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1000 SNPs with greatest statistical association with cumulative docetaxel dose at grade 3+ neuropathy in CALGB 90401 discovery GWAS.

Peripheral neuronal cells (Peri.4U) treated with docetaxel were found to have a significant decrease in sensitivity for A) mean process lengths but not for B) mean outgrowth intensity or C) relative straightness as measured after 24 hours post-drug treatment. For paclitaxel treatment at the same time point, the cells were also found to have significantly decreased sensitivity for D) relative mean process length and E) mean outgrowth intensity but not for F) relative straightness. Neurite parameters measured with MetaXPress® software were averaged from 3 independent experiments. Error bars represent the standard error of the mean from three independent transfection experiments. NTC = non-targeting control, UT= untransfected control.

Number of patients who experienced neuropathy, completed treatment without neuropathy and discontinued treatment early without having neuropathy while on study and within each range of cumulative treatment.

Sensitivity to mechanical stimuli with Von Frey filaments for C57BL/6J mice and litter-mates heterozygous for VAC14 prior to docetaxel treatment. The figure displays the estimate of the proportion of mice without a hind-paw withdrawal response to stimulation by each Von Frey fiber weight, e.g., no mice respond to fibers {less than or equal to}0.2 g and all mice respond to fibers{greater than or equal to}1.4 g. The VAC14 heterozygous mice (hatched line) are more likely than wild-type mice (solid line) to respond, meaning they are more sensitive to nociceptive stimuli (p=0.0012). Gray lines denote 95% confidence intervals.

CONSORT diagram illustrating patient flow from enrollment on parent study to population included in pharmacogenetic discovery analysis and quality control filtering of SNPs from the Illumina HumanHap610-Quad into the pharmacogenetic analysis.

Most Highly Enriched Canonical Pathways

Purpose: Discovery of SNPs that predict a patient's risk of docetaxel-induced neuropathy would enable treatment individualization to maximize efficacy and avoid unnecessary toxicity. The objectives of this analysis were to discover SNPs associated with docetaxel-induced neuropathy and mechanistically validate these associations in preclinical models of drug-induced neuropathy.Experimental Design: A genome-wide association study was conducted in metastatic castrate-resistant prostate cancer patients treated with docetaxel, prednisone and randomized to bevacizumab or placebo on CALGB 90401. SNPs were genotyped on the Illumina HumanHap610-Quad platform followed by rigorous quality control. The inference was conducted on the cumulative dose at occurrence of grade 3+ sensory neuropathy using a cause-specific hazard model that accounted for early treatment discontinuation. Genes with SNPs significantly associated with neuropathy were knocked down in cellular and mouse models of drug-induced neuropathy.Results: A total of 498,081 SNPs were analyzed in 623 Caucasian patients, 50 (8%) of whom experienced grade 3+ neuropathy. The 1,000 SNPs most associated with neuropathy clustered in relevant pathways including neuropathic pain and axonal guidance. An SNP in VAC14 (rs875858) surpassed genome-wide significance (P = 2.12 × 10−8, adjusted P = 5.88 × 10−7). siRNA knockdown of VAC14 in stem cell–derived peripheral neuronal cells increased docetaxel sensitivity as measured by decreased neurite processes (P = 0.0015) and branches (P < 0.0001). Prior to docetaxel treatment, VAC14 heterozygous mice had greater nociceptive sensitivity than wild-type litter mate controls (P = 0.001).Conclusions: VAC14 should be prioritized for further validation of its potential role as a predictor of docetaxel-induced neuropathy and biomarker for treatment individualization. Clin Cancer Res; 22(19); 4890–900. ©2016 AACR.

