Monthly Archives: May 2020

Stem cell researchers at Lund University in Sweden have developed a new research model of the early embryonic brain. The aim of the model is to study the very earliest stages of brain to understand how different regions in the brain are formed during embryonic development. With this new insight, researchers hope to be able to produce different types of neural cells for the treatment of neurological diseases more efficiently. The study is published in the journal Nature Biotechnology.

In order to develop stem cell treatments for neurological diseases such as Parkinson's Disease, epilepsy and stroke, researchers must first understand how the human brain develops in the embryonic stage. With knowledge of how neural cells are formed at different developmental stages, researchers have the opportunity to develop new stem cell therapies more quickly in the laboratory.

"The challenge is that there are thousands of different sub-types of neural cells in the human brain, and for each disease we need to be able to produce exactly the right type of neural cell", says Agnete Kirkeby, researcher at the Wallenberg Centre for Molecular Medicine and the Department of Experimental Medical Science at Lund University.

Studies on how each individual neural cell forms in the embryo during brain development are essential for the researchers to be able to understand how to produce these specific cells in the laboratory.

Research on the early development of the human brain, from five days after the fertilisation of the cell to approximately seven weeks, have so far been difficult as researchers have not had access to human embryonic tissue from these early stages of development. Therefore, nearly all knowledge of the earliest development of the brain is based on studies in flies, chickens and mice.

"However, the composition of the human brain differs greatly from the animals' brains. Therefore, this period in the development of the human brain has long been viewed as the black box of neurology", says Agnete Kirkeby.

Together with colleagues from the University of Copenhagen and bioengineers Thomas Laurell and Marc Isaksson from the Faculty of Engineering at Lund University, Agnete and her team have now created a model that mimics the early developmentalstages of the human brain through the use of stem cells. The stem cells are cultivated in a custom-built cell culture chamber where they are exposed to an environment which resembles the environment in the early embryonic brain.

"In the laboratory model called MiSTR (Microfluidic-controlled Stem cell Regionalisation), we can create tissue that contains different brain regions next to each other, similar to an embryonic brain approximately four to five weeks after fertilisation."

"We start with a small group of cells that will form the brain and instruct the cells by exposing them to a gradient of a specific growth factor (WNT) so that they form different regions of the brain. Our model is better than previously published models because it is much more reproducible and contains more brain regions. We can now use it to study unknown characteristics in the early development of the human brain", explains Agnete Kirkeby.

Agnete Kirkeby believes that the new method may be used to investigate how brain cells in the early embryonic stages react to certain chemicals surrounding us in our daily lives

"This is a significant step forward for stem cell research. For the first time, we now have access to tissue that resembles the early embryonic brain and can therefore study processes behind brain development in a way that has not been possible before. We can for instance use it for testing how chemical substances in our environment might impact on embryonic brain development." explains Kirkeby.

Another aim for the future is to use the model to create a complete map of the development of the human brain. This will help to speed up the development of new stem cell treatments for neurological diseases.

"Once we have the map we will also become better at producing human neural cells in the laboratory that could be used for transplantations, regenerative therapy and to study the brain's function as well as different disease states. . It took us ten years to develop a stem cell treatment for Parkinson's disease because our methods were dependent on trial and error. Our goal is that this process will be much faster in the future for other diseases", concludes Agnete Kirkeby.

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New method provides unique insight into the development of the human brain - Science Codex

ROCKVILLE, Md., May 26, 2020 (GLOBE NEWSWIRE) -- Cerecor Inc. (NASDAQ: CERC) and Myriad Genetics Inc. (NASDAQ: MYGN) today announced that levels of novel cytokine, LIGHT, were highly correlated with disease severity and mortality in a COVID-19 acute respiratory distress syndrome (ARDS) biomarker study. The biomarker study was conducted using the serum samples of 47 hospitalized COVID-19 patients and 30 healthy controls from Hackensack Meridian Health Network.

