Liquid fructose intake related to fatty liver disease

 A high-fat diet is not enough to cause short-term fatty liver disease. However, if this diet is combined with the intake of beverages sweetened with liquid fructose, the accumulation of fats in the liver accelerates and hypertriglyceridemia -- a cardiovascular risk factor -- can appear.

This is explained in a study on a mouse experimental model, published in the journal Molecular Nutrition and Food Research and led by Professor Juan Carlos Laguna, from the Faculty of Pharmacy and Food Sciences, the Institute of Biomedicine of the University of Barcelona (IBUB) and the Physiopathology of Obesity and Nutrition Networking Biomedical Research Centre (CIBEROBN).

The study counts on the collaboration of the researchers Aleix Sala-Vila and Iolanda Lázaro, from the Hospital del Mar Medical Research Institute (IMIM), and José Rodríguez-Morató, from IMIM-Hospital del Mar and MELIS-Pompeu Fabra University, among other experts.

Fructose and lipid metabolism

Fructose is one of the most common sweeteners in the food industry. This simple sugar (monosaccharide) is industrially obtained from corn syrup, a product derived from this gramineae. With a great sweetener power and low production costs, fructose is used by the food industry to sweeten beverages, sauces and processed foods, despite the scientific evidence that associates it with metabolic diseases which are risk factors of cardiovascular pathologies.

According to the new study, the effect caused by fructose in the increase in the synthesis of fatty acids in the liver is more decisive than the external introduction of fats through the diet. "In high-fat diets which are supplemented with liquid fructose, this monosaccharide is able to induce an increase in the de novo lipogenesis -- that is, the formation of fats through sugar -- and an inhibition of the lipid oxidation in the liver," says Professor Juan Carlos Laguna, from the Department of Pharmacology, Toxicology and Therapeutical Chemistry.

"In particular, fructose intake affects directly the expression and activity of the nuclear factor ChREBP. Once activated, this factor causes an increase in the expression of enzymes that control the hepatic synthesis of fatty acids," he continues. "Parallelly, fructose intake reduces the activity of the nuclear receptor PPARalfa, which is the main responsible for the controlling of the expression of genes that code the enzymes involved in the fatty acid oxidation (mitochondrial and peroxisome) in the liver."

As stated in the preclinical study, the combination of the saturated fat from dietary origin and the induction of the endogen synthesis of fatty acids is what causes the emergence of the fatty liver. "Moreover, we are describing for the first time that fructose -- unlike high-fat diets -- increases the expression of the PNPLA3 protein, associated with the appearance of hypertriglyceridemia, a risk factor for cardiovascular diseases," notes Núria Roglans, co-author of the study and member of the mentioned Department.

Fatty liver disease in humans

Several epidemiologic studies related the consumption of drinks that are sweetened with fructose to the non-alcoholic fatty liver disease (NAFLD), a pathology for which there is no specific pharmacological therapy. In these patients, de novo lipogenesis contributes up to a 30% of the lipids accumulated in the liver, while in healthy people, this synthesis brings only the 5% of hepatic lipids.

The animal model characterized by the team will be of potential interest to study future drugs to treat the non-alcoholic fatty liver disease (NAFLD). "People with this pathology have a higher endogenous synthesis of lipids in the liver than healthy people. Therefore, the effects described in this study might appear in humans as well," note the experts.

"Unfortunately, -- they continue -- the fatty liver is the starting point for more serious pathologies, such as steatohepatitis and cirrhosis. It is a practically asymptomatic pathology, although in some cases, some mild unspecific digestive disorders can appear. Apart from following a healthy diet and physical activity, there is no efficient treatment against this pathology for now."

The effects described in the study are only observable if fructose is taken in its liquid form. "Regarding sweetened beverages, fructose is quickly absorbed and it reaches the liver massively, producing the described metabolic alterations. To find a comparison, we could talk about the appearance of a fructose overdose when this is taken in sweetened drinks," notes the team.

"However, when we eat fruit, the amount of taken fructose is a lot lower compared to a sweetened drink. Also, the process of chewing it and the presence of other elements in the fruit, such as fiber, slows down the absorption of fructose and its arrival to the liver," conclude the authors.

