Auranofin inhibits the occurrence of colorectal cancer by promoting mTOR-dependent autophagy and inhibiting epithelial-mesenchymal transformation.

Colorectal cancer (CRC) is one of the world's most common and deadly cancers. According to GLOBOCAN2020's global incidence rate and mortality estimates, CRC is the third main cause of cancer and the second leading cause of cancer-related deaths worldwide. The US Food and Drug Administration has approved auranofin for the treatment of rheumatoid arthritis. It is a gold-containing chemical that inhibits thioredoxin reductase. Auranofin has a number of biological activities, including anticancer activity, although it has not been researched extensively in CRC, and the mechanism of action on CRC cells is still unknown. The goal of this research was to see how Auranofin affected CRC cells in vivo and in vitro . The two chemical libraries were tested for drugs that make CRC cells more responsive. The CCK-8 technique was used to determine the cell survival rate. The invasion, migration, and proliferation of cells were assessed using a transwell test and a colony cloning experiment. An electron microscope was used to observe autophagosome formation. Western blotting was also used to determine the degree of expression of related proteins in cells. Auranofin's tumor-suppressing properties were further tested in a xenograft tumor model of human SW620 CRC cells. Auranofin dramatically reduced the occurrence of CRC by decreasing the proliferation, migration, and invasion of CRC cells, according to our findings. Through a mTOR-dependent mechanism, auranofin inhibits the epithelial-mesenchymal transition (EMT) and induces autophagy in CRC cells. Finally, in-vivo tests revealed that auranofin suppressed tumor growth in xenograft mice while causing no harm. In summary, auranofin suppresses CRC cell growth, invasion, and migration. Auranofin inhibits the occurrence and progression of CRC by decreasing EMT and inducing autophagy in CRC cells via a mTOR-dependent mechanism. These findings suggest that auranofin could be a potential chemotherapeutic medication for the treatment of human CRC.

A Retrospective Analysis of the Efficacy of Endoscopic Variceal Ligation versus Endoscopic Tissue Adhesive Injection in the Treatment of Esophagogastric Variceal Bleeding.

BACKGROUND: The aim of the study was to investigate the effectiveness and safety of endoscopic variceal ligation (EVL) and endoscopic tissue adhesive injection (TAI) in the treatment of esophagogastric variceal bleeding (EVB). METHODS: A total of 245 patients with EVB who attended the First Affiliated Hospital of Bengbu Medical College from December 2017 to June 2021 were retrospectively collected. The participants were divided into the esophageal EVL (E-EVL) + gastric EVL (G-EVL) group (n = 103) and E-EVL + gastric TAI (G-TAI) group (n = 142), according to the procedure, comparing and assessing the clinical characteristics, laboratory results, operation time, rebleeding rate, efficacy, and complications. RESULTS: The E-EVL + G-EVL group had significantly less varicose vein diameter and operative time than the E-EVL + G-TAI group (p < 0.05). No statistical difference in the length of hospital stay between the two groups was noted (p > 0.05). The total rebleeding rate in the E-EVL + G-EVL group was 9.7%, whereas that of the E-EVL + G-TAI group was 11.9%; no statistical difference between the two groups was noted (p > 0.05). The overall effective rate of the E-EVL + G-EVL group was 90.21%, whereas that of the E-EVL + G-TAI group was 92.81%; no statistical difference between the two groups was observed (p > 0.05). The postoperative ulcer in the E-EVL + G-EVL group was smaller and more superficial than that in the E-EVL + G-TAI group, and the wound surface was smoother. CONCLUSION: Both EVL and TAI have good therapeutic effects on EVB. Furthermore, owing to its effectiveness in preventing rebleeding, no reduction in efficacy and no increase in complications, shortened operative time, smaller and superficial ulcer, and smoother wounds, gastric EVL is worthy of further clinical promotion.

Synergism between SLC6A14 blockade and gemcitabine in pancreactic cancer: a 1H-NMR-based metabolomic study in pancreatic cancer cells.

