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Due to the complexity of terrain and climate in the mountain–plain transition zone, it is difficult to simulate and forecast the flow discharge of river basins accurately. The poor regularity of the river thus leads to uncertain flood control scheduling. Meanwhile, reservoirs and flood detention areas are constructed to store and divert water when severe floods threaten the safety of the basin. In order to improve the accuracy of flood forecasts and the effectiveness of flood control, a hydrological and 1D/2D hydrodynamic coupling model was developed to enable the joint computation of multiple objects, including mountainous streams, plains river networks, hydraulic control structures, and flood detention areas. For the hydrological component, the Xin’anjiang model with the Muskingum module is employed to simulate mountainous flow discharge. For the hydrodynamic component, the Saint–Venant equations and shallow water equations are applied to estimate flood processes in rivers and on land surfaces, respectively. The Dongtiaoxi River Basin in Zhejiang Province, China, serves as the case study, where river flow is influenced by both upstream mountainous floods and downstream backwater effects. Using the integrated model, flood routing and scheduling are simulated and visualized. Both the Xin’anjiang model and the 1D hydrodynamic model demonstrate over 80% acceptability in calibration and validation, confirming their robustness and reliability. Meanwhile, inundation in flood detention areas can be effectively estimated by coupling the 1D and 2D hydrodynamic models with a flood diversion scheduling model. The coupled model proves capable of simulating flood routing in complex river basins that include mountains, plains, and hydraulic control structures, accounting for the interactions between hydrological elements. These findings provide a new perspective on flood simulation in other similarly complex river basins.

Abstract The Bangong-Nujiang Suture Zone (BNSZ) of Tibet (Xizang) has been interpreted to represent a relic of the Bangong-Nujiang Ocean. However, the existence of this ocean during Triassic time remains a point of contention. A sedimentary succession spanning the Upper Permian through Triassic described from the central BNSZ suggests that the Lhasa and South Qiangtang terranes were contiguous thus negating the existence of a terrane-separating ocean during Triassic time. However, the apparent lack of Triassic deposits in the west BNSZ has called into question the existence of Triassic deposits in the central region of the BNSZ. Our biostratigraphic work in the Wuga Formation of the Gaize area has yielded abundant Norian conodonts thus confirming the existence of Upper Triassic deposits in the west BNSZ. The clastic deposits of the Wuga Formation are herein interpreted to be of Rhaetian age. Moreover, intercalated limestone and chert are termed the Dongnale Formation of Norian age. The Norian to Rhaetian succession can be correlated with strata of the central BNSZ as well as with deposits of the Lhasa Terrane and the South Qiangtang Terrane. Similar stratigraphies among these regions through the Late Triassic suggests a shared depositional setting and that the BNSZ was not an ocean in Norian and Rhaetian time.

Abstract Viral encephalitis is characterized by inflammation of the brain parenchyma caused by a variety of viruses, among which the Japanese encephalitis (JE) virus (JEV) is a typical representative arbovirus. Neuronal death, neuroinflammation, and breakdown of the blood brain barrier (BBB) constitute vicious circles of JE progression. Currently, there is no effective therapy to prevent this damage. Growth arrest specific gene 6 (GAS6) is a secreted growth factor that binds to the TYRO3, AXL, and MERTK (TAM) family of receptor tyrosine kinases and has been demonstrated to participate in neuroprotection and suppression of inflammation in many central nervous system (CNS) diseases which has great potential for JE intervention. In this study, we found that GAS6 expression in the brain was decreased and was reversely correlated with viral load and neuronal loss. Mice with GAS6/TAM signalling deficiency showed higher mortality and accelerated neuroinflammation during peripheral JEV infection, accompanied by BBB breakdown. GAS6 directly promoted the expression of tight junction proteins in bEnd.3 cells and strengthened BBB integrity, partly via AXL. Mice administered GAS6 were more resistant to JEV infection due to increased BBB integrity, as well as decreased viral load and neuroinflammation. Thus, targeted GAS6 delivery may represent a strategy for the prevention and treatment of JE especially in patients with impaired BBB.

