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It has been reported that Dendrobium officinale polysaccharides (DOPS) could alleviate colitis in animal model and suppress the activation of NLRP3 inflammasome and β-arrestin1 in vitro. However, it remains unclear whether DOPS has effect on protecting against colitis-induced pulmonary injury. The purpose of this study was to explore the protective effect and mechanism of DOPS on colitis-induced lung injury. A dextran sodium sulfate (DSS)-induced mice colitis model and lipopolysaccharide (LPS)-stimulated BEAS-2B cells model were applied in this study. The results showed that DOPS treatment restored histopathological changes, reduced inflammatory cells infiltration, pro-inflammatory cytokines levels, reactive oxygen species (ROS) formation and MDA generation, and increased anti-oxidative enzymes activities including SOD and GSH-Px in colitis mice. Further investigation showed that DOPS significantly inhibited the protein expression of TLR4, and apparently up-regulated proteins expressions of nuclear-Nrf2, HO-1 and NQO-1 in lung tissues of colitis mice and in BEAS-2B cells. These results indicated that DOPS significantly inhibited inflammation and oxidative stress to alleviate colitis-induced secondary lung injury, and its mechanisms are closely related to the inhibition of TLR4 signaling pathway and the activation of Nrf2 signaling pathway. DOPS may be a promising drug for alleviating colitis-induced lung injury. [Display omitted] 1 Polysaccharides from Dendrobium officinale (DOPS) can attenuate colitis-induced pulmonary injury. 2. Mechanism of DOPS on protecting against colitis-induced pulmonary injury involved the inhibition of inflammation. 3 Mechanism of DOPS on alleviating colitis-induced pulmonary injury was related to the restoration of oxidative stress. 4. DOPS may be a promising drug for alleviating colitis-induced lung injury. [ABSTRACT FROM AUTHOR]

Abstract: Angiogenesis is essential for transplantation of mesenchymal stem cells (MSCs). Vascular endothelial growth factor (VEGF) is one of the most potent angiogenic factors identified to date. Elevated VEGF levels in MSCs correlate with the potential of MSCs transplantation. As an indirect angiogenic agent, transforming growth factor-β1 (TGF-β1) plays a pivotal role in the regulation of vasculogenesis and angiogenesis. However, the effect of TGF-β1 on VEGF synthesis in MSCs is still unknown. Besides, the intracellular signaling mechanism by which TGF-β1 stimulates this process remains poorly understood. In this article, we demonstrated that exposure of MSCs to TGF-β1 stimulated the synthesis of VEGF. Meanwhile, TGF-β1 stimulated the phosphorylation of Akt and extracellular signal-regulated kinase 1/2 (ERK1/2). Moreover, Ly 294002, a specific inhibitor of phosphatidylinositol-3-kinase (PI3K)/Akt significantly attenuated the VEGF synthesis stimulated by TGF-β1. Additionally, U0126, a specific inhibitor of ERK1/2, also significantly attenuated the TGF-β1-stimulated VEGF synthesis. These results indicated that TGF-β1 enhanced VEGF synthesis in MSCs, and the Akt and ERK1/2 activation were involved in this process. [Copyright &y& Elsevier]

Abstract: Optimization of the biological activity for 5,6-diarylpyridines as CB1 receptor inverse agonists is described. Food intake and pharmacokinetic evaluation of 3f and 15c indicate that these compounds are effective orally active modulators of CB1. [Copyright &y& Elsevier]

Abstract: Hf1−x Ta x Fe2 pseudobinary alloy with x =0.18 was prepared. It was found to crystallize in C14 type Laves phase structure examined by X-ray diffraction (XRD). Mössbauer spectra at varied temperatures show there are two transition temperatures, one for paramagnetic (PM) to antiferromagnetic (AFM) state at about 330K, and the other for AFM to ferromagnetic (FM) state at about 180K. In the latter transition, spin reorientation is observed. The spin of Fe magnetic moment at 6h is along c axis in AFM state while lie close to ab-plane in FM state. No magnetic interaction at 2a site is found in AFM state but FM. The hyperfine field anisotropy at 6h site in FM state is also analyzed. [Copyright &y& Elsevier]

OBJECTIVE: RNA interference (RNAi) refers to the phenomenon of sequence-specific degradation of homologous mRNA induced by double-stranded RNA. It has been successfully utilized to down-regulate endogenous gene expression or suppress the replication of various pathogens in mammalian cells. In this study, the effect of vector-based small interfering RNA (siRNA) promoted by pSilencer2.0-U6 inhibit hepatitis B virus (HBV) replication in cell culture was evaluated. METHODS: Three fragments of short nucleic acids, respectively, targeting on S, X and C region of HBV genome were inserted into pSilencer vectors after they were annealed with their partly antisense strands. The recombination plasmids were pS, pX and pC. These expression plasmids were transfected into HepG2-N10 cells, a cell line which stably expresses hepatitis B virus surface antigen (HBsAg), hepatitis B virus e antigen (HBeAg) and adw2 subtype Dane particles. The effect of RNAi was evaluated from the changes of DNA, RNA and protein levels. Viral antigens were measured by ELISA. Viral mRNA was analyzed by RT-PCR. The covalent closed circular DNA and genome DNA of HBV secreted into the culture media were measured by quantitative real-time PCR. Analysis of variance was performed for the results. RESULTS: Vector-based RNA interference could potently reduce HBsAg (pS vs pN: 47%, pX vs pN: 30%, and pC vs pN: 25%, P < 0.001) and HBeAg (pX vs pN: 57% and pC vs pN: 66%, P < 0.001) expression in cell culture. Furthermore, RT-PCR analysis showed that viral mRNAs were effectively degraded, thus eliminating the messengers for protein expression as well as templates for reverse transcription (pS and pC vs pN, P < 0.001; pX vs pN, P = 0.003). Quantitative real-time PCR analysis of HBV DNA revealed that vector-based RNA interference can inhibit HBV replication efficiently (pS, pX and pC vs pN, P < 0.001). CONCLUSIONS: Our results indicate that RNAi can inhibit HBV gene expression and replication, and it might have the potential to revolutionize the treatment of HBV. [ABSTRACT FROM AUTHOR]

