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Background & Aims: This study aimed to investigate the temporal changes in body composition following esophagectomy in patients with esophageal cancer using bioelectrical impedance analysis and to assess the prognostic implications of these changes., Methods: Our study included 528 patients who underwent esophagectomy and preoperative body composition measurements between January 2013 and June 2020. Postoperative body composition was measured in 493 patients at discharge as follows: 184 at 1 month, 144 at 2 months, 143 at 3 months, 103 at 6 months, 58 at 9 months, and 78 at 12 months., Results: Body weight (BW) continuously decreased until the 6 postoperative months (POMs), reaching -11.5% compared with preoperative levels. Subsequently, almost no change was observed at 12 POMs. Skeletal muscle mass (SMM) decreased until 3 POMs but gradually recovered after 3 POMs. Conversely, body fat mass (BFM) consistently decreased over time post-esophagectomy. The patients were categorized into moderate (>-10%) and severe (≤-10%) groups based on % BW, % SMM, and % BFM losses at 3 POMs. Severe SMM loss at 3 POMs correlated with reduced overall survival (OS) (3-year OS: 85.9% in moderate vs. 75.1% in severe, p = 0.035). BFM loss was associated with reduced recurrence-free survival (3-year RFS: 83.3% in moderate vs. 62.0% in severe, p = 0.011). Multivariate analysis identified pStages Ⅲ and Ⅳ, % SMM loss ≤ -10%, and % BFM loss ≤ -10% as independent factors for worse OS., Conclusion: Post-esophagectomy, distinct temporal changes in BW, SMM, and BFM are observed. Significant reductions in SMM and BFM 3 POMs indicate a poor long-term prognosis., Competing Interests: Conflict of interest Authors declare no conflict of interests for this article., (Copyright © 2024. Published by Elsevier Ltd.)

