Single-cell RNA sequencing reveals cell type-specific immune regulation associated with human neuromyelitis optica spectrum disorder.

Introduction: One rare type of autoimmune disease is called neuromyelitis optica spectrum disorder (NMOSD) and the peripheral immune characteristics of NMOSD remain unclear. Methods: Here, single-cell RNA sequencing (scRNA-seq) is used to characterize peripheral blood mononuclear cells from individuals with NMOSD. Results: The differentiation and activation of lymphocytes, expansion of myeloid cells, and an excessive inflammatory response in innate immunity are observed. Flow cytometry analyses confirm a significant increase in the percentage of plasma cells among B cells in NMOSD. NMOSD patients exhibit an elevated percentage of CD8+ T cells within the T cell population. Oligoclonal expansions of B cell receptors are observed after therapy. Additionally, individuals with NMOSD exhibit elevated expression of CXCL8, IL7, IL18, TNFSF13, IFNG, and NLRP3. Discussion: Peripheral immune response high-dimensional single-cell profiling identifies immune cell subsets specific to a certain disease and identifies possible new targets for NMOSD.

Ofatumumab, a Fully Human Anti-CD20 Monoclonal Antibody, in the Treatment of Severe Refractory Anti-N-methyl-D-Aspartate Receptor Encephalitis: Two Case Reports.

Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is a type of autoimmune encephalitis (AE) characterized by antibodies against NMDA receptor. As the most common AE, anti-NMDAR encephalitis affects 54% ~ 80% of patients with AE. It is associated with a high percentage of severe illness. It typically manifests as behavioral and psychiatric disturbance, epilepsy, cognitive decline, decreased level of consciousness, involuntary movements, autonomic dysfunction, central hypoventilation, etc. We report two refractory anti-NMDAR encephalitis. One of them describes a case of anti-NMDA encephalitis coexisting with MOG antibodies. The two patients were administered first-line therapy with glucocorticoids and intravenous immunoglobulin but did not improve clinically. Therefore, the patient was switched to the fully human anti-CD20 monoclonal antibody, ofatumumab. Their consciousness, behavioral and psychiatric disturbance, and capacity to conduct daily tasks improved markedly after sequential therapy with ofatumumab, as demonstrated by the modified Rankin scale (mRS) score. For the first time, we report a successful approach to the treatment of refractory anti-NMDAR encephalitis using the fully human anti-CD20 monoclonal antibody ofatumumab, which serves as an important reference for the treatment of AE.

The assessment of Ki-67 for prognosis of gastroenteropancreatic neuroendocrine neoplasm patients: a systematic review and meta-analysis.

Background: Neuroendocrine neoplasm (NEN) is a group of rare tumors. Among which, gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN) is the most common group. The World Health Organization (WHO) classified these tumors into three different grades (G1, G2, and G3) based on Ki-67 and mitotic rate, and updated the classification in 2019. Several previous studies proved that Ki-67 was related to tumor prognosis, but others still reported that Ki-67 had no predictive value for tumor prognosis. There are different conclusions between studies regarding the correlation between Ki-67 and tumor prognosis, and there is a lack of studies about this correlation of GEP-NENs. Further analysis is still needed to evaluate the prognostic value of Ki-67 in GEP-NENs, to provide reference for clinical decisions. Methods: A total of 303 studies were retrieved that included Ki-67, GEP-NENs, prognosis, survival, and other subject terms and keywords. We excluded studies that did not show complete Ki-67 index, number of patients and 5-year survival data available for meta-analysis, non-cohort studies, articles published before 2000 or not published in English. Fifteen studies were finally included to assess the value of Ki-67 in the prognosis of patients with GEP-NENs using a random-effects model. Results: The cumulative 5-year survival rate for GEP-NEN G1 (Ki-67 ≤2%), G2 (Ki-67 2-20%) and G3 (Ki-67 >20%) was 86%, 65%, 25% respectively. The 5-year survival rate of GEP-NEN G1 (Ki-67 <3%, first revised in WHO classification 2017, redefined WHO classification 2019) and G1 (Ki-67 ≤2%, WHO classification 2010) was 97% and 84% respectively. Conclusions: The overall prognosis of GEP-NENs patients showed a decreasing trend with the increase of Ki-67, which confirmed the significance of Ki-67 index as a prognostic marker for the prognosis of GEP-NENs. Increasing the cut-off value of Ki-67 index for G1 grade from ≤2% to <3% according to WHO classification 2019 did not significantly decrease the 5-year survival rate.

