Citations

ObjectiveCD8+ T cells lacking CD28 were originally reported to be a characteristic feature of juvenile idiopathic arthritis (JIA), but the relevance of these unusual cells to this disease remains to be elucidated. Because of recent evidence that loss of CD28 cells is typical of terminally differentiated lymphocytes, the aim of this study was to examine functional subsets of CD8+ T cells in patients with JIA.MethodsBlood and/or waste synovial fluid samples were collected from children with a definite diagnosis of JIA (n = 98). Deidentified peripheral blood (n = 33) and cord blood (n = 13) samples from healthy donors were also collected. CD8+ and CD4+ T cells were screened for novel receptors, and where indicated, bioassays were performed to determine the functional relevance of the identified receptor.ResultsJIA patients had a naive T cell compartment with shortened telomeres, and their entire T cell pool had reduced proliferative capacity. They had an overabundance of CD31+CD28nullCD8+ T cells, which was a significant feature of oligoarticular JIA (n = 62) as compared to polyarticular JIA (n = 36). CD31+ CD28nullCD8+ T cells had limited mitotic capacity and expressed high levels of the senescence antigens histone γH2AX and/or p16. Ligation of CD31, which was independent of the T cell receptor (TCR), sufficiently induced tyrosine phosphorylation, vesicle exocytosis, and production of interferon‐γ and interleukin‐10.ConclusionThese data provide the first evidence of cell senescence, as represented by CD31+CD28null CD8+ T cells, in the pathophysiology of JIA. Activation of these unusual cells in a TCR‐independent manner suggests that they are maladaptive and could be potential targets for immunotherapy.

Background: Symptomatic femoroacetabular impingement (FAI) is associated with hip pain, functional limitations, and secondary osteoarthritis. There is limited information from large patient cohorts defining the specific population affected by FAI. Establishing a large cohort will facilitate the identification of “at-risk” patients and will provide a population for ongoing clinical research initiatives. The authors have therefore established a multicenter, prospective, longitudinal cohort of patients undergoing surgery for symptomatic FAI. Purpose: To report the clinical epidemiology, disease characteristics, and contemporary surgical treatment trends in North America for patients with symptomatic FAI. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Upon approval of the institutional review boards at 8 institutions, 12 surgeons enrolled consecutive patients undergoing surgical intervention for symptomatic FAI. Patient demographics, physical examination data, radiographic data, diagnoses, operative data, and standardized patient-reported outcome measures were collected. The first 1130 cases are summarized in this study. Results: A total of 1076 consecutive patients (1130 hips) were enrolled; 55% (n = 622) were female, and 45% (n = 508) were male, with an average age of 28.4 years and average body mass index (BMI) of 25.1. Demographics revealed that 88% of patients who were predominantly treated for FAI were white, 19% reported a family history of hip surgery, 47.6% of hips had a diagnosis of cam FAI, 44.5% had combined cam/pincer FAI, and 7.9% had pincer FAI. Preoperative clinical scores (pain, function, activity level, and overall health) indicated a major dysfunction related to the hip. Surgical interventions were arthroscopic surgery (50.4%), surgical dislocation (34.4%), reverse periacetabular osteotomy (9.4%), limited open osteochondroplasty with arthroscopic surgery (5.8%), and limited open by itself (1.5%). More than 90% of the hips were noted to have labral and articular cartilage abnormalities at surgery; femoral head-neck osteochondroplasty was performed in 91.6% of the surgical procedures, acetabular rim osteoplasty in 36.7%, labral repair in 47.8%, labral debridement in 16.3%, and acetabular chondroplasty in 40.1%. Conclusion: This multicenter, prospective, longitudinal cohort is one of the largest FAI cohorts to date. In this cohort, FAI occurred predominantly in young, white patients with a normal BMI, and there were more female than male patients. The disease pattern of cam FAI was most common. Contemporary treatment was predominantly arthroscopic followed by surgical hip dislocation.

