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1.
Huan Wang Jing Huang Xiaojin Yu Shuhua Han Xing Yan Siqing Sun Xiaoli Zhu 《Journal of cancer research and clinical oncology》2014,140(11):1901-1909
Background
Nearly 85 % of lung-cancer-specific epidermal growth factor receptor (EGFR) sensitive mutations comprise a substitution at position 858 (21L858R) and deletion mutants in exon 19 (19del). The aim of this study was to assess the role of EGFR mutation subtypes in predicting the efficacy of EGFR tyrosine kinase inhibitors (EGFR TKIs) and the prognosis of patients with advanced non-small cell lung cancer (NSCLC).Method
We systematically searched for eligible articles investigating the association between EGFR mutation subtypes and the efficacy of EGFR TKIs and the prognosis of patients with NSCLC. The summary risk ratio (RR) and mean difference (MD) were calculated using meta-analysis. In addition, we used variance analysis for the progression-free survival data (PFS) and used the rank sum test for the overall survival data.Results
We identified 22 eligible trials involving 1,082 patients. The objective response rate of the 19del mutation group was significantly higher than the 21L858R mutation group (RR 1.23; 95 % CI 1.12–1.36; P < 0.0001). The PFS (MD 3.55; 95 % CI 0.90–6.20; P = 0.009; MD 2.57; 95 % CI 0.51–4.62; P = 0.01) and overall survival (OS) (MD 10.52; 95 % CI 5.10–15.93; P = 0.0001) of the 19del mutation group were significantly longer than the 21L858R mutation group; the same results were observed in the variance analysis and rank sum test.Conclusion
The 19del mutation may be a more efficient clinical marker for predicting the response of patients with NSCLC to EGFR TKIs. Furthermore, patients with the 19del mutation have both a longer PFS and OS. The 19del mutation is also the prognostic factor for patients with NSCLC. 相似文献2.
Jair Bar Arnold Cyjon Dov Flex Hadas Sorotsky Haim Biran Julia Dudnik Nili Peylan-Ramu Nir Peled Hovav Nechushtan Maya Gips Rivka Katsnelson Shoshana Keren Rosenberg Ofer Merimsky Amir Onn Maya Gottfried 《Lung》2014,192(5):759-763
Purpose
Testing tumor samples for the presence of a mutation in the epithelial growth factor receptor (EGFR) gene is recommended for advanced non-squamous non-small cell lung cancer (NSCLC) patients. We aimed to collect data about common practice among Medical Oncologists treating lung cancer patients, regarding EGFR mutation testing in advanced NSCLC patients.Methods
An internet-based survey was conducted among members of the Israeli Society for Clinical Oncology and Radiotherapy involved in the treatment of lung cancer patients.Results
24 Oncologists participated in the survey. The participants encompass the Oncologists treating most of the lung cancer patients in Israel. 79 % of them use EGFR testing routinely for all advanced NSCLC patients. Opinions were split regarding the preferable biopsy site for EGFR testing material. 60 % of participants recommend waiting for EGFR test results prior to initiation of first-line therapy.Conclusions
EGFR testing is requested in Israel routinely by most treating Oncologists for all advanced NSCLC patients, regardless of histology. In most cases, systemic treatment is deferred until the results of this test are received. 相似文献3.
