Exploring potential plasma drug targets for cholelithiasis through multiancestry Mendelian randomization.

BACKGROUND: Cholelithiasis poses significant health and economic burdens, necessitating novel pharmacological targets to enhance treatment efficacy. METHOD: Based on genome-wide association analysis (GWAS) studies, we performed two-sample Mendelian randomization (MR) analysis based on plasma proteomics to explore potential drug targets in European (nCase=40,191 and nControl=361,641) and Asian (nCase=9,305 and nControl=168,253) populations. We confirmed the directionality and robust correlation of the drug targets with the results through reverse MR analysis, Steiger filtering, Bayesian colocalization, phenotype scanning and replication in multiple databases. Further exploration of the safety and possible mechanisms of action of phenome-wide MR analysis and protein‒protein interactions (PPIs) as individual drug targets was performed. RESULTS: Our proteomics-based MR analyses suggested that FUT3 (OR=0.87; 95% CI, 0.84-0.89; P=4.70×10-32), NOE1 (OR=0.58; 95% CI, 0.52-0.66; P=4.21×10-23), UGT1A6 (OR=0.68; 95% CI, 0.64-0.73; P=9.58×10-30) and FKBP52 (OR=1.75; 95% CI, 1.37-2.24; P=8.61×10-6) were potential drug targets in Europeans, whereas KLB (OR=1.11; 95% CI, 1.07-1.16; P=7.59×10-7) and FGFR4 (OR=0.94; 95% CI, 0.91-0.96; P=4.07×10-6) were valid targets in East Asians. There was no reverse causality for these drug targets. Evidence from Bayesian colocalization analyses supported that exposure and outcome shared consistent genetic variables. Phenome-wide MR analysis suggested the potential deleterious effects of NOE1 and FGFR4. PPI analysis confirmed the pathways associated with the potential targets involved in bile acid metabolism. CONCLUSIONS: Genetically predicted levels of the plasma proteins FUT3, NOE1, UGT1A6 and FKBP52 have potential as prospective targets in Europeans. Moreover, the plasma levels of KLB and FGFR4 may serve as potential targets for the treatment of cholelithiasis in East Asians.

N6-methylation in the development, diagnosis, and treatment of gastric cancer.

Gastric cancer (GC) ranks third among cancers in terms of mortality rate worldwide. A clear understanding of the mechanisms underlying the genesis and progression of GC will contribute to clinical decision making. N6-methyladenosine (m6A) is the most abundant among diverse mRNA modification types and regulates multiple facets of RNA metabolism. In recent years, emerging studies have shown that m6A modifications are involved in gastric carcinoma tumorigenesis and progression and can potentially be valuable new prospects for diagnosis and prognosis. This article reviews the recent progress regarding m6A in GC.

Both extracellular vesicles from helicobacter pylori-infected cells and helicobacter pylori outer membrane vesicles are involved in gastric/extragastric diseases.

Bacterial-derived extracellular vesicles (EVs) have emerged as crucial mediators in the cross-talk between hosts and pathogens, playing a significant role in infectious diseases and cancers. Among these pathogens, Helicobacter pylori (H. pylori) is a particularly important bacterium implicated in various gastrointestinal disorders, gastric cancers, and systemic illnesses. H. pylori achieves these effects by stimulating host cells to secrete EVs and generating internal outer membrane vesicles (OMVs). The EVs derived from H. pylori-infected host cells modulate inflammatory signaling pathways, thereby affecting cell proliferation, apoptosis, cytokine release, immune cell modification, and endothelial dysfunction, as well as disrupting cellular junctional structures and inducing cytoskeletal reorganization. In addition, OMVs isolated from H. pylori play a pivotal role in shaping subsequent immunopathological responses. These vesicles incite both inflammatory and immunosuppressive reactions within the host environment, facilitating pathogen evasion of host defenses and invasion of host cells. Despite this growing understanding, research involving H. pylori-derived EVs remains in its early stages across different domains. In this comprehensive review, we present recent advancements elucidating the contributions of EV components, such as non-coding RNAs (ncRNAs) and proteins, to the pathogenesis of gastric and extragastric diseases. Furthermore, we highlight their potential utility as biomarkers, therapeutic targets, and vehicles for targeted delivery.

Endoscopic diagnosis and treatment of superficial non-ampullary duodenal epithelial tumors: A review.

