Efficacy and safety of simeprevir and sofosbuvir with and without ribavirin in subjects with recurrent genotype 1 hepatitis C postorthotopic liver transplant: the randomized GALAXY study

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136282/1/tri12896.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136282/2/tri12896_am.pd

Model for End‐Stage Liver Disease‐Lactate and Prediction of Inpatient Mortality in Patients With Chronic Liver Disease

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163652/3/hep31199.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163652/2/hep31199_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163652/1/hep31199-sup-0001-Supinfo.pd

Sofosbuvir and Ribavirin Prevent Recurrence of HCV Infection After Liver Transplantation: An Open-Label Study

Background & AimsPatients with detectable hepatitis C virus (HCV) RNA at the time of liver transplantation universally experience recurrent HCV infection. Antiviral treatment before transplantation can prevent HCV recurrence, but existing interferon-based regimens are poorly tolerated and are either ineffective or contraindicated in most patients. We performed a trial to determine whether sofosbuvir and ribavirin treatment before liver transplantation could prevent HCV recurrence afterward.MethodsIn a phase 2, open-label study, 61 patients with HCV of any genotype and cirrhosis (Child–Turcotte–Pugh score, ≤7) who were on waitlists for liver transplantation for hepatocellular carcinoma, received up to 48 weeks of sofosbuvir (400 mg) and ribavirin before liver transplantation. The primary end point was the proportion of patients with HCV-RNA levels less than 25 IU/mL at 12 weeks after transplantation among patients with this HCV-RNA level at their last measurement before transplantation.ResultsSixty-one patients received sofosbuvir and ribavirin, and 46 received transplanted livers. The per-protocol efficacy population consisted of 43 patients who had HCV-RNA level less than 25 IU/mL at the time of transplantation. Of these 43 patients, 30 (70%) had a post-transplantation virologic response at 12 weeks, 10 (23%) had recurrent infection, and 3 (7%) died (2 from nonfunction of the primary graft and 1 from complications of hepatic artery thrombosis). Of all 61 patients given sofosbuvir and ribavirin, 49% had a post-transplantation virologic response. Recurrence was related inversely to the number of consecutive days of undetectable HCV RNA before transplantation. The most frequently reported adverse events were fatigue (in 38% of patients), headache (23%), and anemia (21%).ConclusionsAdministration of sofosbuvir and ribavirin before liver transplantation can prevent post-transplant HCV recurrence. ClinicalTrials.gov: NCT01559844

Protein tyrosine phosphatases expression during development of mouse superior colliculus

Protein tyrosine phosphatases (PTPs) are key regulators of different processes during development of the central nervous system. However, expression patterns and potential roles of PTPs in the developing superior colliculus remain poorly investigated. In this study, a degenerate primer-based reverse transcription-polymerase chain reaction (RT-PCR) approach was used to isolate seven different intracellular PTPs and nine different receptor-type PTPs (RPTPs) from embryonic E15 mouse superior colliculus. Subsequently, the expression patterns of 11 PTPs (TC-PTP, PTP1C, PTP1D, PTP-MEG2, PTP-PEST, RPTPJ, RPTPε, RPTPRR, RPTPσ, RPTPκ and RPTPγ) were further analyzed in detail in superior colliculus from embryonic E13 to postnatal P20 stages by quantitative real-time RT-PCR, Western blotting and immunohistochemistry. Each of the 11 PTPs exhibits distinct spatiotemporal regulation of mRNAs and proteins in the developing superior colliculus suggesting their versatile roles in genesis of neuronal and glial cells and retinocollicular topographic mapping. At E13, additional double-immunohistochemical analysis revealed the expression of PTPs in collicular nestin-positive neural progenitor cells and RC-2-immunoreactive radial glia cells, indicating the potential functional importance of PTPs in neurogenesis and gliogenesis

Recellularization of rat liver: An in vitro model for assessing human drug metabolism and liver biology

<div><p>Liver-like organoids that recapitulate the complex functions of the whole liver by combining cells, scaffolds, and mechanical or chemical cues are becoming important models for studying liver biology and drug metabolism. The advantages of growing cells in three-dimensional constructs include enhanced cell-cell and cell-extracellular matrix interactions and preserved cellular phenotype including, prevention of de-differentiation. In the current study, biomimetic liver constructs were made via perfusion decellularization of rat liver, with the goal of maintaining the native composition and structure of the extracellular matrix. We optimized our decellularization process to produce liver scaffolds in which immunogenic residual DNA was removed but glycosaminoglycans were maintained. When the constructs were recellularized with rat or human liver cells, the cells remained viable, capable of proliferation, and functional for 28 days. Specifically, the cells continued to express cytochrome P450 genes and maintained their ability to metabolize a model drug, midazolam. Microarray analysis showed an upregulation of genes involved in liver regeneration and fibrosis. In conclusion, these liver constructs have the potential to be used as test beds for studying liver biology and drug metabolism.</p></div

Acellular matrix characterization.

<p>Acellular matrix characterization.</p

Heat map showing gene expression levels (z-scores) on days 2, 15, and 28 after recellularization with twenty million rat liver cells and clustering of microarray data.

<p>Heat map showing gene expression levels (z-scores) on days 2, 15, and 28 after recellularization with twenty million rat liver cells and clustering of microarray data.</p

Acellular matrix characterization.

<p>Acellular matrix characterization.</p

Functional activity including production of albumin and urea, and consumption of glucose in liver constructs recellularized with twenty million rat liver cells.

<p>(A-C) Albumin production (A), urea production (B), and glucose concentration (C) were measured in culture medium from recellularized liver constructs over a 28-day period. Values shown are the average for 4 different recellularized constructs. Error bars depict the standard error of the mean. These livers were decellularized using the same protocol (3.2 L of 1% SDS followed by DNase treatment).</p