Gemcitabine is the first-line chemotherapy for pancreatic cancer. To overcome the often-acquired gemcitabine resistance, other drugs are used in combination with gemcitabine. It is well-known that cancer cells reprogram cellular metabolism, coupled with the up-regulation of selective nutrient transporters to feed into the altered metabolic pathways. Our previous studies have demonstrated that the amino acid transporter SLC6A14 is markedly up-regulated in pancreatic cancer and that it is a viable therapeutic target. α-Methyltryptophan (α-MT) is a blocker of SLC6A14 and is effective against pancreatic cancer in vitro and in vivo. In the present study, we tested the hypothesis that α-MT could synergize with gemcitabine in the treatment of pancreatic cancer. We investigated the effects of combination of α-MT and gemcitabine on proliferation, migration, and apoptosis in a human pancreatic cancer cell line, and examined the underlying mechanisms using 1H-NMR-based metabolomic analysis. These studies examined the intracellular metabolite profile and the extracellular metabolite profile separately. Combination of α-MT with gemcitabine elicited marked changes in a wide variety of metabolic pathways, particularly amino acid metabolism with notable alterations in pathways involving tryptophan, branched-chain amino acids, ketone bodies, and membrane phospholipids. The metabolomic profiles of untreated control cells and cells treated with gemcitabine or α-MT were distinctly separable, and the combination regimen showed a certain extent of overlap with the individual α-MT and gemcitabine groups. This represents the first study detailing the metabolomic basis of the anticancer efficacy of gemcitabine, α-MT and their combination.

Mir-488 alleviates chemoresistance and glycolysis of colorectal cancer by targeting PFKFB3.

BACKGROUND: Considering the boosting effect of glycolysis on tumor chemoresistance, this investigation aimed at exploring whether miR-488/PFKFB3 axis might reduce drug resistance of colorectal cancer (CRC) by affecting glycolysis, proliferation, migration, and invasion of CRC cells. METHOD: Totally, 288 CRC patients were divided into metastasis/recurrence group (n = 107) and non-metastasis/recurrence group (n = 181) according to their prognosis about 1 year after the chemotherapy, and their 3-year overall survival was also tracked. Besides, miR-488 expression was determined in peripheral blood of CRC patients and also in CRC cell lines (ie, W620, HT-29, Lovo, and HCT116). The targeted relationship between miR-488 and PFKFB3 was predicted by Targetscan software and confirmed by dual-luciferase reporter gene assay. Moreover, glycolysis and drug tolerance of CRC cells lines were assessed. RESULTS: MiR-488 expression was significantly decreased in metastatic/recurrent CRC patients than those without metastasis/recurrence (P < .05), and lowly expressed miR-488 was suggestive of unfavorable 3-year survival, large tumor size, poor differentiation, in-depth infiltration, and advanced Duke stage of CRC patients (P < .05). Besides, CRC cell lines transfected by miR-488 mimic demonstrated decreases in glucose uptake and lactate secretion, increases in oxaliplatin/5-Fu-sensistivity, as well as diminished capability of proliferating, invading, and migratory (P < .05), which were reversible by extra transfection of pcDNA3.1-PFKFB3 (ie, miR-488 mimic + pcDNA3.1-PFKFB3 group). Finally, the mRNA level of PFKFB3 was down-regulated by miR-488 mimic in CRC cell lines after being targeted by it (P < .05). CONCLUSION: The miR-488/PFKFB3 axis might clinically refine chemotherapeutic efficacy of CRC, given its modifying glycolysis and metastasis of CRC cells.

Aloperine can reverse the cisplatin resistance of colorectal cancer cells via suppressing the HIF-1α/ERK signaling pathway.

Background: Aloperine can exert antitumor effects in colorectal cancer; however, it remains obscure whether aloperine can reverse the cisplatin resistance in colorectal cancer (CRC). Objective: To explore the roles of aloperine in the chemosensitivity of the DDP-resistant colorectal cancer cell line HT-29 (HT-29/DDP) and the related mechanism. Results: Aloperine can inhibit the proliferation of both HT-29 and HT-29/DDP cells in a dose-dependent manner; moreover, aloperine can significantly increase the sensitivity of HT-29/DDP cells to DDP; finally, HIF-1α and p-ERK was upregulated in HT-29/DDP cells and transient over-expression of HIF-1α has blocked aloperine+DDP induced anti-proliferative and pro-apoptotic effects on HT-29/DDP cells. Conclusion: We are reporting for the first time that aloperine can increase the sensitivity of HT-29/DDP cells to DDP and reverse cisplatin resistance via downregulating the HIF-1α /ERK signaling pathway.

Alantolactone sensitizes human pancreatic cancer cells to EGFR inhibitors through the inhibition of STAT3 signaling.

