Association of a Rare Variant with Mismatch Negativity in a Region Between <Emphasis Type="Italic">KIAA0319</Emphasis> and <Emphasis Type="Italic">DCDC2</Emphasis> in Dyslexia

It has been repeatedly shown that mismatch negativity (MMN), an event related potential measurement, reveals differences between dyslexic children and age-matched controls. MMN reflects the automatic detection of deviance between a stream of incoming sounds presented to the passive listener, and deficits in MMN (i.e. attenuated amplitudes) have been especially reported in dyslexia for detecting differences between speech sounds (e.g./ba/vs./da/). We performed an association analysis in 200 dyslexic children. This analysis focused on two MMN components, an early MMN (188–300 ms) and a late MMN (300–710 ms), and the dyslexia candidate genes KIAA0319 and DCDC2 on chromosome 6. Additionally, we imputed rare variants located in this region based on the 1000 genomes project. We identified four rare variants that were significantly associated with the late MMN component. For three of these variants, which were in high LD to each other, genotyping confirmed the association signal. Our results point to an association between late MMN and rare variants in a candidate gene region for dyslexia.     

Genetic markers for PTSD risk and resilience among survivors of the World Trade Center attacks

We have previously reported the differential expression of 17 probe sets in survivors of the 9/11 attacks with current posttraumatic stress disorder (PTSD) compared to similarly exposed survivors with no lifetime PTSD. The current study presents an expanded analysis of these subjects, including genotype at FKBP5, a modulator of glucocorticoid receptor (GR) sensitivity. It includes data from additional subjects who developed PTSD following 9/11 but then recovered, distinguishing expression profiles associated with risk for developing PTSD, resilience, and symptom recovery. 40 Caucasians (20 with and 20 without PTSD, matched for exposure, age, and gender) were selected from a population-representative sample of persons exposed to the 9/11 attacks from which longitudinal data had been collected in four previous waves. Whole blood gene expression and cortisol levels were obtained and genome-wide gene expression was analyzed. 25 probe sets were differentially expressed in PTSD. Identified genes were generally involved in hypothalamic-pituitary-adrenal axis, signal transduction, or in brain and immune cell function. STAT5B, a direct inhibitor of GR, and nuclear factor I/A, both showed reduced expression in PTSD. Comparison of lifetime versus current PTSD identified overlapping genes with altered expression suggesting enduring markers, while some markers present only in current PTSD may reflect state measures. As a follow-up, direct comparisons of expression in current PTSD, lifetime-only PTSD, and control groups identified FKBP5 and MHC Class II as state markers, and also identified several trait markers. An analysis of indirect effects revealed that homozygosity for any of 4 PTSD risk-related polymorphisms at FKBP5 predicted FKBP5 expression, which mediated indirect effects of genotype on plasma cortisol and PTSD severity.     

Estimating glomerular number: Why we do it and how

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Quality of Life in Patients With Metastatic Renal Cell Carcinoma: Assessment of Long-Term Survivors

BackgroundAn emerging literature describes the potential for long-term survival with targeted agents, but the health-related quality of life (HR-QOL) in patients who receive chronic therapy with these agents is poorly defined.MethodsFrom an institutional database including 562 patients with renal cell carcinoma (RCC), patients were identified who (1) were alive 3 years beyond initiation of systemic therapy for metastatic renal cell carcinoma (mRCC) and (2) received a targeted therapy as a component of their treatment. European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 36 (QLQ-C30) and Functional Assessment of Cancer Therapy–Kidney Symptom Index (FKSI-15) questionnaires were administered by telephone survey. Data from questionnaires were compared with historical estimates derived from pivotal studies evaluating targeted agents.ResultsA total of 38 patients met eligibility criteria for the study, and 28 patients participated in the telephone survey. Most were male patients and had clear cell histologic type (75% for both). All patients had either good- or intermediate-risk disease by Heng criteria. The mean QLQ-C30 Global QOL score in the present cohort was higher than the mean score among patients evaluated at baseline in the phase III evaluations of pazopanib (73.5 vs. 65.8; P = .07) and everolimus (73.5 vs. 61.0; P = .007). The FKSI-15 score in the present cohort was similar to the mean score among patients evaluated at baseline in the phase III evaluation of sunitinib (45.1 and 46.5, respectively; P = .41).ConclusionIn this small pilot study, long-term survivors with mRCC who received targeted therapies appear to have an HR-QOL comparable to that of patients who participated in relevant phase III studies. Given the many emerging treatment options for mRCC, the HR-QOL of long-term survivors warrants greater attention.     

