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Aim: To determine the impact of direct‐acting antiviral therapy on the long‐term prognosis of decompensated cirrhotic patients. Methods: A total of 37 patients with hepatitis C virus‐induced decompensated cirrhosis treated with sofosbuvir and velpatasvir (SOF/VEL group) were prospectively enrolled. For historical control, 65 hepatitis C virus‐positive decompensated cirrhotic patients who did not receive direct‐acting antiviral therapy were included (control group). The incidence rates of hepatocellular carcinoma (HCC), decompensated events with hospitalization, and overall survival were compared between both groups. Results: A total of 41 patients experienced decompensated events during 15.0 months in the control group, and six patients during 21.6 months in the SOF/VEL group. The cumulative incidence rates of decompensated events after 2 years were significantly higher in the control group (53.1%) than in the SOF/VEL group (14.5%; p < 0.001). A total of 27 patients died within 22.0 months in the control group, and three patients died within 25.6 months in the SOF/VEL group. The overall survival rates after 2 years were significantly lower in the control group (67.6%) than in the SOF/VEL group (91.3%; p = 0.010). A total of 13 patients in the control group developed HCC during 15.8 months, and 10 patients during 17.3 months in the SOF/VEL group. The HCC incidence rates after 2 years were 20.3% and 29.6% in the control and SOF/VEL groups, respectively, with no significant difference (p = 0.327). Conclusions: SOF/VEL therapy may suppress the development of decompensated events and improve the prognosis in decompensated cirrhotic patients; however, the incidence of HCC remains prevalent in these patients irrespective of SOF/VEL therapy. [ABSTRACT FROM AUTHOR]

Aim: Atezolizumab plus bevacizumab and lenvatinib have each shown efficacy as primary systemic chemotherapies for hepatocellular carcinoma (HCC) in clinical trials. However, comparative trials of these two treatments have not been conducted. This study aimed to compare the therapeutic outcomes of these two treatments. Methods: This prospectively registered multicenter study analyzed 272 patients with HCC who received atezolizumab plus bevacizumab (the Atezo + Beva group; n = 90) or lenvatinib (the Len group; n = 182) as primary systemic chemotherapy. After propensity score matching (PSM), 66 patients were assigned to each group. Results: After PSM, the median progression‐free survival (PFS) was significantly longer in the Atezo + Beva group than in the Len group (8.8 vs. 5.2 months; p = 0.012). No significant differences were noted between the two groups in terms of median overall survival (not reached vs. 20.6 months; p = 0.577), objective response rates (43.8% vs. 52.4%; p = 0.330), and disease control rates (76.6% vs. 82.5%; p = 0.404). The percentage of patients with modified albumin‐bilirubin grades of one or 2a was maintained during treatment in the Atezo + Beva group but decreased over time in the Len group. The rate of discontinuation due to adverse events (AEs) was lower in the Atezo + Beva group than in the Len group (12.1% vs. 28.8%; p = 0.018). Conclusions: Atezolizumab plus bevacizumab showed prolonged PFS, maintained hepatic reserve, and had lower rates of severe AEs compared with that on using lenvatinib as primary systemic chemotherapy for HCC. [ABSTRACT FROM AUTHOR]

Summary: Background: After hepatitis C virus (HCV) elimination, patients should be followed up due to risk of hepatocellular carcinoma (HCC). Growth differentiation factor 15 (GDF15) is a cytokine induced by mitochondrial dysfunction or oxidative stress. Aim To evaluate the prognostic value of GDF15 for HCC occurrence after HCV elimination. Methods: We measured GDF15 levels in stored serum from patients with chronic HCV infection without a history of HCC who had achieved sustained virological response with direct‐acting antiviral agents (DAAs). The patients were randomly divided into derivation (n = 964) and validation (n = 642) cohorts. Results: In the derivation cohort, serum GDF15 levels were higher in those with HCC occurrence after DAA treatment than in those without. Multivariate Cox proportional hazards analysis revealed baseline GDF15 (>1350 pg/mL, HR 2.54), AFP (>5 ng/mL, HR 2.00), and the FIB‐4 index (>3.25, HR 2.69) to be independent risk factors for HCC. Scoring based on GDF15, AFP and the FIB‐4 index stratified HCC occurrence risk. In the validation cohort, the cumulative HCC occurrence rate at 3 years was 0.64%, 3.27% and 15.3% in low‐score (N = 171), medium‐score (N = 300) and high‐score (N = 166) groups, respectively. In the total cohort, scoring divided patients with a FIB‐4 index ≤3.25, whose HCC occurrence rate was 2.0% at 3 years, into medium‐score and low‐score groups with HCC occurrence rates at 3 years of 3.76% and 0.24%, respectively. Conclusions: Serum GDF15 predicts de novo HCC occurrence. Scoring using GDF15, AFP, and the FIB‐4 index can predict de novo HCC occurrence risk after HCV elimination. [ABSTRACT FROM AUTHOR]