Detailed characterization of PD-1/PD-L1 and CTLA4 expression and tumor-infiltrating lymphocytes in yolk sac tumors.

BACKGROUND: Immune checkpoint blockade (ICB) is considered as a promising approach for cancer treatment. However, the potency of ICB therapy in yolk sac tumors (YSTs) has not been confirmed, and the comprehensive analysis of tumor immune microenvironment and the expression of PD-1/PD-L1 and CTLA4 were also not thoroughly evaluated. METHODS: Immunohistochemistry was performed in formalin-fixed, paraffin-embedded tumor specimens from 23 YSTs patients to detect the density and distribution of tumor-infiltrating T cells, tertiary lymphoid structures (TLSs), as well as the expression of PD-1/PD-L1 and CTLA4. RESULTS: Overall, more than half (61 %) of all patients exhibited an immune-desert phenotype based on CD3+ T cells. PD-1 expression was identified in five tumor samples (21.7 %), and PD-L1 expression exhibited a different positive rate in tumor cells (TCs) and tumor-infiltrating lymphocytes (TILs) (39.1 % and 17.4 %). Noteworthily, the rate of positive CTLA4 expression in both TCs and TILs was markedly higher (69.6 % and 56.5 %) than those of PD-1 and PD-L1 expression. Furthermore, TLSs were observed in 21.74 % of all tissues, and samples with TLSs exhibited significantly higher densities of TILs and higher expression of immune checkpoint molecules, particularly PD-1/PD-L1. In addition, tumors located in testes also exhibited a higher density of TILs and higher expression of immune checkpoint molecules. CONCLUSION: Generally a high frequency of CTLA4 expression was found, PD-1/PD-L1 expression, the immune-inflamed phenotype, and TLSs were low frequency in YSTs, however, YSTs in testes showed a higher density of TILs and higher expression of immune checkpoint molecules.

Comparing clinical features, severity and prognosis of autoimmune encephalitis and with and without oligoclonal bands.

