Autophagy requires endoplasmic reticulum targeting of the PI3-kinase complex via Atg14L

Generation of PI3P in the normally PI3P-deficient ER membrane makes the organelle a platform for autophagosome formation

Neoadjuvant chemotherapy in locally advanced colorectal cancer: a Japanese multicenter study

Purpose: The impact of neoadjuvant chemotherapy for locally advanced colorectal cancer has not yet been investigated; thus, this study aimed to examine the safety, feasibility, and oncological effects of neoadjuvant chemotherapy for locally advanced colorectal cancer.Methods: In this multicenter study, we retrospectively reviewed the data of 83 locally advanced colorectal cancer patients (cT3/4 or N1/2) who received neoadjuvant chemotherapy followed by radical resection between April 2016 and September 2020. The NAC regimens were FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin), XELOX (capecitabine and oxaliplatin), or SOX (S-1 and oxaliplatin). We evaluated the pathological responses as well as the short- and long-term outcomes.Results: A pathological complete response was achieved in 4 patients (4.8%). Tumor down-staging and nodal down-staging were achieved in 57 (68.7%) and 49 (59.0%) patients, respectively. One patient (1.2%) experienced progressive disease. Postoperative complications occurred in 21 patients (25.3%). Multivariate analysis revealed that the pathological N positive status (p = 0.015; odds ratio, 4.458; 95% confidence interval, 1.331 to 7.9300) was an independent predictive factor for relapse-free survival.Conclusion: Neoadjuvant chemotherapy for colorectal cancer could achieve good tumor control and down-staging without increasing the rate of complications. Appropriate preoperative treatment that can reduce the rate of the pathological nodepositive disease may improve oncological outcomes

Phamacogenomics of Clozapine-Induced Agranulocytosis

Background: Clozapine-induced agranulocytosis (CIA)/clozapine-induced granulocytopenia (CIG) (CIAG) is a life-threatening event for schizophrenic subjects treated with clozapine. Methods: To examine the genetic factor for CIAG, a genome-wide pharmacogenomic analysis was conducted using 50 subjects with CIAG and 2905 control subjects. Results: We identified a significant association in the human leukocyte antigen (HLA) region (rs1800625, p = 3.46 × 10−9, odds ratio [OR] = 3.8); therefore, subsequent HLA typing was performed. We detected a significant association of HLA-B*59:01 with CIAG (p = 3.81 × 10−8, OR = 10.7) and confirmed this association by comparing with an independent clozapine-tolerant control group (n = 380, p = 2.97 × 10−5, OR = 6.3). As we observed that the OR of CIA (OR: 9.3~15.8) was approximately double that in CIG (OR: 4.4~7.4), we hypothesized that the CIG subjects were a mixed population of those who potentially would develop CIA and those who would not develop CIA (non-CIA). This hypothesis allowed the proportion of the CIG who were non-CIA to be calculated, enabling us to estimate the positive predictive value of the nonrisk allele on non-CIA in CIG subjects. Assuming this model, we estimated that 1) ~50% of CIG subjects would be non-CIA; and 2) ~60% of the CIG subjects without the risk allele would be non-CIA and therefore not expected to develop CIA. Conclusions: Our results suggest that HLA-B*59:01 is a risk factor for CIAG in the Japanese population. Furthermore, if our model is true, the results suggest that rechallenging certain CIG subjects with clozapine may not be always contraindicated

Cancer Risk in Diabetic Patients Treated with Metformin: A Systematic Review and Meta-analysis

BACKGROUND: A growing body of evidence has suggested that metformin potentially reduces the risk of cancer. Our objective was to enhance the precision of estimates of the effect of metformin on the risk of any-site and site-specific cancers in patients with diabetes. METHODS/PRINCIPAL FINDINGS: We performed a search of MEDLINE, EMBASE, ISI Web of Science, Cochrane Library, and ClinicalTrials.gov for pertinent articles published as of October 12, 2011, and included them in a systematic review and meta-analysis. We calculated pooled risk ratios (RRs) for overall cancer mortality and cancer incidence. Of the 21,195 diabetic patients reported in 6 studies (4 cohort studies, 2 RCTs), 991 (4.5%) cases of death from cancer were reported. A total of 11,117 (5.3%) cases of incident cancer at any site were reported among 210,892 patients in 10 studies (2 RCTs, 6 cohort studies, 2 case-control studies). The risks of cancer among metformin users were significantly lower than those among non-metformin users: the pooled RRs (95% confidence interval) were 0.66 (0.49-0.88) for cancer mortality, 0.67 (0.53-0.85) for all-cancer incidence, 0.68 (0.53-0.88) for colorectal cancer (n = 6), 0.20 (0.07-0.59) for hepatocellular cancer (n = 4), 0.67 (0.45-0.99) for lung cancer (n = 3). CONCLUSION/SIGNIFICANCE: The use of metformin in diabetic patients was associated with significantly lower risks of cancer mortality and incidence. However, this analysis is mainly based on observational studies and our findings underscore the more need for long-term RCTs to confirm this potential benefit for individuals with diabetes

Reservoir environment of the Onuma geothermal power plant, northeast Japan, estimated by forward analysis of long-term artificial-tracer concentration change, using single-box-model simulator

A single-box-model numerical simulator for personal computer analysis was developed in order to estimate macroscopic parameter values for exploited geothermal reservoirs and essential fluids coming from the depth. The simulator was designed to compute history data concerning total production and reinjection fluids at geothermal power plants from the assumed parameter values, based on conservation laws for water mass, heat energy and masses of conservative chemical constituents of geothermal fluids. Using two kinds of forward analysis techniques, i.e. the cast-net and pursuit methods, programs containing the simulator can semiautomatically select the optimum combination of the unknown parameter values by minimizing the differences between the simulated and measured history data for specific enthalpy and chemical compositions of the production fluids. The forward analysis programs were applied to the history data from the Onuma geothermal power plant (production capacity, 10MWe) where waste hot water reinjection, chemical monitoring and artificial tracer tests have been conducted since 1970, almost the beginning of the geothermal exploitation. Using the history data, enthalpy and iodine concentrations of the total production fluids with the amounts of KI tracer injected as spikes, the macroscopic parameter values for the exploited reservoir and the essential hot water from the depth were uniquely determined as follows: mass of the hot water convecting in the exploited reservoir (M0), 3.23x109kg; recycling fraction of the reinjected waste hot water to the reservoir (R), 0.74; specific enthalpy of the essential water from the depth (H1), 385kcalkg; iodine concentration of the water (I1), 0.086mg/kg with chlorine concentration (C1), 259mg/kg. These results support the conceptual model that the exploited Onuma reservoir mainly in the Tertiary volcanics is supplied with the neutral Na-Cl type hot water of abnormally high B/CI mole ratio of around 1.0 by a large essential reservoir distributed at depth in the Paleozoic to Mesozoic detrital marine sedimentary rocks