Unraveling the prognostic significance of RGS gene family in gastric cancer and the potential implication of RGS4 in regulating tumor-infiltrating fibroblast.

Regulator of G-protein signaling (RGS) proteins are regulators of signal transduction mediated by G protein-coupled receptors (GPCRs). Current studies have shown that some molecules in the RGS gene family are related to the occurrence, development and poor prognosis of malignant tumors. However, the RGS gene family has been rarely studied in gastric cancer. In this study, we explored the mutation and expression profile of RGS gene family in gastric cancer, and evaluated the prognostic value of RGS expression. Then we established a prognostic model based on RGS gene family and performed functional analysis. Further studies showed that RGS4, as an independent prognostic predictor, may play an important role in regulating fibroblasts in the immune microenvironment. In conclusion, this study explores the value of RGS gene family in gastric cancer, which is of great significance for predicting the prognosis and guiding the treatment of gastric cancer.

The regulation and potential role of interleukin-32 in tuberculous pleural effusion.

The possible protective effect of interleukin-32 (IL-32) in Mycobacterium tuberculosis (Mtb) infection has been indicated. However, few studies have been focused on IL-32 in tuberculosis patients. Additionally, the regulation of IL-32 production has rarely been reported. In the present study, the production, regulation, and role of IL-32 in tuberculous pleurisy (TBP) were investigated. We found that the content of IL-32 in tuberculous pleural effusion (TPE) was higher than the level in the malignant pleural effusion and transudative pleural effusion. The level of IL-32 mRNA in pleural fluid mononuclear cells (PFMCs) was higher than that in peripheral blood mononuclear cells (PBMCs) of patients with TBP, and this difference was mainly reflected in the splice variants of IL-32α, IL-32ß, and IL-32γ. Compared with the PBMCs, PFMCs featured higher IL-32ß/IL-32γ and IL-32α/IL-32γ ratios. In addition, lipopolysaccharide (LPS), Bacillus Calmette-Guérin (BCG), and H37Ra stimulation could induce IL-32 production in the PFMCs. IL-32 production was positively correlated with the TNF-α, IFN-γ, and IL-1Ra levels in TPE, whereas IFN-γ, but not TNF-α or IL-1Ra, could induce the production of IL-32 in PFMCs. Furthermore, IL-32γ could induce the TNF-α production in PFMCs. Monocytes and macrophages were the main sources of IL-32 in PFMCs. Nevertheless, direct cell-cell contact between lymphocytes and monocytes/macrophages plays an important role in enhancing IL-32 production by monocyte/macrophage cells. Finally, compared with the non-tuberculous pleural effusion, the purified CD4+ and CD8+ T cells in TPE expressed higher levels of intracellular IL-32. Our results suggested that, as a potential biomarker, IL-32 may play an essential role in the protection against Mtb infection in patients with TBP. However, further studies need to be carried out to clarify the functions and mechanisms of the IFN-γ/IL-32/TNF-α axis in patients with TBP.

Dual immunotherapy in advanced or metastatic non-small cell lung cancer: A network meta-analysis.

Objectives: Recently, there has been extensive research on dual immunotherapy for advanced or metastatic non-small cell lung cancer (NSCLC), yet a comprehensive evaluation is lacking. This study aimed to rank the available treatment options and assess the efficacy and safety of dual immunotherapy regimens through the implementation of a Bayesian network meta-analysis (NMA). Materials and methods: A thorough search was conducted to recognize eligible randomized controlled trials (RCTs) on March 20, 2023. Overall survival (OS), progression-free survival (PFS), treatment-related adverse events (TRAEs) and grade ≥3 TRAEs were evaluated to identify the efficacy and safety of dual immunotherapy regimens. The surface under the cumulative ranking curve (SUCRA) and P score were employed to rank the treatments. Results: Eleven clinical trials involving six different regimens were included in this study. The combination of anti-programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) antibodies with anti-T-cell immunoglobulin and ITIM domain (TIGIT) antibodies emerged as the most promising regimen for improving OS and PFS, followed by anti-PD-1/PD-L1 + anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) + chemotherapy treatment and anti-PD-1/PD-L1 + anti-CTLA-4 treatment. The forest plots demonstrated that these three regimens were all superior to chemotherapy. The above results were observed in both unselected treatment line and first-line settings. The least likely to be associated with TRAEs and grade ≥3 TRAEs were respectively anti-CTLA-4 treatment and anti-PD-1/PD-L1 + anti-TIGIT treatment, with anti-PD-1/PD-L1 + anti-CTLA-4 + chemotherapy treatment to be the worst. Conclusions: This NMA validated the promising efficacy and safety of dual immunotherapy in advanced or metastatic NSCLC. Among them, anti-PD-1/PD-L1 + anti-TIGIT regimen emerges as a highly potential therapeutic approach. Ongoing research efforts should focus on improving treatment regimens, identifying biomarkers, and managing TRAEs to optimize the patient benefits of dual immunotherapy.

