A Georeferenced Dataset for Mapping and Assessing Subgrade Defects in China's High-Speed Railways.

China has the world's longest high-speed rail (HSR) network, marked by dense transportation and complex operations. However, frequent train use coupled with extreme weather conditions has led to rising subgrade issues. Existing railway defect records suffer from inconsistency, hindering direct applicability. Currently, there is a lack of a relevant dataset dedicated to HSR subgrade defects. To bridge this gap, we developed a comprehensive georeferenced dataset that encompasses defect records extracted from peer-reviewed literature published between 1999 and 2023 in China. Rigorous quality control procedures were implemented to eliminate duplicate data and ensure the accuracy of the dataset. The dataset consists of georeferenced records for eight different defects, spanning across 661 locations and categorized at various scales, ranging from provinces to townships. The most commonly reported defect types include subgrade settlement, frost damage, uplift deformation, and mud pumping. This dataset provides a comprehensive map of historical subgrade defects affecting high-speed railways in China. It could facilitate operational risk assessments and the prediction of subgrade performance.

Multi-defect risk assessment in high-speed rail subgrade infrastructure in China.

This study addresses the escalating risk of high-speed railway (HSR) infrastructure in China, amplified by climate warming, increased rainfall, frequent extreme weather, and geohazard events. Leveraging a georeferenced dataset of recent HSR defects obtained through an extensive literature review, we employ machine learning techniques for a quantitative multi-defect risk assessment. Climatic, geomorphological, geohydrological, and anthropogenic variables influencing HSR subgrade safety are identified and ranked. Climatic factors significantly impact frost damage and mud pumping, while geomorphological variables exhibit greater influence on settlement and uplift deformation defects. Notably, frost damage is prevalent in the northeast and northwest, mud pumping along the southeast coast, and settlement and uplift deformation in the northwest and central areas. The generated comprehensive risk map underscores high-risk zones, particularly the Menyuan Hui Autonomous and Minle County sections of the Lanzhou-Urumqi HSR, emphasizing the need for focused attention and preventive actions to mitigate potential losses and ensure operational continuity.

The value of endoscopic duodenal papilloplasty with titanium clip in improving post-operative complications of choledocholithiasis.

OBJECTIVE: To investigate the value of endoscopic duodenal papillary sphincterotomy combined with balloon dilatation in the treatment of duodenal papilloplasty with titanium clip after choledocholithiasis in post-operative complications. MATERIALS AND METHODS: One hundred and twenty-five patients (69 males and 56 females) with a median age of 65 (32-81) years were included. The treatment plan was randomly divided into Group A (n = 59) and Group B (n = 66) according to the random number table. Patients in Group A were treated with endoscopic sphincterotomy (EST) combined with endoscopic papillary large balloon dilation (EPLBD), followed by a titanium clip for duodenal papilloplasty and then indwelling nasobiliary drainage, whereas those in Group B were treated with EST combined EPLBD to remove stones and then indwelling nasobiliary drainage. RESULTS: In patients with choledocholithiasis or with anatomical changes that make stone extraction difficult, this prospective study attempted to perform duodenal papilloplasty with titanium clips after EST and EPLBD lithotripsy to compare and observe post-operative papillary healing, biliary reflux, and complication rates. CONCLUSIONS: The use of endoscopic duodenal papilloplasty with a titanium clip can improve biliary reflux after lithotripsy and reduce the incidence of post-operative cholangitis complications.

OBJETIVO: Investigar el valor de la esfinterotomía papilar duodenal endoscópica combinada con dilatación con balón en el tratamiento de la papiloplastia duodenal con clip de titanio después de coledocolitiasis en complicaciones postoperatorias. MATERIALES Y MÉTODOS: Se incluyeron un total de 125 pacientes (69 hombres y 56 mujeres) con una mediana de edad de 65 (32-81) años. Los pacientes del Grupo A se trataron con esfinterotomía endoscópica (EST) combinada con dilatación papilar endoscópica con balón grande (EPLBD), seguida de clip de titanio para papiloplastia duodenal y luego drenaje nasobiliar permanente, mientras que los del Grupo B se trataron con EPLBD combinado con EST para eliminar cálculos y luego drenaje nasobiliar permanente. RESULTADOS: En pacientes con coledocolitiasis o con cambios anatómicos que dificultan la extracción de cálculos, este estudio prospectivo intentó realizar papiloplastia duodenal con clips de titanio después de litotricia EST y EPLBD para comparar y observar la cicatrización papilar postoperatoria, el reflujo biliar y las tasas de complicaciones. CONCLUSIÓN: El uso de papiloplastia duodenal endoscópica con clips de titanio puede mejorar el reflujo biliar después de la litotricia y reducir la incidencia de complicaciones de colangitis postoperatorias.

