Добірка наукової літератури з теми "621.391 (0.43)"

13049 Background: The irinotecan active metabolite, SN38, is inactivated through glucuronidation mainly by uridine diphosphate glucuronosyltransferase (UGT) 1A1. The (TA)7 allele of a polymorphism in UGT1A1 promoter has been associated with reduced SN38-glucuronidation rate and more severe toxicity. Since other UGT1A family isoforms, the extrahepatic UGT1A7 and the hepatic UGT1A9, are involved in SN38 glucuronidation, it has been suggested that also polymorphic variants of these genes may affect irinotecan toxicity. Methods: 84 patients with advanced colorectal cancer received an irinotecan-based (180 mg/m2 q.2wks) combination treatment. Polymorphisms of UGT1A1 [(TA)6>7], UGT1A7 [387T > G, 391–2CG > AA, 622T > C] and UGT1A9 [-118(T)9>10, -87G > A, 98T > C, I152G > A] were identified by sequencing on DNA from blood samples obtained under an IRB approved protocol. Toxicity has been graded according to NCI-CT criteria. Results: Patient median age was 64 y (range: 31–82); median PS was 0 (range: 0–2). Severe toxicity (diarrhea or/and neutropenia ≥G3) has been observed in 32 patients: diarrhea in 11, neutropenia in 25 (4 patients had both). The estimated allele frequencies were as follows: UGT1A1, (TA)7 (0.35); UGT1A7, 387T and the completely linked 391–2CG (0.39), 622C (0.39); UGT1A9, -118(T)10 (0.39), -87A (0.05), T98C (0.02), I152A (0.21). Severe toxicity was significantly associated only with: (a) the UGT1A1 (TA)7 allele [severe toxicity in 25% of (TA) 6/6, in 46% of (TA) 6/7, in 55% of (TA) 7/7 (Mantel-Haenszel trend test, P < 0.03)]; and (b) the low activity UGT1A7 622C allele [severe toxicity in 26% of 622 T/T, in 39% of 622 T/C, in 67% of 622 C/C (Mantel-Haenszel, P < 0.02)]. In addition, the analysis of the combined genotypes [(TA)6>7 and 622T > C] has shown severe toxicity in 21% of patients with none of (TA)7 and of 622C alleles, in 43% of patients in which the sum of the number of (TA)7 and of 622C alleles is 1 or 2, in 57% of patients in which this sum is ≥3 (the latter includes all patients with both toxicities) (Mantel-Haenszel, P < 0.02). Conclusions: These data show that both the low activity UGT1A1 (TA)7 and UGT1A7 622C alleles are significantly associated with irinotecan severe toxicity. It is to evaluate if their combined genotype may be a better predictor of toxicity. No significant financial relationships to disclose.

