[Chemotherapy Strategy in a Case of MSI-High Patients with Gastric Cancer-Case Report].

A 73-year-old woman was referred to our hospital with a chief complaint of black stools and abdominal distention. She was diagnosed with advanced gastric cancer with pyloric stenosis and multiple lymph node metastasis(cT4aN3M0, cStage Ⅲ)and was administered preoperative chemotherapy after laparoscopy and gastric jejunal bypass surgery. The surgical diagnosis was sT4aN3M0P0CY0. After surgery, 2 courses of DS therapy were administered. However, a new liver metastatic lesion was found, and XELOX therapy was selected as the second-line of treatment. Subsequently, enlarged hepatic hilar lymph nodes were found; microsatellite instability testing confirmed MSI-High cancer. Nivolumab was selected as the third- line therapy. After 15 courses, a new liver metastatic lesion appeared. Although Ram+nab-PTX therapy was chosen as the fourth-line therapy, the patient developed myelosuppression after 3 courses. Two years and 4 months after the initial treatment, the patient was considered to have achieved CR. Because drug-induced liver injury had occurred, the Ram therapy was discontinued. The patient has remained in CR for 1 year without receiving any anticancer drugs. This case suggests that for MSI-high patients with gastric cancer, the consideration of treatment strategy should be based on the molecular biological background.

Simple and fast one-step FRET assay of therapeutic mAb bevacizumab using anti-idiotype DNA aptamer for process analytical technology.

We developed an aptamer-based fluorescence resonance energy transfer (FRET) assay capable of recognizing therapeutic monoclonal antibody bevacizumab and rapidly quantifying its concentration with just one mixing step. In this assay, two fluorescent dyes (fluorescein and tetramethylrhodamine) labeled aptamers bind to two Fab regions on bevacizumab, and FRET fluorescence is observed when both dyes come into close proximity. We optimized this assay in three different formats, catering to a wide range of analytical needs. When applied to hybridoma culture samples in practical settings, this assay exhibited a signal response that was concentration-dependent, falling within the range of 50-2000 µg/mL. The coefficients of determination (r2) ranged from 0.998 to 0.999, and bias and precision results were within ±24.0 % and 20.3 %, respectively. Additionally, during thermal and UV stress testing, this assay demonstrated the ability to detect denatured samples in a manner comparable to conventional Size Exclusion Chromatography. Notably, it offers the added advantage of detecting decreases in binding activity without changes in molecular weight. In contrast to many existing process analytical technology tools, this assay not only identifies bevacizumab but also directly measures the quality attributes related to mAb efficacy, such as the binding activity. As a result, this assay holds great potential as a valuable platform for providing highly reliable quality attribute information in real-time. We consider this will make a significant contribution to the worldwide distribution of high-quality therapeutic mAbs in various aspects of antibody manufacturing, including production monitoring, quality control, commercial lot release, and stability testing.

Evaluation of Steroid-Induced Osteoporosis Prevention Using Tracing Reports in Collaboration between Hospitals and Community Pharmacists.

Glucocorticoid-induced osteoporosis (GIOP) is a side effect of glucocorticoid (GC) treatment; however, despite established prevention guidelines in various countries, a gap persists between these guidelines and clinical practice. To address this gap, we implemented a collaborative intervention between hospitals and community pharmacists, aiming to assess its effectiveness. Pharmacists recommended to the prescribing doctor osteoporosis treatment for patients who did not undergo osteoporosis treatment with a fracture risk score of ≥3 via tracing reports (TRs), between 15 December 2021, and 21 January 2022. Data were extracted from electronic medical records, including prescriptions, concomitant medications, reasons for not pursuing osteoporosis treatment, and TR contents. Of 391 evaluated patients, 45 were eligible for TRs, with 34 (75.6%) being males. Prednisolone was the most common GCs administered, and urology was the predominant treatment department. Among the 45 patients who received TRs, prescription suggestions were accepted for 19 (42.2%). After undertaking the intervention, guideline adherence significantly increased from 87% to 92.5%. This improvement indicates that TRs effectively bridged the evidence-practice gap in GIOP prevention among GC patients, suggesting their potential utility. Expansion of this initiative is warranted to further prevent GIOP.