Effect of lipid accumulation product on the development of hypertension among nondiabetic individuals in eastern China: A cross-sectional study.

This study was aimed at assessing the risk factors for hypertension (HTN) and prehypertension (PHT) in order to clarify the role of lipid accumulation product (LAP) in the development of HTN among nondiabetic individuals. A large cross-sectional study was conducted in community health service centers in urban Bengbu, Anhui Province, China. All participants completed an interview questionnaire and procedures to obtain physical measurements and biochemical indicators. Multivariate logistic regression was used to test for the prevalence of HTN and PHT in relation to each quartile increase in LAP level and family history of HTN. The resulting interaction effects were evaluated by relative excess risk of interaction (RERI), attributable proportion due to interaction (AP), and synergy index (SI). A total of 7733 subjects were enrolled in the study. The overall prevalence rates of PHT and HTN were 37.1% and 24.8%, respectively. After adjusting for confounding factors, multinomial logistic regression analysis showed that compared with subjects in LAP quartile 1, those in quartile 3 (OR, 1.257; 95% CI, 1.062-1.494) and quartile 4 (OR, 1.323; 95% CI, 1.101-1.592) had a significantly higher risk for HTN (p for trend < .001). A significant interaction was observed between LAP and family history of HTN in men (AP, 0.1661; 95% CI, 0.0024-0.3296; SI, 1.4037; 95% CI, 1.0599-1.8593) and in women (RERI, 1.4111; 95% CI, 0.1458-2.9678; AP, 0.1662; 95% CI, 0.0085-0.3237; SI, 1.3886; 95% CI, 1.0568-1.8247). The results demonstrated that the interactive effects of LAP with family history of HTN may influence the development of HTN synergistically.

Different gender-derived gut microbiota influence stroke outcomes by mitigating inflammation.

BACKGROUND AND PURPOSE: Stroke is associated with high disability and mortality rates and increases the incidence of organ-related complications. Research has revealed that the outcomes and prognosis of stroke are regulated by the state of the intestinal microbiota. However, the possibility that the manipulation of the intestinal microbiota can alter sex-related stroke outcomes remain unknown. METHODS: To verify the different effects of microbiota from different sexes on stroke outcomes, we performed mouse fecal microbiota transplantation (FMT) and established a model of ischemic stroke. Male and female mice received either male or female microbiota through FMT. Ischemic stroke was triggered by MCAO (middle cerebral artery occlusion), and sham surgery served as a control. Over the next few weeks, the mice underwent neurological evaluation and metabolite and inflammatory level detection, and we collected fecal samples for 16S ribosomal RNA analysis. RESULTS: We found that when the female mice were not treated with FMT, the microbiota (especially the Firmicutes-to-Bacteroidetes ratio) and the levels of three main metabolites tended to resemble those of male mice after experimental stroke, indicating that stroke can induce an ecological imbalance in the biological community. Through intragastric administration, the gut microbiota of male and female mice was altered to resemble that of the other sex. In general, in female mice after MCAO, the survival rate was increased, the infarct area was reduced, behavioral test performance was improved, the release of beneficial metabolites was promoted and the level of inflammation was mitigated. In contrast, mice that received male microbiota were much more hampered in terms of protection against brain damage and the recovery of neurological function. CONCLUSION: A female-like biological community reduces the level of systemic proinflammatory cytokines after ischemic stroke. Poor stroke outcomes can be positively modulated following supplementation with female gut microbiota.

Topological Crystalline Insulator Candidate ErAsS with Hourglass Fermion and Magnetic-Tuned Topological Phase Transition.