The fibroblast growth factor receptor (FGFR) is a crucial receptor tyrosine kinase involved in essential biological processes, including growth, development, and tissue repair. However, FGFR gene mutations, including amplification, fusion, and mutation, can disrupt epigenetics, transcriptional regulation, and tumor microenvironment interactions, leading to cancer development. Targeting these kinase mutations with small molecule drugs or antibodies has shown clinical benefits. For example, erdafitinib is approved for treating locally advanced or metastatic urothelial cancer patients with FGFR2/FGFR3 mutations, and pemigatinib is approved for treating cholangiocarcinoma with FGFR2 fusion/rearrangement. Effective screening of FGFR variant patients is crucial for the clinical application of FGFR inhibitors. Various detection methods, such as polymerase chain reaction, next-generation sequencing, fluorescence in situ hybridization, and immunohistochemistry, are available, and their selection should be based on diagnostic and treatment decision-making needs. Our developed expert consensus aims to standardize the diagnosis and treatment process for FGFR gene mutations and facilitate the practical application of FGFR inhibitors in clinical practice.

Abstract Objective To evaluate the safety and efficacy of the granisetron transdermal delivery system (GTDS) combined with Dexamethasone for preventing chemotherapy-induced nausea and vomiting (CINV) in patients receiving Capecitabine plus Oxaliplatin (CapeOX) therapy. Design Open-label, prospective, multi-center phase II trial. Setting Three institutions. Participants Fifty-four patients scheduled to receive CapeOX chemotherapy. Interventions Participants received GTDS (3.1 mg applied to the upper arm 48 h before chemotherapy, replaced on day 5, and discarded on day 12) and Dexamethasone. Main outcome measures The primary endpoint was the complete control rate of CINV. Secondary endpoints included the duration of delayed complete control, complete control rate in the acute phase, safety, and quality of life. Results The complete control rate for delayed CINV over the entire period (25–480 h) was 72.7% (95% CI 0.57–0.88). The duration of delayed complete control was 17.2 ± 4.5 days, with 51.5% of patients experiencing no nausea during the delayed phase. The complete control rate in the acute phase was 81.8% (95% CI 0.69–0.95). No serious adverse events related to the antiemetic regimen were reported. Conclusion Prolonged administration of GTDS is safe and effective for preventing CINV in patients with gastrointestinal malignancies treated with CapeOX. Trial Registration ClinicalTrials.gov registry (NCT05325190); registered on October 10, 2021.

The fusion genes NRG1 and NRG2, members of the epidermal growth factor (EGF) receptor family, have emerged as key drivers in cancer. Upon fusion, NRG1 retains its EGF-like active domain, binds to the ERBB ligand family, and triggers intracellular signaling cascades, promoting uncontrolled cell proliferation. The incidence of NRG1 gene fusion varies across cancer types, with lung cancer being the most prevalent at 0.19 to 0.27%. CD74 and SLC3A2 are the most frequently observed fusion partners. RNA-based next-generation sequencing is the primary method for detecting NRG1 and NRG2 gene fusions, whereas pERBB3 immunohistochemistry can serve as a rapid prescreening tool for identifying NRG1-positive patients. Currently, there are no approved targeted drugs for NRG1 and NRG2. Common treatment approaches involve pan-ERBB inhibitors, small molecule inhibitors targeting ERBB2 or ERBB3, and monoclonal antibodies. Given the current landscape of NRG1 and NRG2 in solid tumors, a consensus among diagnostic and treatment experts is proposed, and clinical trials hold promise for benefiting more patients with NRG1 and NRG2 gene fusion solid tumors.

