198 results match your criteria: "Baruch S. Blumberg Institute[Affiliation]"

New insights into protein-protein interaction modulators in drug discovery and therapeutic advance.

Signal Transduct Target Ther

December 2024

BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang, Republic of Korea.

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Cholangiocarcinoma (CCA) is a rare cancer that arises from the bile duct and is broadly classified by the location of the tumor as either intrahepatic (iCCA) or extrahepatic (eCCA). Immunotherapy has revolutionized cancer treatment, yet its utility in CCA has been limited as the tumor microenvironment (TME) in CCA is poorly understood compared to other common cancers. Utilizing previously published transcriptome data, our re-analysis has revealed that CCA has one of the highest relative levels of natural killer (NK) cells, a potent cytotoxic immune cell, compared to other cancers.

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  • * Recent efforts to stop smoking haven't been put into action yet, and it’s important to see what could happen if smoking rates stay the same or improve.
  • * Researchers used models to predict health outcomes by 2050 based on different scenarios of smoking rates, showing that cutting smoking could greatly improve health and life expectancy.
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  • Researchers studied strokes from 1990 to 2021 to understand how many people get them and how they are affected around the world.
  • In 2021, strokes caused about 7.3 million deaths and were a major cause of health problems, especially in specific regions like Southeast Asia and Oceania.
  • There are differences in stroke risks based on where people live and their age, and some areas actually saw more strokes happening since 2015.
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Chronic hepatitis B virus (HBV) infection is due to the failure of host immune system to resolve the viral infection. Accordingly, restoration or reconstitution of a functional antiviral immune response to HBV is essential to achieve durable control of HBV replication leading to a functional cure of chronic hepatitis B (CHB). Noninfectious subviral particles (SVPs), comprised of HBV surface antigen (HBsAg), are the predominant viral products secreted by HBV-infected hepatocytes.

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Type 1 polyketides are a major class of natural products used as antiviral, antibiotic, antifungal, antiparasitic, immunosuppressive, and antitumor drugs. Analysis of public microbial genomes leads to the discovery of over sixty thousand type 1 polyketide gene clusters. However, the molecular products of only about a hundred of these clusters are characterized, leaving most metabolites unknown.

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Hepatitis B virus (HBV) integration exists throughout the clinical course of chronic hepatitis B (CHB). This study investigated the effects of long-term antiviral therapy on the level and profiles of transcriptionally active HBV integration. Serial liver biopsies and paired blood samples were obtained from 16, 16, and 22 patients with CHB at baseline, 78, and 260 weeks of entecavir monotherapy or combined with pegylated interferon alfa, respectively.

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An allosteric inhibitor of sirtuin 2 blocks hepatitis B virus covalently closed circular DNA establishment and its transcriptional activity.

Antiviral Res

June 2024

Evrys Bio, LLC, Pennsylvania Biotechnology Center, Doylestown, PA, 18902, USA; Department of Molecular Biology, Princeton University, Princeton, NJ, 08540, USA.

296 million people worldwide are predisposed to developing severe end-stage liver diseases due to chronic hepatitis B virus (HBV) infection. HBV forms covalently closed circular DNA (cccDNA) molecules that persist as episomal DNA in the nucleus of infected hepatocytes and drive viral replication. Occasionally, the HBV genome becomes integrated into host chromosomal DNA, a process that is believed to significantly contribute to circulating HBsAg levels and HCC development.

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Antigenic drift is a major driver of viral evolution and a primary reason why influenza vaccines must be reformulated annually. Mismatch between vaccine and circulating viral strains negatively affects vaccine effectiveness and often contributes to higher rates of influenza-related hospitalizations and deaths, particularly in years dominated by A(H3N2). Several countries recommend enhanced influenza vaccines for older adults, who are at the highest risk of severe influenza complications and mortality.

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Precore mutation enhances viral replication to facilitate persistent infection especially in HBeAg-negative patients.

Virol Sin

April 2024

Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, 100044, China; Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing, 100191, China. Electronic address:

Naturally occurred precore (PC, G1896A) and/or basal core promoter (BCP, A1762T/G1764A) mutations are prevalent in chronic HBV-infected patients, especially those under HBeAg-negative status. However, the replicative capacity of HBV with PC/BCP mutations remains ambiguous. Herein, meta-analysis showed that, only under HBeAg-negative status, the serum HBV DNA load in patients with PC mutation was 7.

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Dihydroquinolizinones (DHQs) that inhibit cellular polyadenylating polymerases 5 and 7 (PAPD5 & 7), such as RG7834, have been shown to inhibit both hepatitis A (HAV) and hepatitis B virus (HBV) in vitro and in vivo. In this report, we describe RG7834-based proteolysis-targeting chimeras (PROTACs), such as compound 12b, (6S)-9-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-21-oxo-3,6,9,12,15,18-hexaoxa-22-azapentacosan-25-yl)oxy)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid. The PROTAC DHQs described here inhibited an HAV reporter virus in vitro with an IC of 277 nM.

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microbeMASST, a taxonomically informed mass spectrometry (MS) search tool, tackles limited microbial metabolite annotation in untargeted metabolomics experiments. Leveraging a curated database of >60,000 microbial monocultures, users can search known and unknown MS/MS spectra and link them to their respective microbial producers via MS/MS fragmentation patterns. Identification of microbe-derived metabolites and relative producers without a priori knowledge will vastly enhance the understanding of microorganisms' role in ecology and human health.