Abstract: The occurrence of Asian dust storms, and the subsequent transport of yellow dust (YD) greatly influences the air quality of lee-side countries such as Korea and Japan. The dust is also frequently transported in a southward direction by a strong cold high-pressure system that affects the air quality in Taiwan. This study reports the aerosol properties that were monitored continuously at the Taiwan aerosol supersite during YD events in 2002. Based on the observations of meteorology and aerosols, we divided the time interval of a YD event into a before period, during period, and after period. Among the seven observed YD events, the second event was marked with the maximum hourly PM10 level at 502μgm−3, and with the longest during period for a total of 147h. The averages of the hourly PM10 and PM2.5−10 were much higher in the during period as compared to those in the before period. It is interesting to note that the time lapse in the during period was well correlated with the maximum level of both PM10 and PM2.5−10. It must be noted that the PM2.5 levels were dramatically increased in the after period, which was due to the accumulation of particles influenced by the anticyclonic outflow. The aerosol size distribution in the third YD event verified that supermicron particles dominated in the during period, and that submicron particles were predominant in the before and after periods. For the chemical properties of the aerosols, time series results indicated that sulfates were mostly contributed by the dust transport, and the others were more related to vehicle exhausts. However, they all accumulated in the period of atmospheric stagnancy. [Copyright &y& Elsevier]

Introduction The effect of medical education is often hard to evaluate. We tried to assess whether a 2-hour, small-group discussion could alter student perspectives on truth telling. Currently, in Taiwan it is common practice to consult with the family of a terminally ill patient before telling the truth to the patient, which may be in conflict with patient autonomy. Methods The study was based on content analysis of self-reflective written texts after a 2-hour group discussion on a clinical case describing a truth-telling situation. The changes in decision patterns regarding the emphasis placed on patient autonomy versus family paternalism and the connection to related moral reasoning were subjected to focus analysis. Results The students' initial attitudes regarding the subject of truth telling were categorised into 4 patterns, namely, patient-centred ( n = 46), family-centred ( n = 20), simultaneous informing ( n = 1), and situational informing ( n = 5) modes. The discussion stimulated perspective changes in many of the students and their attitudes were then regrouped as patient-comprehensive ( n = 35), family-centred ( n = 1), and family-comprehensive ( n = 36) modes. It was found that variations on ‘common sense’ and moral reasoning existed prior to the class and the students initially tended to overlook the complexity of truth telling in terminal cancer. Through the discussion and reflective learning, they were enabled to acknowledge the vulnerability of both the patient and his or her family, and to make decisions based on more comprehensive considerations. Conclusion Group discussion seemed to be able to enhance ethical consideration. Further research is required to determine whether the benefits of this approach can be translated into behavioural changes in practice. [ABSTRACT FROM AUTHOR]

Abstract: Inactivated severe acute respiratory syndrome-associated coronavirus (SARS-CoV) has been tested as a candidate vaccine against the re-emergence of SARS. In order to understand the efficacy and safety of this approach, it is important to know the antibody specificities generated with inactivated SARS-CoV. In the current study, a panel of twelve monoclonal antibodies (mAbs) was established by immunizing Balb/c mice with the inactivated BJ01 strain of SARS-CoV isolated from the lung tissue of a SARS-infected Chinese patient. These mAbs could recognize SARS-CoV-infected cells by immunofluorescence analysis (IFA). Seven of them were mapped to the specific segments of recombinant spike (S) protein: six on S1 subunit (aa 12–798) and one on S2 subunit (aa 797–1192). High neutralizing titers against SARS-CoV were detected with two mAbs (1A5 and 2C5) targeting at a subdomain of S protein (aa 310–535), consistent with the previous report that this segment of S protein contains the major neutralizing domain. Some of these S-specific mAbs were able to recognize cleaved products of S protein in SARS-CoV-infected Vero E6 cells. None of the remaining five mAbs could recognize either of the recombinant S, N, M, or E antigens by ELISA. This study demonstrated that the inactivated SARS-CoV was able to preserve the immunogenicity of S protein including its major neutralizing domain. The relative ease with which these mAbs were generated against SARS-CoV virions further supports that subunit vaccination with S constructs may also be able to protect animals and perhaps humans. It is somewhat unexpected that no N-specific mAbs were identified albeit anti-N IgG was easily identified in SARS-CoV-infected patients. The availability of this panel of mAbs also provided potentially useful agents with applications in therapy, diagnosis, and basic research of SARS-CoV. [Copyright &y& Elsevier]

In this study, 116 patients, at least 1 month of age but younger than 5 years, were identified with culture-proven bacterial meningitis. A comparison was made between the clinical data of the patients with and without seizures during hospitalization. Seizures during acute bacterial meningitis accounted for 47% (55/116) of the episodes. Time interval between the onset of bacterial meningitis and that of seizures was 1 to 20 days (mean, 4 days). Twelve of these 55 patients had one or more afebrile seizures after completing the treatment. At follow-up of at least 1 year after completing treatment, 26 patients had good outcomes, whereas the other 29 patients had poor outcomes. A strong correlation between the findings of abnormalities through neuroimaging and the occurrence of seizures during hospitalization was observed. The long-term outcomes of patients with infantile and childhood bacterial meningitis, who had seizures during the acute phase of bacterial meningitis, were worse than the outcomes of those who did not have such seizures. No child developed late seizures unless there were acute seizures. Factors associated with seizures during acute bacterial meningitis include disturbed consciousness on admission, abnormal neuroimaging findings, and low glucose and high concentration of total proteins in cerebrospinal fluid. [Copyright &y& Elsevier]

This 16-year (1986–2001) retrospective study enrolled 80 infantile patients (aged, 30–365 days old) with culture-proven bacterial meningitis. The most prevalent pathogens were Salmonellaspecies, Streptococcus (S.) agalactiae, Escherichia (E.) coli, and Haemophilus (H.) influenzae, accounting for about 59% of the episodes. Meningitis caused by Salmonella species, E. coli and H. influenzae occurs more often in the older infants, while that caused by S. agalactiae occurs more often in young infants. Our study revealed a decrease in the proportion of Salmonella meningitis from 27% in the first 8 years to 9% in the second 8 years with E. coli replacing Salmonella species as the leading pathogen of this disease during the second period. Overall mortality rate for both periods of time was 11%. However, if we take those with undesirable poor outcomes into account, 43% of patients could be considered treatment failures. The study also reveals a high prevalence of neurological complications when this disease is caused by H. influenzae, S. pneumoniae, and Salmonella species. Stepwise logistic regression analysis revealed that only initial changing levels of consciousness (P=0.006) were independently associated with treatment failure. The most frequent neurological complications associated with this disease included subdural empyema, hydrocephalus, cerebral infarctions, and seizures. Because therapeutic regimens may require attention to the eradication of bacterial pathogen but also the neurological complications, early diagnosis and choice of appropriate antibiotics are essential to increasing the possibility of survival. [Copyright &y& Elsevier]