Possible involvement of NAMPT in neuronal survival in cerebral ischemic injury under high-glucose conditions through the FoxO3a/LC3 pathway.

The incidence of cerebral infarction triggered by abnormal glucose tolerance has increased; however, the relationship between glucose concentration in the brain and the detailed mechanism of post ischemic cell death remains unclear. Nicotinamide phosphoribosyltransferase (NAMPT), an adipocytokine, is the rate-limiting enzyme for NAD+ synthesis in the salvage pathway. Although NAMPT activation prevents neuronal injury, the relationship between NAMPT activity, glucose metabolism disorders, and cerebral ischemia-induced neuronal cell death is unknown. In this study, we determined changes in NAMPT on cerebral ischemic injuries with diabetes using a db/db mouse model of type 2 diabetes and then identified the underlying mechanisms using Neuro2a cells. The expression of inflammatory cytokine mRNAs was increased in db/db and db/+ middle cerebral artery occlusion and reperfusion (MCAO/R) mice. Although NeuN-positive cells were decreased after MCAO/R, the number of NAMPT and NeuN double-positive cells in NeuN-positive neuronal cells increased in db/db MCAO/R mice. Next, the role of NAMPT in Neuro2a cells under conditions of high glucose (HGC) and oxygen-glucose deprivation (OGD), which mimics diabetes-complicated cerebral infarction, was examined. Treatment with P7C3-A20, a NAMPT activator, suppressed the decrease in cell viability caused by HGC/OGD; however, there were no significant differences in the levels of cleaved caspase-3 and Bax proteins. Moreover, increased FoxO3a and LC3-II levels after HGC/OGD were inhibited by P7C3-A20 treatment. Our findings indicate that NAMPT activation is associated with neuronal survival under ischemic conditions with abnormal glucose tolerance through the regulation of FoxO3a/LC3.

Skill Proficiency, Efficacy, and Safety of the Transradial Approach in Transarterial Treatments for Hepatocellular Carcinoma.

Introduction Abdominal angiography procedures such as transarterial chemoembolization (TACE) are essential for hepatocellular carcinoma treatment. One method commonly used is transfemoral access (TFA). However, issues associated with this method, which include postoperative compression of the puncture site and long periods of bed rest, can affect patient satisfaction. Thus, transradial access (TRA), a minimally invasive treatment method that improves treatment quality, was developed for TACE. This retrospective, multicenter study aimed to investigate the efficacy and safety of abdominal angiography using the radial artery approach. Methods In total, 1,601 patients underwent abdominal angiography using TRA and received treatment (radial access for visceral intervention (RAVI)) at 14 institutions in Japan. The treatment time, procedure completion rate, patient satisfaction, and complications were investigated. Results The success rate of RAVI was 99.4%, and the complication rate was 1.2%. Approximately 98.2% of the patients requested the radial artery approach again. There were no significant differences in the success rate of RAVI and the incidence of complications based on the operator's years of experience or the patient's age. Some patients developed minor complications such as puncture site bleeding, hematoma, vascular pain, and vasospasm. Further, serious complications (cerebral infarction (n = 1), cerebellar infarction (n = 1), and aortic dissection (n = 1)) were observed. Conclusion Similar to the conventional TFA, RAVI helped in facilitating peritoneal angiography safely. In abdominal angiography, this method can reduce patient burden and can be widely used in the future from the perspective of clinical benefit.

Prevention of amyloid ß fibril deposition on the synaptic membrane in the precuneus by ganglioside nanocluster-targeting inhibitors.

