The effect of istradefylline for Parkinson’s disease : A meta-analysis

Adenosine A2A receptor antagonists are an alternative treatment strategy for Parkinson’s disease. Several randomized placebo controlled studies have tested the effect of A2A receptor antagonist istradefylline, and more robust evidence has been acquired. This meta-analysis aimed to provide evidence for its efficacy and safety on patients with Parkinson’s disease. After a systematic literature search, we calculated the pooled standardized mean difference and risk ratio for continuous and dichotomous variables, respectively. Further, sensitivity analyses were performed to confirm the effect estimated by meta-analyses. Publication bias was assessed by funnel plot and deviation of intercept. Six studies satisfied our inclusion criteria. Istradefylline (40 mg/day) decreased off time and improved motor symptoms of Parkinson’s disease in homogeneous studies. Istradefylline at 20 mg/day decreased off time and improved motor symptoms, but heterogeneity was found in the analysis of the former among studies. There was a significant effect of istradefylline on dyskinesia in homogeneous studies. Publication bias, however, was observed in the comparison of dyskinesia. Other adverse events showed no significant difference. The present meta-analysis suggests that istradefylline at 40 mg/day could alleviate off time and motor symptoms derived from Parkinson’s disease. Dyskinesia might be worsened, but publication bias prevents this from being clear

B1 SINE-binding ZFP266 impedes mouse iPSC generation through suppression of chromatin opening mediated by reprogramming factors

Induced pluripotent stem cell (iPSC) reprogramming is inefficient and understanding the molecular mechanisms underlying this inefficiency holds the key to successfully control cellular identity. Here, we report 24 reprogramming roadblock genes identified by CRISPR/Cas9-mediated genome-wide knockout (KO) screening. Of these, depletion of the predicted KRAB zinc finger protein (KRAB-ZFP) Zfp266 strongly and consistently enhances murine iPSC generation in several reprogramming settings, emerging as the most robust roadblock. We show that ZFP266 binds Short Interspersed Nuclear Elements (SINEs) adjacent to binding sites of pioneering factors, OCT4 (POU5F1), SOX2, and KLF4, and impedes chromatin opening. Replacing the KRAB co-suppressor with co-activator domains converts ZFP266 from an inhibitor to a potent facilitator of iPSC reprogramming. We propose that the SINE-KRAB-ZFP interaction is a critical regulator of chromatin accessibility at regulatory elements required for efficient cellular identity changes. In addition, this work serves as a resource to further illuminate molecular mechanisms hindering reprogramming.Induced pluripotent stem cell (iPSC) reprogramming is inherently inefficient. Here the authors identify 24 reprogramming roadblock genes through a CRISPR/Cas9-mediated genome-wide knockout screen including a KRAB-ZFP Zfp266, knockout of which consistently enhances murine iPSC generation.Peer reviewe

Perioperative Clinical Course Variables Associated with Length of Hospital Stay after Primary Intracranial Meningioma Resection

The relationship between perioperative clinical course variables and postoperative length of hospital stay (LOS) in patients undergoing primary intracranial meningioma resection has not been fully elucidated. We therefore aimed to identify the perioperative clinical course variables that predict postoperative LOS in such patients. We retrospectively collected data concerning demographics, tumor characteristics, and perioperative clinical course variables in 76 patients who underwent primary intracranial meningioma resection between January 2010 and December 2019, and tested for associations with postoperative LOS. Univariate analyses showed that younger age, fewer days to postoperative initiation of standing/walking, preoperative independence in activities of daily living (ADL), and ADL independence one week after surgery were associated with shorter postoperative LOS. Multiple regression analyses with these factors identified that days to stand/walk initiation and ADL independence one week after surgery were associated with postoperative LOS. Based on these results, we conclude that rehabilitation programs that promote early mobilization and the early acquisition of independence may reduce postoperative LOS in patients who undergo primary intracranial meningioma resection