Objective: To investigate somatosensory pathway function in patients with amyotrophic lateral sclerosis (ALS) dependent on invasive ventilation and in a completely locked-in state (CLIS)., Methods: We examined median nerve somatosensory evoked potentials (SEPs) in 17 ALS patients in a CLIS, including 11 patients with sporadic ALS, one with familial ALS with genes not examined, four with a Cu/Zn superoxide-dismutase-1 (SOD1) gene variant (Val118Leu, Gly93Ser, Cys146Arg), and one with a fused-in-sarcoma gene variant (P525L). We evaluated N9, N13, N20 and P25, and central conduction time (CCT); the data were compared with those of 73 healthy controls., Results: N20 and N13 were abolished in 12 and 10 patients, and their latencies was prolonged in four and three patients, respectively. The CCT was prolonged in five patients with measurable N13 and N20. Two patients with SOD1 gene mutations had absent or slightly visible N9. Compared to the CCT and latencies and amplitudes of N13 and N20 in the controls, those in the patient cohort were significantly abnormal., Conclusions: The central somatosensory pathway is severely involved in patients with ALS in a CLIS., Significance: Our findings suggest that median nerve SEP cannot be utilized for communication in patients with ALS in a CLIS., Competing Interests: Declarations of Competing Interest None., (Copyright © 2023 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Pancreatic ductal adenocarcinoma (PDAC) is the cancer with the poorest prognosis. One of the major properties reflecting its poor prognosis is high-grade heterogeneity, which leads to insensitivity to anticancer treatments. Cancer stem cells (CSCs) acquire phenotypic heterogeneity, generating abnormally differentiated cells by asymmetric cell division. However, the detailed mechanism leading to phenotypic heterogeneity is largely unknown. Here, we showed that PDAC patients with co-upregulation of PKCλ and ALDH1A3 had the poorest clinical outcome. PKCλ knockdown by DsiRNA in the ALDH1 high population of PDAC MIA-PaCa-2 cells attenuated the asymmetric distribution of the ALDH1A3 protein. To monitor asymmetric cell division of ALDH1A3-positive PDAC CSCs, we established stable Panc-1 PDAC clones expressing ALDH1A3-turboGFP (Panc-1-ALDH1A3-turboGFP cells). In addition to MIA-PaCa-2-ALDH1 high cells, turboGFP high cells sorted from Panc-1-ALDH1A3-turboGFP cells showed asymmetric cell propagation of ALDH1A3 protein. PKCλ DsiRNA in Panc-1-ALDH1A3-turboGFP cells also attenuated the asymmetric distribution of ALDH1A3 protein. These results suggest that PKCλ regulates the asymmetric cell division of ALDH1A3-positive PDAC CSCs. Furthermore, Panc-1-ALDH1A3-turboGFP cells can be useful for the visualization and monitoring of CSC properties such as asymmetric cell division of ALDH1A3-positive PDAC CSCs in time-lapse imaging., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The C-terminal Ig-domain of lamin A plays critical roles in cell function via interaction with proteins, DNA, and chromatin. Mutations in this domain are known to cause various diseases including Emery-Dreifuss muscular dystrophy (EDMD) and familial partial lipodystrophy (FPLD). Here we examined the biophysical and biochemical properties of mutant Ig-domains identified in patients with EDMD and FPLD. EDMD-related mutant Ig-domain showed decreased stability to heat and denaturant. This result was also confirmed by experiments using full-length mutant lamin A, although the decrease in melting temperature was much less than that of the mutant Ig-domain alone. The unstable EDMD Ig-domain disrupted the proper assembly of lamin A, resulting in abnormal paracrystal formation and decreased viscosity. In contrast, FPLD-related mutant Ig-domains were thermally stable, although they lost DNA binding function. Alanine substitution experiments revealed a functional domain of DNA binding in the Ig-domain. Thus, the overall biophysical property of Ig-domains is closely associated with clinical phenotype., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Cystatin C (CST3), a ubiquitously expressed cysteine protease inhibitor, is implicated in several neurological diseases. Here, we have developed an accurate CST3 measurement system based on liquid chromatography tandem mass spectrometry (LC-MS/MS)., Methods: LC-MS/MS based measurement for CSF CST3 was validated by determination of assay precision, accuracy and recovery. The values were compared with those measured by immunoassay. Glycosylation of CST3 in CSF was analyzed by Western blotting and lectin blotting., Results: Measuring standard CST3 by LC-MS/MS produced a linear standard curve that correlated with assigned values (r 2 =0.99). Both intra- and inter-assay variation was <10%. Although showed a correlation, the average CST3 concentration measured by LC-MS/MS was significantly higher than that of immunoassay. Western blotting showed the presence of a 25KDa species along with CST3 monomer (14KDa) in CSF. The volume of 25KDa species was decreased by deglycosylation. Lectin blotting revealed a 25KDa glycosylated protein in sialidase-treated CSF, which was decreased by deglycosylation. However, deglycosylation did not alter CST3 concentration measured by immunoassay., Conclusions: Our results suggest that LC-MS/MS-based CST3 measurement is a robust method with higher detection ability. Such method could be useful for the diagnosis and monitoring of neurological diseases., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Backgrounds: Preventing distant recurrence and achieving local control are important challenges in rectal cancer treatment, and use of adjuvant chemotherapy has been studied. However, no phase III study comparing adjuvant chemotherapy regimens for rectal cancer has demonstrated superiority of a specific regimen. We therefore conducted a phase III study to evaluate the superiority of S-1 to tegafur-uracil (UFT), a standard adjuvant chemotherapy regimen for curatively resected stage II/III rectal cancer in Japan, in the adjuvant setting for rectal cancer., Patients and Methods: The ACTS-RC trial was an open-label, randomized, phase III superiority trial conducted at 222 sites in Japan. Patients aged 20-80 with stage II/III rectal cancer undergoing curative surgery without preoperative therapy were randomly assigned to receive UFT (500-600 mg/day on days 1-5, followed by 2 days rest) or S-1 (80-120 mg/day on days 1-28, followed by 14 days rest) for 1 year. The primary end point was relapse-free survival (RFS), and the secondary end points were overall survival and adverse events., Results: In total, 961 patients were enrolled from April 2006 to March 2009. The primary analysis was conducted in 480 assigned to receive UFT and 479 assigned to receive S-1. Five-year RFS was 61.7% [95% confidence interval (CI) 57.1% to 65.9%] for UFT and 66.4% (95% CI 61.9% to 70.5%) for S-1 [P = 0.0165, hazard ratio (HR): 0.77, 95% CI 0.63-0.96]. Five-year survival was 80.2% (95% CI 76.3% to 83.5%) for UFT and 82.0% (95% CI 78.3% to 85.2%) for S-1. The main grade 3 or higher adverse events were increased alanine aminotransferase and diarrhea (each 2.3%) in the UFT arm and anorexia, diarrhea (each 2.6%), and fatigue (2.1%) in the S-1 arm., Conclusion: One-year S-1 treatment is superior to UFT with respect to RFS and has therefore become a standard adjuvant chemotherapy regimen for stage II/III rectal cancer following curative resection., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Interferon regulatory factor-3 (IRF-3), a key transcriptional factor in the type I interferon system, is frequently impaired by hepatitis C virus (HCV), in order to establish persistent infection. However, the exact mechanism by which the virus establishes persistent infection has not been fully understood yet. The present study aimed to investigate the effects of various HCV proteins on IRF-3 activation, and elucidate the underlying mechanisms. To achieve this, full-length HCV and HCV subgenomic constructs corresponding to structural and each of the nonstructural proteins were transiently transfected into HepG2 cells. IFN-β induction, plaque formation, and IRF-3 dimerization were elicited by Newcastle disease virus (NDV) infection. The expressions of IRF-3 homodimer and its monomer, Ser386-phosphorylated IRF-3, and HCV core protein were detected by immunofluorescence and western blotting. IFN-β mRNA expression was quantified by real-time PCR (RT-PCR), and IRF-3 activity was measured by the levels of IRF-3 dimerization and phosphorylation, induced by NDV infection or polyriboinosinic:polyribocytidylic acid [poly(I:C)]. Switching of the expression of the complete HCV genome as well as the core proteins, E1, E2, and NS2, suppressed IFN-β mRNA levels and IRF-3 dimerization, induced by NDV infection. Our study revealed a crucial region of the HCV core protein, basic amino acid region 1 (BR1), to inhibit IRF-3 dimerization as well as its phosphorylation induced by NDV infection and poly (I:C), thus interfering with IRF-3 activation. Therefore, our study suggests that rescue of the IRF-3 pathway impairment may be an effective treatment for HCV infection., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Persistent infection with hepatitis C virus (HCV) is a major cause of liver diseases such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Here we report that inhibition of heat shock protein 90 (Hsp90) is highly effective in suppressing HCV genome replication. In HCV replicon cells, HCV replication was reduced by Hsp90 inhibitors and by knockdown of endogenous Hsp90 expression mediated by small-interfering RNA (siRNA). The suppression of HCV replication by an Hsp90 inhibitor was prevented by transfection with Hsp90 expression vector. We also tested the anti-HCV effect of Hsp90 inhibition in HCV-infected chimeric mice with humanized liver. Combined administration of an Hsp90 inhibitor and polyethylene glycol-conjugated interferon (PEG-IFN) was more effective in reducing HCV genome RNA levels in serum than was PEG-IFN monotherapy. These results suggest that inhibition of Hsp90 could provide a new therapeutic approach to HCV infection.