Alzheimer's disease (AD), a progressive neurodegenerative condition, is one of the most common causes of dementia. Senile plaques, a hallmark of AD, are formed by the accumulation of amyloid ß protein (Aß), which starts to aggregate before the onset of the disease. Gangliosides, sialic acid-containing glycosphingolipids, play a key role in the formation of toxic Aß aggregates. In membrane rafts, ganglioside-bound complexes (GAß) act as nuclei for Aß assembly, suggesting that GAß is a promising target for AD therapy. The formation of GAß-induced Aß assemblies has been evaluated using reconstituted planar lipid membranes composed of synaptosomal plasma membrane (SPM) lipids extracted from human and mouse brains. Although the effects of gangliosides on Aß accumulation in the precuneus have been established, effects on Aß fibrils have not been determined. In this study, Aß42 fibrils on reconstituted membranes composed of SPM lipids prepared from the precuneus cortex of human autopsied brains were evaluated by atomic force microscopy. In particular, Aß42 accumulation, as well as the fibril number and size were higher for membranes with precuneus lipids than for membranes with calcarine cortex lipids. In addition, artificial peptide inhibitors targeting Aß-sensitive ganglioside nanoclusters cleared Aß assemblies on synaptic membranes in the brain, providing a novel therapeutic strategy for AD.

Hepatic inflammation and fibrosis are profiles related to mid-term mortality in biopsy-proven MASLD: A multicenter study in Japan.

AIMS: A multi-stakeholder consensus has proposed MASLD (metabolic dysfunction-associated steatotic liver disease). We aimed to investigate the pathological findings related to the mid-term mortality of patients with biopsy-proven MASLD in Japan. METHODS: We enrolled 1349 patients with biopsy-proven MASLD. The observational period was 8010 person years. We evaluated independent factors associated with mortality in patients with MASLD by Cox regression analysis. We also investigated pathological profiles related to mortality in patients with MASLD using data-mining analysis. RESULTS: The prevalence of MASH and stage 3/4 fibrosis was observed in 65.6% and 17.4%, respectively. Forty-five patients with MASLD died. Of these, liver-related events were the most common cause at 40% (n = 18), followed by extrahepatic malignancies at 26.7% (n = 12). Grade 2/3 lobular inflammation and stage 3/4 fibrosis had a 1.9-fold and 1.8-fold risk of mortality, respectively. In the decision-tree analysis, the profiles with the worst prognosis were characterised by Grade 2/3 hepatic inflammation, along with advanced ballooning (grade 1/2) and fibrosis (stage 3/4). This profile showed a mortality at 8.3%. Furthermore, the random forest analysis identified that hepatic fibrosis and inflammation were the first and second responsible factors for the mid-term prognosis of patients with MASLD. CONCLUSIONS: In patients with biopsy-proven MASLD, the prevalence of MASH and advanced fibrosis was approximately 65% and 20%, respectively. The leading cause of mortality was liver-related events. Hepatic inflammation and fibrosis were significant factors influencing mid-term mortality. These findings highlight the importance of targeting inflammation and fibrosis in the management of patients with MASLD.

Validation study of age-independent fibrosis score (Fibrosis-3 index) in patients with metabolic dysfunction-associated steatotic liver disease.

BACKGROUND AND AIMS: Because the accuracy of the Fibrosis-4 (FIB-4) index for predicting liver fibrosis changes with age, the need for different cut-offs in various age groups has frequently been discussed. We developed the age-independent score, the Fibrosis-3 (FIB-3) index, and have shown its usefulness in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). This study aimed to validate the diagnostic ability of the FIB-3 index to predict fibrosis progression using a large new patient cohort. METHODS: The ability of the FIB-3 index to predict liver fibrosis was analyzed by comparing it with that of the FIB-4 index using data from 1398 patients with MASLD enrolled in the Asia-based clinical outcome NAFLD study. RESULTS: The areas under the receiver operating characteristic curves for predicting fibrosis stage F3 or higher were not different between the FIB-3 and FIB-4 indices in the entire cohort. Using the single ideal cut-offs of the indices (3.41 for FIB-3 index and 2.01 for FIB-4 index), the predictive accuracy of the FIB-3 index was not significantly different from that of the FIB-4 index among patients aged <60 years; however, the accuracy of the FIB-3 index was significantly higher than that of the FIB-4 index in those aged ≥60 years (0.645 and 0.529, respectively; p < 0.0001). CONCLUSION: The high ability of the FIB-3 index with a single cut-off to predict liver fibrosis in patients with MASLD was confirmed. The FIB-3 index could serve as a useful tool for assessing liver fibrosis regardless of age.

