Causes of recurrence of paediatric inguinal hernia after single-port laparoscopic closure.

PURPOSE: This paper explores the causes of paediatric inguinal hernia (PIH) recurrence after single-port laparoscopic percutaneous extraperitoneal closure (SPLPEC). METHOD: From January 2015 to December 2020, the clinical data of 3480 children with PIHs who underwent SPLPEC were retrospectively reviewed, including 644 children who underwent SPLPEC with a homemade single-hook hernia needle from January 2015 to December 2016 and 2836 children who underwent the SPLPEC with a double-hook hernia needle and hydrodissection from January 2017 to December 2020. There were 39 recurrences (including communicating hydrocele) during the 2-5 years of follow-up. The findings of redo-laparoscopy were recorded and correlated with the revised video of the first operation to analyse the causes of recurrence. RESULT: Thirty-three males and 6 females experienced recurrence, and 8 patients had a unilateral communicating hydrocele. The median time to recurrence was 7.1 months (0-38). There were 20 cases (3.11%) in the single-hook group and 19 cases (0.67%) in the double-hook group. Based on laparoscopic findings, recurrence most probably resulted from multiple factors, including uneven tension of the ligation (10 cases), missing part of the peritoneum (14 cases), loose ligation (8 cases), broken knot (5 cases), and knot reaction (2 cases). All children who underwent repeat SPLPEC were cured by double ligations or reinforcement with medial umbilical ligament. CONCLUSION: The main cause of recurrence is improper ligation. Tension-free and complete PIH ligation are critical to the success of surgery, which requires avoiding the peritoneum skip area and the subcutaneous and muscular tissues. Redo-laparoscopic surgery was suitable for the treatment of recurrent inguinal hernia (RIH). For giant hernias, direct ligation of the internal ring incorporating the medial umbilical ligament (DIRIM) may be needed.

Validation of metagenomic next-generation sequencing of bronchoalveolar lavage fluid for diagnosis of suspected pulmonary infections in patients with systemic autoimmune rheumatic diseases receiving immunosuppressant therapy.

Background: The accuracy and sensitivity of conventional microbiological tests (CMTs) are insufficient to identify opportunistic pathogens in patients with systemic autoimmune rheumatic diseases (SARDs). The study aimed to assess the usefulness of metagenomic next-generation sequencing (mNGS) vs. CMTs for the diagnosis of pulmonary infections in patients with SARDs receiving immunosuppressant therapy. Methods: The medical records of 40 patients with pulmonary infections and SARDs treated with immunosuppressants or corticosteroids were reviewed retrospectively. Bronchoalveolar lavage fluid (BALF) samples were collected from all patients and examined by mNGS and CMTs. Diagnostic values of the CMTs and mNGS were compared with the clinical composite diagnosis as the reference standard. Results: Of the 40 patients included for analysis, 37 (92.5%) were diagnosed with pulmonary infections and 3 (7.5%) with non-infectious diseases, of which two were considered primary diseases and one an asthma attack. In total, 15 pathogens (7 bacteria, 5 fungi, and 3 viruses) were detected by CMTs as compared to 58 (36 bacteria, 12 fungi, and 10 viruses) by mNGS. Diagnostic accuracy of mNGS was superior to that of the CMTs for the detection of co-infections with bacteria and fungi (95 vs. 53%, respectively, p < 0.01), and for the detection of single infections with fungi (97.5 vs. 55%, respectively, p < 0.01). Of the 31 patients diagnosed with co-infections, 4 (12.9%) were positive for two pathogens and 27 (87.1%) for three or more. The detection rate of co-infection was significantly higher for mNGS than CMTs (95 vs. 16%, respectively, p < 0.01). Conclusion: The accuracy of mNGS was superior to that of the CMTs for the diagnosis of pulmonary infections in patients with SARDs treated with immunosuppressants. The rapid diagnosis by mNGS can ensure timely adjustment of treatment regimens to improve diagnosis and outcomes.