J. C. von Einem V. Heinemann L. Fischer von Weikersthal U. Vehling-Kaiser M. Stauch H. G. Hass T. Decker S. Klein S. Held A. Jung T. Kirchner M. Haas J. Holch M. Michl P. Aubele S. Boeck C. Schulz C. Giessen S. Stintzing D. P. Modest 《Journal of cancer research and clinical oncology》2014,140(9):1607-1614
Purpose
AIO KRK-0104 investigated first-line therapy of metastatic colorectal cancer (mCRC) with cetuximab, capecitabine and irinotecan versus cetuximab, capecitabine and oxaliplatin. This analysis investigated the impact of primary tumor location on outcome of patients.Patients and methods
Left-sided primary tumors were defined as tumors from rectum to left flexure, while tumors in the remaining colon were regarded right sided. Overall survival (OS), progression-free survival (PFS) and response rate were correlated with primary tumor location. A Cox regression model was used to evaluate interaction between primary tumor location and KRAS mutation.Results
Of 146 patients of the AIO KRK-0104 trial, 100 patients presented left-sided (of those 68 KRAS codon 12/13 wild-type) and 46 patients right-sided primary tumors (of those 27 KRAS codon 12/13 wild-type). Left-sided tumors were associated with significantly longer OS (p = 0.016, HR = 0.63) and PFS (p = 0.02, HR = 0.67) as compared to right-sided tumors. These effects were present in the KRAS codon 12/13 wild-type population (HR OS: 0.42; HR PFS: 0.54), while no impact of primary tumor location was evident in patients with KRAS codon 12/13 mutant tumors (HR OS: 1.3; HR PFS: 1.01). A significant interaction of KRAS status and primary tumor location concerning OS and PFS was observed.Conclusion
Our findings suggest that primary tumor location and KRAS codon 12/13 mutational status interact on the outcome of patients with mCRC receiving cetuximab-based first-line therapy. Left-sided primary tumor location might be a predictor of cetuximab efficacy. 相似文献4.
T. Ignatov H. Eggemann S. D. Costa A. Roessner T. Kalinski A. Ignatov 《Journal of cancer research and clinical oncology》2014,140(9):1457-1463
Background
The aim of the current study was to investigate the role of BRCA1 promoter methylation as predictive factor of response to platinum–taxane-based therapy in sporadic ovarian cancer.Patients and methods
BRCA1 promoter methylation was analyzed in 42 sporadic epithelial ovarian cancers. The results were validated in a second cohort of 137 ovarian cancer patients.Results
BRCA1 promoter methylation was observed in 35.7 % of patients in the first group and in 33.6 % in the second group. BRCA1 promoter methylation was associated with significant increase in median progression-free survival (PFS) of ovarian cancer patients receiving adjuvant platinum–taxane-based chemotherapy (P = 0.008). Multivariate analysis revealed that BRCA1 promoter methylation remains a favorable factor in regard to PFS (HR 0.52; 95 % CI 0.32–0.85, P = 0.009) after adjustment for other prognostic factors. Under the patients with recurrent disease, BRCA1 promoter methylation was associated with significant longer median PFS of 18.5 months in comparison with 12.8 months PFS for patients without BRCA1 promoter methylation.Conclusions
BRCA1 promoter methylation is predictive for better response to platinum–taxane-based therapy in EOC. 相似文献5.
Anup K. Nair Yunhua Li Muller Nellie A. McLean Maryam Abdussamad Paolo Piaggi Sayuko Kobes E. Jennifer Weil Jeffrey M. Curtis Robert G. Nelson William C. Knowler Robert L. Hanson Leslie J. Baier 《Diabetologia》2014,57(11):2334-2338
Aim/hypothesis
A recent genome-wide trans-ancestry meta-analysis identified seven new loci associated with type 2 diabetes. We assessed the replication of the seven lead single nucleotide polymorphisms (SNPs) and evaluated these loci for additional signals in American Indians.Methods
Seven SNPs were genotyped in 7,710 individuals from a longitudinally studied American Indian population, and associations with type 2 diabetes, BMI and related phenotypes were assessed. Previous genome-wide association study (GWAS) data from these individuals were used to screen for additional type 2 diabetes signals at these loci. A variant independent of the trans-ancestry meta-analysis was identified within LPP, and its replication was assessed in an additional 3,106 urban American Indians.Results
SNP rs6813195 near to TMEM154 was nominally associated with type 2 diabetes (p?=?0.01, OR 1.12 [95% CI 1.03, 1.22]) and adiposity: the type 2 diabetes risk allele was associated with a lower percentage body fat (β?=??1.451%, p?=?4.8?×?10?4). Another SNP, rs3130501 near to POU5F1–TCF19, was associated with BMI (β?=??0.012, p?=?0.004), type 2 diabetes adjusted for BMI (p?=?0.02, OR 1.11 [95% CI 1.02, 1.22]), 2 h glucose concentrations (β?=?0.080 mmol/l, p?=?0.02) and insulin resistance estimated by homeostatic model (β?=?0.039, p?=?0.009). The independent variant identified at the LPP locus in our American Indian GWAS for type 2 diabetes was replicated in the additional samples (all American Indian meta-analysis, p?=?8.9?×?10?6, OR 1.29 [95% CI 1.15, 1.45]).Conclusions/interpretation
For two of the seven newly identified variants, there was nominal evidence for association with type 2 diabetes and related traits in American Indians. Identification of an independent variant at the LPP locus suggests the existence of more than one type 2 diabetes signal at this locus. 相似文献6.