In this 16-year (1986-2001) retrospective study, 23 childhood patients were identified with Guillain-Barre´ syndrome. According to clinical and electrophysiologic findings, 18 patients manifested acute inflammatory demyelinating polyradiculoneuropathy, 2 had Miller Fisher syndrome, 1 had axonal forms, and 2 were unclassified. Seasonal preponderance was evident in 39% of patients with Guillain-Barre´ syndrome, developing the disease in the winter (November to January) with upper respiratory infection the most frequent preceding event. The most common manifestation was limb weakness, with various degrees of motor weakness in 22 patients. Bulbar involvement was the most common cranial palsy, and it was evident in 30% of the episodes. Only one of these progressed to mechanical ventilation during hospitalization. Altogether, approximately 61% of the episodes exhibited sensory symptoms. At a follow-up of 1 year or more, 20 patients recovered and 3 had residua. Furthermore, no fatality occurred in our study. Our study also demonstrates that the clinical course of childhood Guillain-Barre´ syndrome has a shorter recovery time as compared with an adult patient group. Therapeutic outcome is favorable for patients who receive prompt treatment. [Copyright &y& Elsevier]

To determine the epidemiologic trends, prognostic factors, and therapeutic results of neonatal bacterial meningitis, 60 neonatal patients with culture-proven neonatal bacterial meningitis were enrolled in this study. To compare changes over time, the appearance of disease among the patients was divided into two equal periods (1986-1993 and 1994-2001). Group B streptococci were the most common causative pathogens, accounting for approximately 32% of the episodes. Escherichia coli, the next most common pathogen, was more frequently observed in the second period. Seventy-seven percent of gram-negative bacilli isolates were resistant to ampicillin. Moreover, oxacillin-resistant Staphylococcus and ampicillin-resistant group B streptococci strains occurred in the second periods as late-onset neonatal bacterial meningitis. The overall mortality rates for the first and second study period were 17% and 8%, respectively. However, if individuals with poor outcomes were taken into account, 38% of patients were considered treatment failures. Significant prognostic factors included the presence of seizures, thrombocytopenia, and high cerebrospinal fluid protein and low cerebrospinal fluid glucose concentration. Although the mortality rate was significantly reduced in the second period, there has been increasing incidence of the emergence of resistant strains presenting a therapeutic challenge. The presentation in neonatal bacterial meningitis might be nonspecific, and blood culture results were negative in 45% of the episodes. Early diagnosis, choice of appropriate antibiotics, and correction of metabolic derangement are essential to improving outcomes. Chang C-J, Chang W-N, Huang L-T, Huang S-C, Chang Y-C, Hung P-L, Tasi C-Y, Lu C-H, Cheng B-C, Lee P-Y, Chang H-W. Neonatal bacterial meningitis in southern Taiwan. [Copyright &y& Elsevier]

Aims To investigate the distribution of CYP3A activity in the Chinese population, and to test for gender-related differences in CYP3A activity. Methods Using midazolam as a probe drug, CYP3A activity in 202 Chinese healthy subjects (104 men) was measured by plasma 1′-hydroxymidazolam:midazolam (1′-OH-MDZ:MDZ) ratio at 1 h after oral administration of 7.5 mg midazolam. The different phases of the menstrual cycle including preovulatory, ovulatory and luteal phases of 66 women phenotyped with midazolam were recorded. The concentrations of 1′-OH-MDZ and MDZ in plasma were measured by HPLC Results A 13-fold variation of CYP3A activity (log1′-OH-MDZ:MDZ: range -0.949–0.203) was shown. The CYP3A activity was normally distributed as indicated by the frequency distribution histogram, the probit plot and the Kolmogorov–Smirnov test (P > 0.05). The CYP3A activity of women was higher than that of men (median: -0.36 vs -0.43, P < 0.05; 95% CI for difference: -0.127, -0.012). There was a significant difference in CYP3A activity between the three phases of the menstrual cycle. The activity was highest in the preovulatory phase and decreased sequentially in the ovulatory and luteal phases (P < 0.05). Conclusions A normal distribution of CYP3A activity was observed in the Chinese population. The CYP3A activity is higher in female subjects than in males. CYP3A activity differed across the phases of the menstrual cycle. [ABSTRACT FROM AUTHOR]

Periodic lateralized epileptiform discharges are special electroencephalographic abnormalities present in adults with stroke, brain tumor, intracranial hemorrhage, or other rare etiologies. Few reports focused on the etiologies in pediatric patients. We retrospectively reviewed 8002 of our pediatric electroencephalographic records for the past 12 years and listed all associated illness and their outcomes. Forty-four children with periodic lateralized epileptiform discharges were collected. We found that there was an obvious difference in etiologies of our pediatric patients from those reported in the literature. Nearly two thirds of our patients (28 children) were associated with central nervous system infections. The other etiologies included head injury, encephalopathy, epilepsy, and others. Herpes simplex virus was responsible for two thirds (12) of the 18 children with identified pathogens causing a central nervous system infection. Ten patients failed to have a defined pathogen. Periodic lateralized epileptiform discharges have a different clinical significance in pediatric patients than in adults. In Taiwan, central nervous system infection is the most common etiology of periodic lateralized epileptiform discharges in pediatric patients. Herpes simplex virus, although the most common pathogen, should not be considered to be the only cause of encephalitis in children with periodic lateralized epileptiform discharges. [Copyright &y& Elsevier]

1. The aim was to investigate the phenotype distribution characteristic and gender-related differences of CYP2E1 activity in a healthy Chinese population. 2. Two hundred and three healthy Chinese subjects (105 men, 98 women) were enrolled in this study. 3. CYP2E1 activity was determined by plasma 6-hydroxychlorzoxazone-to-chlorzoxazone concentration ratio (CHZ-MR) 4h after chlorzoxazone dosing. The concentrations of 6-hydroxychlorzoxazone and chlorzoxazone in plasma were detected by reversed-phase HPLC. 4. The results showed an almost 9-fold variation of CYP2E1 activity at a range of from 0.23 to 1.99. The coefficient of variation CY % was demonstrated with skewness and kurtosis of the ratios in the studied population were 44%, 0.96 and 1.10, respectively. 5. CYP2E1 activity was normally distributed in logarithmic form of 6-OH-CHZ/CHZ as evaluated by Kolmogorov-Smirnov test of normality (p = 0.20). Probit plots of the CYP2E1 activity index of men shifted to the right as compared with that of women. The mean CHZ-MR in men was significantly higher than that in women (0.76 ± 0.30 versus 0.60 ± 0.28, p < 0.001), and this difference still existed when normalized by weight (0.73 ± 0.28 versus 0.66 ± 0.32, p = 0.016). Body weight correlated positively with CYP2E1 activity in the total group(r < 0.212, p < 0.01). [ABSTRACT FROM AUTHOR]

