Helicobacter pylori infection increases risk of bleeding during endoscopic submucosal dissection for early gastric cancer.

BACKGROUND: Endoscopic submucosal dissection (ESD) is commonly used to treat early gastric cancer (EGC). The effects of Helicobacter pylori (HP) infection on ESD and the potential benefits of preoperative eradication of HP remain unclear. The study aims to evaluate the impact of HP infection on bleeding and lesion detection during ESD in patients with EGC. METHODS: We retrospectively analyzed 634 consecutive patients who underwent ESD for EGC at our center between January 2018 and January 2023. Logistic regression was used to assess the impact of HP infection status on intraoperative bleeding and lesion detection rates. We developed a predictive model based on selected indicators and evaluated its performance using the ROC curve. RESULTS: HP-positive patients experienced a higher rate of intraoperative bleeding (28.8%) compared with HP-negative patients (8.9%) (P < 0.001). HP-positive patients also had longer procedure time (median: 58.5 vs. 50.0 min, P < 0.001) and postoperative hospital stays (median: 4.35 vs. 4.07 days, P = 0.036). Multivariate analysis identified HP-positive (OR = 4.84), multiple lesions (OR = 1.81), specimen size > 40 mm (OR = 3.67), and submucosal invasion (OR = 2.27) as independent risk factors for intraoperative bleeding. The predictive model achieved an AUC of 0.807 (95%CI 0.761-0.852), with a sensitivity of 72.1% and specificity of 75.9%. Preoperative HP eradication was associated with an increased rate of lesion detection (OR = 2.82). CONCLUSIONS: Eradicating HP before ESD in patients with EGC reduces intraoperative bleeding and improves lesion detection. Preoperative HP eradication is therefore recommended in patients with EGC.

Integrated bioinformatics analysis identifies PCSK9 as a prognosticator correlated with lipid metabolism in pancreatic adenocarcinoma.

BACKGROUND: Pancreatic adenocarcinoma (PAAD) is the most frequent kind of pancreatic cancer (PC). Recent studies suggest that lipid metabolism facilitates tumorigenesis, disease progression, and resistance to therapy by promoting lipid synthesis, accumulation, and breakdown. Thus, exploring the lipid metabolism network could unveil novel therapeutic avenues for early detection, precision medicine, and prognostication in PAAD. This project intends to develop new lipid metabolism-related biomarkers for PAAD diagnosis and investigate the link between important genes and immune cell infiltration (ICI). METHODS: Tissue samples from 20 PAAD patients and 20 healthy controls were obtained. Analysis were focused on the datasets GSE71729 and GSE16515, which include samples of PAAD (n = 161) and those from healthy human tissue (n = 61), derived from the GEO database. Knockdown of PCSK9 on PC cells were conducted by si-RNA and sh-RNA. Migration and cell functional experiments were performed to assess the role of PCSK9 in cell multiplication. Furthermore, a xenograft mouse model was employed to confirm PCSK9's function in vivo. RESULTS: The expression level of Proprotein convertase subtilisin/kexin type 9 (PCSK9) is significantly elevated in tissues affected by PAAD when compared to normal tissues. Survival analyses indicated that increased PCSK9 levels are inversely related to overall and disease-free survival (DFS). PCSK9's functional annotation associated it with the cell cycle and metabolism, especially energy metabolism. Examination of ICI data determined that PCSK9 expression demonstrated an unambiguous association with the M0 macrophages, T follicular helper cells (Tfh), gamma delta T cells and activated DC, and an inverse relationship with Monocytes, CD8+ T cells, memory B cells, resting CD4+ memory T cells, activated NK cells and resting DC abundance. PCSK9 expression knockdown has the ability to impede PC cells' migration and proliferation. CONCLUSION: Our study identified PCSK9 as a critical gene in PAAD. Expression levels of PCSK9 varied between PAAD and normal samples. ROC analysis verified PCSK9's strong capacity to differentiate PC from normal samples. Importantly, PCSK9 expression was considerably elevated in PC cell lines and tissues. Furthermore, PCSK9 stimulates the migration and proliferation of tumor cells in vivo and vitro.

Thirdhand smoke exposure promotes gastric tumor development in mouse and human.