Roxadustat Improves Erythropoietin Antibody-Mediated Pure Red Cell Aplasia in a Patient with Hemodialysis.

Anemia is a common complication of chronic kidney disease (CKD). Recombinant human erythropoietin (rHu-EPO) is used extensively in patients with CKD. However, anti-erythropoietin (anti-EPO) antibody has been reported during rHu-EPO treatment, which causes pure red cell aplasia (PRCA). We presented a case of 75-year-old man, who underwent hemodialysis for 2 years. He developed PRCA during rHu-EPO treatment. The rHu-EPO was immediately discontinued, and the patient was given roxadustat treatment. After 6 months of roxadustat treatment, the anti-EPO antibody was disappeared, and hemoglobin recovered normal range. The results suggest that roxadustat can be used to treat patients with anti-EPO antibody-mediated PRCA without immunosuppressive therapy.

Pharmacokinetics and Pharmacodynamics of Sacubitril/Valsartan in Maintenance Hemodialysis Patients with Heart Failure.

BACKGROUND: Heart failure (HF) is one of the main comorbidities in patients receiving maintenance hemodialysis (HD). Sacubitril/valsartan (SAC/VAL) is widely used in HF patients with reduced ejection fraction (HFrEF) or HF mid-range ejection fraction (HFmrEF). However, the pharmacokinetic (PK) and pharmacodynamic properties of SAC/VAL in HD patients with HF remain uncertain. OBJECTIVES: This study aimed to analyze the efficacy and PK properties of SAC/VAL in HD patients with HFrEF or HFmrEF. METHODS: HD patients with HFrEF or HFmrEF were treated with SAC/VAL 50 or 100 mg twice a day (BID) and the concentrations of valsartan and LBQ657 (active metabolite of SAC) were determined by high-performance liquid chromatography-tandem mass spectrometry during HD and on the days between HD sessions (interval days). N-terminal-pro B-type natriuretic peptide and high-sensitivity troponin T were measured, and left ventricular ejection fraction (LVEF) was evaluated by echocardiography. RESULTS: The mean maximum plasma concentrations (Cmax) of LBQ657 and VAL on the interval days were 15.46 ± 6.01 and 2.57 ± 1.23 mg/L, respectively. Compared with previous values in patients with severe renal impairment and healthy volunteers, these levels both remained within the safe concentration ranges during treatment with SAC/VAL 100 mg BID. Moreover, SAC/VAL significantly improved LVEF in HD patients with HFrEF or HFmrEF (p < 0.05). CONCLUSIONS: HD did not remove the SAC metabolite LBQ657 or VAL in patients with HF. However, SAC/VAL 100 mg BID was safe and effective in patients undergoing HD.

Receptor activator of NF-κB mediates podocyte injury in diabetic nephropathy.

Receptor activator of NF-κB (RANK) expression is increased in podocytes of patients with diabetic nephropathy. However, the relevance of RANK to diabetic nephropathy pathobiology remains unclear. Here, to evaluate the role of podocyte RANK in the development of diabetic nephropathy, we generated a mouse model of podocyte-specific RANK depletion (RANK-/-Cre T), and a model of podocyte-specific RANK overexpression (RANK TG), and induced diabetes in these mice with streptozotocin. We found that podocyte RANK depletion alleviated albuminuria, mesangial matrix expansion, and basement membrane thickening, while RANK overexpression aggravated these indices in streptozotocin-treated mice. Moreover, streptozotocin-triggered oxidative stress was increased in RANK overexpression but decreased in the RANK depleted mice. Particularly, the expression of NADPH oxidase 4, and its obligate partner, P22phox, were enhanced in RANK overexpression, but reduced in RANK depleted mice. In parallel, the transcription factor p65 was increased in the podocyte nuclei of RANK overexpressing mice but decreased in the RANK depleted mice. The relevant findings were largely replicated with high glucose-treated podocytes in vitro. Mechanistically, p65 could bind to the promoter regions of NADPH oxidase 4 and P22phox, and increased their respective gene promoter activity in podocytes, dependent on the levels of RANK. Taken together, these findings suggested that high glucose induced RANK in podocytes and caused the increase of NADPH oxidase 4 and P22phox via p65, possibly together with the cytokines TNF- α, MAC-2 and IL-1 ß, resulting in podocyte injury. Thus, we found that podocyte RANK was induced in the diabetic milieu and RANK mediated the development of diabetic nephropathy, likely by promoting glomerular oxidative stress and proinflammatory cytokine production.

