The potential role of circulating exosomes in protecting myocardial injury in acute myocardial infarction via regulating miR-190a-3p/CXCR4/CXCL12 pathway.

Exosomes of different origins have been found to be protective against ischemic-induced myocardial injury. This study examined the protective effects of circulating exosomes in the mice model of acute myocardial infarction (AMI) and explored the underlying molecular mechanisms. The effects of exosomes on myocardial injury were assessed in the AMI mice model. The in vivo studies showed that circulating exosomes reduced the infarcted size, improved the morphology of heart tissues and also reduced apoptosis of the heart tissues. In addition, the model mice showed an increase in the CD34 + /VEGFR2 + cell population and CD31, CXCR4 and CXCL12 expression after exosomes treatment. MiR-190a-3p was significantly down-regulated in the exosomes derived from the culture medium of hypoxia-treated human cardiomyocytes (HCMs). Further analysis revealed that miR-190a-3p could physically interact with CXCR4/CXCL12 by targeting the respective 3'UTRs. These exosomes could up-regulated CXCR4 and CXCL12 expression in the EPCs; in addition, miR-190a-3p mimics repressed CXCR4/CXCL12 expression in EPCs, while its inhibitor had opposite effects. The in vitro functional assays showed that miR-190a-3p overexpression suppressed the cell viability, proliferation, migration, adhesion and tube formation of EPCs; while miR-190a-3p inhibitor had the opposite effects; exosomes derived from the culture medium of hypoxia-treated HCMs exhibited similar actions of miR-190a-3p inhibitor. Moreover, miR-190a-3p was down-regulated in exosomes from serum in the AMI group when compared to that from sham group. Treatment with exosomes from serum in the AMI group promoted cell proliferation, migration, adhesion and tube formation of EPCs when compared to that in the sham group. More importantly, IT1t attenuated the enhanced effects of miR-190a-3p inhibition on EPC proliferation, migration, adhesion and tube formation. In conclusion, circulating exosomes exerted protective effects on myocardial injury in the AMI mice model, and down-regulation of miR-190a-3p in the circulating exosomes may exert protective effects against myocardial injury. Hypoxia induced the downregulation of miR-190a-3p in the culture medium of HCMs, and the mechanistic investigations indicated that exosomes of hypoxia-conditioned HCM culture medium promoted the cell viability, proliferation, migration, adhesion and tube formation of EPCs via regulating miR-190a-3p/CXCR4/CXCL12 pathway.

Feasibility of contrast-enhanced ultrasound and flank position during percutaneous nephrolithotomy in patients with no apparent hydronephrosis: a randomized controlled trial.

PURPOSE: To investigate the puncture accuracy and feasibility of contrast-enhanced ultrasound (CEUS) guided percutaneous nephrolithotomy (PCNL) in flank position for patients with no apparent hydronephrosis. METHODS: Between May 2018 and June 2020, 72 kidney stone patients with no or mild hydronephrosis were randomized into two groups: a CEUS-guided PCNL group and a conventional ultrasound (US)-guided group. Patients' demographics and perioperative outcomes were compared, including the success rate of puncture via calyceal fornix, the success rate of a single-needle puncture, puncture time, operative time, postoperative hemoglobin loss, stone-free rate, incidence of complications and postoperative stay. RESULTS: The success rate of puncture via calyceal fornix for CEUS-guided group was significantly higher than that for conventional US-guided group (86.1 vs. 47.2%, p = 0.002). Patients performed with CEUS-guided PCNL required shorter renal puncture time than those guided with conventional US (36.5 s vs. 61.0 s, p < 0.001). The median postoperative hemoglobin loss in the CEUS-guided group was significantly lower than that in conventional US-guided group (2.5 vs. 14.5 g/L, p < 0.01). There was no statistically significant difference in the success rate of a single-needle puncture, operative time, stone-free rate, incidence of complications and postoperative stay between the two groups. CONCLUSION: CEUS guidance facilitates identification of the renal calyx fornix, and benefits more precise renal puncture and less hemoglobin loss in PCNL. CEUS-guided PCNL in flank position is a feasible approach to the treatment of kidney stone patients with no apparent hydronephrosis. TRIAL REGISTRATION NUMBER: ChiCTR1800015417.

