Citations

Abstract A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1α (IL1A) is both regulated by and able to activate NF-κB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-κB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76–0.93; P = 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75–0.95; P = 0.006). Considering a multiple-testing–corrected significance threshold of P < 2.5 × 10−5, only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79–0.91; P = 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted. Cancer Res; 74(3); 852–61. ©2013 AACR.

AbstractBackground & AimsChronic kidney disease (CKD) after liver transplant (LT) is associated with increased long‐term mortality. The impact of gender on CKD before and after LT is unknown. To further define risk factors and analyse gender differences in the incidence and progression of CKD after liver transplant.MethodsFour hundred and fifty‐five consecutive adult primary solitary LT recipients were included. Iothalamate clearance tests performed over time were analysed.ResultsMean age was 51.4 ± 10.4 years with 63% males. A percentage of 29.1% of females and 21.1% of males had a GFR<60 ml/min/1.73 m2 and 10.2% of females and 5.9% of males had GFR<30 ml/min/1.73 m2 prior to transplant. At 1 year, 52.6% of recipients tested (69.6% females, 43.0% males) had GFR<60 ml/min/1.73 m2 and 7.3% (11.6% females, 4.9% males) had GFR<30 ml/min/1.73 m2. Pre‐LT GFR<60 ml/min/1.73 m2 [OR 3.28, (1.76–6.10), P ≤ 0.001], female gender (OR 2.96, (1.72–5.10), P < 0.001) and age [OR 1.09, (1.05–1.12), P < 0.001] were independently predictive of stage ≥3 CKD at 1 year post‐LT. Female gender [OR 2.52, (1.25–4.71), P = 0.004], age [OR 1.05, (1.02–1.08), P = 0.003] and NASH [OR 2.95, (1.06–8.21), P = 0.039] were independently predictive of ≥stage 3 CKD at 5 years post‐LT. Pre‐LT diabetes was associated with stage 4 CKD at 5 years [OR 2.91, (1.33–6.36), P = 0.008] post‐LT.ConclusionsIn addition to age and pre‐LT CKD, female gender and NASH are independent predictors of ≥stage 3 CKD post‐LT. Gender‐based approaches to optimize modifiable risk factors are needed to improved post‐transplant renal function.

Although intelligibility deficits are common across various forms of dysarthria, it was hypothesized that the causes of intelligibility reductions depend on the ways the degraded signal challenges listener cognitive-perceptual strategies. This hypothesis was confirmed by analyzing the lexical boundary errors (LBE) elicited by 44 speakers with one of four forms of dysarthria (ataxic, hypokinetic, hyperkinetic, mixed spastic-flaccid). Error patterns from 60 listener transcripts revealed reliance on metrical stress to segment the 80 six-syllable phrases. However, reductions and disturbances in the acoustic cues to syllabic stress associated with each form of dysarthria resulted in different LBE patterns. Explanations for these unique patterns are found, in part, in the metrical structures of the dysarthric speech. For example, the temporal relationships among stressed and unstressed syllables varied widely in hyperkinetic speech, which ostensibly prevented listeners from optimally exploiting metrical stress as a cue for segmentation. The equal-even temporal structure of the spastic-flaccid speech resulted in the highest proportion of boundary insertions. The presence of interword pauses facilitated the assignment of word onset to strong syllables. Results will be presented relative to models of lexical segmentation and clinical implications for targets of remediation in the dysarthrias. [Work supported from NIH-NIDCD 5R01 DC6859.]

The detrimental effect of speaker variability on word recognition has been reported using a wide variety of tasks and stimuli. In this study, the use of dysarthric speech alongside unimpaired speech allowed us to examine the effect of indexical variability from a new perspective. We compared voice-specificity effects in words produced by healthy speakers and the same words produced by dysarthric patients suffering from Huntington’s disease (HD). The speech of persons with HD is particularly suited to this issue because of its idiosyncratic and variable manifestation. Reaction time and accuracy results provided confirmatory evidence for Luce et al.’s (2003) time-course hypothesis: The slower responses occasioned by processing dysarthric stimuli were accompanied with greater reliance on surface details of the stimuli. Thus, specificity effects can be seen as resulting from a coping strategy called upon when the system is presented with an input that is highly dissimilar from canonical lexical representations. In addition, we found some evidence that the time-course hypothesis holds even when intelligibility is controlled. This finding confirms that time, rather than processing effort, is the cause of specificity effects, with activation confined to abstract representations in an early stage and spreading to episodic traces later on.

Disturbances in speech rhythm are common in dysarthria, and deficit patterns vary among dysarthria subtypes. Attempts to quantify differences in disordered rhythm patterns have met with limited success. Here, we attempt to differentiate various forms of dysarthria using metrics designed to quantify linguistic rhythm on a stress-timed versus syllable-timed continuum. Speakers with hypokinetic, ataxic, hyperkinetic, or mixed flaccid-spastic dysarthria read sentences. Rhythm metrics were calculated for these utterances based on vocalic and consonantal interval durations. Differences among groups were discovered for %V (percentage of utterance duration comprised of vocalic intervals), VarcoV (rate-normalized standard deviation of vocalic interval durations), and nPVI-V (normalized pairwise variability index for vocalic intervals). Differences were independent of variable speaking rates among groups. All dysarthric groups produced rhythm patterns less stress-timed than the control American English speakers, with lower VarcoV and nPVI-V and higher %V. Those with flaccid-spastic dysarthria secondary to amyotrophic lateral sclerosis exhibited a syllable-timed pattern more extreme than even control Spanish speakers, indicating minimal differentiation of stressed and unstressed syllables. These results show that the various types of rhythmic disturbance accompanying dysarthria can be effectively described and distinguished within a stress-/syllable-timed continuum and relative to healthy speech.