Abstract Background Autoimmune hepatitis is a chronic inflammatory hepatic disorder with no effective treatment. Mesenchymal stromal cells (MSCs) have emerged as a promising treatment owing to their unique advantages. However, their heterogeneity is hampering use in clinical applications. Methods Wharton’s jelly derived MSCs (WJ-MSCs) were isolated from 58 human donors using current good manufacturing practice conditions. Gene expression profiles of the WJ-MSCs were analyzed by transcriptome and single-cell RNA-sequencing (scRNA-seq), and subsequent functional differences were assessed. Expression levels of programmed death-ligand 1 (PD-L1) were used as an indicator to screen WJ-MSCs with varied immunomodulation activities and assessed their corresponding therapeutic effects in a mouse model of concanavalin A-induced autoimmune hepatitis. Results The 58 different donor-derived WJ-MSCs were grouped into six gene expression profile clusters. The gene in different clusters displayed obvious variations in cell proliferation, differentiation bias, trophic factor secretion, and immunoregulation. Data of scRNA-seq revealed four distinct WJ-MSCs subpopulations. Notably, the different immunosuppression capacities of WJ-MSCs were positively correlated with PD-L1 expression. WJ-MSCs with high expression of PD-L1 were therapeutically superior to WJ-MSCs with low PD-L1 expression in treating autoimmune hepatitis. Conclusion PD-L1 expression levels of WJ-MSCs could be regarded as an indicator to choose optimal MSCs for treating autoimmune disease. These findings provided novel insights into the quality control of MSCs and will inform improvements in the therapeutic benefits of MSCs.

Abstract The rearranged during transfection (RET) gene is one of the receptor tyrosine kinases and cell‐surface molecules responsible for transmitting signals that regulate cell growth and differentiation. In non‐small cell lung cancer (NSCLC), RET fusion is a rare driver gene alteration associated with a poor prognosis. Fortunately, two selective RET inhibitors (sRETi), namely pralsetinib and selpercatinib, have been approved for treating RET fusion NSCLC due to their remarkable efficacy and safety profiles. These inhibitors have shown the ability to overcome resistance to multikinase inhibitors (MKIs). Furthermore, ongoing clinical trials are investigating several second‐generation sRETis that are specifically designed to target solvent front mutations, which pose a challenge for first‐generation sRETis. The effective screening of patients is the first crucial step in the clinical application of RET‐targeted therapy. Currently, four methods are widely used for detecting gene rearrangements: next‐generation sequencing (NGS), reverse transcription‐polymerase chain reaction (RT‐PCR), fluorescence in situ hybridization (FISH), and immunohistochemistry (IHC). Each of these methods has its advantages and limitations. To streamline the clinical workflow and improve diagnostic and treatment strategies for RET fusion NSCLC, our expert group has reached a consensus. Our objective is to maximize the clinical benefit for patients and promote standardized approaches to RET fusion screening and therapy.

Abstract Malignant pleural mesothelioma (MPM) is a malignant tumor originating from the pleura, and its incidence has been increasing in recent years. Due to the insidious onset and strong local invasiveness of MPM, most patients are diagnosed in the late stage and early screening and treatment for high‐risk populations are crucial. The treatment of MPM mainly includes surgery, chemotherapy, and radiotherapy. Immunotherapy and electric field therapy have also been applied, leading to further improvements in patient survival. The Mesothelioma Group of the Yangtze River Delta Lung Cancer Cooperation Group (East China LUng caNcer Group, ECLUNG; Youth Committee) developed a national consensus on the clinical diagnosis and treatment of MPM based on existing clinical research evidence and the opinions of national experts. This consensus aims to promote the homogenization and standardization of MPM diagnosis and treatment in China, covering epidemiology, diagnosis, treatment, and follow‐up.

Abstract Thymic epithelial tumors (TETs) are a relatively rare type of thoracic tumor, accounting for less than 1% of all tumors. The incidence of TETs is about 3.93/10000 in China, slightly higher than that of European and American countries. For resectable TETs, complete surgical resection is recommended. Radiotherapy or chemotherapy may be used as postoperative adjuvant treatment. Treatment for advanced, unresectable TETs consist mainly of radiotherapy and chemotherapy, but there is a lack of standard first‐ and second‐line treatment regimens. Recently, targeted therapies and immune checkpoint inhibitors have shown promising outcomes in TETs. Based on the currently available clinical evidences and the opinions of the national experts, the Thymic Oncology Group of Yangtze River Delta Lung Cancer Cooperation Group (East China LUng caNcer Group, ECLUNG; Youth Committee) established this Chinese expert consensus on the clinical diagnosis and treatment of TETs, covering the epidemiology, diagnosis, treatment, prognosis and follow‐up of TETs.