Systematic external evaluation of published population pharmacokinetic models of mycophenolate mofetil in adult kidney transplant recipients co-administered with tacrolimus.

AIMS: Various mycophenolate mofetil (MMF) population pharmacokinetic (popPK) models have been developed to describe its PK characteristics and facilitate its optimal dosing in adult kidney transplant recipients co-administered with tacrolimus. However, the external predictive performance has been unclear. Thus, this study aimed to comprehensively evaluate the external predictability of published MMF popPK models in such populations and investigate the potential influencing factors. METHODS: The external predictability of qualified popPK models was evaluated using an independent dataset. The evaluation included prediction- and simulation-based diagnostics, and Bayesian forecasting. In addition, factors influencing model predictability, especially the impact of structural models, were investigated. RESULTS: Fifty full PK profiles from 45 patients were included in the evaluation dataset and 11 published popPK models were identified and evaluated. In prediction-based diagnostics, the prediction error within ±30% was less than 50% in most published models. The prediction- and variability-corrected visual predictive check and posterior predictive check showed large discrepancies between the observations and simulations in most models. Moreover, the normalized prediction distribution errors of all models did not follow a normal distribution. Bayesian forecasting demonstrated an improvement in the model predictability. Furthermore, the predictive performance of two-compartment (2CMT) models incorporating the enterohepatic circulation (EHC) process was not superior to that of conventional 2CMT models. CONCLUSIONS: The published models showed large variability and unsatisfactory predictive performance, which indicated that therapeutic drug monitoring was necessary for MMF clinical application. Further studies incorporating potential covariates need to be conducted to investigate the key factors influencing model predictability of MMF.

[Expert consensus statement on Kangfu Xiaoyan Suppository in treatment of pelvic inflammatory in clinical practice].

Kangfu Xiaoyan Suppository is widely used in the treatment of gynecological inflammatory diseases. Long-term clinical application and a certain amount of research evidences show that Kangfu Xiaoyan Suppository can alleviate the clinical symptoms of pelvic inflammatory diseases,reduce the recurrence rate,and relieve sequelae,with a better safety and economic characteristics. As a type of nationally protected traditional Chinese medicine and type B medicine included in medical insurance,it has been selected as a Chinese patent medicine for rectal administration. It was included in the Guidelines for diagnosis and treatment of common gynecological diseases of traditional Chinese medicine published by the Chinese Academy of Traditional Chinese Medicine in 2012,the Pelvic inflammatory diseases diagnosis and treatment guidelines issued by the Infectious Diseases Collaborative Group of the Obstetrics and Gynecology Branch of the Chinese Medical Association in 2014,and the group standard of Single use of traditional Chinese medicine/combined antibiot guidelines for clinical practice-pelvic inflammatory diseases of the Chinese Academy of Traditional Chinese Medicine in 2017. To further enhance clinicians' understanding of the drug and better guide its rational clinical use,experts from the field of gynecology of traditional Chinese and Western medicine were invited to develop and compile this expert consensus. This consensus takes full account of clinical evidences and expert clinical experience,and form recommendations for clinical problems based on evidences and consensus recommendations for clinical problems without evidence by nominal grouping method. The expert consensus is mainly formed in the consideration of six factors: quality of evidence,economy,efficacy,adverse reactions,patient acceptability and others. Based on clinical research evidences and expert experience,this consensus provides a preliminary reference for the clinical use of the drug in a concise and clear format. However,evidence-based support is still required in a large number of high-quality studies,and this consensus will be revised in the future according to new clinical problems and the update of evidence-based evidence in practical application.

Clinical significance of the ubiquitin ligase UBE3C in hepatocellular carcinoma revealed by exome sequencing.