An experiment was designed to compare pregnancy rates in lactating dairy cows synchronized with a 7-day CIDR-Synch or a 5-day CIDR-Synch program and to determine if the addition of a second prostaglandin F2α (PGF) injection to the 7-day CIDR-Synch program would improve pregnancy rates following fixed-time AI (FTAI). The experiments were performed on 2 dairy farms in Argentina, with year-round calving and a mixed feeding system (35% grazing plus 65% corn silage and grain). Cows (n = 621) were 39.3 ± 6.5 days in milk (DIM, mean ± SD) when they were enrolled in the program, had 2.4 ± 1.5 lactations and a body condition score (BCS) of 3.1 ± 0.2 (range: 2.7 to 4.0). All cows received a pre-synchronization treatment with 2 doses of prostaglandin (PGF, 25 mg of dinoprost, Lutalyse, Pfizer Animal Health, Argentina) 14 days apart, and 11 days after the second PGF (Day 0) received 10 µg of Buserelin (GnRH, Receptal, MSD-Intervet, Argentina) and a CIDR device (1.9 g of progesterone, Pfizer Animal Health). Cows were randomly allocated to 1 of 3 groups. The CIDR devices were removed and PGF was administered to cows in Groups 1 and 2 on Day 7. A second GnRH was given 56 h later and cows experienced FTAI 16 h after gonadotropin-releasing hormone (GnRH) injection (i.e. 72 h after CIDR removal). Cows in Group 2 also received a second PGF injection on the afternoon of Day 7. Cows in Group 3 had the CIDR removed and received 2 PGF injections 12 h apart on Day 5. A second dose of GnRH was given and FTAI was performed at the same time, on Day 8 (i.e. 72 h after CIDR removal). All cows were examined by ultrasonography (Aloka 500V, Aloka, Tokyo, Japan) on the day of the first PGF injection and at CIDR removal to determine the presence and number of corpora lutea (CL), and 30 days after FTAI to determine pregnancy status. Data were analyzed by logistic regression to determine the effects of treatment, parity, days postpartum, milk production, BCS, presence of a CL at enrollment, and number of CL at the time of CIDR removal on pregnancy rates. Overall pregnancy rates did not differ among groups: 32.9% (68/207), 38.2% (78/204), and 38.3% (80/209) for Groups 1, 2, and 3, respectively (P = 0.2). Although the number of CL present at CIDR removal did not significantly affect pregnancy rates (P = 0.4), pregnancy rates in cows with 1 CL in Groups 1 and 2 tended to differ [29.0% (11/38) v. 48.9% (21/43); P < 0.07], but neither differed from that in Group 3 [37.2% (16/43)]. No differences were detected among groups in cows without a CL at CIDR removal [overall pregnancy rate: 29.4% (5/17)] and those with ≥2 CL [overall pregnancy rate: 36.1% (173/479)]. Among the other variables evaluated, first-parity cows had 1.96 (1.38–2.78) times more chance of getting pregnant than second-or-more-parity cows (P = 0.002) and cows with BCS >3 had 1.63 (1.16–2.28) times more chance of getting pregnant than those with BCS <3 (P = 0.003). Finally, herd, days postpartum, milk production, and presence of a CL at enrollment did not significantly affect pregnancy rates. We concluded that the 3 treatments resulted in similar pregnancy rates for lactating dairy cows and that the benefit of adding a second PGF injection to the 7-day protocol was only marginal in cows with 1 CL at CIDR removal.

The effect of increasing levels of zearalenone (ZEA) artificially supplemented to milk on the coagulation characteristics and the viability of Lactobacillus bulgaricus and Streptococcus thermophilus was examinated. Cow milk was inoculated with the yogurt culture YC-180 – YO-Flex and divided into 72, 25-ml flasks. Two samples were collected before fermentation (0 h) and remaining 70 flasks were divided into 7 groups – control (C), Z0 with 0.5 ml of ethanol and Z10, Z100, Z250, Z500, and Z1000 that were spiked with ZEA to reach the final ZEA concentrations of 10, 100, 250, 500, and 1000 µg/l, respectively. Samples were fermented at 43 ± 2°C for 5 hours. Two samples per group were collected at 1-h intervals and analysed on pH, titratable acidity, ZEA and count of Lb. bulgaricus and Str. thermophilus. The addition of ZEA resulted in slower acidification in Z100, Z250, Z500, and Z1000. The highest ZEA binding capacity (25%) was observed in Z10 and the lowest (3.1%) was found in Z1000.

AbstractDietary fat intake is correlated with increased insulin resistance (IR). However, it is unknown whether gene–diet interaction modulates the association. This study estimated heritability of IR measures and the related genetic correlations with fat intake, and tested whether dietary fat intake modifies the genetic influence on type 2 diabetes (T2D)-related traits in Chinese child twins. We included 622 twins aged 7–15 years (n 311 pairs, 162 monozygotic (MZ), 149 dizygotic (DZ)) from south-eastern China. Dietary factors were measured using FFQ. Structural equation models were fit using Mx statistical package. The intra-class correlation coefficients for all traits related to T2D were higher for MZ twins than for DZ twins. Dietary fat and fasting serum insulin (additive genetic correlation (rA) 0·20; 95 % CI 0·08, 0·43), glucose (rA 0·12; 95 % CI 0·01, 0·40), homoeostasis model of assessment-insulin resistance (Homa-IR) (rA 0·22; 95 % CI 0·10, 0·50) and the quantitative insulin sensitivity check index (Quicki) (rA −0·22; 95 % CI −0·40, 0·04) showed strong genetic correlations. Heritabilities of dietary fat intake, fasting glucose and insulin were estimated to be 52, 70 and 70 %, respectively. More than 70 % of the phenotypic correlations between dietary fat and insulin, glucose, Homa-IR and the Quicki index appeared to be mediated by shared genetic influence. Dietary fat significantly modified additive genetic effects on these quantitative traits associated with T2D. Analysis of Chinese twins yielded high estimates of heritability of dietary fat intake and IR. Genetic factors appear to contribute to a high proportion of the variance for both insulin sensitivity and IR. Dietary fat intake modifies the genetic influence on blood levels of insulin and glucose, Homa-IR and the Quicki index.

