From bench to bedside: targeting lymphocyte activation gene 3 as a therapeutic strategy for autoimmune diseases.

BACKGROUND: Immune checkpoints negatively regulate immune response, thereby playing an important role in maintaining immune homeostasis. Substantial studies have confirmed that blockade or deficiency of immune checkpoint pathways contributes to the deterioration of autoimmune diseases. In this context, focusing on immune checkpoints might provide alternative strategies for the treatment of autoimmunity. Lymphocyte activation gene 3 (LAG3), as a member of immune checkpoint, is critical in regulating immune responses as manifested in multiple preclinical studies and clinical trials. Recent success of dual-blockade of LAG3 and programmed death-1 in melanoma also supports the notion that LAG3 is a crucial regulator in immune tolerance. METHODS: We wrote this review article by searching the PubMed, Web of Science and Google Scholar databases. CONCLUSION: In this review, we summarize the molecular structure and the action mechanisms of LAG3. Additionally, we highlight its roles in diverse autoimmune diseases and discuss how the manipulation of the LAG3 pathway can serve as a promising therapeutic strategy as well as its specific mechanism with the aim of filling the gaps from bench to bedside.

Agomir miRNA-150-5p alleviates pristane-induced lupus by suppressing myeloid dendritic cells activation and inflammation via TREM-1 axis.

OBJECTIVE: Triggering receptors expressed on myeloid cells-1 (TREM-1) has been shown to participate in inflammatory autoimmune diseases. Nevertheless, the detailed underlying mechanisms and therapeutic benefits by targeting TREM-1 remain elusive, especially in myeloid dendritic cells (mDCs) and systemic lupus erythematosus (SLE). Disorders of epigenetic processes including non-coding RNAs give rise to SLE, resulting in complicated syndromes. Here, we aim to address this issue and explore the miRNA to inhibit the activation of mDCs and alleviate the progress of SLE by targeting TREM-1 signal axis. METHODS: Bioinformatics methods were used to analyze the differentially expressed genes (DEGs) between patients with SLE and healthy individuals by four mRNA microarray datasets from Gene Expression Omnibus (GEO). Then we identified the expression of TREM-1 and its soluble form (sTREM-1) in clinical samples by ELISA, quantitative real-time PCR and Western blot. Phenotypic and functional changes of mDCs elicited by TREM-1 agonist were determined. Three databases of miRNAs target prediction and a dual-luciferase reporter assay were used to screen and verify miRNAs that can directly inhibit TREM-1 expression in vitro. Moreover, pristane-induced lupus mice were injected with miR-150-5p agomir to evaluate the effects of miR-150-5p on mDCs in lymphatic organs and disease activity in vivo. RESULTS: We screened TREM-1 as one of the hub genes closely correlated with the progression of SLE and identified sTREM-1 in serum as a valuable diagnostic biomarker for SLE. Moreover, activation of TREM-1 by its agonist promoted activation and chemotaxis of mDCs and increased the production of inflammatory cytokines and chemokines, showing higher expression of IL-6, TNF-α, and MCP-1. We showed that lupus mice displayed a unique miRNA signature in spleen, among which miR-150 was the most significantly expressed miRNA that targeting TREM-1 compared with wild type group. Transfection of miRNA-150-5p mimics directly suppressed the expression of TREM-1 by binding to its 3' UTR. Our in vivo experiments first indicated that administration of miR-150-5p agomir effectively ameliorated lupus symptoms. Intriguingly, miR-150 inhibited the over activation of mDCs through TREM-1 signal pathway in lymphatic organs and renal tissues. CONCLUSIONS: TREM-1 represents a potentially novel therapeutic target and we identify miR-150-5p as one of the mechanisms to alleviate lupus disease, which is attributable for inhibiting mDCs activation through TREM-1 signaling pathway.

Kaistella flava sp. nov., isolated from Antarctic tundra soil, and emended descriptions of Kaistella yonginensis, Kaistella jeonii, Kaistella antarctica and Kaistella chaponensis.

