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Platinum sensitivity is an important prognostic factor in patients with ovarian cancer. Chromodomain-helicase-DNA-binding protein 4 (CHD4) is a core member of the nucleosome remodeling and deacetylase complex, which functions as a chromatin remodeler. Emerging evidence indicates that CHD4 could be a potential therapeutic target for cancer therapy. The purpose of this study was to clarify the role of CHD4 in ovarian cancer and investigate its therapeutic potential focusing on platinum sensitivity. In an analysis of the Cancer Genome Atlas ovarian cancer dataset, CHD4 gene amplification was associated with worse overall survival. CHD4 mRNA expression was significantly higher in platinum-resistant samples in a subsequent clinical sample analysis, suggesting that CHD4 overexpression conferred platinum resistance to ovarian cancer cells, resulting in poor patient survival. In concordance with these findings, CHD4 knockdown enhanced the induction of apoptosis mediated by cisplatin in ovarian cancer cells TOV21G and increased cisplatin sensitivity in multiple ovarian cancer cells derived from different subtypes. However, CHD4 knockdown did not affect the expression of RAD51 or p21, the known targets of CHD4 in other cancer types that can modulate platinum sensitivity. Knockdown and overexpression assays revealed that CHD4 positively regulated the expression of multi-drug transporter MDR1 and its coding protein p-glycoprotein. In addition, a first-in-class CHD4/SMARCA5 inhibitor ED2-AD101 showed synergistic interactions with cisplatin. Our findings suggest that CHD4 mediates platinum sensitivity by modulating MDR1 expression in ovarian cancer. Further, CHD4 suppression has a potential to be a novel therapeutic strategy in combination with platinum agents.

Introduction Persistent descending mesocolon is a congenital fixation abnormality where the left‐sided colon deviates medially. When significantly displaced to the right, it may affect sacrocolpopexy. We report two cases of persistent descending mesocolon in which robot‐assisted sacrocolpopexy was successfully performed with mesh fixation to the sacral promontory from the left side of the mesosigmoid. Case Presentation Two patients with pelvic organ prolapse underwent robot‐assisted sacrocolpopexy. In both cases, the sigmoid colon was displaced to the right, making exposure of the sacral promontory from the right side of the mesosigmoid challenging. Therefore, the sacral promontory was exposed and mesh fixed from the left side of the mesosigmoid. The postoperative course was uneventful. Conclusion When the sigmoid colon is displaced rightward due to persistent descending mesocolon, sacral promontory fixation from the left mesosigmoid may be a safe, feasible option.

IntroductionOvarian cancer is one of the most lethal gynecologic malignancies. Many patients are diagnosed in advanced stages of disease where the prognosis is poor due to the inevitable acquired resistance to platinum agents. Thus, novel therapeutic strategies effective for platinum-resistant cases are required. Zinc Finger Homeobox 4 (ZFHX4) has been known as one of the major transcription regulators in nerve and muscle differentiation. Recent researches including our genome-wide exploration indicate ZFHX4 is also involved in carcinogenesis and cancer progression. The objective of this study was to investigate the potential of ZFHX4 as a novel therapeutic target in ovarian cancer.MethodsCorrelations between ZFHX4 mRNA expression and overall survival in 61 ovarian cancer cases treated at our institute and in the cases registered in TCGA database respectively were assessed by log-lank test. RNAi knockdown was introduced to several ovarian cancer cells to investigate the influence of ZFHX4 on cancer cell proliferation, migration and platinum sensitivity.[Results] Both in our clinical dataset and TCGA data, the overall survival was significantly poor in the group in which ZFHX4 is highly expressed. In cell model assay, ZFHX4 knockdown significantly suppressed ovarian cancer cell proliferation. Decreased motility was observed in the cells treated with siRNA targeting ZFHX4 by scratch assay. Furthermore, ZFHX4 knockdown increased cisplatin sensitivity.ConclusionsAltogether, our results suggest ZFHX4 functions to promote cancer cell proliferation, migration and platinum-resistance. Interruption of ZFHX4 function independently or in combination with platinum agents has a potential to bring benefit for the treatment of ovarian cancer.