In April 2020, approximately 1,500 people in the United States died each day from COVID-19. The viral infection triggers a hyperactive immune response leading to cytokine storm and Acute Respiratory Distress Syndrome (ARDS), which is a leading cause of death in patients who die of COVID-19. Although this hyperinflammatory process is poorly understood, the data from this study implicates the inflammatory cytokine, LIGHT, as a potential key driver of cytokine storm leading to ARDS and death.

LIGHT levels were significantly elevated in the serum of hospitalized patients with COVID-19 versus healthy controls (p value < 0.0001). The highest LIGHT levels were found in patients who required ventilator support, particularly in patients over 60. Importantly, the data demonstrated elevated LIGHT levels were also strongly linked with mortality (p=0.02).

Dr. David Perlin, Ph.D., chief scientific officer, senior vice president of the Center for Discovery and Innovation, and Professor of Medical Sciences at the Hackensack Meridian School of Medicine at Seton Hall University, commented These data are compelling and demonstrate that the inflammatory cytokine LIGHT may play a key role in cytokine storm associated with COVID-19 ARDS that leads to increased morbidity and mortality. Reducing LIGHT levels might be a key to dampening the cytokine storm in these patients, preventing the need for ventilator support and reducing mortality.

Dr. Garry Neil, M.D. chief scientific officer, Cerecor commented, As a company, we recognized the impact of cytokine storm-induced ARDS and the need for treatment options for patients in this area of high unmet need. We remain focused on the CERC-002 clinical program and rapidly moving it forward for the treatment of cytokine storm induced ARDS.

Role of LIGHT in Acute Inflammatory Response

LIGHT (homologous to Lymphotoxin, exhibits inducible expression and competes with HSV glycoprotein D for binding to herpesvirus entry mediator, a receptor expressed on T lymphocytes) is a cytokine with inflammatory actions encoded by the TNFSF14 gene. LIGHT has been shown to play a key role in the immune response to viral pneumonia. LIGHT plays an important role in regulating immune responses in the lung, gut and skin. It stimulates T Cell and B Cell response as well as induces the release of other cytokines such as IL1, IL6, IL-8, IL-10, TNF and GM-CSF.

CERC-002 (anti-LIGHT monoclonal antibody)

CERC-002 is a fully human monoclonal antibody with neutralizing action against LIGHT (TNFSF14), for treatment of children with Pediatric Crohns Disease. Cerecor holds an open IND with FDA and the drug is currently being studied in a Phase I clinical trial for patients with refractory severe Crohns disease, currently not recruiting due to COVID-19.

Free LIGHT Assay from Myriad RBM

Myriad RBM, a subsidiary of Myriad Genetics, Inc., in collaboration with Cerecor has developed an ultrasensitive assay for the detection of free LIGHT. The assay is validated for serum or plasma samples and has sufficient sensitivity to reliably measure LIGHT from normal and disease subjects.

About Myriad

Myriad Genetics Inc., is a leading personalized medicine company dedicated to being a trusted advisor transforming patient lives worldwide with pioneering molecular diagnostics. Myriad discovers and commercializes molecular diagnostic tests that: determine the risk of developing disease, accurately diagnose disease, assess the risk of disease progression, and guide treatment decisions across six major medical specialties where molecular diagnostics can significantly improve patient care and lower healthcare costs. Myriad is focused on three strategic imperatives: transitioning and expanding its hereditary cancer testing markets, diversifying its product portfolio through the introduction of new products and increasing the revenue contribution from international markets. For more information on how Myriad is making a difference, please visit the Company's website: http://www.myriad.com.

