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Background & Aims: Hepatic stellate cells (HSCs) play an essential role in liver fibrogenesis. The induction of cellular senescence has been reported to inhibit HSC activation. Previously, we demonstrated that CWHM12, a small molecule arginine-glycine-aspartic acid (RGD) peptidomimetic compound, inhibits HSC activation. This study investigated whether the inhibitory effects of CWHM12 on HSCs affected cellular senescence., Methods: The immortalized human HSC lines, LX-2 and TWNT-1, were used to evaluate the effects of CWHM12 on cellular senescence via the disruption of RGD-mediated binding to integrins., Results: CWHM12 induces cell cycle arrest, senescence-associated beta-galactosidase activity, acquisition of senescence-associated secretory phenotype (SASP), and expression of senescence-associated proteins in HSCs. Further experiments revealed that the phosphorylation of AKT and murine double minute 2 (MDM2) was involved in the effects of CWHM12, and the inhibition of AKT phosphorylation reversed these effects of CWHM12 on HSCs., Conclusions: Pharmacological inhibition of RGD-mediated integrin binding induces senescence in activated HSCs., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: Although systemic chemotherapy for pancreatic ductal adenocarcinoma (PDAC) has made progress, ensuring long-term survival remains difficult. There are several reports on the usefulness of neutrophil-to-lymphocyte ratio (NLR) in predicting the prognosis of PDAC, but few reports in systemic chemotherapy. We hereby investigated the usefulness of NLR in systemic chemotherapy for PDAC., Materials and Methods: A retrospective study was conducted on patients with advanced PDAC treated with first-line systemic chemotherapy. Cox regression hazards models were performed to analyze the association between baseline patient characteristics and the initial treatment response, and overall survival (OS)., Results: A total of 60 patients with PDAC were enrolled. At baseline, there were significant differences in NLR and carbohydrate antigen 19-9 (CA19-9), as well as the selection rate of combination chemotherapy, between patients with partial response or stable disease and those with progressive disease. Univariate and multivariate analysis showed that NLR < 3.10, combination chemotherapy, and CA19-9 < 1011 U/mL were significant and independent predictive factors of the initial treatment response. Meanwhile, NLR < 3.10 and combination chemotherapy were independently associated with longer OS. Moreover, OS was significantly prolonged in patients with NLR < 3.10, regardless of whether combination chemotherapy or monotherapy. Patients with NLR < 3.10 at baseline had a significantly higher conversion rate to third-line chemotherapy and a longer duration of total chemotherapy., Conclusions: This study suggests that NLR may be a useful marker for predicting the initial treatment response to first-line chemotherapy and the prognosis for patients with advanced PDAC.

Background & Aims: Ferroptosis is a form of regulated cell death and its promotion in hepatic stellate cells (HSCs) attenuates liver fibrosis. Statins, which are 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, may induce ferroptosis via the downregulation of glutathione peroxidase 4 (GPX4) by inhibiting the mevalonate pathway. However, little evidence is available regarding the association between statins and ferroptosis. Therefore, we investigated the association between statins and ferroptosis in HSCs., Methods: Two human HSC cell lines, LX-2 and TWNT-1, were treated with simvastatin, an HMG-CoA reductase inhibitor. Mevalonic acid (MVA), farnesyl pyrophosphate (FPP), and geranylgeranyl pyrophosphate (GGPP) were used to determine the involvement of the mevalonate pathway. We performed a detailed analysis of the ferroptosis signaling pathway. We also investigated human liver tissue samples from patients with nonalcoholic steatohepatitis to clarify the effect of statins on GPX4 expression., Results: Simvastatin reduced cell mortality and inhibited HSCs activation, accompanied by iron accumulation, oxidative stress, lipid peroxidation, and reduced GPX4 protein expression. These results indicate that simvastatin inhibits HSCs activation by promoting ferroptosis. Furthermore, treatment with MVA, FPP, or GGPP attenuated simvastatin-induced ferroptosis. These results suggest that simvastatin promotes ferroptosis in HSCs by inhibiting the mevalonate pathway. In human liver tissue samples, statins downregulated the expression of GPX4 in HSCs without affecting hepatocytes., Conclusions: Simvastatin inhibits the activation of HSCs by regulating the ferroptosis signaling pathway., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

A 59-year-old woman presented to our hospital with liver dysfunction. Imaging revealed multiple lesions in the liver. The patient was diagnosed with peliosis hepatis using percutaneous and laparoscopic biopsies. However, her condition worsened with the appearance of new, obvious mass-forming lesions. Therefore, she underwent a second percutaneous biopsy of these lesions and was diagnosed with hepatic angiosarcoma. Her condition progressed rapidly, and she died two weeks after the diagnosis. Diagnosis of hepatic angiosarcoma in the early stages is difficult. It should be noted that hepatic angiosarcoma may be associated with the development of peliosis hepatis.