UNLABELLED: Virus-induced hepatocarcinogenesis involves a series of histological developmental processes with the stepwise acquisition of several genetic changes that are necessary for the malignant transformation of hepatocytes. Although genetic alterations are known to be involved in the pathogenesis of hepatocellular carcinoma (HCC), little is known about the contributions of specific genes to this process. To gain insight into the genetic alterations involved in the neoplastic evolution from chronic hepatitis B virus infection to dysplastic nodules (DN) to HCC, we captured and sequenced the exomes of four DNA samples: one DN sample, two HCC samples, and one control peripheral blood sample from a single HCC patient. Mutations in the UBE3C gene (encoding ubiquitin ligase E3C) were observed in both tumor tissues. Then we resequenced the UBE3C gene in a cohort of 105 HCC patients and identified mutations in 17 out of a total of 106 (16.0%) HCC patients. The subsequent experiments showed that UBE3C promoted HCC progression by regulating HCC cells epithelial-mesenchymal transition. Clinically, a tissue microarray study of a cohort containing 323 HCC patients revealed that the overexpression of UBE3C in primary HCC tissues correlated with decreased survival (hazard ratio [HR] =1.657, 95% confidence interval [CI] =1.220-2.251, P=0.001) and early tumor recurrence (HR=1.653, 95% CI=1.227-2.228, P=0.001) in postoperative HCC patients. CONCLUSION: Our findings indicate that UBE3C is a candidate oncogene involved in tumor development and progression and therefore a potential therapeutic target in applicable HCC patients.

Hepatoma-derived growth factor: a novel prognostic biomarker in intrahepatic cholangiocarcinoma.

Hepatoma-derived growth factor (HDGF) is an acidic heparin-binding protein involved in tumor progression and poor prognosis of kinds of cancers. Aimed at investigating the functions of HDGF in intrahepatic cholangiocarcinoma (IHCC), we detected the expression of HDGF by immunohistochemistry in 83 patients. Associations of HDGF with clinicopathologic features, microvascular density (MVD), and overall survival rates were further analyzed by Chi-square method, univariate or multivariate analysis. HDGF functions in IHCC proliferation, invasion, and angiogenesis were detected by MTT, transwell, and tube formation assays, respectively. As a result, we found that HDGF-positive expression rate in IHCC was 51.8 % (43/83) in IHCC. HDGF expression was significantly correlated to MVD (P = 0.031), lymphatic invasion (P = 0.030), distant metastasis (P = 0.002), and TNM stage (P = 0.037). HDGF was further identified as an independent prognostic factor in IHCC with Kaplan-Meier method (P = 0.003) and Cox-regression model (P = 0.008). Moreover, both intracellular and extracellular HDGF were proved to promote the proliferation, invasion, and angiogenesis of IHCC cell lines. In conclusion, HDGF was identified as an independent prognostic biomarker in IHCC. HDGF can promote IHCC cells progression, including proliferation, invasion, and angiogenesis, indicating HDGF could become a new promising and potential drug target of IHCC.

[A multi-center, randomized, double-blind clinical study on Bushen Huoxue in treatment of ovulatory dysfunction caused infertility].

OBJECTIVE: The multi-center, randomized, double-blind, double-simulated and positive-control trial was used to verify the contribution degree of Bushen Huoxue for the treatment of ovulatory dysfunction caused infertility, which provided scientific basis for clinical treatment. METHOD: According to diagnostic, inclusion and exclusion criteria, we observed 349 patients which were divided into the treated group (n = 177, treated with Bushen Huoxue ricipe) and control group (n = 172, treated with clomiphene). Ovulation rate, pregnancy rate, clinical effective rate of traditional Chinese medicine, endometrium and diameter of dominant follicle were observed. Serum reproductive endocrine hormones were assayed before and after treatment. RESULT: The treated group showed ovulation rate of 69.34%, with pregnancy rate of 41.35%. The clinical effective rate of treated group and control group were 91.73% and 80.77%. There was remarkable difference in endometrium (P < 0.05) and remarkbale difference in sex hormones PRL and E2in treated group at prior-treatment and post-treatment (P < 0.05). No adverse effects were found in the experiment. Security indicators did not show abnormal change. CONCLUSION: The comparison between the two groups showed that the treated group was significantly different from control group in the pregnancy rate (P < 0.05), without notable difference in ovulation rate. There was significant difference in clinical effective rate between the treated group and control group. Both the two groups could contribute to the mature development and discharge of the follicles. The growth of endometrium and endometrial receptivity in the treated group were higher than control group. The treated group has regulatory effect on PRL and E2.