A case of laparoscopic revision surgery 30 years after vertical banded gastroplasty for morbid obesity.

As the number of bariatric and metabolic surgeries being performed is increasing, the importance of revision surgeries is escalating. In this report, we describe a case of revision surgery performed 30 years after vertical banded gastroplasty (VBG), including a review of the surgical techniques. The patient was a male in his 50s who had previously undergone VBG for morbid obesity (body mass index of 72.6 kg/m2 ), resulting in gradual weight loss. Twenty-eight years later, reflux symptoms due to stenosis of the mesh area developed. Despite conservative treatment, the symptoms recurred, and aspiration pneumonia developed. Gastrojejunal and Y-anastomoses were performed laparoscopically. Postoperatively, the patient progressed well with no weight regain. In revision surgery, it is essential to accurately assess the patient's pathophysiology, as the surgical technique must consider improvement in symptoms, risk of weight regain, and the need for observation of the residual stomach.

Prognosis of biopsy-confirmed metabolic dysfunction- associated steatotic liver disease: A sub-analysis of the CLIONE study.

BACKGROUND/AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) was recently proposed as an alternative disease concept to nonalcoholic fatty liver disease (NAFLD). We aimed to investigate the prognosis of patients with biopsy-confirmed MASLD using data from a multicenter study. METHODS: This was a sub-analysis of the Clinical Outcome Nonalcoholic Fatty Liver Disease (CLIONE) study that included 1,398 patients with NAFLD. Liver biopsy specimens were pathologically diagnosed and histologically scored using the NASH Clinical Research Network system, the FLIP algorithm, and the SAF score. Patients who met at least one cardiometabolic criterion were diagnosed with MASLD. RESULTS: Approximately 99% of cases (n=1,381) were classified as MASLD. Patients with no cardiometabolic risk (n=17) had a significantly lower BMI than patients with MASLD (20.9 kg/m2 vs. 28.0 kg/m2, P<0.001), in addition to significantly lower levels of inflammation, ballooning, NAFLD activity score, and fibrosis stage based on liver histology. These 17 patients had a median follow-up of 5.9 years, equivalent to 115 person-years, with no deaths, liver-related events, cardiovascular events, or extrahepatic cancers. The results showed that the prognosis for pure MASLD was similar to that for the original CLIONE cohort, with 47 deaths and one patient who underwent orthotopic liver transplantation. The leading cause of death was extrahepatic cancer (n=10), while the leading causes of liver-related death were liver failure (n=9), hepatocellular carcinoma (n=8), and cholangiocarcinoma (n=4). CONCLUSION: Approximately 99% of NAFLD cases were considered MASLD based on the 2023 liver disease nomenclature. The NAFLD-only group, which is not encompassed by MASLD, had a relatively mild histopathologic severity and a favorable prognosis. Consequently, the prognosis of MASLD is similar to that previously reported for NAFLD.

Marked alteration of phosphoinositide signaling-associated molecules in postmortem prefrontal cortex with bipolar disorder.

AIM: The etiology of bipolar disorder (BD) remains unknown; however, lipid abnormalities in BD have received increasing attention in recent years. In this study, we examined the expression levels of enzyme proteins associated with the metabolic pathway of phosphoinositides (PIs) and their downstream effectors, protein kinase B (Akt1) and glycogen synthase kinase 3ß (GSK3ß), which have been assumed to be the targets of mood stabilizers such as lithium, in the postmortem brains of patients with BD. METHODS: The protein expression levels of phosphatidylinositol 4-phosphate 5-kinase type-1 gamma (PIP5K1C), phosphatidylinositol 4-kinase alpha (PIK4CA), phosphatase and tensin homolog deleted from chromosome 10 (PTEN), Akt1, and GSK3ß were measured using enzyme-linked immunosorbent assays and multiplex fluorescent bead-based immunoassays in the prefrontal cortex (PFC). Specifically, PTEN, Akt1, GSK3ß, and PIP5K1C were measured in seven BD patients and 48 controls. Additionally, PIK4CA was analyzed in 10 cases and 34 controls. RESULTS: PTEN expression levels were markedly decreased in the PFCs of patients with BD, whereas those of Akt and GSK3ß were prominently elevated. Moreover, patients medicated with lithium exhibited higher Akt1 expression levels and lower PTEN expression levels in comparison with the untreated group. CONCLUSION: Our results suggest that the expression levels of Akt1/GSK3ß and its upstream regulator PTEN are considerably altered.

