MicroRNA-451 from Human Umbilical Cord-Derived Mesenchymal Stem Cell Exosomes Inhibits Alveolar Macrophage Autophagy via Tuberous Sclerosis Complex 1/Mammalian Target of Rapamycin Pathway to Attenuate Burn-Induced Acute Lung Injury in Rats.

Objective: Our previous studies established that microRNA (miR)-451 from human umbilical cord mesenchymal stem cell-derived exosomes (hUC-MSC-Exos) alleviates acute lung injury (ALI). This study aims to elucidate the mechanisms by which miR-451 in hUC-MSC-Exos reduces ALI by modulating macrophage autophagy. Methods: Exosomes were isolated from hUC-MSCs. Severe burn-induced ALI rat models were treated with hUC-MSC-Exos carrying the miR-451 inhibitor. Hematoxylin-eosin staining evaluated inflammatory injury. Enzyme-linked immunosorbnent assay measured lipopolysaccharide (LPS), tumor necrosis factor-α, and interleukin-1ß levels. qRT-PCR detected miR-451 and tuberous sclerosis complex 1 (TSC1) expressions. The regulatory role of miR-451 on TSC1 was determined using a dual-luciferase reporter system. Western blotting determined TSC1 and proteins related to the mammalian target of rapamycin (mTOR) pathway and autophagy. Immunofluorescence analysis was conducted to examine exosomes phagocytosis in alveolar macrophages and autophagy level. Results: hUC-MSC-Exos with miR-451 inhibitor reduced burn-induced ALI and promoted macrophage autophagy. MiR-451 could be transferred from hUC-MSCs to alveolar macrophages via exosomes and directly targeted TSC1. Inhibiting miR-451 in hUC-MSC-Exos elevated TSC1 expression and inactivated the mTOR pathway in alveolar macrophages. Silencing TSC1 activated mTOR signaling and inhibited autophagy, while TSC1 knockdown reversed the autophagy from the miR-451 inhibitor-induced. Conclusion: miR-451 from hUC-MSC exosomes improves ALI by suppressing alveolar macrophage autophagy through modulation of the TSC1/mTOR pathway, providing a potential therapeutic strategy for ALI.

Adjuvant sintilimab in resected high-risk hepatocellular carcinoma: a randomized, controlled, phase 2 trial.

Hepatocellular carcinoma (HCC), particularly when accompanied by microvascular invasion (MVI), has a markedly high risk of recurrence after liver resection. Adjuvant immunotherapy is considered a promising avenue. This multicenter, open-label, randomized, controlled, phase 2 trial was conducted at six hospitals in China to assess the efficacy and safety of adjuvant sintilimab, a programmed cell death protein 1 inhibitor, in these patients. Eligible patients with HCC with MVI were randomized (1:1) into the sintilimab or active surveillance group. The sintilimab group received intravenous injections every 3 weeks for a total of eight cycles. The primary endpoint was recurrence-free survival (RFS) in the intention-to-treat population. Key secondary endpoints included overall survival (OS) and safety. From September 1, 2020, to April 23, 2022, a total of 198 eligible patients were randomly allocated to receive adjuvant sintilimab (n = 99) or undergo active surveillance (n = 99). After a median follow-up of 23.3 months, the trial met the prespecified endpoints. Sintilimab significantly prolonged RFS compared to active surveillance (median RFS, 27.7 versus 15.5 months; hazard ratio 0.534, 95% confidence interval 0.360-0.792; P = 0.002). Further follow-up is needed to confirm the difference in OS. In the sintilimab group, 12.4% of patients experienced grade 3 or 4 treatment-related adverse events, the most common of which were elevated alanine aminotransferase levels (5.2%) and anemia (4.1%). These findings support the potential of immune checkpoint inhibitors as effective adjuvant therapy for these high-risk patients. Chinese Clinical Trial Registry identifier: ChiCTR2000037655 .

Biomarkers for distinguishing tuberculous pleural effusion from non-tuberculosis effusion: a retrospective study.