The pollution of indoor environments and the consequent health risks associated with thirdhand smoke (THS) are increasingly recognized in recent years. However, the carcinogenic potential of THS and its underlying mechanisms have yet to be thoroughly explored. In this study, we examined the effects of short-term THS exposure on the development of gastric cancer (GC) in vitro and in vivo. In a mouse model of spontaneous GC, CC036, we observed a significant increase in gastric tumor incidence and a decrease in tumor-free survival upon THS exposure as compared to control. RNA sequencing of primary gastric epithelial cells derived from CC036 mice showed that THS exposure increased expression of genes related to the extracellular matrix and cytoskeletal protein structure. We then identified a THS exposure-induced 91-gene expression signature in CC036 and a homologous 84-gene signature in human GC patients that predicted the prognosis, with secreted phosphoprotein 1 (SPP1) and tribbles pseudokinase 3 (TRIB3) emerging as potential targets through which THS may promote gastric carcinogenesis. We also treated human GC cell lines in vitro with media containing various concentrations of THS, which, in some exposure dose range, significantly increased their proliferation, invasion, and migration. We showed that THS exposure could activate the epithelial-mesenchymal transition (EMT) pathway at the transcript and protein level. We conclude that short-term exposure to THS is associated with an increased risk of GC and that activation of the EMT program could be one potential mechanism. Increased understanding of the cancer risk associated with THS exposure will help identify new preventive and therapeutic strategies for tobacco-related disease as well as provide scientific evidence and rationale for policy decisions related to THS pollution control to protect vulnerable subpopulations such as children.

Hypoxia Stimulates PYGB Enzymatic Activity to Promote Glycogen Metabolism and Cholangiocarcinoma Progression.

Cholangiocarcinoma (CCA) displays enhanced glycolysis, pivotal for fulfilling the heightened energy demands intrinsic to its malignant progression. Recent research has indicated that endogenous glycogen rather than exogenous glucose acts as the major carbon source for glycolysis, highlighting the need to better understand the regulation of glycogen homeostasis in CCA. Here, through comprehensive integrative analysis, we identified that glycogen phosphorylase brain form (PYGB), the main enzyme involved in glycogen homeostasis, was markedly upregulated in CCA tissues, serving as an independent prognostic indicator for human CCA patients. Moreover, elevated PYGB expression potentiated cholangiocarcinogenesis and augmented CCA cell proliferation in both organoid and xenograft models. Hypoxia stimulated PYGB activity in a phosphoglycerate kinase 1 (PGK1)-dependent manner, leading to glycogenolysis and the subsequent release of glucose-6-phosphate (G6P) and thereby facilitating aerobic glycolysis. Notably, a virtual screening pinpointed the beta-blocker carvedilol as a potent pharmacological inhibitor of PYGB that could attenuate CCA progression. Collectively, these findings position PYGB as a promising prognostic biomarker and therapeutic target for CCA.

Risk factors of missed early gastric cancer in endoscopic resected population: a retrospective, case-control study.

BACKGROUND: Missed early gastric cancer (MEGC) is prevalent during esophagogastroduodenoscopy (EGD), which is the first-line recommended strategy for detecting early gastric cancer (EGC). Hence, we explored the risk factors for MEGC and different types of MEGC, based on the endoscopic resected population. METHODS: This retrospective, case-control study was conducted at Nanjing Drum Tower Hospital (NJDTH). We included patients who were diagnosed with EGC during screening EGD, underwent endoscopic resection, and were confirmed by postoperative pathology at the NJDTH from January 2014 to December 2021, and classified them into different types according to the different root causes of misses. Univariable, multivariable, subgroup and propensity score analyses were used to explore the risk factors for MEGC and different types of MEGC. RESULTS: A total of 447 patients, comprising 345 with initially detected early gastric cancer (IDEGC) and 102 with MEGC, were included in this study. Larger size (≥ 1 cm) (OR 0.45, 95% CI 0.27-0.74, P = 0.002) and invasion depth of submucosa (OR 0.26, 95% CI 0.10-0.69, P = 0.007) were negatively associated with MEGC. Use of sedation (OR 0.32, 95% CI 0.20-0.52, P < 0.001) and longer observation time (OR 0.60, 95% CI 0.37-0.96, P = 0.034) exhibited protective effect on MEGC. CONCLUSIONS: Smaller and more superficial EGC lesions are more susceptible to misdiagnosis. The use of sedation and prolonged observation time during EGD could help reduce the occurrence of MEGC.

