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Susan Uprichard

Peter Kumberger, Karina Durso-Cain, Susan L Uprichard, Harel Dahari, Frederik Graw
Mathematical models based on ordinary differential equations (ODE) that describe the population dynamics of viruses and infected cells have been an essential tool to characterize and quantify viral infection dynamics. Although an important aspect of viral infection is the dynamics of viral spread, which includes transmission by cell-free virions and direct cell-to-cell transmission, models used so far ignored cell-to-cell transmission completely, or accounted for this process by simple mass-action kinetics between infected and uninfected cells...
April 17, 2018: Viruses
Yuji Ishida, Tje Lin Chung, Michio Imamura, Nobuhiko Hiraga, Suranjana Sen, Hiroshi Yokomichi, Chise Tateno, Laetitia Canini, Alan S Perelson, Susan L Uprichard, Harel Dahari, Kazuaki Chayama
BACKGROUND: Chimeric uPA/SCID mice reconstituted with humanized livers are useful for studying HBV infection in the absence of an adaptive immune response. However, the detailed characterization of HBV infection kinetics necessary to enable in-depth mechanistic studies in this novel in vivo HBV infection model is lacking. METHODS: To characterize HBV kinetics post-inoculation (p.i.) to steady state, 42 mice were inoculated with HBV. Serum HBV DNA was frequently measured from 1 minute to 63 days p...
March 23, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Thomas R Aunins, Katherine A Marsh, Gitanjali Subramanya, Susan L Uprichard, Alan S Perelson, Anushree Chatterjee
Hepatitis C virus infection is a global health problem, with nearly 2 million new infections occurring every year and up to 85% of these becoming chronic infections that pose serious long-term health risks. To effectively reduce the prevalence of HCV infection and associated diseases, it is important to understand the intracellular dynamics of the viral lifecycle. Here, we present a detailed mathematical model that represents the full hepatitis C lifecycle. It is the first full HCV model to be fit to acute intracellular infection data and the first to explore the functions of distinct viral proteins, probing multiple hypotheses of cis - and trans -acting mechanisms to provide insights for drug targeting...
March 21, 2018: Journal of Virology
Laetitia Canini, Christopher Koh, Scott J Cotler, Susan L Uprichard, Mark A Winters, Ma Ai Thanda Han, David E Kleiner, Ramazan Idilman, Cihan Yurdaydin, Jeffrey S Glenn, Theo Heller, Harel Dahari
The prenylation inhibitor lonafarnib (LNF) is a potent antiviral agent providing a breakthrough for the treatment of hepatitis delta virus (HDV). The current study used a maximum likelihood approach to model LNF pharmacokinetic (PK) and pharmacodynamic (PD) parameters and predict the dose needed to achieve 99% efficacy using data from 12 patients chronically infected with HDV and treated with LNF 100 mg twice daily (bid) (group 1) or 200 mg bid (group 2) for 28 days. The LNF-PK model predicted average steady-state LNF concentrations of 860 ng/mL and 1,734 ng/mL in groups 1 and 2, respectively, with an LNF absorption rate ka = 0...
June 2017: Hepatology Communications
Laetitia Canini, Michio Imamura, Yoshiiku Kawakami, Susan L Uprichard, Scott J Cotler, Harel Dahari, Kazuaki Chayama
BACKGROUND & AIMS: High cure rates are achieved in HCV genotype-1b patients treated with daclatasvir and asunaprevir, DCV/ASV. Here we analyzed early HCV kinetics in genotype-1b infected Japanese subjects treated with DCV/ASV and retrospectively projected, using mathematical modeling, whether shorter treatment durations might be effective. METHODS: HCV RNA levels were measured frequently during DCV/ASV therapy in 95 consecutively treated patients at a single center in Japan...
2017: PloS One
Thi Huyen Tram Nguyen, Jérémie Guedj, Susan L Uprichard, Anita Kohli, Shyam Kottilil, Alan S Perelson
High sustained virologic response (SVR) rates have been observed after 6 weeks of anti-HCV treatment using sofosbuvir, ledipasvir and a non-nucleoside polymerase-inhibitor (GS-9669) or a protease-inhibitor (GS-9451) and after 12 weeks with sofosbuvir + ledipasvir. Here we analyze the viral kinetics observed during these treatments to decipher the origin of the rapid cure and to evaluate the possibility of further reducing treatment duration. We found that viral kinetics were surprisingly slow in all treatment groups and could not reproduce the high SVR rates observed...