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Materials provided by University of Barcelona. Note: Content may be edited for style and length.

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Journal Reference:

1. Ana Magdalena Velázquez, Roger Bentanachs, Aleix Sala‐Vila, Iolanda Lázaro, Jose Rodríguez‐Morató, Rosa M. Sánchez, Marta Alegret, Núria Roglans, Juan Carlos Laguna. ChREBP‐driven DNL and PNPLA3 Expression Induced by Liquid Fructose are Essential in the Production of Fatty Liver and Hypertriglyceridemia in a High‐Fat Diet‐Fed Rat Model. Molecular Nutrition & Food Research, 2022; 2101115 DOI: 10.1002/mnfr.202101115

https://www.sciencedaily.com/releases/2022/03/220304112024.htm

Cellular rejuvenation therapy safely reverses signs of aging in mice

 Age may be just a number, but it's a number that often carries unwanted side effects, from brittle bones and weaker muscles to increased risks of cardiovascular disease and cancer. Now, scientists at the Salk Institute, in collaboration with Genentech, a member of the Roche group, have shown that they can safely and effectively reverse the aging process in middle-aged and elderly mice by partially resetting their cells to more youthful states.

"We are elated that we can use this approach across the life span to slow down aging in normal animals. The technique is both safe and effective in mice," says Juan Carlos Izpisua Belmonte, co-corresponding author and a professor in Salk's Gene Expression Laboratory. "In addition to tackling age-related diseases, this approach may provide the biomedical community with a new tool to restore tissue and organismal health by improving cell function and resilience in different disease situations, such as neurodegenerative diseases."

As organisms age, it is not just their outward appearances and health that change; every cell in their bodies carries a molecular clock that records the passage of time. Cells isolated from older people or animals have different patterns of chemicals along their DNA -- called epigenetic markers -- compared to younger people or animals. Scientists know that adding a mixture of four reprogramming molecules -- Oct4, Sox2, Klf4 and cMyc, also known as "Yamanaka factors" -- to cells can reset these epigenetic marks to their original patterns. This approach is how researchers can dial back adult cells, developmentally speaking, into stem cells.

In 2016, Izpisua Belmonte's lab reported for the first time that they could use the Yamanaka factors to counter the signs of aging and increase life span in mice with a premature aging disease. More recently, the team found that, even in young mice, the Yamanaka factors can accelerate muscle regeneration. Following these initial observations, other scientists have used the same approach to improve the function of other tissues like the heart, brain and optic nerve, which is involved in vision.

In the new study, Izpisua Belmonte and his colleagues tested variations of the cellular rejuvenation approach in healthy animals as they aged. One group of mice received regular doses of the Yamanaka factors from the time they were 15 months old until 22 months, approximately equivalent to age 50 through 70 in humans. Another group was treated from 12 through 22 months, approximately age 35 to 70 in humans. And a third group was treated for just one month at age 25 months, similar to age 80 in humans.

"What we really wanted to establish was that using this approach for a longer time span is safe," says Pradeep Reddy, a Salk staff scientist and co-first author of the new paper. "Indeed, we did not see any negative effects on the health, behavior or body weight of these animals."

Compared to control animals, there were no blood cell alterations or neurological changes in the mice that had received the Yamanaka factors. Moreover, the team found no cancers in any of the groups of animals.

When the researchers looked at normal signs of aging in the animals that had undergone the treatment, they found that the mice, in many ways, resembled younger animals. In both the kidneys and skin, the epigenetics of treated animals more closely resembled epigenetic patterns seen in younger animals. When injured, the skin cells of treated animals had a greater ability to proliferate and were less likely to form permanent scars -- older animals usually show less skin cell proliferation and more scarring. Moreover, metabolic molecules in the blood of treated animals did not show normal age-related changes.

This youthfulness was observed in the animals treated for seven or 10 months with the Yamanaka factors, but not the animals treated for just one month. What's more, when the treated animals were analyzed midway through their treatment, the effects were not yet as evident. This suggests that the treatment is not simply pausing aging, but actively turning it backwards -- although more research is needed to differentiate between the two.

The team is now planning future research to analyze how specific molecules and genes are changed by long-term treatment with the Yamanaka factors. They are also developing new ways of delivering the factors.