About Hackensack Meridian Health

Hackensack Meridian Health is a leading not-for-profit health care organization that is the largest, most comprehensive and truly integrated health care network in New Jersey, offering a complete range of medical services, innovative research and life-enhancing care. Hackensack Meridian Health comprises 17 hospitals from Bergen to Ocean counties, which includes three academic medical centers Hackensack University Medical Center in Hackensack, Jersey Shore University Medical Center in Neptune, JFK Medical Center in Edison; two children's hospitals - Joseph M. Sanzari Children's Hospital in Hackensack, K. Hovnanian Children's Hospital in Neptune; nine community hospitals Bayshore Medical Center in Holmdel, Mountainside Medical Center in Montclair, Ocean Medical Center in Brick, Palisades Medical Center in North Bergen, Pascack Valley Medical Center in Westwood, Raritan Bay Medical Center in Old Bridge, Raritan Bay Medical Center in Perth Amboy, Riverview Medical Center in Red Bank, and Southern Ocean Medical Center in Manahawkin; a behavioral health hospital Carrier Clinic in Belle Mead; and two rehabilitation hospitals JFK Johnson Rehabilitation Institute in Edison and Shore Rehabilitation Institute in Brick. Additionally, the network has more than 500 patient care locations throughout the state which include ambulatory care centers, surgery centers, home health services, long-term care and assisted living communities, ambulance services, lifesaving air medical transportation, fitness and wellness centers, rehabilitation centers, urgent care centers and physician practice locations. Hackensack Meridian Health has more than 34,100 team members, and 6,500 physicians and is a distinguished leader in health care philanthropy, committed to the health and well-being of the communities it serves.

About the Center for Discovery and Innovation

The Center for Discovery and Innovation (CDI), a newly established member of Hackensack Meridian Health, seeks to translate current innovations in science to improve clinical outcomes for patients with cancer, infectious diseases and other life-threatening and disabling conditions. The CDI, housed in a fully renovated state-of-the-art facility, offers world-class researchers a support infrastructure and culture of discovery that promotes science innovation and rapid translation to the clinic.

About Cerecor

Cerecor is a biopharmaceutical company focused on becoming a leader in development and commercialization of treatments for rare pediatric and orphan diseases. The Company is advancing an emerging clinical-stage pipeline of innovative therapies. The Companys pediatric rare disease pipeline is led by CERC-801, CERC-802 and CERC-803 (CERC-800 programs), which are therapies for inborn errors of metabolism, specifically disorders known as Congenital Disorders of Glycosylation (CDGs). The FDA granted Rare Pediatric Disease Designation and Orphan Drug Designation (ODD) to all three CERC-800 programs, thus potentially qualifying the Company to receive a Priority Review Voucher (PRV) upon approval of a new drug application (NDA). The Company is also developing CERC-002, CERC-006 and CERC-007. CERC-007 is an anti-IL-18 monoclonal antibody being developed for the treatment of autoimmune inflammatory diseases such as Adult Onset Stills Disease (AOSD) and Multiple Myeloma (MM). CERC-006 is a dual mTOR inhibitor being developed for the treatment of complex Lymphatic Malformations. CERC-002 is an anti-LIGHT monoclonal antibody being developed for the treatment of Pediatric-onset Crohns Disease.

For more information about Cerecor, please visit http://www.cerecor.com.

Forward-Looking Statements

This press release may include forward-looking statements made pursuant to the Private Securities Litigation Reform Act of 1995. Forward-looking statements are statements that are not historical facts. Such forward-looking statements are subject to significant risks and uncertainties that are subject to change based on various factors (many of which are beyond Cerecors control), which could cause actual results to differ from the forward-looking statements. Such statements may include, without limitation, statements with respect to Cerecors plans, objectives, projections, expectations and intentions and other statements identified by words such as projects, may, might, will, could, would, should, continue, seeks, aims, predicts, believes, expects, anticipates, estimates, intends, plans, potential, or similar expressions (including their use in the negative), or by discussions of future matters such as: the development of product candidates or products; timing and success of trial results and regulatory review; potential attributes and benefits of product candidates; and other statements that are not historical. These statements are based upon the current beliefs and expectations of Cerecors management but are subject to significant risks and uncertainties, including: drug development costs, timing and other risks, including reliance on investigators and enrollment of patients in clinical trials, which might be slowed by the COVID-19 pandemic; regulatory risks; Cerecor's cash position and the need for it to raise additional capital; general economic and market risks and uncertainties, including those caused by the COVID-19 pandemic; and those other risks detailed in Cerecors filings with the Securities and Exchange Commission. Actual results may differ from those set forth in the forward-looking statements. Except as required by applicable law, Cerecor expressly disclaims any obligations or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in Cerecors expectations with respect thereto or any change in events, conditions or circumstances on which any statement is based.