Fraxinellone alleviates colitis-related intestinal fibrosis by blocking the circuit between PD-1+ Th17 cells and fibroblasts.

BACKGROUND: Excessive activation of colonic fibroblasts and differentiation of T helper 17 (Th17) cells are the key steps for intestinal fibrogenesis in the process of inflammatory bowel disease (IBD). Although both transforming growth factor-beta (TGF-ß)/Mothers Against Decapentaplegic Homolog (SMAD) 3-induced fibroblasts activation and interleukin (IL)-6/signal transducer and activator of transcription (STAT) 3-induced Th17 differentiation have been well studied, the crosstalk between fibroblasts and Th17 cells in the process of intestinal fibrogenesis needs to be unveiled. METHODS: In this study, the activation of colonic fibroblasts was induced with dextran sulfate sodium salt (DSS) and TGF-ß in vivo and in vitro respectively. P-SMAD3 and its downstream targets were quantified using RT-PCR, western blot and immunofluorescence. The differentiation of programmed death 1 (PD-1) + Th17 and activation of fibroblasts were quantified by FACS. PD-1+ Th17 cells and fibroblasts were co-cultured and cytokines in the supernatant were tested by ELISA. The anti-fibrosis effects of different chemical compounds were validated in vitro and further confirmed in vivo. RESULTS: The colonic fibroblasts were successfully activated by DSS and TGF-ß in vivo and in vitro respectively, as activation markers of fibroblasts (p-SMAD3 and its downstream targets such as Acta2, Col1a1 and Ctgf) were significantly increased. The activated fibroblasts produced more IL-6 compared with their inactivated counterparts in vivo and in vitro. The proinflammatory cytokine IL-6 induced PD-1+ Th17 differentiation and TGF-ß that in return promoted the activation of colonic fibroblasts. Fraxinellone inhibited TGF-ß+ PD-1+ Th17 cells via deactivating STAT3. CONCLUSIONS: The reciprocal stimulation constructed a circuit of PD-1+ Th17 cells and fibroblasts that accelerated the fibrosis process. Fraxinellone was selected as the potential inhibitor of the circuit of PD-1+ Th17 cells and fibroblasts in vivo and in vitro. Inhibiting the circuit of PD-1+ Th17 cells and fibroblasts could be a promising strategy to alleviate intestinal fibrosis.

HHLA2 deficiency inhibits pancreatic cancer progression and THP-1 macrophage M2 polarization via EGFR/MAPK/ERK and mTOR/AKT pathway.

BACKGROUND: Human endogenous retrovirus subfamily H long terminal repeat associating protein 2, (HHLA2), a member of B7 family, exhibits heightened expression in various malignant tumors. However, the exact functions of HHLA2 in pancreatic cancer (PC) remain incompletely elucidated. METHODS: We initially conducted an analysis of the B7 family members' expression pattern in pancreatic tumor samples and adjacent normal tissues using The Cancer Genome Atlas (TCGA) database. Subsequently, immunohistochemistry, RT-qPCR and western blot methods were used to assess HHLA2 expression levels in PC tissues and cell lines. Furthermore, after silencing HHLA2 in PC cell lines, cell migration and proliferation of PC cells were detected by wound healing and CCK-8 assays, and cell invasion of PC cells was detected by transwell assays. We also investigated the regulation of epithelial-mesenchymal transition (EMT) markers and levels of EGFR, MEK, ERK1/2, mTOR and AKT via western blot analysis. Finally, the correlation between HHLA2 expression and immune infiltration was further explored. RESULTS: Silencing of HHLA2 resulted in the inhibition of PC cell proliferation, migration and invasion, potentially through the suppression of the EGFR/MAPK/ERK and mTOR/AKT signaling pathway. Additionally, silencing HHLA2 led to the inhibition of M2-type polarization of tumor associated macrophages (TAMs). CONCLUSION: The knockdown of HHLA2 was observed to inhibit the migration and invasion of PC cells through the regulation of the EMT process and EGFR/MAPK/ERK and mTOR/AKT pathway. Furthermore, silencing HHLA2 was found to modulate M2 polarization of TAMs. These finding suggest that HHLA2 could be a promising therapeutic target for Pancreatic cancer.

High-throughput enrichment of portal venous circulating tumor cells for highly sensitive diagnosis of CA19-9-negative pancreatic cancer patients using inertial microfluidics.