BACKGROUND: Pleural effusion (PE) is a common clinical feature that presents a diagnostic challenge for clinicians. In this retrospective study, we aimed to assess the biomarkers, ratios, and multiple indicators in serum and Pleural effusion for the differential diagnosis of tuberculous pleural effusion (TPE) from non-tuberculosis effusion (non-TPE). METHODS: The participants, who were divided into two groups: TPE and non-TPE (MPE and PPE), from Ningbo First Hospital, were incorporated in this study. The clinical and laboratory features were collected and analyzed using logistic regression analysis. Twelve biomarkers and their ratios in serum and PE were investigated for TPE versus non-TPE. Additionally, the value of multiple indicators for joint diagnosis was estimated. RESULTS: Biomarkers and ratios showed good diagnostic performance. The five variables including Serum ADA, IGRA, Effusion ADA, Effusion ADA/Serum ADA and Effusion LDH/Effusion ADA were identified as valuable parameters for differential diagnosis of TPE from non-TPE. The combined diagnosis of the five indexes yielded the highest diagnostic accuracy for TPE with an AUC (0.919), sensitivity (90.30%), and specificity (94.50%). CONCLUSIONS: The biomarkers and ratios demonstrated strong diagnostic performance, and the utilization of multiple indicators for joint diagnosis can improve the diagnostic efficacy of tuberculous pleurisy.

Network embeddedness, digital transformation, and enterprise performance-The moderating effect of top managerial cognition.

Under the new background of the explosive growth of digital economy and the deep integration of real economy, how to improve the performance level through digital transformation has become the key for enterprises to achieve high-quality development. Based on the embeddedness theory and the upper echelons theory, this paper studies the logic and mechanism of network embeddedness affecting enterprise performance, in order to describe the pre-motivations and complete influencing paths of digital transformation affecting enterprise performance, and promote enterprises to achieve high-quality development by means of digital transformation. Taking the middle and senior managers of 239 enterprises as the research objects, this paper applies hierarchical regression, bootstrap and other analysis methods for empirical test, and draws the following conclusions: (1) Relational embeddedness and cognitive embeddedness have a positive impact on digital transformation, while structural embeddedness has no significant impact on digital transformation. (2) Digital transformation has a significant positive impact on enterprise performance. (3) Digital transformation plays a significant mediating role between relational embeddedness, cognitive embeddedness and enterprise performance. (4) In the context of top managerial cognition, cognitive embeddedness can better improve enterprise performance through digital transformation. These results extend the previous literature on digital transformation, proves that digital transformation has a positive effect on enterprise performance. Meanwhile, top managerial cognition is conducive to shaping the dynamic capability of enterprises, and thus plays an important moderating role in the influence path of digital transformation on enterprise performance. This study further affirms the important role of top managerial cognition, which is conducive to enriching enterprises' digital practices and improving enterprise performance.

Does institutional quality moderate the relationship between corporate governance and stock liquidity? Evidence from the emerging market of Pakistan.

The main aim of this study was to empirically analyze whether Institutional Quality moderates the relationship between corporate governance and stock liquidity through the light of agency and information asymmetry theory. To the best of our knowledge, this is the first finance study. The sample consists of 230 non-financial firms listed on the Pakistan stock exchange during the period of 2009-2019. We used an instrumental variable approach and our new Institutional Quality index composed of world governance indicators and a corporate governance index, developed via principal component analysis, to demonstrate a relationship between corporate governance and stock liquidity and check the moderating role of Institutional Quality by following the resources complementary phenomenon. Our results show a significant, positive relationship between the corporate governance index and stock liquidity, suggesting that well-governed firms have high liquidity. The results show that the Institutional Quality index has a positive moderating impact on the relationship between corporate governance and stock liquidity, suggesting that corporate governance in Pakistan is weak. Our results are robust to a series of endogeneity checks using alternative proxies of stock liquidity.

Adipose-derived mesenchymal stem cells protect against CMS-induced depression-like behaviors in mice via regulating the Nrf2/HO-1 and TLR4/NF-κB signaling pathways.

