The metabolite profiling of DAPA-7012 and DAAN-4442, the lead compounds from two new kinds of non-nucleoside reverse transcriptase inhibitors (NNRTIs), was performed using an ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS/MS), with the assistance of a metabolite data processing software. By utilizing the mass defect filter (MDF) technique, the data acquired from the 0 h-incubation and the 2 h-incubation were compared and analyzed with the MetaboLynx software. After incubation, 14 metabolites of DAPA-7012 and 14 metabolites of DAAN-4442 were found in rat liver microsome. The MS2 spectra for some metabolites were obtained using the MS(E) technique to get fragment ions for structural elucidation. The results indicated that both compounds could undergo extensive metabolism in rat liver microsomes. The major phase I reaction was oxidation/hydroxylation. The major phase II reaction was S-glutathione conjugation. The metabolic pathways were similar between the two lead compounds, though they have different backbone structures. Besides, the 4-NO2 of ring B in DAAN-4442 was susceptible to reduction, the benzyl of ring C in DAPA-7012 was tend to be oxidized. The common metabolic soft spots were primary amine of ring B and two methyl groups of ring C. Early SAR results showed that the primary amine and methyl were necessary substituent groups. The stability of these active groups needs to be improved and optimized. The approach of combining metabolites information and structure-activity analysis can provide a reference for further structural optimization.

Objective To investigate the factors influencing basic rehabilitation service needs of people with disability at Zhabei District in Shanghai .Methods Primary rehabilitation demands and services of 10 311 disabled persons in Zhabei District were surveyed.Results The screening rate of persons with disability having primary rehabilitation demands was 83.5%. And the gender, age, type of disability, disability level, education, employment might be the factors affecting the primary rehabilitation demands of people with disability.Conclusion The primary rehabilitation service demands vary in deferent types of people with disability. The various services based on the extensive rehabilitation services should be provided to deferent categories of people with disability.

Objective To understand the status of special rehabilitation service demands of people with disability at Zhabei District in Shanghai and to provide the basis for the policy development.Methods Screen rate (SR) was used to indicate the level of demand of rehabilitation service, the data were analyzed with SPSS 13.0 statistical software.Results There were 4 349 persons with disability who demanded the special rehabilitation service; the SR of “on-site rehabilitation service” demands was the highest among the whole persons with disability; the SR of “personalized allotment of supplies and appliances” demands of the intellectual disability and mental disability was lower than the other types; the SR of special rehabilitation service demands of the female, the elderly, the low cultural level, the unemployed and the people with severe disability were relatively higher.Conclusion The form of “on-site rehabilitation services” needs to improve based on the demand of the disabilities; “personalized supplies and appliances” for the intellectual disability and mental disability needs to further develop; the rehabilitation services targeted to the female, the elderly, the low cultural level, the unemployed and the people with severe disability need to improve.

Objective To provide the advice on how to optimize the allocation of resources and make other policy through the analysis factors affecting rehabilitation services needs of people with disability at Zhabei district in Shanghai.Methods The factors affecting rehabilitation services needs such as types of disability, disability levels, education, employment, marital status, age and sex were analyzed with Logistic analysis.Results The factors affecting primary rehabilitation services were types of disability, education, employment situation, marital status and sex. And people with disability had the characters of female, hearing disability, retired returned to more primary rehabilitation services, with OR values being 1.219, 1.544 and 1.533 respectively compared with itself controls. And the high educational disable people' will, returning to primary rehabilitation services, was weaker compared with low educational disable people. The factors affecting special rehabilitation services were types of disability and employment situation. And people with disability had the characters of hearing disability, unemployment returned to more special rehabilitation services, with OR values being 2.380 and 1.310 respectively compared with itself controls.Conclusion The rehabilitation needs are different among different groups people with disability, so the factors affecting rehabilitation services needs such as types of disability, education, employment situation, marital status and sex should be taken into consideration while activating primary rehabilitation services, while the types of disability and employment situation should be taken into more consideration while activating special rehabilitation services.