For media and investor inquiries for Cerecor, Inc.

James Harrell,Investor RelationsChief Commercial OfficerCerecor Inc.jharrell@cerecor.com623.439.2220 office

For media and investor inquiries for Myriad Genetics, Inc.

Scott GleasonSVP of Investor Relations and Corporate StrategyMyriad Genetics, Inc.sgleason@myriad.com801.584.1143 office

Original post:
Cerecor and Myriad Genetics Announce that Levels of LIGHT, a Novel Cytokine, Were Highly Correlated with Disease Severity and Mortality in COVID-19...

NEW YORK, May 26, 2020 (GLOBE NEWSWIRE) -- Applied Therapeutics, Inc. (Nasdaq: APLT), a clinical-stage biopharmaceutical company developing a pipeline of novel drug candidates against validated molecular targets in indications of high unmet medical need, announced todaythe appointment of Dr. Charles (Chuck) Silberstein, MD, MBA, CFA as Chief Financial Officer and Head of Business Development, effective immediately. Dr. Silberstein is replacing Dr. Mark Vignola, who will be moving on to pursue new business opportunities.

We are thrilled to have Chuck joining the management team at Applied as we embark on this exciting phase of commercialization and program expansion, said Dr. Shoshana Shendelman PhD, Founder, CEO and Chair of the Board. His experience across all aspects of the business, including corporate strategy and business development, solidifies our capabilities as we move forward. We thank Dr. Mark Vignola for his contributions as CFO in the critical year following our IPO and wish him well in his future endeavors.

Dr. Silberstein was formerly Senior Vice President of Corporate Business Development at Allergan plc (recently acquired by AbbVie). Along with broad corporate strategy and business development skills, Dr. Silberstein brings more than 20 years of investment and capital markets experience to Applied, as a portfolio manager and equity healthcare analyst at The Boston Company Asset Management and Goldman Sachs Asset Management and as a senior healthcare equity analyst at JP Morgan Asset Management. Dr. Silberstein received his MD from Albert Einstein College of Medicine and his MBA from Columbia Business School.

AboutApplied Therapeutics Inc.

Applied Therapeutics is a clinical-stage biopharmaceutical company developing a pipeline of novel drug candidates against validated molecular targets in indications of high unmet medical need. The Companys lead drug candidate, AT-007, is a novel central nervous system penetrant aldose reductase inhibitor (ARI) for the treatment of Galactosemia, a rare pediatric metabolic disease. The Company initiated a pivotal Phase 1/2 clinical trial inJune 2019, read out positive top-line biomarker data in adult Galactosemia patients inJanuary 2020and announced full data from the trial inApril 2020. The Company is also developing AT-001, a novel potent ARI that is being developed for the treatment of Diabetic Cardiomyopathy, or DbCM, a fatal fibrosis of the heart. The Company initiated a Phase 3 registrational study in DbCM in September 2019. The preclinical pipeline also includes AT-003, an ARI designed to cross through the back of the eye when dosed orally, for the treatment of diabetic retinopathy, as well as novel dual PI3k inhibitors in preclinical development for orphan oncology indications.

Investors:Maeve Conneighton(212) 600-1902 orappliedtherapeutics@argotpartners.com

Media:Gleb Sagitovmedia@appliedtherapeutics.com

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Applied Therapeutics Announces Appointment of Dr. Chuck Silberstein, MD, MBA, CFA as Chief Financial Officer and Head of Business Development -...