Increasing studies show that inflammatory processes may be involved in depressive disorders. Nuclear factor erythroid-2 related factor 2 (Nrf2) modulates tissue microglial M1 phenotypic changes to the M2 phenotype, which is implicated in protection against inflammatory diseases. We have reported that the adipose-derived mesenchymal stem cells (ADSCs) display anti-inflammatory activity. In this study we explored whether the mechanism of anti-inflammatory activity of ADSCs was related to Nrf2. ADSCs were isolated from mouse fat pads and intravenously administered to chronic mild stress (CMS)-exposed C57BL/6 mice at the dose of 1 × 106 once a week for 3 weeks. We showed that ADSC administration significantly remedied CMS-induced depressive-like behaviors in sucrose preference test, tail suspension test, and forced swim test accompanied by suppressing microglial activation and the expression of inflammatory factors including MCP-1, TNF-α, IL-1ß, and IL-6. Furthermore, ADSC administration promoted both the expression of BDNF and TrkB, and promoted Nrf2/HO-1 signaling but suppressed TLR4/NF-κB signaling in brain tissue. In order to elucidate the role of Nrf2/HO-1 signaling in ADSC-caused neuroprotection, Nrf2-modified ADSCs were cocultured with BV2 microglial cells, then exposed to lipopolysaccharide (LPS). Downregulation of Nrf2 in ADSCs decreased the protective effects of ADSCs against LPS-induced microglial activation and M1 polarization. Nrf2 overexpression in ADSCs markedly suppressed LPS-induced TLR4 and NF-κB expression in microglial cells. These results suggest a possible antidepressive mechanism correlated with microglial polarization for anti-inflammatory agents, which may provide a new microglia-targeted strategy for depression therapy.

Metabolomic profiling for identification of metabolites and relevant pathways for taurine in hepatic stellate cells.

AIM: To develop a reliable and simple method to identify important biological metabolites and relevant pathways for taurine in hepatic stellate cells (HSCs), in order to provide more data for taurine therapy. METHODS: All the biological samples were analyzed by using high-performance liquid chromatography-time electrospray ionization/quadrupole-time of flight mass spectrometry. Principal component analysis and partial least squares discriminant analysis were used to identify statistically different metabolites for taurine in HSCs, and metabolomic pathway analysis was used to do pathway analysis for taurine in HSCs. The chemical structure of the related metabolites and pathways was identified by comparing the m/z ratio and ion mode with the data obtained from free online databases. RESULTS: A total of 32 significant differential endogenous metabolites were identified, which may be related to the mechanism of action of taurine in HSCs. Among the seven relevant pathways identified, sphingolipid metabolism pathway, glutathione metabolism pathway and thiamine metabolism pathway were found to be the most important metabolic pathways for taurine in HSCs. CONCLUSION: This study showed that there were distinct changes in biological metabolites of taurine in HSCs and three differential metabolic pathways including sphingolipid pathway, glutathione pathway and thiamine metabolism pathway might be of key importance in mediating the mechanism of action of taurine in HSCs.

A retrospective study of epidural and intravenous steroids after percutaneous endoscopic lumbar discectomy for large lumbar disc herniation.

OBJECTIVE: To assess the early curative effect of epidural or intravenous administration of steroids during a percutaneous endoscopic lumbar discectomy (PELD). METHODS: 28 consecutive patients who underwent PELD due to large lumbar disc herniation between November 2014 and January 2016 were followed up for 6 months. These patients were divided into two groups according to the treatment they received after PELD. 14 patients (Group A) were treated by PELD and epidural steroids, while the other 14 patients (Group B) were treated by PELD and intravenous steroids. We evaluated the effectiveness by the preoperative and postoperative visual analogue scale (VAS) scores for back and leg pain, and the postoperative Oswestry disability index (ODI) at 3 weeks after surgery via the clinical charts and telephone interview. Postoperative hospital stay and time return to work were investigated as well. RESULTS: There is a significant decrease in VAS (back, leg), ODI, and time return to work (p < 0.05). For VAS (back), Group A showed a significant decrease compared with Group B at 1 day and 1 week after surgery (p = 0.011, p = 0.017). As for VAS (leg), Group A showed a significant decrease compared with Group B at 1 day, 1 week, 3 weeks, and 3 months follow-up examinations (p = 0.002, p = 0.006, p < 0.001, p < 0.001). For ODI, Group A showed a notable decrease compared with Group B (p < 0.001). The postoperative hospital stay in two groups was not statistically different (p = 0.636). But the time return to work in Group A was significantly shorter than that in Group B (p = 0.023). CONCLUSION: Patients who underwent PELD with epidural steroid administration for large lumbar disc herniation showed favorable curative effect compared with those who underwent PELD with intravenous steroid administration.

Impact of novel techniques on minimally invasive adrenal surgery: trends and outcomes from a contemporary international large series in urology.