Molecular Insights into the Differential Effects of Acetylation on the Aggregation of Tau Microtubule-Binding Repeats.

Aggregation of tau protein into intracellular fibrillary inclusions is characterized as the hallmark of tauopathies, including Alzheimer's disease and chronic traumatic encephalopathy. The microtubule-binding (MTB) domain of tau, containing either three or four repeats with sequence similarities, plays an important role in determining tau's aggregation. Previous studies have reported that abnormal acetylation of lysine residues displays a distinct effect on the formation of pathological tau aggregates. However, the underlying molecular mechanism remains mostly elusive. In this study, we performed extensive replica exchange molecular dynamics (REMD) simulations of 144 µs in total to systematically investigate the dimerization of four tau MTB repeats and explore the impacts of Lys280 (K280) or Lys321 (K321) acetylation on the conformational ensembles of the R2 or R3 dimer. Our results show that R3 is the most prone to aggregation among the four repeats, followed by R2 and R4, while R1 displays the weakest aggregation propensity with a disordered structure. Acetylation of K280 could promote the aggregation of R2 peptides by increasing the formation of ß-sheet structures and strengthening the interchain interaction. However, K321 acetylation decreases the ß-sheet content of the R3 dimer, reduces the ability of R3 peptides to form long ß-strands, and promotes the stable helix structure formation. The salt bridge and Y310-Y310 π-π stacking interactions of the R3 dimer are greatly weakened by K321 acetylation, resulting in the inhibition of dimerization. This study uncovers the structural ensembles of tau MTB repeats and provides mechanistic insights into the influences of acetylation on tau aggregation, which may deepen the understanding of the pathogenesis of tauopathies.

The bibliometric and altmetric analysis of chronic traumatic encephalopathy research: how great is the impact?

Background: The study of chronic traumatic encephalopathy (CTE) has received great attention from academia and the general public. This study aims to analyze the research productivity on CTE and investigate the most discussed articles in academia and the general public by conducting bibliometric and altmetric analyses. Methods: Data of articles were obtained from the Web of Science Core Databases and Altmetric Explore. VOSviewer and CiteSpace software were used to analyze and visualize the articles. The correlation between Altmetric attention scores (AAS) and citation counts were assessed by Spearman correlation coefficient. Results: 788 publications of CTE were eventually gathered and analyzed, and 100 articles with highest citation counts (Top-cited) and 100 articles with highest AASs (Top-AAS) were then identified. The keywords density map showed both the general public and the scientists were particularly interested in the risk factors and pathology of CTE, and scientists were interested in the causes and characteristics of neurodegenerative diseases while the public became increasingly concerned about the detection and prevention of CTE. By examining the shared characteristics of the 44 articles (High-High articles) that overlapped between Top-cited and Top-AAS articles, we identified certain traits that may potentially contribute to their high citation rates and high AASs. Besides, significant positive correlations with varied strength between AAS and citation were observed in the 788 articles, Top-cited, Top-AAS and High-High datasets. Conclusion: This study is the first to link bibliometric and altmetric analyses for CTE publications, which may provide deeper understanding of the attention of the scientists and the general public pay to the study of CTE, and offer some guidance and inspiration for future CTE in the selection of research topics and directions.

Genome-Wide Analysis of MBF1 Family Genes in Five Solanaceous Plants and Functional Analysis of SlER24 in Salt Stress.