Teneligliptin mitigates diabetic cardiomyopathy by inhibiting activation of the NLRP3 inflammasome.

BACKGROUND: Diabetic cardiomyopathy (DCM), which is a complication of diabetes, poses a great threat to public health. Recent studies have confirmed the role of NLRP3 (NOD-like receptor protein 3) activation in DCM development through the inflammatory response. Teneligliptin is an oral hypoglycemic dipeptidyl peptidase-IV inhibitor used to treat diabetes. Teneligliptin has recently been reported to have anti-inflammatory and protective effects on myocardial cells. AIM: To examine the therapeutic effects of teneligliptin on DCM in diabetic mice. METHODS: Streptozotocin was administered to induce diabetes in mice, followed by treatment with 30 mg/kg teneligliptin. RESULTS: Marked increases in cardiomyocyte area and cardiac hypertrophy indicator heart weight/tibia length reductions in fractional shortening, ejection fraction, and heart rate; increases in creatine kinase-MB (CK-MB), aspartate transaminase (AST), and lactate dehydrogenase (LDH) levels; and upregulated NADPH oxidase 4 were observed in diabetic mice, all of which were significantly reversed by teneligliptin. Moreover, NLRP3 inflammasome activation and increased release of interleukin-1ß in diabetic mice were inhibited by teneligliptin. Primary mouse cardiomyocytes were treated with high glucose (30 mmol/L) with or without teneligliptin (2.5 or 5 µM) for 24 h. NLRP3 inflammasome activation. Increases in CK-MB, AST, and LDH levels in glucose-stimulated cardiomyocytes were markedly inhibited by teneligliptin, and AMP (p-adenosine 5'-monophosphate)-p-AMPK (activated protein kinase) levels were increased. Furthermore, the beneficial effects of teneligliptin on hyperglycaemia-induced cardiomyocytes were abolished by the AMPK signaling inhibitor compound C. CONCLUSION: Overall, teneligliptin mitigated DCM by mitigating activation of the NLRP3 inflammasome.

PD-1 antibody in combination with chemotherapy for the treatment of SMARCA4-deficient advanced undifferentiated carcinoma of the duodenum: Two case reports.

BACKGROUND: SMARCA4 is a component of chromatin remodeling of SWItch/sucrose-nonfermenting (SWI/SNF) complexes and plays an essential role in oncogenesis. SMARCA4-deficient malignancies arising from the gastrointestinal tract are rare and have a poor prognosis. There is no standard treatment for advanced and undifferentiated SMARCA4-deficient duodenal malignancies. Programmed death 1 (PD-1) antibodies, known as immune checkpoint inhibitor antibodies, potentially play a role in treating gastrointestinal tract malignancies. CASE SUMMARY: We present two patients with SMARCA4 deficiency and TP53 gene mutation in advanced undifferentiated carcinomas of the duodenum. For both patients, SMARCA4 deficiency was confirmed by immunohistochemical staining for the BRG1 protein, while TP53 gene mutations were observed via next-generation sequencing. Both patients were administered chemotherapy in combination with an anti-PD-1 antibody. The two patients exhibited completely different responses to treatment and had different prognoses. Case 1 experienced rapid progression after PD-1 infusion and chemotherapy, case 2 experienced a remarkable response after treatment, and the progression-free survival was more than 6 months. CONCLUSION: This study described our clinical and pathological observations of SMARCA4-deficient advanced undifferentiated carcinoma of the duodenum. PD-1 combined with chemotherapy showed a certain efficacy in select patients, providing options for treating these highly malignant tumors. Patients with liver metastases had a worse prognosis than did those with only lymph node metastasis.

Correlation of vascular endothelial growth factor expression with tumor recurrence and poor prognosis in patients with pN0 gastric cancer.