Protein A immunoadsorption combination with immunosuppressive therapy improves neuropsychiatric systemic lupus erythematosus: A case report.

We described protein A immunoadsorption combination with immunosuppressive treatment improved rapidly a patient with Neuropsychiatric systemic lupus erythematosus.

Treatment of Uremic Tumoral Calcinosis in Maintenance Hemodialysis Patients.

BACKGROUND/AIMS: Uremic tumoral calcinosis (UTC) is a rare disease with metastatic tissue calcification in maintenance hemodialysis (HD) patients. However, limited data are available on the treatment of UTC in HD patients. This article mainly discusses the diagnostic findings and efficacy of treatment on HD patients with UTC. METHODS: A retrospective analysis was conducted based on the data of 13 cases of UTC, including their clinical features, biochemical indicators, imaging findings, diagnosis, therapeutic methods, and follow-up results. Parathyroidectomy (PTX) or drug treatment was determined based on intact parathyroid hormone (iPTH) levels and clinical symptoms. RESULTS: All 13 patients were diagnosed as UTC definitely by imaging examination. The predominant areas involved were the buttocks (4 cases, 30.77%), shoulders (4 cases, 30.77%), and elbows (3 cases, 23.08%). Based on the levels of iPTH, cases were categorized into 2 different groups: PTX treatment group was associated with high levels of iPTH, while drug treatment group (lanthanum carbonate or sevelamer with sodium thiosulfate) was associated with lower iPTH levels. After PTX treatment, there was a significant decrease in serum iPTH, calcium (Ca), phosphate (P), and alkaline phosphatase levels (p < 0.05). In drug treatment group, the serum p levels were decreased significantly, along with a finding that hemoglobin levels were increased (p < 0.05). All the UTC had lessened or even disappeared after 4-6 months treatment. CONCLUSIONS: Although most UTC patients have an increased iPTH, a small number had lower iPTH levels. Based on iPTH levels and clinical symptoms, the patients were treated with PTX or drug therapy. With proper treatment, UTC disappeared without the need for surgery to remove calcinosis tissue.

[NFAT2 mediates high glucose-induced apoptosis in glomerular podocytes in vitro].

OBJECTIVE: To determine whether hyperglycemia activates NFAT2 in cultured podocytes to cause podocyte apoptosis and explore the role of NFAT2 in high glucose-induced podocyte apoptosis. METHODS: Immortalized mouse podocytes were cultured in the presence of normal (5.3 mmol/L) or high glucose (10, 20, 30, and 40 mmol/L) or pretreated with 11R-vivit (100 nmol/L) or cyclosporine A (500 nmol/L) before exposure to 20 mmol/L glucose for different durations (0.5-48 h). The activation of NFAT2 in the podocytes was detected using Western blotting and immunofluorescence assay. The role of NFAT2 in hyperglycemia-induced podocyte apoptosis was explored by observing the inhibition of NFAT2 activation by 11R-vivit using flow cytometry. Intracellular Ca2+ was monitored in high glucose-treated podocytes using Fluo-3/AM. The mRNA and protein expressions of the apoptosis gene Bax were detected using real time-qPCR and Western blotting. RESULTS: Exposure to high glucose in the medium time- and dose-dependently activated NFAT2 in cultured podocytes. Pretreatment with cyclosporine A or 11R- VIVIT completely blocked nuclear accumulation of NFAT2. Treatment with 11R- vivit also inhibited high glucoseinduced apoptosis in cultured podocytes. Exposure to high glucose obviously increased [Ca2 +]I in the podocytes to cause activation of calcineurin and the subsequent increment of nuclear accumulation of NFAT2 and Bax expression. CONCLUSIONS: High glucose-induced apoptosis in podocytes is mediated by calcineurin/NFAT2/Bax signaling pathway, which may serve as a potential target for therapeutic intervention.

