Pretransplant serum hepatitis C virus RNA levels predict response to antiviral treatment after living donor liver transplantation.

[Background]Given the limited efficacy and high adverse event rate associated with treatment of recurrent hepatitis C after liver transplantation, an individualized treatment strategy should be considered. The aim of this study was to identify predictors of response to antiviral therapy for hepatitis C after living donor liver transplantation (LDLT) and to study the associated adverse events. [Methods]A retrospective chart review was performed on 125 hepatitis C virus (HCV)-positive LDLT recipients who received interferon plus ribavirin and/or peginterferon plus ribavirin therapy at Kyoto University between January 2001 and June 2011. [Results]Serum HCV RNA reached undetectable levels within 48 weeks in 77 (62%) of 125 patients, and these patients were defined as showing virological response (VR). Of 117 patients, 50 (43%) achieved sustained VR (SVR). Predictive factors associated with both VR and SVR by univariate analysis included low pretransplant serum HCV RNA levels, a non-1 HCV genotype, and low pretreatment serum HCV RNA levels. In addition, LDLT from ABO-mismatched donors was significantly associated with VR, and white cell and neutrophil counts before interferon therapy were associated with SVR. Multivariate analysis showed that 2 variables–pretransplant serum HCV RNA level less than 500 kIU/mL and a non-1 HCV genotype–remained in models of both VR and SVR and that an ABO mismatch was associated with VR. No variables with a significant effect on treatment withdrawal were found. [Conclusions]Virological response to antiviral therapy in patients with hepatitis C recurring after LDLT can be predicted prior to transplant, based on pretransplant serum HCV-RNA levels and HCV genotype. LDLT from ABO-mismatched donors may contribute to more efficacious interferon therapy

The clinical significance of 5% change in vital capacity in patients with idiopathic pulmonary fibrosis: extended analysis of the pirfenidone trial

<p>Abstract</p> <p>Background</p> <p>Our phase III clinical trial of pirfenidone for patients with idiopathic pulmonary fibrosis (IPF) revealed the efficacy in reducing the decline of vital capacity (VC) and increasing the progression-free survival (PFS) time by pirfenidone. Recently, marginal decline in forced VC (FVC) has been reported to be associated with poor outcome in IPF. We sought to evaluate the efficacy of pirfenidone from the aspects of 5% change in VC.</p> <p>Methods</p> <p>Improvement ratings based on 5% change in absolute VC, i.e., "improved (VC ≥ 5% increase)", "stable (VC < 5% change)", and "worsened (VC ≥ 5% decrease)" at month 3, 6, 9 and 12 were compared between high-dose pirfenidone (1800 mg/day; n = 108) and placebo (n = 104) groups, and (high-dose and low-dose (1200 mg/day; n = 55)) pirfenidone (n = 163) and placebo groups. PFS times with defining the disease progression as death or a ≥ 5% decline in VC were also compared between high-dose pirfenidone and placebo groups, and low-dose pirfenidone and placebo groups. Furthermore, considering "worsened" and "non-worsened (improved and stable)" of the ratings at months 3 and 12 as "positive" and "negative", respectively, and the positive and negative predictive values of the ratings were calculated in each group.</p> <p>Results</p> <p>In the comparison of the improvement ratings, the statistically significant differences were clearly revealed at months 3, 6, 9, and 12 between pirfenidone and placebo groups. Risk reductions by pirfenidone to placebo were approximately 35% over the study period. In the comparison of the PFS times, statistically significant difference was also observed between pirfenidone and placebo groups. The positive/negative predictive values in placebo and pirfenidone groups were 86.1%/50.8% and 87.1%/71.7%, respectively. Further, the baseline characteristics of patients worsened at month 3 had generally severe impairment, and their clinical outcomes including mortality were also significantly worsened after 1 year.</p> <p>Conclusions</p> <p>The efficacy of pirfenidone in Japanese phase III trial was supported by the rating of 5% decline in VC, and the VC changes at month 3 may be used as a prognostic factor of IPF.</p> <p>Trial Registration</p> <p>This clinical trial was registered with the Japan Pharmaceutical Information Center (JAPIC) on September 13^th, 2005 (Registration Number: JAPICCTI-050121).</p

Development of a Reduction‐Responsive Amino Acid that Induces Peptide Bond Cleavage in Hypoxic Cells

Utilization of a hypoxia-responsive amino acid is indispensable in the preparation of hypoxic tumor-specific peptidyl prodrugs. Bioreduction of a nitro group is among the most attractive triggering reactions in the hypoxia-responsive prodrugs. In this paper, design and synthesis of a reduction-responsive amino acid that induces peptide bond cleavage after reduction of the nitro group are described. Application to hypoxia-responsive peptide bond cleavage system is also reported

Development of a Reduction‐Responsive Amino Acid that Induces Peptide Bond Cleavage in Hypoxic Cells

Utilization of a hypoxia-responsive amino acid is indispensable in the preparation of hypoxic tumor-specific peptidyl prodrugs. Bioreduction of a nitro group is among the most attractive triggering reactions in the hypoxia-responsive prodrugs. In this paper, design and synthesis of a reduction-responsive amino acid that induces peptide bond cleavage after reduction of the nitro group are described. Application to hypoxia-responsive peptide bond cleavage system is also reported

Kansei Evaluation in Agent Rearing Game

In this paper， We have studied the Kansei evaluation of the agent rearing game. The agent rearing game is a game by which the characters who are the agents are brouht up. The Kansei evaluation is an evaluation by Kansei engineering like the sensibility and feelings， etc. to treat technological1y. In this research， We produced the agent rearing game. We propose the method of the interesting the game using the technique of Kansei engineering for the evaluation

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Heme Iron Coordination Structure of Heme Transport Protein HutB from Vibrio Cholerae

HutB is a putative heme transport protein located in the periplasmic space in Vibrio cholerae. Here, we purified HutB and characterized its heme binding properties. An analysis of the Soret band showed that there are two types of heme binding geometries depending on the heme concentration: 404-nm species are dominant at lower concentrations of heme, and 394-nm species dominate at higher concentrations. Moreover, a mutational study revealed that either Tyr65 or Tyr198 binds heme with the help of histidine, a property shared with another V. cholerae heme transport protein, HutX, despite the absence of sequence similarity, indicating that HutB acts as a heme transport protein in the periplasm