"At the end of the day, we want to bring resilience and function back to older cells so that they are more resistant to stress, injury and disease," says Reddy. "This study shows that, at least in mice, there's a path forward to achieving that."

Belmonte is currently an Institute Director at Altos Labs, Inc., in addition to being a professor at the Salk Institute.

Other authors included Mako Yamamoto, Isabel Guillen Guillen, Sanjeeb Sahu, Chao Wang, Yosu Luque, Javier Prieto, Lei Shi, Kensaku Shojima, Tomoaki Hishida and Concepcion Rodriguez Esteban of Salk; Kristen Browder, Zijuan Lai, Qingling Li, Feroza Choudhury, Weng Wong, Yuxin Liang, Dewakar Sangaraju, Wendy Sandoval, Michal Pawlak, Jason Vander Heiden and Heinrich Jasper of Genentech, Inc.; Amin Haghani and Steve Horvath of UCLA; Estrella Nuñez Delicado of Universidad Católica San Antonio de Murcia; and Pedro Guillen Garcia of Clínica CEMTRO.

The study was supported by Universidad Católica San Antonio de Murcia (UCAM), and Fundación Dr. Pedro Guillén.

Video: https://youtu.be/XryS6SnGTho

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Story Source:

Materials provided by Salk Institute. Note: Content may be edited for style and length.

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Journal Reference:

1. Browder, K.C., Reddy, P., Yamamoto, M. et al. In vivo partial reprogramming alters age-associated molecular changes during physiological aging in mice. Nat Aging, 2022 DOI: 10.1038/s43587-022-00183-2

https://www.sciencedaily.com/releases/2022/03/220307113027.htm

Novel antiviral drug combinations demonstrate COVID-19 therapeutic potential

 Researchers from Columbia Engineering, Fiocruz's Center for Technological Development in Health and the Oswaldo Cruz Institute in Brazil, Memorial Sloan Kettering Cancer Center, and Rockefeller University recently reported that, by combining inhibitors of polymerases and exonucleases -- enzymes that allow SARS-CoV-2 to reproduce -- they were able to reduce SARS-CoV-2 replication 10 times more than when using just the polymerase inhibitors. They also identified a polymerase inhibitor with a unique modification that largely resists its removal from the RNA by the exonuclease. Their findings from both the molecular and cellular levels reveal the great potential of novel antiviral drug combinations to stop the spread of COVID-19 and other coronavirus diseases. The study was published February 22 by Communications Biology, an open access journal from Nature Portfolio.

"COVID has created an unprecedented public health crisis, with severe effects on the global economy and infrastructure; however, we can use the power of science to stop this pandemic," said the Columbia team leader Jingyue Ju, Samuel Ruben-Peter G. Viele Professor of Engineering; professor of chemical engineering and pharmacology; and director, Center for Genome Technology & Biomolecular Engineering. "We expect drug combinations like the ones we found will powerfully inhibit RNA viruses such as SARS-CoV-2 and other coronaviruses that could lead to future pandemics. Because polymerase and exonuclease are highly conserved enzymes in coronaviruses with very rare mutations appearing in variants, we anticipate that therapeutics developed to target these enzymes should be widely applicable to all coronaviruses with the potential to cause serious disease."

SARS-CoV-2, the coronavirus causing the global COVID-19 pandemic, uses a protein called polymerase to replicate its RNA genome inside infected human cells. In theory, terminating the polymerase reaction should stop the propagation of the coronavirus, leading to its eradication by the human host's immune system. However, SARS-CoV-2 has two key enzymes that allow it to replicate: the polymerase which reproduces its RNA and a proofreading exonuclease that corrects errors in the replication process.

The presence of the exonuclease for proofreading is unique to the coronaviruses and is needed to reduce the number of mutations and thereby maintain the integrity and function of the large RNA genomes of coronaviruses. Thus, the vaccine approach has been quite effective in containing the COVID-19 pandemic because the coronaviruses do not mutate as frequently as influenza virus and HIV, which have no proofreading function and therefore mutate more frequently.