Peripherally inserted central catheter securement with cyanoacrylate glue and bloodstream infection: A retrospective cohort study.

BACKGROUND: Treatment via a peripherally inserted central venous catheter is important for anticancer treatment, perioperative management, and nutrition management. In this study, we aimed to investigate the usefulness of cyanoacrylate glue (CG) in managing peripherally inserted central venous catheters in adults. METHODS: This retrospective cohort study enrolled 411 adults requiring a central venous catheter for treatment in the Chiba University Esophageal-Gastro-Intestinal Surgery department between January 2021 and October 2022. The preventive effect of CG in reducing adverse events, including infection, tip migration, and thrombus formation, was evaluated by reviewing electronic medical records, chest radiographs, and contrast-enhanced computed tomography scans. RESULTS: CG and other dressings were used in 158 (CG group) and 253 (control group) patients, respectively. The incidence of catheter infection based on the clinical course was lower in the CG group (3.2%) than in the control group (9.1%; P = 0.03). However, cases of infection confirmed by blood or catheter cultures did not differ between the CG (1.3%) and control (1.9%) groups (P = 1.0). Chest radiographs revealed that catheter tip migration (mean ± SD) was lesser in the CG group (8.2 ± 6.7 mm) than in the control group (15.0 ± 15.8 mm; P < 0.01). There were two cases of venous thrombus formation in the control group. CONCLUSION: In a population dominated by esophago-gastroenterological malignancy, peripherally inserted central catheter securement via CG was associated with decreased catheter removal because of suspected catheter infection. Further research on larger cohorts is needed to determine if other adverse events decrease following peripherally inserted central catheter securement via CG.

Accuracy of the Enhanced Liver Fibrosis Test in Patients With Type 2 Diabetes Mellitus and Its Clinical Implications.

BACKGROUND AND AIMS: The diagnostic performance of the Fibrosis-4 (FIB-4) index and nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS) is poor in patients with type 2 diabetes mellitus (T2DM). We determined the usefulness of the Enhanced Liver Fibrosis (ELF) test in patients with T2DM. METHODS: A total of 1228 patients with biopsy-proven NAFLD were enrolled. The diagnostic performance of the ELF test for predicting advanced fibrosis in participants with or without T2DM was evaluated in comparison with the FIB-4 index and NFS. RESULTS: Overall, the area under the curve of the ELF test for predicting advanced fibrosis was greater (0.828) than that of the FIB-4 index (0.727) and NFS (0.733). The diagnostic performance of the ELF test (area under the curve, 0.820) was also superior to that of the FIB-4 index (0.698) and NFS (0.700) in patients with T2DM. With the low cutoff values for each noninvasive test, the ELF test provided an acceptable false negative rate (cutoff value 9.8, 6.7%) in this population, unlike the FIB-4 index (1.30, 14.5%) and NFS (-1.455, 12.4%). After propensity score matching to avoid selection bias including age, sex, body mass index, and the prevalence of advanced fibrosis, the ELF test with a low cutoff value showed a high sensitivity (≥91.4%) and a high negative predictive value (≥96.8%), irrespective of the presence or absence of T2DM. CONCLUSIONS: The high diagnostic performance of the ELF test for predicting advanced fibrosis in individuals with or without T2DM could address an unmet medical need for accurate assessment of liver fibrosis in patients with diabetes and NAFLD.