Abstract Background Non-small cell cancer (NSCLC) patients with concomitant epidermal growth factor receptor (EGFR) and TP53 mutations have a poor prognosis with the treatment of tyrosine kinase inhibitors (TKIs), and may benefit from a combination regimen preferentially. The present study aims to compare the benefits of EGFR-TKIs and its combination with antiangiogenic drugs or chemotherapy in patients with NSCLC harboring EGFR and TP53 co-mutation in a real-life setting. Methods This retrospective analysis included 124 patients with advanced NSCLC having concomitant EGFR and TP53 mutations, who underwent next-generation sequencing prior to treatment. Patients were classified into the EGFR-TKI group and combination therapy group. The primary end point of this study was progression-free survival (PFS). The Kaplan–Meier (KM) curve was drawn to analyze PFS, and the differences between the groups were compared using the logarithmic rank test. Univariate and multivariate cox regression analysis was performed on the risk factors associated with survival. Results The combination group included 72 patients who received the regimen of EGFR-TKIs combined with antiangiogenic drugs or chemotherapy, while the EGFR-TKI monotherapy group included 52 patients treated with TKI only. The median PFS was significantly longer in the combination group than in the EGFR-TKI group (18.0 months; 95% confidence interval [CI]: 12.1–23.9 vs. 7.0 months; 95% CI: 6.1–7.9; p

Abstract Human epidermal growth factor receptor 2 (HER2) possesses tyrosine kinase activity and participates in cell growth, differentiation and migration, and survival. Its alterations, mainly including mutations, amplifications, and overexpression are associated with poor prognosis and are one of the major drivers in non–small cell lung cancer (NSCLC). Several clinical trials had been investigating on the treatments of HER2‐altered NSCLC, including conventional chemotherapy, programmed death 1 (PD‐1) inhibitors, tyrosine kinase inhibitors (TKIs) and antibody‐drug conjugates (ADCs), however, the results were either disappointing or encouraging, but inconsistent. Trastuzumab deruxtecan (T‐DXd) was recently approved by the Food and Drug Administration as the first targeted agent for treating HER2‐mutant NSCLC. Effective screening of patients is the key to the clinical application of HER2‐targeted agents such as TKIs and ADCs. Various testing methods are nowadays available, including polymerase chain reaction (PCR), next‐generation sequencing (NGS), fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), etc. Each method has its pros and cons and should be reasonably assigned to appropriate patients for diagnosis and guiding treatment decisions. To help standardize the clinical workflow, our expert group reached a consensus on the clinical management of HER2‐altered NSCLC, focusing on the diagnosis and treatment strategies.

Abstract Immune checkpoint inhibitors (ICIs) have successfully treated a number of different types of cancer, which is of great significance for cancer treatment. With the widespread use of ICIs in clinical practice, the increasing checkpoint inhibitor pneumonia (CIP) will be a challenge to clinicians. To guide the diagnosis and treatment of CIP, we conducted in‐depth discussions based on the latest evidence, forming a consensus among Chinese experts on the multidisciplinary management of CIP.

