Combination of disulfiram and Copper-Cysteamine nanoparticles induces mitochondria damage and promotes apoptosis in endometrial cancer.

Endometrial cancer (EC) stands as one of the most prevalent gynecological malignancies affecting women, with its incidence and disease-related mortality steadily on the rise. Disulfiram (DSF), an FDA-approved medication primarily used for treating alcohol addiction, has exhibited promising anti-tumor properties. Studies have revealed DSF's capacity for enhanced anti-tumor activity, particularly when combined with copper. The novel Copper-Cysteamine (CuCy) compound, Cu3Cl(SR)2 (R[bond, double bond]CH2CH2NH2), showcases photodynamic effects and demonstrates significant anti-tumor potential under various conditions, including exposure to ultraviolet light, X-ray, microwave, and ultrasound. This study delves into exploring the synergistic anti-tumor effects and underlying mechanisms by utilizing copper-cysteamine in conjunction with DSF against endometrial cancer. The investigation involved comprehensive analyses encompassing in vitro experiments utilizing Ishikawa cells, in vivo studies, and transcriptomic analyses. Remarkably, the combined administration of both compounds at a low dose of 0.5 µM exhibited pronounced efficacy in impeding tumor growth, inhibiting blood vessel formation, and stimulating cell apoptosis. Notably, experiments involving transplanted tumors in nude mice vividly demonstrated the significant in vivo anti-tumor effects of this combination treatment. Detailed examination through transmission electron microscopy unveiled compelling evidence of mitochondrial damage, cellular swelling, and rupture, indicative of apoptotic changes in morphology due to the combined treatment. Moreover, transcriptomic analysis unveiled substantial downregulation of mitochondrial-related genes at the molecular level, coupled with a significant hindrance in the DNA repair pathway. These findings strongly suggest that the combined application of CuCy and DSF induces mitochondrial impairment in Ishikawa cells, thereby fostering apoptosis and ultimately yielding potent anti-tumor effects.

CXCR4, regulated by HIF1A, promotes endometrial breakdown via CD45+ leukocyte recruitment in a mouse model of menstruation.

Menstruation is a specific physiological phenomenon in female humans that is regulated by complex molecular mechanisms. However, the molecular network involved in menstruation remains incompletely understood. Previous studies have suggested that C-X-C chemokine receptor 4 (CXCR4) is involved; however, how CXCR4 participates in endometrial breakdown remains unclear, as do its regulatory mechanisms. This study aimed to clarify the role of CXCR4 in endometrial breakdown and its regulation by hypoxia-inducible factor-1 alpha (HIF1A). We first confirmed that CXCR4 and HIF1A protein levels were significantly increased during the menstrual phase compared with the late secretory phase using immunohistochemistry. In our mouse model of menstruation, real-time PCR, western blotting, and immunohistochemistry showed that CXCR4 mRNA and protein expression levels gradually increased from 0 to 24 h after progesterone withdrawal during endometrial breakdown. HIF1A mRNA and HIF1A nuclear protein levels significantly increased and peaked at 12 h after progesterone withdrawal. Endometrial breakdown was significantly suppressed by the CXCR4 inhibitor AMD3100 and the HIF1A inhibitor 2-methoxyestradiol in our mouse model, and HIF1A inhibition also suppressed CXCR4 mRNA and protein expression. In vitro studies using human decidual stromal cells showed that CXCR4 and HIF1A mRNA expression levels were increased by progesterone withdrawal and that HIF1A knockdown significantly suppressed the elevation in CXCR4 mRNA expression. CD45+ leukocyte recruitment during endometrial breakdown was suppressed by both AMD3100 and 2-methoxyestradiol in our mouse model. Taken together, our preliminary findings suggest that endometrial CXCR4 expression is regulated by HIF1A during menstruation and may promote endometrial breakdown, potentially via leukocyte recruitment.

Exosomes from Human Umbilical Cord Mesenchymal Stem Cells Facilitates Injured Endometrial Restoring in Early Repair Period through miR-202-3p Mediating Formation of ECM.