Multiprotein bridging factor 1 (MBF1) is an ancient family of transcription coactivators that play a crucial role in the response of plants to abiotic stress. In this study, we analyzed the genomic data of five Solanaceae plants and identified a total of 21 MBF1 genes. The expansion of MBF1a and MBF1b subfamilies was attributed to whole-genome duplication (WGD), and the expansion of the MBF1c subfamily occurred through transposed duplication (TRD). Collinearity analysis within Solanaceae species revealed collinearity between members of the MBF1a and MBF1b subfamilies, whereas the MBF1c subfamily showed relative independence. The gene expression of SlER24 was induced by sodium chloride (NaCl), polyethylene glycol (PEG), ABA (abscisic acid), and ethrel treatments, with the highest expression observed under NaCl treatment. The overexpression of SlER24 significantly enhanced the salt tolerance of tomato, and the functional deficiency of SlER24 decreased the tolerance of tomato to salt stress. SlER24 enhanced antioxidant enzyme activity to reduce the accumulation of reactive oxygen species (ROS) and alleviated plasma membrane damage under salt stress. SlER24 upregulated the expression levels of salt stress-related genes to enhance salt tolerance in tomato. In conclusion, this study provides basic information for the study of the MBF1 family of Solanaceae under abiotic stress, as well as a reference for the study of other plants.

Light-Induced TaHY5-7A and TaBBX-3B Physically Interact to Promote PURPLE PERICARP-MYB 1 Expression in Purple-Grained Wheat.

Purple-grained wheat (Triticum aestivum L.) is an important germplasm source in crop breeding. Anthocyanin biosynthesis in the pericarps of purple-grained wheat is largely light-dependent; however, the regulatory mechanisms underlying light-induced anthocyanin accumulation in the wheat pericarp remain unknown. Here we determined that anthocyanins rapidly accumulate in the pericarps of the purple-grained wheat cultivar Heixiaomai 76 (H76) at 16 days after pollination under light treatment. Using transcriptome sequencing, differential gene expression analysis, and phylogenetic analysis, we identified two key genes involved in light signaling in wheat: ELONGATED HYPOCOTYL 5-7A (TaHY5-7A) and B-BOX-3B (TaBBX-3B). TaHY5-7A and TaBBX-3B were highly expressed in purple-grained wheat pericarps. The heterologous expression of TaHY5-7A partially restored the phenotype of the Arabidopsis (Arabidopsis thaliana) hy5 mutant, resulting in increased anthocyanin accumulation and a shortened hypocotyl. The heterologous expression of TaBBX-3B in wild-type Arabidopsis had similar effects. TaHY5-7A and TaBBX-3B were nucleus-localized, consistent with a function in transcription regulation. However, TaHY5-7A, which lacks a transactivation domain, was not sufficient to activate the expression of PURPLE PERICARP-MYB 1 (TaPpm1), the key anthocyanin biosynthesis regulator in purple pericarps of wheat. TaHY5-7A physically interacted with TaBBX-3B in yeast two-hybrid and bimolecular fluorescence complementation assays. Additionally, TaHY5-7A, together with TaBBX-3B, greatly enhanced the promoter activity of TaPpm1 in a dual luciferase assay. Overall, our results suggest that TaHY5-7A and TaBBX-3B collaboratively activate TaPpm1 expression to promote light-induced anthocyanin biosynthesis in purple-pericarp wheat.

Deciphering the Inhibitory Mechanism of Naphthoquinone-Dopamine on the Aggregation of Tau Core Fragments PHF6* and PHF6.