Risk of Bone Wax Migration During Retrosigmoid Craniotomy for Microvascular Decompression: Case-Control Study.

BACKGROUND AND OBJECTIVES: Bone wax is a flexible hemostatic agent commonly used for surgery in the posterior cranial fossa to control bleeding from the mastoid emissary vein. A large amount of bone wax can migrate into the sigmoid sinus through the mastoid emissary canal (MEC). We aimed to identify clinical factors related to intraoperative bone wax migration through the MEC during microvascular decompression (MVD) surgery, which may result in sigmoid sinus thrombosis. METHODS: We retrospectively collected the clinical data of patients with trigeminal neuralgia, hemifacial spasm, or trigeminal neuralgia accompanied by painful tic convulsif who underwent MVD. Basic information and the residual width and length (from the bone surface to the sigmoid sinus) of the MEC on computed tomography images were collected. We compared the collected clinical data between 2 groups of cases with and without intraoperative bone wax migration in the sigmoid sinus. RESULTS: Fifty-four cases with intraoperative bone wax migration and 187 patients without migration were enrolled. The t -test revealed significant differences in the width and length of the MEC ( P = .013 and P = .003, respectively). These variables were identified as significant factors in predicting intraoperative bone wax migration using multivariate logistic regression analysis. CONCLUSION: The large size of the MEC may be related to intraoperative bone wax migration into the sigmoid sinus in MVD. Neurosurgeons should be aware of these risks. Bone wax should be applied appropriately and hemostasis should be considered to control bleeding from the mastoid emissary vein in patients with a large MEC.

Pathogenic role of NAMPT in the perivascular regions after ischemic stroke in mice with type 2 diabetes mellitus.

Ischemic stroke in patients with abnormal glucose tolerance results in poor outcomes. Nicotinamide phosphoribosyltransferase (NAMPT), an adipocytokine, exerts neuroprotective effects. However, the pathophysiological role of NAMPT after ischemic stroke with diabetes and the relationship of NAMPT with cerebrovascular lesions are unclear. The purpose of this study was to clarify the pathophysiological role of NAMPT in cerebral ischemia with diabetes, using db/db mice as a type 2 diabetes animal model. The number of degenerating neurons increased after middle cerebral artery occlusion and reperfusion (MCAO/R) in db/db mice compared with the degenerating neurons in db/+ mice. Extracellular NAMPT (eNAMPT) levels, especially monomeric eNAMPT, increased significantly in db/db MCAO/R mice but not db/+ mice in isolated brain microvessels. The increased eNAMPT levels were associated with increased expression of inflammatory cytokine mRNA. Immunohistochemical analysis demonstrated that NAMPT colocalized with GFAP-positive cells after MCAO/R. In addition, both dimeric and monomeric eNAMPT levels increased in the conditioned medium of primary cortical astrocytes under high glucose conditions subsequent oxygen/glucose deprivation. Our findings are the first to demonstrate the ability of increased monomeric eNAMPT to induce inflammatory responses in brain microvessels, which may be located near astrocyte foot processes.

Inflammatory and Nutritional Indices as Prognostic Markers in Elderly Patients With Gastric Cancer.

BACKGROUND/AIM: Peripheral blood inflammatory and nutritional indices are independent prognostic factors for various cancers. However, as society's longevity and the demand for surgery in the elderly increase, it remains unclear whether these indices are valuable for patients aged ≥80 years. This study aimed to assess the utility of peripheral blood indices as prognostic markers in elderly patients with gastric cancer (GC). PATIENTS AND METHODS: This study included 103 elderly patients (aged ≥80 years) who underwent radical gastrectomy at our hospital between 2008 and 2020. Preoperative systemic inflammatory and nutritional indices, including the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), and prognostic and nutritional index (PNI), were evaluated. Prognostic evaluation was performed using Kaplan-Meier analysis and Cox regression. RESULTS: There were no statistically significant differences in NLR, PLR, and LMR regarding overall survival (OS) and relapse-free survival (RFS). However, patients with low PNI had a markedly worse prognosis (3-year OS: 63.9% vs. 81.2%, p=0.002; 3-year RFS: 55.3% vs. 77.6%, p=0.002). Multivariate analysis revealed that male sex and low PNI were independent predictors of OS (p=0.007p=0.003, respectively) and RFS, with only PNI showing significance (p=0.023). CONCLUSION: Preoperative PNI is an independent prognostic factor for survival in elderly patients with GC who undergo radical gastrectomy.