8019 Background: The detection of driver mutations in the EGFR and ALK genes and targeted therapy has transformed treatment of lung cancer. The LCMC was established in 2009 to assay lung adenocarcinomas for driver genomic alterations in 10 genes and to study and treat patients by their molecular subtypes. Methods: The 14-member LCMC enrolled patients with metastatic adenocarcinoma of the lung and tested their tumors in CLIA laboratories for KRAS, EGFR, HER2, BRAF, PIK3CA, AKT1, MEK1, and NRAS mutations using multiplexed assays, and for ALK rearrangements and MET amplifications using fluorescence in situ hybridization (FISH). Results: 1,102 eligible patients were enrolled; 1,007 underwent testing for at least one genomic alteration with 733 undergoing testing for all 10 genes. 600 patients were women (60%) with a median age of 63; 341 were never smokers (34%) and 589 former smokers (58%). A driver alteration was detected in 622 (62%) of the 1,007 with any genotyping, and in 465 (63%) of the 733 fully genotyped cases. Among the tumors with full genotyping, drivers were found as follows: KRAS 182 (25%), sensitizing EGFR 107 (15%), ALK rearrangements 56 (8%), other EGFR 43 (6%), two genes 29 (4%), BRAF 16 (2%), HER2 15 (2%), PIK3CA 6 (1%), MET amplification 5 (1%), NRAS 5 (1%), MEK1 1 (<1%), and AKT1 0 (0%). Results were used to select targeted therapy or targeted trials in 279 patients with a driver alteration (28% of 1,007 total). Among 938 patients with clinical follow-up and treatment information, 264 with a driver alteration treated with a targeted agent had a median survival of 3.5 years; 313 with a driver who did not receive targeted therapy had a median survival of 2.4 years; while 361 without an identified driver had a median survival of 2.1 years (p<0.0001). Conclusions: An actionable driver alteration was detected in 62% of tumors from patients with lung adenocarcinomas, leading to use of a targeted therapy in 28%. The patients with an identified driver treated with a targeted agent lived longer than those patients who did not receive targeted therapy. Multiplexed genomic testing can aid physicians in matching patients with targeted treatments and appropriate clinical trials.

Background: Laparoscopic cholecystectomy has become a standard technique for gall bladder surgery of symptomatic cholelithiasis. However, conversion to open cholecystectomy is sometimes necessary. The aim of the present study was to assess the predictive factors that increase the possibility of conversion of laparoscopic cholecystectomy to open cholecystectomy.Methods: A total of 621 laparoscopic cholecystectomies were attempted at AL-Mawanee General Hospital and AL-Sader Teaching Hospital in Basrah, IRAQ from June 2012 till June 2016.Of these,43 had to be converted to open cholecystectomies. Patients assessed according to different factors, including age, sex, acute cholecystitis, adhesions of gallbladder and calot's triangle, obesity, previous abdominal surgery, anatomical variation of gallbladder and Calot's triangle and intraoperative complications (bleeding, bile duct injury, visceral injury).Results: Conversion to open cholecystectomy was performed in 43 patients (6.92%). The significant factors for conversions were adhesions of gallbladder and Calot's triangle(39.53%) followed by acute cholecystitis(34.88%). Rate of conversion in other factors are as the following i.e., isolated male gender (0%), age (0%), previous abdominal surgery (9.3%), obesity (2.33%), anatomical variations of gall bladder and calot's triangle (2.33%), intra operative complications including bleeding (4.65%), bile duct injury (4.65%), visceral injury (2.33%) were insignificant factors for conversion.Conclusions: Adhesions of gallbladder and calot's triangle is the most common predictive factor and cause for conversion from laparoscopic cholecystectomy to open cholecystectomy. Acute cholecystitis found to be the strongest factor for conversion despite its incidence is lower than adhesions of gall bladder and calots triangle. Male gender and age more than fifty years are not direct predictive factors for conversions.