The carbohydrate antigen 19-9 (CA19-9) is commonly used as a representative biomarker for pancreatic cancer (PC); however, it lacks sensitivity and specificity for early-stage PC diagnosis. Furthermore, some patients with PC are negative for CA19-9 (<37 U/mL), which introduces additional limitations to their accurate diagnosis and treatment. Hence, improved methods to accurately detect PC stages in CA19-9-negative patients are warranted. In this study, tumor-proximal liquid biopsy and inertial microfluidics were coupled to enable high-throughput enrichment of portal venous circulating tumor cells (CTCs) and support the effective diagnosis of patients with early-stage PC. The proposed inertial microfluidic system was shown to provide size-based enrichment of CTCs using inertial focusing and Dean flow effects in slanted spiral channels. Notably, portal venous blood samples were found to have twice the yield of CTCs (21.4 cells per 5 mL) compared with peripheral blood (10.9 CTCs per 5 mL). A combination of peripheral and portal CTC data along with CA19-9 results showed to greatly improve the average accuracy of CA19-9-negative PC patients from 47.1% with regular CA19-9 tests up to 87.1%. Hence, portal venous CTC-based microfluidic biopsy can be used with high sensitivity and specificity for the diagnosis of early-stage PC, particularly in CA19-9-negative patients.

Melatonin ameliorates multiorgan injuries induced by severe acute pancreatitis in mice by regulating the Nrf2 signaling pathway.

Severe acute pancreatitis (SAP) is a complicated inflammatory reaction that impacts the pancreas, often resulting in damage to numerous organs. This disorder encompasses a range of processes such as inflammation, oxidative stress, and pancreatitis. The hormone melatonin (MT) is primarily secreted by the pineal gland and plays a crucial role in mitigating inflammation, countering the harmful effects of free radicals, and regulating oxidative stress. The aim of this research was to investigate the potential protective impact and the underlying mechanism of melatonin in mice afflicted with SAP. The biochemical and histological assessments unequivocally demonstrated that melatonin effectively inhibited necrosis, infiltration, edema and cell death in pancreatic tissues, thereby suppressing acute pancreatitis. Notably, melatonin also alleviated the consequent harm to distant organs, notably the lungs, liver, and kidneys. Furthermore, both preventive and therapeutic administration of melatonin prompted nuclear factor E2-related factor 2 (Nrf2) activation followed by Nrf2 target gene expression. Nrf2 initiates the activation of antioxidant genes, thereby providing defense against oxidative stress. Conversely, Nrf2 reduction may contribute to impaired antioxidant protection in SAP. The beneficial impact of Nrf2 on antioxidants was absent in Nrf2-knockout mice, leading to the accumulation of LDH and exacerbation of cell death. This deterioration in both pancreatitis and injuries in distant organs intensified significantly. The results indicate that melatonin has an enhanced ability to protect against multiorgan damage caused by SAP, which is accomplished through the increase in Nrf2 expression. Additionally, Nrf2 initiates the activation of antioxidant genes that offer defense against cell death.

Lipid Metabolism-Related Gene Signature Predicts Prognosis and Indicates Immune Microenvironment Infiltration in Advanced Gastric Cancer.

Objective: Abnormal lipid metabolism is known to influence the malignant behavior of gastric cancer. However, the underlying mechanism remains elusive. In this study, we comprehensively analyzed the biological significance of genes involved in lipid metabolism in advanced gastric cancer (AGC). Methods: We obtained gene expression profiles from The Cancer Genome Atlas (TCGA) database for early and advanced gastric cancer samples and performed differential expression analysis to identify specific lipid metabolism-related genes in AGC. We then used consensus cluster analysis to classify AGC patients into molecular subtypes based on lipid metabolism and constructed a diagnostic model using least absolute shrinkage and selection operator- (LASSO-) Cox regression analysis and Gene Set Enrichment Analysis (GSEA). We evaluated the discriminative ability and clinical significance of the model using the Kaplan-Meier (KM) curve, ROC curve, DCA curve, and nomogram. We also estimated immune levels based on immune microenvironment expression, immune checkpoints, and immune cell infiltration and obtained hub genes by weighted gene co-expression network analysis (WGCNA) of differential genes from the two molecular subtypes. Results: We identified 6 lipid metabolism genes that were associated with the prognosis of AGC and used consistent clustering to classify AGC patients into two subgroups with significantly different overall survival and immune microenvironment. Our risk model successfully classified patients in the training and validation sets into high-risk and low-risk groups. The high-risk score predicted poor prognosis and indicated low degree of immune infiltration. Subgroup analysis showed that the risk model was an independent predictor of prognosis in AGC. Furthermore, our results indicated that most chemotherapeutic agents are more effective for AGC patients in the low-risk group than in the high-risk group, and risk scores for AGC are strongly correlated with drug sensitivity. Finally, we performed qRT-PCR experiments to verify the relevant results. Conclusion: Our findings suggest that lipid metabolism-related genes play an important role in predicting the prognosis of AGC and regulating immune invasion. These results have important implications for the development of targeted therapies for AGC patients.