Abstract Gene fusions can drive tumor development for multiple types of cancer. Currently, many drugs targeting gene fusions are being approved for clinical application. At present, tyrosine receptor kinase (TRK) inhibitors targeting neurotrophic tyrosine receptor kinase (NTRK) gene fusions are among the first “tumor agnostic” drugs approved for pan‐cancer use. Representative TRK inhibitors, including larotrectinib and entrectinib, have shown high efficacy for many types of cancer. At the same time, several second‐generation drugs designed to overcome first‐generation drug resistance are undergoing clinical development. Due to the rarity of NTRK gene fusions in common cancer types and technical issues regarding the complexity of fusion patterns, effectively screening patients for TRK inhibitor treatment in routine clinical practice is challenging. Different detection methods including immunohistochemistry, fluorescence in situ hybridization, reverse transcription‐polymerase chain reaction, and (DNA and/or RNA‐based) next‐generation sequencing have pros and cons. As such, recommending suitable tests for individual patients and ensuring the quality of tests is essential. Moreover, at present, there is a lack of systematic review for the clinical efficacy and development status of first‐ and second‐generation TRK inhibitors. To resolve the above issues, our expert group has reached a consensus regarding the diagnosis and treatment of NTRK gene fusion solid tumors, aiming to standardize clinical practice with the goal of benefiting patients with NTRK gene fusions treated with TRK inhibitors.

Abstract. Hemorrhagic fever with renal syndrome (HFRS) is an acute zoonosis with a global distribution. China is one of the countries with a high incidence of HFRS, which has long endangered the lives and health of the Chinese people. The Infectious Disease Branch of the Chinese Preventive Medicine Association and the Infectious Diseases Branch of the Chinese Medical Association organized national multidisciplinary experts, based on domestic and international research results combined with experts’ practical experiences, to reach this consensus after thorough discussion. This consensus contains 17 recommendations aimed at prevention and identification of important clinical issues to further standardize the prevention, diagnosis, and treatment of HFRS.

Abstract Background Cancer‐related cachexia is a major cause of treatment resistance and poor prognosis, which is characterized by anorexia and skeletal muscle depletion. To date, there have been no reports on the relationship between IL‐35 and cancer‐related cachexia in patients with stage IV non‐small cell lung cancer. Methods Serum IL‐35 levels in 86 patients with stage IV NSCLC were measured and statistically analyzed based on patients' clinicopathological parameters. Serum albumin levels, C‐reactive protein, and skeletal muscle index (SMI) of the patients were also determined. In vivo studies using a mouse model were also conducted by subcutaneously injecting immunodeficiency (SCID) mice with overexpressing IL‐35 cell lines and determining their daily food intake, bodyweight and muscle atrophy. Cachexia indicators were measured again after administering the mice with an anti‐IL35 neutralizing antibody. Results Patients with stage IV NSCLC had significantly higher serum IL‐35 levels than the healthy controls. Similarly, circulating IL‐35 levels were significantly higher in patients with cachexia than those without. The SMI values of patients with high serum IL‐35 levels were significantly lower than those with low serum IL‐35 levels. Mice subcutaneously injected with LLC PLV‐IL‐35 cell lines exhibited anorexia, weight loss, and muscle atrophy. Moreover, these symptoms were significantly reduced after administering the mice with an anti‐IL35 neutralizing antibody. Conclusions This study reveals that high serum IL‐35 expression is associated with non‐small cell lung cancer cachexia and skeletal muscle atrophy. These findings highlight its potential as a biomarker and therapeutic target for controlling cachexia of advanced lung cancer.

Abstract Background This study focused on comparing the safety and therapeutic effects between icotinib monotherapy and icotinib plus bevacizumab combined therapy in non‐small cell lung cancer (NSCLC) cases harboring EGFR mutations. Methods Data were collected retrospectively from the Cancer Institute and Hospital of Tianjin Medical University between October 2018 and December 2019, where the NSCLC cases that harbored EGFR mutations underwent first‐line therapy with icotinib in the presence or absence of bevacizumab. This study included 90 cases, of which 60 patients were in the icotinib group (I) and 30 in the icotinib plus bevacizumab group (IB). Results The follow‐up period to evaluate median PFS in our study was 18 months. Median PFS was 18.0 months (95% confidence interval [CI]: 14.7–21.3) with icotinib plus bevacizumab and 11 months (95% CI: 8.9–13.1) with icotinib alone (hazard ratio 0·54, 95% CI: 0.31–0.92; p = 0.029). According to the subgroup analyses based on the type of EGFR genomic aberration, a prolonged median PFS was observed in the cases harboring exon 21 point mutation (Ex21.L858R) in the IB group compared to the I group (not reached vs. 11 months [8.8–13.2], p = 0.021). However, the difference between the cases harboring exon 19 deletions in the EGFR gene was not significant. The DCR and ORR were comparable between both groups. Substantially higher incidences of hypertension and proteinuria were observed in the combined group compared to the icotinib monotherapy group. Conclusions This is the first study to provide further evidence of the benefits of applying icotinib in combination with bevacizumab as first‐line treatment for advanced NSCLC cases harboring EGFR mutations. However, these findings need to be verified through prospective phase 3 clinical studies.