Endometrial damage repair disorder is the main reason of intrauterine adhesions (IUA) and thin endometrium (TA), which is caused by curettage or infection. Exosomal miRNAs derived from human umbilical cord mesenchymal stem cells (hucMSCs) were reported to play an important role in damage repair disorder, including endometrial fibrosis. In this study, we aimed to investigate the role of hucMSCs-derived exosomal microRNA-202-3p (miR-202-3p) in endometrial damage repair. We established rat endometrial injury model according to curettage to mimic women curettage abortion operation. The miRNA array analysis indicated that miR-202-3p was increased and matrix metallopeptidase 11 (MMP11) was decreased in the exosomes-treated rat uterine tissues. Bioinformatics analysis suggested that MMP11 is the target gene of miR-202-3p. We observed that the mRNA and protein of MMP11 were significantly decreased in exosome treatment group on day 3, and the components of extracellular matrix (ECM) COL1A1, COL3A1, COLVI and fibronectin (FN) protein were increased. And we found that when the injured human stromal cells were treated with miR-202-3p overexpression exosomes, the COLVI and FN were also upregulated in protein and mRNA expression level. For the first time MMP11 was proved to be the target gene of miR-202-3p by dual luciferase reporter system. At last, we found the state of stromal cells was better in miR-202-3p overexpression exosomes group compared to exosomes group, and miR-202-3p overexpression exosomes markedly upregulated the FN and collagen on day 3 after endometrial injury. We thought that miR-202-3p overexpression exosomes promoted endometrial repair by regulating ECM remodeling in early repair of damaged endometrium. Taken together, these experimental findings may provide a theoretical basis for understanding endometrial repair and an insight into the clinical treatment for IUA. Human umbilical cord mesenchymal stem cells exosomal miR-202-3p could regulate the expression of MMP11 and promote the accumulation of extracellular matrix, such as COL1A1, COL3A1, COLVI, FN, in the early repair period of endometrial injury.

Injectable self-assembled dual-crosslinked alginate/recombinant collagen-based hydrogel for endometrium regeneration.

The disadvantages of mainstream therapies for endometrial injury are difficult to resolve, herein, we suggest an omnibearing improvement strategy by introducing an injectable multifunctional self-assembled dual-crosslinked sodium alginate/recombinant collagen hydrogel. The hydrogel possessed a reversible and dynamic double network based on dynamic covalent bonds and ionic interactions, which also contributed to excellent capability in viscosity and injectability. Moreover, it was also biodegradable with a suitable speed, giving off active ingredients during the degradation process and eventually disappearing completely. In vitro tests exhibited that the hydrogel was biocompatible and able to enhance endometrial stromal cells viability. These features synergistically promoted cell multiplication and maintenance of endometrial hormone homeostasis, which accelerated endometrial matrix regeneration and structural reconstruction after severe injury in vivo. Furthermore, we explored the interrelation between the hydrogel characteristics, endometrial structure, and postoperative uterine recovery, which would benefit deep research on regulation of uterine repair mechanism and optimization of hydrogel materials. The injectable hydrogel could achieve favourable therapeutic efficacy without the need of exogenous hormones or cells, which would be of clinical value in endometrium regeneration.

Repairing and Regenerating Injured Endometrium Methods.

Good endometrium is the prerequisite and guarantee for reproduction and maternal and child health. Endometrial injury caused by operation or non-operation can lead to menstrual irregularities, amenorrhea, abortion, infertility, and other gynecological diseases to bother women. Intrauterine adhesions (IUA) and thin endometrium are common diseases caused by abnormal repair after endometrium damage. The incidence of IUA is not low after uterine operative surgery, and the recurrence is pretty high after uterine adhesiolysis. At present, there were many methods for endometrial repair in clinic or in the laboratory, but the efficacy was different from methods to methods. They are mainly including estrogen therapy, stem cell therapy, complementary medicine therapy, and some physical barrier therapy. In order to guide the effective repair and regeneration of endometrium in clinic, this paper reviews the merit and demerit of these methods for endometrium regeneration and repair that have been proved to be effective in experiments and clinical in recent years.

Clinical significance of neutrophil extracellular traps biomarkers in thrombosis.

Neutrophil extracellular traps (NETs) may be associated with the development of thrombosis. Experimental studies have confirmed the presence of NETs in thrombi specimens and potential role of NETs in the mechanisms of thrombosis. Clinical studies also have demonstrated significant changes in the levels of serum or plasma NETs biomarkers, such as citrullinated histones, myeloperoxidase, neutrophil elastase, nucleosomes, DNA, and their complexes in patients with thrombosis. This paper aims to comprehensively review the currently available evidence regarding the change in the levels of NETs biomarkers in patients with thrombosis, summarize the role of NETs and its biomarkers in the development and prognostic assessment of venous thromboembolism, coronary artery diseases, ischemic stroke, cancer-associated thromboembolism, and coronavirus disease 2019-associated thromboembolism, explore the potential therapeutic implications of NETs, and further discuss the shortcomings of existing NETs biomarkers in serum and plasma and their detection methods.