Topological crystalline insulators (TCIs) with hourglass fermion surface state have attracted a lot of attention and are further enriched by crystalline symmetries and magnetic order. Here, the emergence of hourglass fermion surface state and exotic phases in the newly discovered, air-stable ErAsS single crystals are shown. In the paramagnetic phase, ErAsS is expected to be a TCI with hourglass fermion surface state protected by the nonsymmorphic symmetry. Dirac-cone-like bands and nearly linear dispersions in large energy range are experimentally observed, consistent well with theoretical calculations. Below TN  ≈ 3.27 K, ErAsS enters a collinear antiferromagnetic state, which is a trivial insulator breaking the time-reversal symmetry. An intermediate incommensurate magnetic state appears in a narrow temperature range (3.27-3.65 K), exhibiting an abrupt change in magnetic coupling. The results reveal that ErAsS is an experimentally available TCI candidate and provide a unique platform to understand the formation of hourglass fermion surface state and explore magnetic-tuned topological phase transitions.

JAK2/STAT3 Axis Intermediates Microglia/Macrophage Polarization During Cerebral Ischemia/Reperfusion Injury.

BACKGROUND: Subtypes of microglia/macrophage regulate the inflammation in the opposite direction during ischemic stroke. JAK2/STAT3 signaling pathway participates in the development of stroke-related inflammation via ischemic stimulation. However, the relationship between JAK2/STAT3 pathway and microglia/macrophage phenotype transformation is unclear. METHODS: This study established a transient middle cerebral artery occlusion (tMCAO) model in male STAT3f/f and STAT3f/f LysMcre+ mice and evaluated the neurological deficit on the 3rd day using Longa score. The brains were stained by TTC to determine the infarction volume. Western blotting and QPCR were used to determine the expression of JAK2/STAT3 pathway and microglia/macrophage-related markers. Immunofluorescence staining was used to detect the levels of polarization-related indexes. QPCR also assessed the effect of STAT3 knockout on inflammatory factors in the infarction. Moreover, established the OGD/R model using BV2 cells to further verify the role of STAT3 on microglia/macrophage polarization. RESULTS: For the conditioned STAT3-KO mice, the infarction was significantly increased after MCAO, accompanied by the aggravation of neurological deficit. Higher expression of iNOS and CD16/32 than Arg-1, Ym-1, and CD206 in vivo and in vitro, and decreased p-STAT3/STAT3 ratio in STAT3f/f LysMcre+ mice, while the p-JAK2/JAK2 ratio increased. In addition, increased M1/M2 ratio and elevated expression of IL-1ß, IL-6, TNF-α with STAT3 deletion, as well as increased CD68+/iNOS+ cell numbers. CONCLUSION: Collectively, these results reveal that JAK2/STAT3 signaling pathway regulates the microglia/macrophage polarization (skewing toward the M2 polarization) during the CIRI, thus alleviating brain damage. Therefore, approaches targeting JAK2/STAT3 activation are promising therapies for ischemic stroke.

The Role of the Gut Microbiota in the Development of Ischemic Stroke.

An increasing number of studies have focused on the gut microbiota and its relationship with various neurological diseases. The gut microbiota can affect the metabolic status of the body, in addition to having an important impact on blood pressure, blood glucose, and atherosclerosis, all of which are risk factors for ischemic stroke. In this review, we summarized studies that included the physiological function of the gut microbiota and gut microbiota disorders related to the central nervous system, thus providing novel ideas for the prevention and treatment of ischemic stroke.

Clinical value of preferred endoscopic ultrasound-guided antegrade surgery in the treatment of extrahepatic bile duct malignant obstruction.

OBJECTIVES: To explore the clinical value of preferred ultrasound endoscopic guided biliary drainage in patients with extrahepatic biliary obstruction with intrahepatic biliary ectasis. METHODS: A total of 58 patients with malignant obstruction and intrahepatic bile duct expansion, including 32 males, 26 females and median age 65 (58‒81) were selected. A prospective randomized controlled study was randomized into EUS-AG and ERCP-BD, with 28 patients in EUS-AG and 30 in ERCP-BD. The efficacy of the two treatments, operation success rate, operation time, the incidence of complications, hospitalization days, cost, unimpeded stent duration, and survival time were compared. RESULTS: 1) The surgical success rate in group EUS-AG was 100%, and in group, ERCP-BD was 96.67%. There was no statistical difference in surgical success rate in the two groups (p>0.05). 2) Average operating time in EUS-AG was (23.69±11.57) min, and in ERCP-BD was (36.75±17.69) min. The difference between the two groups has statistical significance (p<0.05). 3) The clinical symptoms of successful patients were significantly relieved. Compared with the preoperative procedure, the differences in group levels had statistical significance (p<0.05); TBIL, ALP, WBC and CRP levels, no statistical significance difference in groups (p>0.05). CONCLUSION: EUS-AG operation has short time, low incidence of complications, safe, effective, and can be used as the preferred treatment plan for patients with extrahepatic biliary duct malignant obstruction associated with intrahepatic biliary duct expansion; EUS-AG operation has more unique clinical advantages for patients with altered gastrointestinal anatomy or upper gastrointestinal obstruction.