Several studies have implicated the feedback activation of signal transducer and activator of transcription 3 (STAT3) as a new cancer drug-resistance mechanism and linked it to the failure of epidermal growth factor receptor (EGFR)-targeted therapies. In this study, we discovered that Alantolactone, a natural sesquiterpene lactone, potently inhibited human pancreatic cancer cells and suppressed constitutively activated STAT3. In contrast, Alantolactone had little effect on the EGFR pathway. Moreover, combination of Alantolactone and an EGFR inhibitor, Erlotinib or Afatinib, demonstrated a remarkable synergistic anti-cancer effect against pancreatic cancer cells both in vitro and in vivo. Our results suggested that Alantolactone could sensitize human pancreatic cancer cells to EGFR inhibitors possibly through down-regulating the STAT3 signaling. Alantolactone, when combined with other EGFR targeted agents, could be further developed as a potential therapy for pancreatic cancer.

Synergistic antitumor effect of 3-bromopyruvate and 5-fluorouracil against human colorectal cancer through cell cycle arrest and induction of apoptosis.

3-Bromopyruvic acid (3-BP) is a well-known inhibitor of energy metabolism. It has been proposed as an anticancer agent as well as a chemosensitizer for use in combination with anticancer drugs. 5-Fluorouracil (5-FU) is the first-line chemotherapeutic agent for colorectal cancer; however, most patients develop resistance to 5-FU through various mechanisms. The aim of this study was to investigate whether 3-BP has a synergistic antitumor effect with 5-FU on human colorectal cancer cells. In our study, combined 3-BP and 5-FU treatment upregulated p53 and p21, whereas cyclin-dependent kinase CDK4 and CDK2 were downregulated, which led to G0/G1 phase arrest. Furthermore, there was an increase in reactive oxygen species levels and a decrease in adenosine triphosphate levels. It was also observed that Bax expression increased, whereas Bcl-2 expression reduced, which were indicative of mitochondria-dependent apoptosis. In addition, the combination of 3-BP and 5-FU significantly suppressed tumor growth in the BALB/c mice in vivo. Therefore, 3-BP inhibits tumor proliferation and induces S and G2/M phase arrest. It also exerts a synergistic antitumor effect with 5-FU on SW480 cells.

A novel STAT3 inhibitor HO-3867 induces cell apoptosis by reactive oxygen species-dependent endoplasmic reticulum stress in human pancreatic cancer cells.

Pancreatic cancer is the most commonly diagnosed malignancy among solid tumors and has shown an increasing trend year by year. Thus, there is an urgent need for the discovery of new anticancer drugs for the treatment of pancreatic cancer. In recent years, it has been reported that the compound HO-3867, a novel analog of the natural product curcumin, showed antitumor activity with low toxicity. However, the underlying mechanism of this compound's attack on cancer cells is not very clear. In the present study, it was found that HO-3867 showed good antitumor activity at the concentration of 2 µmol/l in PANC-1 and BXPC-3 cells. Importantly, it was also found that HO-3867 treatment significantly induced reactive oxygen species (ROS) production in human pancreatic cancer cell lines, inducing PANC-1 and BXPC-3 cells. Co-treatment with the ROS scavenger, N-acetyl cysteine, partially abrogated HO-3867-induced cell apoptosis. The activation of mitogen-activated protein kinase and endoplasmic reticulum stress indicated a downstream event of ROS generation in mediating the anticancer effect of the HO-3867. In addition, independent of the ROS pathway, direct STAT3 inhibition was observed in HO-3867-induced cell apoptosis. Taken together, the results of this work suggest that both the ROS-dependent ER stress and STAT3 pathways were implicated in the cell apoptosis induced by the novel compound HO-3867.

[Effect of oridonin on apoptosis and intracellular reactive oxygen species level in triple-negative breast cancer MDA-MB-231 cells].