The formation of neurofibrillary tangles by abnormal aggregation of tau protein is considered to be an important pathological characteristic of tauopathies, including Alzheimer's disease and chronic traumatic encephalopathy. Two hexapeptides 275VQIINK280 and 306VQIVYK311 in the microtubule binding region, named PHF6* and PHF6, are known to be aggregation-prone and responsible for tau fibrillization. Previous experiments reported that naphthoquinone-dopamine (NQDA) could effectively inhibit the aggregation of PHF6* and PHF6 and disrupt the fibrillar aggregates into nontoxic species, displaying a dual effect on the amyloid aggregation. However, the underlying molecular mechanism remains mostly elusive. Herein, we performed all-atom molecular dynamics (MD) simulations for 114 µs in total to systematically investigate the impacts of NQDA on the oligomerization of PHF6* and PHF6. The conformational ensembles of PHF6* and PHF6 peptides generated by replica exchange MD simulations show that NQDA could effectively prevent the hydrogen bond formation, reduce the ability of peptides to self-assemble into long ß-strand and large ß-sheets, and induce peptides to form a loosely packed and coil-rich oligomer. The interaction analysis shows that the binding of NQDA to PHF6* is mainly through hydrophobic interactions with residue I277 and hydrogen bonding interactions with Q276; for the PHF6 peptides, NQDA displays a strong π-π stacking interaction with residue Y310, thus impeding the Y310-Y310 π-π stacking and I308-Y310 CH-π interactions. The DA group of NQDA displays a stronger cation-π interaction than the NQ group, while the NQ group exhibits a stronger π-π stacking interaction. MD simulations demonstrate that NQDA prevents the conformational conversion to ß-sheet-rich aggregates and displays an inhibitory effect on the oligomerization dynamics of PHF6* and PHF6. Our results provide a complete picture of inhibitory mechanisms of NQDA on PHF6* and PHF6 oligomerization, which may pave the way for designing drug candidates for the treatment of tauopathies.

OsFAR1 is involved in primary fatty alcohol biosynthesis and promotes drought tolerance in rice.

MAIN CONCLUSION: OsFAR1 encodes a fatty acyl-CoA reductase involved in biosynthesis of primary alcohols and plays an important role in drought stress response in rice. Cuticular waxes cover the outermost surface of terrestrial plants and contribute to inhibiting nonstomatal water loss and improving plant drought resistance. Primary alcohols are the most abundant components in the leaf cuticular waxes of rice (Oryza sativa), but the biosynthesis and regulation of primary alcohol remain largely unknown in rice. Here, we identified and characterized an OsFAR1 gene belonging to the fatty acyl-CoA reductases (FARs) via a homology-based approach in rice. OsFAR1 was activated by abiotic stresses and abscisic acid, resulting in increased production of primary alcohol in rice. Heterologous expression of OsFAR1 enhanced the amounts of C22:0 and C24:0 primary alcohols in yeast (Saccharomyces cerevisiae) and C24:0 to C32:0 primary alcohols in Arabidopsis. Similarly, OsFAR1 overexpression significantly increased the content of C24:0 to C30:0 primary alcohols on rice leaves. Finally, OsFAR1 overexpression lines exhibited reduced cuticle permeability and enhanced drought tolerance in rice and Arabidopsis. Taken together, our results demonstrate that OsFAR1 is involved in rice primary alcohol biosynthesis and plays an important role in responding to drought and other environmental stresses.

Reactivation of mutant p53 in esophageal squamous cell carcinoma by isothiocyanate inhibits tumor growth.

p53 mutations are prevalent in human cancers; approximately half of patients with esophageal cancer present these mutations. Mutant p53 (mutp53) exerts oncogenic functions that promote malignant tumor progression, invasion, metastasis, and drug resistance, resulting in poor prognosis. Some small molecules have been shown to mitigate the oncogenic function of mutp53 by restoring its wild-type activity. Although these molecules have been evaluated in clinical trials, none have been successfully used in the clinic. Here, we investigated the antitumor effects of phenethyl isothiocyanate (PEITC) in p53-mutant esophageal squamous cell carcinoma (ESCC) and elucidated its mechanism to identify new therapeutic strategies. We observed that p53R248Q is a DNA contact mutation and a structural mutation and that PEITC can restore the activity of p53R248Q in vitro and in vivo, further clarifying the antitumor activity of PEITC in cancers with different types of p53 mutations. PEITC can inhibit ESCC growth, induce apoptosis, and arrest cell cycle progression and has a preferential selectivity for ESCC with p53 mutations. Mechanistic studies showed that PEITC induced apoptosis and arrested cells at G2/M transition in cells expressing the p53R248Q mutant by restoring the wild-type conformation and transactivation function of p53; these effects were concentration dependent. Furthermore, PEITC inhibited the growth of subcutaneous xenografts in vivo and restored p53 mutant activity in xenografts. According to these findings, PEITC has antitumor effects, with its ability to restore p53R248Q activity being a key molecular event responsible for these effects.