The lack of specific symptoms and signs in patients with tuberculous meningitis makes early diagnosis difficult. To our knowledge, there has been no report in the literature focusing on tuberculous meningitis patients younger than 1 year of age. In this report, we reviewed the clinical features and laboratory findings of seven infants with tuberculous meningitis encountered during a 15-year period. All patients had fever, cough, and alternation of consciousness at presentation. Five patients had bulging anterior fontanel, and five had generalized tonic-clonic seizures. The purified protein derivative skin test was positive in six patients. Six patients had hyponatremia. All seven patients had abnormal cerebrospinal fluid findings, and six of them demonstrated cell counts less than 500 cells/mm3 with lymphocytic predominance. Brain sonography examination revealed hydrocephalus in all seven patients. Therefore we conclude that antituberculosis therapy should be promptly initiated in any young infant with a clinical impression of meningitis in the context of cerebrospinal fluid white cell count of less than 500 cells/mm3 and lymphocytic predominance, hyponatremia, and hydrocephalus. [Copyright &y& Elsevier]

An gas chromatography–electron-capture detection method has been developed for simultaneous determination of fluoxetine and p-trifluoromethylphenol (TFMP), an O-dealkylated metabolite of fluoxetine in human liver microsomes. Prior to the analysis, aliquots of alkalinized microsomal mixture were extracted with ethyl acetate solvent containing acetonitrile (10%, v/v) and the derivatizing reagent, pentafluorobenzenesulfonyl chloride (0.1%, v/v). The organ phase was retained and taken to dryness, the residue was reconstituted in methanol, and the aliquot of extracts was injected directly into a gas chromatograph equipped with an electron-capture detector. 2,4-Dichlorophenol was added to the initial incubation mixture and carried through the procedure as the internal standard. The method provided the mean recoveries of up to 103% for fluoxetine and 104% for TFMP. Acceptable relative standard deviations were found for both within-run and day-to-day assays. The practical limit of detection (signal-to-noise ratio=3) was 1.62 ng/ml for TFMP and 6.92 ng/ml for fluoxetine in human liver microsomes, and the limit of quantitation was 8.1 pg for TFMP and 34.6 pg for fluoxetine. The assay is rapid and sensitive and has been applied successfully to simultaneous quantification of fluoxetine and TFMP in human liver microsomes with different CYP2C19 genotypes. [Copyright &y& Elsevier]

Background: Ventilator dependence (VD) has been considered as a serious complication in critically ill patients in the intensive care unit (ICU). Acute kidney injury (AKI) is associated with VD as a result of lung–kidney interaction. The aim of our study was to investigate novel biomarkers in predicting ventilator dependence in critically ill surgical patients. Methods: Patients who were admitted to surgical ICU were enrolled and their serum and urine samples were collected. Novel biomarkers including gelatinase-associated lipocalin (NGAL), calprotectin, kidney injury molecule-1 (KIM-1), cystatin C, and growth differentiation factor 15 (GDF-15) were analyzed and correlated with clinical outcome. Results: A total of 33 patients were enrolled and analyzed. The majority of them received abdominal surgery prior to ICU admission. Thirteen patients were classified into the VD group, while the remaining 20 were in a non-ventilator dependence group (nVD). Statistical analysis demonstrated that the following were significantly higher in the VD group than in the nVD group: serum NGAL (420.25 ± 45.18 ng/mL vs. 314.68 ± 38.12 ng/mL, p-value 0.036), urinary NGAL (420.87 ± 41.08 ng/mL vs. 250.84 ± 39.45 ng/mL, p-value 0.002), SOFA score (11.3 ± 1.5 vs. 5.6 ± 0.7, p-value 0.001), and APACHE II score (23.2 ± 2.6 vs. 13.6 ± 0.8, p-value 0.001). The area under the ROC curve (AUROC) of urinary NGAL for VD was 0.808. The combination of urinary NGAL and SOFA score could further increase AUROC for VD to 0.835. Conclusions: The current study demonstrated the predictive capability of urinary NGAL for ventilator dependence among critically ill surgical patients. When combined with SOFA score, the predictive ability was further augmented. Further large-scale studies are warranted to validate our findings. [ABSTRACT FROM AUTHOR]

The small punch test (SPT) can be recognized as an alternative to uniaxial tensile testing. Many attempts have been made to extract tensile strength properties from SPT results, but few works on estimating true stress-plastic strain curves. This paper aims to propose an approach for deriving a true stress-plastic strain curve from the force-deflection curve of SPT. Engineering stresses at different plastic strains are extracted from a force-deflection curve using a database method. These engineering stress and plastic strain points are employed to determine the parameters of Ludwik hardening law, then a true stress-plastic strain curve before necking is generated using those parameters. To verify the accuracy in estimating true stress-plastic strain curves in this way, the procedure was applied to three hypothetical materials. It is found that true stress-plastic strain curves before necking are accurately extracted from SPT data. The proposed procedure was also used to process the force-deflection curves of 3Cr1MoV, 2.25Cr1Mo and 16MnR. The results show that the obtained stress and strain relation can predict the force responses of SPT specimens well. Using a database to evaluate true stress-plastic strain curves is effective and with the support of theory that could promote the application of SPT in characterizing material mechanical properties. [Display omitted] • A database was used to extract engineering stresses from a force-deflection curve of small punch test. • The engineering stress and plastic strain points were employed to determine plastic parameters. • True stress-plastic curves before necking were obtained through plastic parameters. • True stress-plastic curve estimated by a database method can predict the force responses of SPT specimens well. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to investigate a new procedure with reserving the ascending part of duodenum and using Y loop of jejunal interposition for bile and pancreatic internal drainage. Methods From April 2006 to June 2012, 5 patients complicated with pancreatic calculi and very early stage of distal common bile duct malignancy were performed pancreatoduodenectomy in our department, and their clinical data were retrospectively analyzed. Results The procedure of this operation was easy and simple compared with ordinary pancreatoduodenectomy. There were no pancreatic or bile leakage, massive hemorrhage of digestive tract and intraperitoneal abdominal infection happened post-operation. The average postoperative hospital stay was 22 days. All patients were followed up for 12 months, and the survival rate was 100% . Conclusion The modified pancreaticoduodenectomy with reserving the ascending part of duodenum and using Y loop of jejunal interposition anastomosis for internal drainage can decrease the occurrence of postoperative complications and increase the safety of pancreatoduodenectomy. [ABSTRACT FROM AUTHOR]