August 31, 2017: Scientific Reports
Ashish Goyal, Yoav Lurie, Eric G Meissner, Marian Major, Natasha Sansone, Susan L Uprichard, Scott J Cotler, Harel Dahari
BACKGROUND: Cases of sustained-virological response (SVR or cure) after an ultra-short duration (≤27 days) of direct-acting antiviral (DAA)-based therapy, despite HCV being detected at end of treatment (EOT), have been reported. Established HCV mathematical models that predict the treatment duration required to achieve cure do not take into account the possibility that the infectivity of virus produced during treatment might be reduced. The aim of this study was to develop a new mathematical model that considers the fundamental and critical concept that HCV RNA in serum represents both infectious virus (Vi) and non-infectious virus (Vni) in order to explain the observation of cure with ultrashort DAA therapy...
June 30, 2017: Antiviral Research
Miguel Malespin, Tamara Benyashvili, Susan L Uprichard, Alan S Perelson, Harel Dahari, Scott J Cotler
BACKGROUND: Some chronic hepatitis C virus (HCV), genotype 1 infected patients treated with direct antiviral agents (DAAs) remain viremic at end of treatment (EOT+), yet go on to achieve sustained virological response 12 weeks after completion of therapy (SVR12 ). The incidence of EOT+/SVR in patients with genotype 1 and other genotypes, as well as whether such patients achieve SVR24 remain in question. The aims of this study were to evaluate the frequency and durability of EOT+/SVR12&24 and other response categories in HCV genotype 1, 2, or 3 infected patients treated with DAA in clinical practice...
January 2017: Therapeutic Advances in Gastroenterology
Yaakov Hasin, Shimon Shteingart, Harel Dahari, Inna Gafanovich, Sharon Floru, Marius Braun, Amir Shlomai, Anthony Verstandig, Ilana Dery, Susan L Uprichard, Scott J Cotler, Yoav Lurie
The United States Food and Drug Administration recently warned that the direct acting antiviral (DAA) combination hepatitis C virus (HCV) treatment of Paritaprevir, Ombitasvir, Dasabuvir, Ritonavir, and Ribavirin (PODr + R) can cause severe liver injury in patients with advanced liver disease. Drug induced liver injury was observed in a small number of patients with decompensated cirrhosis treated with other DAAs, but has not been reported in patients with compensated cirrhosis. We report a case of a 74-year-old woman with chronic HCV and Child-Pugh class A cirrhosis (compensated cirrhosis) treated with PODr + R...
July 18, 2016: World Journal of Hepatology
Harel Dahari, Laetitia Canini, Frederik Graw, Susan L Uprichard, Evaldo S A Araújo, Guillaume Penaranda, Emilie Coquet, Laurent Chiche, Aurelie Riso, Christophe Renou, Marc Bourliere, Scott J Cotler, Philippe Halfon
BACKGROUND & AIMS: Recent clinical trials of direct-acting-antiviral agents (DAAs) against hepatitis C virus (HCV) achieved >90% sustained virological response (SVR) rates, suggesting that cure often took place before the end of treatment (EOT). We sought to evaluate retrospectively whether early response kinetics can provide the basis to individualize therapy to achieve optimal results while reducing duration and cost. METHODS: 58 chronic HCV patients were treated with 12-week sofosbuvir+simeprevir (n=19), sofosbuvir+daclatasvir (n=19), or sofosbuvir+ledipasvir in three French referral centers...
June 2016: Journal of Hepatology
Kevin Anthony, Gitanjali Subramanya, Susan Uprichard, Faiza Hammouda, Mahmoud Saleh
Milk thistle dietary supplements that contain silymarin are widely marketed and used in the USA and other countries for liver enhancement and recovery. More recently, silymarin has also been identified as a possible antiviral for the treatment of hepatitis C virus (HCV) infection. To assess different brands of commercially sold silymarin, 45 products were collected from local stores and analyzed for their silymarin content, antioxidant activities, and antiviral activity against HCV. Antioxidant activity was measured as radical scavenging activity using DPPH and by estimating their antioxidant capacity as trolox equivalent...
February 6, 2013: Antioxidants (Basel, Switzerland)
Christopher Koh, Laetitia Canini, Harel Dahari, Xiongce Zhao, Susan L Uprichard, Vanessa Haynes-Williams, Mark A Winters, Gitanjali Subramanya, Stewart L Cooper, Peter Pinto, Erin F Wolff, Rachel Bishop, Ma Ai Thanda Han, Scott J Cotler, David E Kleiner, Onur Keskin, Ramazan Idilman, Cihan Yurdaydin, Jeffrey S Glenn, Theo Heller
BACKGROUND: Therapies for chronic hepatitis delta virus (HDV) infection are unsatisfactory. Prenylation is essential for HDV and inhibition abrogates HDV production in experimental models. In a proof-of-concept study, we aimed to assess the effect on HDV RNA levels, safety, and tolerability of the prenylation inhibitor lonafarnib in patients with chronic delta hepatitis. METHODS: In this phase 2A double-blind, randomised, placebo-controlled study, patients aged 18 years or older with chronic HDV infection were randomly assigned (3:1 in group 1 and 2:1 in group 2) to receive lonafarnib 100 mg (group 1) or lonafarnib 200 mg (group 2) twice daily for 28 days with 6 months' follow-up...