DDX3X interacts with SIRT7 to promote PD-L1 expression to facilitate PDAC progression.

Pancreatic ductal adenocarcinoma (PDAC) is recognized as the most aggressive and fatal malignancy. A previous study reported that PDAC patients who exhibit elevated levels of DDX3X have a poor prognosis and low overall survival rate. However, the underlying molecular mechanism remains unclear. This study aimed to investigate the specific roles of DDX3X in PDAC. Multiple bioinformatics analyses were used to evaluate DDX3X expression and its potential role in PDAC. In vitro and in vivo studies were performed to assess the effects of DDX3X on PDAC cell growth. Furthermore, Western blotting, quantitative PCR, immunohistochemistry, immunofluorescence, mass spectrometry, coimmunoprecipitation and multiplexed immunohistochemical staining were conducted to identify the specific regulatory mechanism in PDAC. The results verified that DDX3X expression is notably upregulated in the tumor tissue vs. normal tissue of PDAC patients. DDX3X knockdown markedly suppressed the proliferation, invasion and migration of PDAC cells in vitro and inhibited tumor growth in vivo. Conversely, overexpression of DDX3X induced the opposite effect. Further studies supported that the DDX3X protein can associate with sirtuin 7 (SIRT7) to stimulate PDAC carcinogenesis and progression. Furthermore, SIRT7 inhibition significantly impeded DDX3X-mediated tumor growth both ex vivo and in vivo. The results also revealed that programmed death ligand 1 (PD-L1) expression is positively correlated with DDX3X expression. These results reveal significant involvement of the DDX3X-SIRT7 axis in the initiation and advancement of PDAC and offer previously undiscovered therapeutic options for PDAC management.

Senescence of Hepatic Stellate Cells by Specific Delivery of Manganese for Limiting Liver Fibrosis.

Senescence of activated hepatic stellate cells (HSCs) is crucial for the regression of liver fibrosis. However, impaired immune clearance can result in the accumulation of senescent HSCs, exacerbating liver fibrosis. The activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is essential for both senescence and the innate immune response. Additionally, the specific delivery to activated HSCs is hindered by their inaccessible anatomical location, capillarization of liver sinusoidal endothelial cells (LSECs), and loss of substance exchange. Herein, we propose an antifibrotic strategy that combines prosenescence with enhanced immune clearance through targeted delivery of manganese (a cGAS-STING stimulator) via albumin-mediated transcytosis, specifically aimed at inducing senescence and eliminating activated HSCs in liver fibrosis. Our findings demonstrate that only albumin efficiently transfers manganese to activated HSCs from LSECs via transcytosis compared to liposomes, resulting in significant antifibrotic effects in vivo while exhibiting negligible toxicity.

An oncolytic system produces oxygen selectively in pancreatic tumor cells to alleviate hypoxia and improve immune activation.