Objective To research expression changes of COX-2 gene in Barrett′s esophageal mucosa before and after argon plasma coagulation (APC)operation and to explore it′s clinical curative effect and possible mechanism .Methods 66 barrett′s e-sophageal diagnosed with gastroscope and pathology were randomly divided into normal esophageal group (the negative control group ,group A) ,the APC with acid suppression therapy group(group B) ,Acid antimicrobial drug treatment group(group C) .Ob-serve symptom relief condition ,barrett esophagus epithelium ablation under gastroscope before and after treatment ,esophageal mu-cosa tissue samples was detected by real-time fluorescent quantitative PCR technique .Expression of COX-2 gene in barrett′s esoph-ageal mucosa were compared among groups .Results Compared with group A ,both Group B and group C could effectively relieve symptoms (P<0 .05) .Symptom remission rate had no no statistically significant difference in Group B and group C .Barrett esopha-gus epithelium was not significantly narrowed under gastroscope follow-up Group A and group C ,while Barrett esophageal mucosal occurred ablation with pink mucous covered in Group B .The expression of Cox-2 mRNA in group B decreased ,which was similar to group A .The expression of Cox-2 mRNA in group C also decrease ,but there was no significant differences before and after treat-ment .Conclusion APC with acid suppression therapy could effectively relieve symptoms ,melting Barrett esophagus epithelium ,and is of a safe and effective treatment on Barrett′s esophagus .

The metabolite profiling of DAPA-7012 and DAAN-4442, the lead compounds from two new kinds of non-nucleoside reverse transcriptase inhibitors (NNRTIs), was performed using an ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS/MS), with the assistance of a metabolite data processing software. By utilizing the mass defect filter (MDF) technique, the data acquired from the 0 h-incubation and the 2 h-incubation were compared and analyzed with the MetaboLynx software. After incubation, 14 metabolites of DAPA-7012 and 14 metabolites of DAAN-4442 were found in rat liver microsome. The MS2 spectra for some metabolites were obtained using the MS(E) technique to get fragment ions for structural elucidation. The results indicated that both compounds could undergo extensive metabolism in rat liver microsomes. The major phase I reaction was oxidation/hydroxylation. The major phase II reaction was S-glutathione conjugation. The metabolic pathways were similar between the two lead compounds, though they have different backbone structures. Besides, the 4-NO2 of ring B in DAAN-4442 was susceptible to reduction, the benzyl of ring C in DAPA-7012 was tend to be oxidized. The common metabolic soft spots were primary amine of ring B and two methyl groups of ring C. Early SAR results showed that the primary amine and methyl were necessary substituent groups. The stability of these active groups needs to be improved and optimized. The approach of combining metabolites information and structure-activity analysis can provide a reference for further structural optimization.
Aniline Compounds ; chemistry ; metabolism ; Animals ; Anti-HIV Agents ; chemistry ; metabolism ; Chromatography, High Pressure Liquid ; Microsomes, Liver ; metabolism ; Molecular Structure ; Pyridines ; chemistry ; metabolism ; Rats ; Reverse Transcriptase Inhibitors ; chemistry ; metabolism ; Spectrometry, Mass, Electrospray Ionization

This study was aimed to explore the expression of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) in adult acute leukemia and its correlation with clinical characteristics, karyotype and prognosis. Indirect immunofluorescent cytometry was used to detect the expression of DNA-PKcs in bone marrow mononuclear cells of 105 patients with acute leukemia before chemotherapy and 41 of them after 2 cycles of chemotherapy. Cytogenetic data were obtained from 26 of them by R band karyotypic analysis. The results showed that the expression of DNA-PKcs was correlated with higher WBC count level in peripheral blood (p < 0.05), but was not obviously associated with median age, gender, percentage of bone marrow blasts, clinical classification, median hemoglobin level and median platelet count (p > 0.05). The middle and strong positive expression of DNA-Pkcs in non-remission group was significantly higher than that in remission group (p < 0.05). The positive rate of DNA-PKcs in abnormal chromosome group was significantly higher than that in chromosome normal group (p < 0.05). It is concluded that the DNA-PKcs expression level is closely related with the increased WBC count, and the expression of DNA-PKcs is correlated also with karyotype and clinical prognosis in adult acute leukemia.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Chromosome Aberrations ; DNA-Activated Protein Kinase ; genetics ; metabolism ; Female ; Humans ; Karyotype ; Leukemia ; diagnosis ; genetics ; metabolism ; Male ; Middle Aged ; Nuclear Proteins ; genetics ; metabolism ; Prognosis ; Young Adult

BACKGROUNDWith a trend that renal tumors are being detected at an earlier stage, classical radical nephrectomy is being reconsidered. More conservative techniques are being proposed. To clarify the indication for synchronous adrenalectomy in radical nephrectomy for renal cell carcinoma which has been questioned since the 1980s, this study evaluates the role of adrenalectomy and recommends a new indication for adrenalectomy in renal cell carcinoma.