Plasmacytoid dendritic cells (pDC) sense viral RNA through toll-like receptor 7 (TLR7), form self-adhesive pDC–pDC clusters, and produce type I interferons. This cell adhesion enhances type I interferon production, but little is known about the underlying mechanisms. Here we show that MyD88-dependent TLR7 signaling activates CD11a/CD18 integrin to induce microtubule elongation. TLR7 + lysosomes then become linked with these microtubules through the GTPase Arl8b and its effector SKIP/Plekhm2, resulting in perinuclear to peripheral relocalization of TLR7. The type I interferon signaling molecules TRAF3, IKKα, and mTORC1 are constitutively associated in pDCs. TLR7 localizes to mTORC1 and induces association of TRAF3 with the upstream molecule TRAF6. Finally, type I interferons are secreted in the vicinity of cell–cell contacts between clustered pDCs. These results suggest that TLR7 needs to move to the cell periphery to induce robust type I interferon responses in pDCs. Antiviral immune responses involve clustering of plasmacytoid dendritic cells (pDC) in response to endosomal TLR7-mediated sensing of viral RNA. Here the authors show the GTPase Arl8b controls translocation of TLR7 + endosomes to the periphery of the cell via microtubule interactions, thus enabling pDC clustering and type I interferon production.

Atypical teratoid/rhabdoid tumor (AT/RT) is a rare intracranial tumor occurring predominantly in young children. The prognosis is poor, and no effective treatment is currently available. To develop novel effective therapies, there is a need for experimental models for AT/RT. In this research, we established a cell line from a patient’s AT/RT tissue (designated ATRT_OCGH) and performed drug screening using 164 FDA-approved anti-cancer agents, to identify candidates for therapeutic options. We found that bortezomib, a proteasome inhibitor, was among the agents for which the cell line showed high sensitivity, along with tyrosine kinase inhibitors, topoisomerase inhibitors, and histone deacetylase inhibitors, which are known to exert anti-AT/RT effects. Concomitant use of panobinostat potentiated the inhibitory effect of bortezomib on AT/RT cell proliferation. Our findings may provide a rationale for considering combination therapy of panobinostat and bortezomib for treatment of AT/RT.

As a base for human transcriptome and functional genomics, we created the “full-length long Japan” (FLJ) collection of sequenced human cDNAs. We determined the entire sequence of 21,243 selected clones and found that 14,490 cDNAs (10,897 clusters) were unique to the FLJ collection. About half of them (5,416) seemed to be protein-coding. Of those, 1,999 clusters had not been predicted by computational methods. The distribution of GC content of nonpredicted cDNAs had a peak at ∼58% compared with a peak at ∼42%for predicted cDNAs. Thus, there seems to be a slight bias against GC-rich transcripts in current gene prediction procedures. The rest of the cDNAs unique to the FLJ collection (5,481) contained no obvious open reading frames (ORFs) and thus are candidate noncoding RNAs. About one-fourth of them (1,378) showed a clear pattern of splicing. The distribution of GC content of noncoding cDNAs was narrow and had a peak at ∼42%, relatively low compared with that of protein-coding cDNAs.

Background and Aim Anti‐tumor necrosis factor alpha (TNF‐α) therapy is an effective therapy for Crohn's disease (CD). We investigated FoxP3+ and CD127− regulatory T cells (Tregs) before and after administration of anti‐TNF‐α therapy in CD. Methods Eight patients with active CD who had received anti‐TNF‐α antibodies were enrolled. Treatment responses were followed by physical examination and Crohn's disease activity index (CDAI) scoring before and 2 weeks after the initial administration of anti‐TNF‐α antibodies. Peripheral blood samples were collected before and 2 weeks after treatment. White blood cell count and serum levels of C‐reactive protein (CRP) and albumin were measured. FoxP3+ expression and CD127− Tregs were measured by fluorescence activated cell sorting (FACS) analysis of whole blood samples. Results Median values of CDAI decreased significantly after treatment. The proportion of FoxP3+ Tregs increased significantly after treatment. There was a significant negative correlation between ΔCD127− Tregs and Δlymphocyte. Conclusions Anti‐TNF‐α therapy would enhance Tregs, which may account for the mechanism underlying the positive effect of the anti‐TNF‐α treatment in CD patients. We investigated regulatory T cells before and after administration of anti‐TNF‐a therapy in Crohn's disease. The proportion of FoxP3+ Tregs increased significantly after treatment. There was a significant negative correlation between ΔCD127− Tregs and Δlymphocyte.