Hong In Yoon Ik Jae Lee Kwang-Hyub Han Jinsil Seong 《Journal of cancer research and clinical oncology》2014,140(9):1595-1605
Aim
To investigate whether image-guided intensity-modulated radiation therapy (IG-IMRT) improves survival in hepatocellular carcinoma (HCC) relative to 3-dimensional conformal radiotherapy (3D-CRT).Methods
Between 2006 and 2011, 187 HCC patients treated with definitive RT were reviewed. Median age was 53(range 51–83). All patients were stage III or IV-A. Concurrent chemoradiation was received by 178 patients (95.2 %). Overall actuarial survival (OS), progression-free survival (PFS), and infield-failure-free survival (IFFS) analyses were performed by Kaplan–Meier method. A Cox proportional hazards model was used for univariate and multivariate analysis. Pearson’s chi-square test or Fisher’s exact test was used to compare patient characteristics and treatment-related toxicity between the groups.Results
Sixty-five patients were treated with IG-IMRT and 122 patients with 3D-CRT. No significant differences were seen between the groups for all patient characteristics. IG-IMRT delivered higher doses than 3D-CRT (median biological effective dose 62.5 vs 53.1 Gy, P < 0.001). IG-IMRT showed significantly higher 3-year OS (33.4 vs 13.5 %, P < 0.001), PFS (11.1 vs 6.0 %, P = 0.004), and IFFS (46.8 vs 28.2 %, P = 0.007) than 3D-CRT. On univariate and multivariate analysis, RT modality was significant prognostic factor for OS (HR 2.18; 95 % CI 1.45–3.25; P < 0.001), PFS (HR 1.64; 95 % CI 1.17–2.29; P = 0.004). There was no significant difference between the two modalities for radiation-induced liver disease (P = 0.716).Conclusion
Our findings suggest that IG-IMRT could be an effective treatment that provides survival benefit without increasing severe toxicity in locally advanced HCC. 相似文献7.
Sung Hoon Sim Bhumsuk Keam Dong-Wan Kim Tae Min Kim Se-Hoon Lee Doo Hyun Chung Dae Seog Heo 《Journal of cancer research and clinical oncology》2014,140(12):2135-2142
Purpose
Gefitinib is safe for the treatment of non-small cell lung cancer (NSCLC), but some patients experience toxicities and require dose reduction. The purpose of this study was to evaluate the effect of gefitinib dose reduction on survival.Methods
We retrospectively analyzed 263 patients with NSCLC harboring sensitive epidermal growth factor receptor (EGFR) mutation. All patients had recurred or metastatic disease and received gefitinib 250 mg daily as palliative chemotherapy.Results
Of the 263 patients, 23 had gefitinib dose reduction due to toxicities (1 due to mucositis, 5 due to skin rash, 11 due to hepatotoxicity and 6 for both skin and hepatotoxicity). In the dose reduction group, the mean dose intensity was 0.84 (range 0.48–0.98). Patients with dose reduction showed significantly prolonged progression-free survival (PFS) and overall survival (OS) compared to those receiving the standard dose (median PFS: 14.0 vs. 10.6 months, P = 0.042, median OS: 54.5 vs. 29.6, P = 0.020). In multivariate analysis, the effect of dose reduction was not significantly associated with prolonged PFS [hazard ratio (HR) 0.619, 95 % confidence interval (CI) 0.357–1.073, P = 0.085], or OS (HR 0.625, 95 % CI 0.287–1.362, P = 0.237). However, patients receiving low-dose gefitinib tended to have superior survival outcomes compared to those receiving standard-dose gefitinib.Conclusions
The patients experiencing gefitinib dose reduction or short-term treatment interruption due to toxicities did not show inferior survival, compared to those receiving full dose of gefitinib in NSCLC patients with EGFR mutation. 相似文献8.