Role of senkyunolide I in the promotion of neural stem/progenitor cell proliferation via the Akt/ß-catenin pathway.

Following brain injury, neural stem cells (NSCs) can generate mature neurons and replace damaged cells. However, the capacity of endogenous NSCs to self-repair from injured brain is limited as most NSCs die before becoming mature neurons. Therefore, a boosting endogenous NSCs by pharmacological support offers the potential to repair the damaged brain. Recently, small molecules have hold considerable promise for neuron regeneration and repair as they can penetrate the blood-brain barrier easily. Senkyunolide I (SEI) is a bioactive constituent derived from traditional Chinese medicines Ligusticum chuanxiong Hort. and Angelica sinensis (Oliv.) Diels, and was found to able to prevent ischemic stroke. This study examined the effects of SEI on the proliferation and neuronal lineage differentiation of prepared neural stem/progenitor cells (NS/PCs). The NS/PC proliferation was determined by 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt, and neurosphere formation assays. The NS/PC differentiation was also investigated by immunocytochemistry, and western blotting was employed to measure phosphorylated Akt (pAkt) and GSK-3ß (pGSK-3ß), and active-ß-catenin protein levels. We showed that the NS/PC proliferation was enhanced after SEI exposure. Elevated cell numbers were also observed in neurospheres, which were incubated with SEI for 3 days, whereas the NS/PC differentiation was decreased after SEI exposure for 5 days. Furthermore, SEI upregulated pAkt/Akt and active-ß-catenin levels and increased NS/PC proliferation after SEI treatment was reversed by phosphatidylinositol 3-kinase inhibitor LY294002. downregulated differentiated processes. Thus, SEI promoted the NS/PC proliferation and suppressed NS/PC differentiation into neurons and/or astrocytes, therefore SEI could be an interesting and promising candidate for stimulating NSCs.

Ethnicity-dependent effect of rs1799971 polymorphism on OPRM1 expression in the postmortem brain and responsiveness to antipsychotics.

Schizophrenia is associated with aberration of inhibitory neurons. Although the mu-opioid receptor (MOR) is an essential modulator of inhibitory neurons, the effect of rs1799971 polymorphism in the MOR gene on risk of schizophrenia is controversial. Moreover, the disturbance of opioids systems in patients with schizophrenia has not been fully examined. We firstly conducted preliminary meta-analyses integrating Asian and European populations separately over 12,000 subjects to assess the effect of rs1799971 on risk of schizophrenia. Based on the above result, we also investigated the effect on the expression levels of MOR mRNA in the prefrontal cortex (PFC) and caudate nucleus of 41 postmortem brains. In addition, we determined whether these levels were related to antemortem schizophrenia symptoms and pharmacotherapeutic effects. The rs1799971 G-allele reduced the risk of schizophrenia in Asian populations (OR: 0.56, 95%CI: 0.32-0.98, p = 0.042) but increased it in European populations (OR: 1.66, 95%CI: 1.08-2.56, p = 0.022). It decreased MOR mRNA levels in PFC in the Japanese population (p = 0.031). Increased MOR mRNA level in PFC correlated with higher total score of antemortem schizophrenia symptoms (p = 0.017). Furthermore, the pharmacotherapeutic effect of first-generation antipsychotics was higher for genotype AA than AG/GG of rs1799971 (p = 0.036). The rs1799971 affects risk of schizophrenia and MOR mRNA expression and the effect varies according to ethnicity. Overexpression of MOR might induce severe schizophrenia symptoms. Therefore, MOR modulation may be the key clue for treating antipsychotics-resistant schizophrenia, and genotyping rs1799971 may provide a better pharmacotherapeutic strategy.