Objective: This study aimed to examine the clinical distinctions among patients diagnosed with autoimmune encephalitis (AE) based on the presence or absence of cerebrospinal fluid (CSF) oligoclonal bands (OCBs). Additionally, it sought to explore the relationship between OCBs and the severity and prognosis of autoimmune encephalitis. Methods: A retrospective analysis was conducted on 94 patients diagnosed with AE at the People's Hospital of Zhengzhou University between October 2016 and June 2022. The patients were divided into OCB-positive and OCB-negative groups based on CSF-OCBs. Patient severity at admission was assessed utilizing the Clinical Assessment Scale for Autoimmune Encephalitis (CASE) and the modified Rankin scale (mRS). Additionally, some oligoclonal-positive patients underwent dynamic longitudinal analysis of cerebrospinal fluid test indices. The mRS score was ultimately employed to evaluate patients' short-term prognosis (6 months) and long-term prognosis (at least 12 months) following immunotherapy. Results: Of the 94 patients, 34 (36.2%) belonged to the OCB-positive group, while 60 (63.8%) belonged to the OCB-negative group. The group with anti-n-methyl-d-aspartate receptor (anti-NMDAR) encephalitis exhibited the highest rate of oligoclonal positivity at 27 (49.1%), followed by anti-aminobutyric acid B receptor (GABABR) encephalitis with 4 cases (30.8%), anti-contactin-associated protein-like 2 (CASPR2) encephalitis with 2 cases (20%), and anti-leucine-rich glioma inactivating protein 1 (LGI1) encephalitis with 1 case (6.25%). No statistically significant differences were found between the two groups regarding gender, age, prodromal symptoms, psychiatric disorders, seizures, language disorders, motor dysfunction, cognitive dysfunction, tumor incidence, and magnetic resonance imaging (MRI) abnormalities (p > 0.05). The OCB-positive group exhibited higher rates of autonomic dysfunction, intensive care unit (ICU) admission, CSF leukocytes, and IgG index compared to the OCB-negative group (p < 0.05). Additionally, the OCB-positive group had significantly higher median CASE and mRS scores prior to immunotherapy than the OCB-negative group (p < 0.001 and p < 0.001). Furthermore, in both short-term follow-up and long-term follow-up, the OCB-positive group had a significantly lower proportion of patients with a favorable prognosis compared to the OCB-negative group (50% vs. 71.7, 61.8% vs. 83.3%; p = 0.036, p = 0.002). Conclusion: Autonomic dysfunction, ICU admission, leukocytes in the cerebrospinal fluid, and elevated IgG index are more commonly observed in OCB-positive patients. OCB-positivity has also been linked to the severity and prognosis of AE, making it a potential biomarker. Initial OCB testing aids clinicians in identifying potentially critically ill patients early and monitoring disease progression, thereby optimizing clinical treatment decisions.

Single-cell transcriptomics reveals cell type-specific immune regulation associated with anti-NMDA receptor encephalitis in humans.

Introduction: Anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE) is a rare autoimmune disease, and the peripheral immune characteristics associated with anti-NMDARE antibodies remain unclear. Methods: Herein, we characterized peripheral blood mononuclear cells from patients with anti-NMDARE and healthy individuals by single-cell RNA sequencing (scRNA-seq). Results: The transcriptional profiles of 129,217 cells were assessed, and 21 major cell clusters were identified. B-cell activation and differentiation, plasma cell expansion, and excessive inflammatory responses in innate immunity were all identified. Patients with anti-NMDARE showed higher expression levels of CXCL8, IL1B, IL6, TNF, TNFSF13, TNFSF13B, and NLRP3. We observed that anti-NMDARE patients in the acute phase expressed high levels of DC_CCR7 in human myeloid cells. Moreover, we observed that anti-NMDARE effects include oligoclonal expansions in response to immunizing agents. Strong humoral immunity and positive regulation of lymphocyte activation were observed in acute stage anti-NMDARE patients. Discussion: This high-dimensional single-cell profiling of the peripheral immune microenvironment suggests that potential mechanisms are involved in the pathogenesis and recovery of anti-NMDAREs.

Associations of IFT20 and GM130 protein expressions with clinicopathological features and survival of patients with lung adenocarcinoma.

BACKGROUND: Lung cancer is the leading cause of malignancy-related mortality and lung adenocarcinoma accounts for about 40% of lung malignancies. The aim of this study was to investigate the associations of intraflagellar transport protein 20 (IFT20) and Golgi matrix protein 130 (GM130) expression with clinicopathological features and survival in patients with lung adenocarcinoma. METHODS: The expressions of IFT20 and GM130 protein in cancerous and matched adjacent lung tissues of 235 patients with lung adenocarcinoma were assessed by tissue microarray and immunohistochemistry, which were indicated by the mean optical density (IOD/area), the rate of positive staining cells and staining intensity score. The correlation between IFT20 and GM130 protein was assessed by Spearman's rank correlation. Associations of IFT20 and GM130 protein expression with clinicopathological features of patients were analyzed by multivariate logistic regression models. The survival analysis of patients was performed by Cox proportional hazard regression models. RESULTS: With adjustment for multiple potential confounders, each one-point increase in IFT20 protein staining intensity score was significantly associated with 32% and 29% reduced risk for TNM stage in II ~ IV and lymphatic metastasis of patients, respectively (P < 0.05). And each one-point increase in GM130 protein staining intensity score was associated with a significant reduction in the risk of poor differentiation and tumors size > 7 cm by 29% and 38% for lung adenocarcinoma patients, respectively (P < 0.05). In stratified Cox model analysis, enhanced IFT20 staining intensity score was significantly decreased the risk of death by 16% for patients without distant metastasis. And elevated the IOD/area of GM130 expression significantly decreased the death risk of lung adenocarcinoma patients with tumor size > 7 cm or distant metastasis by 54% and 65%, respectively (P < 0.05). CONCLUSION: IFT20 and GM130 protein expressions were negatively associated with tumor differentiated types, size, TNM stage and lymphatic metastasis of lung adenocarcinoma. Both IFT20 and GM130 proteins have some protective effects on the survival of lung adenocarcinoma patients with specific clinicopathological features.