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The delivery of a drug to a specific organ or tissue at an efficacious concentration is the pharmacokinetic (PK) hallmark of promoting effective pharmacological action at a target site with an acceptable safety profile. Sub-optimal pharmaceutical or ADME profiles of drug candidates, which can often be a function of inherently poor physicochemical properties, pose significant challenges to drug discovery and development teams and may contribute to high compound attrition rates. Medicinal chemists have exploited prodrugs as an informed strategy to productively enhance the profiles of new chemical entities by optimizing the physicochemical, biopharmaceutical, and pharmacokinetic properties as well as selectively delivering a molecule to the site of action as a means of addressing a range of limitations.

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The essential G-cyclin, CCND1, is frequently overexpressed in cancer, contributing to tumorigenesis by driving cell-cycle progression. D-type cyclins are rate-limiting regulators of G-S progression in mammalian cells via their ability to bind and activate CDK4 and CDK6. In addition, cyclin D1 conveys kinase-independent transcriptional functions of cyclin D1.

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  • * The study examined tissue samples to see if integrated HBV DNA (iDNA) was the main factor behind ongoing pre-S expression in GGHs after antiviral therapy, finding detectable iDNA and specific genetic integrations in many patients.
  • * Long-read sequencing confirmed the presence of varying pre-S deletions across different tissues, suggesting that these deletions may occur after iDNA integration, highlighting the complexity of HBV's effects on liver cells.
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  • The study presents a novel method for creating C-N axial enantiomers using an atroposelective Chan-Lam coupling technique.
  • The reaction achieved good yields and high enantiomeric excess (ee), demonstrating its effectiveness.
  • A manganese oxide (MnO) additive was found to be essential for the success of the coupling, addressing a significant challenge in making chiral C-N linked atropisomers.
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Hepatitis B virus (HBV) chronically infects 296 million people worldwide and causes more than 820,000 deaths annually due to cirrhosis and hepatocellular carcinoma. Current standard-of-care medications for chronic hepatitis B (CHB) include nucleos(t)ide analogue (NA) viral DNA polymerase inhibitors and pegylated interferon alpha (PEG-IFN-α). NAs can efficiently suppress viral replication and improve liver pathology, but not eliminate or inactivate HBV covalently closed circular DNA (cccDNA).

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An optimized hepatocellular carcinoma (HCC)-targeted methylation next generation sequencing assay was developed to discover HCC-associated methylation markers directly from urine for HCC screening. Urine cell-free DNA (ucfDNA) isolated from a discovery cohort of 31 non-HCC and 30 HCC was used for biomarker discovery, identifying 29 genes with differentially methylated regions (DMRs). Methylation-specific qPCR (MSqPCR) assays were developed to verify the selected DMRs corresponding to 8 genes (GRASP, CCND2, HOXA9, BMP4, VIM, EMX1, SFRP1, and ECE).

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This study evaluated the impact of cell debris and 7-day room temperature storage on the quality and yield of transrenal DNA. Archived urine specimens collected from five hepatocellular carcinoma (HCC) patients and two pregnant women carrying male fetuses were used to assess the impact of cell debris on urine cell-free DNA (ucfDNA) isolation as measured by quantitative PCR for Y-chromosome DNA, or HCC-associated mutation and methylation markers, and by capillary electrophoresis. Prospectively collected urine from 21 HCC patients was aliquoted after collection for paired immediate freezing versus 7-day room temperature storage followed by freezing for further analysis.

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The G-protein-coupled receptor C-C chemokine receptor 5 (CCR5) functions as a co-receptor for the entry of HIV into immune cells. CCR5 binds promiscuously to a diverse array of ligands initiating cell signaling that includes guided migration. Although well known to be expressed on immune cells, recent studies have shown the induction of CCR5 on the surface of breast cancer epithelial cells.

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RNA binding protein TIAR modulates HBV replication by tipping the balance of pgRNA translation.

Signal Transduct Target Ther

September 2023

Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.

Article Synopsis
  • The pregenomic RNA (pgRNA) of hepatitis B virus (HBV) functions as a messenger RNA for translating core protein and DNA polymerase, while also serving as a template for viral DNA replication within the nucleocapsid.* -
  • A study identified TIAR as a cellular protein that binds pgRNA and influences HBV DNA replication, showing that manipulating TIAR levels doesn't change HBV transcript or antigen secretion but affects the translation rates of core protein and polymerase.* -
  • Data suggest that TIAR binds to a specific structure in pgRNA, altering the translation balance between core protein and polymerase, with its activity being regulated by HBV replication itself, highlighting TIAR's role in optimizing HBV replication in
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Characterization of CCoV-HuPn-2018 spike protein-mediated viral entry.

J Virol

September 2023

Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.

Article Synopsis
  • - CCoV-HuPn-2018 is a newly identified human pneumonia-causing coronavirus that originated from a canine virus, highlighting cross-species transmission.
  • - Research shows that while CCoV-HuPn-2018 usually can't enter human cells, it can use receptors from Mexican free-tailed bats and can infect certain human cancer cell lines without needing human receptors.
  • - The study enhances our understanding of the virus's ability to infect across species and the factors that restrict its entry into human cells, suggesting it has not yet become a highly efficient human pathogen.
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Sub-stoichiometric Modulation of Viral Targets-Potent Antiviral Agents That Exploit Target Vulnerability.

ACS Med Chem Lett

August 2023

Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, Pennsylvania 18902, United States.

The modulation of oligomeric viral targets at sub-stoichiometric ratios of drug to target has been advocated for its efficacy and potency, but there are only a limited number of documented examples. In this Viewpoint, we summarize the invention of the HIV-1 maturation inhibitor fipravirimat and discuss the emerging details around the mode of action of this class of drug that reflects inhibition of a protein composed of 1,300-1,600 monomers that interact in a cooperative fashion. Similarly, the HCV NS5A inhibitor daclatasvir has been shown to act in a highly sub-stoichiometric fashion, inhibiting viral replication at concentrations that are ∼23,500 lower than that of the protein target.

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