Oridonin, which is an ent-kaurene diterpenoid isolated from traditional Chinese medicine Rabdosia rubescens, displays various bioactivities, including anti-inflammation, anti-bacteria and anti-tumor. This study aimed to investigate the effect of oridonin on apoptosis of triple-negative breast cancer MDA-MB-231 cells and its underlying mechanisms. The inhibitory effect of oridonin on proliferation of MDA-MB-231 cells was measured by MTT assay; Apoptosis was analyzed by flow cytometry with PI staining and Annexin V-FITC/PI staining; Intracellular reactive oxygen species (ROS) level was determined by ROS detection kit, and expressions of PARP, Bcl-2, caspase-3 were analyzed by Western blot. The results showed that oridonin exhibited a significant effect in inducing apoptosis of MDA-MB-231 cells, enhancing intracellular ROS level, down-regulating expression of Bcl-2 protein, and promoting cleavage of caspase-3 and its substrate PARP. These results indicated that the apoptosis-inducing effect of oridonin on MDA-MB-231 cells might be correlated with increase of intracellular ROS level, down-regulation of Bcl-2 protein and activation of caspase-3.

miR-30c affects the pathogenesis of ulcerative colitis by regulating target gene VIP.

MicroRNAs play a crucial role in regulating the epithelial barrier and immune response, which are implicated in the pathogenesis of ulcerative colitis (UC). This study aimed to investigate the role and molecular mechanism of miR-30c in the pathogenesis of UC using a dextran sulfate sodium salt (DSS)-induced colitis model, which is similar to ulcerative colitis. Wild-type (WT) and miR-30c knockout (KO) mice were assigned to either control or DSS-treated groups to evaluate the influence of aberrant miR-30c expression on UC pathogenesis. The disease activity index, inflammatory factors, and the extent of pathological and histological damage in colon tissues were analyzed. The effect of miR-30c on vasoactive intestinal peptide (VIP) gene expression was validated through luciferase reporter assay, qRT-PCR, Western blotting, and immunohistochemistry. The results showed that miR-30c KO mice with DSS-induced colitis model showed more severe phenotypes: significantly higher disease activity indices, significant body weight loss, reduced length of the colon of mice, increased number of aberrant crypt structures, reduced mucus secretion, and significant differences in inflammatory factors. These findings suggested that the absence of miR-30c might promote DSS-induced colitis, and the targe-regulatory effect of miR-30c on VIP might play an important role in the development of colitis.

Risk prediction of cholangitis after stent implantation based on machine learning.

The risk of cholangitis after ERCP implantation in malignant obstructive jaundice patients remains unknown. To develop models based on artificial intelligence methods to predict cholangitis risk more accurately, according to patients after stent implantation in patients' MOJ clinical data. This retrospective study included 218 patients with MOJ undergoing ERCP surgery. A total of 27 clinical variables were collected as input variables. Seven models (including univariate analysis and six machine learning models) were trained and tested for classified prediction. The model' performance was measured by AUROC. The RFT model demonstrated excellent performances with accuracies up to 0.86 and AUROC up to 0.87. Feature selection in RF and SHAP was similar, and the choice of the best variable subset produced a high performance with an AUROC up to 0.89. We have developed a hybrid machine learning model with better predictive performance than traditional LR prediction models, as well as other machine learning models for cholangitis based on simple clinical data. The model can assist doctors in clinical diagnosis, adopt reasonable treatment plans, and improve the survival rate of patients.

Multifunctional iron-apigenin nanocomplex conducting photothermal therapy and triggering augmented immune response for triple negative breast cancer.

Triple negative breast cancer (TNBC) presents a formidable challenge due to its low sensitivity to many chemotherapeutic drugs and a relatively low overall survival rate in clinical practice. Photothermal therapy has recently garnered substantial interest in cancer treatment, owing to its swift therapeutic effectiveness and minimal impact on normal cells. Metal-polyphenol nanostructures have recently garnered significant attention as photothermal transduction agents due to their facile preparation and favorable photothermal properties. In this study, we employed a coordinated approach involving Fe3+ and apigenin, a polyphenol compound, to construct the nanostructure (nFeAPG), with the assistance of ß-CD and DSPE-PEG facilitating the formation of the complex nanostructure. In vitro research demonstrated that the formed nFeAPG could induce cell death by elevating intracellular oxidative stress, inhibiting antioxidative system, and promoting apoptosis and ferroptosis, and near infrared spectrum irradiation further strengthen the therapeutic outcome. In 4T1 tumor bearing mice, nFeAPG could effectively accumulate into tumor site and exhibit commendable control over tumor growth. Futher analysis demonstrated that nFeAPG ameliorated the suppressed immune microenvironment by augmenting the response of DC cells and T cells. This study underscores that nFeAPG encompasses a multifaceted capacity to combat TNBC, holding promise as a compelling therapeutic strategy for TNBC treatment.

Sinomenine hydrochloride improves DSS-induced colitis in mice through inhibition of the TLR2/NF-κB signaling pathway.

