Mutation in PTEN has not yet been detected, but its function as a tumor suppressor is inactivated in many cancers. In this study we determined that, activated Notch signaling disables PTEN by ...phosphorylation and thereby contributes to gastric tumorigenesis. Notch inhibition by small interfering RNA or γ-secretase inhibitor (GSI) induced mitotic arrest and apoptosis in gastric cancer cells. Notch inhibition induced dephosphorylation in the C-terminal domain of PTEN, which led to PTEN nuclear localization. Overexpression of activated Notch1-induced phosphorylation of PTEN and reversed GSI-induced mitotic arrest. Dephosphorylated nuclear PTEN caused prometaphase arrest by interaction with the cyclin B1-CDK1 complex, resulting in their accumulation in the nucleus and subsequent apoptosis. We found a correlation between high expression levels of Notch1 and low survival rates and, similarly, between reduced nuclear PTEN expression and increasing the TNM classification of malignant tumours stages in malignant tissues from gastric cancer patients. The growth of Notch1-depleted gastric tumors was significantly retarded in xenografted mice, and in addition, PTEN deletion restored growth similar to control tumors. We also demonstrated that combination treatment with GSI and chemotherapeutic agents significantly reduced the orthotopically transplanted gastric tumors in mice without noticeable toxicity. Overall, our findings suggest that inhibition of Notch signaling can be employed as a PTEN activator, making it a potential target for gastric cancer therapy.
Low-dose organochlorine (OC) pesticides have recently been associated with type 2 diabetes in several non-Asian general populations. As there is currently epidemic type 2 diabetes in Asia, we ...investigated the associations between OC pesticides and type 2 diabetes in Koreans. Among subjects who participated in a community-based health survey, we randomly selected 40 diabetic patients and 40 normal controls. Ten OC pesticides (beta-hexachlorocyclohexane, hexachlorobenzene, heptachlor epoxide, p,p′-DDE, p,p′-DDD, p,p′-DDT, o,p′-DDT, oxychlordane, trans-nonachlor, and mirex) detectable in ≥
70% of controls were analyzed in relation to diabetes. Most OC pesticides showed strong associations with type 2 diabetes after adjusting for age, sex, BMI, alcohol consumption, and cigarette smoking. Compared with subjects in the lowest tertile of each OC pesticide, adjusted odds ratios (ORs) in the 3rd tertile ranged from 3.1 (95% CI 0.8–12.1) for heptachlor epoxide to 26.0 (95% CI 1.3–517.4) for oxychlordane. In the case of chemicals belonging to the DDT family, adjusted ORs in the 3rd tertile were in the range of 10.6 (95% CI 1.3–84.9) for p,p′-DDT to 12.7 (95% CI 1.9–83.7) for p,p′-DDE. In this exploratory study with small sample, low-dose background exposure to OC pesticides was strongly associated with prevalent type 2 diabetes in Koreans even though absolute concentrations of OC pesticides were no higher than in other populations. Asians may be more susceptible to adverse effects of OC pesticides than other races.
Every day, students and instructors are faced with the decision of when to study information. The timing of study, and how it affects memory retention, has been explored for many years in research on ...human learning. This research has shown that performance on final tests of learning is improved if multiple study sessions are separated—i.e., "spaced" apart—in time rather than massed in immediate succession. In this article, we review research findings of the types of learning that benefit from spaced study, demonstrations of these benefits in educational settings, and recent research on the time intervals during which spaced study should occur in order to maximize memory retention. We conclude with a list of recommendations on how spacing might be incorporated into everyday instruction.
ABO incompatibility is no longer considered a contraindication for adult living donor liver transplantation (ALDLT) due to various strategies to overcome the ABO blood group barrier. We report the ...largest single‐center experience of ABO‐incompatible (ABOi) ALDLT in 235 adult patients. The desensitization protocol included a single dose of rituximab and total plasma exchange. In addition, local graft infusion therapy, cyclophosphamide, or splenectomy was used for a certain time period, but these treatments were eventually discontinued due to adverse events. There were three cases (1.3%) of in‐hospital mortality. The cumulative 3‐year graft and patient survival rates were 89.2% and 92.3%, respectively, and were comparable to those of the ABO‐compatible group (n = 1301). Despite promising survival outcomes, 17 patients (7.2%) experienced antibody‐mediated rejection that manifested as diffuse intrahepatic biliary stricture; six cases required retransplantation, and three patients died. ABOi ALDLT is a feasible method for expanding a living liver donor pool, but the efficacy of the desensitization protocol in targeting B cell immunity should be optimized.
This article presents the clinical results of ABO‐incompatible adult living donor liver transplantation in a single institution.
Summary
Recent studies found that hepatitis C virus (HCV) may invade the central nervous system, and both HCV and Parkinson's disease (PD) have in common the overexpression of inflammatory ...biomarkers. We analysed data from a community‐based integrated screening programme based on a total of 62 276 subjects. We used logistic regression models to investigate association between HCV infection and PD. The neurotoxicity of HCV was evaluated in the midbrain neuron–glia coculture system in rats. The cytokine/chemokine array was performed to measure the differences of amounts of cytokines released from midbrain in the presence and absence of HCV. The crude odds ratios (ORs) for having PD were 0.62 95% confidence interval (CI), 0.48–0.81 and 1.91 (95% CI, 1.48–2.47) for hepatitis B virus (HBV) and HCV. After controlling for potential confounders, the association between HCV and PD remained statistically significant (adjusted OR = 1.39; 95% CI, 1.07–1.80), but not significantly different between HBV and PD. The HCV induced 60% dopaminergic neuron death in the midbrain neuron–glia coculture system in rats, similar to that of 1‐methyl‐4‐phenylpyridinium (MPP+) but not caused by HBV. This link was further supported by the finding that HCV infection may release the inflammatory cytokines, which may play a role in the pathogenesis of PD. In conclusion, our study demonstrated a significantly positive epidemiological association between HCV infection and PD and corroborated the dopaminergic toxicity of HCV similar to that of MPP+.