BackgroundJapanese encephalitis virus (JEV) is the main cause of viral encephalitis in Asia. Nowadays, no effective and specific therapy for JE patients is available except supportive treatment. The fatality rate of JE patients is still about 30%, and more than half of survivors suffered from various neuropsychiatric sequelae. Thus, more attention should be paid to JE.MethodsIn this study, a retrospective cohort of JE patients was collected and the general features of JE patients admitted into the Department of Infectious Diseases were analyzed. Meanwhile, the dynamic change of plasma cytokines and immune cells in JE patients with divergent prognosis was detected and analyzed.ResultsWe found a mounted proportion of adult/old patients in JE cases. The level of IL-6 and IL-18 increased in JE patients especially in fatal individuals. There was a continuous decreased percentage of CD4+ T and B cells in severe JE patients with fatal outcome compared with the surviving JE patients.ConclusionsThe consistent high level of IL-6 and IL-18 in the plasma and low proportion of CD4+ T and B cells in the PBMCs might be the indicators of poor prognosis.

Background Lung adenocarcinoma is the most common pathological lung cancer and an important cause of cancer‐related death. Metastasis is a major underlying reason for poor prognosis of lung adenocarcinoma. Opsin3 (OPN3), a member of the guanine nucleotide‐binding protein‐coupled receptor superfamily, has been identified to affect the apoptosis of hepatoma cells by modulating the phosphorylation of Akt and Bcl2/Bax. However, the expression and role of OPN3 in lung adenocarcinoma remains unclear. Methods Opsin3 expression in lung adenocarcinoma tissues was detected by western blot, qPCR, and immunohistochemistry. Changes in cell migration and invasion ability resulting from the change of OPN3 expression level were detected by wound healing and transwell migration assays. Changes in the markers of epithelial‐mesenchymal transformation were detected by western blot and qPCR. Results Opsin3 expression in lung adenocarcinoma tissues was higher than that in normal lung tissues. Patients with high expression of OPN3 had lower survival rates. Owing to overexpression of OPN3, the HCC827 cells showed enhanced invasion and migration ability in vitro. Upon decreasing the expression of OPN3, the invasion and migration ability of the A549 cells decreased. Conclusion Our study demonstrated for the first time that OPN3 gene enhanced the metastasis in lung adenocarcinoma, and its overexpression promoted epithelial‐mesenchymal transition. Key points A significant finding of the study was that OPN3 acted an oncogene in promoting lung adenocarcinoma metastasis. Our study complemented the research on the expression and function of OPN3 in lung adenocarcinoma.

Abstract Background Radiation resistance is the main cause of recurrence after radiotherapy, and increased autophagy after radiotherapy is related to radiotherapy resistance. This study aims to investigate the reversal effect of baicalin on radioresistance and its related mechanism. Methods CCK-8 and flow cytometry were used to detect the effect of proliferation and apoptosis by baicalin. Clone formation test was used to verify the effect of baicalin radiosensitization. Western blot analysis and electron microscopy were employed to observe the effect of baicalin on autophagy. Results Compared with the radiation therapy (RT) group, the RT combined baicalin (RT + BA) group showed a significantly low 2 Gy survival fraction of radiation therapy (P