リポポリサッカライドの外因性投与はコリン欠乏 L-アミノ酸置換食誘発脂肪性肝炎モデルマウスにおいて肝線維化を促進する

Various rodent models have been proposed for basic research; however, the pathogenesis of human nonalcoholic steatohepatitis (NASH) is difficult to closely mimic. Lipopolysaccharide (LPS) has been reported to play a pivotal role in fibrosis development during NASH progression via activation of toll-like receptor 4 (TLR4) signaling. This study aimed to clarify the impact of low-dose LPS challenge on NASH pathological progression and to establish a novel murine NASH model. C57BL/6J mice were fed a choline-deficient l-amino-acid-defined (CDAA) diet to induce NASH, and low-dose LPS (0.5 mg/kg) was intraperitoneally injected thrice a week. CDAA-fed mice showed hepatic CD14 overexpression, and low-dose LPS challenge enhanced TLR4/NF-κB signaling activation in the liver of CDAA-fed mice. LPS challenge potentiated CDAA-diet-mediated insulin resistance, hepatic steatosis with upregulated lipogenic genes, and F4/80-positive macrophage infiltration with increased proinflammatory cytokines. It is noteworthy that LPS administration extensively boosted pericellular fibrosis with the activation of hepatic stellate cells in CDAA-fed mice. Exogenous LPS administration exacerbated pericellular fibrosis in CDAA-mediated steatohepatitis in mice. These findings suggest a key role for LPS/TLR4 signaling in NASH progression, and the authors therefore propose this as a suitable model to mimic human NASH.博士（医学）・甲第738号・令和2年3月16日© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)

アンギオテンシン受容体を遮断することによりYes関連蛋白質の発癌活性が阻害されて胆管癌細胞増殖が抑制される

Cholangiocarcinoma (CCA) is a destructive malignancy with limited responsiveness to conventional chemotherapy. Although angiotensin receptor blockers (ARBs) have gained attention for their potential anticancer activity, little is known about their effects on CCA. The transcriptional co-activator, Yes-associated protein (YAP) is a critical oncogene in several cancers, including CCA. Following recent evidence showing that YAP is regulated by angiotensin II (AT-II), we investigated the effects of an ARB, losartan, on two human CCA cell lines (KKU-M213 and HuCCT-1) with regards to YAP oncogenic regulation. Losartan suppressed AT-II-induced CCA cell proliferation in a dose-dependent manner, induced apoptosis, decreased YAP (Ser127), and downregulated the YAP target genes CTGF, CYR61, ANKRD1, and MFAP5. However, losartan did not affect epithelial-mesenchymal transition, differentiation, or stemness in the CCA cells. Xenograft tumor growth assay showed that oral administration of a low clinical dose of losartan considerably reduced subcutaneous tumor burden and attenuated intratumor vascularization in CCA cell-derived xenograft tumors in BALB/c nude mice. These results indicate that ARB therapy could serve as a potential novel strategy for CCA treatment.博士（医学）・甲第728号・令和2年3月16日Copyright © 2018 Elsevier B.V. All rights reserved

フルクトースの経口投与はラット脂肪性肝炎モデルにおいて腸管透過性亢進作用を介して肝線維化および肝発癌を悪化させる

Recent reports have revealed the impact of a western diet containing large amounts of fructose on the pathogenesis of non-alcoholic steatohepatitis (NASH). Fructose exacerbates hepatic inflammation in NASH by inducing increasing intestinal permeability. However, it is not clear whether fructose contributes to the progression of liver fibrosis and hepatocarcinogenesis in NASH. The aim of this study was to investigate the effect of fructose intake on NASH in a rat model. A choline-deficient/L-amino acid diet was fed to F344 rats to induce NASH. Fructose was administrated to one group in the drinking water. The development of liver fibrosis and hepatocarcinogenesis were evaluated histologically. Oral fructose administration exacerbated liver fibrosis and increased the number of preneoplastic lesions positive for glutathione S-transferase placental form. Fructose-treated rats had significantly higher expression of hepatic genes related to toll-like receptor-signaling, suggesting that fructose consumption increased signaling in this pathway, leading to the progression of NASH. We confirmed that intestinal permeability was significantly higher in fructose-treated rats, as evidenced by a loss of intestinal tight junction proteins. Fructose exacerbated both liver fibrosis and hepatocarcinogenesis by increasing intestinal permeability. This observation strongly supports the role of endotoxin in the progression of NASH.博士（医学）・乙第1432号・令和元年9月27日Copyright © 2018 Impact Journals, LLCCopyright © Seki et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0 https://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