A rod-shaped, yellow-pigmented, Gram-stain-negative, non-motile and aerobic bacterium, designated 7-3AT, was isolated from soil from King George Island, maritime Antarctica, and subjected to a polyphasic taxonomic study. Growth occurred at 4-37 °C (optimum, 20°C) and at pH 5.0-9.0 (optimum, pH 7.0-8.0). Tolerance to NaCl was up to 4 % (w/v) with optimum growth in the absence of NaCl. The results of phylogenetic analysis based on 16S rRNA gene sequences indicated that strain 7-3AT represented a member of the family Flavobacteriaceae. Strain 7-3AT showed the highest sequence similarities with Kaistella yonginensis HMD 1043T (96.65 %), Kaistella carnis NCTC 13525T (96.53 %), Kaistella chaponensis DSM 23145T (96.27 %), Kaistella antarctica LMG 24720T (96.13 %) and Kaistella jeonii DSM 17048T (96.06 %). A whole genome-level comparison of 7-3AT with K. jeonii DSM 17048T, K. antarctica LMG 24720T, K. chaponensis DSM 23145T, and Kaistella palustris DSM 21579T revealed average nucleotide identity (ANI) values of 79.03, 82.25, 78.12, and 74.42 %, respectively. The major respiratory isoprenoid quinone was identified as MK-6 and a few ubiquinones Q-10 were identified. In addition, flexirubin-type pigments were absent. The polar lipid profile of 7-3AT was found to contain one phosphatidylethanolamine, six unidentified aminolipids (AL) and two unidentified lipids (L). The G+C content of the genomic DNA was determined to be 34.54 mol%. The main fatty acids were iso-C15 : 0, summed feature 9 (comprising iso-C17 : 1ω9c and/or C16 : 0 10-methyl), anteiso-C15 : 0, iso-C13 : 0 and summed feature 3 (comprising C16 : 1ω7c and/or C16 : 1ω6c). On the basis of the evidence presented in this study, a novel species of the genus Kaistella, Kaistella flava sp. nov., is proposed, with the type strain 7-3AT (=CCTCC AB 2016141T= KCTC 52492T). Emended descriptions of Kaistella yonginensis, Kaistella jeonii, Kaistella antarctica and Kaistella chaponensis are also given.

Spirosoma flavum sp. nov., isolated from Arctic tundra soil.

A yellow-pigmented strain, designated Y4AR-5T, was characterized by using a polyphasic approach. The strain was isolated from a tundra soil from near Longyearbyen, Svalbard Islands, Norway. The cells were Gram-stain-negative, aerobic, rod-shaped and non-motile. Growth occurred at 4-28 °C (optimum 20 °C) and pH 6.0-9.0 (optimum pH 8.0) and with 0-0.5 % (w/v) NaCl (optimum 0 %). The major respiratory quinone was MK-7. The polar lipids were phosphatidylethanolamine (PE), an aminophospholipid (APL), a phospholipid (PL), an unidentified aminolipid (AL) and two unidentified lipids. The results of analysis of the 16S rRNA gene indicated that the novel strain was most closely related to members of the genus Spirosoma (96.2 % sequence similarity with Spirosoma endophyticum). The genomic DNA G+C content was 45.9 mol%. The major cellular fatty acids were summed feature 3 (C16 : 1ω7c and/or C16 : 1ω6c), C16 : 1ω5c, iso-C17 : 0 3-OH and iso-C15 : 0. On the basis of its phenotypic and genotypic properties, strain Y4AR-5T should be classified as representing a novel species of the genus Spirosoma, for which the name Spirosomaflavum sp. nov. is proposed. The type strain is Y4AR-5T (=CCTCC AB 2015352T=KCTC 52490T).

Association between type 2 diabetes, alcohol intake frequency, age at menarche, and gallbladder cancer: a two-sample Mendelian randomization study.