Actual evapotranspiration (λET) can be estimated with meteorological parameters using the Penman-Monteith (PM) model where the canopy resistance (r c) plays an important role but is difficult to determine. The Katerji-Perrier (KP) and Todorovic (TD) models are widely used to determine the r c. A comparative study was conducted to evaluate the performances of two models, on hourly and daily scales, in simulating the λET for a tea and a wheat field in southeast China. The estimated λET was compared with the measured λET by the Bowen ratio energy balance (BREB) method. The results indicated that the KP model simulated the λET of tea and wheat well for both hourly and daily scales, while the TD model simulated the λET well for the wheat for both time scales but significantly overestimated the tea λET by 44.9%. Therefore, the KP model was preferred to estimate λET for both crops, the TD model should be avoided in tea fields. • Two canopy resistance models（KP and TD）were evaluated for the λET estimation. • The KP model was the superior method for predicting λET of tea and wheat. • The TD model was suitable for simulating λET of wheat, but not for λET of tea. • The different calculation methods of aerodynamic resistance were not responsible for the error of TD model. • The estimation error of TD model was closely related to VPD. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is not sensitive to current endocrine treatments, so new treatment strategies need to be explored. Based on previous antitumour studies on anti-TNFα nanobody, we designed a novel fusion nanobody to enhance antitumour activity of the anti-TNFα nanobody in TNBC. The RGD4C contains RGD sequence, which is the smallest recognition unit binding to the αvβ3 receptor on tumour cell membranes and involved in tumour cell adhesion, proliferation, and metastasis. RGD4C was fused to anti-TNFα nanobody to investigate the antitumour activity in vitro and in vivo. The antitumour effects of fusion nanobody V-L-R-H could effectively bind to αvβ3 and inhibit cell migration and proliferation of MDA-MB-231, which had satisfying purification efficiency and approving antigen or receptor binding activity. V-L-R-H could inhibit the TNFα-mediated PI3K/AKT/NF-κB signal pathway and integrin αvβ3 correlative FAK focal adhesion signal pathway. Mouse xenograft tumour experiments showed that the V-L-R-H could inhibit tumour proliferation and metastasis; reduce the TNFα, HIFα, Ki67, and CD31 concentrations in tumour; and inhibit the process of epithelial-mesenchymal transition. The fusion nanobody enhanced antitumour activity of the anti-TNFα nanobody on TNBC. It provided a reference for the design of dual functional fusion proteins and development of tumour treatment strategies of antagonistic TNFα and αvβ3, and a new therapeutic strategy and research direction for the treatment of TNBC. [ABSTRACT FROM AUTHOR]

Side effects of chemotherapy are burning questions for physicians and patients involved in cancers. Ganoderma lucidum is a widely consumed traditional Chinese medicine and edible mushroom with multiple functional properties. The present study aims to investigate the potential of polysaccharides from spore of G. lucidum (SGP) on small intestinal barrier function recovery against paclitaxel (PTX) challenge in a breast cancer mice model and IEC-6 cell line. The 4T1 tumor-bearing mice were treated with PTX together with four-week daily oral administration of SGP. Results indicated that combination of PTX and SGP reversed body weight lost and remolded the histology of small intestine, accompanied with promoted proliferation but suppressed apoptosis in intestinal cells. Intestinal barrier function was enhanced by the combination as indicated by reduced endotoxemia and the up-regulation of tight junction proteins, including Zonula occludens-1 (ZO-1), E-cadherin, β-catenin and Occludin. The protection of SGP was further confirmed in IEC-6 cells affected by PTX in vitro. The combination treatment prevented PTX-induced apoptosis in IEC-6 by inhibiting microtubule polymerization, and the aforementioned tight junction proteins were also upregulated. These findings suggest a promising protective effect of SGP against small intestinal barrier injury caused by PTX, highlighting its clinical implication against the chemotherapy side effects. [ABSTRACT FROM AUTHOR]

Evidences showed that chronic stress (CS) can aggravate the situation of nonalcoholic fatty liver disease (NAFLD). Vitexin is one of the major components in hawthorn, which is widely used to reduce blood lipid. This study was aimed to explore the therapeutic effects and potential mechanisms of vitexin on chronic stress mice with high-fat diet (CSHFD). The results showed that 5-week vitexin administration (40 mg/kg, i.g.) could obviously reduce hepatic fat deposition, alleviate lipid metabolism, and inhibit liver inflammation in CSHFD mice. In addition, vitexin significantly reduced hepatic macrophage infiltration, obviously down-regulated the mRNA and protein expressions of hepatic SREBP-1c, FAS, ACC. Moreover, we also found that vitexin treatment could significantly inhibit the expressions of TLR4/NF-κB signaling in CSHFD mice. This results suggested that vitexin could ameliorate chronic stress combined with high-fat diet induced NAFLD, and its mechanisms is closely related to inhibit TLR4/NF-κB signaling and reduce fatty acid synthesis proteins. Image 1 [ABSTRACT FROM AUTHOR]

• A unified multilocus marker system for snake systematics was developed. • A comprehensive systematic framework of the snakes in China was constructed. • The marker system enables better understanding of the snake evolutionary histories. • The snake divergence times were estimated with the substantial new molecular data. Snakes are one of the most diverse groups of terrestrial vertebrates, with approximately 3500 extant species. A robust phylogeny and taxonomy of snakes is crucial for us to know, study and protect them. For a large group such as snakes, broad-scale phylogenetic reconstructions largely rely on data integration. Increasing the compatibility of the data from different researches is thus important, which can be facilitated by standardization of the loci used in systematic analyses. In this study, we proposed a unified multilocus marker system for snake systematics by conflating 5 mitochondrial markers, 19 vertebrate-universal nuclear protein coding (NPC) markers and 72 snake-specific noncoding intron markers. This marker system is an addition to the large squamate conserved locus set (SqCL) for studies preferring a medium-scale data set. We applied this marker system to over 440 snake samples and constructed the currently most comprehensive systematic framework of the snakes in China. Robust snake phylogenetic relationships were recovered at both deep and shallow evolutionary depths, demonstrating the usefulness of this multilocus marker system. Discordance was revealed by a parallel comparison between the snake tree based on the multilocus marker system and that based on only the mitochondrial loci, highlighting the necessity of using multiple types of markers to better understand the snake evolutionary histories. The divergence times of different snake groups were estimated with the nuclear data set. Our comprehensive snake tree not only confirms many important nodes inferred in previous studies but also contributes new insights into many snake phylogenetic relationships. Suggestions are made for the current Chinese snake taxonomy. [ABSTRACT FROM AUTHOR]

This paper presents a two-layer controller for accurate and robust lateral path tracking control of highly automated vehicles. The upper-layer controller, which produces the front wheel steering angle, is implemented with a Linear Time-Varying MPC (LTV-MPC) whose prediction and control horizon are both optimized offline with particle swarm optimization (PSO) under varying working conditions. A constraint on the slip angle is imposed to prevent lateral forces from saturation to guarantee vehicle stability. The lower layer is a radial basis function neural network proportion-integral-derivative (RBFNN-PID) controller that generates electric current control signals executable by the steering motor to rapidly track the target steering angle. The nonlinear characteristics of the steering system are modeled and are identified on-line with the RBFNN so that the PID controller's control parameters can be adjusted adaptively. The results of CarSim-Matlab/Simulink joint simulations show that the proposed hierarchical controller achieves a good level of path tracking accuracy while maintaining vehicle stability throughout the path tracking process, and is robust to dynamic changes in vehicle velocities and road adhesion coefficients. [ABSTRACT FROM AUTHOR]