Christiane Winkler Jan Krumsiek Florian Buettner Christof Angermüller Eleni Z. Giannopoulou Fabian J. Theis Anette-Gabriele Ziegler Ezio Bonifacio 《Diabetologia》2014,57(12):2521-2529
Aims/hypothesis
More than 40 regions of the human genome confer susceptibility for type 1 diabetes and could be used to establish population screening strategies. The aim of our study was to identify weighted sets of SNP combinations for type 1 diabetes prediction.Methods
We applied multivariable logistic regression and Bayesian feature selection to the Type 1 Diabetes Genetics Consortium (T1DGC) dataset with genotyping of HLA plus 40 SNPs within other type 1 diabetes-associated gene regions in 4,574 cases and 1,207 controls. We tested the weighted models in an independent validation set (765 cases, 423 controls), and assessed their performance in 1,772 prospectively followed children.Results
The inclusion of 40 non-HLA gene SNPs significantly improved the prediction of type 1 diabetes over that provided by HLA alone (p?=?3.1?×?10?25), with a receiver operating characteristic AUC of 0.87 in the T1DGC set, and 0.84 in the validation set. Feature selection identified HLA plus nine SNPs from the PTPN22, INS, IL2RA, ERBB3, ORMDL3, BACH2, IL27, GLIS3 and RNLS genes that could achieve similar prediction accuracy as the total SNP set. Application of this ten SNP model to prospectively followed children was able to improve risk stratification over that achieved by HLA genotype alone.Conclusions
We provided a weighted risk model with selected SNPs that could be considered for recruitment of infants into studies of early type 1 diabetes natural history or appropriately safe prevention. 相似文献9.
Dong N Yu J Wang C Zheng X Wang Z Di L Song G Zhu B Che L Jia J Jiang H Zhou X Wang X Ren J 《Journal of cancer research and clinical oncology》2012,138(7):1197-1203
Purpose
Docetaxel plus capecitabine, a commonly used chemotherapeutic regimen for metastatic breast cancer (MBC), is highly variable in its effectiveness. We aimed to investigate whether allelic variants of cytochrome P450 (CYP450) affected objective response, progression-free survival (PFS), and overall survival (OS) in MBC.Patients and methods
79 SNPs in CYP450, whose minor allele frequency were ≥10%, were genotyped in 69 MBC patients who were treated with docetaxel plus capecitabine. Pearson’s χ2 test or Fisher’s exact test was used to investigate the influence of SNPs on objective response as appropriate. Log-rank test was used to assess the association between SNPs and survival outcomes.Results
There is no significant association between polymorphisms and both objective response and OS. Only one SNP, CYP1A1 rs1048943 A>G (Ile462Val), was significantly associated with PFS (P?=?0.0003). Multivariate analysis confirmed its prognostic significance for PFS (P?=?0.004).Conclusion
CYP1A1 rs1048943 A>G (Ile462Val) polymorphism is a potential prognostic marker for survival outcome after docetaxel plus capecitabine chemotherapy in MBC patients. However, confirmatory study is needed to validate this finding. 相似文献10.