Background: Gallbladder cancer (GBC) is a rare malignancy of the digestive tract, characterized by a remarkably poor prognosis. Currently, there is a controversy on the relationship between type 2 diabetes (T2D) and GBC. Additionally, no definitive conclusions were established regarding the causal relationships between alcohol intake frequency (AIF), age at menarche (AAM) and GBC. The objective of this study was to elucidate the causal association between T2D, AIF, AAM, and GBC. Methods: Single-nucleotide polymorphisms (SNPs) associated with exposures and outcomes were sourced from the Integrative Epidemiology Unit (IEU) Open Genome-Wide Association Study (GWAS) database. Specifically, the data of GBC comprised 907 East Asians (pathological results of all cases were registered into Biobank Japan) and 425,707 SNPs; T2D comprised 655,666 Europeans with 5,030,727 SNPs; AIF comprised 462,346 Europeans and 9,851,867 SNPs; AAM comprised 243,944 Europeans and 9,851,867 SNPs. The measurement of exposure traits is collected uniformly from the UK Biobank (UKB) database and presented in the form of standard deviation (SD) or the logarithmic form of the odds ratio (logOR). We employed a two-sample Mendelian randomization (MR) analysis to discern the causalities between T2D, AIF, AAM, and GBC. Sensitivity analyses were conducted to identify and address potential heterogeneity, horizontal pleiotropy, and outliers. Results: Our findings indicated that T2D reduced GBC risk [odds ratio (OR) =0.044; 95% confidence interval (CI): 0.004-0.55; P=0.015, inverse variance-weighted (IVW)]. However, no causal relationship was observed between AIF (OR =0.158; 95% CI: 5.33E-05 to 466.84; P=0.65, IVW), AAM (OR =0.19; 95% CI: 0.0003-140.34; P=0.62, IVW), and GBC. Sensitivity analysis revealed no evidence of horizontal pleiotropy, heterogeneity, or outliers, suggesting the robustness and reliability of our conclusions. Conclusions: T2D emerged as a potentially protective factor against GBC, whereas neither AIF nor AAM demonstrated a causal relationship with GBC risk. Regulation of glucose metabolism may be one of the methods for preventing GBC.

Molecular pathway of mitochondrial preprotein import through the TOM-TIM23 supercomplex.

Over half of mitochondrial proteins are imported from the cytosol via the pre-sequence pathway, controlled by the TOM complex in the outer membrane and the TIM23 complex in the inner membrane. The mechanisms through which proteins are translocated via the TOM and TIM23 complexes remain unclear. Here we report the assembly of the active TOM-TIM23 supercomplex of Saccharomyces cerevisiae with translocating polypeptide substrates. Electron cryo-microscopy analyses reveal that the polypeptide substrates pass the TOM complex through the center of a Tom40 subunit, interacting with a glutamine-rich region. Structural and biochemical analyses show that the TIM23 complex contains a heterotrimer of the subunits Tim23, Tim17 and Mgr2. The polypeptide substrates are shielded from lipids by Mgr2 and Tim17, which creates a translocation pathway characterized by a negatively charged entrance and a central hydrophobic region. These findings reveal an unexpected pre-sequence pathway through the TOM-TIM23 supercomplex spanning the double membranes of mitochondria.

Laparoscopic vs open radical resection in management of gallbladder carcinoma: A systematic review and meta-analysis.

BACKGROUND: Radical resection offers the only hope for the long-term survival of patients with gallbladder carcinoma (GBC) above the T1b stage. However, whether it should be performed under laparoscopy for GBC is still controversial. AIM: To compare laparoscopic radical resection (LRR) with traditional open radical resection (ORR) in managing GBC. METHODS: A comprehensive search of online databases, including Medline (PubMed), Cochrane Library, and Web of Science, was conducted to identify comparative studies involving LRR and ORR in GBCs till March 2023. A meta-analysis was subsequently performed. RESULTS: A total of 18 retrospective studies were identified. In the long-term prognosis, the LRR group was comparable with the ORR group in terms of overall survival and tumor-free survival (TFS). LRR showed superiority in terms of TFS in the T2/tumor-node-metastasis (TNM) Ⅱ stage subgroup vs the ORR group (P = 0.04). In the short-term prognosis, the LRR group had superiority over the ORR group in the postoperative length of stay (POLS) (P < 0.001). The sensitivity analysis showed that all pooled results were robust. CONCLUSION: The meta-analysis results show that LRR is not inferior to ORR in all measured outcomes and is even superior in the TFS of patients with stage T2/TNM Ⅱ disease and POLS. Surgeons with sufficient laparoscopic experience can perform LRR as an alternative surgical strategy to ORR.

Evaluation of PD-L1 as a biomarker for immunotherapy for hepatocellular carcinoma: systematic review and meta-analysis.