Development and structure-activity relationship of tacrine derivatives as highly potent CDK2/9 inhibitors for the treatment of cancer.

CDK2/9 are members of the CDKs family, which play key roles in the occurrence and development of many cancers by regulating cell cycle and transcriptional prolongation, respectively. To further optimize and discuss the structure-activity relationships (SARs), a series of tacrine-based compounds were designed and synthesized from the compound ZLWT-37, which was studied by our group previously but no detailed SARs study was conducted on CDK2/9. Among this series, compounds ZLMT-12 (35) exhibited the most potent antiproliferative activity (GI50 = 0.006 µM for HCT116) and superior CDK2/9 inhibitory properties (CDK2: IC50 = 0.011 µM, CDK9: IC50 = 0.002 µM). Meanwhile, ZLMT-12 showed a weak inhibitory effect on acetylcholinesterase (AChE, IC50 = 19.023 µM) and butyrylcholinesterase (BuChE, IC50 = 2.768 µM). In addition, ZLMT-12 can suppress colony formation and migration in HCT116 cells, as well as induce the apoptosis and arrest the cell cycle in the S phase and G2/M phase. In vivo investigations revealed that ZLMT-12 inhibits tumor growth in the HCT116 xenograft tumor model at a low dose of 10 mg/kg without causing hepatotoxicity. The acute toxicity test showed low toxicity with a median lethal dosage (LD50) of 104.417 mg/kg. These findings showed that ZLMT-12 might be used as a drug candidate by targeting CDK2/9.

DHW-221, a Dual PI3K/mTOR Inhibitor, Overcomes Multidrug Resistance by Targeting P-Glycoprotein (P-gp/ABCB1) and Akt-Mediated FOXO3a Nuclear Translocation in Non-small Cell Lung Cancer.

Multidrug resistance (MDR) is considered as a primary hindrance for paclitaxel failure in non-small cell lung cancer (NSCLC) patients, in which P-glycoprotein (P-gp) is overexpressed and the PI3K/Akt signaling pathway is dysregulated. Previously, we designed and synthesized DHW-221, a dual PI3K/mTOR inhibitor, which exerts a remarkable antitumor potency in NSCLC cells, but its effects and underlying mechanisms in resistant NSCLC cells remain unknown. Here, we reported for the first time that DHW-221 had favorable antiproliferative activity and suppressed cell migration and invasion in A549/Taxol cells in vitro and in vivo. Importantly, DHW-221 acted as a P-gp inhibitor via binding to P-gp, which resulted in decreased P-gp expression and function. A mechanistic study revealed that the DHW-221-induced FOXO3a nuclear translocation via Akt inhibition was involved in mitochondrial apoptosis and G0/G1 cell cycle arrest only in A549/Taxol cells and not in A549 cells. Interestingly, we observed that high-concentration DHW-221 reinforced the pro-paraptotic effect via stimulating endoplasmic reticulum (ER) stress and the mitogen-activated protein kinase (MAPK) pathway. Additionally, intragastrically administrated DHW-221 generated superior potency without obvious toxicity via FOXO3a nuclear translocation in an orthotopic A549/Taxol tumor mouse model. In conclusion, these results demonstrated that DHW-221, as a novel P-gp inhibitor, represents a prospective therapeutic candidate to overcome MDR in Taxol-resistant NSCLC treatment.

What Is the Most Suitable Agent Combined With Apatinib for Transarterial Chemoembolization Treatment in Advanced Hepatocellular Carcinoma Patients? A Systematic Review and Network Meta-analysis.