BACKGROUND: Sinomenine hydrochloride (SH) has anti-inflammatory and immunosuppressive effects, and its effectiveness in inflammatory diseases, such as rheumatoid arthritis, has been demonstrated. However, whether SH has a therapeutic effect on dextran sodium sulfate (DSS)-induced ulcerative colitis (UC) in mice and its mechanism of action have not been clarified. This study aimed to investigate the therapeutic effects and mechanism of action of SH on UC. METHODS: Twenty-four mice were randomly divided into control, model, SH low-dose (SH-L, 20mg/kg), and SH high-dose (SH-H, 60mg/kg) groups with six mice in each group. Disease activity index (DAI), colonic mucosal damage index, and colonic histopathology scores were calculated. The expression levels of related proteins, genes, and downstream inflammatory factors in the Toll-like receptor 2/NF-κB (TLR2/NF-κB) signaling pathway were quantified. RESULTS: SH inhibited weight loss, decreased DAI and histopathological scores, decreased the expression levels of TLR2, MyD88, P-P65, P65 proteins, and TLR2 genes, and also suppressed the expression of inflammatory factors TNF-α, IL-1 ß, and IL-6 in the peripheral blood of mice. CONCLUSION: The therapeutic effect of SH on DSS-induced UC in mice may be related to the inhibition of the TLR2/NF-κB signaling pathway.

Downregulation of CLDN6 inhibits cell migration and invasion and promotes apoptosis by regulation of the JAK2/STAT3 signaling pathway in hepatocellular carcinoma.

Background: High expression of CLDN6 in hepatocellular carcinoma (HCC) has been widely reported. During this research, CLDN6's effect on the infiltration, migration, and apoptosis of HCC cells was investigated. Methods: Initially, the knockdown and overexpression of CLDN6 in HCC cells were carried out by short interfering RNA (siRNA) and plasmid transfection. The transfection efficiency was detected by means of a quantitative real-time polymerase chain reaction (qRT-PCR) assay, immunofluorescence staining, and Western blot analysis. Transwell and wound-healing assays were employed for the detection of invasion and migration ability. CCK-8 assay and flow cytometry were utilized for the detection of apoptosis. Finally, analysis of the expression of pathway-related proteins (JAK2, STAT3, p-JAK2, and p-STAT3) and the regulation of apoptotic responses (by measurement of cleaved caspase-3, Bax, and Bcl-2 levels) was carried out. Results: When CLDN6 was knocked down, the cellular invasion and migration ability decreased, and apoptosis increased, which decreased p-JAK2, p-STAT3, and anti-apoptotic protein bcl-2 expression. Furthermore, an elevation was observed in cleaved caspase-3 and Bax expression levels. Contrarily, upon overexpression of CDLN6, the aforementioned experimental results were reversed. Conclusions: CLDN6 knockdown results in the inhibition of HCC cells' infiltration and migration and promotes apoptosis via downregulation of the JAK2/STAT3 signaling pathway.

Cinobufagin exerts an antitumor effect in non-small-cell lung cancer by blocking STAT3 signaling.

Background: Non-small-cell lung cancer (NSCLC) is the most common histological subtype of lung cancer with significant morbidity and mortality rates worldwide. Cinobufagin, the primary component of Chansu and the major active ingredient of cinobufacini, has attracted widespread attention for its excellent anticancer effects, but its activity remains poorly characterized in NSCLC. Methods: The functions of cinobufagin treatment in anti-tumor was evaluated using various in vitro and in vivo assays. The change of STAT3 signaling by cinobufagin was analyzed using molecular docking, immunofluorescence technic and western blotting. Results: In vitro, we confirmed the inhibitory effect of cinobufagin on cell viability, proliferation, migration, epithelial-mesenchymal transition (EMT), as well as an apoptosis-inducing effect. The antitumor effects of cinobufagin were confirmed in vivo by measuring tumor growth in a mouse xenograft model. Cinobufagin was found to significantly inhibit the phosphorylation of signal transducer and activator of transcription 3 (STAT3) at tyrosine 705 (Y705) in a time- and concentration-dependent manner. Moreover, cinobufagin reversed IL-6-induced nuclear translocation of STAT3. Conclusions: Our study has demonstrated that cinobufagin exerts an antitumor effect in non-small-cell lung cancer by blocking STAT3 signaling, and cinobufagin is a promising candidate agent for NSCLC therapy.

