Essential Role of the \u3ci\u3eCrk\u3c/i\u3e Family-Dosage in DiGeorge-Like Anomaly and Metabolic Homeostasis

CRK and CRKL (CRK-like) encode adapter proteins with similar biochemical properties. Here, we show that a 50% reduction of the family-combined dosage generates developmental defects, including aspects of DiGeorge/del22q11 syndrome in mice. Like the mouse homologs of two 22q11.21 genes CRKL and TBX1, Crk and Tbx1 also genetically interact, thus suggesting that pathways shared by the three genes participate in organogenesis affected in the syndrome. We also show that Crk and Crkl are required during mesoderm development, and Crk/Crkl deficiency results in small cell size and abnormal mesenchyme behavior in primary embryonic fibroblasts. Our systems-wide analyses reveal impaired glycolysis, associated with low Hif1a protein levels as well as reduced histone H3K27 acetylation in several key glycolysis genes. Furthermore, Crk/Crkl deficiency sensitizes MEFs to 2deoxy-D-glucose, a competitive inhibitor of glycolysis, to induce cell blebbing. Activated Rapgef1, a Crk/Crkl-downstream effector, rescues several aspects of the cell phenotype, including proliferation, cell size, focal adhesions, and phosphorylation of p70 S6k1 and ribosomal protein S6. Our investigations demonstrate that Crk/Crkl-shared pathways orchestrate metabolic homeostasis and cell behavior through widespread epigenetic controls

Chemical Signature Indicating A Lack of Massive Stars in Dwarf Galaxies

Growing evidence supports an unusual elemental feature appearing in nearby dwarf galaxies, especially dwarf spheroidals (dSphs), indicating a key process of galaxy evolution that is different from that of the Galaxy. In addition to the well-known deficiency of alpha-elements in dSphs, recent observations have clearly shown that s-process elements (Ba) are significantly enhanced relative to Fe, alpha-, and r-process elements. This enhancement occurs in some dSphs as well as in the Large Magellanic Cloud, but is unseen in the Galaxy. Here we report that this feature is evidence of the lack of very massive stars (> 25 solar mass) as predicted in the low star formation rate environment, and we conclude that the unique elemental feature of dwarf galaxies including a low-alpha/Fe ratio in some low-metallicity stars is, at least in some part, characterized by a different form of the initial mass function. We present a detailed model for the Fornax dSph galaxy and discuss its complex chemical enrichment history together with the nucleosynthesis site of the light s-process element Y.Comment: 7 pages including 6 figures, accepted for publication in Ap

Real Life Study of Lenvatinib Therapy for Hepatocellular Carcinoma: RELEVANT Study

Introduction: In the REFLECT trial, lenvatinib was found to be noninferior compared to sorafenib in terms of overall survival. Here, we analyze the effects of lenvatinib in the real-life experience of several centers across the world and identify clinical factors that could be significantly associated with survival outcomes. Methods: The study population was derived from retrospectively collected data of HCC patients treated with lenvatinib. The overall cohort included western and eastern populations from 23 center in five countries. Results: We included 1,325 patients with HCC and treated with lenvatinib in our analysis. Median OS was 16.1 months. Overall response rate was 38.5%. Multivariate analysis for OS highlighted that HBsAg positive, NLR >3, and AST >38 were independently associated with poor prognosis in all models. Conversely, NAFLD/NASH-related etiology was independently associated with good prognosis. Median progression-free survival was 6.3 months. Multivariate analysis for progression-free survival revealed that NAFLD/NASH, BCLC, NLR, and AST were independent prognostic factors for progression-free survival. A proportion of 75.2% of patients suffered from at least one adverse effect during the study period. Multivariate analysis exhibited the appearance of decreased appetite grade ≥2 versus grade 0-1 as an independent prognostic factor for worse progression-free survival. 924 patients of 1,325 progressed during lenvatinib (69.7%), and 827 of them had a follow-up over 2 months from the beginning of second-line treatment. From first-line therapy, the longest median OS was obtained with the sequence lenvatinib and immunotherapy (47.0 months), followed by TACE (24.7 months), ramucirumab (21.2 months), sorafenib (15.7 months), regorafenib (12.7 months), and best supportive care (10.8 months). Conclusions: Our study confirms in a large and global population of patients with advanced HCC, not candidates for locoregional treatment the OS reported in the registration study and a high response rate with lenvatinib

Interleukin-1 and tumor necrosis factor-α trigger restriction of hepatitis B virus infection via a cytidine deaminase activation-induced cytidine deaminase (AID).