A Novel Predictor of Pathologic Complete Response for Neoadjuvant Immunochemotherapy in Resectable Locally Advanced Esophageal Squamous Cell Carcinoma.

Purpose: Neoadjuvant immunochemotherapy (nICT) for resectable locally advanced esophageal squamous cell carcinoma (LA-ESCC) has attracted widespread attention recently, whose safety and clinical benefit was observed in clinical researches. This study aimed to develop and validate a novel predictor systemic inflammation-tumor markers index (SITI) to predict the pathological complete response (pCR) for resectable LA-ESCC patients receiving nICT. Patients and Methods: A total of 147 LA-ESCC patients who underwent nICT followed by surgery from February 2020 to April 2022 were included in the study. The dynamic change of inflammatory indexes was compared at baseline, after two cycles of nICT and postoperative one month. Least absolute shrinkage and selection operator (LASSO) regression was performed to avoid collinearity and identify key indexes, with SITI constructed. After univariate and multivariate stepwise forward logistic analyses, a nomogram for pCR prediction was developed. Results: 41(27.9%) patients achieved pCR among 147 resectable LA-ESCC patients received nICT. Compared with baseline, most inflammatory indexes were significantly decreased at postoperative one month. 5 key indexes were identified and then a predictive index named SITI was constructed. The result showed that lower SITI and earlier clinical tumor node metastasis (cTNM) stage were more likely to achieve pCR. The nomogram for pCR prediction had excellent discrimination performance (C-index = 0.791). Conclusion: The SITI is an independent predictor for pCR in resectable LA-ESCC patients received nICT. To our knowledge, our nomogram is the first model using systemic inflammation-tumor markers for pCR prediction and may be a promising predictor to effectively differentiate pCR for nICT in LA-ESCC patients.

Placental Mesenchymal Stem Cells Alleviate Podocyte Injury in Diabetic Kidney Disease by Modulating Mitophagy via the SIRT1-PGC-1alpha-TFAM Pathway.

The use of mesenchymal stem cells (MSCs) has become a new strategy for treating diabetic kidney disease (DKD). However, the role of placenta derived mesenchymal stem cells (P-MSCs) in DKD remains unclear. This study aims to investigate the therapeutic application and molecular mechanism of P-MSCs on DKD from the perspective of podocyte injury and PINK1/Parkin-mediated mitophagy at the animal, cellular, and molecular levels. Western blotting, reverse transcription polymerase chain reaction, immunofluorescence, and immunohistochemistry were used to detect the expression of podocyte injury-related markers and mitophagy-related markers, SIRT1, PGC-1α, and TFAM. Knockdown, overexpression, and rescue experiments were performed to verify the underlying mechanism of P-MSCs in DKD. Mitochondrial function was detected by flow cytometry. The structure of autophagosomes and mitochondria were observed by electron microscopy. Furthermore, we constructed a streptozotocin-induced DKD rat model and injected P-MSCs into DKD rats. Results showed that as compared with the control group, exposing podocytes to high-glucose conditions aggravated podocyte injury, represented by a decreased expression of Podocin along with increased expression of Desmin, and inhibited PINK1/Parkin-mediated mitophagy, manifested as a decreased expression of Beclin1, the LC3II/LC3I ratio, Parkin, and PINK1 associated with an increased expression of P62. Importantly, these indicators were reversed by P-MSCs. In addition, P-MSCs protected the structure and function of autophagosomes and mitochondria. P-MSCs increased mitochondrial membrane potential and ATP content and decreased the accumulation of reactive oxygen species. Mechanistically, P-MSCs alleviated podocyte injury and mitophagy inhibition by enhancing the expression of the SIRT1-PGC-1α-TFAM pathway. Finally, we injected P-MSCs into streptozotocin-induced DKD rats. The results revealed that the application of P-MSCs largely reversed the markers related to podocyte injury and mitophagy and significantly increased the expression of SIRT1, PGC-1α, and TFAM compared with the DKD group. In conclusion, P-MSCs ameliorated podocyte injury and PINK1/Parkin-mediated mitophagy inhibition in DKD by activating the SIRT1-PGC-1α-TFAM pathway.

Atomistic Insights into the Inhibitory Mechanism of Tyrosine Phosphorylation against the Aggregation of Human Tau Fragment PHF6.