This paper deals with the tribological study of the laser remelted surfaces of the ECAP-processed AZ61 magnesium alloy and AZ61–Al2O3 metal matrix composite with 10 wt.% addition of Al2O3 nanoparticles. The study included the experimental optimization of the laser surface remelting conditions for the investigated materials by employing a 400 W continual wave fiber laser source. Tribological tests were performed in a conventional "ball-on-disc" configuration with a ceramic ZrO2 ball under a 5 N normal load and a sliding speed of 100 mm/s. The results showed that both the incorporation of Al2O3 nanoparticles and the applied laser treatments led to recognizable improvements in the tribological properties of the studied AZ61–Al2O3 composites in comparison with the reference AZ61 alloy. Thus, the best improvement has been obtained for the laser modified AZ61–10 wt.% Al2O3 nanocomposite showing about a 48% decrease in the specific wear rate compared to the laser untreated AZ61 base material. [ABSTRACT FROM AUTHOR]

In the present study, we aimed to investigate the therapeutic effect of Vitexin on inhibiting ethanol-induced liver damage and explore the underling mechanism. In vitro , the injury was induced in LO2 cell by 100 mM ethanol. Cell viability, AST, oxidative stress, inflammation, apoptosis rate, and related gene and protein expressions were assessed. Alcoholic liver injury model was made by intragastric infusion of alcohol for 4 weeks on male KM mice. Liver index, AST, ALT, TC, TG, TP, TBIL in serum and liver pathology were evaluated. Meanwhile, the level of SOD, MDA and TNF-α also were detected by Kits. Quantitative RT-PCR and Western blotting analysis the Sirt1/p53 pathway related gene and protein expressions. In vitro , Vitexin restored cytoactive and inhibited the releasing of AST induced by ethanol in LO2 cell. Vitexin treatment significantly suppressed the elevation of aminotransferase, blood lipid, UA in mice. Vitexin ameliorated liver pathological changes induced by ethanol. Vitexin supplement restored the decrease of Sirt1/Bcl-2 expression, restrained the elevation of caspase3, cleaved caspse-3, p53 and ac-p53 expression in vivo and in vitro. Vitexin has a protective effect against ethanol-induced liver damage, and the underlying mechanism is probably through Sirt1/p53 mediated mitochondrial apoptotic pathway. Vitexin, a flavone C-glycoside in kinds of traditional medicinal plants which is commonly used in treatment of liver disorder, has extensive bioactivities, but the role of vitexin on alcoholic liver injury remains to be elucidated. Here we report that vitexin inhibits the enlargement of the liver, reverses related biochemical indicators, improves mortality and liver pathological changes induced by ethanol in mice. Besides, vitexin can also ameliorate LO2 cell viability and apoptosis rate induced by ethanol. The mechanism underlying vitexin's protective effect on alcoholic liver injury is related with its regulating on Sirt1/p53 mediated mitochondrial apoptotic pathway. Image 1 [ABSTRACT FROM AUTHOR]

• Large area well-aligned Ge nanoisland arrays were prepared by femtosecond laser. • SEM, TEM, AFM, Raman, and XPS analyses revealed high quality Ge nanoisland arrays. • Field emission measurements indicated enhanced performance of Ge nanoisland arrays. Si-based field emitters with high and stable current densities have gained increasing attention owing to their relevant compatibility with other silicon-based microelectronic and photonic devices. Currently, well-aligned Ge nanostructure arrays can be used in fabrication of Si-based field emitters with excellent performance. In this study, large-area well-aligned Ge nanoisland arrays are induced by femtosecond laser (120 fs, 800 nm, 1 kHz). Scanning electron microscopy (SEM), transmission electron microscopy (TEM), atomic force microscopy (AFM), Raman analyses, and X-ray photoelectron spectroscopy (XPS) reveal that well-aligned Ge nanoisland arrays with good quality. Field emission (FE) measurements indicate Ge nanoisland arrays with high emission current densities and good stability. Overall, the excellent FE properties of the proposed Ge nanoisland arrays will make them potential for applications in high-performance field emitters integrated with Si nanodevices. [ABSTRACT FROM AUTHOR]

• Twenty-one patients successfully recovered active wrist extension. • Motor imagery based BCI control of wrist CPM training was applied. • Typical spatial and spectrum patterns of ERD/ERS formed after training. Motor recovery of wrist and fingers is still a great challenge for chronic stroke survivors. The present study aimed to verify the efficiency of motor imagery based brain-computer interface (BCI) control of continuous passive motion (CPM) in the recovery of wrist extension due to stroke. An observational study was conducted in 26 chronic stroke patients, aged 49.0 ± 15.4 years, with upper extremity motor impairment. All patients showed no wrist extension recovery. A 24-channel highresolution electroencephalogram (EEG) system was used to acquire cortical signal while they were imagining extension of the affected wrist. Then, 20 sessions of BCI-driven CPM training were carried out for 6 weeks. Primary outcome was the increase of active range of motion (ROM) of the affected wrist from the baseline to final evaluation. Improvement of modified Barthel Index, EEG classification and motor imagery pattern of wrist extension were recorded as secondary outcomes. Twenty-one patients finally passed the EEG screening and completed all the BCI-driven CPM trainings. From baseline to the final evaluation, the increase of active ROM of the affected wrists was (24.05 ± 14.46)˚. The increase of modified Barthel Index was 3.10 ± 4.02 points. But no statistical difference was detected between the baseline and final evaluations (P > 0.05). Both EEG classification and motor imagery pattern improved. The present study demonstrated beneficial outcomes of MI-based BCI control of CPM training in motor recovery of wrist extension using motor imagery signal of brain in chronic stroke patients. [ABSTRACT FROM AUTHOR]

• Vitexin could alleviate liver injury caused by ulcerative colitis. • Vitexin could inhibit the activation of TLR4/NF-κB signaling pathway. • Vitexin could be a promising drug for liver injury induced by acute ulcerative colitis. As one of commonly used herbs with dual-purpose of drug and food, it has been reported that vitexin has hepatoprotective effects. However, the protective effects of vitexin on colitis-induced liver injury as well as the underlying molecular mechanisms remain unclear. The purpose of the current study was to investigate the effects and mechanisms of vitexin on liver injury induced by acute ulcerative colitis in mice. In this study, the mice model of acute ulcerative colitis was induced by 4 % dextran sodium sulphate (DSS). And then, the degree of liver injury in colitis mice was evaluated, the hepatic ALT, AST, TC and TG levels were measured by specific determination kits, the levels of TNF-α, IL-6 and IL-1β were examined by ELISA, the expressions of TLR4/NF-κB pathway related protein were detected by western blot analysis. The results indicated that hepatic histopathological changes induced by DSS were normalized by vitexin treatment, administration of vitexin decreased the liver levels of ALT and TC in mice with liver injury and reduced the release amounts of DSS-induced pro-inflammatory cytokines TNF-α, IL-6 and IL-1β. Furthermore, we found that vitexin inhibited the activation of TLR4/NF-κB signaling pathway induced by DSS. In conclusion, vitexin possess hepatoprotective activities against colitis-induced liver injury, it has potential application prospects in the treatment of liver injury induced by ulcerative colitis. [ABSTRACT FROM AUTHOR]

