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Purpose Vascular endothelial growth factor receptor (VEGFR) kinases are important drug targets in oncology that affect function of systemic endothelial cells. To discover genetic markers that affect VEGFR inhibitor pharmacodynamics we performed a genome-wide association study of serum soluble vascular endothelial growth factor receptor-2 concentrations [sVEGFR2], a pharmacodynamic biomarker for VEGFR2 inhibitors. Experimental Design We conducted a genome-wide association study (GWAS) of [sVEGFR2] in 736 healthy Old Order Amish volunteers. Gene variants identified from the GWAS were genotyped serially in a cohort of 128 advanced solid tumor patients with baseline [sVEGR2] measurements, and in 121 renal carcinoma patients with [sVEGFR2] measured before and during pazopanib therapy. Results rs34231037 (C482R) in KDR, the gene encoding sVEGFR2 was found to be highly associated with [sVEGFR2], explaining 23% of the variance (p=2.7×10−37). Association of rs34231037 with [sVEGFR2] was replicated in 128 patients with cancer with comparable effect size (p = 0.025). Furthermore rs34231037 was a significant predictor of changes in [sVEGFR2] in response to pazopanib (p = 0.01). Conclusion Our findings suggest that genome-wide analysis of phenotypes in healthy populations can expedite identification of candidate pharmacogenetic markers. Genotyping for germ-line variants in KDR may have clinical utility in identifying cancer patients with unusual sensitivity to effects of VEGFR2 kinase inhibitors.

neutrophil). Higher baseline levels have been associated with improved survival in various types of cancers including lung cancer. The PROCLAIM trial is published randomized study comparing two different chemotherapy regimens, cisplatin-etoposide (ETO) vs. cisplatin-pemetrexed (PEM) in combination with radiation for the treatment of stage III non-squamous NSCLC. Using secondary data from the PROCLAIM clinical trial, we aimed to determine if SII measured at the middle of treatment (3 weeks) is a predictor of overall survival (OS) among patients with Stage-III NSCLC. Materials/Methods: Data from PROCLAIM trial was collected after approval of data sharing agreement. The Neutrophil, lymphocyte and platelet count were collected at mid treatment. SII was calculated for each patient. The OS was computed from the date of diagnosis until the last follow up. Patients were censored if alive on last FU. Hazard-ratios (HR) for survival were computed using a matched-set proportional-hazards model to account for the underlying correlated structure of the data. Results: A total of n Z 545 patients in our analysis dataset received CRT. The median follow-up was 24 months (IQR Z 22 months). Controlling for age, sex, BMI, stage (IIIA vs. IIIB), and chemotherapy regimen treatment (ETO vs. PEM), higher values of SII during the third week of RT significantly predicted shorter OS times (HR: Q4 vs. Q1 Z 1.4, 95% CI Z 1.2-1.6; P-for-Trend: Q1-Q4 <0.0001). Patients falling in the highest quartile had only a 50% probability of surviving beyond 2 years vs. 62% for those in the lowest category. In comparison with SII, lymphocyte nadir alone was less predictive of OS (HR: Q4 vs. Q1 Z 1.2, p Z .0015) and the trend across quartiles was not strictly linear. Conclusion: This result from a prospective randomized trial suggests that SII is an informative mid-treatment marker of OS and may be a valuable tool for gauging the effectiveness of CRT than lymphocyte nadir alone. Future studies are needed to confirm our result.

Visual recognition is a computational challenge that is thought to occur via efficient coding. An important concept is sparseness, a measure of coding efficiency. The prevailing view is that sparseness supports efficiency by minimizing redundancy and correlations in spiking populations. Yet, we recently reported that “choristers”, neurons that behave more similarly (have correlated stimulus preferences and spontaneous coincident spiking), carry more generalizable object information than uncorrelated neurons (“soloists”) in macaque inferior temporal (IT) cortex. The rarity of choristers (as low as 6% of IT neurons) indicates that they were likely missed in previous studies. Here, we report that correlation strength is distinct from sparseness (choristers are not simply broadly tuned neurons), that choristers are located in non-granular output layers, and that correlated activity predicts human visual search efficiency. These counterintuitive results suggest that a redundant correlational structure supports efficient processing and behavior.