Abnormal aggregation of the microtubule-associated protein tau into intracellular fibrillary inclusions is characterized as the hallmark of tauopathies, including Alzheimer's disease and chronic traumatic encephalopathy. The hexapeptide 306VQIVYK311 (PHF6) of R3 plays an important role in the aggregation of tau. Recent experimental studies reported that phosphorylation of residue tyrosine 310 (Y310) could decrease the propensity of PHF6 to form fibrils and inhibit tau aggregation. However, the underlying inhibitory mechanism is not well understood. In this work, we systematically investigated the influences of phosphorylation on the conformational ensembles and oligomerization dynamics of PHF6 by performing extensive all-atom molecular dynamics (MD) simulations. Our replica exchange MD simulations demonstrate that Y310 phosphorylation could effectively suppress the formation of ß-structure and shift PHF6 oligomers toward coil-rich aggregates. The interaction analyses show that hydrogen bonding and hydrophobic interactions among PHF6 peptides, as well as Y310-Y310 π-π stacking and I308-Y310 CH-π interactions, are weakened by phosphorylation. Additional microsecond MD simulations show that Y310 phosphorylation could inhibit the oligomerization of PHF6 by preventing the formation of large ß-sheet oligomers and multi-layer ß-sheet aggregates. This study provides mechanistic insights into the phosphorylation-inhibited tau aggregation, which may be helpful for the in-depth understanding of the pathogenesis of tauopathies.

Risk factors and prediction models of lymph node metastasis in papillary thyroid carcinoma based on clinical and imaging characteristics.

BACKGROUND: Papillary thyroid carcinoma (PTC) commonly presents with lymph node metastasis, which may be associated with worsened prognosis. This study aimed to comprehensively evaluate the risk factors of lymph node metastasis in PTC based on preoperative clinical and imaging data and to construct a nomogram model to predict the risk of lymph node metastasis. METHODS: A total of 989 patients with PTC were enrolled and randomly divided into training and validation cohorts in an 8:2 ratio. Independent risk factors for lymph node metastasis in PTC were analyzed using univariate and stepwise multivariate logistic regression. An importance analysis of independent risk factors affecting lymph node metastasis was performed according to the random forest method. Subsequently, a nomogram to predict lymph node metastasis was constructed, and the predictive effect of the nomogram was evaluated using receiver operating characteristic analysis and calibration curves. RESULTS: Univariate regression analysis revealed that age, sex, body weight, systolic blood pressure, free triiodothyronine, nodule location, nodule number, Thyroid Imaging Reporting and Data System (TI-RADS) grade on color Doppler ultrasound, enlarged lymph node present on imaging, and nodule diameter could affect lymph node metastasis in PTC. Stepwise multivariate regression analysis showed that sex, age, enlarged lymph node present on imaging, nodule diameter, and color Doppler TI-RADS grade were independent risk factors for lymph node metastasis in PTC. Combining these five independent risk factors, a nomogram prediction model was constructed. The area under the curve (AUC) of the nomogram in the training and validation cohorts was 0.742 and 0.765, respectively, with a well-fitted calibration curve. CONCLUSION: Our study showed that independent risk factors for lymph node metastasis in PTC were sex, age, enlarged lymph node present on imaging, nodule diameter, and color Doppler TI-RADS grade. The nomogram constructed based on these independent risk factors can better predict the risk of lymph node metastasis.

One hundred most cited articles related to Endoscopic retrograde cholangiopancreatography: A bibliometric analysis.