Alterations of Notch pathway in patients with adenoid cystic carcinoma of the trachea and its impact on survival.

INTRODUCTION: Adenoid cystic carcinoma (ACC) of the trachea lacks of well-characterized molecular markers. There is currently no specific treatment for metastatic ACC of the trachea. This study aimed to identify genomic mutations of Notch pathway and investigate the efficacy of NOTCH inhibitor in ACC of the trachea. METHODS: 73 Patients with ACC of the trachea at four institutions from 2008 to 2016 were identified. Analysis of hotspot mutations in cancer-related genes of Notch pathway was performed using next generation sequencing. Gene-expression and functional analyses were performed to study the mechanism of activation through mutation. Univariable and multivariable Cox regression models were used to predict overall survival (OS). Patient-derived xenograft (PDX) models were established and treated with NOTCH inhibitor Brontictuzumab. RESULTS: Gain-of-function mutations of the NOTCH1 gene occurred in 12 (16.4%) tumors, leading to stabilization of the intracellular cleaved form of NOTCH1 (ICN1). NOTCH1 mutation was associated with increased NOTCH1 activation and its target gene HES1. Mutations in NOTCH2 (3/73), NOTCH4 (2/73), JAG1 (1/73) and FBXW7 (2/73) were also identified in 8 (11.0%) patients. A strong inverse correlation of expression was observed between FBXW7 and HES1. NOTCH1 mutation was associated with solid subtype (P = 0.02), younger age at diagnosis (P = 0.041) and shorter overall survival (OS) (P = 0.017). NOTCH1 mutation was not an independent prognostic factor in the presence of histologic subtype and resection margin. Brontictuzumab significantly reduced tumor growth in NOTCH1-mutated PDX. CONCLUSION: NOTCH1 mutation is associated with activation of Notch pathway in ACC of the trachea. NOTCH1 is a potential target for therapeutic intervention in patients with ACC of the trachea.

Inducible ATF3-NFAT axis aggravates podocyte injury.

Podocyte injury and loss contribute to proteinuria, glomerulosclerosis, and eventually kidney failure. Activating transcription factor 3 (ATF3) is a stress inducible transcription factor that is transiently expressed following stimulation. However, we show for the first time an induction of ATF3 in podocytes from patients with chronic kidney disease, including minimal change disease, focal segmental glomerulosclerosis, and diabetic nephropathy. The role of ATF3 induction in podocytes under chronic conditions is currently unknown. Compared with the control (C57 or BKS), ATF3 expression was elevated in animal model of proteinuria (LPS-treated C57 mice) and the model of diabetic nephropathy (db/db mice). Similarly, ATF3 was increased in high glucose (HG)-treated, lipopolysaccharide (LPS)-treated, or Ionomycin-treated podocytes in vitro. Overexpression of ATF3 increased podocyte apoptosis and decreased expression of podocin, the cell marker of podocyte; in contrast, ATF3-small interfering RNA knockdown reduced podocyte apoptosis and increased podocin expression. The translocation of ATF3 to the nucleus was increased upon stimulation. ATF3 directly modulates the regulation of NFATc1 gene promoter activity and alters the expression of Wnt6 and Fzd9, direct target genes of NFATc1 signaling. The ATF3 binding site of NFATc1 gene promoter is located at the region 671-775 base pairs upstream of the transcription start site. These results indicate a novel inducible axis of ATF3-NFAT in podocyte injury and loss. KEY MESSAGES: • The stress factor ATF3 is induced in podocytes from proteinuric patients, including diabetes. • ATF3 increased podocyte apoptosis and injury. • ATF3 directly modulates the regulation of NFATc1 gene promoter activity.