Purpose: Combined therapy with transarterial chemoembolization (TACE) and apatinib is superior in therapeutic effect compared with TACE alone in patients with hepatocellular carcinoma (HCC). To determine the most suitable agent combined with apatinib for TACE treatment, we did a systematic review and network meta-analysis. Methods: Four electronic databases were searched from inception until November 2021. Randomized controlled trials (RCTs) and retrospective studies that combined therapy of TACE and apatinib (TACE+A) compared with TACE alone were included. We performed random-effect pairwise and network meta-analyses to summarize the outcomes about efficacy and safety. Results: Forty-five original studies including 3,876 patients were included. In terms of efficacy, we evaluated treatment response, 6 months overall survival (OS), 1 year OS, 6 months progression-free survival (PFS), 1 year PFS, alphafetoprotein (AFP), matrix metalloproteinase 9 (MMP9), and vascular endothelial growth factor (VEGF). Significant differences always appear in TACE agent subgroups of adriamycin, platinum, and fluorouracil from both pairwise and network meta-analysis, while significant differences could also be found in apatinib dosage of 500 and >500 mg/day subgroups and in both RCT and retrospective study subgroups. From second time network analysis, compared with TACE alone, subgroups with TACE agents of oxaliplatin, cisplatin, pirarubicin, epirubicin, and 5-fluorouracil ranked front. In addition, the safety of adriamycin, platinum, and fluorouracil subgroups is acceptable. Conclusions: In conclusion, the most suitable agents in TACE combined with apatinib were adriamycin+platinum ± fluorouracil combination therapy. Systematic Review Registration: The study was registered with https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=311650, PROSPERO, CRD4202022311650.

DZW-310, a novel phosphoinositide 3-kinase inhibitor, attenuates the angiogenesis and growth of hepatocellular carcinoma cells via PI3K/AKT/mTOR axis.

Hepatocellular carcinoma (HCC) is one of the most malignant tumors worldwide with high lethality and prevalence. The deregulated phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway plays an indispensable role in mediating the progression of HCC. Among them, PI3K acts as the most pivotal initiator, contributing to multiple malignant biological processes, like proliferation, apoptosis and angiogenesis. Many PI3K inhibitors (PI3Kis) have been proved or proceeded into clinical as antineoplastic drugs. Nevertheless, the application of PI3Kis for the treatment of HCC remains a blank. Accordingly, our study identified a novel PI3Ki (DZW-310) with strong anti-HCC activity in vitro and in vivo. This study aimed to evaluate its anti-HCC effect and elucidate its potential mechanism. Our current results revealed that DZW-310 significantly attenuated HCC cell growth through promoting intrinsic apoptosis and G0/G1 phase cell arrest. Moreover, DZW-310 suppressed angiogenesis by regulating the HIF-1α/VEGFA axis. Further mechanistic investigation demonstrated that DZW-310, functioned as a PI3Ki, exerted strong anti-HCC activity by acting on PI3Kα (a major subtype of PI3K) and ulteriorly deactivating the PI3K/AKT/mTOR pathway. Collectively, our studies identified that DZW-310 is expected to become a promising HCC therapeutic agent and broaden clinical application of PI3Ki in HCC chemotherapy.

ZDQ-0620, a Novel Phosphatidylinositol 3-Kinase Inhibitor, Inhibits Colorectal Carcinoma Cell Proliferation and Suppresses Angiogenesis by Attenuating PI3K/AKT/mTOR Pathway.

The PI3K/AKT pathway plays a central role in human cancers, aberrant activation of this pathway is associated with tumorigenesis, cancer progression and angiogenesis. Based on the importance of the PI3K/AKT pathway in malignancies, we developed a 4-aminoquinazoline derivative, ZDQ-0620, initially envisioned as a novel pan-PI3K inhibitor. This study aimed to evaluate the potential target of ZDQ-0620 and its anticancer effect in human colorectal carcinoma (CRC). PI3K-kinase activity test showed IC50 of ZDQ-0620 against PI3Ka was 0.5 nM; molecular docking, CETSA assay and western blotting was further performed to predict ZDQ-0620 was a PI3K/AKT pathway inhibitor by targeting PI3K. To identify the effect of ZDQ-0620 on CRC cells, Sulforhodamine B (SRB) assay, flow cytometry, and Cell morphology analysis were conducted. The results showed that ZDQ-0620 inhibited the proliferation, migration and invasion of CRC cells, induced apoptosis through G0/G1 cell cycle arrest and mitochondrial pathway. Additionally, ZDQ-0620 inhibited the migration and tube formation of human umbilical vein endothelial cells (HUVECs). In vivo, neovascularization of rat aortic ring and chick chorioallantoic membrane (CAM) induced by VEGF was diminished when treated with ZDQ-0620. These results indicate that ZDQ-0620 induce apoptosis and anti-angiogenesis via inhibits the PI3K/AKT pathway. We suggest that the great potential of ZDQ-0620 as an effective treatment candidate against CRC.