Predictors of Lung Adenocarcinoma With Leptomeningeal Metastases: A 2022 Targeted-Therapy-Assisted molGPA Model.

Objective: To explore prognostic indicators of lung adenocarcinoma with leptomeningeal metastases (LM) and provide an updated graded prognostic assessment model integrated with molecular alterations (molGPA). Methods: A cohort of 162 patients was enrolled from 202 patients with lung adenocarcinoma and LM. By randomly splitting data into the training (80%) and validation (20%) sets, the Cox regression and random survival forest methods were used on the training set to identify statistically significant variables and construct a prognostic model. The C-index of the model was calculated and compared with that of previous molGPA models. Results: The Cox regression and random forest models both identified four variables, which included KPS, LANO neurological assessment, TKI therapy line, and controlled primary tumor, as statistically significant predictors. A novel targeted-therapy-assisted molGPA model (2022) using the above four prognostic factors was developed to predict LM of lung adenocarcinoma. The C-indices of this prognostic model in the training and validation sets were higher than those of the lung-molGPA (2017) and molGPA (2019) models. Conclusions: The 2022 molGPA model, a substantial update of previous molGPA models with better prediction performance, may be useful in clinical decision making and stratification of future clinical trials.

A novel prognostic signature of metastasis-associated genes and personalized therapeutic strategy for lung adenocarcinoma patients.

Lung adenocarcinoma (LUAD) is a highly invasive and metastatic malignant tumor with high morbidity and mortality. This study aimed to construct a prognostic signature for LUAD patients based on metastasis-associated genes (MAGs). RNA expression profiles were downloaded from the Cancer Genome Atlas (TCGA) database. RRA method was applied to identify differentially expressed MAGs. A total of 192 significantly robust MAGs were determined among seven GEO datasets. MAGs were initially selected through the Lasso Cox regression analysis and 6 MAGs were included to construct a prognostic signature model. Transcriptome profile, patient prognosis, correlation between the risk score and clinicopathological features, immune cell infiltration characteristics, immunotherapy sensitivity and chemotherapy sensitivity differed between low- and high-risk groups after grouping according to median risk score. The reliability and applicability of the signature were further validated in the GSE31210, GSE50081 and GSE68465 cohort. CMap predicted 62 small molecule drugs on the base of the prognostic MAGs. Targeted drug staurosporine had hydrogen bonding with Gln-172 of SLC2A1, which is one of MAGs. Staurosporine could inhibit cell migration in A549 and H1299. We further verified mRNA and protein expression of 6 MAGs in A549 and H1299. The signature can serve as a promising prognostic tool and may provide a novel personalized therapeutic strategy for LUAD patients.

Nanopore sequencing of cerebrospinal fluid of three patients with cryptococcal meningitis.