Hans-Joachim Schmoll Burghardt Wittig Dirk Arnold Jorge Riera-Knorrenschild Dieter Nitsche Hendrik Kroening Frank Mayer Johannes Andel Reinhard Ziebermayr Werner Scheithauer 《Journal of cancer research and clinical oncology》2014,140(9):1615-1624
Purpose
This phase II study evaluated the synthetic DNA-based immunomodulator and Toll-like receptor 9 agonist MGN1703 as maintenance treatment in metastatic colorectal carcinoma (mCRC).Methods
Fifty-nine patients with mCRC and disease control after standard first-line chemotherapy were randomised to MGN1703 60 mg (N = 43) or placebo (N = 16).Results
The hazard ratio (HR) for the primary endpoint [progression-free survival (PFS) from the start of maintenance] was 0.56 (95 % CI 0.29–1.08; P = 0.07) and 0.55 (95 % CI 0.3–1.0; P = 0.04) by independent and investigator review, respectively. MGN1703 significantly improved PFS measured from the start of induction therapy versus placebo on independent (HR 0.49; 95 % CI 0.26–0.94; P = 0.03) and investigator review (HR 0.50; 95 % CI 0.31–1.02; P = 0.02). Overall survival (OS) data remain immature (HR 95 %; 95 % CI 0.3–1.5; P = 0.29) with 28/43 patients alive after a medium follow-up of >17 months. Retrospective subgroup analysis showed a significant effect of MGN1703 on PFS versus placebo in patients with greater than median tumour size reduction and normalised carcinoembryonic antigen concentrations following induction therapy, and in patients with elevated activated NKT cells ≥3.08 %. Adverse events were mild to moderate and limited to injection-site reactions or linked to general immune system activation.Conclusions
MGN1703 maintenance treatment was well tolerated and appears to induce durable and prolonged PFS and disease control in a subgroup of patients with mCRC following induction therapy. Activated NKT cells may be a predictive biomarker for selecting patients likely to benefit more from MGN1703. 相似文献11.
Sanne de Haas Paul Delmar Aruna T. Bansal Matthieu Moisse David W. Miles Natasha Leighl Bernard Escudier Eric Van Cutsem Peter Carmeliet Stefan J. Scherer Celine Pallaud Diether Lambrechts 《Angiogenesis》2014,17(4):909-920
Background
Despite extensive translational research, no validated biomarkers predictive of bevacizumab treatment outcome have been identified.Methods
We performed a meta-analysis of individual patient data from six randomized phase III trials in colorectal, pancreatic, lung, renal, breast, and gastric cancer to explore the potential relationships between 195 common genetic variants in the vascular endothelial growth factor (VEGF) pathway and bevacizumab treatment outcome.Results
The analysis included 1,402 patients (716 bevacizumab-treated and 686 placebo-treated). Twenty variants were associated (P < 0.05) with progression-free survival (PFS) in bevacizumab-treated patients. Of these, 4 variants in EPAS1 survived correction for multiple testing (q < 0.05). Genotype-by-treatment interaction tests revealed that, across these 20 variants, 3 variants in VEGF-C (rs12510099), EPAS1 (rs4953344), and IL8RA (rs2234671) were potentially predictive (P < 0.05), but not resistant to multiple testing (q > 0.05). A weak genotype-by-treatment interaction effect was also observed for rs699946 in VEGF-A, whereas Bayesian genewise analysis revealed that genetic variability in VHL was associated with PFS in the bevacizumab arm (q < 0.05). Variants in VEGF-A, EPAS1, and VHL were located in expression quantitative loci derived from lymphoblastoid cell lines, indicating that they affect the expression levels of their respective gene.Conclusions
This large genetic analysis suggests that variants in VEGF-A, EPAS1, IL8RA, VHL, and VEGF-C have potential value in predicting bevacizumab treatment outcome across tumor types. Although these associations did not survive correction for multiple testing in a genotype-by-interaction analysis, they are among the strongest predictive effects reported to date for genetic variants and bevacizumab efficacy. 相似文献12.