Risk Factors for Esophageal Collateral Veins in Cirrhosis with and without Previous Endoscopic Esophageal Variceal Therapy.

Background: Portosystemic collateral vessels are a sign of portal hypertension in liver cirrhosis. Esophageal collateral veins (ECVs) are one major type of portosystemic collateral vessels, which increase the recurrence of esophageal varices and bleeding after variceal eradication. However, the risk factors for ECVs were still unclear. Methods: We retrospectively screened cirrhotic patients who had contrast-enhanced computed tomography (CT) images to evaluate ECVs and upper gastrointestinal endoscopic reports to evaluate gastroesophageal varices at our department. Univariate and multivariate logistic regression analyses were performed to explore the independent risk factors for ECVs. Odds ratios (ORs) were calculated. Subgroup analyses were performed in patients with and without previous endoscopic variceal therapy which primarily included endoscopic variceal ligation (EVL) and endoscopic injection sclerotherapy (EIS). Results: Overall, 243 patients were included, in whom the prevalence of ECVs was 53.9%. The independent risk factors for ECVs were hepatitis C virus infection (OR = 0.250, p = 0.026), previous EVL (OR = 1.929, p = 0.044), platelet (OR = 0.993, p = 0.008), and esophageal varices needing treatment (EVNTs) (OR = 2.422, p = 0.006). The prevalence of ECVs was 60.8% (73/120) in patients undergoing EVL, 50% (10/20) in those undergoing EIS, and 47.5% (48/101) in those without previous endoscopic variceal therapy. The independent risk factors for ECVs were the use of nonselective beta-blockers (OR = 0.294, p = 0.042) and EVNTs (OR = 3.714, p = 0.006) in subgroup analyses of patients with and without previous endoscopic variceal therapy, respectively. Conclusions: The presence of ECVs should be closely associated with the severity of portal hypertension in liver cirrhosis. Risk of ECVs might be increased by previous EVL.

Pharmacokinetics, tissue distribution, and antitumor activity of a novel compound, NY-2, in non-small cell lung cancer.

Introduction: ZLDI-8, which has a relatively strong antitumor activity, is an inhibitor of ADAM-17 and acts on the Notch signaling pathway. To further optimize its structure and improve its activity, a series of derivatives of ZLDI-8 was synthesized. NY-2 was the most effective derivative based on preliminary activity screening in vitro, with no obvious toxicity after administration in vivo. Method: The study aimed to determine the pharmacokinetics, tissue distribution, hepatotoxicity, nephrotoxicity, and antitumor activity of compound NY-2 on non-small cell lung cancer (NSCLC) in vitro and in vivo. Results: The in vivo pharmacokinetics parameters of NY-2 were better than those of ZLDI-8. The tissue distribution analysis showed that tail vein injection of 6 mg/kg of NY-2 in rats resulted in the highest concentration in the lung, so we hypothesized that NY-2 might be effective in the treatment of non-small cell lung cancer. In vitro assays showed that NY-2 significantly inhibited tumor colony formation, invasion, and migration and increased LDH activity and apoptosis in a concentration-dependent manner in non-small cell lung cancer cells. NY-2 also inhibited the formation of lung metastases without significant toxicity to major organs in nude mice. Conclusion: Compared with the parent compound, ZLDI-8, the activity and safety of NY-2 were higher. NY-2 acts on ADAM17 and simultaneously affects the downstream Notch1 and integrinß1 signaling pathways resulting in antitumor activity. Thus, NY-2 could be a potential antitumor agent, inhibiting the organization and development of non-small cell lung cancer.

Role of Galectins in the Liver Diseases: A Systematic Review and Meta-Analysis.