BACKGROUND: Cryptococcal meningitis (CM) has a high morbidity and mortality due to the low detection of Cryptococcus in cerebrospinal fluid (CSF) during the early stage of the disease with traditional methods. CASE PRESENTATION: In addition to the traditional methods of India ink staining and cryptococcal antigen (CrAg), we used nanopore sequencing and next-generation sequencing (NGS) to detect pathogenic DNA in CSF samples of three patients with CM. The CSF samples of all three patients were positive by India ink staining and CrAg. NGS also detected Cryptococcus in all three CSF samples. Nanopore sequencing detected Cryptococcus in two CSF samples. CONCLUSION: Nanopore sequencing may be useful in assisting with the clinical diagnosis of CM. Further research is needed to determine the sensitivity and specificity of nanopore sequencing of CSF.

Osimertinib Improves Overall Survival in Patients with Leptomeningeal Metastases Associated with EGFR-Mutated Non-Small-Cell Lung Cancer Regardless of Cerebrospinal Fluid T790M Mutational Status.

Osimertinib has demonstrated promising efficacy against leptomeningeal metastasis (LM) associated with T790M-positive non-small-cell lung cancer (NSCLC). However, the effect of cerebrospinal fluid's (CSF's) epidermal growth factor receptor (EGFR) T790M mutation on osimertinib efficacy remains unclear.Seventy-eight patients were studied with EGFR-mutated NSCLC and LM. Case data were collected and EGFR mutation status of circulating cell-free DNA from paired CSF, and plasma of 23 patients with LM was detected using droplet digital PCR. The median overall survival (mOS) was 8.08 months (95% CI: 6.07-10.09) in the study. Forty-four osimertinib-treated patients had an improved mOS of 13.15 (95% CI: 5.74-20.57) and a median progression-free survival (PFS) of 9.50 months (95% CI: 6.77-12.23) when compared with patients treated with first- or second-generation EGFR-TKI (mOS = 3.00 months (95% CI: 1.32-4.68) and median PFS = 1.50 months (95% CI: 0.00-3.14)). In the osimertinib group, mOS values for CSF with and without T790M mutation were 22.15 months (95% CI: 9.44-34.87) and 13.39 months (95% CI: 7.01-19.76), respectively, with no statistical differences. Regardless of the CSF T790M mutation status, osimertinib demonstrated significant efficacy against LM associated with NSCLC.

Development and validation of a novel epigenetic-related prognostic signature and candidate drugs for patients with lung adenocarcinoma.

BACKGROUND: Epigenetic dysregulation has been increasingly proposed as a hallmark of cancer. Here, the aim of this study is to establish an epigenetic-related signature for predicting the prognosis of lung adenocarcinoma (LUAD) patients. RESULTS: Five epigenetic-related genes (ERGs) (ARRB1, PARP1, PKM, TFDP1, and YWHAZ) were identified as prognostic hub genes and used to establish a prognostic signature. According our risk score system, LUAD patients were stratified into high and low risk groups, and patients in the high risk group had a worse prognosis. ROC analysis indicated that the signature was precise in predicting the prognosis. A new nomogram was constructed based on the five hub genes, which can predict the OS of every LUAD patients. The calibration curves showed that the nomogram had better accuracy in prediction. Finally, candidate drugs that aimed at hub ERGs were identified, which included 47 compounds. CONCLUSIONS: Our epigenetic-related signature nomogram can effectively and reliably predict OS of LUAD patients, also we provide precise targeted chemotherapeutic drugs. METHODS: The genomic data and clinical data of LUAD cohort were downloaded from the TCGA database and ERGs were obtained from the EpiFactors database. GSE31210 and GSE50081 microarray datasets were included as independent external datasets. Univariate Cox, LASSO regression, and multivariate Cox analyses were applied to construct the epigenetic-related signature.

Establishment and validation of a prognostic signature for lung adenocarcinoma based on metabolism-related genes.