Aisling M. Lynch Nupur Pathak Varun Pathak Finbarr P. M. O’Harte Peter R. Flatt Nigel Irwin Victor A. Gault 《Diabetologia》2014,57(9):1927-1936
Aims/hypothesis
Modification of the structure of glucagon could provide useful compounds for the potential treatment of obesity-related diabetes.Methods
This study evaluated N-acetyl-glucagon, (d-Ser2)glucagon and an analogue of (d-Ser2)glucagon with the addition of nine amino acids from the C-terminal of exendin(1-39), namely (d-Ser2)glucagon-exe.Results
All analogues were resistant to dipeptidyl peptidase IV degradation. N-Acetyl-glucagon lacked acute insulinotropic effects in BRIN BD11 cells, whereas (d-Ser2)glucagon and (d-Ser2)glucagon-exe evoked significant (p?0.001) insulin release. (d-Ser2)glucagon-exe stimulated cAMP production (p?0.001) in glucagon- and GLP-1-receptor (GLP-1R)-transfected cells but not in glucose-dependent insulinotropic polypeptide-receptor-transfected cells. In normal mice, N-acetyl-glucagon and (d-Ser2)glucagon retained glucagon-like effects of increasing (p?0.001) plasma glucose and insulin levels. (d-Ser2)glucagon-exe was devoid of hyperglycaemic actions but substantially (p?0.001) increased plasma insulin levels. (d-Ser2)glucagon-exe reduced the glycaemic excursion (p?0.01) and increased the insulin secretory (p?0.01) response following a glucose challenge 12 h after administration. Studies in GLP-1R knockout mice confirmed involvement of the GLP-1R pathway in the biological actions of (d-Ser2)glucagon-exe. Twice-daily administration of (d-Ser2)glucagon-exe to high-fat-fed mice for 28 days significantly (p?0.05 to p?0.001) reduced body weight, energy intake and non-fasting glucose levels, as well as increasing insulin concentrations. Glucose tolerance and insulin sensitivity were significantly (p?0.01) improved and energy expenditure, O2 consumption and locomotor activity were (p?0.05 to p?0.001) augmented. The metabolic benefits were accompanied by increases in pancreatic islet number (p?0.001) and area (p?0.05), as well as beta cell area (p?0.05). Beneficial effects were largely retained for 14 days following cessation of treatment.Conclusions/interpretation
This study emphasises the potential of (d-Ser2)glucagon-exe for the treatment of obesity-related diabetes. 相似文献13.
J. H. Song S. Y. Kim K. S. Chung C. M. Moon S. W. Kim E. Y. Kim J. Y. Jung M. S. Park Y. S. Kim S. K. Kim J. Chang D. J. Shin Y. A. Kang 《Infection》2014,42(4):655-660
Purpose
To investigate immunity-related guanosine triphosphatase family M (IRGM) genetic variants associated with susceptibility to tuberculosis (TB) in a Korean population.Methods
We conducted a prospective case–control study including 193 patients with active TB in Severance Hospital and 230 age- and sex-matched unrelated controls registered in Yonsei Cardiovascular Genome Center. Based on associations with other chronic inflammatory conditions, we analyzed the allele and genotype frequencies of rs72553867, rs10065172, and rs12654043 among patients with TB and healthy controls.Results
The T allele of rs10065172 was significantly associated with protection against developing TB based on allele frequency [P = 0.042; odds ratio (OR) 0.75] and genotype distribution in the codominant model (P = 0.036; OR 0.73).Conclusions
This is the first study to identify a significant association between the IRGM single-nucleotide polymorphism (SNP) rs10065172 and susceptibility to active TB disease in an Asian population. The results suggest that IRGM genetic variants could be associated with susceptibility to active TB disease in the Korean population. 相似文献14.
Maria Luisa Torre Giuseppina T. Russo Marta Ragonese Annalisa Giandalia Ernesto De Menis Giorgio Arnaldi Angela Alibrandi Carmelo Buda Giovanni Romanello Elisabetta L. Romeo Domenico Cucinotta Francesco Trimarchi Salvatore Cannavo 《Pituitary》2014,17(3):257-266
Background
Acromegalic patients have a higher risk of developing colorectal tumours (CRT). The common C677T polymorphism in methylenetetrahydrofolate reductase (MTHFR) gene is a well-documented CRT risk factor in the general population, but its role in acromegaly has never been examined.Purpose
We investigated the influence of MTHFR C677T polymorphism, folate status and other lifestyle, nutritional and disease-specific variables on CRT risk in acromegaly.Methods
Clinical data were collected from 115 acromegalic patients (25 with active disease) who underwent a complete colonoscopy. C677T MTHFR genotype, homocysteine, vitamin B12, insulin growth factor and insulin levels, as well as metabolic variables were evaluated.Results
Colorectal tumours were identified in 51 patients (3 adenocarcinomas). MTHFR C677T distribution was in the Hardy–Weinberg equilibrium and similar in patients with or without CRT. There was a correlation between patients with TT genotype and CRT occurrence (Spearman’s test: P = 0.03), with an Odds Ratio (OR) of 1.32 (95 % CI 0.522–3.362, P NS). A folate–MTHFR genotype interaction on CRT risk was found (P = 0.037): in the lower folate subgroup, TT patients showed a 2.4 higher OR for CRT (95 % CI 0.484–11.891; P NS) than C-allele carriers. Smoking (P = 0.007), increased HbA1c levels (P = 0.021), dyslipidaemia (P = 0.049), acromegaly control (P = 0.057), and folate–MTHFR genotype interaction (P = 0.088) were associated with CRT at multivariate analysis.Conclusions
In this cohort of acromegalic patients, CRT risk is increased in 677TT MTHFR patients with low plasma folate levels. Smoking, high HbA1c levels, dyslipidaemia and disease activity were also associated with increased CRT risk. 相似文献15.