Rajasekharreddy Pala,1,2 VT Anju,3 Madhu Dyavaiah,3 Siddhardha Busi,4 Surya M Nauli1,2

1Department of Biomedical and Pharmaceutical Sciences, Harry and Diane Rinker Health Science Campus, Chapman University, Irvine, CA 92618, USA; 2Department of Medicine, University of California Irvine, Irvine, CA 92868, USA; 3Department of Biochemistry and Molecular Biology, School of Life Sciences, Pondicherry University, Puducherry, India; 4Department of Microbiology, School of Life Sciences, Pondicherry University, Puducherry, India

Correspondence: Rajasekharreddy Pala; Surya M Nauli Tel +714-516-5462; +714-516-5480Fax +714-516-5481Email rrpala@chapman.edu; nauli@chapman.edu

Abstract: Cardiovascular diseases (CVDs) are one of the foremost causes of high morbidity and mortality globally. Preventive, diagnostic, and treatment measures available for CVDs are not very useful, which demands promising alternative methods. Nanoscience and nanotechnology open a new window in the area of CVDs with an opportunity to achieve effective treatment, better prognosis, and less adverse effects on non-target tissues. The application of nanoparticles and nanocarriers in the area of cardiology has gathered much attention due to the properties such as passive and active targeting to the cardiac tissues, improved target specificity, and sensitivity. It has reported that more than 50% of CVDs can be treated effectively through the use of nanotechnology. The main goal of this review is to explore the recent advancements in nanoparticle-based cardiovascular drug carriers. This review also summarizes the difficulties associated with the conventional treatment modalities in comparison to the nanomedicine for CVDs.

Keywords: cardiovascular diseases, nanoscience, nanoparticles, nanomedicine, nanocarriers, treatment

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

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Nanoparticle-Mediated Drug Delivery for the Treatment of Cardiovascula | IJN - Dove Medical Press

Naptime is over.

Ilhem Messaoudi Powers, associate professor of molecular biology & biochemistry at UCI, is enjoying a rare weekend at home with her husband, Dr. Michael Powers, when they hear the rustling of their two young children.

He bounds up the stairs to retrieve Owen, 3, and Olivia, 6 months, from a Saturday afternoon slumber. Soon the living room is full of the joyous noises of a toddler and an infant.

When theyre not wearing their mommy and daddy hats, Ilhem and Michael Powers are exploring and immersing themselves in an entirely different world: the COVID-19 pandemic.

A virologist and immunologist, Ilhem Powers leads a team of researchers whove launched a surveillance study of UCI Health workers to determine how many have antibodies against the coronavirus.

Michael Powers is a pulmonologist who works as a critical care doctor at the Naval Medical Center San Diego, caring for patients with COVID-19, as well as others.

Because of his unpredictable schedule, he often stays for days at an apartment in San Diego while his wife, with the assistance of a part-time nanny, juggles kids and career from the couples on-campus home and her laboratory.

Mike and I have been through a lot together, she says. Weve really learned to focus on the now.

Indeed, her husband was just two weeks into medical school at New Orleans Tulane University when Hurricane Katrina hit in late August of 2005. Ilhem Powers had accepted a job at the school as an assistant professor and was getting ready to relocate from their previous home in Portland, Oregon.

The New Orleans duplex that the couple had renovated with most of their savings wound up under 8 feet of water. It took them more than a year to recover.

One of the biggest lessons Ive learned in life is to focus on the things you have some control over, Michael Powers says. You just have to let go of the rest.

Surveillance study

Ilhem Powers lab cohort have pivoted from their usual work to conduct COVID-19 research as members of UCIs Institute for Immunology and Center for Virus Research.

Their surveillance study, funded by a $60,000 UCI grant and expected to last a year, will repeatedly examine 300 healthcare providers. The collection of samples has already begun.

We want to know how many of them may have already been exposed [to COVID-19] and didnt know about it and how many of them potentially have immunity, Ilhem Powers says. Well take blood samples and nose swabs to measure antibodies and T cell responses, which kill infected cells, as well as potential asymptomatic shedding. Its a multipronged approach.