BACKGROUND: Given that dysregulated metabolism has been recently identified as a hallmark of cancer biology, this study aims to establish and validate a prognostic signature of lung adenocarcinoma (LUAD) based on metabolism-related genes (MRGs). METHODS: The gene sequencing data of LUAD samples with clinical information and the metabolism-related gene set were obtained from The Cancer Genome Atlas (TCGA) and Molecular Signatures Database (MSigDB), respectively. The differentially expressed MRGs were identified by Wilcoxon rank sum test. Then, univariate cox regression analysis was performed to identify MRGs that related to overall survival (OS). A prognostic signature was developed by multivariate Cox regression analysis. Furthermore, the signature was validated in the GSE31210 dataset. In addition, a nomogram that combined the prognostic signature was created for predicting the 1-, 3- and 5-year OS of LUAD. The accuracy of the nomogram prediction was evaluated using a calibration plot. Finally, cox regression analysis was applied to identify the prognostic value and clinical relationship of the signature in LUAD. RESULTS: A total of 116 differentially expressed MRGs were detected in the TCGA dataset. We found that 12 MRGs were most significantly associated with OS by using the univariate regression analysis in LUAD. Then, multivariate Cox regression analyses were applied to construct the prognostic signature, which consisted of six MRGs-aldolase A (ALDOA), catalase (CAT), ectonucleoside triphosphate diphosphohydrolase-2 (ENTPD2), glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1), lactate dehydrogenase A (LDHA), and thymidylate synthetase (TYMS). The prognostic value of this signature was further successfully validated in the GSE31210 dataset. Furthermore, the calibration curve of the prognostic nomogram demonstrated good agreement between the predicted and observed survival rates for each of OS. Further analysis indicated that this signature could be an independent prognostic indicator after adjusting to other clinical factors. The high-risk group patients have higher levels of immune checkpoint molecules and are therefore more sensitive to immunotherapy. Finally, we confirmed six MRGs protein and mRNA expression in six lung cancer cell lines and firstly found that ENTPD2 might played an important role on LUAD cells colon formation and migration. CONCLUSIONS: We established a prognostic signature based on MRGs for LUAD and validated the performance of the model, which may provide a promising tool for the diagnosis, individualized immuno-/chemotherapeutic strategies and prognosis in patients with LUAD.

A Novel Metabolism-Related Signature as a Candidate Prognostic Biomarker for Hepatocellular Carcinoma.

PURPOSE: Given that metabolic reprogramming has been recognized as an essential hallmark of cancer cells, this study sought to investigate the potential prognostic values of metabolism-related genes (MRGs) for the diagnosis and treatment of hepatocellular carcinoma (HCC). METHODS: In total, 2752 metabolism-related gene sequencing data of HCC samples with clinical information were obtained from the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). One hundred and seventy-eight the differentially expressed MRGs were identified from the ICGC cohort and TCGA cohort. Then, univariate Cox regression analysis was performed to identify these genes that were related to overall survival (OS). A novel metabolism-related prognostic signature was developed using the least absolute shrinkage and selection operator (Lasso) and multivariate Cox regression analyses in the ICGC dataset. The Broad Institute's Connectivity Map (CMap) was used in predicting which compounds on the basis of the prognostic MRGs. Furthermore, the signature was validated in the TCGA dataset. Finally, the expression levels of hub genes were validated in HCC cell lines by Western blotting (WB) and quantitative real-time PCR (qRT-PCR). RESULTS: We found that 17 MRGs were most significantly associated with OS in HCC. Then, the Lasso and multivariate Cox regression analyses were applied to construct the novel metabolism-relevant prognostic signature, which consisted of six MRGs. The prognostic value of this prognostic model was further successfully validated in the TCGA dataset. Further analysis indicated that this particular signature could be an independent prognostic indicator after adjusting to other clinical factors. Six MRGs (FLVCR1, MOGAT2, SLC5A11, RRM2, COX7B2, and SCN4A) showed high prognostic performance in predicting HCC outcomes. Candidate drugs that aimed at hub ERGs were identified. Finally, hub genes were chosen for validation and the protein, mRNA expression of FLVCR1, SLC5A11, and RRM2 were significantly increased in human HCC cell lines compared to normal human hepatic cell lines, which were in agreement with the results of differential expression analysis. CONCLUSION: Our data provided evidence that the metabolism-related signature could serve as a reliable prognostic and predictive tool for OS in patients with HCC.