Background:Juvenile systemic sclerosis (jSSc) is a rare disease with a prevalence of around 3 in 1,000,000 children. To better capture the clinical manifestations of jSSc the juvenile systemic sclerosis inception cohort (jSScC) has been prospectively enrolling patients with predetermined clinical variables over the past 12 years. One of the goals is to study the demographic, clinical features, and physician and patient reported outcome differences between those with juvenile limited cutaneous (lc) compared to diffuse cutaneous (dc) disease subtypes, to determine if characteristics are similar or different between dc and lc jSSc.Objectives:Evaluation of the baseline clinical characteristics of jSSc patients in the jSScC. Compare clinical phenotype between diffuse (dcjSSc) and limited cutaneous (lcjSSc) subtypes.Methods:Demographic, physical examination, organ system evaluation, autoantibody profile, treatment, and patient and physician reported outcome variables were evaluated from the jSSc Inception cohort and summary statistics applied using chi-square test and Mann Whitney U-test comparing lcjSSc and dcjSSc subtypes.Results:At the time of data extraction, 175 jSSc patients were enrolled in the cohort, 81% were Caucasian and 81% female. Diffuse cutaneous jSSc subtype predominated (73%). Mean disease duration was 3.1 year (±2.7). Mean age at Raynaud´s was 10 years (+3.8) and mean age of first non-Raynaud´s was 10.2 years (±3.8). Significant differences were found between dcjSSc versus lcjSSc, regarding several clinical characteristics. Patients with diffuse cutaneous subtype had significantly higher modified Rodnan skin score (p=0.001), presence of sclerodactyly (p=0.02), presence of Gottron’s papules (p=0.003), presence of telangiectasia (p=0.001), history of digital tip ulceration (p=0.01), and frequency of elevated CK value (p=0.04). Cardiac involvement was significantly higher in limited cutaneous jSSc subtype (p=0.02). Diffuse cutaneous jSSc patients had significantly worse scores for Physician Global Assessment of disease activity (38 vs 25; p=0.002) and disease damage (34 vs 19; p=0.008).Table 1.Comparison of demographic data and significant differences between dcjSSc and lcjSSc at time of inclusionWhole CohortN=175Diffuse SubtypeN=128Limited SubtypeN=47P valueFemale to Male Ratio4.3:1 (142/33)4.1:1 (103/25)4.8:1 (39/8)0.829Cutaneous subtypeDiffuse subtype73% (128)1280Limited subtype27% (47)047Mean Disease duration (years)3.1 (± 2.7)3.3 (± 2.9)2.6 (± 2.2)0.135Mean age of onset of Raynaud´s (years)10.0 (± 3.8)17 non-Raynaud9.8 (± 3.6)10 non-Raynaud10.6 (± 4.3)7 non-Raynaud0.219Mean age of onset of non-Raynaud´s (years)10.2 (± 3.9)10.0 (± 3.7)10.9 (± 4.3)0.173Disease modifying drugs88% (154)89% (114)85% (40)0.446CutaneousMean modified Rodnan skin score14.3 (0-51)17.4 (0-51)6.1 (0-24)0.001Gottron Papules27% (46/171)33% (41/124)11% (5)0.003Sclerodactyly78% (126/162)82% (98/119)65% (28/43)0.020Laboratory valuesElevated CK25% (30/122)30% (26/88)12% (4/34)0.041VascularTelangiectasia36% (56/154)44% (49/111)16% (7/43)0.001History of ulceration53% (91/173)61% (77/127)30% (14/46)0.001CardiacCardiac Involvement6% (10)2% (3)15% (7)0.002Patient Related OutcomesPhysician global disease activity(0-100) min -max35(0-90) n=14138(0-90) n=10825(0-80) n=330.002Physician global disease damage(0-100) min -max31(0-85) n=14034(0-85) n=10819(0-60) n=320.008Conclusion:Results from this large international cohort of jSSc patients demonstrate significant differences between dcjSSc and lcjSSc patients. According to the general organ involvement and physician global scores, the dcjSSc patients had significantly more severe disease. These observations strengthen our previous findings of the unique organ pattern of pediatric patients.Supported by the “Joachim Herz Stiftung”Disclosure of Interests:None declared.

