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After nearly a decade of research, a new test that detects the magnetic properties of malaria-infected blood could soon be used to help eliminate the mosquito-borne disease.

Dr Stephan Karl, a Senior Research Fellow in Malaria and Vector Biology at James Cook University's Australian Institute of Tropical Health and Medicine, has led an international study to field-test a new tool in the fight to eliminate the disease, which had 229 million reported cases in 2019.

"Malaria is easily treated but it is actually hard to diagnose, and because of that there can be over-treatment, which we have seen can lead to the spread of drug-resistant malaria," Dr Karl said.

"Improving malaria diagnosis, especially through the development of practical methods for resource-limited places, is important and timely."

The international team including the University of Augsburg's Professor Istvan Kezsmarki, with the PNG Institute of Medical Research and the Burnet Institute, developed and tested the method called rotating-crystal magneto-optical detection (RMOD).

Dr Karl said malaria parasites break down blood in such a way that heme molecules in the blood assemble themselves into organic crystallites containing magnetic iron, which is detected by the RMOD method.

"I've studied the magnetic properties of malaria infected blood since 2006, and we engaged with Professor Kezsmarki's team in 2013 to demonstrate the sensitivity of this test using human malaria parasites," Dr Karl said.

Professor Kezsmarki said the success of the field study, which involved nearly 1000 suspected malaria patients in a high-transmission area of Papua New Guinea, was an exciting breakthrough.

"After years of in-lab optimisation of the device, in collaboration with Dr Karl we demonstrated the great potential of RMOD in fast and reliable malaria field tests performed in Papua New-Guinea," Prof Kezsmarki said.

"We showed that RMOD performs well in comparison to the most reliable existing method," he said.

"It's very promising, as RMOD testing can be conducted after a short training session and provides test results within 10 minutes. From a funding perspective the cost is very low since no expensive reagents are used," said Dr Karl.

He said the team aimed to refine the prototype device so that, eventually, performing a test would be as simple as pushing a button.

"There are other hurdles to overcome too, at the moment the RMOD has difficulty discriminating between current and previous malaria infections and we are working on a solution for this," said Dr Karl.

An international team of researchers has developed a framework for assessing brand reputation in real time and over time, and built a tool for implementing the framework. In a proof of concept demonstration looking at leading brands, the researchers found that changes in a given brand's stock shares reflected real-time changes in the brand's reputation.

"We've developed something we call the Brand Reputation Tracker that mines social media text on Twitter and uses 11 different measures to give us an in-depth understanding of how users feel about individual brands," says Bill Rand, co-lead author of the paper and an associate professor of marketing in North Carolina State University's Poole College of Management.

The Brand Reputation Tracker is a way of implementing a framework based on the Rust-Zeithaml-Lemon value-brand-relationship framework. Measures include things like "coolness," "goods quality," "social responsibility," and "trustworthiness," but are then aggregated into three scores: value driver, brand driver and relationship driver.

The value driver score effectively measures whether stakeholders think a brand is a good value. The relationship driver score assesses how closely stakeholders identify themselves with the brand. And the brand driver score accounts for pretty much everything else, such as style and popularity.

"The text mining allows us to give a numeric value to each of the measures and each of the driver scores," says Rand, who is also executive director of NC State's Business Analytics Initiative. "And we are able to place those numeric values in context by comparing them to the measures and aggregate scores of other brands."

Because social media data are updated constantly, the researchers were able to identify changes in brand reputation in real time - as well as looking at trend data across days, weeks, months and years.

For this paper, the researchers looked at 100 popular brands as a proof of concept, demonstrating not just how the tool works but that it works. For example, the researchers found that - for those brands that were publicly traded on the stock market - changes in value, relationship and brand driver score were reflected in each brand's stock valuation.

"One possible path forward is to significantly expand the dataset of brands that we're assessing to get a broader understanding of the brand landscape," Rand says. "And because we lay out the methodology we used, this paper allows users to create their own versions of the tool. For example, users could choose to look only at brands within a given industry category. Or users could modify the tool to focus on other aspects of brand, such as using a framework to assess the extent to which a brand is viewed as 'green' or 'sustainable.'"

Rand also notes that previous ways of assessing brand reputation in a meaningful way required either access to a tremendous amount of corporate data or the ability to survey thousands of people on a regular basis.

"But the approach we've developed here is more accessible to medium-sized businesses. It requires only the creation of the initial tool - which is very doable. Then you can plug in publicly available user data from Twitter and start getting usable brand assessment information in real time."

PHILADELPHIA (February 18, 2021) - With stressors mounting daily on the health care system due to the COVID-19 pandemic, a de-prioritization of the childbearing family has been noted. Their care has changed, resulting in mothers forced to go through labor and birth without their partners, parents barred from NICU visitation, and discharge of mothers and newborns early without enough expert lactation care. There is great concern that these changes in childbearing families' care may become permanent - to the detriment of the health of both mother and child.