STRUCTURED ABSTRACTBackgroundPreeclampsia is a severe pregnancy complication that affects about 2-8% of pregnant women globally and is one of the leading causes of maternal and fetal mortality and morbidity. Telomere length change has been associated with aging, environmental stress, and various diseases. Studying the telomere length change in preeclampsia complicated placentas may shed light on the pathophysiology of preeclampsia.ObjectivesIn this study, we aimed to explore if associations exist between placental telomere length and preeclampsia, gestational age, and other demographic, clinical and physiological factors related to pregnancy.Study DesignWe collected placentas samples from 120 severe preeclamptic deliveries and 129 healthy full-term deliveries in Hawaii between year 2006 and 2013 and measured the average absolute placental telomeres with quantitative polymerase chain reaction (qPCR). We retrieved their pre-recorded demographic, clinical and physiological data and conducted multiple linear regressions to associate placental telomeres with preeclampsia and other variables.ResultsPlacental telomere length of severe preeclampsia cases showed no significant difference (P=0.20) from healthy controls after controlling for gestational age difference. Instead, we identified that placental telomere length consistently decreases as gestation progresses (P=6.10e-05). Male babies have shorter placental telomere than female babies in the early trimester (p = 0.024), but the placentas of male babies have a reduced rate of telomere shortening along pregnancies, compared to those of female babies (p = 0.029). Latino mothers show longer placenta telomeres than other ethnicities (P=0.012), whereas mothers of blood type O have shorter placenta telomeres than those of other blood types (P=0.039).ConclusionsUsing the largest multiethnic cohort to date, we showed the lack of association between preeclampsia and placental telomere length. Rather, gestational age is the most dominant variable associated with placental telomere shortening.CondensationPlacental telomere length shows no significant association with preeclampsia but significantly shortens with the progressing gestational age at different rates for male and female babies.AJOG At A GlanceA.Why was this study conducted?Understanding the TL change in healthy and preeclampsia complicated placenta may help us better understand the physio-pathological impact of preeclampsia.B.What are the key findings?We found no significant association between severe preeclampsia and placental TL in the largest multi-ethnic cohort to date.Placental TL shortens consistently largely due to gestational age increase.Placentas of male babies have shorter TLs at the early third trimester but slower TL shortening compared to those of female babies.Latino mothers have longer placental TL compared to non-Latino mothers.Mothers of blood type O have shorter placenta TL than others.C.What does this study add to what is already known?We showed that placental telomere length shortening is not associated with preeclampsia but the gestational age in a large multi-ethnical cohort.

Preeclampsia is a pregnancy specific syndrome characterized by hypertension and proteinuria after 20 weeks of gestation. To reveal the relationship between lipids and preeclampsia, we conduct lipidomic profiling of maternal serums of 44 severe preeclamptic and 20 healthy pregnancies from a multi-ethnic cohort in Hawaii. Correlation network analysis shows that oxidized phospholipids (OxPLs) have increased inter-correlations and connections in preeclampsia, while other lipids, including triacylglycerols (TAGs), have reduced network correlations and connections. Thirty-one lipid species from various lipid classes demonstrate predominantly reductions and causal relationships with preeclampsia. They include phosphatidylglycerol (PG), TAG, diacylglycerol (DAG), phosphatidylcholine (PC), cholesterol esters (CE), phosphatidylethanolamine (PE), sphingomyelin (SM), ceramides (Cer-NS), hexosyl ceramides (HexCer-NS), lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), and free fatty acid (FFA). Many of these lipids are also selected as important features by a linear discriminant analysis (LDA) classifier with high predictive accuracy (F-1 statistic 0.941 and balanced accuracy 0.88), indicating their potential to serve as biomarkers for severe preeclampsia. Our study supports the hypothesis of a phospholipid (PL) centered, dysregulated lipidomic metabolic atlas. That is, severe preeclampsia may be originated from hypoxia, which induces the accumulation of OxPLs through oxidative stress whereas reduces many other lipids (eg. reduced PCs, TAGs and ceramides). These molecular changes coherently lead to dysregulated biological functions, such as insulin signaling and inflammation/infections. Moreover, the lipid changes may also be responsible for the comorbidity between preeclampsia and gestational diabetes, a clinically known risk factor for preeclampsia.

Preeclampsia is a medical condition affecting 5–10% of pregnancies. It has serious effects on the health of the pregnant mother and developing fetus. While possible causes of preeclampsia are speculated, there is no consensus on its etiology. The advancement of big data and high-throughput technologies enables to study preeclampsia at the new and systematic level. In this review, we first highlight the recent progress made in the field of preeclampsia research using various omics technology platforms, including epigenetics, genome-wide association studies (GWAS), transcriptomics, proteomics and metabolomics. Next, we integrate the results in individual omic level and studies, and show that despite the lack of coherent biomarkers in all omics studies, inhibin is a potential preeclamptic biomarker supported by GWAS, transcriptomics and DNA methylation evidence. Using the network analysis on the biomarkers of all literatures reviewed here, we identify four striking sub-networks with clear biological functions supported by previous molecular-biology and clinical observations. In summary, omics integration approach offers the promise to understand molecular mechanisms in preeclampsia.