The Prognostic Significance of Notch1 and Fatty Acid Binding Protein 7 (FABP7) Expression in Resected Tracheobronchial Adenoid Cystic Carcinoma: A Multicenter Retrospective Study.

PURPOSE: Adenoid cystic carcinoma (ACC) of the trachea and bronchus is a rare tumor. Although MYB-NFIB oncogene fusion and Notch1 mutation have been identified in ACC, little is known about the expression and clinical significance of Notch1 and its target gene fatty acid binding protein 7 (FABP7) in tracheobronchial ACC. MATERIALS AND METHODS: Primary tracheobronchial ACC that were resected between 1998 and 2014 were identified through the pathology and oncology database from five thoracic oncology centers in China. A tissue array was constructed from the patients' samples and the expressions of Notch1 and FABP7 were evaluated by immunohistochemistry. The association between the expression of both markers and survival was determined. RESULTS: Overexpression of Notch1 and FABP7, detected in 37.8% and 38.3% of 368 patients with tracheobronchial ACC, respectively, was an independent prognostic indicator for recurrencefree survival (RFS) by multivariable Cox proportional hazard model (p=0.032 and p=0.048, respectively). Overexpression of Notch1, but not of FABP7, predicted overall survival (OS) (p=0.018). When categorized into four groups according to coexpression of Notch1 and FABP7, patients with overexpression of both Notch1 and FABP7 belonged to the group with the shortest RFS and OS (p=0.01 and p=0.048, respectively). CONCLUSION: Expression of Notch1 and FABP7, and coexpression of Notch1 and FABP7, is strongly associated with poor survival in resected tracheobronchial ACC. These data are consistent with the hypothesis that poor differentiation of tracheobronchial ACC correlates with the activation of Notch signaling.

[Association of heart valve calcification with cardiovascular outcomes in patients on maintenance hemodialysis].

OBJECTIVE: To investigate the impact of heart valve calcification (HVC) on cardiovascular outcomes in patients on maintenance hemodialysis (MHD). METHODS: We enrolled 302 Chinese patients on MHD between 2009 and 2011 including 99 with HVC identified by echocardiography screening. All the patients were followed up for 2 years and survival analysis was performed with all-cause mortality, cardiovascular mortality and new onset cardiovascular events as the endpoints. Cox regression analysis was used for analyzing the impact of heart valve calcification on the cardiovascular outcomes of the patients. RESULTS: The mean age of the total patients was 58.2∓15.0 years when receiving the initial MHD, and 53.6% were male patients. The overall mortality, cardiovascular mortality and new on-set cardiovascular events in HVC and non-HVC groups were 30.3% vs 16.3%, 22.2% vs 6.9%, and 48.5% vs 25.6%, respectively (P<0.05). Kaplan-Meier survival analysis showed a significant difference in all-cause mortality (P=0.006), cardiovascular mortality (P<0.001) and new-onset cardiovascular events (P<0.001) between HVC and non-HVC groups. After adjustment, Cox regression analysis identified HVC as a risk factor for increased all-cause mortality (HR=1.88; 95%CI: 1.11-3.19), cardiovascular mortality (HR=3.47, 95%CI: 1.76-6.84) and cardiovascular events (HR=1.64, 95% CI: 1.09-2.47). CONCLUSIONS: HVC is an independent risk factor for increased cardiovascular mortality and new cardiovascular events in patients on MHD.

[Relationship between Expression of TGF-ß1, Smad2, Smad4 and Prognosis 
of Patients with Resected Non-small Cell Lung Cancer].