In an article in the journal Frontiers in Pediatrics, an international group of medical professionals led by a University of Pennsylvania School of Nursing (Penn Nursing) researcher present global findings that illustrate concern. They explain how, during the pandemic, birth and breastfeeding experiences of families have not been prioritized and care has changed in ways that may negatively impact birth outcomes and the establishment of breastfeeding. They also explain the importance of changing these prenatal and post-birth practice paradigms to ensure that all families in need receive equal access to evidence-based lactation education, care and technical assistance.

"We must use the pandemic to underscore the importance of human milk and breastfeeding as lifesaving medical interventions," says Diane Spatz, PhD, RN-BC, FAAN, Professor of Perinatal Nursing and Helen M. Shearer Term Professor of Nutrition at Penn Nursing. "This is an opportunity for health care professionals to undertake a call to action to protect and prioritize human milk and breastfeeding."

HOUSTON -- The first randomized Phase II clinical trial to report on single and combined neoadjuvant immune checkpoint inhibitor therapy in stage I-III non-small cell lung cancer (NSCLC) found combination therapy produced a significant clinical benefit, as assessed by major pathologic response (MPR) rate, as well as enhanced tumor immune cell infiltration and immunological memory. Researchers from The University of Texas MD Anderson Cancer Center published the study results today in Nature Medicine.

The NEOSTAR trial tested combined neoadjuvant therapy of nivolumab plus ipilimumab, as well as neoadjuvant nivolumab monotherapy in patients with operable NSCLC. The trial met its prespecified primary endpoint efficacy threshold in the combination arm, with eight of 21 treated patients (38%) achieving major pathological response, defined as ?10% viable tumor at surgery. MPR has been shown to correlate with improved survival outcomes after neoadjuvant chemotherapy in NSCLC. The prespecified efficacy boundary for each treatment to be considered promising for further testing was six or more MPRs in 21 evaluable patients. With MPR in five of 23 treated patients (22%), monotherapy did not meet the efficacy boundary.

While combination immunotherapy has been approved for a subset of patients with metastatic NSCLC, this is the first randomized study to report on the role of combination checkpoint inhibitors for operable, early stage disease.

"More than 50% of patients with localized non-small cell lung cancer will relapse if treated with surgery alone. Adding chemotherapy produces only a modest improvement in overall survival, and it comes with toxicity," said Tina Cascone, MD., Ph.D., assistant professor of Thoracic/Head & Neck Medical Oncology and lead author of the study. "The results from our study with neoadjuvant combination immunotherapy are particularly encouraging in that we found that this dual treatment can induce higher pathologic responses and trigger immunological memory. This may translate into a reduced risk for tumor relapse in more patients with early stage non-small cell lung cancer."

Study design and secondary endpoints

The Phase II single-institution study enrolled 44 patients with surgically resectable stage IA to IIIA NSCLC between June 2017 and November 2018. The median age of trial participants was 66 years old, and 64% were male. Participants were 84% white, 9% Black and 5% Asian. Most participants had a history of smoking: 23% identified as current smokers and 59% as former smokers.

Patients were randomized to one of two treatment arms with immune checkpoint inhibitors prior to surgery: 23 received three doses of nivolumab alone and 21 received three doses of nivolumab plus one dose of ipilimumab. Each arm was compared against historical controls of neoadjuvant chemotherapy. Overall, 41 patients completed the planned three doses of therapies, 37 patients had surgery on trial and two patients underwent surgery off trial after additional therapies.

Among the 37 patients who had surgical resection on the study, the combination arm showed higher MPR rates (50% versus 24%) and fewer viable tumor cells at resection than monotherapy (a median of 9% versus 50%). Combination therapy also showed better pathological complete response rates than monotherapy (38% versus 10%). After a median follow-up of 22 months, median overall survival and lung cancer-related recurrence-free survival were not reached.

Toxicities were manageable overall, with no new safety concerns compared to known adverse event profiles of either drug. The median time to surgery was 31 days after the last dose of nivolumab. Some patients experienced nodal immune flare (NIF), or the appearance of nodal disease progression on radiographic imaging, which invasive node biopsy revealed to be immune cell infiltration rather than malignant disease.

Exploratory analyses reveal immune impact, potential biomarkers

In an exploratory analysis of resected tissues, investigators found -- and reported for the first time -- higher levels of immune cell infiltration in tumors treated with combination therapy, including an abundance of CD3+ and CD3+CD8+ T lymphocytes, tissue-resident memory and effector memory T cells. Tumors that responded better to treatment had higher PD-L1 expression at baseline, but responses were also observed in those without PD-L1 expression in tumor cells.

The researchers analyzed the gut microbiome, as well, and found that pathologic response to combination therapy was associated with the presence of certain fecal microbes that also have been correlated with immunotherapy response in melanoma and other cancers. Immune checkpoint inhibitor therapy did not significantly affect the diversity or composition of the microbiome in this study.

"Our exploratory results suggest the gut microbiome may play a role in responses to neoadjuvant immune checkpoint inhibitors in lung cancer," Cascone said. "The immune microenvironment findings also give us an opportunity to look at immune cell populations and potential biomarkers that can be evaluated in the future to identify those patients who are most likely to benefit from these agents in new prospective trials."

The NEOSTAR trial has been amended to a modular platform design, which provides the opportunity to add treatment arms to rapidly test and advance promising new neoadjuvant therapeutic combinations. Results from a third arm testing neoadjuvant nivolumab plus chemotherapy are expected later this year. A fourth arm testing the combination of dual immunotherapy plus chemotherapy is ongoing.

"The NEOSTAR trial results set the stage for evaluating the role of dual immunotherapy added to neoadjuvant chemotherapy, which we are currently exploring, and expediting the investigation of novel agents in the perioperative setting," Cascone said. "This is a population with potentially curable disease. We should do whatever it takes to minimize the risk of relapse and increase the cure rates for these patients."

UCLA RESEARCH ALERT

FINDINGS

UCLA Jonsson Comprehensive Cancer Center researchers have uncovered a potential new way to target pancreatic tumors that express high intratumoral interferon signaling (IFN). The team found that high type I IFN signaling is present in a subset of pancreatic tumors and it triggers a decrease in the level of NAD and NADH in pancreatic cancer cells, which are vital cofactors in critical metabolic processes.

After the researchers delineated the mechanism by which the NAD depletion occurs, they demonstrated that cells with high IFN signaling were more sensitive to NAMPT inhibitors, which inhibit a major pathway in NAD synthesis. Based on this mechanism, recently developed second-generation NAMPT inhibitors could potentially be used in combination with new systemic drugs, called STING agonists, which increase type I IFN signaling. When tested in mice, the combination of IFN signaling and NAMPT inhibitors not only decreased pancreatic tumor growth, but also resulted in fewer liver metastases.

"With the advent of these two new and improved therapeutics, our findings are timely as their combination may sensitize tumors to NAD depletion," said lead author Dr. Alexandra Moore, a resident physician in the department of surgery at the David Geffen School of Medicine at UCLA.

BACKGROUND

Pancreatic cancer continues to be one of the most difficult cancers to treat. One of the hallmarks of the disease is its extensively reprogrammed metabolic network. All cells, including cancer cells, have the need to transform nutrients from the environment into building blocks for cellular processes and many of these processes require NAD or NADH as a vital cofactor. This research focused on harnessing IFN-induced NAD depletion in combination with the inhibition of NAD synthesis to develop new approaches to better treat pancreatic cancer.

METHOD

The team first used cell lines and cell culture to determine the mechanism of NAD depletion induced by IFN signaling by looking at the mRNA levels of NAD-consuming enzymes after treatment with IFN. There was an increase in mRNA levels as well as protein expression of PARP9, PARP10, and PARP14. After confirming the findings, the team translated the research into an in vivo model. Researchers used two different mouse models and injected cancer cells into the pancreas of mice prior to treatment.

IMPACT

The findings provide evidence that if tumors with high IFN signaling can be identified, or if IFN signaling can be amplified in tumor cells, those tumors may have greater sensitivity to treatment with NAMPT inhibitors. If so, the combination could potentially help improve the prognosis for one of the most difficult cancers to treat.

"This is a study that identifies a potential vulnerability created by type I IFNs in pancreatic cancer that can be leveraged for what appears to be an effective therapeutic strategy," said senior author Dr. Timothy Donahue, professor of surgery and chief of surgical oncology.

A recent study by University of Alberta cardiologists at the Canadian VIGOUR Centre shows that a particular group of patients with stable ischemic heart disease have better outcomes with percutaneous coronary intervention (also called angioplasty with stent) or coronary artery bypass surgery and medication, versus conservative management with medication alone.

In a study published in the Journal of the American Heart Association, associate professor of medicine and academic interventional cardiologist Kevin Bainey and his team reviewed the patient information of more than 9,000 Albertans with stable ischemic heart disease. While able to function as outpatients, these patients had arteries in the heart that had narrowed and were restricting blood supply. They also had other heart issues--referred to as high-risk cardiac anatomy--including blockages in important locations of the heart's blood vessels, or restriction in the left main artery of the heart.

The data showed that in patients with both stable ischemic heart disease and high-risk cardiac anatomy, coronary revascularization (stents or bypass surgery) led to better health outcomes, including a reduction in the risk of death or heart attack, than a more conservative approach. As well, after one year, the risk of death was 2.7 per cent for patients with revascularization versus 6.8 per cent for those without.

"We strongly believe coronary anatomy is an important prognostic indicator of health outcomes," said Bainey, who is also director of the Adult Cardiac Catheterization and Interventional Cardiology Laboratory and the Interventional Cardiology Fellowship Program. "In a patient who has a higher-risk stress test and is showing symptoms, we think it's valuable to perform a coronary angiogram to get a complete picture, rather than just managing them with medications."

Bainey's study builds on the landmark ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial, published in April 2020, which showed that in patients with stable ischemic heart disease, an invasive approach such as stents or bypass surgery did not reduce the risk of death or future coronary events in following years.

While Bainey said he agrees there is a role for conservative management in these patients, high-risk anatomy was not addressed in the ISCHEMIA trial. This prompted him to investigate further, to find out whether Alberta patients with high-risk anatomy might actually benefit from invasive approaches.

"What our results are saying is that medical management is important, but there might be a small group that would benefit from revascularization, and we need to find ways to identify that group of patients," he said.

The results of his study also underline the importance of cardiac anatomy in determining a diagnosis and treatment options--something Bainey hopes more cardiologists will take into consideration when treating patients with stable ischemic cardiac disease.

"The main message I want clinicians to know is that it's important to know the anatomy," Bainey said. "Whether they decide to do a CT scan or send patients for an angiogram, you have to define that anatomy and then make the decision for revascularization or not."

Researchers from Dana-Farber Cancer Institute, the U.S. Food and Drug Administration (FDA) and the American Association for Cancer Research (AACR) are releasing recommendations designed to address the under-representation of African Americans in clinical trials for multiple myeloma (MM), a blood cancer that is twice as deadly in this demographic as in whites.

The initiative, publishing today in the AACR journal Blood Cancer Discovery, is a "road map" for designing myeloma clinical trials to eliminate racial bias by including more African American patients, as well as gathering "real-world" data from health records about the effects of drugs in African American patients. Through this joint workshop initiated by the FDA and AACR, a cohort of researchers, physicians, patients, statisticians, the pharmaceutical industry and regulators reviewed existing issues with the goal of improving effectiveness of MM therapies in African Americans.

Multiple myeloma is diagnosed in about 30,000 people in the United States annually, resulting in more than 12,500 deaths. African Americans are more than twice as likely as whites to be diagnosed with myeloma - 15.9 vs 7.5 cases per 100,000 population - and to die from the disease - 5.6 vs 2.4 myeloma deaths per 100,000 for African Americans compared with whites.

Although the disease is not presently curable, an array of new treatments in recent years has generally improved outcomes for myeloma patients. It is concerning, however, that data from large multiple myeloma clinical trials shows a decrease in enrollment of African Americans by 3.5% over a recent 10-year period, and even more critically, most racial and ethnic minority patients participated in trials that did not involve novel agents."There hasn't been as much progress in African Americans as there has been in other groups," says Dana-Farber Cancer Institute's Kenneth C. Anderson, MD, the corresponding author of the study and program director of the Lebow Institute for Myeloma Therapeutics and the Jerome Lipper Multiple Myeloma Center. "The number of African Americans enrolled in clinical trials of novel agents or treatments of multiple myeloma has been tragically low. When they have enrolled, their outcome to treatment with novel therapies has been the same or even better than other patients," he said.

African Americans comprise 20% of people diagnosed with myeloma, but between 2003 and 2017 only 4.5% of patients in new drug and biological license applications for myeloma were African American. This disparity has raised concerns that the findings of therapeutic clinical trials may not be entirely valid for African Americans, due to underlying genetic and biological differences that have been discovered between African American and white myeloma patients.

The new recommendations emerged from a February 2020 workshop in Washington D.C. which was co-chaired by Nicole Gormley, MD and Lola Fashoyin-Aje MD, MPH from the FDA, as well as Anderson, who heads the Regulatory Science and Policy Subcommittee of the AACR. The group recommended a number of changes to the design of clinical trials of drugs for which manufacturers are seeking approval. They included:

Broadening eligibility criteria whenever possible. For example, study criteria that reject patients with conditions like high blood pressure and kidney disease may disproportionately exclude African Americans. Including such patients may allow researchers to collect more data in racial and ethnic subpopulations.

Requiring trial sponsors to complete a diversity study plan that sets targets for enrolling diverse participants.

Appointing a diversity officer to assist with trial design and recruitment. Trial design should encompass disease subtypes and features most commonly seen in African Americans. Patients and patient advocates involved in the workshop strongly supported the recommendation of a diversity officer "to define strategies that support African American participation in clinical trials." The presence of a diversity officer "will hold researchers and industry accountable to conduct more inclusive and patient-centric trials," the recommendations stressed.

Other recommendations concerned gathering clinical trial data in the post-approval period. Studies conducted after the drug has entered clinical use could identify differences among racial and ethnic subpopulations with regard to safety and efficacy.

The recommendations also seek to increase diversity by directing stakeholders to devise strategies to overcome clinical, social, and socioeconomic impediments to trial access.

Anderson emphasized the importance of myeloma patients' participation in the workshop that formulated the recommendations.

"Our patients are truly the inspiration and heroes of this collaborative effort to eliminate the glaring issue of racial disparities in clinical trials," he said. "If we can make clinical trials more inclusive and representative of real-world patients, we may not only enhance participation of African American patients, but also provide a paradigm for new drug development more broadly."

Researchers have published new insights into the causes of mortality in sepsis

Loss of endothelial function is induced through two different pathophysiological processes and is a major driver of septic shock, a life-threatening drop in blood pressure

The first pathway originates in the loss of the endothelial barrier triggering an increased production of the repair hormone bioactive Adrenomedullin (bio-ADM), which also has the undesired side effect of vasodilation

The second threat acting on the endothelial function is the release of the protease DPP3 into the bloodstream which degrades angiotensin II, a process resulting in decreased vascular tone and cardiac output

The different pathways require different treatment strategies thus opening new approaches for personalized medicine in sepsis

New diagnostics for quantification of bio-ADM and DPP3 are available as laboratory and near-patient rapid tests

Biomarker-guided approaches for therapies targeting these pathways are showing promising results

Hennigsdorf/Berlin, Germany, February 18, 2021 - Diagnostics company SphingoTec GmbH (SphingoTec) announced today that two distinct processes are involved in the development of septic shock and that SphingoTec's biomarkers for endothelial function (vascular integrity) and cardiovascular depression allow early identification of these underlying mechanisms requiring different interventions. Sepsis, a global burden with nearly 50 million cases worldwide, is a life-threatening condition that is diagnostically and therapeutically underserved. With the availability of such pathway-specific biomarkers, new avenues for diagnosing and monitoring sepsis are opened and biomarker-guided trials for personalized therapies targeting these mechanisms are enabled.

Researchers have summarized the available evidence (1) on two distinct pathophysiological processes leading to endothelial dysfunction and the subsequent development of shock and organ failure in sepsis. The two biologically active molecules acting on the vasculature and influencing patient outcomes are bioactive Adrenomedullin (bio-ADM) and Dipeptidyl peptidase 3 (DPP3). One distinct pathway originates in the loss of endothelial barrier integrity, causing edema and the loss of intravascular volume. To compensate for this leakage, the production of the repair hormone bio-ADM is increased. But bio-ADM has also the second function of vascular relaxation, therefore the increased production leads to a dangerous side effect of vasodilation, generating a loss of tissue resistance which ultimately culminates in shock. Data from the observational study AdrenOSS-1 show (3) that elevations of bio-ADM levels reflect the loss of endothelial function and translate into poor outcome in sepsis. Furthermore, the results of the biomarker-guided AdrenOSS-2 trial (2) confirm that this pathway is a valid therapeutic target. According to the second underlying mechanism accountable for the loss of the endothelial function, the depletion of angiotensin II affects the renin-angiotensin-aldosterone system (RAAS), ultimately leading to a cardiovascular depression (4,5) and reduced vascular tone, a deadly combination in need of selective treatment strategies. The main process generating the depletion of the cardiovascular stimulating hormone angiotensin II is the release of the protease DPP3 into the bloodstream through sepsis-induced cell damage (6).

Personalized medicine has shown significant progress in areas such as oncology or cardiology, but in intensive care units, it has remained challenging to identify biomarkers that facilitate personalized treatments. In the context of a life-threatening condition such as septic shock, taking therapeutic decisions is time-critical, aiming to respond in the best possible way and especially on a patient-specific basis. The review (1) summarizes that the biomarkers bio-ADM and DPP3 can identify these pathways, supporting an early and precise diagnosis and monitoring of sepsis patients. Moreover, data from the biomarker-guided interventional study AdrenOSS-2 show that clinical trials can benefit from the use of biomarker as an enrichment strategy. Within the AdrenOSS-2 study, patients with sepsis-associated endothelial dysfunction were identified by increased bio-ADM to receive therapy with placebo or Adrecizumab (2), an antibody targeting the loss of vascular integrity by maintaining protective bio-ADM concentrations in the blood. When excluding patients with additionally high DPP3 blood concentrations, outcomes could further be improved. Therapies blocking DPP3-activity have also been shown to improve outcomes in various preclinical models. (7)

Dr. Andreas Bergmann, founder of various companies fighting sepsis mortality and CEO of critical care diagnostics company SphingoTec commented: "Following a deep understanding of the disease biology, we have developed diagnostic solutions that can now unravel the etiology of the mortality drivers in sepsis. The evidence confirms the utility of our biomarkers in supporting clinicians make more informed decisions and ultimately improve patient management. "

The new diagnostics for quantification of bio-ADM and DPP3 are available as microtiter plate assays as well as point-of-care tests on the Nexus IB10 immunoassay platform. The Nexus IB10 analyzer provides test results on whole blood samples in only 20 minutes and can be flexibly deployed in emergency departments, intensive care units, and any laboratory setting.