Impact of age on treatment trends and clinical outcome in patients with metastatic renal cell carcinoma

ObjectivesClinical outcomes in older adults with metastatic renal cell carcinoma (mRCC) are poorly understood, particularly in the era of targeted therapies. We characterize survival and relevant treatment-related variables in a modern series.Materials and MethodsFrom an institutional database including 562 patients with RCC, a total of 219 patients with metastatic disease were identified for the current analysis. Survival was assessed in four age-based cohorts: (1) age < 55, (2) age 55–64, (3) age 65–74, and (4) age ≥ 75. The number of lines of therapy rendered was collected for each patient, and the reason for treatment discontinuation was characterized.ResultsOf the 219 patients assessed, median age was 58 (range, 26–87), and most patients had clear cell histology (82%) and prior nephrectomy (70.9%). The majority of patients were characterized as intermediate-risk (53%) by MSKCC criteria. Median survival in patients age ≥ 75 was 12.5 months, as compared to 26.4 months for patients age < 75 (P = 0.003). Patients age ≥ 75 received fewer lines of systemic therapy as compared to other age-based subsets, and more frequently discontinued therapies due to toxicity.ConclusionsOlder adults represent a unique subpopulation of patients with mRCC, with distinct clinical outcomes. Further research is warranted to better understand the safety and tolerability of current therapies for mRCC in this group.     

Octa-functional PLGA nanoparticles for targeted and efficient siRNA delivery to tumors

Therapies based on RNA interference, using agents such as siRNA, are limited by the absence of safe, efficient vehicles for targeted delivery in vivo. The barriers to siRNA delivery are well known and can be individually overcome by addition of functional modules, such as conjugation of moieties for cell penetration or targeting. But, so far, it has been impossible to engineer multiple modules into a single unit. Here, we describe the synthesis of degradable nanoparticles that carry eight synergistic functions: 1) polymer matrix for stabilization/controlled release; 2) siRNA for gene knockdown; 3) agent to enhance endosomal escape; 4) agent to enhance siRNA potency; 5) surface-bound PEG for enhancing circulatory time; and surface-bound peptides for 6) cell penetration; 7) endosomal escape; and 8) tumor targeting. Further, we demonstrate that this approach can provide prolonged knockdown of PLK1 and control of tumor growth in vivo. Importantly, all elements in these octa-functional nanoparticles are known to be safe for human use and each function can be individually controlled, giving this approach to synthetic RNA-loaded nanoparticles potential in a variety of clinical applications.     

The role of the alternative coreceptor GPR15 in SIV tropism for human cells

Many SIV isolates can employ the orphan receptor GPR15 as coreceptor for efficient entry into transfected cell lines, but the role of endogenously expressed GPR15 in SIV cell tropism is largely unclear. Here, we show that several human B and T cell lines express GPR15 on the cell surface, including the T/B cell hybrid cell line CEMx174, and that GPR15 expression is essential for SIV infection of CEMx174 cells. In addition, GPR15 expression was detected on subsets of primary human CD4⁺, CD8⁺ and CD19⁺ peripheral blood mononuclear cells (PBMCs), respectively. However, GPR15⁺ PBMCs were not efficiently infected by HIV and SIV, including cells from individuals homozygous for the defective Δ32 ccr5 allele. These results suggest that GPR15 is coexpressed with CD4 on PBMCs but that infection of CD4⁺, GPR15⁺ cells is not responsible for the well documented ability of SIV to infect CCR5⁻ blood cells.