The surface of the small bowel mucosa is covered more than any other section of the digestive canal; however, the overall prevalence of small bowel tumors of the whole gastrointestinal tract is evidently low. Owing to the improvement in endoscopic techniques, the prevalence of small bowel tumors has increased across multiple countries, which is mainly due to an increase in duodenal tumors. Superficial non-ampullary duodenal epithelial tumors (SNADETs) are defined as tumors originating from the non-ampullary region in the duodenum that share similarities and discrepancies with their gastric and colorectal counterparts in the pathogenesis and clinicopathologic characteristics. To date, white light endoscopy (WLE) remains the cornerstone of endoscopic diagnosis for SNADETs. Besides, narrow-band imaging (NBI) techniques and magnifying endoscopy (ME) have been widely used in the clinic and endorsed by multiple guidelines and consensuses for SNADETs' evaluation. Confocal laser endomicroscopy (CLE), endocytoscopy (ECS), and artificial intelligence (AI) are also up-and-coming methods, showing an exceptional value in the diagnosis of SNADETs. Similar to the endoscopic treatment for colorectal polyps, the choices for SNADETs mainly include cold snare polypectomy (CSP), endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), and laparoscopic endoscopic cooperative surgery (LECS). However, owing to the narrow lumen, rich vascularity, weak muscle layer, abundant Brunner's gland, and the hardship of endoscope control, the duodenum ranks as one of the most dangerous operating areas in the digestive tract. Therefore, endoscopists must anticipate the difficulties in endoscopic maneuverability, remain aware of the increased risk of complications, and then select the appropriate treatment according to the advantages and disadvantages of each method.

The role of GPLD1 in chronic diseases.

Glycosylphosphatidylinositol-specific phospholipase D (GPLD1) is a specific enzyme for glycosylphosphatidylinositol (GPI) anchors, thereby exerting its biological functions by cleaving membrane-associated GPI molecules. GPLD1 is abundant in serum, with a concentration of approximately 5-10 µg/mL. Previous studies have demonstrated that GPLD1 plays a crucial role in the pathogenesis of numerous chronic diseases including disorders of lipid and glucose metabolism, cancer, and neurological disorders. In the present study, we reviewed the structure, functions, and localization of GPLD1 in chronic diseases, as well as exercise-mediated regulation of GPLD1, thus providing a theoretical support to develop GPLD1 as a new therapeutic target for chronic diseases.

Long-term effect of Helicobacter pylori eradication on colorectal cancer incidences.

Background: There is evidence supporting the association between Helicobacter pylori infection and colorectal cancer (CRC), but whether H. pylori eradication reduces the risk of CRC is still unknown. Objectives: To compare the incidence of CRC in subjects who had received H. pylori eradication therapy with general population. Design: A population-based retrospective cohort study. Methods: This study included all H. pylori-infected subjects who had received their first course of clarithromycin-containing triple therapy in 2003-2015 in Hong Kong. We compared the observed incidences of CRC in this H. pylori eradicated cohort with the expected incidences in the age- and sex-matched general population. The standardized incidence ratio (SIR) with 95% confidence interval (CI) was computed. Results: Among 96,572 H. pylori-eradicated subjects with a median follow-up of 9.7 years, 1417 (1.5%) developed CRC. Primary analysis showed no significant difference in the observed and expected incidences of CRC (SIR: 1.03, 95% CI: 0.97-1.09). However, when stratified according to the follow-up period, higher incidence of CRC was only observed in the first 5 years after eradication (SIR: 1.47, 95% CI: 1.39-1.55), but it was lower (SIR: 0.85, 95% CI: 0.74-0.99) than general population after 11 years. When stratified by tumor location, the observed incidence was higher for colon (SIR: 1.20, 95% CI: 1.12-1.29) but lower for rectal cancer (SIR: 0.90, 95% CI: 0.81-0.999) among H. pylori-eradicated subjects. Conclusions: H. pylori-infected subjects appeared to have a higher incidence of CRC initially, which declined progressively to a level lower than general population 10 years after H. pylori eradication, particularly for rectal cancer.

m6 A-Dependent Modulation via IGF2BP3/MCM5/Notch Axis Promotes Partial EMT and LUAD Metastasis.