BACKGROUND AND OBJECTIVE: It has been proven that any changes of transforming growth factor ß (TGF-ß)-Smad signal transduction pathway will lead to abnormalities of signal transmission and the out of control during cell growth and differentiation, resulting in cancer development. The aim of this study is to investigate the prognostic values of TGF-ß1, Smad2 and Smad4 in resected non-small cell lung cancer (NSCLC). METHODS: The expression of TGF-ß1, Smad2, and Smad4 was evaluated by immunohistochemistry in 85 patients with NSCLC. The relationships among the expression of these proteins, clinicopathological factors, and prognosis were also analyzed. RESULTS: TGF-ß1 positive expression was significantly correlated with the late stage and lymph node involvement. No significant association existed between the expression of Smad2 and the clinicopathological characteristics. The lack of Smad4 expression was associated with the advanced tumor stage (P=0.014). Multivariate analysis indicated that lymph node involvement (P=0.001) was an independent prognostic factor in the 85 NSCLC patients. The positive expression levels of TGF-ß1 (P=0.032) and N stage (P=0.028) were demonstrated to be independent risk factors for survival among 47 lung adenocarcinoma patients. Adenocarcinoma patients with TGF-ß1 positive expression demonstrated an unfavorable survival outcome (P=0.0376). CONCLUSIONS: TGF-ß1 may be an independent predictor of survival in resected lung adenocarcinoma patients.
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IL-13 receptor α2 is a negative prognostic factor in human lung cancer and stimulates lung cancer growth in mice.

IL-13 receptor subunit alpha-2 (IL13Rα2) is associated with poor prognosis in some cancers. However, the role of IL13Rα2 in lung cancer remains unknown. We showed that IL13Rα2 overexpression was associated with late stages of disease progression and shorter disease-free survival (DFS) as well as overall survival (OS) in resected lung cancer patients. IL13Rα2 promoted the migration, invasion and anoikis resistance of lung cancer cells in vitro. Silencing of IL13Rα2 in lung cancer cells decreased invasion in vitro and lung metastasis in vivo. IL13Rα2 activated phosphatidylinositol 3 kinase (PI3K), Akt, and transcriptional coactivator with PDZ-binding motif (TAZ). Inhibition of PI3K attenuated activation of TAZ and its downstream target genes by IL13Rα2. We suggest that inhibition of IL13Rα2 is a potential therapeutic approach in lung cancer.

[A prognostic model for predicting extracorporeal circuit clotting in patients with continuous renal replacement therapy].

OBJECTIVE: To establish a prognostic model for predicting extracorporeal circulation clotting in patients with continuous renal replacement therapy (CRRT). METHODS: 425 patients with CRRT were involved in the study. We built a predictive risk model of extracorporeal blood clotting with the 302 participants, and 103 participants were used to validate the model. The primary endpoint of CRRT was extracorporeal circulation pipe blockage. RESULTS: We used a score of 0-5 point evaluating system to predict the risk of 24 hours CRRT integral model of cardiopulmonary bypass clogging. The area under the CRRT predictive model of cardiopulmonary bypass clogging integral system ROC curve was 0.790 (95% CI 0.719-0.826) (P<0.001). The evaluating system can determine the blockage of 24 hours CRRT extracorporeal circulation. The results showed that CRRT extracorporeal plugging prediction fitted the integral model and could predict the chance of plugging. The actual plugging rate showed no significant difference from the predicted rate (R² = 0.301, P=0.232). The cardiopulmonary pipe survival time between the 3 groups(low risk, intermediate risk, and high risk) showed a significant difference (P<0.05). CONCLUSION: We established a continuity extracorporeal blood purification plugging risk score model, to predict plugging risks during CRRT treatment.

γ Secretase inhibitor BMS-708163 reverses resistance to EGFR inhibitor via the PI3K/Akt pathway in lung cancer.