Background: Management of diminutive pharyngeal neoplasms is controversial. Thus, we conducted a single‐center, prospective pilot study to investigate the efficacy and safety of endoscopic excision with cold forceps biopsy (CFB) of these lesions. Patients and Methods: Thirty‐nine lesions endoscopically diagnosed with narrow‐band imaging as pharyngeal neoplasms of 3 mm or smaller were excised with CFB using jumbo biopsy forceps (cap diameter 2.8 mm, jaw volume 12.4 mm3). The primary outcome was endoscopically determined local remnant/recurrence rate 3 months after CFB. The secondary outcomes were histopathologically determined local remnant/recurrence rate; risk factors associated with the endoscopic remnant/recurrence; and incidence of intraoperative or delayed bleeding and other adverse events. Results: Histological diagnosis of the 39 CFB‐excised lesions were: 11 high‐grade dysplasia (28.2%), 22 low‐grade dysplasia (56.4%), two basal cell hyperplasia (5.1%) and four atypical squamous epithelium (10.3%).Twenty‐seven patients (30 lesions) underwent follow‐up endoscopy 3 months after CFB; the endoscopic and pathological local remnant/recurrence rate was 20% (6/30; 95% confidence interval (CI), 7.7–36.6%) and 16.7% (5/30; 95% CI, 5.6–34.7%), respectively. Location of the lesion in the hypopharynx was a significant risk factor associated with the endoscopic local remnant/recurrence (P = 0.049). No significant adverse events occurred. Conclusions: Cold forceps biopsy with jumbo biopsy forceps appears to be a safe and effective technique for excising diminutive pharyngeal neoplasms. Although small, the excised lesions may have a remarkably high frequency of high‐grade dysplasia. (Clinical trial registration number: UMIN000037980). [ABSTRACT FROM AUTHOR]

Aim Several case reports have shown that hepatitis B virus (HBV) reactivation developed in hepatitis C patients with a current or previous HBV infection during direct-acting antiviral (DAA) treatment, which led to severe hepatitis or death in some cases. However, its precise frequency and risk factors are not entirely clear. We analyzed a prospective cohort. Methods We analyzed HBV reactivation in 461 consecutive hepatitis C patients who received 12 weeks of ledipasvir/sofosbuvir for genotype 1 or sofosbuvir plus ribavirin for genotype 2 at multiple centers. Results By the examination of the preserved sera at baseline, 159 patients (34%) were identified as seropositive for HBV core antibody (anti-HBc) and were included in the subsequent analysis; 4 patients were positive for HBV surface antigen (HBsAg), and the others were negative. Serum HBV DNA was undetectable or was detectable but <20 IU/mL at baseline for all patients. Serial measurement of HBV DNA at 4 weeks and 12 weeks in the preserved serum samples was available in 147 patients and identified HBV reactivation (defined as the appearance of serum HBV DNA ≥20 IU/mL) in 2 HBsAg-positive and 3 HBsAg-negative patients. No patient developed HBV-associated hepatitis. Patients who developed HBV reactivation had significantly lower anti-HBs titers and higher serum alanine transferase levels before treatment. Conclusion Hepatitis B virus reactivation during direct-acting antiviral therapies occurs in 3.4% (5/147) of patients who are positive for anti-HBc. A low titer of anti-HBs and a high serum alanine transferase level prior to treatment are associated with reactivation in this patient group. [ABSTRACT FROM AUTHOR]

LINKED CONTENT: This article is linked to Myojin.et al's paper. To view this article, visithttps://doi.org/10.1111/apt.16691 and https://doi.org/10.1111/apt.16834 [ABSTRACT FROM AUTHOR]

Pmk1, a fission yeast homologue of mammalian ERK MAPK, regulates cell wall integrity, cytokinesis, RNA granule formation and ion homeostasis. Our screen for vic (viable in the presence of immunosuppressant and chloride ion) mutants identified regulators of the Pmk1 MAPK signaling, including Cpp1 and Rho2, based on the genetic interaction between calcineurin and Pmk1 MAPK. Here, we identified the vic2-1 mutants carrying a mis-sense mutation in the cwg2+ gene encoding a beta subunit of geranylgeranyltransferase I ( GGTase I), which participates in the post-translational C-terminal modification of several small GTPases, allowing their targeting to the membrane. Analysis of the vic2-1/ cwg2-v2 mutant strain showed that the localization of Rho1, Rho4, Rho5 and Cdc42, both at the plasma and vacuolar membranes, was impaired in the vic2-1/ cwg2-v2 mutant cells. In addition, Rho4 and Rho5 deletion cells exhibited the vic phenotype and cell wall integrity defects, shared phenotypes among the components of the Pmk1 MAPK pathway. Consistently, the phosphorylation of Pmk1 MAPK on heat shock was decreased in the cwg2-v2 mutants, and rho4- and rho5-null cells. Moreover, Rho4 and Rho5 associate with Pck1/Pck2. Possible roles of Cwg2, Rho4 and Rho5 in the Pmk1 signaling will be discussed. [ABSTRACT FROM AUTHOR]