Methotrexate (MTX) is among the best-tolerated disease-modifying antirheumatic drugs for the treatment of rheumatoid arthritis (RA); major drawbacks of MTX therapy are the large interpatient variability in clinical response and the unpredictable appearance of a large spectrum of side effects. Several studies have demonstrated gene polymorphism that may regulate intracellular methotrexate metabolic pathway enzymes linked to drug efficacy and safety, but the evidence available is not yet conclusive. We decided to run a pilot study to determine the incidence of Methylene tetrahydrofolate (MTHFR; C677T, A1298C) and Thymidylate synthase (TS; 5′ UTR repeat, 3′ UTR deletion) gene polymorphism in rheumatoid arthritis patients in our community (Indian Asian) and further explore its association with MTX response (efficacy, toxicity). Thirty-four naïve RA patients on supervised MTX therapy and 139 healthy controls were genotyped for A1298C and C677T polymorphism of the MTHFR gene and 5′ UTR repeat and 3′ UTR deletion polymorphism of the TYMS gene by polymerase chain reaction-restriction fragment length polymorphism. Association, if any, between gene polymorphism and MTX response in RA patients was analyzed. The MTHFR A1298C ‘C’ allele incidence among RA patients (46%) was significantly higher (χ 2?=?4.24, P?0.05, OR?=?1.68). None of the other allele tested showed any association. Although a small sample study, our findings do not suggest a significant association of MTHFR/TS allele/genotype with MTX response in our ethnically distinct Indian (Asian) RA patients. 相似文献
16.
Andreas Peter Marketa Kovarova Silvio Nadalin Tomas Cermak Alfred Königsrainer Fausto Machicao Norbert Stefan Hans-Ulrich Häring Erwin Schleicher 《Diabetologia》2014,57(10):2103-2107
Aims/hypothesis
The common sequence variant I148M of the patatin-like phospholipase domain-containing protein 3 gene (PNPLA3) is associated with increased hepatic triacylglycerol (TAG) content, but not with insulin resistance, in humans. The PNPLA3 I148M variant was previously reported to alter the specificity of the encoded enzyme and subsequently affect lipid composition.Methods
We analysed the fatty acid composition of five lipid fractions from liver tissue samples from 52 individuals, including 19 carriers of the minor PNPLA3 I148M variant.Results
PNPLA3 I148M was associated with a strong increase (1.75-fold) in liver TAGs, but with no change in other lipid fractions. PNPLA3 I148M minor allele carriers had an increased n-3 polyunsaturated fatty acid (PUFA) α-linolenic acid content and reductions in several n-6 PUFAs in the liver TAG fraction. Furthermore, there was a strong inverse correlation between n-6 PUFA and TAG content independent of PNPLA3 genotype. In a multivariate model including liver fat content, PNPLA3 genotype and fatty acid composition, two significant differences could be exclusively attributed to the PNPLA3 I148M minor allele: reduced stearic acid and increased α-linolenic acid content in the hepatic TAG fraction.Conclusions
These changes therefore suggest a mechanism to explain the PNPLA3 I148M-dependent increase in liver fat content without causing insulin resistance. Stearic acid can induce insulin resistance, whereas α-linolenic acid may protect against it. 相似文献17.