Background: Galectins, a family of ß-galactoside-binding proteins, are related to the development and progression of various human diseases such as cancer, heart failure, and chronic kidney disease. However, its role in liver diseases is unclear. Methods: The PubMed, Embase, and Cochrane Library databases were searched. Hazard ratios (HRs), odds ratios (ORs), and mean differences (MDs) with 95% CIs were pooled to evaluate the association of the galectins with the outcomes and risk of liver diseases by a random effects model. Results: Thirty three studies involving 43 cohorts and 4,168 patients with liver diseases were included. In the patients with hepatocellular carcinoma (HCC), high expression of galectin-1 and -3 in the tissues was significantly associated with worse overall survival (galectin-1: HR = 1.94, 95% CI = 1.61-2.34, p < 0.001; galectin-3: HR = 3.29, 95% CI = 1.62-6.68, p < 0.001) and positive vascular invasion (galectin-1: OR = 1.74, 95% CI = 1.18-2.58, p = 0.005; galectin-3: OR = 2.98, 95% CI = 1.58-5.60, p = 0.001); but, high expression of galectin-4 and -9 in the tissues was significantly associated with better overall survival (galectin-4: HR = 0.53, 95% CI = 0.36-0.79, p = 0.002; galectin-9: HR = 0.56, 95% CI = 0.44-0.71, p < 0.001) and negative vascular invasion (galectin-4: OR = 0.36, 95% CI = 0.19-0.72, p = 0.003; galectin-9: OR = 0.60, 95% CI = 0.37-0.97, p = 0.037). Serum galectin-3 level was significantly higher in HCC (MD = 3.06, 95% CI = 1.79-4.32, p < 0.001), liver failure (MD = 0.44, 95% CI = 0.23-0.66, p < 0.001), liver cirrhosis (MD = 1.83, 95% CI = 1.15-2.51, p < 0.001), and chronic active hepatitis B (MD = 18.95, 95% CI = 10.91-27.00, p < 0.001); serum galectin-9 level was significantly higher in HCC (MD = 3.74, 95% CI = 2.57-4.91, p < 0.001) and autoimmune hepatitis (MD = 8.80, 95% CI = 7.61-9.99, p < 0.001). Conclusion: High galectin-1 and -3 and low galectin-4 and -9 expression indicate worse outcomes of patients with HCC. Serum galectin-3 and -9 levels are positively associated with the risk of chronic liver diseases.

CHN1 promotes epithelial-mesenchymal transition via the Akt/GSK-3ß/Snail pathway in cervical carcinoma.

BACKGROUND: Metastasis and invasion are crucial in determining the mortality of cervical carcinoma (CC) patients. The epithelial-mesenchymal transition (EMT) is now a universal explanation for the mechanisms of tumor metastasis. Α-chimeric protein (α-chimaerin, CHN1) plays an important role in the regulation of signal transduction and development. However, the molecular regulatory relationships between CHN1 and CC progression in relation to EMT have not yet been identified. METHODS: The expression of CHN1 in CC tissues, adjacent tissues, and lymph node metastases from CC patients was detected by immunohistochemistry. Upregulation and knockdown of CHN1 were achieved by transfection of CC cells. The effect of CHN1 on cell proliferation was determined by CCK-8 and plate clone formation assays. Changes in migration and invasion capabilities were evaluated using scratch migration and transwell invasion assays. The effect of CHN1 overexpression and interference on xenograft tumor growth was determined by tumor weight and pathological analyses. The expression of EMT-related mRNAs was measured by qRT-PCR in transfected CC cells. EMT-related proteins and Akt/GSK-3ß/Snail signaling pathway-related proteins were also evaluated by western blotting. RESULTS: CHN1 was overexpressed in CC tissues and was associated with lymph node metastasis and low survival in CC patients. Overexpression of CHN1 promoted cell proliferation, migration, and invasion in CC cells. In contrast, silencing of CHN1 inhibited these phenomena. Overexpression of CHN1 promoted tumor formation in an in vivo xenograft tumor mouse model, with increased tumor volumes and weights. In addition, CHN1 induced the expression of EMT-related transcription factors, accompanied by the decreased expression of epithelial markers and increased expression of mesenchymal markers. The Akt/GSK-3ß/Snail signaling pathway was activated by overexpression of CHN1 in vitro, and activation of this pathway was inhibited by the signaling pathway inhibitor LY294002. CONCLUSION: These results suggest that CHN1 promotes the development and progression of cervical carcinoma via the Akt/GSK-3ß/Snail pathway by inducing EMT.

Portal venous system thrombosis after bariatric surgery: A systematic review and meta-analysis.