Aim: To determine if PD-L1 can be used as a biomarker to predict the efficacy of anti-PD-1/PD-L1 inhibitors in hepatocellular carcinoma (HCC). Methods: Relevant studies from a specific search of the four databases from October 2014 to December 2022 were included in this meta-analysis. Results: Higher PD-L1 expression levels were associated with a higher objective response rate (ORR). Higher PD-L1 expression levels on tumor cells and tumor proportion score were associated with higher ORR. PD-L1 was capable of predicting the effectiveness of nivolumab. Dako 28-8 is a promising assay for HCC. Conclusion: PD-L1 is a predictive biomarker for ORR in HCC. Tumor proportion score and PD-L1 expression levels on tumor cells are potential scoring algorithms.

Clinically, liver cancer patients with high PD-L1 levels may not benefit from immunotherapy. Conversely, some patients with low PD-L1 level can benefit from it. Therefore, the concept of PD-L1 as a predictive indicator in liver cancer is defective. Whether PD-L1 can serve as an indicator in liver cancer patients receiving immunotherapy needs urgent confirmation. In this work, we evaluated the feasibility of PD-L1 as a prognostic biomarker for immunotherapy. The results suggested that high expression of PD-L1 by tumor cells rather than tumor tissue was correlated with better prognosis.

Novel Immune Checkpoints in Esophageal Cancer: From Biomarkers to Therapeutic Targets.

Esophageal cancer ranks as the sixth most common cause of cancer death worldwide. Due to the limited efficacy of conventional therapeutic strategies, including surgery, chemotherapy, and radiotherapy, treatments are still far from satisfactory in terms of survival, prompting the search for novel treatment methods. Immune checkpoints play crucial roles in immune evasion mediated by tumor cells, and successful clinical outcomes have been achieved via blocking these pathways. However, only a small fraction of patients can benefit from current immune checkpoint inhibitors targeting programmed cell death ligand-1 (PD-L1) and cytotoxic T-lymphocyte-associated protein-4. Unfortunately, some patients show primary and/or acquired resistance to immune checkpoint inhibitors. Until now, novel immune checkpoint pathways have rarely been studied in esophageal cancer, and there is a great need for biomarkers to predict who will benefit from existing strategies. Herein, we primarily discuss the roles of new immune checkpoints as predictive biomarkers and therapeutic targets for esophageal cancer. In addition, we summarize the ongoing clinical trials and provide future research directions targeting these pathways.

Enhanced Recovery Care vs. Traditional Care in Laparoscopic Hepatectomy: A Systematic Review and Meta-Analysis.

Background: Enhanced recovery care could alleviate surgical stress and accelerate the recovery rates of patients. Previous studies showed the benefits of enhanced recovery after surgery program in liver surgery, but the exact role in laparoscopic hepatectomy is still unclear. Aim: We aimed to perform a meta-analysis to evaluate the safety and efficacy of enhanced recovery after a surgery program in laparoscopic hepatectomy. Methods: The relative studies from a specific search of PUBMED, EMBASE, OVID, and Cochrane database from June 2008 to February 2022 were selected and included in this meta-analysis. The primary outcomes included length of hospital stay, duration to functional recovery, and overall postoperative complication rate. The secondary outcomes included operative time, intraoperative blood loss, cost of hospitalization, readmission rate, Grade I complication rate, and Grade II-V complication rate. Results: A total of six studies with 643 patients [enhanced recovery care (n = 274) vs. traditional care (n = 369)] were eligible for analysis. These comprised three randomized controlled trials and three retrospective studies. Enhanced recovery care group was associated with decreased hospital stay [standard mean difference (SMD) = -0.56, 95% confidence interval (CI) = -0.83~-0.28, p < 0.0001], shorter duration to functional recovery (SMD = -1.14, 95% CI = -1.92~-0.37, p = 0.004), and lower cost of hospitalization Mean Difference (MD) = -1,539.62, 95% CI = -1992.85~-1086.39, p < 0.00001). Moreover, a lower overall postoperative complication rate was observed in enhanced recovery care group [Risk ratio (RR) = 0.64, 95% CI = 0.51~0.80, p < 0.0001] as well as lower Grade II-V complication rate (RR = 0.55, 95% CI = 0.38~0.80, p = 0.002), while there was no significant difference in intraoperative blood loss (MD = -65.75, 95% CI = -158.47~26.97, p = 0.16), operative time (MD = -5.44, 95% CI = -43.46~32.58, p = 0.78), intraoperative blood transfusion rate [Odds ratio (OR) = 0.71, 95% CI = 0.41~1.22, p = 0.22], and Grade I complication rate (RR = 0.73, 95% CI = 0.53~1.03, p = 0.07). Conclusion: Enhanced recovery care in laparoscopic hepatectomy should be recommended, because it is not only safe and effective, but also can accelerate the postoperative recovery and lighten the financial burden of patients.