Clinico-pathologic determinants of non-e-curative outcome following en-bloc endoscopic submucosal dissection in patients with early gastric neoplasia.

BACKGROUND: Endoscopic submucosal dissection (ESD) is gaining enormous popularity in the treatment of early gastric cancers (EGCs) in many institutions across the world. However, appropriate selection of candidates for endoscopic resection is crucial to sufficiently mitigate non-e-curative (NEC) resection. This study aims at identifying the various clinico-pathologic factors that independently predict the NEC outcome and depth of submucosal invasion following ESD procedure in patients with EGC. METHODS: Multiple logistic regression analysis was applied to investigate factors that independently predict both non-curability phenomenon and the level of submucosal invasion in patients with early gastric neoplasia. Statistical Packages for the Social Sciences version 23 was used for analysis. RESULTS: A total of 153 patients (162 EGC lesions) underwent en-bloc ESD after which the rate of complete resection and non-e-curative outcome were 95% and 22.2%, correspondingly. Multivariate analysis depicted that tumor location in the upper two third of stomach (odds ratio [OR], 5.46; 95% confidence interval [95% CI], 1.65-18.12; p = 0.006), tumor size > 2 cm (OR, 7.63; 95% CI, 2.29-25.42; p = 0.001), histologically undifferentiated tumor (OR, 15.54; 95% CI, 1.65-146.22; p = 0.001), and tumors with 0-IIa/0-IIc or their mixed variants with predominant 0-IIa/0-IIc (OR, 9.77; 95% CI, 1.23-77.65; p = 0.031) were all independent predictors of NEC resection for early gastric tumors. Additionally, location in the upper two third of the stomach (OR, 8.88; 95% CI, 2.90-27.17; p < 0.001), ulcerated lesions (OR, 3.70; 95% CI, 1.15-11.90; p = 0.028), lesions with > 2 cm (OR, 2.94; 95% CI, 1.08-8.02; p = 0.036) and those with poor differentiation (OR, 6.51; 95% CI, 2.23-18.98; p = 0.001) were found to have significant association with submucosal invasion. CONCLUSIONS: Tumors located in the upper two third of the stomach having a larger size (> 2 cm), poor histo-differentiation and a gross type of 0-IIa/0-IIc or their mixed variants with predominant 0-IIa/0-IIc were significantly associated with a risk of NEC after ESD procedure. Thus, early gastric tumors displaying these features need to be handled carefully during endoscopic resection. Our findings may shed light on the pre-procedural detection of clinicopathologic factors that determine non-e-curability in patients with EGC.

A Novel Human Acute Encephalitis Caused by Pseudorabies Virus Variant Strain.

BACKGROUND: Pseudorabies virus (PRV) is a common pathogen in multiple animal species, particularly in pigs. However, PRV infection in humans is rare and, to the best of our knowledge, PRV has never been isolated from human cases before. METHODS: Four acute encephalitis cases in humans were confirmed as PRV infection based on clinical symptoms, laboratory diagnosis, and metagenomic next-generation sequencing (mNGS). Cerebrospinal fluid (CSF) samples were collected and applied for virus isolation. Etiological and genetic characteristics of this PRV human isolate were further determined. RESULTS: The patients manifested respiratory dysfunction and acute neurological symptoms. The mNGS revealed PRV-specific nucleotide sequences in patients' CSF samples (7-6198 reads and 0.2446%-80.58% coverage). The PRV envelope glycoprotein B antibody, glycoprotein E antibody, and neutralizing antibody were positively detected. For the first time, a PRV strain, designated hSD-1/2019, was isolated and identified from a CSF sample, and transmission electron microscopy revealed that hSD-1/2019 had typical morphology similar to that of swine PRV. Phylogenetic analysis illustrated that hSD-1/2019 was genetically closest to those PRV variant strains currently circulating in pigs in China, and this strain showed similar etiological characteristics to Chinese PRV variant strains, while different from Chinese classical strain. Moreover, hSD-1/2019 showed high pathogenicity and induced acute neurological symptoms in pigs. CONCLUSIONS: A PRV strain was isolated from an acute human encephalitis case. This isolate showed close phylogenetic relationships and similar etiological characteristics to Chinese PRV variant strains, implying the great risk of PRV transmission from pigs to humans.