Kohei Shitara Keitaro Matsuo Kei Muro Toshihiko Doi Atsushi Ohtsu 《Journal of cancer research and clinical oncology》2013,139(8):1383-1389
Purpose
The impact of post-progression survival (PPS) on the overall survival (OS) of patients with advanced gastric cancer (AGC) has not yet been reported in detail. We analyzed prospectively collected data from AGC patients who received first-line chemotherapy including fluoropyrimidine plus platinum.Methods
We partitioned OS into progression-free survival (PFS) and PPS in each patient and analyzed correlations between OS and either PFS or PPS using the Spearman rank correlation coefficient (ρ).Results
A total of 291 AGC patients met the inclusion criteria with median PFS, PPS, and OS of 5.3, 8.1, and 14.8 months, respectively. PFS and OS for each patient showed a correlation of ρ = 0.75 [95 % confidence interval (CI) 0.69–0.81]. PPS and OS showed a correlation of ρ = 0.87 (95 % CI 0.84–0.91). According to multivariate analysis, performance status at progression, PFS of first-line chemotherapy, and use of second-line chemotherapy were independently associated with PPS.Conclusions
These results indicate that both PFS and PPS are correlated with OS in first-line chemotherapy for AGC, suggesting the importance of reporting detailed patient characteristics and treatment course after disease progression in clinical trials of first-line chemotherapy for AGC. 相似文献18.
Minghua Zheng Jianling Bai Bosi Yuan Feng Lin Jie You Mingqin Lu Yuewen Gong Yongping Chen 《BMC gastroenterology》2008,8(1):1-8
Background
Genetic factors as well as environmental factors are important in the development of NAFLD and in this study we investigated associations between polymorphisms of peroxisome proliferators-activated receptor γ coactivator 1α polymorphism (PPARGC1A) and NAFLD.Aims
We recruited 115 patients with biopsy-proven NAFLD, 65 with NASH and 50 with simple steatosis, and 441 healthy control subjects and investigated 15 SNPs of PPARGC1A.Results
SNP rs2290602 had the lowest p value in the dominant mode (p = 0.00095), and the odds ratio for NAFLD (95% CI) was 2.73 (1.48 – 5.06). rs2290602 was significantly associated with NAFLD even when the most conservative Bonferroni's correction was applied (p = 0.0143). The frequency of the T allele of rs2290602 was significantly higher in the NASH patients than in the control subjects (p = 0.00093, allele frequency mode), and its frequency in the NASH patients tended to be higher than in the simple steatosis patients (p = 0.09). The results of the real-time RT-PCR study showed that intrahepatic mRNA expression of PPARGC1A was lower in the TT group than in the GG or GT group at SNP rs2290602 (p = 0.0454).Conclusion
This is the first study to demonstrate a significant association between genetic variations in PPARGC1A and NAFLD. This finding suggested that PPARGC1A polymorphism and lower expression of PPARGC1A mRNA in the liver are an important genetic contribution to etiology of NAFLD. 相似文献19.
Zhou Y Du WD Chen G Ruan J Xu S Zhou FS Zuo XB Lv ZJ Zhang XJ 《Journal of cancer research and clinical oncology》2012,138(6):939-945
Purpose
To investigate associations between genetic variants involved in microRNA networks (microRNA biogenesis, microRNA and microRNA binding sites) and risk of gastric cancer.Methods
We genotyped 19 SNPs of the microRNA-related genes in a case–control study of 311 gastric cancers and 425 cancer-free controls in a Chinese Han population.Results
We found that two of the SNPs were significantly associated with gastric cancer. Inhibitory effect of minor allele T of rs2071504 SNP within the exon of POLR2A gene was significantly associated with gastric carcinogenesis (p?=?0.033, aOR?=?0.742, 95%CI?=?0.564–0.977) and the SNP rs895819 in the miR-27a gene with the minor allele C presented significantly reduced risk to gastric cancer (p?=?0.037, aOR?=?0.771, 95%CI?=?0.604–0.985). Further stratified analysis with regard to clinical pathological parameters of the patients indicated that the SNP rs2071504 was associated with lymph node metastasis (p?=?0.021, aOR?=?0.529, 95%CI?=?0.307–0.910) and TMN stage (p?=?0.021, aOR?=?0.532, 95%CI?=?0.311–0.908), respectively.Conclusions
Our findings provided evidence that the SNP rs2071504 in the exon of POLR2A gene would not only confer a decreased risk of gastric cancer, but also influence lymph node metastasis and TMN stage of gastric cancer in the Chinese population. 相似文献20.