How Sensitive Are Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitors for Squamous Cell Carcinoma of the Lung Harboring EGFR Gene–Sensitive Mutations?

Introduction:Epidermal growth factor receptor (EGFR) mutations are found mostly in adenocarcinoma, and rarely in squamous cell carcinoma (SQC). Little is known about SQC harboring EGFR mutations.Methods:Between April 2006 and October 2010, we investigated the incidence of EGFR activating mutations in SQC of the lung using the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method. The efficacy of EGFR-tyrosine kinase inhibitors (TKIs) was retrospectively evaluated in patients with EGFR-mutated SQC. Further pathologic analyses were performed using immunohistochemistry.Results:Thirty-three of 249 patients with SQC (13.3%) had EGFR mutations, including exon 19 deletion (19 of 33 patients, 58%), L858R point mutation in exon 21 (12 of 33, 36%), and G719S point mutation in exon 18 (2 of 33, 6%). Twenty of these 33 patients received EGFR-TKI therapy, and five of these 20 responded to EGFR-TKIs with a response rate of 25.0% (95% confidence interval [CI], 8.7%–49.1%). The patients’ median progression-free survival and median overall survival were 1.4 months (95% CI, 0.7–5.8 months) and 14.6 months (95% CI, 2.9–undeterminable months), respectively. Approximately one third of the EGFR-mutated SQC patients achieved progression-free survival for longer than 6 months. Some of these patients had high carcinoembryonic antigen levels or a history of never smoking, or were positive for thyroid transcription factor-1.Conclusions:Although EGFR-TKIs seem to be generally less effective in EGFR-mutated SQC than in EGFR-mutated adenocarcinoma, some EGFR-mutated SQC patients can obtain clinical benefit from EGFR-TKIs. To better identify these patients, not only EGFR mutation status, but also clinical factors and pathologic findings should be taken into consideration

Acute Loss of Cited2 Impairs Nanog Expression and Decreases Self-Renewal of Mouse Embryonic Stem Cells

Identifying novel players of the pluripotency gene regulatory network centered on Oct4, Sox2, and Nanog as well as delineating the interactions within the complex network is key to understanding self-renewal and early cell fate commitment of embryonic stem cells (ESC). While overexpression of the transcriptional regulator Cited2 sustains ESC pluripotency, its role in ESC functions remains unclear. Here, we show that Cited2 is important for proliferation, survival, and self-renewal of mouse ESC. We position Cited2 within the pluripotency gene regulatory network by defining Nanog, Tbx3, and Klf4 as its direct targets. We also demonstrate that the defects caused by Cited2 depletion are, at least in part, rescued by Nanog constitutive expression. Finally, we demonstrate that Cited2 is required for and enhances reprogramming of mouse embryonic fibroblasts to induced pluripotent stem cells.National Portuguese through FCT-Fundacao para a Ciencia e a Tecnologia [PEst-OE/EQB/LA0023/2013, PTDC/SAU-ENB/111702/2009]; Camara Municipal de Oeiras; Merck Sharp & Dhome Foundation-Portugal; CRUK; Leukaemia & Lymphoma Research; Kay Kendall Leukaemia Fund; Wellcome Trust; Medical Research Council; Cancer Research UK [12796, 14633]; Great Ormond Street Hospital Childrens Charity [W1062]; Medical Research Council [MC_U137973817, G1000801g, MC_qA137913