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1. 发明申请

WO2004027088A2 METHOD FOR DETERMINING PREDISPOSITION TO A PHYSIOLOGICAL REACTION IN A PATIENT. 审中-公开
标题翻译：用于确定患者生理反应的预测方法。
公开(公告)号：WO2004027088A2
公开(公告)日：2004-04-01
申请号：PCT/CA2003/001269
申请日：2003-08-20
申请人： UNIVERSITÉ LAVAL , GUILLEMETTE, Chantal
发明人： GUILLEMETTE, Chantal
IPC分类号： C12Q1/68
CPC分类号： C12Q1/6886 , C12Q1/6883 , C12Q2600/106 , C12Q2600/156 , C12Q2600/172
摘要： The present invention relates to a method for determining predisposition to a physiological reaction in a patient. Particularly, the present invention relates to a method for determining a predisposition to toxicity induced by a camptothecin analog or to an immunosuppressive mycophenolic acid-based therapy. This method comprises the characterization of nucleic acid sequences from the patient. The nucleic acid sequence encodes for an amino acid sequence or regulates the expression of UGT1A1, UGT1A7, UGT1A9 or their polymorphic variants. The method also comprises the analysis of haplotypic variation within these genes.
摘要翻译：本发明涉及一种确定患者生理反应倾向的方法。特别地，本发明涉及一种确定由喜树碱类似物或基于免疫抑制霉酚酸治疗引起的毒性倾向的方法。该方法包括来自患者的核酸序列的表征。核酸序列编码氨基酸序列或调节UGT1A1，UGT1A7，UGT1A9或其多态性变体的表达。该方法还包括对这些基因内的单倍型变异的分析。

2. 发明申请

WO2012071665A1 PROGNOSTIC MARKERS OF INHERITED VARIATIONS IN THE UGT2B GENES FOR PROSTATE CANCER RECURRENCE 审中-公开
标题翻译： UGT2B基因中前列腺癌复发的入选标记
公开(公告)号：WO2012071665A1
公开(公告)日：2012-06-07
申请号：PCT/CA2011/001338
申请日：2011-12-02
申请人： UNIVERSITE LAVAL , LEVESQUE, Eric , GUILLEMETTE, Chantal , FRADET, Yves , LACOMBE, Louis
发明人： LEVESQUE, Eric , GUILLEMETTE, Chantal , FRADET, Yves , LACOMBE, Louis
IPC分类号： C12Q1/68 , C07H21/00 , C40B30/04
CPC分类号： C12Q1/6886 , C12Q2600/156
摘要： The present application discloses that reduced copy number variations (CNVs) in UGT2B17 and UGT2B28 were significantly associated with bRFS while no significant association was observed for additional UGT variants tested. The co-occurrence of two or more deletions of UGT2B17 and UGT2B28 genes resulted in an HR of 1.377 (95% CI [1.105; 1.716]; p=0.004) for Caucasians and 2.151 (95% CI [1.239; 3.372]; p=0.006) for Asians. In all studied men, risk of BCR was 1.510; 95% CI [1.178 - 1.950]; p=0.001 ). The addition of the UGT2B CNV status in the D'Amico risk classification further enhanced the risk prediction mainly for the low and intermediate risk categories (Log-rank test, p=0.022 and 0.011, respectively). In addition, after adjusting for all clinicopathologic risk factors, we found a strong association between the risk of BCR and 7 SNPs in SRD5A genes. The combination of 2 SNPs respectively in SRD5A1 and SRD5A2 were highly favourable, reducing drastically the risk of BCR for carriers of 3-4 alleles (HR=0.34; 95% CN0.18- 0.64; P=9x10"4). Other variations in the SRD5A2 gene were associated with an increased rate of BCR, namely the coding SNPs rs523349 with a HR of 2.12 (95% CI, 1.21 -3.75; P=0.009) and reaching 4.97 when combined with deleted copies of UGT2B genes (95% CI, 2.38-10.36; P=0.00002). Further, BCR-free survival rate was significantly reduced to 27% in patients with unfavourable genotypes compared to 75% for patients with favourable genotypes (P=7x10 -6 ). This study is the first to recognize CNV in genes at the end of the androgenic signal as significant and independent predictors of PCa recurrence after prostatectomy. In addition, inherited polymorphisms in the SRD5A and UGT2B genes are independent predictors of biochemical recurrence after radical prostatectomy.
摘要翻译：本申请公开了UGT2B17和UGT2B28中的减少的拷贝数变异（CNV）与bRFS显着相关，而对于另外的测试的UGT变体，没有观察到显着的关联。 UGT2B17和UGT2B28基因的两个或多个缺失的共同发生导致白种人的HR为1.377（95％CI [1.105; 1.716]; p = 0.004），而2.151（95％CI [1.239; 3.372]; p = 0.006）亚洲人。在所有研究的男性中，BCR的风险为1.510; 95％CI [1.178 - 1.950]; p = 0.001）。在D'Amico风险分类中增加UGT2B CNV状态进一步增强了风险预测，主要针对中低风险类别（Log-rank检验，分别为p = 0.022和0.011）。此外，在调整所有临床病理危险因素后，我们发现BCR和SRD5A基因中7个SNP的风险之间存在很强的相关性。 SRD5A1和SRD5A2中2个SNP的组合非常有利，大大降低了3-4个等位基因携带者的BCR风险（HR = 0.34; 95％CN0.18-0.64; P = 9×10-4），其他变异 SRD5A2基因与BCR的增加率相关，即编码SNPs rs523349，HR为2.12（95％CI，1.21〜3.75; P = 0.009），与UGT2B基因缺失拷贝（95％CI）组合时达到4.97 ，2.38-10.36; P = 0.00002），而不良基因型患者BCR无生存率显着降低至27％，而有良好基因型患者为75％（P = 7×10-6），本研究首次在雄激素信号结束时将基因中的CNV识别为前列腺切除术后PCa复发的重要和独立预测因子，此外，SRD5A和UGT2B基因的遗传多态性是根治性前列腺切除术后生化复发的独立预测因子。