Background Recently, incretin hormones, including glucagon-like peptide-1 (GLP-1) analogue and dipeptidyl peptidase-4 (DPP-4) inhibitor, have been found to regulate glucose metabolism. The aim of this study was to elucidate the efficacy and safety of the clinical usage of DPP-4 inhibitors in Japan. Methods This study was designed as a prospective, open-label, multi-center trial. Patients with diabetes mellitus type 2 (T2DM) with poor glycemic profiles (HbA1c ≥ 6.2%) in spite of receiving a medical diet, therapeutic exercise, and/or medications were eligible for this study. The participants received 50 to 100 mg of the DPP-4 inhibitor sitagliptin once daily for 12 months. Results One hundred and eighty-eight subjects were enrolled. After 12 months of sitagliptin treatment, HbA1c levels decreased (7.65% ± 1.32% to 7.05% ± 1.10%, p < 0.001) as well as fasting plasma glucose (FPG) (145 ± 52 mg/dl to 129 ± 43 mg/dl, p = 0.005). The rate of glycemic control achieved (in accordance with the guidelines of the Japanese Diabetes Society) significantly increased. Blood pressure and serum levels of triglycerides and total cholesterol decreased significantly. Furthermore, the Pittsburgh Sleep Quality Index (PSQI) and Diabetes Symptomatic Scores improved significantly. Adverse events such as hypoglycemia and loss of consciousness occurred in twenty three subjects (11%). Conclusions These results suggest that the actions of DPP-4 inhibitors improve not only glycemic control, but also blood pressure, lipid profiles, and quality of life (QOL). Sitagliptin is a sound agent for use in the comprehensive treatment of patients with T2DM.

Background The purpose of this study was to elucidate the effects of glimepiride on the levels of biomarkers related to cardiovascular regulation in patients with type 2 diabetes mellitus. Methods and results Thirty-four patients with type 2 diabetes received glimepiride for 24 weeks. Significant decreases in the levels of glyceraldehyde-derived advanced glycation end products, (glycer-AGE: toxic AGE), eotaxin and fibroblast growth factor (FGF)-2 were recognized after the administration of glimepiride. Moreover, there were trends for there to be increases in the levels of granulocyte-colony stimulating factor (G-CSF) and granulocyte macrophage-colony stimulating factor (GM-CSF), and decreases in the levels of fractalkine, soluble CD40 ligand (sCD40L), macrophage inflammatory protein (MIP)-β, vascular endothelial growth factor (VEGF) and soluble receptor for AGE (sRAGE). Conclusions Glimepiride may have potent anti-oxidative, anti-inflammatory and angiogenic properties and it may potentially repair tissue damage by decreasing the levels of toxic AGE and increasing colony-stimulating factors.

The β1, β2 and β4 subunits of voltage-gated sodium channels reportedly function as cell adhesion molecules. The present crystallographic analysis of the β4 extracellular domain revealed an antiparallel arrangement of the β4 molecules in the crystal lattice. The interface between the two antiparallel β4 molecules is asymmetric and results in a multimeric assembly. Structure-based mutagenesis and site-directed photo-crosslinking analyses of the β4-mediated cell-cell adhesion revealed that the interface between the antiparallel β4 molecules corresponds to that in the trans homophilic interaction for the multimeric assembly of β4 in cell-cell adhesion. This trans interaction mode is also employed in the β1-mediated cell-cell adhesion. Moreover, the β1 gene mutations associated with generalized epilepsy with febrile seizures plus (GEFS+) impaired the β1-mediated cell-cell adhesion, which should underlie the GEFS+ pathogenesis. Thus, the structural basis for the β-subunit-mediated cell-cell adhesion has been established.