OBJECTIVE: To evaluate contemporary international trends in the implementation of minimally invasive adrenalectomy and to assess contemporary outcomes of different minimally invasive techniques performed at urologic centers worldwide. METHODS: A retrospective multinational multicenter study of patients who underwent minimally invasive adrenalectomy from 2008 to 2013 at 14 urology institutions worldwide was included in the analysis. Cases were categorized based on the minimally invasive adrenalectomy technique: conventional laparoscopy (CL), robot-assisted laparoscopy (RAL), laparoendoscopic single-site surgery (LESS), and mini-laparoscopy (ML). The rates of the four treatment modalities were determined according to the year of surgery, and a regression analysis was performed for trends in all surgical modalities. RESULTS: Overall, a total of 737 adrenalectomies were performed across participating institutions and included in this analysis: 337 CL (46 % of cases), 57 ML (8 %), 263 LESS (36 %), and 80 RA (11 %). Overall, 204 (28 %) operations were performed with a retroperitoneal approach. The overall number of adrenalectomies increased from 2008 to 2013 (p = 0.05). A transperitoneal approach was preferred in all but the ML group (p < 0.001). European centers mostly adopted CL and ML techniques, whereas those from Asia and South America reported the highest rate in LESS procedures, and RAL was adopted to larger extent in the USA. LESS had the fastest increase in utilization at 6 %/year. The rate of RAL procedures increased at slower rates (2.2 %/year), similar to ML (1.7 %/year). Limitations of this study are the retrospective design and the lack of a cost analysis. CONCLUSIONS: Several minimally invasive surgical techniques for the management of adrenal masses are successfully implemented in urology institutions worldwide. CL and LESS seem to represent the most commonly adopted techniques, whereas ML and RAL are growing at a slower rate. All the MIS techniques can be safely and effectively performed for a variety of adrenal disease.

Outcomes of intrahepatic cholangiocarcinoma with portal vein tumor thrombus following hepatic resection.

BACKGROUND AND AIM: Portal vein tumor thrombus (PVTT) is not commonly used in the treatment of intrahepatic cholangiocarcinoma (ICC), and its impact on the prognosis of ICC is unclear. We aimed to assess the outcomes of ICC with or without PVTT after hepatic resection. METHODS: From January 2000 to December 2005, the data from all consecutive patients with ICC who underwent hepatic resection at our hospital were retrospectively analyzed. According to the Cheng's PVTT Classification (types I-IV), we compared the survival outcomes of ICC patients (with or without PVTT) and prognosis of patients with ICC with different types of PVTT. RESULTS: Three hundred and three patients with ICC were enrolled in this study (59 with PVTT). The incidence of PVTT was 19.4% (59/303). The median survival times were 12.68 and 28.91 months for ICC patients with and without PVTT, respectively (P < 0.001). The multivariate analysis demonstrated that PVTT (hazard ratio [HR] 1.783; confidence interval 95% [1.279; 2.487]) was an independent risk factor for overall survival. Patients with type I PVTT exhibited significantly better survival than those with types II and III PVTT. CONCLUSION: The ICC patients with PVTT exhibit a poorer prognosis compared with ICC patients without PVTT after hepatic resection.

Elevated core-fucosylated IgG is a new marker for hepatitis B virus-related hepatocellular carcinoma.

Immunoglubulin G (IgG) and its abnormal glycosylations are associated with carcinogenesis. The present study investigates the relationship between cancer-derived IgG and clinicopathological characteristics in hepatocellular carcinoma (HCC) and assesses the value of serum N-glycosylated IgG in diagnosing and monitoring hepatitis B virus (HBV)-related HCC. Tissue microarray analysis of 90 HCC tissues showed that HCC patients with IgG immunopositivity had higher levels of core-fucosylated α fetoprotein (AFP-L3), larger tumors, and a higher incidence of portal vein tumor thrombus. HCC-derived IgG stimulated the growth of liver cancer cells in vitro. HCC patients presented a significantly increased fraction of Lens culinaris agglutinin binding IgG (core-fucosylated IgG, IgG-L3) among total serum IgG. The clinical diagnostic performance of serum IgG-L3% was evaluated in 3 case-control studies (1 training set and 2 validation cohorts), including 293 patients with HCC, 131 with liver cirrhosis, 132 HBV carriers, and 151 healthy controls. IgG-L3% had better general diagnostic performance than AFP in the training set and validation cohort 1 (accuracy: 81.33-85.11% versus 63.33-78.61%). In validation cohort 2, where we aimed to assess the efficiency of IgG-L3% in patients with AFP-negative HCC, the diagnostic accuracy of IgG-L3% was 72.54-73.60%. Finally, a longitudinal evaluation based on 31 HCC patients demonstrated that IgG-L3% decreased in 24 patients after curative surgery. The remaining 7 patients showed elevated IgG-L3% and post-operative recurrence. HCC patients with higher IgG-L3% had poor survival during a 3-year follow up. We conclude that HCC-derived IgG is correlated with progressive behavior of HCC. Therefore, elevated core-fucosylated IgG is a new diagnostic and prognostic marker in HBV-related HCC.