BACKGROUND: Portal venous system thrombosis can develop after bariatric surgery. A systematic review and meta-analysis was conducted to evaluate the incidence of portal venous system thrombosis after bariatric surgery and clarify the role of anticoagulation for the prevention of portal venous system thrombosis after bariatric surgery. METHODS: PubMed, EMBASE, and Cochrane Library databases were searched. The incidence of portal venous system thrombosis after bariatric surgery was pooled by a random-effect model. Subgroup analyses were performed to explore the incidence of portal venous system thrombosis according to the average duration of prophylactic anticoagulation (extended versus short-term). Meta-regression and sensitivity analyses were performed to explore the source of heterogeneity. RESULTS: Among 2,714 papers initially screened, 68 studies were included. Among 100,964 patients undergoing bariatric surgery, 300 developed portal venous system thrombosis. The pooled overall incidence of portal venous system thrombosis after bariatric surgery was 0.419% (95% confidence interval: 0.341%-0.505%). The pooled incidence of portal venous system thrombosis after bariatric surgery was numerically lower in patients who received extended prophylactic anticoagulation protocol after bariatric surgery than those who received short-term prophylactic anticoagulation protocol (0.184% vs 0.459%). Meta-regression analyses demonstrated that sample size (P = .006), type of surgery (P < .001), and average duration of prophylactic anticoagulation (P = .024) might be sources of heterogeneity, but not region, publication year, history of bariatric surgery, follow-up duration, or use of prophylactic anticoagulation. Sensitivity analyses could not identify any source of heterogeneity. The estimated mortality of portal venous system thrombosis after bariatric surgery was 1.33%. CONCLUSION: Portal venous system thrombosis after bariatric surgery is rare, but potentially lethal. Extended prophylactic anticoagulation protocol may be considered in patients at a high risk of developing portal venous system thrombosis after bariatric surgery.

No Association of Homocysteine, Anticardiolipin Antibody, and Anti-ß2 Glycoprotein I Antibody With Portal Venous System Thrombosis in Liver Cirrhosis.

Portal venous system thrombosis (PVST), a common complication of liver cirrhosis, is closely associated with thrombophilia. To explore the association of homocysteine (Hcy), anticardiolipin antibody (aCL), and anti-ß2 glycoprotein I antibody (aß2GPI), which are possible thrombophilic factors, with PVST in liver cirrhosis. Overall, 654 non-malignant patients (219 with and 435 without liver cirrhosis) admitted between January 2016 and June 2020 were retrospectively evaluated. Presence of PVST, degree of main portal vein (MPV) thrombosis, and clinically significant PVST were identified. Hcy level, hyperhomocysteinemia (HHcy), aCL positivity, and aß2GPI positivity were compared according to the presence of liver cirrhosis and PVST. Positive aß2GPI was significantly more frequent in patients with liver cirrhosis than those without, but Hcy level and proportions of HHcy and positive aCL were not significantly different between them. PVST could be evaluated in 136 cirrhotic patients. Hcy level [10.57 µmol/L (2.71-56.82) versus 9.97 µmol/L (2.05-53.44); P = 0.796] and proportions of HHcy [4/44 (9.1%) versus 13/81 (16.0%); P = 0.413] and positive aCL [1/23 (4.3%) versus 10/52 (19.2%); P = 0.185] and aß2GPI [9/23 (39.1%) versus 21/52 (40.4%); P = 0.919] were not significantly different between cirrhotic patients with and without PVST. There was still no significant association of Hcy level, HHcy, aCL, or aß2GPI with PVST based on Child-Pugh classification, MPV thrombosis >50%, and clinically significant PVST. Hcy, aCL, and aß2GPI may not be associated with PVST in liver cirrhosis, suggesting that routine screening for Hcy, aCL, and aß2GPI should be unnecessary in such patients.

Splanchnic Vein Thrombosis in Liver Cirrhosis After Splenectomy or Splenic Artery Embolization: A Systematic Review and Meta-Analysis.

