Citations

255 Background: In a prior study, we found that 8 single nucleotide polymorphisms (SNPs) from 4 candidate hormone-related genes (JAK2, TRMT11, NKX3-1 and HSD17B12) were associated with overall survival (OS) in CRPC stage in a North American cohort of 519 subjects. We attempt to replicate these findings in an independent cohort of Portuguese patients. Methods: A hundred and forty CRPC stage patients in the new cohort were genotyped fort he candidate SNPs. The primary endpoint was overall survival (OS), defined as time from development of CRPC to death. For SNP level results we estimated hazard ratios (HR) and 95% confidence intervals (CI) under the dominant allele model using Cox regression and adjusted for age and Gleason score (GS). Results: The median age of the Portuguese cohort was 69 years (range 53-84). The GS distribution was 48% subjects with GS≥8; 35% with GS=7 and 17% with GS<7. Median time from castration resistance to death for the cohort was 2.2 years (IQ range: 0.8-3.4, 93 deaths). One of the 3 SNPs (rs2295005; C>G; MAF = 0.16) in the TRMT11gene was associated with OS after adjustment for age and GS: (dominant model p=0.05, HR=0.56; 95 CI=0.31-1.00). No other SNP was observed to have statistical significance with OS (Table 1). Conclusions: Variation in the TRMT11 gene is significantly associated with overall survival in patients with CRPC and warrants further validation as a potential prognostic biomarker. [Table: see text]

209 Background: Predictive markers of response to AA are not known. In a prior study, we found that 8 single nucleotide polymorphisms (SNPs) from 4 candidate hormone-related genes (JAK2, TRMT11, NKX3-1 and HSD17B12) were associated with response to AA in HSPC in a North American cohort of 519 subjects. We attempt to replicate these findings in a cohort of Portuguese patients. Methods: The Portuguese cohort consisted of 308 HSPC patients, and the primary endpoint was time to AA failure, defined as time from initiating continuous AA to two serial PSA increases over the nadir, initiation of chemotherapy for progressive disease, or clinical or imaging based progression, whichever came first. For each SNP, we calculated hazard ratios (HRs) and 95% confidence intervals (CI) for time to AA failure using a recessive model with adjustment for Gleason score (GS). Results: The median age of the Portuguese cohort was 69 years (range 43, 85). The GS distribution was 35% subjects with GS≥8; 35% with GS=7 and 30% with GS<7. Median time to AA failure for the cohort was 1.8 years (IQ range: 0.3, 3.6). Association of each SNP with time to AA failure is shown in the Table. None of the SNPs replicated. However, there was a suggestive inverse association for rs10503733 (NKX3.1) with time to AA failure (P=0.07). Conclusions: While we were not able to replicate our initial findings, there was an unexpected association with rs10503733 (NKX3.1 gene) that may warrant additional clinical validation. [Table: see text]

313 Background: We evaluated variation in candidate genes implicated in either initiation or progression of prostate cancer with survival in CRPC stage. Methods: Germline DNA was extracted from peripheral blood mononuclear cells of CRPC patients enrolled in a clinically annotated registry. Fourteen candidate genes were tagged using single nucleotide polymorphisms (SNPs) from HapMap with minor allele frequency of > 5%. The primary endpoint was overall survival (OS), defined as time from development of CRPC to death. Principal component analysis was used for gene levels tests of significance. For SNP level results the per allele hazard ratios (HR) and 95% confidence intervals (CI) under the additive allele model using Cox regression adjusted for age at CRCP and Gleason score (GS) were used. Results: Two hundred and forty five CRPC patients who met the criteria of having adequate DNA were genotyped (14 genes, 84 SNPs). The median age of the cohort was 69 years (range 43-93). The GS distribution was 55% with GS≥8, 32% with GS = 7 and 13% with GS < 7 or unknown. Median time from castration resistance to death for the cohort was 2.67 years (IQ range: 1.6-4.07, 144 deaths). At the gene level JAK2 was detected to be associated with OS. Six of 18 JAK2 SNPs were associated with OS after adjustment for age and GS as well as pruning of SNPs in high linkage disequilibrium with each other (see table). In our multivariate model including age, GS, rs2149556, and rs4372063, the adjusted HRs for rs2149556 and rs4372063 were 0.67 (95% CI 0.38-1.18) and 2.17 (95% CI 1.25-3.76), respectively. The protective effect of rs2149556 appears after adjusting for the presence of minor alleles for rs4372063 in this dataset. Conclusions: Germline variation in the JAK2gene is associated with survival in CRPC stage and warrants further validation as a potential prognostic biomarker. [Table: see text]

Abstract Human blood eosinophils exposed ex vivo to hematopoietic cytokines (e.g., IL-5 or GM-CSF) subsequently display enhanced responsiveness to numerous chemoattractants, such as chemokines, platelet-activating factor, or FMLP, through a process known as priming. Airway eosinophils, obtained by bronchoalveolar lavage after segmental Ag challenge, also exhibit enhanced responsiveness to selected chemoattractants, suggesting that they are primed during cell trafficking from the blood to the airway. Earlier work has shown that chemoattractants stimulate greater activation of ERK1 and ERK2 following IL-5 priming in vitro, thus revealing that ERK1/ERK2 activity can be a molecular readout of priming under these circumstances. Because few studies have examined the intracellular mechanisms regulating priming as it relates to human airway eosinophils, we evaluated the responsiveness of blood and airway eosinophils to chemoattractants (FMLP, platelet-activating factor, CCL11, CCL5, CXCL8) with respect to degranulation, adherence to fibronectin, or Ras–ERK signaling cascade activation. When compared with blood eosinophils, airway eosinophils exhibited greater FMLP-stimulated eosinophil-derived neurotoxin release as well as augmented FMLP- and CCL11-stimulated adherence to fibronectin. In airway eosinophils, FMLP, CCL11, and CCL5 stimulated greater activation of Ras or ERK1/ERK2 when compared with baseline. Ras activation by FMLP in blood eosinophils was also enhanced following IL-5 priming. These studies are consistent with a model of in vivo priming of eosinophils by IL-5 or related cytokines following allergen challenge, and further demonstrate the key role of priming in the chemoattractant-stimulated responses of eosinophils. These data also demonstrate the importance of the Ras–ERK signaling pathway in the regulation of eosinophil responses to chemoattractants in the airway. Human airway eosinophils respond to several chemoattractants with increased activation of the Ras–ERK cascade, eosinophil-derived neurotoxin release, and adherence to fibronectin relative to blood eosinophils.

A unified model for text categorization and text retrieval is introduced. We use a training set of manually categorized documents to learn word-category associations, and use these associations to predict the categories of arbitrary documents. Similarly, we use a training set of queries and their related documents to obtain empirical associations between query words and indexing terms of documents, and use these associations to predict the related documents of arbitrary queries. A Linear Least Squares Fit (LLSF) technique is employed to estimate the likelihood of these associations. Document collections from the MEDLINE database and Mayo patient records are used for studies on the effectiveness of our approach, and on how much the effectiveness depends on the choices of training data, indexing language, word-weighting scheme, and morphological canonicalization. Alternative methods are also tested on these data collections for comparison. It is evident that the LLSF approach uses the relevance information effectively within human decisions of categorization and retrieval, and achieves a semantic mapping of free texts to their representations in an indexing language. Such a semantic mapping lead to a significant improvement in categorization and retrieval, compared to alternative approaches.