[Analysis of the mechanism of drug resistance of VIM-2-type metallo-ß-lactamase-producing Acineto- bacter baumannii isolated from burn patients and its homology].

OBJECTIVE: To study the drug resistance of Acinetobacter baumannii (AB) producing VIM-2-type metallo-ß-lactamase (MBL) isolated from burn patients of our ward against carbapenem antibiotics and its homology. METHODS: A total of 400 strains of AB (identified) were isolated from sputum, urine, blood, pus, and wound drainage. of burn patients hospitalized in our ward from September 2011 to March 2014. Drug resistance of the 400 strains of AB to 15 antibiotics, including compound sulfamothoxazole, aztreonam, etc. , was tested using the automatic microorganism identifying and drug sensitivity analyzer. Among the carbapenems-resistant AB isolates, modified Hodge test was applied to screen carbapenemase-producing strains. The carbapenemase genes of the carbapenemase-producing strains, and the mobile genetic elements class I-integron (Intl1) gene and conserved sequence (CS) of carbapenemase-producing strains carrying blaVIM-2 gene were determined with PCR and DNA sequencing. For carbapenemase-producing strains carrying blaVIM-2 gene, synergism test with imipenem-ethylene diamine tetraacetic acid (EDTA) and enhancement test with imipenem-EDTA and ceftazidime-EDTA were used to verify the MBL-producing status. Drug resistance of the VIM-2-type MBL-producing AB strains was analyzed. For VIM-2-type MBL-producing AB strains, plasmid conjugation experiment was used to explore the transfer of plasmid; outer membrane protein (OMP) CarO gene was detected by PCR. For VIM-2-type MBL-producing AB strains carrying CarO gene, the protein content of CarO was analyzed with sodium dodecyl sulfate polyacrylamide gel electro- phoresis. The repetitive consensus sequence of Enterobacteriaceae genome PCR (ERIC-PCR) was carried out for gene typing of VIM-2-type MBL-producing AB strains to analyze their homology. RESULTS: (1) The resistant rates of the 400 strains of AB against levofloxacin and compound sulfamethoxazole were low. A total of 381 carbapenems-resistant AB strains were screened, including 240 carbepenemase-producing strains. (2) Out of the 240 carbepenemase-producing strains, 18 strains were found to harbor the blaVIM-2 gene, accounting for 7.5%; 133 strains carried the blaTEM-1 gene, accounting for 55.42%; 195 strains carried the blaOXA23 gene, accounting for 81.25%; 188 strains carried the bla(armA) gene, accounting for 78.33%. (3) Eighteen carbepenemase-producing strains which carried the bla(VIM-2) gene were found to carry the Intl1 gene, showing the Intl1-VIM linkage. Simultaneously, Intl1 variable area CS showed diversity. (4) Eighteen carbepenemase-producing strains which carried the blaVIM-2 gene were verified to produce MBL. The resistant rates of the 18 strains of AB against compound sulfamethoxazole were the lowest, followed by levofloxacin and cefoperazone/sulbactam, and those against the other antibiotics were above 60.00%. (5) Through multiple joint tests, plasmid conjugation experiment positive transfer strain was not found in 18 VIM-2-type MBL-producing AB strains. (6) Nine out of the 18 VIM-2-type MBL-producing AB strains were found to carry CarO gene. The OMP CarO of VIM-2-type MBL-producing AB strains carrying CarO gene was lost or lowered in the protein content. (7) The 18 VIM-2-type MBL-producing AB strains were classified into 6 genotypes by the ERIC-PCR. There were respectively 6, 4, 3, and 1 stain (s) in genotypes A, B, C, and F, and there were 2 strains in genotypes D and E respectively. CONCLUSIONS: The resistance mechanism of AB against carbapenems is mainly mediated by blaTEM-1, blaOXA-23, and bla(arma); meanwhile, VIM-2-type MBL-producing and lack or change in OMP CarO are attributable to carbapenems resistance of clinically isolated AB from burn wards, and the Intl1 gene may take a part in blaVIM-2 gene transmission.