Background: Endoscopic retrograde cholangiopancreatography (ERCP) has developed over the past few decades into a reliable technology for diagnostic and therapeutic purposes. Through a bibliometric analysis, this research attempted to evaluate the characteristics of the top 100 articles on ERCP that had the most citations. Methods: We extracted pertinent publications from the Web of Science Core Collection (WoSCC) on July 9, 2022. The top 100 ERCP articles with the most citations were identified and analyzed. The following data were extracted: publication year, country/region, organization, total citation times, annual citation times, research type and research field, etc. To implement the network's visual analysis, a bibliographic coupling network based on keywords was built using the VOSviewer 1.6.17 program. Results: The journal with the most publications were GASTROINTESTINAL ENDOSCOPY, with 45 articles. Most of the top 100 articles came from the United States (n = 47) and Italy (n = 14). Indiana University and the University of Amsterdam were among the most important institutions in ERCP research. ML Freeman of the University of Minnesota contributed the highest number (n = 9) and the most highly cited paper. The age of the paper and article type is closely related to citation frequency. Of the 100 most-cited articles, clinical application in the field of ERCP has focused on three aspects: diagnosis, treatment, and complications. Clinical use of ERCP has shifted from diagnosis to treatment. Post-ERCP pancreatitis is the focus of attention, and the clinical application of technically complex therapeutic ERCP is the future development trend. Conclusion: This study lists the most influential articles in ERCP by exposing the current state of the field, and showing the evolution of research trends to provide perspective for the future development of ERCP.

Downregulation of HULC Induces Ferroptosis in Hepatocellular Carcinoma via Targeting of the miR-3200-5p/ATF4 Axis.

Hepatocellular carcinoma is a malignant tumor that poses a serious threat to human health. Ferroptosis, which represents an identified type of regulated iron-dependent cell death, may play an important role in hepatocellular carcinoma. However, it is unclear as to whether ferroptosis is involved with the mechanisms of lncRNA HULC in liver cancer cells. Here, we show that knockdown of HULC increases ferroptosis and oxidative stress in liver cancer cells. We also found changes in some related miRNAs in cells treated with HULC siRNA. Differential miRNA expression levels were determined with the use of high-throughput sequencing and prediction target genes identified using bioinformatics analysis. HULC was found to function as a ceRNA of miR-3200-5p, and miR-3200-5p regulates ferroptosis by targeting ATF4, resulting in the inhibition of proliferation and metastasis within HCC cells. In summary, these findings illuminate some of the molecular mechanisms through which downregulation of HULC induces liver cancer cell ferroptosis by targeting the miR-3200-5p/ATF4 axis to modulate the development of hepatocellular carcinoma.

PD-1 Inhibitor Plus Chemotherapy Versus Chemotherapy as First-line Treatment for Advanced Esophageal Cancer: A Systematic Review and Meta-Analysis.

Immunotherapy combined with chemotherapy has recently changed the first-line treatment of several cancers. We performed a systematic review and meta-analysis to assess the efficacy and safety of programmed cell death 1 (PD-1) inhibitor plus chemotherapy as a first-line treatment for advanced esophageal cancer. Data were collected from eligible studies searched from PubMed, Web of Science, Cochrane Library, Embase, and meeting abstracts. The pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) and the pooled odds ratios (ORs) for objective response rate and treatment-related adverse events (TRAEs) were estimated to assess the efficacy and safety of PD-1 inhibitor plus chemotherapy versus chemotherapy. We performed several subgroup analyses to explore the variables affecting immunotherapy efficacy in esophageal cancer. The 5-point Jadad scoring system, the bias risk assessment and sensitivity analyses were used to evaluate the quality of the meta-analysis. Compared with the chemotherapy group, the OS (HR=0.70; P<0.01) and PFS (HR=0.62; P<0.01) were significantly longer and the objective response rate (OR=2.07; P<0.01) was significantly higher in the PD-1 inhibitor plus chemotherapy group. An OS benefit was observed in patients regardless of histology or programmed cell death 1 ligand 1 combined positive score. OS and PFS were generally consistent across subgroups by clinical features. In safety analyses, PD-1 inhibitor plus chemotherapy had a significantly higher incidence of TRAEs (OR=1.85; P<0.01), but there was no significant difference in grade 3 or higher TRAEs (OR=1.24; P=0.05). Compared with chemotherapy, PD-1 inhibitor plus chemotherapy improves antitumor activity and controllable adverse events in the first-line treatment of advanced esophageal cancer.

Metformin Downregulates PD-L1 Expression in Esophageal Squamous Cell Catrcinoma by Inhibiting IL-6 Signaling Pathway.