The importance of mRNA N6-methyladenosine (m6 A) modification during tumor metastasis is controversial as it plays distinct roles in different biological contexts. Moreover, how cancer cell plasticity is shaped by m6 A modification is interesting but remains uncharacterized. Here, this work shows that m6 A reader insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3) is remarkably upregulated in metastatic lung adenocarcinoma (LUAD) and indicates worse prognosis of patients. Interestingly, IGF2BP3 induces partial epithelial-mesenchymal-transition (EMT) and confers LUAD cells plasticity to metastasize through m6 A-dependent overactivation of Notch signaling. Mechanistically, IGF2BP3 recognized m6 A-modified minichromosome maintenance complex component (MCM5) mRNAs to prolong stability of them, subsequently upregulating MCM5 protein, which competitively inhibits SIRT1-mediated deacetylation of Notch1 intracellular domain (NICD1), stabilizes NICD1 protein and contributes to m6 A-dependent IGF2BP3-mediated cellular plasticity. Notably, a tight correlation of the IGF2BP3/MCM5/Notch axis is evidenced in clinical LUAD specimens. Therefore, this study elucidates a critical role of m6 A modification on LUAD cell plasticity in fostering tumor metastasis via the above axis, providing potential targets for metastatic LUAD.

PKMYT1 inhibits lung adenocarcinoma progression by abrogating AKT1 activity.

PURPOSE: AKT hyperactivation drives malignant phenotypes in lung cancer via promoting tumor cell proliferation and survival. However, the relationship between dysregulation of cell cycle progression and AKT1 kinase activity is still not clear. METHODS: Following the expression level of PKMYT1 in lung cancer, we performed cell proliferation, migration, invasion, and xenograft assays to determine the function of PKMYT1. We used RNA-seq to explore the anti-tumor mechanism of PKMYT1 and examined the effect of PKMYT1 on AKT1 activity. RESULTS: In this study, we report that PKMYT1 is downregulated in lung adenocarcinoma (LUAD) tissues and its low expression predicts a poor prognosis in LUAD patients. PKMYT1 exerts potent tumor-suppressive functions in LUAD cells by inhibiting AKT1 activation and thereby repressing cell cycle progression, which depends on its tyrosine and threonine protein kinase activity. Interestingly, PKMYT1 could directly bind AKT1 to abrogate AKT1 activation. Moreover, silencing AKT1 and inhibitors targeting the AKT pathway effectively reverse the promoting effects of PKMYT1 knockdown on proliferation, migration and invasion of LUAD cells. CONCLUSION: This work reveals the anti-tumor effect of PKMYT1 in LUAD and provides evidence to clarify the dual roles of PKMYT1 in tumor progression. Moreover, our findings broaden the current understandings on AKT1 activation and identify PKMYT1 as a potential negative regulator of AKT1 kinase activity, providing further insights into targeting the AKT pathway in LUAD.

Roles of small extracellular vesicles in the development, diagnosis and possible treatment strategies for hepatocellular carcinoma (Review).

Hepatocellular carcinoma (HCC) is the most common malignancy of hepatocytes accounting for 75­85% of primary hepatic carcinoma cases. Small extracellular vesicles (sEVs), previously known as exosomes with a diameter of 30­200 nm, can transport a variety of biological molecules between cells, and have been proposed to function in physiological and pathological processes. Recent studies have indicated that the cargos of sEVs are implicated in intercellular crosstalk among HCC cells, paratumor cells and the tumor microenvironment. sEV­encapsulated substances (including DNA, RNA, proteins and lipids) regulate signal transduction pathways in recipient cells and contribute to cancer initiation and progression in HCC. In addition, the differential expression of sEV cargos between patients facilitates the potential utility of sEVs in the diagnosis and prognosis of patients with HCC. Furthermore, the intrinsic properties of low immunogenicity and high stability render sEVs ideal vehicles for targeted drug delivery in the treatment of HCC. The present review article summarizes the carcinogenic and anti­neoplastic capacities of sEVs and discusses the potential and prospective diagnostic and therapeutic applications of sEVs in HCC.

MiR-1298-5p level downregulation induced by Helicobacter pylori infection inhibits autophagy and promotes gastric cancer development by targeting MAP2K6.