Serine palmitoyltransferase (SPT) is a first-step enzyme in the sphingolipid biosynthetic pathway. Myriocin is an inhibitor of SPT and suppresses replication of the hepatitis C virus (HCV) replicon. However, it is still unknown whether this SPT inhibitor suppresses HCV replication in vivo. We investigated the anti-HCV effect of myriocin against intact HCV using chimeric mice with humanized liver infected with HCV genotype 1a or 1b. We administered myriocin into HCV infected chimeric mice and succeeded in reducing the HCV RNA levels in serum and liver to 1/10-1/100 of the levels prior to the 8 day treatment. Furthermore, combined treatment with pegylated interferon reduced the HCV RNA levels to less than 1/1000 of the control levels. We strongly suggest that suppression of SPT reduces HCV replication, and therefore that the SPT inhibitor is potentially a novel drug in the treatment of HCV infection.

Towards the eventual purpose of facilitating analyses of specificities and functions of LEW rat T lymphocytes involved in the induction and development of organ-specific autoimmune disorders, hybridoma cells expressing class I and class II MHC antigens of LEW rat have been developed. B cell hybridomas produced between a murine B cell tumor M12.4.5 and stimulated LEW B cells expressed high levels of LEW class II MHC antigen but the expression of LEW class I MHC antigens on these cells was rather low. The B hybridoma cells were capable of presenting soluble protein antigens to LEW CD4(+) T cells. Furthermore, The use of this hybridoma revealed antigen-specific cytolytic activity of rat CD4(+) T cells. T cell hybridomas produced between murine thymoma BW5147 and LEW T cells expressed class I MHC antigens of the LEW rat. The expression was confirmed by surface staining and specific cytolysis by rat allogeneic CTL.

We report the case of a patient with lifelong symptoms of xerostomia and a repaired bilateral cleft lip and palate. The clinical evaluation demonstrated aplasia of the major salivary glands. A review of the literature pertaining to salivary gland aplasia is presented, along with a summary of the data regarding patient gender, defect sites, hereditary background, and combined manifestations. The diagnostic methods, possible pathogenesis, and management are also discussed.

The kinetics of heart and liver mitochondrial ATPase (FoF1) were examined using submitochondrial particles (SMPs) purified from the two tissues to obtain information on the role of gamma subunit isoforms. The F1 portion is mainly composed of the catalytic, common alpha beta subunits and tissue-specific gamma subunits. In contrast to the previous reports on the kinetics and crystallography of various F1's, the Vmax and Km of the two isoforms of FoF1 were identical although the SMPs were prepared from different tissues. Moreover sodium azide inhibited the two equally. The ATPase activity of liver SMP showed slightly steeper pH-dependency than that of heart SMP but the pH optima of the two were the same (pH 8).