Assimilation and contrast effects in part-whole question sequences: a conversational logic analysis

Der Arbeitsbericht stellt ein theoretisches Modell zur Erklärung von Antwortverhalten auf spezielle und generalisierende Fragen vor und beschreibt gleichzeitig ein Experiment zur Überprüfung. Das Verhältnis von Angleichung und Kontrastierung von Antwortverhalten wird unter dem Gesichtspunkt differenziert, ob die Fragen im gleichen oder in unterschiedlichen Gesprächskontexten bzw. -sequenzen gestellt werden. Wenn spezifische Fragen der generalisierenden vorausgehen und beide nicht in die gleiche Gesprächssequenz gehören, findet in der Regel eine Angleichung des Antwortverhaltens statt. Werden beide Fragen als zusammengehörig wahrgenommen, tritt eher ein Kontrastierungseffekt auf, weil die Gesprächsnorm Nicht-Redundanz den wiederholenden Gebrauch der Informationen verbietet. Werden allerdings mehrere spezielle Fragen, die der generalisierenden vorausgehen, als Aufforderung zu einem zusammenfassenden Urteil aufgefaßt, kann auch hier ein Angleichungseffekt auftreten, obwohl eigentlich ein Abgrenzungseffekt zu erwarten wäre. (GF)'A theoretical model of the emergence of assimilation and contrast effects in part-whole question sequences is presented, and an experiment that tests its predictions is reported. Assimilation effects are predicted when one specific question precedes the general question and the two are not assigned to the same conversational context. If both questions are perceived as belonging together, however, conversational norms of non-redundancy prohibit the repeated use of information that has already been provided in response to the specific question when making the general judgment. Contrast effects may emerge in that case under specified conditions. If several specific questions precede the general question, however, the general one is always interpreted as a request for a summary judgment, resulting in assimilation effects even under conditions that foster contrast effects if only one specific question is asked. The model is supported by the reported experiment and is consistent with other findings reported in the literature.' (author's abstract

a randomized, open, multicenter phase III trial of lenalidomide/dexamethasone versus lenalidomide/dexamethasone plus subsequent autologous stem cell transplantation and lenalidomide maintenance in patients with relapsed multiple myeloma

Background Despite novel therapeutic agents, most multiple myeloma (MM) patients eventually relapse. Two large phase III trials have shown significantly improved response rates (RR) of lenalidomide/dexamethasone compared with placebo/dexamethasone in relapsed MM (RMM) patients. These results have led to the approval of lenalidomide for RMM patients and lenalidomide/dexamethasone has since become a widely accepted second-line treatment. Furthermore, in RMM patients consolidation with high-dose chemotherapy plus autologous stem cell transplantation has been shown to significantly increase progression free survival (PFS) as compared to cyclophosphamide in a phase III trial. The randomized prospective ReLApsE trial is designed to evaluate PFS after lenalidomide/dexamethasone induction, high-dose chemotherapy consolidation plus autologous stem cell transplantation and lenalidomide maintenance compared with the well-established lenalidomide/dexamethasone regimen in RMM patients. Methods/Design ReLApsE is a randomized, open, multicenter phase III trial in a planned study population of 282 RMM patients. All patients receive three lenalidomide/dexamethasone cycles and - in absence of available stem cells from earlier harvesting - undergo peripheral blood stem cell mobilization and harvesting. Subsequently, patients in arm A continue on consecutive lenalidomide/dexamethasone cycles, patients in arm B undergo high dose chemotherapy plus autologous stem cell transplantation followed by lenalidomide maintenance until discontinuation criteria are met. Therapeutic response is evaluated after the 3rd (arm A + B) and the 5th lenalidomide/dexamethasone cycle (arm A) or 2 months after autologous stem cell transplantation (arm B) and every 3 months thereafter (arm A + B). After finishing the study treatment, patients are followed up for survival and subsequent myeloma therapies. The expected trial duration is 6.25 years from first patient in to last patient out. The primary endpoint is PFS, secondary endpoints include overall survival (OS), RR, time to best response and the influence of early versus late salvage high dose chemotherapy plus autologous stem cell transplantation on OS. Discussion This phase III trial is designed to evaluate whether high dose chemotherapy plus autologous stem cell transplantation and lenalidomide maintenance after lenalidomide/dexamethasone induction improves PFS compared with the well-established continued lenalidomide/dexamethasone regimen in RMM patients. Trial registration: ISRCTN16345835 (date of registration 2010-08-24)

Cytochrome P450 2B6 (CYP2B6) and constitutive androstane receptor (CAR) polymorphisms are associated with early discontinuation of efavirenz-containing regimens

Objectives Cytochrome P450 2B6 (CYP2B6) is responsible for the metabolic clearance of efavirenz and single nucleotide polymorphisms (SNPs) in the CYP2B6 gene are associated with efavirenz pharmacokinetics. Since the constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) correlate with CYP2B6 in liver, and a CAR polymorphism (rs2307424) and smoking correlate with efavirenz plasma concentrations, we investigated their association with early (<3 months) discontinuation of efavirenz therapy. Methods Three hundred and seventy-three patients initiating therapy with an efavirenz-based regimen were included (278 white patients and 95 black patients; 293 male). DNA was extracted from whole blood and genotyping for CYP2B6 (516G → T, rs3745274), CAR (540C → T, rs2307424) and PXR (44477T → C, rs1523130; 63396C → T, rs2472677; and 69789A → G, rs763645) was conducted. Binary logistic regression using the backwards method was employed to assess the influence of SNPs and demographics on early discontinuation. Results Of the 373 patients, 131 withdrew from therapy within the first 3 months. Black ethnicity [odds ratio (OR) = 0.27; P = 0.0001], CYP2B6 516TT (OR = 2.81; P = 0.006), CAR rs2307424 CC (OR = 1.92; P = 0.007) and smoking status (OR = 0.45; P = 0.002) were associated with discontinuation within 3 months. Conclusions These data indicate that genetic variability in CYP2B6 and CAR contributes to early treatment discontinuation for efavirenz-based antiretroviral regimens. Further studies are now required to define the clinical utility of these association

Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170.

We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.352

Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers

The risk of germline copy number variants (CNVs) in BRCA1 and BRCA2 pathogenic variant carriers in breast cancer is assessed, with CNVs overlapping SULT1A1 decreasing breast cancer risk in BRCA1 carriers.The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.Peer reviewe

Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10−8) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction