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LOS ALAMOS, N.M., March 1, 2021-- A novel computer algorithm that could create a broadly reactive influenza vaccine for swine flu also offers a path toward a pan-influenza vaccine and possibly a pan-coronavirus vaccine as well, according to a new paper published in Nature Communications.

"This work takes us a step closer to a pan-swine flu virus vaccine," said Bette Korber, a computational biologist at Los Alamos National Laboratory and a co-author on the paper. "The hope is to eventually be prepared with an effective and rapid response if another swine flu epidemic begins to spread in humans, but this swine flu vaccine could also be useful in a veterinary setting." The immune responses to the vaccine showed very promising breadth against diverse viral variants. "The same basic principles may be applicable to developing a pan-coronavirus vaccine to enable a rapid vaccine response to future coronavirus cross-species jumps," said Korber.

The algorithm, Epigraph, has already been used to predict therapeutic HIV vaccine candidates, and it has also shown promising potential as a pan-filovirus vaccine against highly diverse Ebola and Marburg viruses, protecting against disease when tested in an animal model.

Vaccination with the Epigraph-designed product led to the development of a strong cross-reactive antibody response in mice, the study showed. In swine, it induced strong cross-reactive antibody and T-cell responses. The research was conducted in close collaboration with researchers from the Nebraska Center for Virology at the University of Nebraska, St. Jude Children's Research Hospital, and Los Alamos National Laboratory.

"We developed the Epigraph strategy for this kind of problem, and it can, in theory, be applied to many diverse pathogens," said Korber, who created it in partnership with her husband, James Theiler, a Los Alamos Fellow. "The tool creates a cocktail of vaccine antigens designed to maximize efficacy across a highly diverse population."

Since 2010, more than 460 swine-flu variant infections have been reported in humans in the United States. Pigs are susceptible to swine, avian, and human influenza viruses, making them the perfect "mixing vessel" for novel reassorted influenza viruses, the authors note. These novel reassorted viruses have significant pandemic potential if zoonosis (transfer from pigs to humans) occurs, as seen with 2009 H1N1 swine flu pandemic.

TAMPA, Fla. - Genetic alterations of the KRAS gene are some of the most common mutations in lung cancer patients, but unfortunately these patients have few effective treatment options. Drugs that target the G12C mutation in KRAS have shown some activity in lung cancer; however, alternative signaling pathways are often activated that bypass the KRAS inhibitor, resulting in drug resistance. In a new article published in Clinical Cancer Research, Moffitt Cancer Center researchers show that various subtypes of lung cancer cells activate different signaling pathways in response to KRASG12C inhibitor treatment. These results may help identify potential combination therapy approaches and guide treatment decisions for lung cancer patients in the future.

The G12C mutation of KRAS occurs in approximately 16% of lung adenocarcinomas. Several drugs that target this specific mutation are in clinical development and have shown activity in some lung cancer patients, but these drugs are less effective in certain patients. As a result, combination treatment with other targeted agents may be necessary to see a benefit, but it is not clear which combination treatment strategies would work best.

"Given the diverse responses observed in both preclinical models and human patients, it is critical to understand how cells escape from targeted inhibition, which pathways contribute to resistance and how to predict pathway utilization for escape to enable precision medicine in the form of combination therapy," said Eric Haura, M.D., associate center director of Clinical Science at Moffitt.

The researcher team performed a series of preclinical studies using a technique called mass spectrometry to determine how cells respond to KRASG12C inhibitor treatment and to characterize their different responses. They treated a panel of KRASG12C mutant lung cancer cell lines with the KRASG12C inhibitor and discovered that each cell line displayed varied sensitivity to the drug, which was associated with different protein signaling patterns after treatment.

They characterized the panel of cell lines into either an epithelial or mesenchymal cell type. Epithelial cells are specialized cells that line organs and vessels and have strong cell connections between them, while mesenchymal cells are less specialized, associated with connective tissues, and are typically more motile. Epithelial and mesenchymal cells are known to express particular proteins and act in certain ways; however, they can change protein expression patterns and become similar to the alternative cell type under certain conditions.

The researchers discovered that the cell line that was sensitive to the KRAS inhibitor and displayed epithelial characteristics activated the HER2 and HER3 signaling pathways after KRAS inhibitor treatment, and cotreatment with a drug that targets these proteins resulted in greater cell death than either agent alone. They also demonstrated that activation of the downstream proteins SHP1, SOS1 and IRS1 contributed to responses after KRASG12C inhibitor treatment in this cell line.

After assessing signaling responses of the KRAS inhibitor resistant and moderately sensitive lung cancer cell lines, which have mesenchymal characteristics, they found that activation of the FGFR1 and AXL signaling pathways mediates resistance to KRAS inhibitor treatment in these cell lines, respectively, and that co-treatment with an FGFR or AXL inhibitor sensitized the cells to KRAS inhibition.

These data support the idea that the ideal therapy for lung cancer patients cannot be a one-size-fits-all approach. The researchers hope their results and experimental approach can be used to develop targeted cotreatment approaches for patients.

"Our data highlight the importance of phosphoproteomics-based approach to identify tumor specific adaptive rewiring, which can be utilized to aid personalized patient care in KRASG12C mutants," said Haura.

Oncotarget recently published "Effect of liver fibrosis on survival in patients with intrahepatic cholangiocarcinoma: a SEER population-based study" which reported that the impact of fibrosis on overall and cancer-specific survival 12, 36, and 60 months following diagnosis, was evaluated in the entire cohort and in subgroups stratified according to treatment approach and the American Joint Committee on Cancer tumor stage using a Cox proportional-hazards model.

After adjusting for age, sex, race, year of diagnosis, AJCC stage, and surgical treatment strategy, advanced fibrosis was associated with worse cancer-specific survival across follow-up periods.

Similar effects were observed for overall survival.

Among patients that underwent surgical resection, advanced fibrosis was associated with worse overall survival and cancer-specific survival across follow-up periods.

Fibrosis was associated with worse overall and cancer-specific survival in patients with a later stage at diagnosis but this effect was not demonstrated in early stages.

Patients with iCCA and advanced liver fibrosis have an increased risk of both overall and cancer-specific mortality compared to patients with earlier stages of fibrosis.

Dr. Ofer Isakov from The Tel Aviv Sourasky Medical Center and Sackler School of Medicine said, "Cholangiocarcinoma (CCA) is a malignant neoplasm of the biliary tract. Accounting for ~15% of all primary liver cancers, it is the most common biliary malignancy."

Specific risk factors identified for iCCA include certain parasitic infections and anatomical disorders such as choledochal cysts, hepatolithiasis, and primary sclerosing cholangitis.

Liver cirrhosis is also associated with CCA, especially iCCA.

While there is strong evidence to support the causative role of cirrhosis in the development of iCCA, the role of cirrhosis as a prognostic factor is debatable with contradicting findings from previous studies.

In this study, the Oncotarget authors aimed to assess the effect of cirrhosis on outcomes in iCCA patients.

The Oncotarget authors aimed to assess the effect of cirrhosis on outcomes in iCCA patients

For this purpose, the largest cohort of iCCA patients to-date was analyzed in order to elucidate the association between advanced liver fibrosis and all-cause mortality and cancer-specific mortality in iCCA patients.

The Isakov Research Team concluded in their Oncotarget Research Paper, "we show that patients with iCCA and advanced liver fibrosis have an increased risk of both overall and cancer-specific mortality across the follow up period. This association remains significant regardless of whether or not surgical resection was performed. In a sub-cohort of iCCA patients with early stages of the disease, advanced fibrosis was not associated with mortality and therefore, when no other contra-indications are present, should not affect surgical treatment strategy."

DOI - https://doi.org/10.18632/oncotarget.27820

Full text - https://www.oncotarget.com/article/27820/text/

Correspondence to - Ofer Isakov - oferis@tlvmc.gov.il

Keywords -
liver fibrosis,
cholangiocarcinoma,
SEER,
survival,
cirrhosis

About Oncotarget

Oncotarget is a biweekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

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Journal

Oncotarget

DOI

10.18632/oncotarget.27820

A single letter difference in a single gene, inherited from both parents, spells a lifetime of anemia and pain for 20 million people, mostly of African ancestry, worldwide. Sickle cell disease (SCD) causes red blood cells to assume a sickle shape and jam in capillaries, cutting off oxygen to lungs, brain, bones and other organs. Despite the single genetic origin of SCD, each person's disease experience and even life expectancy depend upon where they live, and the social, physical and environmental factors they encounter.

Now, a new review published by Wiley in the journal Advanced Genetics proposes that it is not only possible and necessary to analyze all these influences to understand disparities in experience and treatment of this disease, but that this approach will advance understanding and healthcare for all diseases with a hereditary component. The research and this new perspective stems from review of existing research on SCD together with preliminary data collected by an international collaboration studying the relationships of sociodemographic, clinical, genetic, and environmental factors to pain among adults with SCD from three countries in Africa and the African Diaspora - Cameroon, Jamaica, and the United States.

SCD is the first molecular disease and may become the first to have an approved molecular cure from gene editing. In the meantime, we must continue to scale up efforts to develop new tools and techniques for reducing and preventing complications in the millions of people worldwide suffering from SCD, most of whom are unlikely to have immediate access to high-tech cures when they become available. The unmet needs of people with SCD are prevalent, even in European and North American countries. The authors write, "large national and multinational integrative studies are needed to better understand SCD globally and catalyze the development, translation, and implementation of locally-appropriate interventions and policies."

LOS ANGELES -- COVID-19 has taken a huge medical, emotional and economic toll on Americans. Now, new Keck Medicine of USC research shows that the pandemic may also have harmful indirect consequences.

Alcohol and tobacco sales nationwide rose in the early months of COVID-19, according to a study appearing in the Annals of Internal Medicine today. From April - June 2020, researchers found that sales of these substances increased 34% and 13% respectively when compared to the same months in 2019.

"These are significant jumps, and show that the stress, boredom and loneliness caused by the pandemic may have led to increased alcohol and tobacco use," said Brian P. Lee, MD, MAS, a hepatologist and liver transplant specialist with Keck Medicine and the USC Institute for Addiction Science, and lead author of the study.

Tobacco and alcohol abuse are the second and ninth largest contributors to global deaths, causing some eight million deaths each year worldwide.

Lee and his colleagues decided to study alcohol and tobacco purchasing patterns after noticing that in 2020, Keck Hospital of USC admissions for alcohol-associated liver disease (cirrhosis or alcoholic hepatitis) were up approximately 30% compared to the year before. Some patients also admitted to using alcohol to handle pandemic-related stressors.

The doctors wondered if the trend they were witnessing locally was also happening nationally. And if one substance was being abused, they wondered if a second -- tobacco -- might be as well.

Seeking national data, they turned to the Nielsen National Consumer Panel, which tracks the spending habits of approximately 70,000 households in the United States over time and is designed to be nationally representative. People are given a handheld scanner or use a smart-phone app to scan products at stores to report their purchases.

Researchers compared alcohol and tobacco sales between the months of April - June in 2020 with the same time period in 2019. They set up controls to offset extenuating factors, such as restaurants and bars being closed during these months, which could independently cause an uptick in alcohol sales.

When they calculated their results, they found that from 2019 to 2020, tobacco sales increased in households across all demographics and alcohol sales increased across nearly all demographics as well. Sales increases for both substances were the highest, however, among younger adults, ethnic minorities, those with younger children and/or large families and those with higher incomes.

"We hypothesized that these subgroups, such as those with younger children, were buying more alcohol and tobacco because they felt more stressed than other segments of the population," said Lee, who is also an assistant professor of clinical medicine at the Keck School of Medicine of USC. "For those with a higher income, sales might have increased simply because they have greater disposable income," he added.

The data also revealed that sales of hard liquor increased more than wine and beer, a result Lee found troubling. "Liquor has the highest alcohol content and could be a sign of problem drinking," he said.

Lee believes that the study may reveal a previously unrecognized COVID-19-related public health issue. "This study draws attention to the fact that many people across the country might be self-medicating as a way to cope," he said. "By spotlighting this issue, individuals can identify this behavior as potentially harmful and substitute drinking or smoking with healthier activities. Mental health professionals and medical institutions, in addition to policymakers, can also develop interventions to help them."

Other Keck Medicine physicians involved in the study are Norah Terrault, MD, a Keck Medicine gastroenterologist and chief of Gastroenterology and Liver Diseases at the Keck School; Jennifer Dodge, MPH, an assistant professor of research medicine and preventive medicine at the Keck School; and Adam Leventhal, PhD, a professor of preventive medicine at the Keck School.

The researchers hope to conduct further studies to see if this three-month trend has sustained throughout the pandemic.

Black Americans have a high level of vaccine hesitancy and mistrust of COVID-19 vaccines, including among Black health care workers, according to a new RAND Corporation survey.

Those who expressed vaccine hesitancy also showed high levels of overall mistrust in the vaccine, concerns about potential harm and side effects, and lack of confidence in vaccine effectiveness and safety.

Participants in the RAND survey reported higher trust in COVID-19 information from health care providers and public health officials than from elected local and federal officials.

The findings are based on a survey of 207 Black Americans who are participants in the RAND American Life Panel, a nationally representative internet panel. Participants were surveyed during November and December 2020.

"Public health messages and communication strategies to address vaccine hesitancy should be tailored through authentic community engagement," said Laura M. Bogart, the study's lead author and a senior behavioral scientist at RAND, a nonprofit research organization. "Messaging about COVID-19 vaccines should first acknowledge systemic racism as a justifiable reason for mistrust before providing transparent information about the vaccine, including specific information about efficacy and safety."

The survey found that mistrust of the government's motives and transparency around COVID-19, as well as beliefs about racism in health care, appear to be contributing to mistrust of the vaccine. In addition, the more participants believed that people close to them would want them to get vaccinated, the more likely they were to say that they would get vaccinated themselves.

Black Americans attribute their medical mistrust, in general and specific to COVID-19 vaccines, to systemic racism, including discrimination and mistreatment in health care, as well as by the government.

Overall, more than one-third of all survey participants agreed or strongly agreed that they would not get a COVID-19 vaccine, and an additional 25% said they "don't know" if they would become vaccinated. Only 40% indicated that they planned to get vaccinated.

Participants in health care fields, including health care practitioners and those in technical and support occupations, showed higher vaccine hesitancy. Specifically, 48% of participants in health care fields indicated that they would not get vaccinated, compared with 32% of participants who were not in health care-related occupations.

When asked about which sources they trusted for information about COVID-19, nearly two-thirds of all respondents said that they trusted health care professionals such as doctors and nurses. Health care providers were trusted by higher percentages of participants who said that they would get the vaccine (72%) than those who said that they would not (56%).

Participants said that public health campaigns should involve trusted, known community members and trusted local organizations. Some participants suggested partnerships with Black celebrities such as hip-hop artists to encourage vaccination.

Youth enrollment in Medicaid managed care across all states increased from 65 percent in 2000 to 94 percent in 2017.

Across the country, receipt of preventive care for youth in Medicaid managed care increased from 49 percent in 2000 to 59 percent in 2017, falling short of the 80 percent annual goal set by the Centers for Medicare and Medicaid Services (CMS).

Receipt of preventive care for youth in Medicaid managed care showed a significant increase in 17 states, a significant drop in six states, and no change in 28 states. Tennessee had the largest increase in preventive care associated with Medicaid managed care, while North Carolina showed the largest decrease.

Nationally, the number of children under age 21 enrolled in Medicaid grew from 23.5 million in 2000 to 40.5 million in 2017, with the proportion of children in Medicaid managed care plans increasing from 65 percent to 94 percent, according to a study from Ann & Robert H. Lurie Children's Hospital of Chicago published in the journal Academic Pediatrics.

A key principle of managed care is access to routine preventive care services. While managed care has become the predominant form of Medicaid coverage for youth, researchers found only a modest increase in the receipt of preventive care services in this population, with marked variation across states. Whereas some states experienced improvements in preventive care services delivery for children as they implemented managed care, others did not.

"State-specific differences in the association of managed care Medicaid with preventive care for youth may include access to primary care, Medicaid reimbursement, availability of clinicians in managed care networks, and state oversight of the quality of care of Medicaid managed care organizations," says lead author Jennifer Kusma, MD, a physician at Lurie Children's and Instructor of Pediatrics at Northwestern University Feinberg School of Medicine. "Managed care by itself is not enough to improve care for children who are covered by Medicaid. States must consider multiple factors that influence access to care and delivery of care at the community and clinic level within managed care systems."

Dr. Kusma and colleagues used annual state-level data from the Centers of Medicare and Medicaid Services (CMS) to assess the relationship between Medicaid managed care and preventive care encounters for youth. Such services include immunizations, growth and development evaluation, anxiety and depression screening, lead level monitoring and oral health surveillance.

CMS has set a yearly goal of 80 percent participation in the Early and Periodic Screening, Diagnostic, and Treatment benefit, meaning that 80 percent of children enrolled in Medicaid should receive at least one visit or screen in a year. The frequency of preventive care expectations is based on recommendations from the American Academy of Pediatrics and US Preventive Services Task Force. Routine screenings are particularly important in promptly detecting developmental delays, such as autism spectrum disorder, when early intervention is known to be beneficial. Regular screenings are also important for adolescent health and well-being, as many engage in higher risk behaviors and up to 20 percent have undiagnosed behavioral health disorders that can be detected during regular check-ups in primary care.

"We found that older children had lower rates of preventive care than younger children," says Dr. Kusma. "This pattern has been reported in other research, and it reveals an opportunity for managed care plans to help improve quality of care by encouraging preventive care visits for adolescents as well as for younger children."

White blood cells or lymphocytes are the soldiers of our immune system that patrol the body via the lymphatic system. While their primary role is to protect the body by scavenging invaders, they can sometimes go rogue and become the enemy. Lymphoma, a type of blood cancer, results from the uncontrolled proliferation of lymphocytes. They are classified as Hodgkins and Non-Hodgkins lymphomas on the basis of the cell of origin and clinical characteristics. Of them, diffuse large B-cell lymphoma (DLBCL) is the most common Non-Hodgkins lymphoma and is highly aggressive and fast-growing.

A combination of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard treatment regimen for DLBCL. The regimen has demonstrated significant improvement of patient prognosis and overall survival. However, about 40% of the patients either develop resistance to therapy and respond poorly, while a large portion of those who initially respond well to the treatment eventually relapse. It is thus imperative to understand the molecular mechanisms underlying treatment response and resistance to R-CHOP therapy to improve patient outcomes. Comprehensive knowledge on the tumor biology and molecular signaling that contribute to DLBCL pathogenesis however is lacking

Now, researchers from China have addressed these lacunae in their review article recently published in Chinese Medical Journal. Their article describes in detail various aspects of tumor biology, including molecular pathways, tumor microenvironment, clonal evolution (selective growth of particular cells) and cell of origin that can help identify potential mechanisms and predictive biomarkers of drug resistance. Dr. Liang Wang, a co-author of the review, uses an interesting analogy to simplify why this is essential. "I would not recommend a high-carbohydrate diet to you if you are diabetic. Similarly, for DLBCL patients, if they harbor certain specific molecular signatures and clinical features that can predict resistance to R-CHOP, they must not be recommended R-CHOP therapy. Our comprehensive review discusses such predictive factors in depth that can help improve patient prognosis", he explains.

While the major signaling pathways that contribute to DLBCL have been uncovered, variations in the genes involved in these pathways can differentially impact treatment response, suggesting that one treatment may not benefit all patients. Sub-groups of the cancer have been identified based on differences in gene expression profiles. Interestingly, these signatures rarely overlap and correlate with specific outcomes. Based on this, genes associated with better or worse prognosis can thus be chalked out as predictors of treatment response and potential resistance.

Molecular signaling pathways control the intracellular decisions of cell growth. However, the tumor microenvironment, comprising a milieu of immune factors, cells, and extracellular components, greatly influences how the tumor responds to the drug. Drug-resistant and unresponsive lymphomas are known to harbor genetic variations that enable the tumor to evade the drug molecules, thereby making them tolerant towards R-CHOP treatment. R-CHOP has even been reported to activate certain oncogenes (genes that can cause cancer) and favor a specific subset of cells also referred to as sub-clonal populations. Such cells harbor genetic variations that confer growth advantages and can thus cause recurrent cancer.

Alterations in the B-cell receptor, PI3K-Akt, NF-kB, and JAK-STAT3 pathways can also cause drug resistance. Besides these, changes in epigenetic modifiers (that induce reversible genetic changes) have also been widely reported in drug-resistant and refractory lymphoma. These pathways could be potential predictive markers that can help screen for R-CHOP-resistant lymphomas. Moreover, some lymphomas bear more than one key alteration also known as "double hit" or "triple hit" lymphomas. In such cases, a combination therapy is likely to work better.

Overall, their review lays the foundation for identifying patients with DLBCL who are likely to develop resistance to R-CHOP treatment and consider alternative therapies that can benefit such patients. Explaining the long-term implications of their work, Dr. Wang remarks, "Patients who are refractory to R-CHOP have a median survival of merely 10 months. If specific clinical features can be identified at the time of diagnosis of DLBCL, patients can be treated with alternative effective therapies apart from R-CHOP. Such tailored treatment will help significantly improve the prognosis and survival rate of such patients."

Armed with a better understanding of the molecular landscape of DLBCL, we can certainly expect improved patient classifications and personalized treatment in the near future.

GALVESTON, Texas -A team from The University of Texas Medical Branch at Galveston (UTMB) focused on drug addiction research have pioneered a new way to study frustration as a factor in substance use disorders. The study was published in the medical journal Psychopharmacology.

Traditional addiction research has focused on three aspects of substance use disorders: craving, impulsivity, or habit. Scientists hypothesized that a fourth factor, frustration, could also lead to escalation of drug use and addiction.

The Psychopharmacology paper noted that research into the role of frustration and substance use disorders is sparse, but a number of studies suggest that persons with substance use disorders have lower frustration tolerance. Studies have shown that sensitivity to frustration correlates with relapse among those with substance use disorders.

The UTMB studies used a rat model to focus on frustration-related behavior. Rats can be trained to press a lever for food or drugs (reinforcers), and frustration is defined as when a subject is unable to achieve a reinforcer, receives less of a reinforcer than anticipated, or has to work harder to achieve a reinforcer.

"An example of frustration behavior is when someone can't get the channel on the TV to change or when an elevator takes too long to arrive. People will often respond to both situations by pressing the button repeatedly or holding the button longer with repeated attempts. This typical human response to frustration is the same in rats. In our study, rats were trained to press a lever for delivery of either a sucrose pellet or an intravenous infusion of a synthetic opioid. If they didn't get what they expected, they would press the lever more frequently and for longer periods of time," said Dr. Thomas A. Green, of UTMB's Department of Pharmacology and Toxicology.

"When a rat presses a lever repeatedly that was supposed to deliver a banana-flavored sucrose pellet, but the pellets never arrive, they hold the levers down longer as the frustration builds," he said.

Tileena Vasquez, a doctoral candidate in UTMB's Department of Pharmacology and Toxicology and the lead author of the paper, said the study showed all rats would press a lever for intravenous infusions of fentanyl, a synthetic opioid, but about 10% of rats would escalate their intake of fentanyl to about double that of the average rat.

"Even as the escalating rats take massive amounts of drug, their bar presses get longer (in some cases up to 10 minutes long), even though long bar presses do not increase the amount of drug delivered," Vasquez said, adding that the conclusion is that these susceptible rats, even though they are taking as much fentanyl as their bodies can handle, are frustrated that they are still not getting enough drug to satisfy them.

Green says the study has obvious implications for future studies of opioid use disorder and will help scientists understand how frustration, as well as craving, impulsivity and habit can lead to opioid escalation.

What The Study Did: Researchers investigated whether home addresses recorded in the electronic medical record could be used to accurately estimate transmission risk of SARS-CoV-2 and identify risk factors for transmission.

Authors: Joshua P. Metlay, M.D., Ph.D., of Massachusetts General Hospital in Boston, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/ 

(doi:10.1001/jamanetworkopen.2021.0304)

Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

HDL cholesterol (high-density lipoprotein cholesterol) or good cholesterol is associated with a decreased risk of cardiovascular disease as it transports cholesterol deposited in the arteries to the liver to be eliminated. This contrasts with the so-called bad cholesterol, LDL (low-density lipoprotein cholesterol), which causes cholesterol to accumulate in the arteries and increases cardiovascular risk. Although drugs that lower bad cholesterol reduce cardiovascular risk, those that raise good cholesterol have not proven effective in reducing the risk of heart disease. This paradox has called into question the relationship between good cholesterol and cardiovascular risk, and researchers are now studying the characteristics of these HDL or good cholesterol particles.

A study led by the Hospital del Mar Medical Research Institute (IMIM), published in the journal Metabolism, Clinical and Experimental, has now demonstrated that not all good cholesterol is healthy. Researchers from the CIBER on Cardiovascular Diseases (CIBERCV), the CIBER on Obesity and Nutrition (CIBEROBN), and the CIBER on Epidemiology and Public Health (CIBERESP), as well as others from Hospital Clínic-IDIBAPS, IDIBELL, the Hospital de la Santa Creu i Sant Pau Research Institute, and the Hospital Clínico Universitario in Zaragoza also took part in this study.

In the work, the researchers analysed genetic characteristics that determine the size of good cholesterol particles, and then studied their relationship with the risk of myocardial infarction. The conclusion is that genetic characteristics linked to the generation of large good cholesterol particles are directly associated with a higher risk of heart attack, while features linked to small good cholesterol particles are related to a lower risk of heart attack. "There is a positive causal relationship between the size of HDL cholesterol particles and the risk of heart attack, so although we have to increase the levels of good cholesterol in the blood, they must always be small particles", explains the study's principal investigator, Dr. Robert Elosua, a researcher at the Hospital del Mar-IMIM, CIBERCV, and the University of Vic-Central University of Catalonia (UVic-UCC).

The good cholesterol particles are more effective in transferring cholesterol to the liver so that it can be eliminated. "If we need to do something in relation to HDL, it is to increase the number of small particles, which are those that adequately perform the function of eliminating cholesterol, those that really move it to the liver for removal, and do not allow it to accumulate in the arteries and cause cardiovascular disease", says Dr. Álvaro Hernáez, a IDIBAPS and CIBEROBN researcher.

Currently, there are no drugs that increase good cholesterol levels and reduce the risk of cardiovascular disease. "This study highlights new and potential therapeutic targets in the field of cardiovascular diseases, including several genes related to the qualitative aspects of HDL particles, which may contribute to cardiovascular prevention", concludes Dr. Albert Prats, a researcher in the Epidemiology and Cardiovascular Genetics Research Group at the Hospital del Mar-IMIM and first author of the study.

NEW YORK, NY (Feb. 26, 2021)--People who took statins to lower cholesterol were approximately 50% less likely to die if hospitalized for COVID-19, a study by physicians at Columbia University Vagelos College of Physicians and Surgeons and NewYork-Presbyterian has found.

"Our study is one of the larger studies confirming this hypothesis and the data lay the groundwork for future randomized clinical trials that are needed to confirm the benefit of statins in COVID-19," says Aakriti Gupta, MD, a cardiologist at NewYork-Presbyterian/Columbia University Irving Medical Center and one of the co-lead authors of the study.

"If their beneficial effect bears out in randomized clinical trials, statins could potentially prove to be a low-cost and effective therapeutic strategy for COVID-19," adds co-lead author Mahesh V. Madhavan, MD, also a cardiologist at NewYork-Presbyterian/Columbia University Irving Medical Center.

Why Look at Statins?

Gupta, Madhavan, and the study's leadership group are cardiologists who cared for hospitalized COVID-19 patients in the spring and summer of 2020 when the first wave of the pandemic swept through New York City. 

"We observed that patients who got very sick and required hospitalization had high rates of hyperinflammation and clotting," says Elaine Wan, MD, the Esther Aboodi Assistant Professor of Medicine in Cardiology and Cardiac Electrophysiology and a cardiac electrophysiologist at NewYork-Presbyterian/Columbia University Irving Medical Center, one of the study's senior authors.

"As cardiologists, statins naturally came to mind," Gupta says. "In addition to their well-known cholesterol-lowering effect, statins are known for their anti-inflammatory, anticoagulant and immunomodulatory properties."

Study Analyzed Data from Electronic Health Records

Based on their observations, the authors looked at outcomes for 2,626 patients with COVID-19 who were admitted to a quaternary academic medical center in Manhattan during the first 18 weeks of the pandemic. 

The researchers compared 648 patients who regularly used statins before developing COVID-19 to 648 patients who did not use statins. Patients in each group were matched so that there were no significant differences in demographics, comorbidities, or use of other medications at home.

50% Fewer Deaths among Statin Users

Among the statin users, 96 (14.8%) died in the hospital within 30 days of admission compared with 172 (26.5%) of patients who did not use statins.

When other differences among the patients were factored in, the researchers found that statin use was significantly associated with a 50% reduction in in-hospital mortality (within 30 days). Patients on statins also tended to have lower levels of C-reactive protein, a marker of inflammation.

Statin use was not associated with a statistically significant decrease in the use of invasive mechanical ventilation (18.6% in statin users vs. 21.9%), days on a ventilator (13.5 vs 12.8), or length of hospital stay (7 vs 7).

Comparison with Other Studies

Other studies and meta-analyses from China have also suggested a survival benefit from statins among COVID-19 patients. However, these results may not apply to patients in Western countries who generally have more cardiovascular disease.

The current study is one of the larger studies confirming the association. Smaller retrospective studies out of North America and Europe have found similar results. 

Randomized Clinical Trials Needed

Although the study compared closely matched participants and adjusted for other variables, as a retrospective analysis, unknown factors could explain the results.

"Only randomized controlled clinical trials can evaluate the benefits of statins in COVID-19 patients," says senior author Sahil A. Parikh, MD, associate professor of medicine and a cardiologist at NewYork-Presbyterian/Columbia University Irving Medical Center.

Several randomized trials are underway, including studies to determine if statins can prevent hospitalization in outpatients, and lower the risk of death when given to hospitalized patients. 

One of the study's authors, Behnood Bikdeli, MD, a former cardiology fellow at Columbia now a fellow in vascular medicine at Brigham and Women's Hospital, is leading a randomized clinical trial looking at the impact of statins in hospitalized ICU patients in Iran.

People living with obesity tend to have unhealthy glucose and lipid levels in their blood, as well as high blood pressure. As a result, they are more at risk of cardiovascular and metabolic diseases. But scientists have observed that up to 45% of people living with obesity have healthy blood pressure and glucose and lipid levels, and therefore may not be at high risk of disease. The reason why this group of people with obesity remain healthy, has been poorly understood.

But now a team of researchers - led by scientists at the University of Copenhagen and Icahn School of Medicine at Mount Sinai, New York - have identified a range of genes that are linked to both elevated levels of body fat, as well as offering protection from some of the negative health impacts of obesity. The results were published in the journal Nature Metabolism.

Associate Professor Tuomas Kilpeläinen from the Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR) at the University of Copenhagen says the findings shed new light on the biology that may disconnect higher level of body fat from higher risk of diabetes and heart disease.

"The identified genes seem to benefit our health by helping to maintain a healthy fat tissue. Some of the genes may offer targets for the development of new therapies that lower the risk of diabetes and heart disease by improving the health of our fat tissue," says Tuomas Kilpeläinen.

The scientists made the discovery by analyzing data from hundreds of thousands people who had been assessed for their body fat and disease risk markers. They identified 62 sections of the genome that were significantly associated with both high levels of body fat and lower risk of cardiometabolic diseases. Further analyses showed that the genes had a range of functions in the body, including the regulation and development of fat cells, distribution of body fat, as well as energy regulation and inflammation.

Staff Scientist Lam Opal Huang from CBMR carried out the computational analyses that identified the genes.

"We used a data-driven approach in this study, which led us to find new genes associated with fat tissue health, instead of the known obesity genes associated with central nervous system, which control satiety and are typically linked to unhealthy obesity," says Lam Opal Huang.

According to Professor Ruth Loos from the Icahn School of Medicine at Mount Sinai, this new knowledge is a step toward a more nuanced approach to treating obesity.

"Clearly, obesity is a complex disease and not every individual with excess body weight is equally at risk of developing cardiometabolic diseases. Knowing which genes protect people from developing diabetes and cardiovascular disease will eventually help us better diagnose and treat individuals with obesity."

Challenging the idea that older people with shorter life expectancies should rank lower in coronavirus immunization efforts, new UC Berkeley research shows that giving vaccine priority to those most at risk of dying from COVID-19 will save the maximum number of lives, and their potential or future years of life.

The findings, published Feb. 25 in the journal Proceedings of the National Academy of Sciences, address the ethical dilemma of who should be first in line for a limited supply of vaccine shots amid a contagion that so far has killed 500,000 in the United States and 2.4 million globally.

"Since older age is accompanied by falling life expectancy, it is widely assumed that means we're saving fewer years of life," said study lead author Joshua Goldstein, a UC Berkeley professor of demography.

"We show this to be mistaken," he added. "The age patterns of COVID-19 mortality are such that vaccinating the oldest first saves the most lives and, surprisingly, also maximizes years of remaining life expectancy."

Taking age and health risks into account, Goldstein, UC Berkeley demographer Kenneth Wachter and Bucknell University mathematician Thomas Cassidy conducted an analysis of life expectancy in the United States, Germany and South Korea in the face of the yearlong coronavirus pandemic.

They based their calculations on the number of lives potentially saved from being vaccinated, multiplied by the life expectancy of those vaccinated. For example, if 1 million vaccinations saved 1,000 lives, and those vaccinated people, on average, were projected to live another 20 years, the total number of years of life saved would be 20,000.

The mathematical arguments upon which they based their conclusion apply not just to a few countries, but generally around the globe, the researchers said.

"Allocating scarce COVID-19 vaccine doses involves many tradeoffs. However, a conflict between minimizing the count of deaths and maximizing remaining life is not one of them," Goldstein said.

Since the approval of various COVID vaccines last fall, and their rollouts in December, a debate has been mounting over which groups to inoculate first, given limited vaccine supplies and, in many cases, chaotic distribution systems.

While some groups have argued that essential workers should take priority to keep health, education and economic systems up and running, others, such as the World Health Organization, have declined the "Years of Life Lost" criterion in ranking vaccine recipients due to older people's disproportionately higher risk of death and the perception that such an approach would be discriminatory and disrespectful.

This latest study should assuage some of those concerns, researchers said.

"Our empirical analysis shows it is easier than thought to set such fears aside and to give vaccine priority to the oldest and those in the most vulnerable states of health," according to the paper, which notes that COVID deaths rise exponentially with age.

The researchers found that the COVID death rate by age increased by about 11% per year of age in the United States, Germany and Korea. Moreover, they found that vaccinating people in their 90s would save three times as many lives as giving the same doses to people in their 80s.

"Before this study, it was suspected that there would be some intermediate age -- not too old and not too young -- which would maximize the benefit of a vaccine, in terms of person years of life saved," Goldstein said. "But surprisingly, we show this is not the case."

The past century or so has seen unprecedented technological, scientific, and sociological evolution worldwide. These have accompanied global shifts in people's lifestyles and rapid changes in the environment, both natural and man-made. An unfavorable consequence of these alterations has been the increasing burden of cancer on human society.

As the country with the largest population, China has borne this burden heavily. Despite the massive progress China has made in healthcare since the 1950s, cancer has become the leading killer in the country. In 2015, nearly 2.4 million lives were taken by this disease. Cancer lies latent for years before it manifests; so perhaps, its burden will only continue to grow in the coming decades.

But when you break down these statistics by type of cancer and risk factor, what do the salient trends look like? A group of researchers reviewed data from various national mortality surveys, cancer registries, and online databases to find out.

Speaking of their motivations to conduct the review, lead researcher Dr. Wanqing Chen, Director of the Office of Cancer Screening, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, China, says: "This review could provide scientists and policy-makers with a tool to find what works, what matters, and what is expected." The paper is published Open Access in Cancer Biology & Medicine.

The team's perusal of 22 Chinese registries revealed an increase in the cancer incidence from 2000 to 2011, with the increase being largely attributable to increased incidences of colorectal, prostate, breast, cervical, and ovarian cancers. Interestingly, the incidences of liver, esophageal, and stomach cancers reduced significantly. This could be because of the widespread hepatitis B vaccination across the country during this period in addition to an overall improvement in food preservation practices and living conditions.

Cancer mortality data from 1990 to 2015 mirrored the incidence data with rising mortality rates seen in the cases of colorectal, pancreatic, and breast cancers and falling rates seen in stomach, esophageal, and liver cancers. Yet, though the burden of these upper gastrointestinal cancers has fallen significantly, it still hangs heavy.

Between 1990 and 2017, lung cancer climbed to the top of the list of different types of cancers responsible for years of healthy life lost to illness, disability, or death (disability-adjusted life years, DALYs). Liver and stomach cancers were second and third in line.

Sadly, further research suggests that quite a large chunk of these cases and deaths could, perhaps, have been prevented. Data from the National Cancer Center, China, attributes 45% of cancer deaths in the country to modifiable risk factors--behavioral, clinical, or environmental. For instance, 23.8% of cancer deaths among men and 4.8% among women in 2014 are attributed to smoking. From 1990 to 2017, cancer deaths caused by smoking increased by over 150%. Given that China currently consumes about 40% of the world's tobacco, if habits don't change, the future looks grave.

Apart from smoking, physical inactivity, an unhealthy diet, and heavy alcohol consumption are major contributing behavioral risk factors for cancer; diabetes, obesity, and infectious diseases are prominent clinical risk factors; and air pollution, as well as occupational exposure to carcinogenic compounds such as soot, asbestos, and silica, are important environmental risk factors.

However, even in these seemingly dark times there is a spot of light. Technological advancement coupled with good healthcare and insurance policies and a growing general awareness among the people have, perhaps, contributed to the improvement in cancer survival rates seen between 2003 and 2015.

Still, prevention remains better than cure. As Dr. Chen explains: ''Taking all this critical information together, one can see that implementing cost-effective approaches for primary prevention is of utmost importance. Our paper highlights the requirement for collaborative efforts by the government, public health organizations, and the people to reduce the cancer burden in the country. We hope that our work can inform policies such as Healthy China 2030."

Perhaps the successful implementation of policies based on such research in China and worldwide can lift the burden of cancer from the world's shoulders.