ATB0,+-targeted nanoparticles initiate autophagy suppression to overcome chemoresistance for enhanced colorectal cancer therapy.

Oxaliplatin (OXA) resistance remains the major obstacle to the successful chemotherapy of colorectal cancer (CRC). As a self-protection mechanism, autophagy may contribute to tumor drug resistance, therefore autophagy suppression could be regarded as a possible treatment option in chemotherapy. Cancer cells, especially drug-resistant tumor cells, increase their demand for specific amino acids by expanding exogenous supply and up-regulating de novo synthesis, to meet the needs for excessive proliferation. Therefore, it is possible to inhibit cancer cell proliferation through pharmacologically blocking the entry of amino acid into cancer cells. SLC6A14 (ATB0,+) is an essential amino acid transporter, that is often abnormally up-regulated in most cancer cells. Herein, in this study, we designed oxaliplatin/berbamine-coloaded, ATB0,+-targeted nanoparticles ((O + B)@Trp-NPs) to therapeutically target SLC6A14 (ATB0,+) and inhibit cancer proliferation. The (O + B)@Trp-NPs utilize the surface-modified tryptophan to achieve SLC6A14-targeted delivery of Berbamine (BBM), a compound that is found in a number of plants used in traditional Chinese medicine, which could suppress autolysosome formation though impairing autophagosome-lysosome fusion. We verified the feasibility of this strategy to overcome the OXA resistance during colorectal cancer treatment. The (O + B)@Trp-NPs significantly inhibited the proliferation and decreased the drug resistance of resistant colorectal cancer cells. In vivo, (O + B)@Trp-NPs greatly suppressed the tumor growth in tumor-bearing mice, which is consistent with the in vitro data. This research offers a unique and promising chemotherapeutic treatment for colorectal cancer.

Resetting amino acid metabolism of cancer cells by ATB0,+-targeted nanoparticles for enhanced anticancer therapy.

Reprogramed cellular metabolism is one of the most significant hallmarks of cancer. All cancer cells exhibit increased demand for specific amino acids, and become dependent on either an exogenous supply or upregulated de novo synthesis. The resultant enhanced availability of amino acids supports the reprogramed metabolic pathways and fuels the malignant growth and metastasis of cancers by providing energy and critical metabolic intermediates, facilitating anabolism, and activating signaling networks related to cell proliferation and growth. Therefore, pharmacologic blockade of amino acid entry into cancer cells is likely to have a detrimental effect on cancer cell growth. Here we developed a nanoplatform (LJ@Trp-NPs) to therapeutically target two transporters, SLC6A14 (ATB0,+) and SLC7A5 (LAT1), that are known to be essential for the sustenance of amino acid metabolism in most cancers. The LJ@Trp-NPs uses tryptophan to guide SLC6A14-targeted delivery of JPH203, a high-affinity inhibitor of SLC7A5. In the process, SLC6A14 is also down-regulated. We tested the ability of this strategy to synergize with the anticancer efficacy of lapatinib, an inhibitor of EGFR/HER1/HER2-assocated kinase. These studies show that blockade of amino acid entry amplifies the anticancer effect of lapatinib via interference with mTOR signaling, promotion of apoptosis, and suppression of cell proliferation and metastasis. This represents the first study to evaluate the impact of amino acid starvation on the anticancer efficacy of widely used kinase inhibitor.

Association between lactate-to-albumin ratio and 28-days all-cause mortality in patients with acute pancreatitis: A retrospective analysis of the MIMIC-IV database.