ABSTRACT The effect of restricting placental growth on maternal glucose, insulin and placental lactogen was investigated in 16 ewes carrying singleton lambs. Uterine caruncles were removed from seven ewes (caruncle ewes) before pregnancy, resulting in reduced placental size and retarded intra-uterine fetal growth. The concentration of insulin in maternal plasma was similar in both control and caruncle ewes. The concentration of glucose was significantly higher in the caruncle than in the control ewes (3·26 ± 0·15 (s.e.m.) mmol/l, number of observations (n) = 9, vs 2·75 ± 0·1, n = 9, P<0·02, and 3·27 ±0·16, n = 7, vs 2·46± 0·11, n = 12, P<0·001, for the carotid artery and utero-ovarian vein respectively). The concentration of ovine placental lactogen (oPL) in the utero-ovarian vein was reduced in the caruncle compared with the control ewes (283± 65 μg/l, n = and 705±106 μg/l, n = 18, P<0·02, respectively). Restriction of placental growth by removal of endometrial caruncles similarly reduced the concentrations of oPL in maternal arterial plasma (231±54 μg/l, n = 9, and 621±96 μg/l, n = 18, P<0·002). Production of oPL by the placenta was also reduced by limiting placental growth to 30±11 μg/min, n = 8, compared with 133±43 μg/min, n = 15, P<0·05, for the controls. Production of oPL per gram of placenta in the caruncle group, although only 34% of the control value, was not reduced significantly. These observations are consistent with the hypothesis that oPL may be involved in the redirection of maternal glucose during pregnancy to maximize the amount available for the fetus. J. Endocr. (1985) 106, 7–11

The Ca intake and food sources of Chinese postmenopausal women are quite different from those of their Western counterparts. But, little information on Ca metabolism is available in Chinese populations. We determined true fractional calcium absorption (TFCA), true Ca absorption ( = TFCA × Ca intake,Va), urinary Ca excretion (Vu) and the difference betweenVaandVu(Va − u), in response to three dietary Ca intake levels. Twenty-one healthy postmenopausal Chinese women aged 49–64 years were recruited for this randomized crossover trial from a general community, Guangzhou, China. Subjects were randomly assigned to receive 0, 500 and 1000 mg Ca/d for 5 weeks separated by 2-week washout periods. TFCA using Ca stable isotopes, total urinary Ca excretion and Ca intake were determined after 4 weeks of adaptation. Mean values for total Ca intake (Vi) of the three phases were 391 (sd197), 880 (sd130) and 1382 (sd160) mg/d. On usual diet, TFCA,Vu,VaandVa − uwere 0·57 (sd0·12), 175 (sd59) mg/d, 216 (sd98) mg/d and 41 (sd99) mg/d, respectively. With the supplementations of 500 and 1000 mg Ca/d, TFCA significantly decreased to 0·52 (sd0·12) and 0·43 (sd0·13) (P < 0·001); whereas urinary Ca (P = 0·003),VaandVa − uincreased significantly (P < 0·001). Using a mixed-effects nonlinear regression model, it was estimated thatVa − uwas approaching a plateau when mean Ca intake reached 1300 mg/d. In conclusion, the present findings suggest postmenopausal Chinese women have high Ca absorption efficiency and a mean Ca intake of about 1300 mg/d is required to maximize theVa − u.