Despite being one of the world's most charismatic species, tigers face uncertain futures primarily due to habitat fragmentation, human-wildlife conflict and poaching. As global tiger populations decline, so does their genetic diversity. But until now it's been unclear how the animals' dwindling numbers are affecting them at the genetic level.

To find out, researchers at Stanford University, the National Centre for Biological Sciences, India, and various zoological parks and NGOs sequenced 65 genomes from four of the surviving tiger subspecies. Their findings confirmed that strong genetic differences exist between different tiger subspecies but showed, surprisingly, that these differences emerged relatively recently, as Earth underwent a major climatic shift and our own species grew increasingly dominant.

The research, detailed in a new paper published this week in the journal Molecular Biology and Evolution, shows how genomics can help guide conservation efforts toward wild tigers and other species, said study co-leader Elizabeth Hadly, the Paul S. and Billie Achilles Professor in Environmental Biology in the School of Humanities and Sciences.

"The increasing dominance of humans across the world means that our understanding of which attributes of species and populations are best suited to the Anthropocene becomes ever more important," said Hadly, referring to the proposed geological epoch marked by significant human impact on the environment.

"Some populations are well adapted to a future dominated by humans and our new climates and others are not, so any type of management of species should be informed by what we can glean from their genomes," added Hadly, who is also a senior fellow at the Stanford Woods Institute for the Environment. "Conservation genomics is far from a perfect science, but this tiger study hints at the power of adequate sampling across both the species range and its genome."

The study reveals that the world's existing tiger subspecies began exhibiting signs of dramatic and recent contractions starting only around 20,000 years ago - a period that coincided with both the global transition out of the Pleistocene Ice Age and the rise of human dominance in Asia. Each subspecies of tiger the team studied showed unique genomic signatures as a consequence of their increasing isolation from one another.

For example, local environmental genomic adaptation to cold temperatures was found in the Siberian (or Amur) tigers, the northernmost tigers found in the Russian Far East. These adaptations were absent in the other tiger subpopulations studied. Tigers from Sumatra, meanwhile, showed evidence of adaptations for body size regulation, which could help explain their overall smaller size. Despite these adaptations, tigers from these populations have low genetic diversity, suggesting that if populations continue to decline, genetic rescue may need to be considered.

One form that rescue might take is through the mating of different tiger subspecies together as a way of increasing their genetic diversity and protecting against the ill effects of inbreeding. Inbreeding occurs when populations are so small and isolated from other populations that related individuals breed with each other. Over time, this leads to lower genomic diversity and to the emergence of recessive diseases, physical deformities and fertility problems that often result in behavioral, health and population declines. Although increasing genetic diversity is one goal, another might be to select for inherited traits that confer higher survival in a changing world.

Even Bengal tigers from India, which comprise about 70 percent of the world's wild tigers and exhibit relatively high genomic diversity compared to other subspecies, showed signs of inbreeding in some populations, the study concluded.

"Some Bengal tiger populations are essentially small islands surrounded by an inhospitable sea of humanity. These tigers cannot disperse and so have only their close relatives to choose as mates," Hadly said.

While many studies investigating endangered species using genomics sequences from a single or just a few individuals, this work reiterates that individuals are not likely to be representative of a population or species status. Further work investigating the consequences of potential inbreeding and diversity declines across the subspecies are needed.

"As genomics has become available to conservation, it is apparent that collaborative studies to investigate the diversity within species are critical," said study first author Ellie Armstrong, a Stanford PhD student in Hadly's lab. "Inferences made from single genomes, while excellent additions to our knowledge of diversity in general, cannot be extrapolated to entire species, especially when using captive animals to infer adaptation to complex habitat change."

African Americans have higher rates of prostate cancer and are more likely to die from the disease than other groups in the United States, likely due to socioeconomic factors, healthcare access problems, and tumor biology. A new review published in Cancer Reports focuses on the biological differences in the development of prostate cancer across ethnicities.

The authors note that these differences could be leveraged to improve the diagnosis and treatment of prostate cancer in African American men, ultimately reducing incidence and mortality rates associated with the disease.

"We provide a comprehensive review of the significant research in recent years that has examined the molecular and genomic reasons for unequal cancer burden in African American and Caucasian American populations and acknowledge the challenges that lie ahead," said senior author Ashutosh K. Tewari, MD, of the Icahn School of Medicine at Mount Sinai. "This article provides specific guidelines for managing prostate cancer in African American men based on their disease's biology and makes a significant contribution to the ongoing national effort to improve African American men's outcomes from prostate cancer."