All-trans retinoic acid potentiates the chemotherapeutic effect of cisplatin by inducing differentiation of tumor initiating cells in liver cancer.

BACKGROUND & AIMS: Systemic chemotherapy serves as an adjuvant treatment for post-operation patients with hepatocellular carcinoma (HCC), and provides curative option for the patients with unresectable HCC. However, its efficiency is largely limited because of the high incidence of chemo-resistance. Increasing evidence has shown that tumor initiating cells (TICs) not only have the ability to self-renew and drive the initiation and progression of cancer, but also exhibit greater resistance to conventional chemo- and radio-therapies than non-TICs. It was the aim of this study to investigate the effects of ATRA with and without cisplatin on TIC differentiation and apoptosis in human HCC. METHODS: In the present study, we evaluated the TICs of HCC cell differentiation induced by all-trans retinoic acid (ATRA), and developed a novel chemotherapeutic approach to HCC, by characterizing the function of combinatorial treatment with cis-diammineplatinum(II) (cisplatin) and ATRA in vitro and in vivo. RESULTS: ATRA effectively induced differentiation of TICs, which potentiated the cytotoxic effects of cisplatin. The combinatorial treatment of ATRA acid and cisplatin reduced protein kinase B (AKT) (Thr308) phosphorylation, and promoted apoptosis of HCC cells more significantly than treatment with cisplatin alone. In addition, the combined treatment with the two drugs exerted stronger inhibition on either HCC cell migration in vitro or metastasis in vivo, when compared to the treatment with either drug alone. CONCLUSIONS: These results indicated that ATRA could significantly improve the effect of cisplatin, which is at least partially attributed to ATRA-induced differentiation of HCC TICs, and the subsequent decrease in this chemo-resistant subpopulation.

Benfotiamine prevents increased ß-amyloid production in HEK cells induced by high glucose.

OBJECTIVE: To determine whether high glucose enhances ß-amyloid (Aß) production in HEK293 Swedish mutant (APPsw) cells with Aß precursor protein (APP) overexpression, and whether under this condition benfotiamine reduces the increased Aß production. METHODS: HEK293 APPsw cells were cultured with different concentrations of glucose for different times. The Aß content in the supernatant was determined by ELISA. To investigate the mechanism by which benfotiamine reduced Aß production, glycogen synthase kinase-3 (GSK-3) activity and expression were measured after the cells were cultured with 5.5 g/L glucose for 12 h. RESULTS: With 1.0, 3.0, 4.5, 5.5, 6.5, 7.5, 8.5, or 10.5 g/L glucose, Aß production by HEK293 APPsw cells was highest in the presence of 5.5 g/L glucose for 6 and 12 h. The difference in Aß content between 5.5 and 1.0 g/L was most marked after incubation for 12 h. Benfotiamine at 20 and 40 µg/mL significantly reduced Aß production in cells incubated with 5.5 g/L glucose for 12 h. Moreover, 40 µg/mL benfotiamine significantly enhanced the ratio of phosphorylated GSK-3 to total GSK-3, together with consistent down-regulation of GSK-3 activity. CONCLUSION: High glucose increases Aß production by HEK293 APPsw cells while benfotiamine prevents this increase. This is correlated with the modulation of GSK-3 activity.

Reducing nocturia in the elderly: a randomized placebo-controlled trial of staggered furosemide and desmopressin.

AIMS: The purpose of this study was to investigate efficacy, safety, and impact on quality of sleep of staggered furosemide and desmopressin in the treatment of nocturia in the elderly. METHODS: Patients aged >60 years with nocturia at least two voids per night were screened for enrollment into the study. A 3-week dose-titration phase established the optimum desmopressin dose (0.1, 0.2, or 0.4 mg). After a 1-week "washout" period, patients who showed sufficient response during the dose-titration period were randomized to receive staggered furosemide and the optimal dose of desmopressin or placebo in a double-blind design for 3 weeks. Voiding diaries were assessed before and after the treatment. RESULTS: In all, 82 patients were randomized to either staggered furosemide and desmopressin (n=41) or placebo (n=41). In the study group, most patients reported a good response with both reduced nocturnal voids (3.5 vs. 2.0, P<0.01) and urine volume (919.6 ml vs. 584.2 ml, P<0.01). The mean duration of the first sleep period was improved by 70 min (133.6 vs. 203.2, P<0.01). Compared to placebo, staggered furosemide and desmopressin resulted in a significant reduction in the mean number of nocturnal voids (43% vs. 9%; P<0.01), nocturnal urine volume (37% vs. 5%; P<0.01), and increase in the mean duration of the first sleep period (52% vs. 19%, P<0.01). Adverse events were mild. CONCLUSIONS: Staggered furosemide and desmopressin provide an effective and well-tolerated treatment for nocturia in the elderly.