Clinical value of preferred endoscopic ultrasound-guided antegrade surgery in the treatment of extrahepatic bile duct malignant obstruction

ABSTRACT Objectives: To explore the clinical value of preferred ultrasound endoscopic guided biliary drainage in patients with extrahepatic biliary obstruction with intrahepatic biliary ectasis. Methods: A total of 58 patients with malignant obstruction and intrahepatic bile duct expansion, including 32 males, 26 females and median age 65 (58-81) were selected. A prospective randomized controlled study was randomized into EUS-AG and ERCP-BD, with 28 patients in EUS-AG and 30 in ERCP-BD. The efficacy of the two treatments, operation success rate, operation time, the incidence of complications, hospitalization days, cost, unimpeded stent duration, and survival time were compared. Results: 1) The surgical success rate in group EUS-AG was 100%, and in group, ERCP-BD was 96.67%. There was no statistical difference in surgical success rate in the two groups (p>0.05). 2) Average operating time in EUS-AG was (23.69±11.57) min, and in ERCP-BD was (36.75±17.69) min. The difference between the two groups has statistical significance (p<0.05). 3) The clinical symptoms of successful patients were significantly relieved. Compared with the preoperative procedure, the differences in group levels had statistical significance (p<0.05); TBIL, ALP, WBC and CRP levels, no statistical significance difference in groups (p>0.05). Conclusion: EUS-AG operation has short time, low incidence of complications, safe, effective, and can be used as the preferred treatment plan for patients with extrahepatic biliary duct malignant obstruction associated with intrahepatic biliary duct expansion; EUS-AG operation has more unique clinical advantages for patients with altered gastrointestinal anatomy or upper gastrointestinal obstruction.

Enriched Environment Attenuates Pyroptosis to Improve Functional Recovery After Cerebral Ischemia/Reperfusion Injury.

Enriched environment (EE) is a complex containing social, cognitive, and motor stimuli. Exposure to EE can promote functional recovery after ischemia/reperfusion (I/R) injury. However, the underlying mechanisms remained unclear. Pyroptosis has recently been identified and demonstrated a significant role in ischemic stroke. The purpose of this study was to explore the effect of EE on neuronal pyroptosis after cerebral I/R injury. In the current study, middle cerebral artery occlusion/reperfusion (MCAO/R) was applied to establish the cerebral I/R injury model. Behavior tests including the modified Neurological Severity Scores (mNSS) and the Morris Water Maze (MWM) were performed. The infarct volume was evaluated by Nissl staining. To evaluate the levels of pyroptosis-related proteins, the levels of GSDMD-N and nod-like receptor protein 1/3 (NLRP1/3) inflammasome-related proteins were examined. The mRNA levels of IL-1ß and IL-18 were detected by Quantitative Real-Time PCR (qPCR). The secretion levels of IL-1ß and IL-18 were analyzed by ELISA. Also, the expression of p65 and p-p65 were detected. The results showed that EE treatment improved functional recovery, reduced infarct volume, attenuated neuronal pyroptosis after cerebral I/R injury. EE treatment also suppressed the activities of NLRP1/NLRP3 inflammasomes. These may be affected by inhabiting the NF-κB p65 signaling pathway. Our findings suggested that neuronal pyroptosis was probably the neuroprotective mechanism that EE treatment rescued neurological deficits after I/R injury.

Ultrasound lighting up AIEgens for potential surgical navigation.

Multifunctional contrast-enhanced agents suitable for application in surgical navigation by taking advantage of the merits of their diverse imaging modalities at different surgical stages are highly sought-after. Herein, an amphipathic polymer composed of aggregation-induced emission fluorogens (AIEgens) and Gd3+ chelates was successfully synthesized and assembled into ultrasound responsive microbubbles (AIE-Gd MBs) to realize potential tri-modal contrast-enhanced ultrasound (US) imaging, magnetic resonance imaging (MRI), and AIEgen-based fluorescence imaging (FI) during the perioperative period. Through ultrasound targeted microbubble destruction (UTMD) and cavitation effect, the as-prepared AIE-Gd MBs went through a MBs-to-nanoparticles (NPs) conversion, which not only resulted in targeted accumulation in tumor tissues but also led to stronger fluorescence being exhibited due to the more aggregated AIE-Gd molecules in the NPs. As a proof-of-concept, our work proposes a strategy of US-lit-up AIEgens in tumors which could offer a simple and powerful tool for surgical navigation in the future.