BACKGROUND: Vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-9 play important roles in tumor angiogenesis, development, and progression. This study investigates the expression of VEGF combined with MMP-9, their correlation with clinical characteristics, and their effect on the prognosis for patients with pN0 gastric cancer after curative surgery. METHODS: A total of 55 patients were enrolled in the study. They were analyzed by immunohistochemistry, and their correlation with clinical characteristics was then investigated. Their relations and the survival time of patients were retrospectively analyzed. RESULTS: VEGF and MMP-9 were positively expressed in 24 (43.6%) and 16 (29.1%) patients, respectively, and had a positive correlation (r = 0.324, p = 0.016) in the Spearman rank correlation analysis. Univariate analysis showed that VEGF, MMP-9 expression, vascular invasion, T stage, and tumor size were associated with tumor recurrence as well as the disease-specific (DSS) and overall (OS) survival rates. Patients with positive VEGF expression showed significantly higher recurrence and poorer DSS and OS rates compared with those with negative VEGF expression. Multivariate analysis showed that VEGF expression, vascular invasion, T stage (serosal invasion), and tumor size were significant independent prognostic factors for tumor recurrence, DSS, and OS in patients with pN0 gastric cancer with the exception that T stage was not for DSS. CONCLUSIONS: VEGF expression, vascular invasion, T stage (serosal invasion), and tumor size can be used as valuable prognosticators in predicting tumor recurrence and prognosis for patients with pN0 gastric cancer after curative surgery. VEGF may have a synergistic effect with MMP-9 during tumor angiogenesis, development, and progression.

Epidemiology, Drug Resistance, and Risk Factors for Mortality Among Hematopoietic Stem Cell Transplantation Recipients with Hospital-Acquired Klebsiella pneumoniae Infections: A Single-Center Retrospective Study from China.

Objective: Infection is the most common complication and cause of death after hematopoietic stem cell transplantation (HSCT). Our study aims to investigate the clinical characteristics and risk factors for death of Klebsiella pneumoniae infections in HSCT recipients, so as to provide evidence for guiding antibiotic use and improving prognosis in the future. Methods: The epidemiology, clinical manifestations and drug resistance rate with K. pneumoniae infections among HSCT recipients between January 1, 2012 and September 30, 2021 were retrospectively reviewed. Logistic regression model and Cox regression model were respectively used to determine the risk factors for carbapenem-resistant Klebsiella pneumoniae (CRKP) acquisition and death. Results: Fifty-nine HSCT recipients suffered from K. pneumoniae infections, with a mortality rate of 42.4%. The most common site was lung, followed by blood stream. The resistance rate of K. pneumoniae to various clinically common antibiotics was high, especially CRKP, which was only sensitive to amikacin and tigecycline. Independent risk factor for CPKP acquisition was a previous infection within 3 months before transplantation (OR=10.981, 95% CI 1.474-81.809, P=0.019). Independent risk factors for mortality included interval from diagnosis to transplantation > 180 days (HR=3.963, 95% CI 1.25-12.561, P=0.019), engraftment period > 20 days (HR=8.015, 95% CI 2.355-27.279, P=0.001), non-use of anti-CMV immunoglobulin/rituximab after transplantation (HR=10.720, 95% CI 2.390-48.089, P=0.002), and PCT > 5 µg/L (HR=5.906, 95% CI 1.623-21.500, P=0.007). Conclusion: K. pneumoniae infection has become a serious threat for HSCT recipients, which reminds us to pay enough attention and actively seek new strategies.

High tumor mutation burden indicates a poor prognosis in patients with intrahepatic cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is malignancies of the biliary duct system and constitutes approximately 10%-20% of all primary liver cancers. Tumor mutation burden (TMB) is a useful biomarker across many cancer types for the identification of patients who will benefit from immunotherapy. Despite the role of TMB in calculating the effectiveness and prognosis of immune checkpoint inhibitors has been confirmed in multiple human cancer types, the prognostic value of TMB in ICC patients is rare investigated. AIM: To investigate the prognostic value of TMB in patients with ICC. METHODS: Data of 412 patients with ICC were included in the study. TMB was calculated as the total number of somatic non-silent protein-coding mutations divided by the coding region. The Kaplan-Meier method was used to analyze overall survival (OS), and relapse free survival (RFS). The cut-off value of TMB was determined by time-dependent receiver operating characteristic (ROC) curve. Cox regression was performed for multivariable analysis of OS. The nomogram and calibration curve were analyzed to construct and evaluate the prognostic model. RESULTS: In the analysis of the time-dependent ROC curve, we defined 3.1 mut/Mb as the cut-off value of TMB. The Kaplan-Meier plot revealed that patients with high TMB had poor OS (HR = 1.47, P = 0.002) and RFS (HR = 1.42, P = 0.035). Cox regression analysis also demonstrated that TMB was an independent risk predictor for ICC (HR = 1.43, P = 0.0240). Furthermore, independent prognostic factors of ICC included CA19-9 (HR = 1.78, P = 0.0005), chronic viral hepatitis (HR = 1.72, P = 0.0468), tumor resection (HR = 2.58, P < 0.0001) and disease progression (metastatic disease vs. solitary liver tumor; HR = 2.55, P = 0.0002). The nomogram and calibration curve also indicated the effectiveness of the constructed prognostic model. CONCLUSION: TMB was an independent prognostic biomarker in patients with ICC. Moreover, patients with ICC with high TMB had poor OS and RFS as compared to those with low TMB.