"Understanding the specific biology of prostate cancer in African American men and integrating clinical and genomic data will enable a 'precision medicine' approach to treating African American men and contribute to the ongoing efforts to improve outcomes in this population," added co-author Sujit S. Nair, PhD.

In an analysis of information on 448 patients with heart failure who were discharged from a hospital in Sweden, 20.3% of patients were readmitted to the hospital within 30 days, and 60.9% were readmitted within 1 year. The ESC Heart Failure analysis found that most of the patients who needed to be rehospitalized were readmitted for heart failure.

Patients who were readmitted were more likely to have kidney dysfunction, lung disease, and psychiatric illness than patients who were not readmitted.

"By targeting high-risk heart failure populations for hospital readmission and directing appropriate interventions towards these patients, many hospital readmissions should be preventable," the authors wrote.

February is American Heart Month.

A new study published in the Journal of Bone and Mineral Research has identified various factors that may indicate whether a person faces a higher likelihood of experiencing a bone fracture over the next two decades.

The study included 30,446 middle-aged women and men who were followed from the early/mid 1990s to 2016. A total of 8,240 participants (27%) had at least one fracture during a median follow-up of 20.7 years.

Older age, female sex, higher body mass index, a previous fracture, a family history of fracture after the age of 50 years, low leisure-time physical activity, heavy work, living alone, smoking, and no or high alcohol consumption were factors independently associated with a greater likelihood of experiencing a fracture. "Our results emphasize the importance of these factors in public health initiatives for fracture prevention," the authors wrote.

EUGENE, Ore. -- Feb. 18, 2021 -- An abnormal suppression of the immune system linked to the onset of numerous diseases has been associated with poor functional regeneration of traumatic bone injuries.

Levels of immune cells and proteins circulating in the blood following traumatic injury combined with advanced data analytics could predict whether patients are likely to respond to treatment, said Robert Guldberg, executive director of the Phil and Penny Knight Campus for Accelerating Scientific Impact.

The project -- detailed in a paper published online ahead of print in the Proceedings of the National Academy of Sciences -- identified myeloid-derived suppressor cells and the immunosuppressive cytokine IL-10 as the strongest predictors of delayed and less effective bone-healing.

That association emerged after a series of experiments in which Guldberg's team ran thousands of data models on hundreds of biomarkers.

Guldberg was the principal investigator on the research, which was supported by the U.S. Armed Forces Institute of Regenerative Medicine and done with colleagues at Georgia Tech and Evolved Analytics.

"Our studies showed that myeloid-derived suppressor cells were consistently elevated in the blood as well as the local tissue in the non-responders to treatment, suggesting that suppression of the immune system may negatively affect musculoskeletal healing," Guldberg said. "That opens up potential novel therapeutic targets to improve patient outcomes following traumatic injuries."

Although standard bone fractures heal 95 percent of the time, complex fractures or trauma that cause damage to bones and surrounding soft tissues such as muscle have higher rates of complications and often require multiple procedures to heal. These non-healing bones are referred to as being in nonunion.

Factors such as age or underlying conditions, Guldberg said, can increase the risk of complications, motivating the need for biomarkers that can predict patient outcomes.

"We were quite intrigued to identify biomarkers that could be measured from the blood that correlated with local healing," he said. "The observation that was most exciting though was that immunosuppressive biomarkers were elevated as early as one week after treatment, well before radiographs could be used to assess the progress of healing."

A similar dysregulated immune response is seen in early stages of infections, cancer and other diseases. Myeloid-derived suppressor cells normally activate along with other cell groups that respond to injury or a pathological condition. In turn, various proteins, such as the cytokines identified in the new paper, activate to control inflammation. Under normal conditions following injury, these compensatory responses return to normal levels.

When that compensation fails to occur, Guldberg said, patients can enter a state of chronic inflammation and sustained immune suppression that appear to be associated with poor treatment outcomes.

Under a recently awarded 2.5 million, five-year grant from the National Institutes of Health, Guldberg will lead a team to further characterize and confirm the immune biomarkers in anticipation of a possible human clinical trial and test a new immunomodulation treatment strategy.

PHILADELPHIA--A significant number of non-Hodgkin lymphoma (NHL) patients in a Penn Medicine-initiated clinical trial continue to be in remission five years after receiving the chimeric antigen receptor (CAR) T cell therapy Kymriah™, researchers in Penn's Abramson Cancer Center reported today in the New England Journal of Medicine. The findings represent the longest follow-up, published data to date for CAR T cell therapies approved by the U.S. Food and Drug Administration for the treatment of relapsed or refractory large B-cell lymphomas.