Nucleotide-based viral polymerase inhibitors are very successful drugs for treating HIV and hepatitis viruses B and C infections. However, because of the presence of the proofreading exonuclease in SARS-CoV-2, which can remove these inhibitors from the RNA, the polymerase inhibitor Remdesivir, the sole FDA-approved drug for COVID-19, is not as effective as hoped for in preventing serious disease. If the exonuclease could be concurrently inhibited or its activity evaded, viral replication would be more efficiently blocked.

The research team, led by Ju and Dr. Thiago Souza, Full Researcher at the Oswaldo Cruz Institute's Center for Technological Development in Health, decided to investigate whether the combination of polymerase and exonuclease inhibitors could work together to inhibit replication of SARS-CoV-2 more effectively, or if polymerase inhibitors with certain modifications could resist removal by the exonuclease. The Columbia Engineering team conceived the overall project and performed the molecular-level studies to identify interactions among the inhibitors and enzymes, using a novel mass-spectrometry-based approach. The Brazilian team designed and conducted the cellular studies to measure the inhibitory effects of drug combinations on virus reproduction. Dr. Thomas Tuschl's group at Rockefeller University and Dr. Dinshaw Patel's team at Memorial Sloan Kettering Cancer Center produced the polymerase and exonuclease complexes used in the molecular studies.

Souza's group demonstrated that the polymerase and exonuclease inhibitors work together to block the virus's ability to reproduce in infected lung cells. "While these results were obtained in a cell culture model, we purposely chose inhibitors already approved as drugs for treatment of other common virus infections, such as those caused by HIV and hepatitis viruses, with the aim of being able to quickly advance them to clinical trials," Souza noted.

The team is now exploring whether the enhanced antiviral effects of the combination drugs can be demonstrated in a COVID-19 animal model, with acceptable pharmacological properties. If the results are positive, these drugs can be moved rapidly to clinical trials as they have been previously approved for treatment of other viral infections. They have also established an initiative with a consortium of pharmacologists, virologists, medicinal chemists, and structural biologists to develop new therapeutics with enhanced potency and safety profiles for COVID-19 based on the discoveries reported in this study.

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Story Source:

Materials provided by Columbia University School of Engineering and Applied Science. Original written by Holly Evarts. Note: Content may be edited for style and length.

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Journal Reference:

1. Xuanting Wang, Carolina Q. Sacramento, Steffen Jockusch, Otávio Augusto Chaves, Chuanjuan Tao, Natalia Fintelman-Rodrigues, Minchen Chien, Jairo R. Temerozo, Xiaoxu Li, Shiv Kumar, Wei Xie, Dinshaw J. Patel, Cindy Meyer, Aitor Garzia, Thomas Tuschl, Patrícia T. Bozza, James J. Russo, Thiago Moreno L. Souza, Jingyue Ju. Combination of antiviral drugs inhibits SARS-CoV-2 polymerase and exonuclease and demonstrates COVID-19 therapeutic potential in viral cell culture. Communications Biology, 2022; 5 (1) DOI: 10.1038/s42003-022-03101-9

https://www.sciencedaily.com/releases/2022/03/220307113048.htm

Novel treatment could make pancreatic cancer susceptible to immunotherapy

 Pancreatic cancer is one of the most aggressive and deadly tumor types and notorious for its resistance to virtually all types of treatment, including newer immunotherapies.

A new study -- in mice -- from Washington University School of Medicine in St. Louis suggests that blocking a major inflammatory pathway that is activated in pancreatic cancer makes the tumors sensitive to chemotherapy and a type of immunotherapy that prompts the immune system's T cells to attack the cancer cells. The therapy more than doubled survival in a mouse model of pancreatic cancer.

The study's results, published March 7 in the journal Gastroenterology, lend additional support for the rationale behind a new national clinical trial that will evaluate the same treatment strategy in patients with pancreatic ductal adenocarcinoma -- the most common malignant tumor of the pancreas. The researchers plan to enroll about 50 patients nationwide.

Washington University researchers at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine will lead the national trial that is part of the National Cancer Institute's (NCI) Experimental Therapeutics Clinical Trials Network, a collaboration of industry, academic medical centers and researchers focused on early clinical investigations of innovative cancer therapies. The network includes more than 30 clinical sites in the U.S. and Canada.