Arriving at UCI in January 2017 after serving as a researcher and assistant professor at UC Riversides School of Medicine, she has years of experience studying how the human immune system interacts with emerging viral diseases such as Ebola, Chikungunya, Zika and monkeypox.

For some viruses, Ilhem Powers explains, antibodies are sufficient [to kill them]. For others, you need more of a T cell response. We dont yet know enough about this novel coronavirus.

More community surveillance needs to be done, she says: How many people have potential COVID-19 antibodies? We also need to look at the immune response in patients those currently in hospitals and then determine the difference between the immune response of those who end up in the ICU versus those who end up being sent home.

Health scare

Michael Powers, who began his residency at the Naval Medical Center San Diego in 2010, says the COVID-19 pandemic has forced him and other doctors to live with a lot of uncertainty.

But he has a stoic air about him despite his relatively new role of treating patients with a little-understood disease. Perhaps experiencing a serious lung-related health scare himself contributes to his even-keeled nature.

During his wifes last year at UC Riverside, Michael Powers went on an outreach mission to Ghana. Shortly after returning home, he developed MRSA in his lungs and had to undergo thoracic surgery. He spent 10 days in the hospital and 30 days in convalescence.

It was a pulmonologists worst nightmare, Ilhem Powers says. It was really scary.

So is COVID-19, her husband says: I think a lot of people have a very romanticized notion of what ICU-level care is and being on a ventilator. The movies definitely dont do it justice.

When people go on ventilators, its not at all uncommon for them to be on them for two weeks or more. Its not a pleasant thing to have a giant plastic tube down your throat and a machine telling you when to breathe.

Enjoying the little moments

Michael Powers says he takes extreme precautions at work and elsewhere in San Diego before driving up to Irvine to spend time with his wife and children.

People ask me all the time, Isnt he worried? Ilhem Powers says. They ask, Shouldnt he just stay in his apartment and not come up here and pose a health risk to you and your kids? And we just say we understand and accept the risk.

She and her colleagues get tested regularly for COVID-19 using equipment in their lab.

Having already weathered a lot of adversity, the couple believe theyre uniquely equipped to cope with COVID-19.

What we both do for a living, and our past experience dealing with crises, has put us in this perfect position to deal with this pandemic, he says.

For many people, she adds, this is the first time that things outside their control have completely dominated their life.

Often, the two will sit down and go over COVID-19 research papers together and compare notes, discussing where the pandemic is headed, possible therapies and longer term potential vaccines.

But they make sure that when theyre together, they shower most of their attention on Owen and Olivia.

When hes home, Ilhem Powers says of her husband, its family time. For us, its all about enjoying the little moments.

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Couple on the coronavirus front lines - UCI News

While in the UK the NHS kept tight control of testing until recently, the Portuguese government quickly realised spreading the load was the answer.

As recently as May 1 to 17, non-state labs were still responsible for more than half of the almost 14,000 tests being conducted daily.

But the roots of Portugals world-class Covid-19 testing regime began much earlier.According to Our World in Data whose testing rates have been cited by the OECD and others Portugal has been among the top 10 countries in the world for testing per capita since mid-April.

On Friday, Denmark (with a GDP per capita 2.7 times that of Portugal) and Lithuania (with a similar GDP per capita to Portugal) were the only nations of more than 2 million people with a higher testing rate.

Like most countries, Portugals initial testing efforts started slowly amid difficulties securing kits in a ferocious global market.

The stress initially was to provide testing, said biology professor Miguel Viveiros, deputy director of IMHT.

We were not prepared for testing in quantity for the speed of transmission. In early March, Portugal was testing less per capita than the UK and much of Europe.

Professor Maria Manuel Mota, director of the institute of molecular medicine at the University of Lisbon, was speaking to doctors at the large university hospital on campus. They were worried about having enough tests to make sure the disease wasnt spreading rapidly in the medical community, let alone for the wider population.