A highly specific probe for the imaging of inflammation-induced endogenous nitric oxide produced during the stroke process.

In this study, a turn-on two-photon fluorescent probe (Lyso-TP-NO) for nitric oxide (NO) was developed. It was synthesized using 4-ethylamino-1,8-naphthalimide as the two-photon fluorophore and N-methylaniline moiety as the reaction site. The probe and fluorophore were tested under one- and two-photon modes. The fluorescence intensity of the system was enhanced 23.1-fold after reacting with NO in the one-photon mode. However, the maximal two-photon action cross-section value of 200 GM was obtained under excitation at 840 nm. The probe exhibits high selectivity and sensitivity over other reactive oxygen species (ROS) and reactive nitrogen species (RNS), with a detection limit as low as 3.3 nM. The two-photon fluorescence imaging of living cells and mouse brain tissues can capture inflammation-induced endogenous NO production in lysosomes during stroke occurrence.

Functional genetic variants in centrosome-related genes CEP72 and YWHAG confer susceptibility to gastric cancer.

Structural and numeric centrosome aberrations can induce chromosome segregation errors and promote tumor development and progression. We systematically evaluated associations of 19,603 single nucleotide polymorphisms (SNPs) across 136 centrosome-related genes with gastric cancer (GC) risk using four GWAS datasets with a total of 3771 cases and 5426 controls. We identified two loci at 15p13.3 and 7q11.23 significantly associated with GC risk, whose risk alleles were correlated with increased mRNA expression of CEP72 (P = 7.30 × 10-4) and YWHAG (P = 1.60 × 10-3), respectively. Dual-luciferase reporter assays confirmed that the risk T allele of rs924607 at 15p13.3 significantly increased a promoter activity of the reporter gene, leading to a higher CEP72 expression level. At 7q11.23, the risk haplotype of rs2961037 [G]-rs2961038 [G] significantly elevated an enhancer activity and the expression of YWHAG. Both the mRNA and protein levels of CEP72 and YWHAG were overexpressed in GC tumor tissues compared with peritumor tissues and overexpression of either gene showed an unfavorable prognosis of GC patients. Moreover, knockdown of either CEP72 or YWHAG inhibited GC cell proliferation, migration and invasion and promoted GC cell apoptosis. The genes coexpressed with CEP72 or YWHAG in GC tumor tissues were enriched in the Ras signaling pathway, which was confirmed that knockdown of either one decreased the expression of cyclin D1 but increased the expression of p21 and p27. In conclusion, genetic variants at 15p13.3 and 7q11.23 may confer GC risk via modulating the biological functions of CEP72 and YWHAG, respectively, suggesting the importance of centrosome-regulated genes in GC development.

Association of Helicobacter pylori babA2 gene and gastric cancer risk: a meta-analysis.

BACKGROUND: The association of Helicobacter pylori (H. pylori) babA2 gene with gastric cancer (GC) was reported by several studies, but results were inconsistent. This meta-analysis was performed to investigate the relationship between H. pylori babA2 gene and GC risk. METHODS: Case-control studies involving the association between H. pylori babA2 gene and GC risk were systematically identified from PubMed databases. A meta-analysis was used to pool studies and to estimate odds ratios (ORs) with 95% confidence intervals (CIs) of H. pylori babA2 gene associated with GC risk. RESULTS: Twenty studies were identified with a total of 1289 GC cases and 1081 controls. H. pylori babA2 gene was associated with an increased risk of GC by 2.05 fold (95% CI, 1.30-3.24, P = 0.002). In subgroup analysis, we found that H. pylori babA2 gene was significantly associated with GC risk in Asian population (OR = 2.63, 95% CI: 1.36-5.09 P = 0.004) but not in South American population (OR = 1.35, 95% CI: 0.69-2.64, P = 0.379). CONCLUSIONS: This meta-analysis indicates that H. pylori babA2 gene may be associated with increased risk of GC, especially in Asian population.