Rapamycin and its derivatives have now emerged as an attractive therapeutic strategy with both immunosuppressant and antitumor properties. In addition, rapamycin has been proposed as a calorie restriction mimetic to extend the life span of various organisms. The fission yeast Schizosaccharomyces pombe ( S. pombe) serves as a valuable genetic model system to study the mechanism(s) of drug action as well as to determine genetic contexts associated with drug sensitivity or resistance. Here, we identified genes that when deleted modulate the rapamycin-sensitive strains in S. pombe. We carried out a chemical genomics screen for rapamycin-sensitive mutants using the genome-deletion library which covers 95.3% of all nonessential fission yeast genes and confirmed 59 genes to be rapamycin sensitive. Gene Ontology (GO) enrichment analysis showed that strains sensitive to rapamycin are highly enriched in processes regulating t RNA modification and mitochondria as well as other ontologies, including cellular metabolic process, chromatin organization, cell cycle, signaling, translation, transport and other cellular processes. Analysis also showed that components of the Elongator complex are overrepresented in the sensitive strains. Here, the data obtained will provide valuable information for speculation on the actions of rapamycin as well as on TORC signaling, thereby presenting a strategy to enhance sensitivity to rapamycin. [ABSTRACT FROM AUTHOR]

In fission yeast, Ppb1, the Ca2+/calmodulin-dependent protein phosphatase calcineurin regulates multiple biological processes, such as cytokinesis, Ca2+-homeostasis, membrane trafficking and cell wall integrity. Calcineurin dephosphorylates the Prz1 transcription factor, leading to its nuclear translocation and gene expression under the control of CDRE (calcineurin-dependent response element). Although the calcineurin-mediated spatial control of downstream transcription factors has been intensively studied in many organisms, less is known about the spatial regulation of calcineurin on stresses. Here, we show that heat shock stimulates calcineurin-dependent nuclear translocation of Prz1 and CDRE-dependent gene expression. Notably, calcineurin exhibited a dramatic change in subcellular localization, translocating from diffuse cytoplasmic to dot-like structures on heat shock. The calcineurin dots colocalized with Dcp2 or Pabp, the constituent of P-bodies or stress granules, respectively, thus suggesting that calcineurin is a component of RNA granules under heat shock. Importantly, the calcineurin inhibitor FK506 markedly inhibited the accumulation of calcineurin granules, whereas the constitutively active calcineurin strongly accumulated in the granules on heat shock, suggesting that phosphatase activity is important for calcineurin localization. Notably, the depletion of calcineurin induced a rapid appearance of Nrd1- and Pabp-positive RNA granules. The possible roles of calcineurin in response to heat shock will be discussed. [ABSTRACT FROM AUTHOR]

Fission yeast its3+ encodes an essential phosphatidylinositol-4-phosphate 5-kinase ( PI4P5 K) that regulates cell integrity and cytokinesis. We performed a genetic screen to identify genes that function in PI4P5 K-mediated signaling, and identified gyp10 + encoding a Rab GTPase-activating protein ( GAP), a negative regulator for Rab GTPase signaling. Its3 overproduction caused growth defects and abnormal cytoplasmic accumulation of the Its3 protein, which can be stained by calcofluor. Notably, Its3 overproducing cells displayed abnormal membranous structures, multilamella Golgi and fragmented vacuoles showed by Electron microscopy. Furthermore, the excess cytoplasmic Its3 structure partly colocalized with the fluorescence of FM4-64. Gyp10 rescued both growth defects and abnormal Its3 localization when it was over-expressed. Gyp10 functionally interacted with the Rab GTPases Ypt3 and Ryh1, both of which regulate Golgi membrane trafficking. Consistently, mutation or deletion of Ypt3 and Ryh1 suppressed phenotypes associated with Its3 overproduction. Importantly, the plasma membrane localization of Its3 was also affected by the impairment of the Ypt3/Ryh1 Rab membrane trafficking, thus suggesting that membrane trafficking events regulated by two Rab GTPases functionally interacts with PI4,5P2 signaling. These results suggest a mechanism whereby PI4P5K signaling/localization is affected by Golgi membrane trafficking, thus provide a functional link between the PI4,5P2 signaling and Rab-mediated trafficking. [ABSTRACT FROM AUTHOR]

The effects of oxygen partial pressure during thermal treatment on the color and microstructure of Bizen, a traditional Japanese stoneware, were studied through model experiments using clay pellets covered lightly with rice straw as a coloring assistant. When heated in flowing nitrogen, the model pellet turned blackish owing to the formation of α-Fe particles coated with graphite. However, schreibersite (Fe3P), which is also blackish, was formed specifically on the pellet surface in direct contact with the straw. The rice straw seems to have generated a strongly reducing atmosphere, strong enough for the metallization to α-Fe, and also to have provided phosphorus through contact. When oxygen content in the surrounding gas atmosphere was raised to N2/O2=99/1, the pellet surface turned yellowish brown because the main coloring material was Fe3+-containing mullite. At oxygen contents of N2/O2=98/2 or more, the formation of hematite (α-Fe2O3) pushed the color to deep red. [ABSTRACT FROM AUTHOR]