Association of preoperative serum CRP with PD-L1 expression in 508 patients with non-small cell lung cancer: A comprehensive analysis of systemic inflammatory markers

Objectives

Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have been approved as a standard therapy for metastatic non-small cell lung cancer (NSCLC). Although PD-L1 expression serves as a predictive biomarker for the efficacy of immunotherapy, there are no established biomarkers to predict the expression of PD-L1. The inflammatory markers C-reactive protein (CRP) and neutrophil-lymphocyte ratio (NLR) were recently shown to predict the efficacy of nivolumab for NSCLC patients. Therefore, here we investigated the potential association of PD-L1 expression with systemic inflammatory markers, including CRP, NLR, lymphocyte-monocyte ratio and platelet-lymphocyte ratio.

Asunaprevir and daclatasvir for recurrent hepatitis C after liver transplantation: A Japanese multicenter experience

The safety and efficacy of an IFN‐free regimen using asunaprevir (ASV) and daclatasvir (DCV) for recurrent hepatitis C virus (HCV) infection after liver transplantation (LT) have not been evaluated in Japan. A multicenter study of LT recipients (n = 74) with recurrent HCV genotype 1b infection treated with ASV‐DCV for 24 weeks was performed. Medical history was positive for pegylated interferon and ribavirin (Peg‐IFN/RBV) in 40 (54.1%) patients, and for simeprevir (SMV) with Peg‐IFN/RBV in 12 (16.2%) patients. Resistance‐associated variants (RAVs) were positive at D168 (n = 1) in the NS3, and at L31 (n = 4), Y93 (n = 4), and L31/Y93 (n = 1) in the NS5A region of the HCV genome. Sixty‐one (82.4%) patients completed the 24‐week treatment protocol. Although sustained viral response (SVR) was achieved in 49 (80.3%) patients, it was achieved in only two (16.7%) patients among those with histories of receiving SMV (n = 12). Univariate analysis showed that a history of SMV (P < .01) and the presence of mutations in NS5A (P = .02) were the significant factors for no‐SVR. By excluding the patients with either a history of SMV‐based treatment or RAVs in NS3/NS5A, the SVR rate was 96.4%. By excluding the patients with a history of SMV and those with RAVs in NS3/NS5A, viral clearance of ASV‐DCV was favorable, with a high SVR rate.     

Ventricular repolarization lability in children with Kawasaki disease

Kawasaki disease (KD) is an acute febrile disease of unknown etiology that develops in children and is sometimes accompanied by myocardial dysfunction and systemic vasculitis. However, myocardial repolarization lability has not yet been fully investigated. Thus, the objective of this study was to evaluate myocardial repolarization lability (QT variability index??QTVI) based on the body surface electrocardiograms in the acute and recovery phases. The subjects were 25 children with acute KD who were hospitalized for treatment. An equal number of age-matched healthy children were selected as controls. The RR-intervals and QT-intervals were measured based on a body surface electrocardiogram of 120 consecutive heartbeats to calculate the QTVI. The QTVI values were then compared with the acute and recovery phases. The relationships between blood biochemistry data and QTVI values were also examined. QTVI was significantly decreased from the acute phase to the recovery phase (P?<?0.05) and then recovered to the same level as that of the control. QTVI in the acute phase showed a significant positive relationship with body temperature and C-reactive protein (P?<0.05). QTVI was high in the acute phase and was correlated with an inflammatory reaction and became normalized during the recovery phase.     

Abnormal lysine acetylation with postovulatory oocyte aging

Background

A postovulatory mammalian oocyte decreases developmental potential with in vivo aging in the oviduct or in vitro aging in the culture dish. The mechanism underlying oocyte aging still largely remains an enigma. Accumulating data suggest that the epigenetic alterations such as histone acetylation are also associated with postovulatory aging.

Objective

To perform a review evaluating a new aspect of oocyte aging in terms of the epigenetic alterations focusing on lysine acetylation.

Methods

In addition to a search of the literature in Pubmed, we introduced our recent published data.

Results

Histone acetylation in the mouse oocyte increases during aging, potentially impacting gene regulation in the subsequent embryonic development. Oocyte aging results in increased acetylation of alpha-tubulin, a non-histone protein, and nicotinamide, an inhibitor of class III HDAC, partially prevents some of oocyte aging phenotypes.

Conclusion

Abnormal regulation of protein acetylation itself is suggested in oocyte aging and could contribute to the aging phenotypes.     

Biliary neoplasia with extensive intraductal spread associated with liver cirrhosis: a hitherto unreported variant of biliary intraepithelial neoplasia

We describe the histopathologic features of 2 cases of biliary neoplasia with extensive intraductal spread arising in liver cirrhosis. The prevalence of this type of biliary neoplasia may be 0.4% from the review of 468 cases of cirrhotic liver. Histologic analysis revealed that the micropapillary proliferation of the atypical biliary epithelium composed of columnar cells with enlarged nuclei diffusely extended superficially from the septal intrahepatic bile duct to the reactive ductules associated with liver cirrhosis. Both cases exhibited prominent fibrous or sclerotic stroma near the biliary lesion. Immunohistochemical analysis revealed a characteristic cytokeratin and mucin expression pattern (CK7++, CK19++, CK20+, MUC1+/-, MUC2-, MUC5AC+, MUC6-). The tumor cytoplasm was focally positive for laminin gamma2 together with linear staining of the basement membrane. Proliferative activity confirmed by Ki67 staining was relatively high. Both patients were disease-free for 3 years after the operation. We believe that the possibility of biliary neoplasia with extensive intraductal spread should be considered to be a variant of biliary intraepithelial neoplasia.     