Activatable Cell-Penetrating Peptide Conjugated Polymeric Nanoparticles with Gd-Chelation and Aggregation-Induced Emission for Bimodal MR and Fluorescence Imaging of Tumors.

Activatable cell-penetrating peptide (ACPP) conjugated polymeric nanoparticles containing gadolinium (Gd)-chelates and aggregation-induced emission fluorogens (AIEgens) have been synthesized and applied as a magnetic resonance imaging (MRI) and fluorescence imaging (FI) bimodal imaging probe with active tumor targeting. The polymeric nanoparticles have been generated by dissolving presynthesized linear block copolymers into water directly. With AIEgens, N-BP5-Gd-ACPPs showed tumor cell penetration, which can be characterized by in vitro FI. Preliminary in vivo experiments of Gd-chelated nanoparticles have demonstrated promising characteristics as a tumor-targeting MRI contrast agent with good biocompatibility. This study impacts the synthesis of functional copolymers and polymeric nanoparticles for their applications in bioimaging.

Meta-analysis of genome-wide association studies and functional assays decipher susceptibility genes for gastric cancer in Chinese populations.

OBJECTIVE: Although a subset of genetic loci have been associated with gastric cancer (GC) risk, the underlying mechanisms are largely unknown. We aimed to identify new susceptibility genes and elucidate their mechanisms in GC development. DESIGN: We conducted a meta-analysis of four genome-wide association studies (GWASs) encompassing 3771 cases and 5426 controls. After targeted sequencing and functional annotation, we performed in vitro and in vivo experiments to confirm the functions of genetic variants and candidate genes. Moreover, we selected 33 promising variants for two-stage replication in 7035 cases and 8323 controls from other five studies. RESULTS: The meta-analysis of GWASs identified three loci at 1q22, 5p13.1 and 10q23.33 associated with GC risk at p<5×10-8 and replicated seven known loci at p<0.05. At 5p13.1, the risk rs59133000[C] allele enhanced the binding affinity of NF-κB1 (nuclear factor kappa B subunit 1) to the promoter of PRKAA1, resulting in a reduced promoter activity and lower expression. The knockout of PRKAA1 promoted both GC cell proliferation and xenograft tumour growth in nude mice. At 10q23.33, the rs3781266[C] and rs3740365[T] risk alleles in complete linkage disequilibrium disrupted and created, respectively, the binding motifs of POU2F1 and PAX3, resulting in an increased enhancer activity and expression of NOC3L, while the NOC3L knockdown suppressed GC cell growth. Moreover, two new loci at 3q11.2 (OR=1.21, p=4.56×10-9) and 4q28.1 (OR=1.14, p=3.33×10-11) were associated with GC risk. CONCLUSION: We identified 12 loci to be associated with GC risk in Chinese populations and deciphered the mechanisms of PRKAA1 at 5p13.1 and NOC3L at 10q23.33 in gastric tumourigenesis.

Multi-marker analysis of genomic annotation on gastric cancer GWAS data from Chinese populations.

BACKGROUND: Gastric cancer (GC) is one of the high-incidence and high-mortality cancers all over the world. Though genome-wide association studies (GWASs) have found some genetic loci related to GC, they could only explain a small fraction of the potential pathogenesis for GC. METHODS: We used multi-marker analysis of genomic annotation (MAGMA) to analyze pathways from four public pathway databases based on Chinese GWAS data including 2631 GC cases and 4373 controls. The differential expressions of selected genes in certain pathways were assessed on the basis of The Cancer Genome Atlas database. Immunohistochemistry was also conducted on 55 GC and paired normal tissues of Chinese patients to localize the expression of genes and further validate the differential expression. RESULTS: We identified three pathways including chemokine signaling pathway, potassium ion import pathway, and interleukin-7 (IL7) pathway, all of which were associated with GC risk. NMI in IL7 pathway and RAC1 in chemokine signaling pathway might be two new candidate genes involved in GC pathogenesis. Additionally, NMI and RAC1 were overexpressed in GC tissues than normal tissues. CONCLUSION: Immune and inflammatory associated processes and potassium transporting might participate in the development of GC. Besides, NMI and RAC1 might represent two new key genes related to GC. Our findings might give new insight into the biological mechanism and immunotherapy for GC.