Rifaximin, a non-absorbable antibiotic, has been demonstrated to be effective against hepatic encephalopathy (HE); however, its efficacy on liver functional reserve remains unknown. Here, we evaluated the efficacy of rifaximin on the liver functional reserve and serological inflammation-based markers in patients with cirrhosis. A retrospective study was conducted on patients who received rifaximin for more than three months at our hospital between November 2016 and October 2021. The recurrence and grade of HE, serological ammonia levels, Child-Pugh score (CPS), and serological inflammation-based markers such as the neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR), platelet-lymphocyte ratio (PLR), C-reactive protein (CRP), and CRP to albumin ratio (CAR) were evaluated. The correlations between serological inflammation-based markers and liver functional reserve were evaluated. HE grades, serum ammonia levels, and inflammation-based markers significantly improved at three months compared with those at baseline. Patients with improved albumin levels showed significantly higher CRP improvement rates at both 3 and 12 months. Patients with an improvement in CAR at 3 months demonstrated a significant improvement in CPS at 12 months. Rifaximin improved the liver functional reserve in patients with cirrhosis. Improvements in inflammation-based markers, particularly CRP and albumin, may be involved in this process.

A 57-year-old woman was diagnosed with adrenocortical carcinoma. Following the adrenalectomy, she underwent adjuvant radiation and mitotane therapy; however, liver metastases were observed. Repeated radiofrequency ablation (RFA) was performed for liver metastases. In addition, a multidisciplinary approach combining systemic chemotherapy, radiotherapy, and surgery was used for lung and distant lymph node metastases that arose during the course of treatment. Notably, 49 months have passed since the adrenalectomy and 36 months since the recurrence of the liver metastases, and the patient remains on multidisciplinary therapy. Thus, RFA for liver metastasis of adrenocortical carcinoma may be an effective component of a multidisciplinary treatment., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background & Aims: Liver fibrosis characterizes advanced chronic liver disease, and persistent activation of hepatic stellate cells (HSCs) is the primary cause of excessive hepatic fibrogenesis. CWHM12, an analog of the arginine-glycine-aspartic acid (RGD) amino acid sequence found in specific integrins, improves liver fibrosis; however, the detailed mechanisms remain unclear. This study aimed to clarify the cell signaling mechanisms of CWHM12 in activated HSCs., Methods: Immortalized human HSC lines, LX-2 and TWNT-1, were used to evaluate the effects of CWHM12 on intracellular signaling via the disruption of RGD-binding integrins., Results: CWHM12 strongly promoted phosphorylation and inhibited the nuclear accumulation of Yes-associated protein (YAP), which is a critical effector of the Hippo signaling pathway, leading to the inhibition of proliferation, suppression of viability, promotion of apoptosis, and induction of cell cycle arrest at the G1 phase in activated HSCs. Further investigations revealed that inhibition of TGF-β was involved in the consequences of CWHM12. Moreover, CWHM12 suppressed focal adhesion kinase (FAK) phosphorylation; consequently, Src, phosphatidylinositol 3-kinase, pyruvate dehydrogenase kinase 1, and serine-threonine kinase phosphorylation led to the translocation of YAP. These favorable effects of CWHM12 on activated HSCs were reversed by inhibiting FAK., Conclusions: These results indicate that pharmacological inhibition of RGD-binding integrins suppresses activated HSCs by blocking the Hippo signaling pathway, a cellular response which may be valuable in the treatment of hepatic fibrosis., Competing Interests: Declaration of Competing Interest The authors disclose no conflicts., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aim: The ursodeoxycholic acid response score (URS) can predict the biochemical response to 12 months of ursodeoxycholic acid (UDCA) treatment in patients with primary biliary cholangitis (PBC). We investigated the relationship between the URS and the histopathological features before and after UDCA treatment., Methods: Patients with PBC (n = 126) were examined for the association between the probability of response (POR) to UDCA based on the URS formulas and clinicopathological features. Furthermore, 30 patients were examined for the association between the POR and pathological changes., Results: The POR area under the receiver operating characteristic curve (AUROC) for predicting the biochemical response to UDCA was 0.861. The PORs of stage 1 in the Nakanuma system and grade 0 in the CK7 grading in hepatocytes were significantly higher than those of stage 3 and grade 3, respectively. The AUROCs for the prediction of stage ≥2, stage ≥3 and stage 4 in the Nakanuma system at pretreatment were 0.592, 0.710 and 0.817, respectively. The AUROCs for the prediction of grade ≥1, grade ≥2 and grade 3 in the CK7 hepatocyte grading were 0.741, 0.824 and 0.970, respectively. Furthermore, the AUROC for predicting the histological stage progression after UDCA treatment in the Scheuer classification and the Nakanuma system were 0.712 and 0.799, respectively., Conclusions: The URS not only predicts the biochemical response, but also reflects the Nakanuma system and the CK7 hepatocyte grading at pretreatment. This scoring system can identify an inadequate histological response to UDCA treatment in the Scheuer classification and the Nakanuma system., (© 2020 The Japan Society of Hepatology.)