Objective: The Lactate-to-Albumin Ratio (LAR) has been applied as a new predictor in sepsis, heart failure, and acute respiratory failure. However, the role of LAR in predicting all-cause mortality in patients with acute pancreatitis has not been evaluated. Therefore, this study aimed to elucidate the correlation between LAR and 28-d all-cause mortality in patients with Acute Pancreatitis (AP). Methods: This study is a retrospective cohort study with the data from the MIMIC-IV (v1.0) database. We included adult patients with acute pancreatitis who were admitted to the intensive care unit in the study. The primary outcome was to evaluate the ability of LAR to predict death at 28-d of hospital admission in patients with AP. Results: A total of 539 patients with acute pancreatitis were included in this study. They were divided into a survival group (486 patients) and a death group (53 patients) according to whether they survived within 28-d of admission, and the mortality rate of patients within 28-d of admission was 9.8%. LAR was shown to be an independent predictor of all-cause mortality within 28-d of admission in patients with AP by multivariate COX regression analysis (HR, 1.59; 95% CI, 1.23 - 2.05; P < 0.001). the Area Under the Curve (AUC) value for LAR was 74.26% (95% CI: 67.02% - 81.50%), which was higher than that for arterial blood lactate (AUC = 71.25%) and serum albumin (AUC = 65.92%) alone. It was not inferior even when compared to SOFA (AUC = 75.15%). The optimal cutoff value for separating the survival and death groups according to Receiver Operating Characteristic (ROC) was found to be 1.1124. plotting Kaplan-Meier analysis with this cutoff value showed that patients with LAR ≥ 1.1124 had significantly higher all-cause mortality within 28-d of admission than those with LAR < 1.1124 (P < 0.001). The final subgroup analysis showed no significant interaction of LAR with each subgroup (P for interaction: 0.06 - 0.974). Conclusion: LAR can be used as an independent predictor of all-cause mortality in AP patients within 28-d of admission, with superior prognostic performance than arterial blood lactate or serum albumin alone.

Diosgenin inhibits the proliferation of gastric cancer cells via inducing mesoderm posterior 1 down-regulation-mediated alternative reading frame expression.

INTRODUCTION: Whether and how mesoderm posterior 1 (MESP1) plays a role in the proliferation of gastric cancer cells remain unclear. METHODS: The expression of MESP1 was compared in 48 human gastric cancer tissues and adjacent normal tissues. Knockdown of MESP1 was performed to investigate the role of MESP1 in the proliferation and apoptosis of BGC-823 and MGC-803 gastric cancer cells. Knockdown of alternative reading frame (ARF) was performed to study the role of ARF in the inhibitory effect of MESP1 knockdown on cell proliferation in gastric cancer cells. Mouse subcutaneous xenograft tumor model bearing BGC-823 cells was used to investigate the role of MESP1 in the growth of gastric tumor in vivo. The effect of seven active ingredients from T. terrestris on MESP1 expression was tested. The anti-cancer effect of diosgenin was confirmed in gastric cancer cells. MESP1 dependence of the anti-cancer effect of diosgenin was confirmed by MESP1 knockdown. RESULTS: MESP1 was highly expressed in human gastric cancer tissues (p < 0.05). MESP1 knockdown induced apoptosis and up-regulated the expression of ARF in gastric cancer cells (p < 0.05). Knockdown of ARF attenuated the anti-cancer effect of MESP1 knockdown (p < 0.05). In addition, MESP1 knockdown also suppressed tumor growth in vivo (p < 0.05). Diosgenin inhibits both mRNA and protein expression of MESP1 (p < 0.05). MESP1 knockdown attenuated the anti-cancer effect of diosgenin (p < 0.05). CONCLUSIONS: MESP1 promotes the proliferation of gastric cancer cells via inhibiting ARF expression. Diosgenin exerts anti-cancer effect through inhibiting MESP1 expression in gastric cancer cells.

Influence of periampullary diverticula on endoscopic retrograde cholangiopancreatography.

The present study aimed to explore the influence of the presence of periampullary diverticula (PAD) on the implementation of endoscopic retrograde cholangiopancreatography (ERCP). A total of 388 patients with pancreaticobiliary disease who underwent ERCP for the first time between January 2017 and December 2018 were included and they were divided into a PAD group (n=179) and non-PAD (N-PAD) group (n=209) according to the presence or absence of PAD. A logistic regression model was used to analyze the risk factors for PAD. The prevalence of PAD in males was higher than that in females [odds ratio (OR)=2.250, 95% CI: 1.670-3.801]. The prevalence of PAD in patients with bile duct stone was 57.92% and higher than that in patients without stone (OR=4.475, 95% CI: 2.932-7.679). The morbidity of PAD in elderly patients with bile duct stone was higher than in those without stone (OR=6.728, 95% CI: 3.790-11.943). Among the elderly patients, the constituent ratio of males in the PAD group was higher than that in the N-PAD group (χ2=13.543, P<0.001). The constituent ratio of patients who underwent endoscopic sphincterotomy (EST) was lower than that in the N-PAD group (χ2=10.800, P<0.001). In conclusion, the occurrence of PAD was high in elderly males and closely related to the occurrence of bile duct stones.