"Washington University has a lot of strengths in bringing science from the lab to the clinic," said senior author Kian-Huat Lim, MD, PhD, an associate professor of medicine and principal investigator for translational science on the national trial. "With this therapy, we are going after a pathway that we know is involved in driving the aggressiveness of pancreatic cancer. The results of this study are promising in that it showed a way to break through the defenses of this tumor type, making it susceptible to our therapeutics, including combinations of chemotherapy and newer immunotherapies that stimulate T cells to fight the cancer."

The researchers, including first author Vikas Somani, PhD, a postdoctoral research associate in Lim's lab in the Division of Oncology in the Department of Medicine, found that a protein called IRAK4 drives inflammation in pancreatic tumors and leads to T cell exhaustion, meaning the T cells can't function as they should to attack harmful cells, including cancer. The researchers tested an IRAK4 inhibitor, called CA-4948, and found that the treatment reduced inflammatory signaling in the tumors in mice and improved the ability of T cells to infiltrate the tumors and kill pancreatic cancer cells. The therapy also sensitized the tumors to a type of immunotherapy called checkpoint immunotherapy, which "take the brakes off" T cells, improving their ability to attack tumor cells.

The researchers found that the IRAK4 inhibitor shuts down a key pathway called NF-kappaB, which has long been known for its roles in driving cancer. Much research is focused on shutting down this pathway and its downstream effects after it becomes activated. A novel element of this therapy is that the IRAK4 inhibitor prevents the harmful pathway from becoming activated in the first place.

In mice with a common aggressive model of pancreatic cancer, the researchers found that the IRAK4 inhibitor alone increased survival compared with a placebo or chemotherapy. In combination, the IRAK4 inhibitor plus chemotherapy increased survival further compared with placebo or chemotherapy alone. In addition, when combined with two immunotherapies, the IRAK4 inhibitor significantly extended survival from an average of 25 days with the inhibitor alone to an average of 46 days with the inhibitor plus immunotherapy combination. Some of the mice survived as long as 100 days on the combination therapy.

The IRAK4 inhibitor is already in national clinical trials investigating its use against blood cancers.

"We look forward to beginning the national clinical trial of this drug in patients with pancreatic cancer -- the trial is a direct translation of this particular paper," said Haeseong Park, MD, an associate professor of medicine and principal investigator of the new trial. "We are excited to be working with the NCI and clinical sites in the Experimental Therapeutics Clinical Trials Network so that we can harness our innovative homegrown science and bring it to the national level."

Soon, Park's team also will begin a single-center trial at Siteman Cancer Center to test the safety and efficacy of the IRAK4 inhibitor CA-4948 in gastric cancer.

This work was supported by the National Institutes of Health (NIH), grant numbers R37CA219697-01 and 1P50CA196510-01A1; the American Cancer Society, grant number RSG- 17-203-01-TBG; the Washington University Specialized Program of Research Excellence (SPORE) in Pancreatic Cancer Career Enhancement Award, grant number 1P50CA196510-01A1; and the Alvin J. Siteman Cancer Center Siteman Investment Program, which is supported by the Barnard Trust and The Foundation for Barnes-Jewish Hospital.

The biotechnology company CURIS provided the IRAK4 inhibitor, CA-4948, used in this study.

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Story Source:

Materials provided by Washington University School of Medicine. Note: Content may be edited for style and length.

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Journal Reference:

1. Vikas Somani, Daoxiang Zhang, Paarth B. Dodhiawala, Varintra E. Lander, Xiuting Liu, Liang-I Kang, Hung-Po Chen, Brett L. Knolhoff, Lin Li, Patrick M. Grierson, Mariana B. Ruzinova, David G. DeNardo, Kian-Huat Lim. IRAK4 signaling drives resistance to checkpoint immunotherapy in pancreatic ductal adenocarcinoma. Gastroenterology, 2022; DOI: 10.1053/j.gastro.2022.02.035

https://www.sciencedaily.com/releases/2022/03/220307113043.htm

World Trade Center responders at higher risk for blood cancer-associated mutations: study

 Scientists from Vanderbilt-Ingram Cancer Center (VICC) collaborated with researchers from New York to determine that 9/11 first responders to the World Trade Center have increased levels of mutations that escalate their risk for blood cancers or cardiovascular disease, according to a study published March 7 in Nature Medicine.

