Survival (EMAS), was sponsored by the U.S. Agency for International Development (USAID) from 2011 to 2017 and supported the Indonesian Ministry of Health's efforts to improve the quality of emergency obstetric and newborn care and referrals in that country.

The study appears in a special supplement of the International Journal of Gynecology & Obstetrics. The researchers found that in the Indonesian health facilities where the EMAS intervention was implemented, maternal and very early newborn mortality rates within 24 hours of birth fell by 50 percent and 21 percent respectively over the four years following the onset of EMAS support.

"These key indicators of the quality of emergency obstetric and newborn care improved significantly at hospitals after EMAS support, suggesting that the program did improve the quality of care," says study lead author Saifuddin Ahmed, PhD, professor in the Bloomberg School's Department of Population, Family and Reproductive Health.

The study involved a collaboration with several international and Indonesian institutions including Jhpiego, a Johns Hopkins-affiliated non-profit organization that led the EMAS program in Indonesia.

Ahmed guest-edited the supplement, "Expanding Maternal and Neonatal Survival Opportunities in Indonesia," in which the study appears, and authored an editorial noting that Indonesia has had persistently high maternal mortality rates, relative to other Southeast Asian nations, of maternal and newborn deaths. More than 10,000 women and 68,000 newborn babies die from childbirth complications each year in the country. "Indonesia has been doing very well economically in recent decades, but economic development doesn't automatically translate into reductions in maternal and newborn mortality," he says.

About 70 percent of maternal deaths from childbirth complications in Indonesia occur in hospitals or clinics, in part due to poor quality or delayed care. The EMAS program was intended to improve that care and lower mortality rates for mothers and their newborns. The initiative was focused in six Indonesian provinces which collectively account for more than half of all maternal deaths in the country. The EMAS program included mentoring of staff at more than 450 hospitals and clinics, improvements in these facilities' health information systems, improving emergency readiness and response, and more rigorous reviews of cases of maternal or newborn mortality.

The new study focused on the largest 101 of these facilities, to which patients presenting at smaller clinics were often referred. Ahmed and his colleagues found that from 2013 through 2016, the overall rate of maternal deaths per 1,000 cases of childbirth complications at these facilities fell from 5.4 to 2.6, a drop of about 50 percent. The rate of newborn deaths within 24 hours of birth also fell sharply, from 4.8 to 3.3 per 1,000 live births, while the rate of newborn deaths within 7 days of birth fell from 33.6 to 23.9 per 1,000 live births.

The analysis revealed increases of 5 percent and 18 percent, respectively, in the appropriate uses of two key interventions: drugs to induce uterine contractions to reduce postpartum bleeding, and magnesium sulfate to treat pre-eclampsia, a condition that can cause seizures and brain hemorrhaging. By the end of the study, the use rates for these interventions, in cases where objective indicators showed they should have been used, were nearly 100 percent.

"Overall, the efficiency in handling patients seems to have improved in facilities that received EMAS support," Ahmed says.

Fatality rates--specifically from postpartum hemorrhage and pre-eclampsia/eclampsia complications--fell by about 23 percent and 20 percent, respectively, during the study period--although these declines involved relatively small numbers of cases and were not statistically significant.

"Sustaining and expanding the approaches of the EMAS program in Indonesia remains critically important to save the lives of mothers and children," Ahmed says.