Construction of novel antiplatelet modified polyethersulfone membrane and study into its blood compatibility.

Blood purification therapy is widely used in patients with renal insufficiency and severe infections, where membrane-associated thrombosis is a side effect. How to improve the hemocompatibility of dialysis membranes and reduce thrombosis is a focus of current research, in which platelets play a key role. However, few dialysis membranes that directly inhibit platelets have been developed to date. In this study, a polyethersulfone (PES) membrane was modified with ticagrelor, a platelet P2Y12 receptor inhibitor, and detailed characterization was performed. The ticagrelor modified PES membrane (TMPES) showed good hydrophilicity and anti-protein adsorption and significantly inhibited platelet adhesion, aggregation, and activation, which demonstrated good antithrombotic properties. In addition, the membrane had excellent red blood cell (RBC) compatibility, anticoagulant, and antiinflammatory effects, which demonstrated superior biosafety in cell and animal experiments. Therefore, the TMPES dialysis membrane could have potential in clinical applications.

Performing robot-assisted pylorus and vagus nerve-preserving gastrectomy for early gastric cancer: A case series of initial experience.

BACKGROUND: Pylorus and vagus nerve-preserving gastrectomy (PPG) is a function-preserving surgery for early gastric cancer (GC) that has gained considerable interest in the recent years. The operative technique performed using the Da Vinci Xi robot system is considered ideal for open and laparoscopic surgery. AIM: To introduce Da Vinci Xi robot-assisted PPG (RAPPG)-based operative procedure and technical points as well as report the initial experience based on the clinical pathology data of eight cases of early GC. METHODS: Da Vinci Xi robot-assisted pylorus and vagus nerve-preserving gastrectomy (RAPPG) was performed for 11 consecutive patients with middle GC from December 2020 to July 2021. Outcome measures were postoperative morbidity, operative time, blood loss, number of lymph nodes harvested, postoperative hospital stay, time to first flatus, time to diet, and resection margins. RESULTS: Eight of the 11 patients who were pathologically diagnosed with early GC were enrolled in a retrospective study to assess the feasibility and safety of RAPPG. The mean operative time, mean blood loss, mean number of lymph nodes harvested, length of preserved pylorus canal, distal margin, and proximal margin were 330.63 ± 47.24 min, 57.50 ± 37.70 mL, 18.63 ± 10.57, 3.63 ± 0.88 cm, 3.50 ± 1.31 cm, and 3.63 ± 1.19 cm, respectively. None of the cases required conversion to laparotomy. Postoperative complications occurred in two (25.0%) patients. Postoperative complications were hyperamylasemia and gastric stasis in one case and incision infection in the other. Time to first flatus was 3.75 ± 2.49 d after the operation, and postoperative hospital stay was 10.13 ± 4.55 d. CONCLUSION: The core technique in the Da Vinci Xi RAPPG is lymph node dissection and the anatomic method of the nerve. Robotic surgical procedures are feasible and safe. With the progress of surgical technology, optimization of medical insurance structure, and emergence of evidence-based medicine, automated surgery systems will have a broad application in clinical treatment.

Somatic mutation and expression of BAP1 in hepatocellular carcinoma: an indicator for ferroptosis and immune checkpoint inhibitor therapies.