The researchers determined that a significantly higher percentage of World Trade Center responders have an increased mutational burden when compared to blood sample data from BioVU, Vanderbilt's biorepository of DNA extracted from discarded blood collected during routine clinical testing. Among the World Trade Center firefighters, 10% had evidence of clonal hematopoiesis compared to 6.7% for firefighters who were not exposed to particulate matter from the burning skyscrapers. Clonal hematopoiesis is an age-associated phenomenon marked by mutations in commonly mutated genes within blood cells that provide those cells a competitive advantage and increases risk of blood cancer and cardiovascular disease.

The VUMC team was able to access the DNA of 203 Nashville firefighters from BioVU. The Vanderbilt team was able to use the de-identified, annotated data within the Synthetic Derivative (SD) to locate over 200 firefighters who were age, sex and smoking-status matched to first responders at the World Trade Center disaster. Combined with 52 firefighters recruited at the annual convention of the International Association of Firefighters, this control group was compared to those exposed to particulate matter at the World Trade Center disaster.

The VICC researchers were led by Michael Savona, MD, holder of the Beverly and George Rawlings Directorship in Hematology Research, professor of Medicine and Head of Hematology, Cellular Therapy and Stem Cell Transplantation at VICC.

"This is the first publication that I am aware of that successfully leveraged BioVU to measure somatic genetic changes to study clonal hematopoiesis," said Savona, one of four corresponding authors on the study.

Alexander Silver, a MD/PhD candidate working in the Savona Lab, is one of seven lead authors of the study.

The research team included scientists and physicians from Vanderbilt, Albert Einstein College of Medicine, Montefiore Medical Center, the Fire Department of the City of New York Bureau of Health Services, Rutgers Cancer Institute of New Jersey, Weill Cornell Medicine, Memorial Sloan Kettering Cancer Center, Sylvester Comprehensive Cancer Center, New York University School of Medicine, Genoptix, The Leukemia Lymphoma Society and Dana Farber Cancer Center.

Researchers also exposed mice to World Trade Center particulate matter thought to be equivalent to what the first responders absorbed. The scientists observed a significant expansion of hematopoietic stem cells 30 days after exposure.

The researchers concluded that first responders to the World Trade Center have an increased mutational burden that puts them at greater risk for blood cancers beyond what normally occurs with aging, and further studies of the particulate matter and the mechanism of blood cancer development are under way.

The research work was supported by the National Institutes of Health, The Leukemia Lymphoma Society, EvansMDS (an initiative of the Edward P. Evans Foundation), the V Foundation for Cancer Research, the Adventure Alle Fund, The Biff Ruttenberg Foundation, the Beverly and George Rawlings Directorship, and a gift from the Dempsey and Leinbach Families.

Other Vanderbilt authors on the study included Cosmin "Adi" Bejan, PhD, assistant professor of Biomedical Informatics, and clinical fellows in Hematology/Oncology, Shannon Stockton, MD, and Travis Spaulding, MD.

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Story Source:

Materials provided by Vanderbilt University Medical Center. Original written by Tom Wilemon. Note: Content may be edited for style and length.

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Journal Reference:

1. Sakshi Jasra, Orsi Giricz, Rachel Zeig-Owens, Kith Pradhan, David G. Goldfarb, Angelica Barreto-Galvez, Alexander J. Silver, Jiahao Chen, Srabani Sahu, Shanisha Gordon-Mitchell, Gaurav S. Choudhary, Srinivas Aluri, Tushar D. Bhagat, Aditi Shastri, Cosmin A. Bejan, Shannon S. Stockton, Travis P. Spaulding, Victor Thiruthuvanathan, Hiroki Goto, Jeannine Gerhardt, Syed Hissam Haider, Arul Veerappan, Matthias Bartenstein, George Nwankwo, Ola Landgren, Michael D. Weiden, Jacqueline Lekostaj, Ryan Bender, Frederick Fletcher, Lee Greenberger, Benjamin L. Ebert, Ulrich Steidl, Britta Will, Anna Nolan, Advaitha Madireddy, Michael R. Savona, David J. Prezant, Amit Verma. High burden of clonal hematopoiesis in first responders exposed to the World Trade Center disaster. Nature Medicine, 2022; DOI: 10.1038/s41591-022-01708-3

https://www.sciencedaily.com/releases/2022/03/220307132057.htm

Scientists identify new gene differences in severe COVID patients

 Scientists have pinpointed 16 new genetic variants in people who developed severe COVID-19 in a large study published on Monday that could help researchers develop treatments for very sick patients.