Association of a variant in MIR 196A2 with susceptibility to hepatocellular carcinoma in male Chinese patients with chronic hepatitis B virus infection.

MicroRNAs (miRNAs) are small noncoding RNAs with regulatory functions as tumor suppressors and oncogenes. Recent studies have implicated that the rs11614913 SNP in MIR196A2 was associated with susceptibility of lung cancer, congenital heart disease, breast cancer and shortened survival time of nonsmall cell lung cancer. To assess whether this polymorphism is associated with susceptibility to and clinicopathologic characteristics of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), a total of 560 patients with chronic HBV infection and 391 healthy volunteers were enrolled, and MIR196A2 polymorphism was genotyped by polymerase chain reaction-ligation detection reaction (PCR-LDR). In our study group, there was no significant association between MIR196A2 polymorphism and the risk of HBV-related HCC in all subjects, however, the risk of HCC was significantly higher with MIR196A2 rs11614913 CC genotype or C allele compared with those with the TT genotype or T allele in male patients. Furthermore, in a subsequent analysis of the association between this polymorphism and clinicopathologic characteristics, there was still no significant difference in both the distribution of genotype or allelic frequency. However, we observed that the T allele was significantly more frequent in male HCC patients with lymphatic metastasis. Our results suggested that MIR196A2 polymorphism was associated with susceptibility to HBV-related HCC in a male Chinese population.

N-glycan based models improve diagnostic efficacies in hepatitis B virus-related hepatocellular carcinoma.

The early diagnosis of hepatocellular carcinoma (HCC) is of great clinical desirable due to lack of specific and sensitive markers. Alterations in the sugar chains of glycoprotein synthesized by the liver contribute to the molecular basis of abnormalities in carcinogenesis. This study aims to construct and assess the diagnostic value of N-glycan based diagnostic model in HCC identification and follow-up. A total of 393 subjects including HBV-related HCC, liver fibrosis and healthy controls were recruited. Follow-up was carried out before and after surgical treatment in HCC. N-glycome of serum glycoprotein was profiled by DNA sequencer-assisted fluorophore-assisted carbohydrate electrophoresis (DSA-FACE). Multiparameters diagnostic models were constructed based on N-glycan markers. The result found that 2 N-glycan structure abundances (NG1A2F, Peak 4; NA3Fb, Peak 9) were useful as N-glycan markers. The diagnostic efficacy of the log ratio [log(p9/4)] was similar to that of AFP in differentiating HCC from fibrosis. The accuracy and sensitivity of the diagnostic model combining AFP and N-glycan markers (Cscore B) were increased 7-10% compared with that of AFP. Log(p9/4) was more efficient in monitoring the progression of HCC with regarding to vascular invasion at improved specificity (16%) and accuracy (8%) compared with that of AFP. The N-glycan markers were found to be changed significantly after surgical resection in HCC follow-up. We conclude that the branching alpha (1,3)-fucosylated triantennary glycan and a biantennary glycan are promising as N-glycan markers. The diagnostic models based on the N-glycan markers and AFP improve the efficacy in HCC diagnosis and progression monitoring.

CTLA-4 +49A>G polymorphism is associated with the risk but not with the progression of colorectal cancer in Chinese.