Lung adenocarcinoma cells harboring epidermal growth factor receptor (EGFR) mutations are sensitive to EGFR tyrosine kinase inhibitor (TKI). Acquired resistance to EGFR TKI develops after prolonged treatment. The aim of this study was to investigate the effect of the novel γ secretase inhibitor BMS-708163 on acquired resistance to the EGFR TKI gefitinib. We did not observe known mechanisms of acquired resistance to EGFR TKI, including the EGFR T790M mutation and MET gene amplification in the gefitinib-resistant PC9/AB2 cells. BMS-708163 inhibited PI3K/Akt expression and sensitized PC9/AB2 cells to gefitinib-induced cytotoxicity. In contrast, BMS-708163 had no significant effect on gefitinib sensitivity in PC9 parental cells. Combined treatment with BMS-708163 and gefitinib induced high levels of apoptosis. Our in vivo studies showed that combined treatment of gefitinib and BMS-708163 inhibited the growth of PC9/AB2 xenografts. In conclusion, our data show that combined treatment of gefitinib and γ secretase inhibitors may be useful for treating lung adenocarcinomas harboring EGFR mutations with acquired gefitinib resistance.

[Amiloride reduces proteinuria and inhibits podocyte uPAR in the 5/6 nephrectomy rats].

OBJECTIVE: To observe the effect of amiloride on the proteinuria of the 5/6 nephrectomy rats. METHODS: To establish the 5/6 nephrectomy rats model and divide the experiment into 3 groups, sham operated group(Sham), 5/6 nephrectomy model group(NTX) and 5/6 nephrectomy with amiloride-treated group (NTX+amiloride, n=15). The concentration of protein and mRNA of uPAR and the change of podocytes motility were detected by coomassiebluestaining, immunofluorence method and real-time PCR. RESULTS: At second week, compared with Control group, the 24 h urine protein of NTX group was significantly increased (47.50 ± 28.05 mg vs 14.28 ± 3.8 mg, P = 0.023). There was no statistical significance in 24-hour urine protein between NTX+amiloride group and NTX group (51.56 ± 21.03 mg vs 47.50 ± 28.05 mg, P = 0.748). The same situation was also observed at the time point of 12 week, comparing with NTX group, 24-hour urine protein decreased in Sham group (188.31 ± 29.82 mg vs 21.32 ± 8.59 mg, P = 0.000) and NTX+amiloride group (188.31 ± 29.82 mg vs 121.37 ± 31.14 mg, P=0.000), with statistical significance when comparing with Sham group, the expression of uPAR mRNA in NTX group was significantly increased (9.74 ± 1.44 vs 1.01 ± 0.13, P = 0.000). In contrast, the expression of uPAR mRNA in NTX rats treated with amiloride was significantly lower than in NTX group (9.74 ± 1.44 vs 5.01 ± 1.36, P = 0.000). CONCLUSION: Amiloride can reduce the proteinuria of the 5/6 nephrectomy rats model of transient proteinuria by inhibiting the induction of uPAR expression.

Notch-1 contributes to epidermal growth factor receptor tyrosine kinase inhibitor acquired resistance in non-small cell lung cancer in vitro and in vivo.

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) occurs in non-small cell lung cancer (NSCLC) patients who initially respond to TKI treatment but whose cancer then progresses. Recent studies have shown that Notch signal is associated with drug resistance. However, the exact mechanism of Notch during acquisition of resistance to EGFR-TKI in human lung cancer remains unclear. In the present study, we showed that the expression of Notch-1 was highly upregulated in EGFR-TKI acquired resistant lung cancer cells. More importantly, Notch-1 contributed to the acquisition of the epithelial-mesenchymal transition (EMT) phenotype, which was critically associated with acquired resistance to EGFR-TKI. Silencing of Notch-1 using siRNA resulted in mesenchymal-epithelial transition (MET), which was associated with impaired invasion and anchorage-independent growth of lung cancer and resensitisation to gefitinib in acquired resistant NSCLC cells. Finally, gefitinib treatment of Balb/c nu/nu with acquired resistant lung cancer xenografts in combination with Notch inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-(S)-phenylglycine t-butyl ester (DAPT) resulted in effective tumour growth retardation, with decreased proliferative activity and increased apoptotic activity. Collectively, these data suggest that Notch-1 might play a novel role in acquired resistance to gefitinib, which could be reversed by inhibiting Notch-1.