Expression level of the mitotic checkpoint protein and G2–M cell cycle regulators and prognosis in gastrointestinal stromal tumors in the stomach

The biological behavior of gastrointestinal stromal tumors (GISTs) ranges from benign to malignant, and the risk of an adverse outcome is correlated with the location of the primary tumor, tumor size, and mitotic counts. Cell cycle regulators are potentially associated with the tumorigenesis and progression of GISTs. Checkpoint with forkhead and ring finger (CHFR) functions as an important checkpoint protein in the early to mid-prophase to regulate mitosis. In this study, we evaluated the expression of CHFR and several cell cycle regulators, including cyclin A, cyclin B1, cdc2, and cdk2, by immunohistochemical staining in 53 cases of primary gastric GISTs, and compared the immunohistochemical results with the clinicopathological factors or the GIST risk grades as modified by Miettinen et al. Of the 53 cases, 18 (34%) showed decreased nuclear CHFR expression. Decreased CHFR expression was correlated with higher mitotic counts [>5/50 high-power fields (HPFs)] (p = 0.039) and a high-risk grade (p = 0.0475), but not with expression of other cell cycle regulators. Higher cyclin A labeling index (LI, >1.5%), cyclin B1 LI (>0.25%), cdc2 LI (>1.16%), Ki-67 LI (>4.9%), mitotic counts (>5/50 HPF) and high-risk grade were each associated with shorter disease-free survival (p = 0.0017, p = 0.003, p = 0.0471, p = 0.002, p < 0.001, and p = 0.0017, respectively). Our results suggest that modified risk grade and increased expression of G2–M regulators such as cyclin A, cyclin B1, and cdc2 are useful for predicting the biological behavior of gastric GISTs. In addition, decreased CHFR expression may play a role in increased proliferative activity of higher grade GISTs.     

Mutations in non-structural 5A and rapid viral response to pegylated interferon-α-2b plus ribavirin therapy are associated with therapeutic efficacy in patients with genotype 1b chronic hepatitis C

For patients chronically infected with hepatitis?C virus (HCV), mutations in the non-structural?5A (NS5A) gene are important predictive factors for the response to interferon (IFN) therapy. In the present study, factor analysis of the therapeutic response of patients following pegylated IFN and ribavirin combination therapy was assessed in a multicenter study. Chronic HCV-infected patients with genotype?1b and high viral load (n=96, mean age 56.5 years; 59 males, 68 females) treated with pegylated IFN-α-2b and ribavirin combination therapy were enrolled. This study was conducted at Kobe University Hospital and 25 affiliated hospitals in Hyogo prefecture. Sixty-five patients (68%) completed treatment with both pegylated IFN and ribavirin at >80% of the weight-based scheduled dosages. Patients who reduced or terminated therapy were frequently aged women (mean age 60.8 years; 11 males, 17 females). Overall, a sustained viral response (SVR) was achieved in 42 (44%) patients out of 96. Based on per-protocol-based (PPB) analysis, the SVR rate in patients with ≥6?amino acid (aa) mutations in the IFN resistance-determining region (IRRDR) (75%) or ≥1?aa mutation in the IFN sensitivity-determining region (ISDR) (61%) was significantly higher than that in patients with <5?aa mutations in IRRDR (30%) or no mutation in ISDR (29%). Multivariate analysis revealed that rapid viral response (RVR) (odds ratio, 18.1) and mutations of ≥6 in IRRDR (odds ratio, 15.5) were significantly associated with SVR. In conclusion, mutations in the NS5A region, particularly in patients with ≥6 aa mutations in IRRDR were strongly associated with a therapeutic response to pegylated IFN and ribavirin combination therapy.     

STX2 is a causative gene for nonobstructive azoospermia

STX2 encodes a sulfoglycolipid transporter. Although Stx2 nullizygosity is known to cause spermatogenic failure in mice, STX2 mutations have not been identified in humans. Here, we performed STX2 mutation analysis for 131 Japanese men clinically diagnosed with nonobstructive azoospermia. As a result, we identified a homozygous frameshift mutation [c.8_12delACCGG, p.(Asp3Alafs*8)] in one patient. The mutation‐positive patient exhibited loss‐of‐heterozygosity for 58.4 Mb genomic regions involving STX2, suggesting possible parental consanguinity. The patient showed azoospermia, relatively small testes, and a mildly elevated follicle stimulating hormone level, but no additional clinical features. Testicular histology of the patient showed universal maturation arrest and multinucleated spermatocytes, which have also been observed in mice lacking Stx2. PCR‐based cDNA screening revealed wildtype STX2 expression in various tissues including the testis. Our results indicate that STX2 nullizygosity results in nonsyndromic maturation arrest with multinucleated spermatocytes, and accounts for a small fraction of cases with nonobstructive azoospermia.