Among 24 patients with diffuse large B-cell lymphoma (DLBCL), the most common form of NHL, who received the therapy after their cancers had come back following standard treatments, 46 percent achieved complete remission and 31 percent achieved progression-free survival at five years. Among 14 patients with relapsed or refractory follicular lymphoma, the second most common form of the disease, 71 percent achieved complete remission and 43 percent achieved progression-free survival at five years.

"We found that most of the patients who achieve a remission lasting one year remain in remission five years after being infused with CAR T cells. This is really exciting and demonstrates the durability of this approach," said lead author Elise A. Chong, MD, an assistant professor of Medicine in the division of Hematology-Oncology in Penn's Perelman School of Medicine. "Patients who do not respond to chemotherapy have another option that may offer them long-lasting remissions."

Co-authors of this research include senior author Stephen J. Schuster, MD, the Robert and Margarita Louis-Dreyfus Professor in Chronic Lymphocytic Leukemia and Lymphoma Clinical Care and Research in Penn's Perelman School of Medicine and director of the Lymphoma Program at the Abramson Cancer Center, and Marco Ruella, MD,, an assistant professor in Hematology-Oncology at the Perelman School of Medicine and scientific director of the Lymphoma Program.

The team also studied the long-term persistence of CAR T cells, and found that 50 percent of the patients who experienced and remained in remission after the first year did not have detectable levels of the CAR19 transgene after five years, while only one of the 18 patients who had a relapse of lymphoma within one year after infusion had loss of the transgene. The results suggest that loss of CAR T cell presence may not be a frequent mechanism of resistance to the therapy.

The study results are a follow up to a study from the same clinical trial published in NEJM in 2017 by Schuster, among other researchers, that included patient outcomes collected at 28 months. The results of a global CAR T cell therapy trial in lymphoma patients, sponsored by Novartis and led in part by Penn, were also published in NEJM, which led to the FDA approval for Kymriah for the treatment of relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including DLBCL, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma, in 2018. Kymriah is a registered trademark of Novartis.

Diffuse large B-cell lymphoma comprises approximately 30 percent of all NHLs, and there are an estimated 27,000 newly diagnosed patients with DLBCL in the U.S. each year. About 6,500 of those patients have relapsed or refractory disease after two or more therapies and may be eligible for approved CAR T cell therapies.

Updated results from the CORONADO study, analysing the outcomes of patients with diabetes admitted to hospital with COVID-19, shows that one in five patients die within 28 days while around half are discharged. The study is published in Diabetologia (the journal of the European Association for the Study of Diabetes [EASD]), and is by Professor Bertrand Cariou and Professor Samy Hadjadj, diabetologists at l'institut du thorax, University Hospital Nantes, INSERM, CNRS, and University of Nantes, France, and colleagues.

In May 2020, preliminary results from CORONADO (Coronavirus SARS-CoV-2 and Diabetes Outcomes), with a smaller sample size, showed that 10% of patients with diabetes and COVID-19 died within 7 days of hospital admission.

This updated analysis included 2796 participants from 68 centres across France: almost two thirds (64%) were men, mean age 70 years, with median body mass index of 28 kg/m² (falling into the overweight range). Microvascular and macrovascular diabetic complications were found in 44% and 39% of participants, respectively.

Within 28 days, 1404 (50%) of the patients were discharged from hospital with a median duration of hospital stay of 9 days, while 577 participants died (21%). Of the remaining patients, 12% remained hospitalised at day 28, while 17% had been transferred to facilities different from their initial hospital.

Computer modelling revealed various factors such as younger age, routine diabetes therapy with the drug metformin, and longer symptom duration on admission were associated with a higher chance of discharge from hospital.

History of microvascular complications, routine anticoagulant therapy (to prevent blood clots), shortness of breath on admission, abnormal levels of liver enzymes, higher white blood cell counts and higher levels of the systemic inflammatory marker C-reactive protein were all associated with a lower chance of discharge and a higher risk of death. Patients whose diabetes was regularly treated with insulin (possibly indicating a more advanced state of diabetes) were at a 44% increased risk of death compared with those not treated with insulin.

An unusual finding from this study was a 42% increased risk of death for patients with diabetes receiving statin treatment for high cholesterol - however, the authors make clear since this is an observational study, it is difficult to make definite conclusions about any relationship with statins, or any other treatment.

The study also found that long term blood sugar control assessed with pre-admission or admission glycated haemoglobin (HbA1c) did not impact on the fate of COVID-19 patients, with no significant association with death or with discharge within 28 days. In contrast, an increased level of plasma glucose on admission was a strong predictor of death and, consistently, of a lower chance of discharge.

The authors conclude: "The identification of favourable variables associated with hospital discharge and unfavourable variables associated with death can lead to patient reclassification and help to use resources adequately according to individual patient profile."