Background and Aims. To examine the changes in serum alpha-fetoprotein (AFP) levels after iron reduction by therapeutic phlebotomy in chronic hepatitis C patients. Methods. This retrospective study included 26 chronic hepatitis C patients. The patients were developed iron depletion by repeated therapeutic phlebotomies. Results. Iron reduction therapy significantly reduced the median level of serum AFP from 13 to 7 ng/mL, ALT from 96 to 50 IU/L, gamma-glutamyl transpeptidase (GGT) from 55 to 28 IU/L, and ferritin from 191 to 10 ng/mL (P < 0.001 for each). The rate of decline in the AFP level correlated positively only with that in GGT (r = 0.695, P = 0.001), although a spurious correlation was observed between the rates of decline for AFP and ALT. The AFP level normalized (<10 ng/mL) posttreatment in eight (50%) of 16 patients who had elevated pretreatment AFP levels. Normalized post-treatment ALT and GGT levels were seen in 12% (3 of 26) and 39% (7 of 18) of the patients, respectively. Multivariate analysis identified a post-treatment GGT level of <30 IU/L as an independent factor associated with post-treatment AFP normalization (odds ratio, 21; 95% confidence interval, 1.5-293; P = 0.024). Conclusions. Iron reduction by therapeutic phlebotomy can reduce serum AFP and GGT levels in chronic hepatitis C patients.

Hepatitis C virus (HCV) RNA is thought to be less stable than HCV core antigen (HCV-Ag), however there have been few studies on comparing the stability of HCV-Ag with that of HCV-RNA in vitro. The aim of this study is to evaluate serial levels of HCV-Ag and HCV-RNA in serum before and after incubation at 4 or 25 degrees C for 7 days to estimate an assay suitable for general laboratory use. In this study, we demonstrate that HCV-Ag levels are highly reproducible (coefficients of variation (CVs); 0.89-6.92%) and stable (84.8% of the initial level) with incubation of even 25 degrees C for 7 days, whereas HCV-RNA levels are much less reproducible (CVs; 9.13-29.66%) and decrease dramatically (15.1% of the initial level) after incubation, particularly at 25 degrees C. The measurement of the HCV-Ag level was found to be suitable for HCV quantification with serum samples stored either at 4 degrees C or under unknown conditions. Additionally, it successfully eliminated inhibitors such as heparin from plasma and could be applied to a variety of clinical specimens. Our data suggest the significance of measuring the HCV-Ag level during clinical management independently of the HCV-RNA level, particularly because of its high stability.

The sensitivity and specificity of the second generation ELISA (2nd ELISA) and RIBA (2nd RIBA) using c 22 and c 200 or c 33 c recombinant antigens encoded in the core and NS 3 of HCV genome have been evaluated preclinically by Ortho and Chiron (USA). Sensitivity of the assay was evaluated by determining the reactivity of 2nd ELISA and RIBA in the following panels: NANBH (N = 35) and high risk groups composed of: hemophiliacs (N = 50), IVDA (N = 50) and renal dialysis cases (N = 279). In the reactive specimens, antibody response to both c 33 c and c 22-3 was present in 93-100% whereas antibody response to 5-1-1 and c 100-3 was seen in 46-84% of these same specimens. Specificity, in turn, was evaluated using 2000 volunteer donors of 29 (1.45%) 2nd ELISA positives, 16/29 (55.2%) were confirmed by 2nd RIBA and 8/29 (27.6%) were 1 band positive (indeterminate), whereas of 27 (1.35%) 1st ELISA positive, 9/27 (33.3%) were confirmed and 4/27 (14.8%) were 1 band positive by 1st RIBA (c 100-3, 5-1-1). The relevance of various band patterns and correlation between PCR positivity with 2nd RIBA reactivity are discussed. The consistency and sensitivity of the 2nd RIBA evaluated using a densitometer are also reported.

HCV infections are diagnosed by determining the circulating antibodies to the C 100 recombinant viral antigen using the ELISA method. Cut-off analysis from normal subjects and well documented NANBH patients suggests that screening of a low risk group such as blood donors might yield a relatively high ratio of false positives. An immunoblot assay (Chiron RIBA) using 3 recombinant antigens, C 100, 5-1-1 and SOD has been developed for evaluating the ELISA reactives as an additional, more specific assay. In the RIBA testing 51.5% were reactive and 28.5% were indeterminate in ELISA positive donor specimens, and 79.5% were reactive and 8.0% were indeterminate in ELISA positive non-A, non-B hepatitis patients specimens. These findings coincide with the ratio of theoretically calculated true positive. In a study done by Ortho U.S.A. viral RNA were detected in 70% of RIBA reactive, 33% of indeterminate and 3.6% non-reactive specimens by polymerase chain reaction (PCR). Furthermore, an advanced system using another immunogenic region of viral polyprotein including c33c encoded in NS3 has been on trial to evaluate the possibility of confirming HCV infection and detecting seroconversion at an earlier stage.