Artificial intelligence in gastroenterology and hepatology: Status and challenges.

Originally proposed by John McCarthy in 1955, artificial intelligence (AI) has achieved a breakthrough and revolutionized the processing methods of clinical medicine with the increasing workloads of medical records and digital images. Doctors are paying attention to AI technologies for various diseases in the fields of gastroenterology and hepatology. This review will illustrate AI technology procedures for medical image analysis, including data processing, model establishment, and model validation. Furthermore, we will summarize AI applications in endoscopy, radiology, and pathology, such as detecting and evaluating lesions, facilitating treatment, and predicting treatment response and prognosis with excellent model performance. The current challenges for AI in clinical application include potential inherent bias in retrospective studies that requires larger samples for validation, ethics and legal concerns, and the incomprehensibility of the output results. Therefore, doctors and researchers should cooperate to address the current challenges and carry out further investigations to develop more accurate AI tools for improved clinical applications.

Cystatin C for predicting all-cause mortality and rehospitalization in patients with heart failure: a meta-analysis.

Circulating cystatin C (cys-C/CYC) has been identified as an independent predictor of all-cause mortality in patients with coronary artery disease and the general population. This meta-analysis aimed to systematically evaluate the association between elevated cys-C level and all-cause mortality and rehospitalization risk amongst patients with heart failure (HF). PubMed and Embase databases were searched until December 2017. All prospective observational studies that reported a multivariate-adjusted risk estimate of all-cause mortality and/or rehospitalization for the highest compared with lowest cys-C level in HF patients were included. Ten prospective studies involving 3155 HF patients were included. Meta-analysis indicated that the highest compared with lowest cys-C level was associated with an increased risk of all-cause mortality (hazard ratio (HR): 2.33; 95% confidence intervals (CI): 1.67-3.27; I2  = 75.0%, P<0.001) and combination of mortality/rehospitalization (HR: 2.06; 95%CI: 1.58-2.69; I2  = 41.6%, P=0.181). Results of stratified analysis indicated that the all-cause mortality risk was consistently found in the follow-up duration, cys-C cut-off value or type of HF subgroup. Elevated cys-C level is possibly associated with an increased risk of all-cause mortality and rehospitalization in HF patients. This increased risk is probably independent of creatinine or estimated glomerular filtration rate (eGFR).

[Effects of riboflavin combined with photosensitization on reduction of Gram-positive and Gram-negative indicating germs in plasma and P-selectin expression of apheresis platelet concentrates].

This study was purposed to confirm the practical efficacy of reducing indicating germs suspended in plasma by riboflavin and photosensitized inactivation and to evaluate its influence on activation of apheresis platelet concentrates. The synergistic effects of riboflavin combined with ultraviolet irradiation on inactivation of germs were investigated by using Escherichia Coli (E. coli) and Staphylococcus Aureus (S. aureus) as Gram⁻ and Gram(+) indicating germs, respectively. The activation status of apheresis-platelet concentrates treated with riboflavin combined with ultraviolet irradiation was detected by flow cytometry. The results showed that when 50 µmol/L of riboflavin was combined with 6.2 J/ml of ultraviolet irradiation, the T/E ratios reached 1.42 for E. coli and 1.68 for S. Aureus, and reduction of E. Coli and S. Aureus were 3.87 Logs and 3.82 Logs respectively; the CD62p expression level on germ-inactivated platelets stored at 22 degrees C for 0 and 5 days were 4.92% and 36.18% respectively, which slightly increased as compared with controls (3.94% and 32.03)% (p < 0.05). It is concluded that combination of riboflavin with ultraviolet irradiation displays well synergistic effects which can reduce E. Coli and S. Aureus counts, but no significantly influence on platelets. The partial activation of liquid platelets mainly presents metabolism damage during storage, which is found at an acceptable level.