Meisoindigo Protects Against Focal Cerebral Ischemia-Reperfusion Injury by Inhibiting NLRP3 Inflammasome Activation and Regulating Microglia/Macrophage Polarization via TLR4/NF-κB Signaling Pathway.

Ischemic stroke is a devastating disease with long-term disability. However, the pathogenesis is unclear and treatments are limited. Meisoindigo, a second-generation derivative of indirubin, has general water solubility and is well-tolerated. Previous studies have shown that meisoindigo reduces inflammation by inhibiting leukocyte chemotaxis and migration. In the present study, we investigated the hypothesis that meisoindigo was also protective against ischemic stroke, then evaluated its underlying mechanisms. In vivo, adult male C57BL/6J wild-type mice were used to produce a middle cerebral artery occlusion (MCAO) stroke model. On day three after reperfusion, obvious improvement in neurological scores, infarct volume reduction and cerebral edema amelioration were observed in meisoindigo treatment. Moreover, immunofluorescence staining and western-blot showed that the expression of NLRP3 inflammasome and its associated proteins in neurons and microglia was inhibited by meisoindigo. The effects of Meisoindigo on NLRP3 inflammasome inactivation and increased the M2 phenotype of microglia/macrophage through shifting from a M1 phenotype, which was possibly mediated by inhibition of TLR4/NF-κB. Furthermore, we verified the inhibitory effect of meisoindigo on TLR4/NF-κB signaling pathway, and found that meisoindigo treatment could significantly suppressed the expression of TLR4/NF-κB pathway-associated proteins in a dose-dependent manner, meanwhile, which resulted in downregulation of HMGB1 and IL-1ß. Next, we established an in vitro oxygen glucose deprivation/Reperfusion (OGD/R) model in HT-22 and BV2 cells to simulate ischemic conditions. Cytotoxicity assay showed that meisoindigo substantially improved relative cell vitality and in HT-22 and BV2 cells following OGD/R in vitro. After suffering OGD/R, the TLR4/NF-κB pathway was activated, the expression of NLRP3 inflammasome-associated proteins and M1 microglia/macrophage were increased, but meisoindigo could inhibit above changes in both HT-22 and BV2 cells. Additionally, though lipopolysaccharide stimulated the activation of TLR4 signaling in OGD/R models, meisoindigo co-treatment markedly reversed the upregulation of TLR4 and following activation of NLRP3 inflammasome and polarization of M1 microglia/macrophages mediated by TLR4. Overall, we demonstrate for the first time that meisoindigo post-treatment alleviates brain damage induced by ischemic stroke in vivo and in vitro experiments through blocking activation of the NLRP3 inflammasome and regulating the polarization of microglia/macrophages via inhibition of the TLR4/NF-κB signaling pathway.

Gastric cancer may share genetic predisposition with esophageal squamous cell carcinoma in Chinese populations.

Many features are shared between esophageal cancer (EC) and gastric cancer (GC). This study aimed to explore whether known EC susceptibility loci are also important in the development of GC. A total of 21 genetic variants associated with EC in genome-wide association studies were evaluated with association of GC risk in 2631 cases and 4373 controls of Chinese ancestry. Single variant and weighted genetic scores (WGS) for esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC), and overall EC were analyzed with GC risk, respectively. Genetic variants of rs2274223 in PLCE1 at 10q23.33 (per G allele: odds ratio (OR) = 1.26, 95% confidence interval (CI): 1.16-1.38, P = 6.51 × 10-8), rs10052657 in PDE4D at 5q11.2 (per C allele: OR = 1.12, 95% CI: 1.01-1.25, P = 3.28 × 10-2) and rs671 in ALDH2 at 12q24.12 (per A-allele: OR = 0.83, 95% CI: 0.75-0.91, P = 1.14 × 10-4) were significantly associated with GC risk. The combined effect of those three variants had stronger influence on GC risk (OR = 1.31, 95% CI: 1.19-1.44, P = 2.34 × 10-8). High WGS of ESCC was also associated with increased risk of GC (P = 5.52 × 10-4 as a continuous variable) (trend test P = 2.71 × 10-4), whereas no statistically significant associations were observed between the WGS of EAC and GC risk (P = 0.66 as a continuous variable) (trend test P = 0.70). ESCC rather than EAC may share genetic susceptibility with GC. Genetic variants at 10q23.33, 5q11.2, and 12q24.12 may be useful as biomarkers to identify individuals with high risk for both ESCC and GC.