Obviously there will be no testing for everyone, they told her. It is a difficult test, it takes a few hours, you know, it's expensive.

Sitting at home on March 11, Professor Mota quickly discovered that didnt have to be the case, thanks to her institutes experience with PCR-based tests for malaria.

The test we do all the time in almost every single lab in our institute is PCR, so it should not be difficult, she remembered thinking. Instead of relying on expensive kits that come from abroad we could design something.

To lead the project, she called on researcher Vanessa Zuzarte Lus, who had a potential testing protocol in mind within a few hours. The next day they were speaking to a Portuguese company about manufacturing the reagents needed for the tests, one factor UK authorities blamed for testing difficulties.

They were ready and working within a week, leaving only accreditation from the Dr Ricardo Jorge National Institute of Health left to secure.

The Portuguese authorities were fantastic, Professor Mota said. As soon as I called the right people they told us okay, let's validate this together. The accreditation process ran smoothly and the tests were being rolled out to nursing homes by the end of March.

Within two or three weeks, university labs and private institutes across Portugal were using the protocol developed at IMM, or developing their own, to bolster public testing efforts.

In the UK, independent labs trying to take similar steps were still complaining their offers to help were being ignored as late as April 10, well after health secretary Matt Hancock set a target of 100,000 tests a day.

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Why Portugal's Covid-19 test rate is more than double almost every other nation - Telegraph.co.uk

Peng Gao,1,2 Shuo Shen,1,2 Xiaodong Li,3 Dandan Liu,1,2 Yuqing Meng,1,2 Yanqing Liu,1,2 Yongping Zhu,1,2 Junzhe Zhang,1,2 Piao Luo,1,2 Liwei Gu1,2

1Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, Peoples Republic of China; 2Artemisinin Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, Peoples Republic of China; 3Institute of Chinese Materia Medica, Gansu Provincial Hospital of Traditional Chinese Medicine, Lanzhou 730050, Peoples Republic of China

Correspondence: Liwei Gu Email lwgu@icmm.ac.cn

Background: Leukemia threatens so many lives around the world. Dihydroartemisinin (DHA), as a typical derivative of artemisinin (ART), can efficiently inhibit leukemia, but the controversial mechanisms are still controversial. Many reports showed that tumor cells acquire energy through the glycolysis pathway, pyruvate kinase M2 (PKM2) plays a crucial role in regulating glycolysis. However, it is unclear whether PKM2 or other key molecules are involved in DHA induced cytotoxicity in leukemia cells. Thus, this paper systematically investigated the anticancer effect and mechanism of DHA on human chronic myeloid leukemia K562 cells.Methods: In vitro, cytotoxicity was detected with CCK-8. Glucose uptake, lactate production and pyruvate kinase activity were investigated to evaluate the effect of DHA on K562 cells. To elucidate the cellular metabolism alterations induced by DHA, the extracellular acidification rate was assessed using Seahorse XF96 extracellular flux analyzer. Immunofluorescence, real-time PCR, and Western blotting were used to investigate the molecular mechanism.Results: We found that DHA prevented cell proliferation in K562 cells through inhibiting aerobic glycolysis. Lactate product and glucose uptake were inhibited after DHA treatment. Results showed that DHA modulates glucose uptake through downregulating glucose transporter 1 (GLUT1) in both gene and protein levels. The cytotoxicity of DHA on K562 cells was significantly reversed by PKM2 agonist DASA-58. Pyruvate kinase activity was significantly reduced after DHA treatment, decreased expression of PKM2 was confirmed in situ.Conclusion: The present study implicated that DHA inhibits leukemia cell proliferation by regulating glycolysis and metabolism, which mediated by downregulating PKM2 and GLUT1 expression. Our finding might enrich the artemisinins antitumor mechanisms.

Keywords: tumor, leukemia, glycolysis, DHA, PKM2, GLUT1

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

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Dihydroartemisinin Inhibits the Proliferation of Leukemia Cells K562 b | DDDT - Dove Medical Press