BRCA1-Associated Protein 1 (BAP1) is a deubiquitylase that is found associated with multiprotein complexes that regulate key cellular pathways, and subsequent researches have revealed that BAP1 acts independently as a tumor suppressor. Somatic BAP1 mutations occur in various malignancies, but malignancies arising from mutation of tumor suppressors have unexplained tissue proclivity. Whether somatic mutation or expression alteration of BAP1 in hepatocellular carcinoma (HCC) influence carcinogenesis or immunogenicity is still unknown. In this study, we analyzed RNA expression, immune infiltration, survival and mutation data of HCC from The Cancer Genome Atlas databases. The association between BAP1 and clinicopathological features was further investigated by immunohistochemistry on tissue microarray. We found that the prognosis of patients with high BAP1 expression was significantly worse than that of patients with low BAP1 expression, and multivariate analyses revealed that BAP1 expression was an independent prognostic factor for poor prognosis. HCC with high BAP1 expression was associated with low ESTIMATE Score, recruitment of more tumor-infiltrating macrophage, and elevated levels of tumor mutation burden, microsatellite instability, neoantigen count, as well as programmed death-ligand1 in HCC. In addition, BAP1 mutated HCC showed reduced ability to promote ferroptosis and high BAP1 expression was correlated with ferroptosis. In conclusion, high BAP1 expression reflects immunosuppression and ferroptosis in HCC. BAP1 is a promising prognostic marker for survival of HCC and may act as a complementary indicator for patients to receive ferroptosis-promoting therapy or immunotherapy.

Hippo/YAP signaling choreographs the tumor immune microenvironment to promote triple negative breast cancer progression via TAZ/IL-34 axis.

Growing evidence suggests that the bidirectional interactions between cancer cells and their surrounding environment, namely the tumor microenvironment (TME), contribute to cancer progression, metastasis, and resistance to treatment. Intense investigation of the Hippo pathway, which controls multiple central cellular functions in tumorigenesis, was focused on cancer cells. However, the role of the Hippo pathway in modulating tumor-stromal interactions in triple-negative breast cancer remains largely unknown. Therefore, this study focused on revealing the effects of Hippo-YAP/TAZ signaling on the immune microenvironment. Our findings reveal that the activity of the Hippo pathway is associated with worse disease outcomes in TNBC and could increase TAM infiltration through the TAZ/IL-34 axis, leading to an immunosuppressive microenvironment and impairing the treatment efficacy of anti-PD-L1. Thus, the TAZ/IL-34 axis may serve as a novel target for TNBC patients.

Expression and clinical significance of hepatoma-derived growth factor as a prognostic factor in human hilar cholangiocarcinoma.

BACKGROUND: Overexpressions of hepatoma-derived growth factor (HDGF) and vascular endothelial growth factor (VEGF) play important roles in the development and progression of cancers. This study investigates the expression of HDGF combined with VEGF, their correlation with clinicopathologic features, and their prognosis in human hilar cholangiocarcinoma. MATERIALS AND METHODS: The expressions of HDGF and VEGF were analyzed by immunohistochemistry using the streptavidin peroxidase complex method for 58 patients with hilar cholangiocarcinoma receiving surgery. Their correlation with clinicopathologic features was then investigated. The relationships between them and the survival time of patients were retrospectively analyzed. RESULTS: HDGF and VEGF were positively expressed in 27 (46.6%) and 42 (72.4%) patients, respectively. HDGF and VEGF had a positive correlation (r = 0.370, P = 0.004) in the Spearman rank correlation analysis. HDGF expression was associated with gender and histological type. Patients with positive HDGF expression had a significantly poorer overall survival rate than those with negative HDGF expression (35.7 vs. 73.3%, P = 0.003). Multivariate analysis showed that HDGF expression is an independent prognostic factor. CONCLUSIONS: HDGF expression significantly correlates with VEGF expression and is a valuable prognostic factor for human hilar cholangiocarcinoma.

Purification, characterization and functional expression of a new peptide with an analgesic effect from Chinese scorpion Buthus martensii Karsch (BmK AGP-SYPU1).