INTRODUCTION: Splenectomy and splenic artery embolization are major treatment options for hypersplenism and portal hypertension in liver cirrhosis, but may lead to splanchnic vein thrombosis (SVT), which is potentially lethal. We conducted a systematic review and meta-analysis to explore the incidence of SVT in liver cirrhosis after splenectomy or splenic artery embolization and the risk factors for SVT. METHODS: All relevant studies were searched through the PubMed, EMBASE, and Cochrane Library databases. The incidence of SVT in liver cirrhosis after splenectomy or splenic artery embolization was pooled. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. RESULTS: Sixty-six studies with 5632 patients with cirrhosis were included. The pooled incidence of SVT after splenectomy and splenic artery embolization was 24.6% (95% CI 20.2-29.3%) and 11.7% (95% CI 7.1-17.3%), respectively. A meta-analysis of three comparative studies demonstrated that the incidence of SVT after splenectomy was statistically similar to that after splenic artery embolization (OR 3.15, P = 0.290). Platelet count, mean platelet volume, preoperative splenic or portal vein diameter, preoperative or postoperative portal blood velocity, splenic volume and weight, and periesophagogastric devascularization were significant risk factors for SVT after splenectomy. Postoperative use of preventive antithrombotic therapy was a significant protective factor against SVT after splenectomy. CONCLUSIONS: SVT is common in liver cirrhosis after splenectomy and splenic artery embolization. Coagulation and hemostasis factors, anatomical factors, and surgery-related factors have been widely identified for the assessment of high risk of SVT after splenectomy. Prophylactic strategy after splenectomy, such as antithrombotic therapy, might be considered in such high-risk patients. STUDY REGISTRATION: This study was registered in PROSPERO with a registration number of CRD42019129673.

Natural history and predictors associated with the evolution of portal venous system thrombosis in liver cirrhosis.

BACKGROUND: Portal venous system thrombosis (PVST) will progress in some cases, indicating worse outcome and the necessity of antithrombotic treatment, but will spontaneously improve in others. It is crucial to understand the natural history of PVST in liver cirrhosis. However, the knowledge regarding how to predict the evolution of PVST in cirrhotic patients is very scant. METHODS: Sixty-nine cirrhotic patients without malignancy, who had undergone repeated contrast-enhanced computed tomography or MRI to evaluate the severity of PVST at the first and last admissions, were included. Logistic regression analysis was performed to identify the risk factors for the evolution of PVST in liver cirrhosis. Odds ratios (ORs) were calculated. RESULTS: Among 42 patients without PVST at the first admission, 10 (23.8%) developed PVST at the last admission. Serum albumin level (OR = 0.873), prothrombin time (OR = 1.619), activated partial thromboplastin time (OR = 1.169), Child-Pugh score (OR = 1.560) and model for end-stage liver disease (MELD) score (OR = 1.292) at the last admission were significant risk factors associated with the development of PVST. Among 27 patients with PVST at the first admission, 11 (40.7%), 4 (14.8%) and 12 (44.4%) had improvement, stabilization and progression of PVST at the last admission, respectively. ΔMELD score (OR = 0.714) was the only significant risk factor associated with the improvement of PVST; additionally, serum albumin level at the first admission (OR = 1.236) was the only significant risk factor associated with the progression of PVST. CONCLUSION: Aggravation and amelioration of liver dysfunction may predict the development and improvement of PVST in liver cirrhosis, respectively.

Use of iron sucrose injection in anemia patients with reduced serum iron concentration during hospitalizations of digestive and liver diseases.

BACKGROUND: Anemia is one of the most common disorders in the world. Serum iron is an essential element for the synthesis of hemoglobin and contribution of the oxygen-carrying ability of red blood cells (RBCs). Iron sucrose injection may effectively correct iron deficiency, increase iron storage, and then improve anemia. The aim of the present study was to evaluate the therapeutic effect of iron sucrose injection in anemia patients with reduced serum iron concentration. METHODS: Overall, 95 anemia patients with digestive and/or liver diseases were included. They were divided according to the infusion of iron sucrose injection during hospitalization. The paired sample t test was used for comparison between last and baseline hemoglobin concentration. The independent sample t test was used for comparison of a dynamic change of hemoglobin concentration between patients who received and did not receive infusion of iron sucrose injection. RESULTS: Iron sucrose injection was infused in 74 (77.90%) patients. Mean hemoglobin concentration after infusion of iron sucrose injection was significantly increased (91.61 vs. 94.98 g/L, P=0.011). Δ Hemoglobin concentration was significantly different between patients who received and did not receive infusion of iron sucrose injection (P=0.007). Mean hemoglobin concentration after infusion of iron sucrose injection remained significantly increased in subgroup analyses of patients with cirrhosis (88.30 vs. 91.98 g/L, P=0.035) and gastrointestinal bleeding (85.70 vs. 92.63 g/L, P<0.01). CONCLUSIONS: Iron sucrose injection can significantly increase the hemoglobin concentration in anemia patients with serum iron concentration below the lower limit of the normal range.