• The power flow analysis is employed to identify. • The acoustic synthesis method is proposed to obtain the main acoustic transfer path. • Relationship between vibration, path participation and sound pressure is obtained. This paper is aimed to analyze and control the structure-borne noise of a vehicle body by using the power flow and acoustic path participation method. The modal test is conducted to calibrate the simulation model, and the sound pressure frequency response analysis is carried out to obtain the critical frequencies. The power flow through the interface of the powertrain and vehicle body is analyzed. Then the main paths are identified. Before carrying out an acoustic path participation analysis, the coupled energy of the vibration transfer path was evaluated. For a decoupled vibration system, the sound pressure synthesis method of the multi-path vibration transmission is proposed. The relative errors between the synthetized sound pressure and the finite element calculated sound pressure are small. The interaction mechanisms between the power flow of a path, the acoustic participation of a path and the control characteristics are investigated. The results indicate that, the positive power flow is reduced by pertinently optimizing the stiffness parameters of the engine mounts. The acoustic participation of the corresponding path decreases and the structure-borne noise gets controlled. [ABSTRACT FROM AUTHOR]

This paper presents the second data release of the Hyper Suprime-Cam Subaru Strategic Program, a wide-field optical imaging survey using the 8.2 m Subaru Telescope. The release includes data from 174 nights of observation through 2018 January. The Wide layer data cover about 300 deg |$^2$| in all five broad-band filters (⁠|$grizy$|⁠) to the nominal survey exposure (10 min in |$gr$| and 20 min in |$izy$|⁠). Partially observed areas are also included in the release; about 1100 deg |$^2$| is observed in at least one filter and one exposure. The median seeing in the i -band is |${0_{.}^{\prime \prime }6}$|⁠ , demonstrating the superb image quality of the survey. The Deep (26 deg |$^2$|⁠) and UltraDeep (4 deg |$^2$|⁠) data are jointly processed and the UltraDeep-COSMOS field reaches an unprecedented depth of |$i\sim 28$| at |$5 \, \sigma$| for point sources. In addition to the broad-band data, narrow-band data are also available in the Deep and UltraDeep fields. This release includes a major update to the processing pipeline, including improved sky subtraction, PSF modeling, object detection, and artifact rejection. The overall data quality has been improved, but this release is not without problems; there is a persistent deblender problem as well as new issues with masks around bright stars. The user is encouraged to review the issue list before utilizing the data for scientific explorations. All the image products as well as catalog products are available for download. The catalogs are also loaded into a database, which provides an easy interface for users to retrieve data for objects of interest. In addition to these main data products, detailed galaxy shape measurements withheld from Public Data Release 1 (PDR1) are now available to the community. The shape catalog is drawn from the S16A internal release, which has a larger area than PDR1 (160 deg |$^2$|⁠). All products are available at the data release site, https://hsc-release.mtk.nao.ac.jp/. [ABSTRACT FROM AUTHOR]

Intact epithelial barrier and mucosal immune system are crucial for maintaining intestinal homeostasis. Previous study indicated that Dendrobium officinale polysaccharides (DOPS) can regulate immune responses and inflammation to alleviate experimental colitis. However, it remains largely unknown whether DOPS can suppress AOM/DSS-induced colorectal cancer (CRC) model through its direct impact on intestinal barrier function and intestinal mucosal immunity. Here, we demonstrated the therapeutic action of DOPS for CRC model and further illustrated its underlying mechanisms. Treatment with 5-aminosalicylic acid (5-ASA) and DOPS significantly improved the clinical signs and symptoms of chronic colitis, relieve colon damage, suppress the formation and growth of colon tumor in CRC mice. Moreover, administration of DOPS effectively preserved the intestinal barrier function via reducing the loss of zonula occludens-1 (ZO-1) and occludin in adjacent tissues and carcinomatous tissues. Further studies demonstrated that DOPS improved the metabolic ability of tumor infiltrated CD8+ cytotoxic T lymphocytes (CTLs) and reduced the expression of PD-1 on CTLs to enhance the anti-tumor immune response in the tumor microenvironments (TME). Together, the conclusions indicated that DOPS restore intestinal barrier function and enhance intestinal anti-tumor immune response to suppress CRC, which may be a novel strategy for the prevention and treatment of CRC. [ABSTRACT FROM AUTHOR]

Background: Gitelman syndrome (GS) is an inherited autosomal recessive renal tubular disorder characterized by low levels of potassium and magnesium in the blood, decreased excretion of calcium in the urine, and elevated blood pH. GS is caused by an inactivating mutation in the SLC12A3 gene, which is located on the long arm of chromosome 16 (16q13) and encodes a thiazide-sensitive sodium chloride cotransporter (NCCT). Case presentation: A 45-year-old man with Graves' disease complicated by paroxysmal limb paralysis had a diagnosis of thyrotoxic periodic paralysis for 12 years. However, his serum potassium level remained low despite sufficiently large doses of potassium supplementation. Finally, gene analysis revealed a homozygous mutation in the SLC12A3 gene. After his thyroid function gradually returned to normal, his serum potassium level remained low, but his paroxysmal limb paralysis resolved. Conclusions: GS combined with hyperthyroidism can manifest as frequent episodes of periodic paralysis; to date, this comorbidity has been reported only in eastern Asian populations. This case prompted us to more seriously consider the possibility of GS associated with thyroid dysfunction. [ABSTRACT FROM AUTHOR]