PURPOSE: To characterize the mechanism by which metformin inhibits PD-L1 expression in esophageal squamous cell carcinoma (ESCC) and to evaluate the effect of metformin on the antitumor immune response. METHODS: The Cancer Genome Atlas (TCGA) database was used to analyze the correlations between IL-6 and prognosis and between IL-6 and PD-L1 gene expression in esophageal cancer. Reverse transcription-quantitative polymerase chain reaction (RT-PCR), Western blotting and immunofluorescence were used to study the mechanism by which metformin affects PD-L1 expression. Additionally, T cell function was assessed in a coculture system containing ESCC cells and peripheral blood mononuclear cells (PBMCs) treated with metformin or IL-6. In an in vivo assay, we used a model established with NPIdKO™ mice, which have a reconstituted immune system generated by transplanting PBMCs through intravenous injection, to evaluate the effect of metformin on tumors. RESULTS: The TCGA esophageal cancer data showed that IL-6 expression was positively correlated with PD-L1 expression and that patients with high IL-6 expression had a significantly lower overall survival rate than patients with low IL-6 expression. PD-L1 expression in ESCC cell lines was significantly inhibited by metformin via the IL-6/JAK2/STAT3 signaling pathway but was not correlated with the canonical AMPK pathway. In the coculture system, the metformin pretreatment group showed higher T cell activation and better T cell killing function than the control group. Animal experiments confirmed that metformin downregulated PD-L1 expression and that combination treatment with metformin and PD-1 inhibitors synergistically enhanced the antitumor response. CONCLUSIONS: Metformin downregulated PD-L1 expression by blocking the IL-6/JAK2/STAT3 signaling pathway in ESCC, which enhanced the antitumor immune response.

Genome wide association study of plant height and tiller number in hulless barley.

Hulless barley (Hordeum vulgare L. var. nudum), also called naked barley, is a unique variety of cultivated barley. The genome-wide specific length amplified fragment sequencing (SLAF-seq) method is a rapid deep sequencing technology that is used for the selection and identification of genetic loci or markers. In this study, we collected 300 hulless barley accessions and used the SLAF-seq method to identify candidate genes involved in plant height (PH) and tiller number (TN). We obtained a total of 1407 M paired-end reads, and 228,227 SLAF tags were developed. After filtering using an integrity threshold of >0.8 and a minor allele frequency of >0.05, 14,504,892 single-nucleotide polymorphisms (SNP) loci were screened out. The remaining SNPs were used for the construction of a neighbour-joining phylogenetic tree, and the three subcluster members showed no obvious differentiation among regional varieties. We used a genome wide association study approach to identify 1006 and 113 SNPs associated with TN and PH, respectively. Based on best linear unbiased predictors (BLUP), 41 and 29 SNPs associated with TN and PH, respectively. Thus, several of genes, including Hd3a and CKX5, may be useful candidates for the future genetic breeding of hulless barley. Taken together, our results provide insight into the molecular mechanisms controlling barley architecture, which is important for breeding and yield.

Unraveling the Influence of K280 Acetylation on the Conformational Features of Tau Core Fragment: A Molecular Dynamics Simulation Study.

Abnormal aggregation of the microtubule-associated protein Tau is closely associated with tauopathies, including Alzheimer's disease and chronic traumatic encephalopathy. The hexapeptide 275VQIINK280 (PHF6*), a fibril-nucleating core motif of Tau, has been shown to play a vital role in the aggregation of Tau. Mounting experiment evidence demonstrated the acetylation of a single-lysine residue K280 in the PHF6* was a critical event for the formation of pathological Tau amyloid deposits. However, the underlying mechanisms by which K280 acetylation affects Tau aggregation at the atomic level remain elusive. In this work, we performed replica exchange molecular dynamics simulations to investigate the influence of acetylation of K280 on the aggregation of PHF6*. Our simulations show that acetylation of K280 not only enhances the self-assembly capability of PHF6* peptides but also increases the ß-sheet structure propensity of the PHF6*. The inter-molecular interactions among PHF6* peptides are strengthened by the acetylation of K280, resulting in an increased ordered ß-sheet-rich conformations of the PHF6* assemblies along with a decrease of the structural diversity. The residue-pairwise contact frequency analysis shows that K280 acetylation increases the interactions among the hydrophobic chemical groups from PHF6* peptides, which promotes the aggregation of PHF6*. This study offers mechanistic insights into the effects of acetylation on the aggregation of PHF6*, which will be helpful for an in-depth understanding of the relationship between acetylation and Tau aggregation at the molecular level.