金沢大学医薬保健研究域医学系Virus infection is restricted by intracellular immune responses in host cells, and this is typically modulated by stimulation of cytokines. The cytokines and host factors that determine the host cell restriction against hepatitis B virus (HBV) infection are not well understood. We screened 36 cytokines and chemokines to determine which were able to reduce the susceptibility of HepaRG cells to HBV infection. Here, we found that pretreatment with IL-1β and TNFα remarkably reduced the host cell susceptibility to HBV infection. This effect was mediated by activation of the NF-κB signaling pathway. A cytidine deaminase, activation-induced cytidine deaminase (AID), was up-regulated by both IL-1β and TNFα in a variety of hepatocyte cell lines and primary human hepatocytes. Another deaminase APOBEC3G was not induced by these proinflammatory cytokines. Knockdown of AID expression impaired the anti-HBV effect of IL-1β, and overexpression of AID antagonized HBV infection, suggesting that AID was one of the responsible factors for the anti-HBV activity of IL-1/TNFα. Although AID induced hypermutation of HBV DNA, this activity was dispensable for the anti-HBV activity. The antiviral effect of IL-1/TNFα was also observed on different HBV genotypes but not on hepatitis C virus. These results demonstrate that proinflammatory cytokines IL-1/TNFα trigger a novel antiviral mechanism involving AID to regulate host cell permissiveness to HBV infection

Effects of canagliflozin on growth and metabolic reprograming in hepatocellular carcinoma cells: Multi-omics analysis of metabolomics and absolute quantification proteomics (iMPAQT).

AIM:Metabolic reprograming is crucial in the proliferation of hepatocellular carcinoma (HCC). Canagliflozin (CANA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, affects various metabolisms. We investigated the effects of CANA on proliferation and metabolic reprograming of HCC cell lines using multi-omics analysis of metabolomics and absolute quantification proteomics (iMPAQT). METHODS:The cells were counted 72 hours after treatment with CANA (10 μM; n = 5) or dimethyl sulfoxide (control [CON]; n = 5) in Hep3B and Huh7 cells. In Hep3B cells, metabolomics and iMPAQT were used to evaluate the levels of metabolites and metabolic enzymes in the CANA and CON groups (each n = 5) 48 hours after treatment. RESULTS:Seventy-two hours after treatment, the number of cells in the CANA group was significantly decreased compared to that in the CON group in Hep3B and Huh7 cells. On multi-omics analysis, there was a significant difference in the levels of 85 metabolites and 68 metabolic enzymes between the CANA and CON groups. For instance, CANA significantly downregulated ATP synthase F1 subunit alpha, a mitochondrial electron transport system protein (CON 297.28±20.63 vs. CANA 251.83±22.83 fmol/10 μg protein; P = 0.0183). CANA also significantly upregulated 3-hydroxybutyrate, a beta-oxidation metabolite (CON 530±14 vs. CANA 854±68 arbitrary units; P<0.001). Moreover, CANA significantly downregulated nucleoside diphosphate kinase 1 (CON 110.30±11.37 vs. CANA 89.14±8.39 fmol/10 μg protein; P = 0.0172). CONCLUSIONS:We found that CANA suppressed the proliferation of HCC cells through alterations in mitochondrial oxidative phosphorylation metabolism, fatty acid metabolism, and purine and pyrimidine metabolism. Thus, CANA may suppress the proliferation of HCC by regulating metabolic reprograming

Histological outcomes between hot and cold snare polypectomy for small colorectal polyps

Background/Aim: To compare the complete resection rate of hot and cold snare polypectomy for small colorectal polyps. Patients and Methods: We retrospectively reviewed the medical records of 233 consecutive patients with 461 colorectal polyps up to 10 mm in diameter that were treated by hot or cold snare polypectomy between April 2014 and August 2016. Lesions treated by hot snare polypectomy (n = 137) and cold snare polypectomy (n = 324) were compared. The histological complete resection rates were evaluated between the two groups. We analyzed the relationship between factors for complete resection and clinical factors using multivariate analysis. Results: There was a significantly higher complete resection rate in hot snare polypectomy than in cold snare polypectomy (70.5% vs. 47.3%; P < 0.001). In the analysis of subgroups categorized according to polyp size, the complete resection rate for hot snare polypectomy was significantly higher than that for cold snare polypectomy among polyps ≥6 mm (69.0% vs. 43.5%; P < 0.001). Among polyps ≤5 mm, no significant difference regarding the complete resection rate was observed between the methods (81.3% vs. 53.4%; P = 0.057). There was no significant difference in the incidence of adverse events between the two groups. Multivariate analysis revealed that using hot snare polypectomy (odds ratio 3.03; P < 0.001), small lesion size (odds ratio 1.57; P = 0.049), and lesion location in the left colon (odds ratio 1.73; P = 0.007) were independent factors for complete resection. Conclusion: Hot snare polypectomy provides a higher complete resection rate than does cold snare polypectomy for larger (6–10 mm) subcentimeter colorectal polyps