INTRODUCTION: Hypoxia is one of the important reasons for the poor therapeutic efficacy of current pancreatic cancer treatment, and the dense stroma of pancreatic cancer restricts the diffusion of oxygen within the tumor. METHODS: A responsive oxygen-self-supplying adv-miRT-CAT-KR (adv-MCK) cascade reaction system to improve hypoxia in pancreatic cancer is constructed. We utilized various experiments at multiple levels (cells, organoids, in vivo) to investigate its effect on pancreatic cancer and analyzed the role of immune microenvironment changes in it through high-throughput sequencing. RESULTS: The adv-MCK system is an oncolytic adenovirus system expressing three special components of genes. The microRNA (miRNA) targets (miRTs) enable adv-MCK to selectively replicate in pancreatic cancer cells. Catalase catalyzes the overexpressed hydrogen peroxide in pancreatic cancer cells to generate endogenous oxygen, which is catalyzed by killerRed to generate singlet oxygen (1O2) and further to enhance the oncolytic effect. Meanwhile, the adv-MCK system can specifically improve hypoxia in pancreatic cancer, exert antitumor effects in combination with photodynamic therapy, and activate antitumor immunity, especially by increasing the level of γδ T cells in the tumor microenvironment. CONCLUSION: The responsive oxygen-self-supplying adv-MCK cascade reaction system combined with photodynamic therapy can improve the hypoxic microenvironment of pancreatic cancer and enhance antitumor immunity, which provides a promising alternative treatment strategy for pancreatic cancer.

Ileitis promotes MASLD progression via bile acid modulation and enhanced TGR5 signaling in ileal CD8+ T cells.

BACKGROUND & AIMS: Clinical evidence substantiates a link between inflammatory bowel disease, particularly Crohn's disease (CD), and metabolic dysfunction-associated steatotic liver disease (MASLD). This study aims to explore the underlying molecular mechanisms responsible for this association. METHODS: MASLD was induced by administering high-fat and western diets, while inflammatory bowel disease was induced using DSS (dextran sulfate sodium) and the Il10 knockout (KO) mouse model. The investigation into the role of secondary bile acids (SBAs) in ileitis involved employing metagenomic sequencing, conducting metabolomics detection, performing fecal microbiota transplantation, and constructing CD8+ T cell-specific gene knockout mice. RESULTS: In MASLD+DSS and Il10 KO MASLD mice, we observed ileitis characterized by T-cell infiltration and activation in the terminal ileum. This condition resulted in decreased bile acid levels in the portal vein and liver, inhibited hepatic farnesoid X receptor (FXR) activation, and exacerbated MASLD. Metagenomic and metabolomic analysis of ileal contents revealed increased Clostridium proliferation and elevated SBA levels in MASLD-associated ileitis. Experiments using germ-free mice and fecal microbiota transplantation suggested an association between SBA and MASLD-related ileitis. In vitro, SBAs promoted CD8+ T-cell activation via the TGR5, mTOR, and oxidative phosphorylation pathways. In vivo, TGR5 KO in CD8+ T cells effectively alleviated ileitis and reversed the MASLD phenotype. Clinical data further supported these findings, demonstrating a positive correlation between ileitis and MASLD. CONCLUSION: MASLD-induced changes in intestinal flora result in elevated levels of SBAs in the ileum. In the presence of a compromised intestinal barrier, this leads to severe CD8+ T cell-mediated ileitis through the TGR5/mTOR/oxidative phosphorylation signaling pathway. Ileitis-induced tissue damage impairs enterohepatic circulation, inhibits hepatic FXR activation, and exacerbates the MASLD phenotype. IMPACT AND IMPLICATIONS: Our study provides a comprehensive investigation of the interplay and underlying mechanisms connecting ileitis and metabolic dysfunction-associated steatotic liver disease (MASLD). Secondary bile acids produced by intestinal bacteria act as the critical link between MASLD and ileitis. Secondary bile acids exert their influence by disrupting liver lipid metabolism through the promotion of CD8+ T cell-mediated ileitis. In future endeavors to prevent and treat MASLD, it is essential to thoroughly account for the impact of the intestinal tract, especially the ileum, on liver function via the enterohepatic circulation.

CAFs Homologous Biomimetic Liposome Bearing BET Inhibitor and Pirfenidone Synergistically Promoting Antitumor Efficacy in Pancreatic Ductal Adenocarcinoma.