3. 发明申请

WO2013049926A1 PROGNOSTIC MARKERS OF INHERITED VARIATIONS IN THE 17β-HYDROXYSTEROID DEHYDROGENASE (HSD17B) GENES FOR PROSTATE CANCER 审中-公开
标题翻译： 17β-羟基脱氢酶脱氢酶（HSD17B）前列腺癌基因的预测标记
公开(公告)号：WO2013049926A1
公开(公告)日：2013-04-11
申请号：PCT/CA2012/000928
申请日：2012-10-05
申请人： UNIVERSITÉ LAVAL
发明人： LÉVESQUE, Éric , GUILLEMETTE, Chantal , FRADET, Yves , LACOMBE, Louis
IPC分类号： C12Q1/68 , C40B30/04
CPC分类号： C12Q1/6886 , C12Q2600/118 , C12Q2600/156
摘要： The relationship between polymorphisms in the 17β -hydroxysteroid dehydrogenase (HSD17B ) family of enzymes, involved in active steroid hormones biotransformation, and the risk of prostate cancer (PCa) progression remains unexplored. Objective. To determine if inherited variations in HSD17B genes are associated with PCa progression. Design. We studied two independent Caucasian cohorts composed of 526 men with organ-confined PCa and 213 with advanced disease who had a median follow-up of 7.4 and 7.8 years after surgery, respectively. Measurements. Patients with localized PCa were genotyped for 88 htSNPs in HSD17B1, HSD17B2, HSD17B3, HSD17B4, HSD17B5 and HSD17B12 genes and their prognostic significance on disease progression was assessed using Kaplan-Meier survival curves and Cox regression models. Positive findings were then investigated in advanced disease. Results. After adjusting for known risk factors, 12 SNPs distributed across the HSD17B2, HSD17B3 and HSD17B12 genes were significantly associated with risk of biochemical relapse (BCR) in localized PCa. In addition, four variants of the HSD17B2 (rs1364287, rs2955162, rs1119933, rs9934209) were significantly associated with progression in advanced disease. HSD17B2 polymorphisms, which occurred in 26% and 15% of patients with localized and advanced PCa respectively, were thus associated with high risk of BCR (HR: 2.63, 95%CI: 1.81-3.80, P =0.0000003), progression free survival (HR: 2.81, 95%CI: 1.43-5.52, P=0.008) and overall survival (HR: 3.07, 95%CI: 1.29-7.30, P =0.011). Conclusion. This study suggests a predominant role for common genetic variants in the HSD17B2 pathway and PCa progression.
摘要翻译：参与活性类固醇激素生物转化的17β-羟基类固醇脱氢酶（HSD17B）家族的多态性与前列腺癌（PCa）发展的风险之间的关系尚未被探索。目的。确定HSD17B基因的遗传变异是否与PCa进展相关。设计。我们研究了两名独立的白种人队列，其中包括526名患有器官限制性PCa的男性和213名患有晚期疾病的男性，分别在手术后中位随访7.4和7.8年。测量。在HSD17B1，HSD17B2，HSD17B3，HSD17B4，HSD17B5和HSD17B12基因中，对局部PCa患者进行88 htSNPs的基因分型，并使用Kaplan-Meier生存曲线和Cox回归模型评估其对疾病进展的预后意义。然后在晚期疾病中调查阳性结果。结果。调整已知风险因子后，分布在HSD17B2，HSD17B3和HSD17B12基因上的12个SNP与局部PCa中生化复发（BCR）的风险显着相关。此外，HSD17B2（rs1364287，rs2955162，rs1119933，rs9934209）的四种变体与晚期疾病的进展显着相关。发生在26％和15％的局部和晚期PCa患者的HSD17B2多态性因此与BCR的高风险相关（HR：2.63,95％CI：1.81-3.80，P = 0.0000003），无进展生存期 HR：2.81,95％CI：1.43-5.52，P = 0.008）和总生存期（HR：3.07,95％CI：1.29-7.30，P = 0.011）。结论。这项研究表明HSD17B2途径和PCa进展中常见遗传变异体的主要作用。

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