Background: Sepsis is a syndrome characterized by a constellation of clinical manifestations and a significantly high mortality rate in the surgical intensive care unit (ICU). It is frequently complicated by acute kidney injury (AKI), which, in turn, increases the risk of mortality. Therefore, it is of paramount importance to identify those septic patients at risk for the development of AKI and mortality. The objective of this pilot study was to evaluate several different biomarkers, including NGAL, calprotectin, KIM-1, cystatin C, and GDF-15, along with SOFA scores, in predicting the development of septic AKI and associated in-hospital mortality in critically ill surgical patients. Methods: Patients admitted to the surgical ICU were prospectively enrolled, having given signed informed consent. Their blood and urine samples were obtained and subjected to enzyme-linked immunosorbent assay (ELISA) to determine the levels of various novel biomarkers. The clinical data and survival outcome were recorded and analyzed. Results: A total of 33 patients were enrolled in the study. Most patients received surgery prior to ICU admission, with abdominal surgery being the most common type of procedure (27 patients (81.8%)). In the study, 22 patients had a diagnosis of sepsis with varying degrees of AKI, while the remaining 11 were free of sepsis. Statistical analysis demonstrated that in patients with septic AKI versus those without, the following were significantly higher: serum NGAL (447.5 ± 35.7 ng/mL vs. 256.5 ± 31.8 ng/mL, P value 0.001), calprotectin (1030.3 ± 298.6 pg/mL vs. 248.1 ± 210.7 pg/mL, P value 0.049), urinary NGAL (434.2 ± 31.5 ng/mL vs. 208.3 ± 39.5 ng/mL, P value < 0.001), and SOFA score (11.5 ± 1.2 vs. 4.4 ± 0.5, P value < 0.001). On the other hand, serum NGAL (428.2 ± 32.3 ng/mL vs. 300.4 ± 44.3 ng/mL, P value 0.029) and urinary NGAL (422.3 ± 33.7 ng/mL vs. 230.8 ± 42.2 ng/mL, P value 0.001), together with SOFA scores (10.6 ± 1.4 vs. 5.6 ± 0.8, P value 0.003), were statistically higher in cases of in-hospital mortality. A combination of serum NGAL, urinary NGAL, and SOFA scores could predict in-hospital mortality with an AUROC of 0.911. Conclusions: This pilot study demonstrated a promising panel that allows an early diagnosis, high sensitivity, and specificity and a prognostic value for septic AKI and in-hospital mortality in surgical ICU. Further study is warranted to validate our findings. [ABSTRACT FROM AUTHOR]

The Planck constant h is one of the most significant constants in quantum physics. Recently, the precision measurement of the value of h has been a hot issue due to its important role for the establishment of both a new SI and a revised fundamental physical constant system. Up to date, two approaches, the watt balance and counting atoms, have been employed to determine the Planck constant at a level of several parts in 108. In this paper, the principle and progress on precision measurement of the Planck constant using watt balance and counting atoms at national metrology institutes are reviewed. Further improvement in determining the Planck constant and possible developments of a revised physical constant system in future are discussed. [ABSTRACT FROM AUTHOR]

Massive quiescent galaxies at z ≈ 2 are apparently much more compact than galaxies of comparable mass today. How robust are these size measurements? We perform comprehensive simulations to determine possible biases and uncertainties in fitting single-component light distributions to real galaxies. In particular, we examine the robustness of the measurements of the luminosity, size, and other structural parameters. We devise simulations with increasing realism to systematically disentangle effects due to the technique (specifically using GALFIT) and the intrinsic structures of the galaxies. By accurately capturing the detailed substructures of nearby elliptical galaxies and then rescaling their sizes and signal-to-noise to mimic galaxies at different redshifts, we confirm that the massive quiescent galaxies at z ≈ 2 are significantly more compact intrinsically than their local counterparts. Their observed compactness is not a result of missing faint outer light due to systematic errors in modeling. In fact, we find that fitting multi-component galaxies with a single Sérsic profile, the procedure most commonly adopted in the literature, biases the inferred sizes higher by up to 10%-20%, which accentuates the amount of size evolution required. If the sky estimation has been done robustly and the model for the point-spread function is fairly accurate, GALFIT can retrieve the properties of single-component galaxies over a wide range of signal-to-noise ratios without introducing any systematic errors. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) have been implicated in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance of many cancers. We evaluated the role of peroxiredoxin (Prx) I in TRAIL resistance governed by coupling of nicotinamide adenosine dinucleotide phosphate oxidase (Nox)-derived ROS signaling with the p38 mitogen-activated protein kinase (MAPK)/caspase-signaling cascade in liver cancer cells. Upregulated Prx I expression was found in neoplastic regions of human patient liver, and Prx I knockdown resulted in accelerated TRAIL-induced cell death in SK-Hep-1 human hepatoma cells. The TRAIL cytotoxicity by Prx I knockdown was dependent on activation of caspase-8/3 cascades, which was ablated by addition of inhibitors for p38 MAPK, ROS or Nox, suggesting the association with Nox-driven redox signaling. Furthermore, we found that Nox4 was constitutively expressed in both SK-Hep-1 cells and tumor regions of patient livers, knockdown of Nox4 expression could alleviate ROS generation and TRAIL-mediated cytotoxicity. In accordance with previous findings, increased activation of both p38 MAPK and caspase cascades by Prx I knockdown was inhibited by either Nox4 knockdown or SB203580 addition. Collectively, these data suggest that Prx I functions to block propagation of Nox-derived ROS signaling to the p38 MAPK/caspase/cell death cascade during TRAIL treatment and also provides a molecular mechanism by which Prx I contributes to TRAIL resistance in liver cancers. [ABSTRACT FROM AUTHOR]

Aims The present study was designed to define the kinetic behaviour of sertraline N-demethylation in human liver microsomes and to identify the isoforms of cytochrome P450 involved in this metabolic pathway. Methods The kinetics of the formation of N-demethylsertraline were determined in human liver microsomes from six genotyped CYP2C19 extensive (EM) and three poor metabolisers (PM). Selective inhibitors of and specific monoclonal antibodies to various cytochrome P450 isoforms were also employed. Results The kinetics of N-demethylsertraline formation in all EM liver microsomes were fitted by a two-enzyme Michaelis-Menten equation, whereas the kinetics in all PM liver microsomes were best described by a single-enzyme Michaelis-Menten equation similar to the low-affinity component found in EM microsomes. Mean apparent K[sub m] values for the high-and low-affinity components were 1.9 and 88 μm and V [sub max] values were 33 and 554 pmol min[sup -1] mg[sup -1] protein, respectively, in the EM liver microsomes. Omeprazole (a CYP2C19 substrate) at high concentrations and sulphaphenazole (a selective inhibitor of CYP2C9) substantially inhibited N-demethylsertraline formation. Of five monoclonal antibodies to various cytochrome P450 forms tested, only anti-CYP2C8/9/19 had any inhibitory effect on this reaction. The inhibition of sertraline N-demethylation by anti-CYP2C8/9/19 was greater in EM livers than in PM livers at both low and high substrate concentrations. However, anti-CYP2C8/9/19 did not abolish the formation of N-demethylsertraline in the microsomes from any of the livers. Conclusions The polymorphic enzyme CYP2C19 catalyses the high-affinity N-demethylation of sertraline, while CYP2C9 is one of the low-affinity components of this metabolic pathway. [ABSTRACT FROM AUTHOR]