BRD4 is a member of the BET protein family involved in chromatin remodeling and transcriptional regulation. Several BET inhibitors (BETi) have entered clinical trials, demonstrating potential in inducing cancer cell apoptosis and tumor regression. However, resistance to BETi is common in solid tumors. In pancreatic cancer, it is found that cancer-associated fibroblasts (CAFs) in the tumor microenvironment reduce the BET inhibitor JQ1 sensitivity by inducing BRD4 expression. Moreover, CAFs play a crucial role in the formation of a dense stromal barrier. Therefore, targeting CAFs in the tumor microenvironment of pancreatic cancer not only enhances cancer cells sensitivity to JQ1 but also increases drug perfusion and improves oxygen supply, thus reducing glycolysis and limiting energy supply. To address this challenge, a homologous targeting mechanism utilizing activated fibroblast membrane-coated liposomes is proposed for specific drug precise target to CAFs-rich pancreatic cancer. Additionally, TAT peptides enable liposomes penetration, delivering PFD for targeted anti-fibrotic therapy, reducing extracellular matrix generation and glycolysis, and enhancing JQ1 delivery and sensitivity. In conclusion, the findings indicate the tremendous potential of this CAFs-targeting liposomal delivery system in pancreatic cancer.

Protective and Adverse Roles of DDX3X in Different Cell Types in Nonalcoholic Steatohepatitis Progression.

Persistent hepatic cellular metabolic stress and liver inflammatory stimuli are key signatures of nonalcoholic steatohepatitis (NASH). DDX3X is a vital molecule involved in cell fate decisions in both pro-survival stress granule (SG) and pro-death NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome assembly in response to stress signals. However, the role of DDX3X in NASH remains unclear. We characterized the cell type-specific roles of DDX3X in NASH. Human liver tissues from NASH patients and normal control subjects were collected to assess DDX3X expression and distribution. Nutritional steatohepatitis models were constructed by feeding macrophage-specific DDX3X knockout (DDX3XΔMφ), hepatocyte-specific DDX3X knockout (DDX3XΔhep), and wild-type control (DDX3Xfl/fl) mice a high-fat and high-cholesterol (HFHC) diet, a methionine- and choline-deficient (MCD) diet, and a high-fat/high-iron/high-fructose/high-cholesterol, low-methionine, and choline-deficient (HFHIHFHC-MCD) diet. The study demonstrated that DDX3X was predominantly expressed in macrophages and hepatocytes in control liver tissues, and its expression was down-regulated in patients or mice with NASH. Compared to DDX3Xfl/fl littermates, DDX3XΔMφ mice showed improved liver histology in nutritional steatohepatitis models. Loss of macrophage DDX3X inhibited NLRP3 inflammasome-mediated pyroptosis, causing anti-inflammatory M2 polarization and alleviating hepatocyte steatohepatitic changes. DDX3XΔhep mice developed marked steatohepatitis in multiple nutritional steatohepatitis models compared to DDX3Xfl/fl littermates. DDX3X-deleted hepatocytes showed impaired SG assembly, leading to increased sensitivity and intolerance to metabolic stimulation and resultant steatohepatitis. In conclusion, DDX3X plays opposite roles in different cell types during the progression of NASH. A better understanding of the cell-specific differences in the crosstalk between SG formation and NLRP3 activation is crucial for developing prospective targeted DDX3X inhibitors for the treatment of NASH.

Erratum: Targeting sphingosine kinase 2 suppresses cell growth and synergizes with BCL2/BCL-XL inhibitors through NOXA-mediated MCL1 degradation in cholangiocarcinoma.

[This corrects the article on p. 546 in vol. 9, PMID: 30949409.].

Feasibility of gallbladder lesion visualization using a novel ultrafine peroral cholangioscopy: A preliminary investigation.

BACKGROUND: Endoscopic visualization of gallbladder lesions by the traditional peroral cholangioscopy (POCS) during the endoscopic retrograde cholangiopancreatography process is challenging. In the present study, we evaluated the feasibility of a newly designed POCS with an ultrafine outer diameter that facilitates gallbladder visualization. METHODS: The novel POCS was designed and manufactured with an outer diameter of 7 French and achieved extremely high performance. The feasibility of this novel POCS for gallbladder observation was assessed in our center between April 2022 and January 2023. The primary outcome was technical success. RESULTS: A total of 16 patients (64.6 ± 18.1 years, 9 males) who underwent novel ultrafine POCS inspection for gallbladder visualization were included. Technical success was achieved in 14 of 16 cases (87.5%); the main reasons for the two unsuccessful inspections were the presence of cystic duct strictures. A total of 1 adverse event occurred, for an overall rate of 6.3%, and there were no serious adverse events during the follow-up. CONCLUSIONS: The results suggest that endoscopic visualization of the gallbladder using the novel ultrafine POCS is feasible. The device is expected to provide a new direction for the management of gallbladder disorders in the future.