In this study, a new peptide named BmK AGP-SYPU1 with an analgesic effect was purified from the venom of Chinese scorpion Buthus martensi Karsch (BmK) through a four-step chromatographic process. The mouse twisting test was used to identify the target peptides in every separation step. The purified BmK AGP-SYPU1 was further qualified by RP-HPLC and HPCE. The molecular mass determined by the MALDI-4800-TOF/TOF MS for BmK AGP-SYPU1 was 7544 Da. Its primary structure of the N-terminal was obtained using Edman degradation. The gene sequence of BmK AGP-SYPU1 was cloned from the cDNA pool and genomic of scorpion glands, respectively, and then expressed in Escherichia coli. The sequence determination showed that BmK AGP-SYPU1 was composed of 66 amino acid residues with a new primary structure. The metal chelating affinity column and cation exchange chromatography were used to purify the recombinant BmK AGP-SYPU1. Consequently, the native and recombinant BmK AGP-SYPU1 showed similar analgesic effects on mice as assayed using a mouse twisting model. These results suggested that BmK AGP-SYPU1 is a new analgesic component found in the Chinese scorpion Buthus martensi Karsch.

[Effect on expression of vascular smooth muscle cell calcium channel in rats exposed in low temperature].

OBJECTIVE: To observe the expression of vascular smooth muscle cells calcium channel α1C subunit (LTCCα1C) in rats exposed in low temperature. METHODS: Cold-induced hypertension was established and blood pressure was measured every two weeks. The mRNA expression of L type calcium channel α1C was determined by RT-PCR. RESULTS: The blood pressure of the rats exposed to cold environment increased. The blood pressure of experimental groups [(102.8 ± 2.25) mm Hg] began to increase from the first two weeks, compared with the control group [(89.2 ± 3.73) mm Hg], there were significant difference (P < 0.05). The blood pressure of experimental groups were (114.5 ± 4.21), (121.9 ± 3.03) mm Hg respectively at 4, 6 weeks. Compared with the control group, the expression of LTCCα1C mRNA of the cold exposure group increased significantly (P < 0.01). There was a significant correlation between the expression of LTCCα1C mRNA and the blood pressure of the rats (r = 0.86, P < 0.01). CONCLUSION: Repeated cold exposure can establish cold-induced hypertension, and the level of vascular smooth muscle cells LTCCα1C expression increase.

Vorapaxar-modified polysulfone membrane with high hemocompatibility inhibits thrombosis.

Hemodialysis therapy is intended for patients suffering from renal insufficiency, pancreatitis, and other serious diseases. Platelets are an important active ingredient in the thrombosis induced by hemodialysis membranes. So far, there are few studies of hemodialysis membranes focusing on the effects of protease-activated receptor 1 (PAR1) activation on the platelet membrane. Among various antithrombotic agents, vorapaxar is a novel PAR1 inhibitor with high efficacy. In this study, we constructed a vorapaxar-modified polysulfone (VMPSf) membrane using immersion-precipitation phase transformation methods and characterized the microstructure in terms of hydrophilicity and mechanical properties. The water contact angle of the VMPSf membrane was 22.45% lower than that of the PSf membrane. A focused determination of platelet morphology was obtained using scanning electron microscopy. Meanwhile, we evaluated the effects of a VMPSf membrane on platelet adhesion. We observed that the VMPSf membrane could reduce the number of adhered platelets without altering their spherical or elliptical shape. The PAR1 levels in VMPSf membranes were 7.4 MFI lower than those in PSf membranes, suggesting that this modified membrane can effectively inhibit platelet activation. Activated partial thromboplastin time (APTT, 5.3 s extension) and thrombin time (TT, 2.1 s extension) reflect good anticoagulant properties. Recalcification time (80.6 s extension) and fibrinogen adsorption (9.9 µg/cm2 reduction) were related to antithrombotic properties. To determine the biosafety of VMPSf membranes, we investigated antianaphylactic and anti-inflammatory properties in vitro and acute toxicity in vivo, it was obvious that C3a and C5a had decreased to 9.6 and 0.8 ng/mL, respectively. The results indicated that the VMPSf membrane has potential for clinical application.