Abstract Ovarian cancer is a clinically and molecularly heterogeneous disease. The driving forces behind this variability are unknown. Here, we report wide variation in the expression of the DNA cytosine deaminase APOBEC3B, with elevated expression in the majority of ovarian cancer cell lines (three SDs above the mean of normal ovarian surface epithelial cells) and high-grade primary ovarian cancers. APOBEC3B is active in the nucleus of several ovarian cancer cell lines and elicits a biochemical preference for deamination of cytosines in 5′-TC dinucleotides. Importantly, examination of whole-genome sequence from 16 ovarian cancers reveals that APOBEC3B expression correlates with total mutation load as well as elevated levels of transversion mutations. In particular, high APOBEC3B expression correlates with C-to-A and C-to-G transversion mutations within 5′-TC dinucleotide motifs in early-stage high-grade serous ovarian cancer genomes, suggesting that APOBEC3B-catalyzed genomic uracil lesions are further processed by downstream DNA "repair" enzymes including error-prone translesion polymerases. These data identify a potential role for APOBEC3B in serous ovarian cancer genomic instability. Cancer Res; 73(24); 7222–31. ©2013 AACR.

Classical myeloproliferative neoplasms (MPNs) are composed of essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF), the etiology of which is largely unknown. We investigated the role of anthropometric, medical and lifestyle factors with risk of MPN in a prospective cohort of 27,370 women aged 55–69 years at enrollment. After >250,000 person‐years of follow‐up, 257 cases of MPN were identified (172 ET, 64 PV, 21 MF). Risk factor profiles were mostly unique for the two most common types, ET and PV. ET was associated with energy balance factors including body mass index (RR = 1.52 for >29.3vs. <23.4 kg/m2;p‐trend = 0.042), physical activity (RR = 0.66 for highvs. low;p‐trend = 0.04) and adult onset diabetes (RR = 1.82;p = 0.009), while PV was not. PV was associated with current smoking (RR = 2.83;p‐trend = 0.016), while ET was not. Regular use of aspirin was associated with lower risk of ET (RR = 0.68;p = 0.017). These results broadly held in multivariate models. Our results suggest distinct etiologies for these MPN subtypes and raise mechanistic hypotheses related to obesity‐related inflammatory pathways for ET and smoking‐related carcinogenic pathways for PV. Regular aspirin use may lower risk for ET.

Study ObjectiveTo assess the relationship of the 33 single nucleotide polymorphisms (SNPs) previously associated with fasting glucose in Caucasians in genome‐wide association studies (GWAS) with glucose response to antihypertensive drugs shown to increase risk for hyperglycemia and diabetes.DesignRandomized, multicenter clinical trial.PatientsA total of 456 Caucasian men and women with uncomplicated hypertension.Measurements and Main ResultsThe Pharmacogenomic Evaluation of Antihypertensives Responses study evaluated blood pressure and glucose response in uncomplicated hypertensive patients randomized to either atenolol or hydrochlorothiazide (HCTZ) monotherapy, followed by combination therapy with both agents. Association of these SNPs with atenolol‐ or HCTZ‐induced glucose response was evaluated in 456 Caucasian patients using linear regression adjusting for age, sex, body mass index, baseline glucose, baseline insulin, and principal component for ancestry.The SNP rs340874 in the 5′ region of PROX1 gene was significantly associated with atenolol‐induced glucose change (p=0.0013). Participants harboring the C allele of this SNP had greater glucose elevation after approximately 9 weeks of atenolol monotherapy (β = +2.39 mg/dl per C allele), consistent with the direction of effect in fasting glucose GWAS, that showed the C allele is associated with higher fasting glucose.ConclusionThese data suggest that PROX1 SNP rs340874, discovered in fasting glucose GWAS, may also be a pharmacogenetic risk factor for antihypertensive‐induced hyperglycemia. β‐blockers and thiazides may interact with genetic risk factors to increase risk for dysglycemia and diabetes.

Shotgun proteomics technology has matured in the research laboratories and is poised to enter clinical laboratories. However, the road to this transition is sprinkled with major technical unknowns such as long‐term stability of the platform, reproducibility of the technology and clinical utility over traditional antibody‐based platforms. Further, regulatory bodies that oversee the clinical laboratory operations are unfamiliar with this new technology. As a result, diagnostic laboratories have avoided using shotgun proteomics for routine diagnostics. In this perspectives article, we describe the clinical implementation of a shotgun proteomics assay for amyloid subtyping, with a special emphasis on standardizing the platform for better quality control and earning clinical acceptance. This assay is the first shotgun proteomics assay to receive regulatory approval for patient diagnosis. The blueprint of this assay can be utilized to develop novel proteomics assays for detecting numerous other disease pathologies. Copyright © 2013 John Wiley & Sons, Ltd.

These case examples depict the use of a smartphone application, Mayo Clinic Anxiety Coach, to enhance the treatment of pediatric obsessive-compulsive disorder (OCD). The presented cases highlight the use of Anxiety Coach as a stand-alone intervention for mild OCD symptoms and as an adjunct to treatment for severe OCD complicated by geographical barriers. Each case includes a description of treatment, patient use of the application, objective assessment of clinical symptoms, and a qualitative interview with the families. Both patients responded well to treatment and had a positive experience with Anxiety Coach. The application encouraged the families to complete exposures between sessions and allowed a detailed examination of the patients’ engagement in homework assignments. Potential uses of smartphone applications to address challenges facing treatment of, and research on, OCD are discussed.