Immunotherapy based on immune checkpoint inhibitors (ICIs) have demonstrated remarkable survival benefits and gained regulatory approval in non-small cell lung cancer (NSCLC) patients without an actionable driver mutation, but currently there is no well-established standard for how to screen the most suitable population for ICIs treatment. Here, we conducted a comprehensive analysis of the somatic mutation landscape of lung adenocarcinoma (LUAD) samples. After the stepwise screening of high-frequency mutated genes, two genes with prominent significance, FAT3 and LRP1B, were finally screened out. Through further analysis, we discovered that the co-mutation of FAT3 and LRP1B was associated with an earlier age of onset and occurred more frequently in Black/African American. Furthermore, co-mutation defines a unique subgroup of lung adenocarcinoma that can increase tumor mutational burden (TMB), boost cytotoxicity and tumor immunogenicity, and facilitate lymphocyte infiltration. The results of gene set enrichment analysis (GSEA) indicated that co-mutation can influence tumorigenesis through a variety of mechanisms. More strikingly, the subset of LUAD with co-mutation of FAT3 and LRP1B exhibited significantly prolonged immunotherapy progression free survival (PFS). In summary, co-mutation of FAT3 and LRP1B is a promising useful biomarker for predicting the efficacy of immunotherapy, which can improve the clinical efficiency of practicing precision medicine in lung adenocarcinoma patients.

Japanese encephalitis virus (JEV), the leading cause of viral encephalitis in Asia, is neurovirulent and neuroinvasive. Neurons are the main target of JEV infection and propagation. Receptor interacting serine/threonine-protein kinase 3 (RIPK3) has been reported to contribute to neuroinflammation and neuronal death in many central nervous system diseases. In this study, we found that the progression of JE was alleviated in RIPK3-knockout (RIPK3–/–) mice in both peripheral and intracerebral infection. RIPK3-knockdown (RIPK3-RNAi) neuro2a cells showed higher cell viability during JEV infection. Moreover, the JEV load was significantly decreased in RIPK3–/– mouse-derived primary neurons and RIPK3-RNAi neuro2a cells compared with wild-type neurons, but this was not observed in microglia. Furthermore, RNA sequencing of brain tissues showed that the level of the interferon (IFN)-induced protein 44-like gene (IFI44L) was significantly increased in JEV-infected RIPK3–/– mouse brains, RIPK3–/– neurons, and RIPK3-RNAi-neuro2a cells. Then, it was demonstrated that the propagation of JEV was inhibited in IFI44L-overexpressing neuro2a cells and enhanced in IFI44L and RIPK3 double knockdown neuro2a cells. Taken together, our results showed that the increased expression of RIPK3 following JEV infection played complicated roles. On the one hand, RIPK3 participated in neuroinflammation and neuronal death during JEV infection. On the other hand, RIPK3 inhibited the expression of IFI44L to some extent, leading to the propagation of JEV in neurons, which might be a strategy for JEV to evade the cellular innate immune response.

Background/Aims: To investigate the cellular effects and clinical significance of microRNA-223 (miR-223) in breast cancer by targeting stromal interaction molecule1 (STIM1). Methods: Breast cancer cell lines (T47D, MCF-7, SKB-R3, MDA-MB-231 and MDA-MB-435) and a normal breast epithelial cell line (MCF-10A) were prepared for this study. MiR-223 mimics, anti-miR-223 and pcDNA 3.1-STIM1 were transiently transfected into cancer cells independently or together, and then RT-qPCR was performed to detect the expressions of miR-223 and STIM1 mRNA, dual-luciferase reporter assay was conducted to examine the effects of miR-223 on STIM1, Western blotting was used to measure the expressions of the STIM1 proteins, MTT and Trans-well assays were performed to detect cell proliferation and invasion. Finally, the correlation of miR-223 and STIM1 was investigated by detecting with ISH and IHC in breast cancer specimens or the corresponding adjacent normal tissues. Results: Compared with normal cells and tissues, breast cancer tissues and cells exhibited significantly lower expression of miR-223, but higher expression of STIM1. MiR-223 could inhibit the proliferation and invasiveness of breast cancer cells by negatively regulating the expressions of STIM1. Reimplantation with STIM1 partially rescued the miRNA-223-induced inhibition of breast cancer cells. Clinical data revealed that high expression of STIM1 and miR-223 was respectively detrimental and beneficial factor impacting patient’s disease-free survival (DFS) rather than overall survival (OS). Moreover, Pearson correlation analysis also confirmed that STIM1 was inversely correlated with miR-223. Conclusion: MiR-223 inhibits the proliferation and invasion of breast cancer by targeting STIM1. The miR-223/STIM1 axis could possibly be a potential therapeutic target for treating breast cancer patients.