Helicobacter pylori infection is a leading cause of gastric cancer (GC). However, the underlying mechanisms have not yet been fully elucidated. We aimed to identify microRNAs (miRNAs) regulated by H. pylori infection and their underlying mechanisms in gastric carcinogenesis. Using a mouse model, it was established that H. pylori infection inhibited autophagy in the gastric mucosa. Importantly, H. pylori infection decreased miR-1298-5p levels in human and mouse gastric tissues and human gastric cell lines. Furthermore, the downregulation of miR-1298-5p levels remarkably inhibited autophagy, ultimately increasing the intracellular H. pylori load, which was detected using a gentamicin protection assay. A series of in vitro assays showed that the downregulation of miR-1298-5p expression promoted GC cell proliferation, migration, and invasion. Mechanistically, using bioinformatics prediction, miRNA pull-down assays, and luciferase reporter assays, mitogen-activated protein kinase kinase 6 (MAP2K6) was found to be the direct target of miR-1298-5p, through which miR-1298-5p regulated autophagy and GC cell viability and motility. Moreover, MAP2K6/p38 mitogen-activated protein kinase (MAPK) axis was determined to be the downstream pathway of miR-1298-5p. These findings revealed that H. pylori infection was found to inhibit autophagy and promote tumor growth by regulating miR-1298-5p expression and the miR-1298-5p/MAP2K6/p38 MAPK axis might be a new avenue for the clinical management of H. pylori infection and H. pylori-associated GC.

The role of GTPase-activating protein ARHGAP26 in human cancers.

Rho GTPases are molecular switches that play an important role in regulating the behavior of a variety of tumor cells. RhoA GTPase-activating protein 26 (ARHGAP26) is a GTPase-activating protein and inhibits the activity of Rho GTPases by promoting the hydrolytic ability of Rho GTPases. It also affects tumorigenesis and progression of various tumors through several methods, including formation of abnormal fusion genes and circular RNA. This review summarizes the biological functions and molecular mechanisms of ARHGAP26 in different tumors, proposes the potential clinical value of ARHGAP26 in cancer treatment, and discusses current issues that need to be addressed.

Comparative outcomes of endoscopic ultrasound-guided lumen-apposing mental stents drainage for pancreatic pseudocysts and walled-off necrosis: Case series and meta-analysis.

BACKGROUND: Endoscopic ultrasound (EUS)-guided transmural drainage for pancreatic fluid collections (PFCs) has become the first-line treatment with quicker recovery and more minor injury compared with surgery and percutaneous drainage. The efficacy of stents implantation and drainage for different PFCs remains controversial, especially lumen-apposing metal stents (LAMS). This study aimed to compare the efficacy and safety of LAMS drainage for pancreatic pseudocysts (PPC) and walled-off necrosis (WON). METHODS: A meta-analysis was performed for LAMS drainage for WON and PPC by systematically searching PubMed, Cochrane, and Embase databases from January 2010 to January 2020. From 2017 to 2019, 12 patients who were treated with LAMS drainage for PFCs in our medical center were also reviewed and included in this study. RESULTS: Combining 11 copies of documents with the data from our medical center, a total of 585 patients with PFCs were enrolled in this meta-analysis, including 343 patients with WON and 242 with PPC. The technical success rate in WON is not significantly different from that of PPC (P = 0.08 > 0.05). The clinical success of LAMS placement was achieved in 99% vs 89% in PPC and WON, respectively (RR = 0.92, 95% CI: 0.86-0.98, P = 0.01 < 0.05). The further intervention of direct endoscopic necrosectomy was required by 60% of patients in WON group. There was no significant difference in the incidence of adverse events, including infection, bleeding, stent migration and stent occlusion, after LAMS placement between WON and PPC. CONCLUSIONS: Endoscopic ultrasound-guided LAMS for PFCs are feasible, effective with preferable technical and clinical success rates. The clinical effect of LAMS on PPC is slightly better than that of WON, but its adverse reactions still need to be verified in a large-sample prospective study.

Small Extracellular Vesicles in the Development, Diagnosis, and Possible Therapeutic Application of Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) persists among the most lethal and broad-spreading malignancies in China. The exosome is a kind of extracellular vesicle (EV) from about 30 to 200 nm in diameter, contributing to the transfer of specific functional molecules, such as metabolites, proteins, lipids, and nucleic acids. The paramount role of exosomes in the formation and development of ESCC, which relies on promoting intercellular communication in the tumor microenvironment (TME), is manifested with immense amounts. Tumor-derived exosomes (TDEs) participate in most hallmarks of ESCC, including tumorigenesis, invasion, angiogenesis, immunologic escape, metastasis, radioresistance, and chemoresistance. Published reports have delineated that exosome-encapsulated cargos like miRNAs may have utility in the diagnosis, as prognostic biomarkers, and in the treatment of ESCC. This review summarizes the function of exosomes in the neoplasia, progression, and metastasis of ESCC, which improves our understanding of the etiology and pathogenesis of ESCC, and presents a promising target for early diagnostics in ESCC. However, recent studies of exosomes in the treatment of ESCC are sparse. Thus, we introduce the advances in exosome-based methods and indicate the possible applications for ESCC therapy in the future.