Coupled plasma filtration adsorption combined with continuous veno-venous hemofiltration treatment in patients with severe acute pancreatitis.

BACKGROUND: Severe acute pancreatitis (SAP) still has a high mortality rate. Coupled plasma filtration adsorption (CPFA) and continuous veno-venous hemofiltration (CVVH) are 2 extracorporeal blood purification techniques. We hypothesized that CPFA combined with CVVH could preferentially improve prognosis and suppress clinical manifestations of SAP. METHODS: In this observational cohort study, 25 patients with SAP were enrolled, in which 12 received CPFA plus CVVH treatment (group 1), and 13 received CVVH therapy (group 2). All the patients underwent a successive 10-day intervention. Clinical indicators were detected before or after the intervention and the results were compared between the 2 groups. The feasibility and the survival rate were evaluated on day 28. RESULTS: Compared with group 2, oxygenation index (PaO(2)/FiO(2)), mean arterial pressure, serum amylase, and blood urine nitrogen showed significant differences (all P<0.01) and serum TNF-α, IL-1ß, IL-6 were reduced and IL-10 was elevated with time in group 1 (all P<0.01). Liver functions, electrolyte, and acid-base balance did not show significant difference before and after the 10-day treatment with CPFA plus CVVH compared with CVVH (P>0.05). No therapy-related adverse reactions were noted in both groups. Twenty-eight-day survival rate of group 1 was higher than that in group 2 [91.7% (11/12) vs. 53.8% (7/13), P<0.05]. CONCLUSIONS: CPFA combined with CVVH was an effective and safe method for treatment of SAP patients, the mechanism being related to its effect on regulating the level of cytokines and serum amylase.

SIRT1 regulates endothelial Notch signaling in lung cancer.

BACKGROUND: Sirtuin 1 (SIRT1) acts as a key regulator of vascular endothelial homeostasis, angiogenesis, and endothelial dysfunction. However, the underlying mechanism for SIRT1-mediated lung carcinoma angiogenesis remains unknown. Herein, we report that the nicotinamide adenine dinucleotide 1 (NAD1)-dependent deacetylase SIRT1 can function as an intrinsic negative modulator of Delta-like ligand 4 (DLL4)/Notch signaling in Lewis lung carcinoma (LLC) xenograft-derived vascular endothelial cells (lung cancer-derived ECs). PRINCIPAL FINDINGS: SIRT1 negatively regulates Notch1 intracellular domain (N1IC) and Notch1 target genes HEY1 and HEY2 in response to Delta-like ligand 4 (DLL4) stimulation. Furthermore, SIRT1 deacetylated and repressed N1IC expression. Quantitative chromatin immunoprecipitation (qChIP) analysis and gene reporter assay demonstrated that SIRT1 bound to one highly conserved region, which was located at approximately -500 bp upstream of the transcriptional start site of Notch1,and repressed Notch1 transcription. Inhibition of endothelial cell growth and sprouting angiogenesis by DLL4/Notch signaling was enhanced in SIRT1-silenced lung cancer-derived EC and rescued by Notch inhibitor DAPT. In vivo, an increase in proangiogenic activity was observed in Matrigel plugs from endothelial-specific SIRT1 knock-in mice. SIRT1 also enhanced tumor neovascularization and tumor growth of LLC xenografts. CONCLUSIONS: Our results show that SIRT1 facilitates endothelial cell branching and proliferation to increase vessel density and promote lung tumor growth through down-regulation of DLL4/Notch signaling and deacetylation of N1IC. Thus, targeting SIRT1 activity or/and gene expression may represent a novel mechanism in the treatment of lung cancer.