The results suggest that people with severe COVID have genes that predispose them to one of two problems: failure to limit the ability of the virus to make copies of itself, or excessive inflammation and blood clotting.

The scientists said their discoveries, published in the journal Nature, could help prioritize the likely treatments that could work against the disease.

Eventually, the information could even help predict which patients were likely to become severely ill.

“It is potentially possible in future that we will be able to make predictions about patients based on their genome at the point of presenting (for) critical care,” said Kenneth Baillie, consultant in critical care medicine at the University of Edinburgh and one of the study authors, told reporters.

The genetic analysis of nearly 56,000 samples from people in Britain showed differences in 23 genes in COVID-19 patients who became critically ill, when compared with the DNA of other groups included in the study, including 16 differences that had not been previously identified.

The new findings could help guide scientists in their search for existing drugs that might be useful for treating COVID-19.

For example, the researchers found changes in key genes that regulate the level of factor VIII, a protein involved in forming blood clots.

“Blood clotting is one of the main reasons why patients with COVID develop a shortage of oxygen. So that’s potentially targetable to prevent those clots from forming,” Baillie said.

But “we can’t know if these medicines will work until we try them in people”.

One of the previously discovered genes, TYK2, is targeted by Eli Lilly’s arthritis drug baricitinib, now being studied as a treatment for COVID-19.

The drug was shown last week to cut the risk of death and hospitalization in COVID-19 patients by 13% in a trial.

https://nypost.com/2022/03/07/scientists-finds-gene-differences-in-severe-covid-patients/

U.S. Lawmakers Seek Permanent Ban on Illicit Types of Fentanyl

 A bipartisan trio of U.S. congressmen on Monday unveiled new legislation that would permanently ban illicit versions of fentanyl, the powerful synthetic painkiller that has helped fuel the nation's opioid epidemic and death toll.

The proposed bill, introduced by Democrat Chris Pappas and Republicans Dan Newhouse and Ted Budd, comes days before a temporary ban on chemical copycats of fentanyl known as analogues expires on Friday.

For years, the Justice Department's Drug Enforcement Administration (DEA) has been trying to crack down on the proliferation of chemical look-alikes of fentanyl, which are often manufactured in China and shipped into the United States from Mexico.

Fentanyl, which is 100 times more potent than morphine, is classified as a Schedule II drug, meaning it is highly addictive but has a medicinal purpose, typically to treat intense cancer pain.

But chemists largely based in China have created numerous slightly altered versions of the drug, which along with actual fentanyl have flooded U.S. streets and contributed to nearly 500,000 U.S. opioid overdose deaths over two decades.

To combat these illicit versions, the DEA previously clamped down by individually placing each illicit new fentanyl analogue into Schedule 1, the same legal category for drugs like heroin which are deemed to have no medical use.

In 2018, the DEA came up with a new approach, using its emergency powers to schedule all copycat illicit versions of fentanyl broadly into Schedule 1 as a single class, effectively banning them.

That authority has remained in place, thanks to repeated temporary extensions from Congress, which has yet to act on a long-term solution over concerns that a permanent ban could stifle scientific research into fentanyl analogues.

"This bill looks to close an important loophole," Pappas said in a phone interview. "We've got to make sure that we're staying ahead of the cartels."

Pappas added that his proposed bill contains provisions that he hopes will address researchers' concerns by making it "less onerous and more streamlined" for scientists.

The new legislation introduced on Monday is not expected to pass before the DEA's latest temporary emergency scheduling of fentanyl analogues expires.

However, Pappas told Reuters that lawmakers are looking into another temporary extension as part of a broader spending bill until a permanent solution is reached.

https://www.usnews.com/news/us/articles/2022-03-07/u-s-lawmakers-seek-permanent-ban-on-illicit-types-of-fentanyl