The Significance of Exosomal RNAs in the Development, Diagnosis, and Treatment of Gastric Cancer.

Gastric cancer (GC) is one of the most common malignancies in the world. Exosomes, a subset of extracellular vesicles with an average diameter of 100 nm, contain and transfer a variety of functional macromolecules such as proteins, lipids, and nucleic acids. A large number of studies indicated that exosomes can play a significant role in the initiation and development of GC via facilitating intercellular communication between gastric cancer cells and microenvironment. Exosomal RNAs, one of the key functional cargos, are involved in the pathogenesis, development, and metastasis of GC. In addition, recent studies elucidated that exosomal RNAs may serve as diagnostic and prognostic biomarkers or therapeutic targets for GC. In this review, we summarized the function of exosomal RNA in the tumorigenesis, progression, diagnosis, and treatment of GC, which may further unveil the functions of exosome and promote the potentially diagnostic and therapeutic application of exosomes in GC.

Prognostic gene profiles in the tumor microenvironment of ovarian serous adenocarcinoma.

Ovarian serous adenocarcinoma is one of the most common and fatal malignancies among women worldwide. The tumor microenvironment plays a critical role in tumor initiation, proliferation, and metastasis. Immune scores and stromal scores of the tumor microenvironment were determined using the ESTIMATE. Immune cell infiltration was assessed using TIMER and differentially expressed genes (DEGs) were determined using the R/Bioconductor package of edgeR. Survival analysis was carried out using a univariate Cox model and Kaplan-Meier survival, and gene functional information was obtained through Gene Ontology and KEGG pathway analysis. Survival analysis revealed 39 DEGs that significantly influenced the prognosis of ovarian serous adenocarcinoma patients and were correlated with immune cell abundance. Functional enrichment and protein-protein interaction network analyses further indicated that these genes are primarily involved in immune-related responses. Finally, we verified the prognostic value of these genes via GEO. The present results reveal the genes associated with the tumor microenvironment of ovarian adenocarcinoma, potentially providing prognostic information.

Vitamin D3 Inhibits Helicobacter pylori Infection by Activating the VitD3/VDR-CAMP Pathway in Mice.

Helicobacter pylori (H. pylori) infection is closely associated with the occurrence and development of gastric diseases. Therefore, eliminating H. pylori infection should help to prevent gastric diseases. Vitamin D3 (VitD3, 1,25(OH)2D3) was previously observed to exhibit anti-H. pylori infection activity in clinic, but these results were reported in heterogeneous in vivo studies without elucidation of the underlying mechanisms. In the present study, we established H. pylori infection models in both wild-type and VDR knockdown (VDR-KD) mice, which were used to demonstrate that VitD3 inhibits H. pylori infection by enhancing the expression of VitD receptor (VDR) and cathelicidin antimicrobial peptide (CAMP). Furthermore, VDR-KD mice that exhibited lower VDR expression were more susceptible to H. pylori infection. In cultured mouse primary gastric epithelial cells, we further demonstrated that the VitD3/VDR complex binds to the CAMP promoter region to increase its expression. These data provide a mechanistic explanation of the anti-H. pylori infection activity of VitD3 at the molecular level in mice and suggest a new avenue for the clinical management of H. pylori eradication therapy.

Exosomal Sonic Hedgehog derived from cancer-associated fibroblasts promotes proliferation and migration of esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the most common and aggressive malignancies in China. Cancer-associated fibroblasts (CAFs) can actively communicate with and stimulate tumor cells, thereby contributing to the development and progression of tumors. Yet, whether CAFs-derived exosomes have a role in the progression of ESCC is largely unknown. Here, we find that Sonic Hedgehog (SHH) is highly expressed in CAFs lysis solution, conditioned medium of cultured CAFs (CAF-CM) and CAFs-derived exosomes, and esophageal cancer cell lines educated by CAF-CM and CAFs-derived exosomes can improve their growth and migration abilities in vitro and in vivo. Besides, those effects can be partly neutralized by cyclopamine, inhibitor of the Hedgehog signaling pathway. Thus, our research elucidates the crucial role of CAFs-derived exosomes in the growth and progression of ESCC, and may open up new avenues in the treatment of ESCC.