October 2015: Lancet Infectious Diseases
Frederik Graw, Danyelle N Martin, Alan S Perelson, Susan L Uprichard, Harel Dahari
UNLABELLED: It has been proposed that viral cell-to-cell transmission plays a role in establishing and maintaining chronic infections. Thus, understanding the mechanisms and kinetics of cell-to-cell spread is fundamental to elucidating the dynamics of infection and may provide insight into factors that determine chronicity. Because hepatitis C virus (HCV) spreads from cell to cell and has a chronicity rate of up to 80% in exposed individuals, we examined the dynamics of HCV cell-to-cell spread in vitro and quantified the effect of inhibiting individual host factors...
July 2015: Journal of Virology
Ali Sabahi, Susan L Uprichard, William C Wimley, Srikanta Dash, Robert F Garry
Hepatitis C virus (HCV), a member of the family Flaviviridae, is a leading cause of chronic liver disease and cancer. Recent advances in HCV therapeutics have resulted in improved cure rates, but an HCV vaccine is not available and is urgently needed to control the global pandemic. Vaccine development has been hampered by the lack of high-resolution structural information for the two HCV envelope glycoproteins, E1 and E2. Recently, Kong and coworkers (Science 342:1090-1094, 2013, doi:10.1126/science.1243876) and Khan and coworkers (Nature 509[7500]:381-384, 2014, doi:10...
September 2014: Journal of Virology
Naina Barretto, Bruno Sainz, Snawar Hussain, Susan L Uprichard
UNLABELLED: Hepatitis C virus (HCV) infects 180 million people worldwide and is a leading cause of liver diseases such as fibrosis, cirrhosis, and hepatocellular carcinoma. It has been shown that HCV can spread to naive cells using two distinct entry mechanisms, "cell-free" entry of infectious extracellular virions that have been released by infected cells and direct "cell-to-cell" transmission. Here, we examined host cell requirements for HCV spread and found that the cholesterol uptake receptor NPC1L1, which we recently identified as being an antiviral target involved in HCV cell-free entry/spread, is also required for the cell-to-cell spread...
May 2014: Journal of Virology
Susan L Uprichard
No abstract text is available yet for this article.
May 2014: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Hyun Lee, Tian Zhu, Kavankumar Patel, Yan-Yan Zhang, Lena Truong, Kirk E Hevener, Joseph L Gatuz, Gitanjali Subramanya, Hyun-Young Jeong, Susan L Uprichard, Michael E Johnson
Development of drug-resistant mutations has been a major problem with all currently developed Hepatitis C Virus (HCV) NS3/4A inhibitors, including the two FDA approved drugs, significantly reducing the efficacy of these inhibitors. The high incidence of drug-resistance mutations and the limited utility of these inhibitors against only genotype 1 highlight the need for novel, broad-spectrum HCV therapies. Here we used high-throughput screening (HTS) to identify low molecular weight inhibitors against NS3/4A from multiple genotypes...
2013: PloS One
Jeremie Guedj, Harel Dahari, Susan L Uprichard, Alan S Perelson
No abstract text is available yet for this article.
July 2013: Expert Review of Gastroenterology & Hepatology
Danyelle N Martin, Susan L Uprichard
Hepatitis C virus (HCV) is a liver tropic pathogen that affects ∼170 million people worldwide and causes liver pathologies including fibrosis, cirrhosis, steatosis, iron overload, and hepatocellular carcinoma. As part of a project initially directed at understanding how HCV may disrupt cellular iron homeostasis, we found that HCV alters expression of the iron uptake receptor transferrin receptor 1 (TfR1). After further investigation, we found that TfR1 mediates HCV entry. Specifically, functional studies showed that TfR1 knockdown and antibody blocking inhibit HCV cell culture (HCVcc) infection...
June 25, 2013: Proceedings of the National Academy of Sciences of the United States of America
Jeremie Guedj, Harel Dahari, Libin Rong, Natasha D Sansone, Richard E Nettles, Scott J Cotler, Thomas J Layden, Susan L Uprichard, Alan S Perelson
The nonstructural 5A (NS5A) protein is a target for drug development against hepatitis C virus (HCV). Interestingly, the NS5A inhibitor daclatasvir (BMS-790052) caused a decrease in serum HCV RNA levels by about two orders of magnitude within 6 h of administration. However, NS5A has no known enzymatic functions, making it difficult to understand daclatasvir's mode of action (MOA) and to estimate its antiviral effectiveness. Modeling viral kinetics during therapy has provided important insights into the MOA and effectiveness of a variety of anti-HCV agents...
March 5, 2013: Proceedings of the National Academy of Sciences of the United States of America
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