PURPOSE: Colorectal cancer (CRC) is one of the most common malignancies in the world and a multipathway disease. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a potent immunoregulatory molecule that suppresses antitumor response by down-regulating T-cell activation. The most studied +49A>G polymorphism of CTLA-4 gene has been associated with several autoimmune or cancer diseases. Our aim was to investigate the association between this genetic variant and the risk as well as progression of colorectal cancer in Chinese. METHODS: We conducted a case-control study of 124 colorectal cancer cases and 407 healthy controls. DNA was extracted from blood specimens, and +49A>G polymorphism in the CTLA-4 gene was genotyped by polymerase chain reaction-ligation detection reaction (PCR-LDR). RESULTS: In our study group, the frequency of AG or GG or carrying at least one G allele at position +49 was significantly different in colorectal cancer patients and the control group, indicating that the risk of CRC was significantly higher among subjects with the AG or GG genotype or carrying at least one G allele at position +49 than among the subjects with the AA genotype. However, we observed no association between CTLA-4 +49A>G polymorphism and the progression of CRC. Interestingly, the CTLA-4 +49A allele was in non-significantly higher numbers in CRC patients with distant metastasis. CONCLUSIONS: Our results suggested that CTLA-4 +49A>G polymorphism was associated with an increased risk of colorectal cancer, but this polymorphism did not play an important role in the progression of CRC in Chinese.

Predictors of the first cardiovascular event in patients with systemic lupus erythematosus - a prospective cohort study.

INTRODUCTION: Cardiovascular disease (CVD) is a major cause of premature mortality among Systemic lupus erythematosus (SLE) patients. Many studies have measured and evaluated risk factors for premature subclinical atherosclerosis, but few studies are prospective and few have evaluated risk factors for hard endpoints, i.e. clinically important cardiovascular events (CVE). We investigated the impact of traditional and lupus associated risk factors for the first ever CVE in a longitudinal cohort of SLE patients. METHODS: A total of 182 SLE patients (mean age 43.9 years) selected to be free of CVE were included. Cardiovascular and autoimmune biomarkers were measured on samples collected after overnight fasting at baseline. Clinical information was collected at baseline and at follow up. End point was the first ever CVE (ischemic heart, cerebrovascular or peripheral vascular disease or death due to CVD). Impact of baseline characteristics/biomarkers on the risk of having a first CVE was evaluated with Cox regression. RESULTS: Follow up was 99.5% after a mean time of 8.3 years. Twenty-four patients (13%) had a first CVE. In age-adjusted Cox regression, any positive antiphospholipid antibody (aPL), elevated markers of endothelial activation (von Willebrand factor (vWf), soluble vascular cellular adhesion molecule-1 (sVCAM-1)) and fibrinogen predicted CVEs. Of SLE manifestations, arthritis, pleuritis and previous venous occlusion were positively associated with future CVEs while thrombocytopenia was negatively associated. Among traditional risk factors only age and smoking were significant predictors. In a multivariable Cox regression model age, any positive aPL, vWf and absence of thrombocytopenia were all predictors of the first CVE. CONCLUSIONS: In addition to age, positive aPL, biomarkers indicating increased endothelial cell activity/damage, and absence of thrombocytopenia were independent predictors of CVEs in this prospective study. Our results indicate that activation of the endothelium and the coagulation system are important features in SLE related CVD. Furthermore, we observed that the risk of CVEs seems to differ between subgroups of SLE patients.

Up-regulation of hTERT expression by low-dose cisplatin contributes to chemotherapy resistance in human hepatocellular cancer cells.

The telomerase is specifically activated in most malignant tumors but is usually inactive in normal somatic cells. It has been reported that telomerase has an anti-apoptotic role and up-regulation of telomerase helps cancer cells to be resistant to chemotherapeutic agent-induced cell death. The effect of cisplatin on telomerase activity is complex, and the exact mechanism remains largely unknown. In this study, we found that cisplatin activated telomerase activity and human telomerase reverse transcriptase (hTERT) expression in SMMC7721 human hepatocellular carcinoma cell line. Low-dose cisplatin up-regulated hTERT and NF-kappaB p65 expression and increased telomerase and NF-kappaB activity. Inhibition of NF-kappaB attenuated the hTERT expression and telomerase activity exposed to cisplatin, suggesting that NF-kappaB is responsible for the cisplatin-induced activation of the hTERT. Furthermore, preincubation of low-dose cisplatin which induced high expression of hTERT help hepatocellular carcinoma SMMC7721 cells survive under the high concentration of anti-cancer drugs. Inhibition of hTERT increased sensitivity of SMMC7721 cells to chemotherapy. Taken together, these results suggested that up-regulation of hTERT expression by low-dose cisplatin is NF-kappaB-dependent and contributes to chemotherapy resistance in human hepatocellular cancer cells.