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) commonly occurs in individuals receiving bisphosphonates (BPs) with clinical manifestations of the exposed necrotic bone. Although defective ...wound healing of soft tissue is frequently, if not always, observed in BRONJ, the effects of BPs on oral soft tissue or cells remain unknown. To investigate the effects of BPs on cells of oral mucosal tissue, we studied the effect of pamidronate (PAM), one of the BPs most commonly administered to cancer patients, on the phenotypes of normal human oral keratinocytes (NHOK) and fibroblasts (NHOF). When exposed to PAM at 10 µM, NHOK, not NHOF, underwent senescence: NHOK overexpressed senescence-associated β-galactosidase (SA-β-Gal), p16INK4A, IL-6, and IL-8. When exposed to a higher level (50 µM) of PAM, NHOK maintained senescent phenotypes, but NHOF underwent apoptosis. PAM-induced senescence in NHOK is mediated, in part, via geranylgeranylation of the mevalonate pathway. Our in vitro 3D oral mucosal tissue construction studies further demonstrated that PAM induced senescence and impaired re-epithelialization of oral mucosa. Analysis of these data indicates that premature senescence of oral mucosal cells and subsequent defective soft-tissue wound healing might be partly responsible for the development of BRONJ in individuals receiving PAM or other BPs.
Our aim was to investigate the association between the triglycerides/glucose index (TyG index) and the homeostasis model assessment-estimated insulin resistance (HOMA-IR) in the prediction of insulin ...resistance (IR) among adolescents.
We conducted a cross-sectional study among 221 Korean adolescents (168 males and 53 females aged 9-13 years) from May to June 2014 in Chung-ju city. The TyG index was calculated as ln triglycerides (mg dl
) × fasting glucose (mg dl
)/2. IR was defined using HOMA-IR >95th percentile for age and sex.
In the IR group, weight, body mass index (BMI), waist circumference, body fat, fasting insulin, fasting plasma glucose, triglyceride levels and triglycerides/high-density lipoprotein cholesterol (TG/HDL-C) were significantly higher than that in the non-IR group. The TG index was significantly different between the IR group (n=22) and non-IR group (n=199), at 8.43±0.45 and 8.05±0.41, respectively (P<0.001). The TyG index was well correlated with HOMA-IR (r=0.41; P<0.001) and showed a strong positive association with TG/HDL-C (r=0.84; P<0.001). The cut-off of the TyG index for diagnosis of insulin resistance was 8.18.
The TyG index is a simple, cost-effective surrogate marker of insulin resistance among adolescents compared with HOMA-IR.
Summary
Because the rate of bone loss is an important risk factor for fracture, we studied longitudinal changes in bone mineral density (BMD). Although the BMD of the hip decreased over time, spine ...BMD remained largely stable or increased. Therefore, spine BMD may not be appropriate for assessing BMD change.
Introduction
The rate of age-dependent bone loss has been shown to be an important risk factor for fracture. However, longitudinal rates of BMD loss in Korea have not yet been reported. The objective of this study was to evaluate longitudinal changes in BMD in Korea.
Methods
This cohort study was performed in a population of individuals 40 years of age or older living in the rural area of Chungju City, Korea. A second BMD examination was conducted approximately 4 years after a baseline examination. A total of 3755 of the 6007 subjects completed the follow-up visit, corresponding to a follow-up rate of 62.51%.
Results
The age-standardized osteoporosis prevalence was 12.81% in males and 44.35% in females. In males, the average annual BMD loss at the total hip increased from −0.25% per year in their 40s to −1.12% per year in their 80s. In females, the average annual BMD loss at the total hip increased from −0.69% per year in their 40s to −1.51% per year in their 80s. However, the average annual percentage change in spine BMD in females increased from −0.91% per year in their 40s to +1.39% per year in their 80s.
Conclusions
A substantial number of subjects had osteoporosis, even though we standardized the prevalence of osteoporosis. In total hip, the mean BMD was decreased during the follow-up period; in addition, the annual percentage loss increased with age. However, spine BMD remained approximately stable or increased over time and therefore may not be appropriate for assessing BMD change.
Chronic cerebral hypoperfusion is associated with vascular dementia (VaD). Cerebral hypoperfusion may initiate complex molecular and cellular inflammatory pathways that contribute to long-term ...cognitive impairment and memory loss. Here we used a bilateral common carotid artery stenosis (BCAS) mouse model of VaD to investigate its effect on the innate immune response-particularly the inflammasome signaling pathway. Comprehensive analyses revealed that chronic cerebral hypoperfusion induces a complex temporal expression and activation of inflammasome components and their downstream products (IL-1β and IL-18) in different brain regions, and promotes activation of apoptotic and pyroptotic cell death pathways. Polarized glial-cell activation, white-matter lesion formation and hippocampal neuronal loss also occurred in a spatiotemporal manner. Moreover, in AIM2 knockout mice we observed attenuated inflammasome-mediated production of proinflammatory cytokines, apoptosis, and pyroptosis, as well as resistance to chronic microglial activation, myelin breakdown, hippocampal neuronal loss, and behavioral and cognitive deficits following BCAS. Hence, we have demonstrated that activation of the AIM2 inflammasome substantially contributes to the pathophysiology of chronic cerebral hypoperfusion-induced brain injury and may therefore represent a promising therapeutic target for attenuating cognitive impairment in VaD.
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