Carbon black nanoparticles induce HDAC6-mediated inflammatory responses in 16HBE cells.

Long-term inhalation of carbon black nanoparticles (CBNPs) leads to pulmonary inflammatory diseases. Histone deacetylase 6 (HDAC6) has been identified as an important regulator in the development of inflammatory disorders. However, the direct involvement of HDAC6 in CBNPs-induced pulmonary inflammatory responses remains unclear. To explore whether HDAC6 participates in CBNPs-induced pulmonary inflammation, human bronchial epithelial cell line (16HBE cells) was transfected with HDAC6 small interference RNA (siRNA) and then exposed to CBNPs at concentrations of 0, 25, and 50 µg/ml for 24 h. Intracellular HDAC6 and intraflagellar transport protein 88 (IFT88) mRNA and protein were determined by real-time polymerase chain reaction and Western blot, respectively. The secretions of inflammatory cytokines including interleukin (IL)-8, tumor necrosis factor (TNF)-α, IL-6, and IL-1ß were measured by enzyme-linked immunosorbent assay. CBNPs induced a significant increase in the expressions of IL-8 and IL-6, accompanied by a high level of intracellular HDAC6 mRNA when compared with a blank control group (p < 0.05). However, there were no significant changes in the levels of TNF-α secretion, intracellular HDAC6 and IFT88 protein induced by CBNPs (p > 0.05). The HDAC6 mRNA expression was significantly suppressed in HDAC6 siRNA-transfected cells (p < 0.05). The secretions of IL-8, TNF-α, and IL-6 were significantly less in HDAC6 siRNA-transfected cells than that in normal 16HBE cells with exposure to 25 or 50 µg/ml of CBNPs, but intracellular IFT88 mRNA expression was markedly increased in HDAC6 siRNA-transfected cells when compared with normal 16HBE cells exposed to 50 µg/ml of CBNPs (all p < 0.05). Downregulation of the HDAC6 gene inhibits CBNPs-induced inflammatory responses in bronchial epithelial cells, partially through regulating IFT88 expression. It is suggested that CBNPs may trigger inflammatory responses in bronchial epithelial cells by an HDAC6/IFT88-dependent pathway.

Toward enhanced photocatalytic activity of graphite carbon nitride through rational design of noble metal-free dual cocatalysts.

The g-C3N4-MoS2-M(OH)x ternary heterostructures were designed and fabricated for the first time. The embedding of noble-metal-free MoS2-M(OH)x dual cocatalysts over g-C3N4 nanosheets led to obvious synergistic effect for improving the transport as well as utilization efficiency of photo-generated charge carriers. Consequently, the optimal ternary heterostructure (g-C3N4-MoS2-Ni(OH)2) exhibited photocatalytic hydrogen production activity 4.5 times larger than the sum of the photocatalytic HER activity of g-C3N4-MoS2 and g-C3N4-Ni(OH)2. More significantly, even in the absence of the sacrificial agent, the g-C3N4-MoS2-Ni(OH)2 ternary heterostructure exhibited a photocatalytic HER activity of 0.3 mmol h-1 g-1 with considerable H2O2 production under UV-visible light.