The demarcation of the Lower-Middle Triassic boundary is a disputed problem in global stratigraphic research. Lower-Middle Triassic strata of different types, from platform to basin facies, are well developed in Southwest China. This is favorable for the study of the Olenekian-Anisian boundary and establishing a stratotype for the Qingyan Stage. Based on research at the Ganheqiao section in Wangmo county and the Qingyan section in Guiyang city, Guizhou province, six conodont zones have been recognized, which can be correlated with those in other regions, in ascending order as follows: 1, Neospathodus cristagalli Interval-Zone; 2, Neospathodus pakistanensis Interval-Zone; 3, Neospathodus waageni Interval-Zone; 4, Neospathodus homeri-N. triangularis Assemblage-Zone; 5, Chiosella timorensis Interval-Zone; and 6, Neogongdolella regalis Range-Zone. An evolutionary series of the Early-Middle Triassic conodont genera Neospathodus-Chiosella-Neogongdolella discovered in the Ganheqiao and Qingyan sections has an intermediate type named Neospathodus qingyanensis that appears between Neospathodus homeri and Chiosella timorensis in the upper part of the Neospathodus homeri-N. triangularis Zone, showing an excellent evolutionary relationship of conodonts near the Lower-Middle Triassic boundary. The Lower-Middle Triassic boundary is located at 1.5 m below the top of the Ziyun Formation, where Chiosella timorensis Zone first appears in the Qingyan section, whereas this boundary is located 0.5 m below the top of the Ziyun Formation, where Chiosella timorensis Zone first appears in the Ganheqiao section. There exists one nearly 6-m thick vitric tuff bed at the bottom of the Xinyuan Formation in the Ganheqiao section, which is usually regarded as a lithologic symbol of the Lower-Middle Triassic boundary in South China. Based on the analysis of high-precision and high-sensitivity Secondary Ion Mass Spectrum data, the zircon age of this tuff has a weighted mean 206Pb/238U age of 239.0 ± 2.9 Ma (2σ), which is a directly measured zircon U-Pb age of the Lower-Middle Triassic boundary. The Ganheqiao section in Wangmo county can therefore provide an excellent section through the Lower-Middle Triassic because it is continuous, the evolution of the conodonts is distinctive and the regionally stable distributed vitric tuff near the Lower-Middle Triassic boundary can be regarded as a regional key isochronal layer. This section can be regarded not only as a standard section for the establishment of the Qingyan Stage in China, but also as a reference section for the GSSP of the Lower-Middle Triassic boundary. [ABSTRACT FROM AUTHOR]

Pembrolizumab, an inhibitor target programmed death 1 (PD-1), was approved into the first line therapy in advanced non-small cell lung cancer (NSCLC). It was a milestone that immune checkpoints drugs have played an important role in the treatment system of NSCLC. The results of clinical trials revealed the superiority of PD-1/programmed death ligand 1 (PD-L1) inhibitors compared with chemotherapy in first-line, second-line and multidrug resistance phase therapy. Objective response rate (ORR) was up to 80% with pembrolizumab plus chemotherapy, and progression-free survival (PFS) with single pembrolizumab in first line was nearly 1 year (10.3 months), the hazard ratio for death fell by 40%. Overall survival (OS) was more or less 1 year with single drug pembrolizumab, nivolumab and atezolizumab for second line therapy. PD-L1 expression was a predictor of PD-1/PD-L1 inhibitors. The positive rate of PD-L1 (more than 1%) in advanced NSCLC was about 60% with little difference between the tissue types. However, there was no gold standard test of PD-L1 expression.