METHODSA systemic search was performed, using PubMed and Google Scholar, of all English language studies published up to March 2012 that compared adrenalectomy with adrenal-sparing surgery, in surgery for renal cell carcinoma. We assessed preoperative imaging for adrenal involvement and the relationship of tumor location with adrenal metastases. Twenty-one studies (20 retrospective and 1 prospective) involving 11 736 patients were included.

RESULTSThe mean incidence of ipsilateral adrenal involvement from renal cell carcinoma was 4.5%. Synchronous adrenalectomy did not alter survival (hazard ratio (HR) = 0.89, 95% confidence interval (CI) 0.67 - 1.19, P = 0.43; odds ratio (OR) = 1.10, 95%CI 0.84 - 1.44, P = 0.49). Upper pole tumors were not associated with a higher incidence of ipsilateral adrenal metastases. Pooled preoperative imaging: sensitivity, specificity, positive predictive value and negative predictive value were 92% (95%CI 0.84 - 0.97), 95% (95%CI 0.93 - 0.96), 71.6% and 98.5% respectively.

CONCLUSIONSAdrenal involvement from renal cell carcinoma is rare, even in advanced tumours. Synchronous adrenalectomy does not offer any benefit, even for "high risk" patients. We suggest that only patients with a positive preoperative adrenal finding on preoperative imaging for a solitary adrenal metastasis should undergo adrenalectomy as part of the radical nephrectomy.

Adrenal Gland Neoplasms ; secondary ; surgery ; Adrenalectomy ; methods ; Carcinoma, Renal Cell ; mortality ; surgery ; Humans ; Kidney Neoplasms ; mortality ; surgery ; Nephrectomy ; methods ; Survival Rate

Objective To elucidate the association of genetic polymorphisms of key molecules in JAK/STAT signaling pathway with susceptibility of hepatocellular carcinoma (HCC).Methods A total of 367 HCC patients and 367 healthy controls were recruited in this sex- and age-matched case-control study.Genetic polymorphisms of IL-6 (rs1800796,-572C＞G),STAT3 (rs744166,+ 26312T＞C; rs3816769,+ 42240T＞C; rs6503695,+ 40980T＞C),EGFR (rs11543848,+ 142530A＞G),and mTOR (rs7211818,+ 170278A＞G; rs9674559,+ 196983A＞G; rs11653499,+65678G＞A) were genotyped using a mass spectrometry method.Odds ratio (OR) and 95％ confidence interval (CI) were calculated.Results Genotype frequency of the 8 polymorphisms of IL-6,STAT3,EGFR,and mTOR were not significantly different between the patients with HCC and the controls.When stratified by sex,the female subjects who carried STAT3 +26312CC,+ 42240CC,or + 40980CC had a decreased risk of HCC when compared to those who carried TT allele (OR=0.192,95％CI:0.047-0.784; OR=0.180,95％CI:0.045-0.725;OR=0.198,95％ CI:0.049-0.806,respectively).When compared with AA genotype on the site of EGFR + 142530,the (AG+ GG) genotype reduced the risk of HCC in women (OR=0.422,95％CI:0.179-0.994).Conclusion The polymorphisms of IL-6 (rs1800796) and mTOR (rs7211818,rs9674559,and rs11653499) were not associated with the HCC susceptibility.Those carrying CC allele in three loci (rs744166,rs3816769,and rs6503695) of STAT3 and (AG + GG) in rs11543848 of EGFR had a decreased risk of HCC in women.However,these results need to be validated using larger sample size.

Objective To study the influence of let-7b on cell proliferation and aerobic glycolysis of human melanoma cell A375.Methods Transfect A375 cell line with hsa-let-7b oligonucleotide or antisense.Glucose and lactate in medium were determined by spectrophotometry at 24 h and 48 h time point after transfection.The cell proliferation was determined by methylthiazol tetrazolium (MTT) assay.Results Over expression of let-7b in melanoma cell reduced cell proliferation notably,compared to the other groups by MTT(P ＜0.05).However,the glucose consumption and lactate production differences were not observed during 24 h or 48 h ( P ＞ 0.05 ),the blank control group transformed about 57％ and 43％ glucose to lactate during 24 h and 48 h.Conclusions Melanoma cell line A375 has notably aerobic glycolysis hallmark,let-7b could inhibit proliferation of melanoma cell line A375,but it may has no influence on glucose metabolism.