ScopeAndrogen receptor (AR) signaling is critical for all aspects of prostate growth and tumorigenesis. The glucosinolate‐derived phenethyl isothiocyanate (PEITC) has recently been demonstrated to reduce the risk of prostate cancer (PCa) and inhibit PCa cell growth. We previously reported that p300/CBP‐associated factor (PCAF), a co‐regulator for AR, is upregulated in PCa cells through suppression of the mir‐17 gene. Here, we assessed the effects of PEITC on PCAF expression and AR‐regulated transcriptional activity in PCa cells.Methods and resultsUsing AR‐responsive LNCaP cells, we observed the inhibitory effects of PEITC on the dihydrotestosterone‐stimulated AR transcriptional activity and cell growth of PCa cells. Interestingly, overexpression of PCAF attenuated the inhibitory effects of PEITC on dihydrotestosterone‐stimulated AR transcriptional activity. Expression of PCAF was upregulated in PCa cells through suppression of miR‐17. PEITC treatment significantly decreased PCAF expression and promoted transcription of miR‐17 in LNCaP cells. Functional inhibition of miR‐17 attenuated the suppression of PCAF in cells treated by PEITC.ConclusionOur results indicate that PEITC inhibits AR‐regulated transcriptional activity and cell growth of PCa cells through miR‐17‐mediated suppression of PCAF, suggesting a new mechanism by which PEITC modulates PCa cell growth.

ABSTRACTVenous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a two‐stage genome‐wide association study (GWAS) among individuals of European ancestry in the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community‐based studies. Genotypes for genome‐wide single‐nucleotide polymorphisms (SNPs) were imputed to approximately 2.5 million SNPs in HapMap and association with VTE assessed using study‐design appropriate regression methods. Meta‐analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (P ≤ 0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case‐control studies. In the combined data from these two stages, additional genome‐wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG; P < 5.0 × 10−13 for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (P < 5.0 × 10−6) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations.

ABSTRACTSearching for rare genetic variants associated with complex diseases can be facilitated by enriching for diseased carriers of rare variants by sampling cases from pedigrees enriched for disease, possibly with related or unrelated controls. This strategy, however, complicates analyses because of shared genetic ancestry, as well as linkage disequilibrium among genetic markers. To overcome these problems, we developed broad classes of “burden” statistics and kernel statistics, extending commonly used methods for unrelated case‐control data to allow for known pedigree relationships, for autosomes and the X chromosome. Furthermore, by replacing pedigree‐based genetic correlation matrices with estimates of genetic relationships based on large‐scale genomic data, our methods can be used to account for population‐structured data. By simulations, we show that the type I error rates of our developed methods are near the asymptotic nominal levels, allowing rapid computation of P‐values. Our simulations also show that a linear weighted kernel statistic is generally more powerful than a weighted “burden” statistic. Because the proposed statistics are rapid to compute, they can be readily used for large‐scale screening of the association of genomic sequence data with disease status.

AbstractBackgroundGenetic variants at the CLU, CR1, and PICALM loci associate with risk for late‐onset Alzheimer's disease (LOAD) in genomewide association studies. In this study, our aim was to determine whether the LOAD risk variants at these three loci influence memory endophenotypes in black and white subjects.MethodsWe pursued an association study between single nucleotide polymorphism genotypes at the CLU, CR1, and PICALM loci and memory endophenotypes. We assessed black subjects (AA series: 44 with LOAD and 224 control subjects) recruited at Mayo Clinic Florida and whites recruited at Mayo Clinic Minnesota (RS series: 372 with LOAD and 1690 control subjects) and Florida (JS series: 60 with LOAD and 529 control subjects). Single nucleotide polymorphisms at the LOAD risk loci CLU (rs11136000), CR1 (rs6656401, rs3818361), and PICALM (rs3851179) were genotyped and tested for association with Logical Memory immediate recall, Logical Memory delayed recall, Logical Memory percent retention, Visual Reproduction immediate recall, Visual Reproduction delayed recall, and Visual Reproduction percent retention scores from the Wechsler Memory Scale–Revised using multivariable linear regression analysis, adjusting for age at exam, sex, education, and apolipoprotein E ε4 dosage.ResultsWe identified nominally significant or suggestive associations between the LOAD‐risky CR1 variants and worse Logical Memory immediate recall scores in blacks (P = .068–.046, β = −2.7 to −1.2). The LOAD‐protective CLU variant is associated with better logical memory endophenotypes in white subjects (P = .099–.027, β = 0.31–0.93). The CR1 associations persisted when the control subjects from the AA series were assessed separately. The CLU associations appeared to be driven by one of the white series (RS) and were also observed when the control subset from RS was analyzed.ConclusionThese results suggest for the first time that LOAD risk variants at CR1 may influence memory endophenotypes in blacks. In addition, the CLU LOAD‐protective variant may confer enhanced memory in whites. Although these results would not remain significant after stringent corrections for multiple testing, they need to be considered in the context of the LOAD associations with which they have biological consistency. They also provide estimates for effect sizes on memory endophenotypes that could guide future studies. The detection of memory effects for these variants in clinically normal subjects, implies that these LOAD risk loci might modify memory prior to clinical diagnosis of AD.

Abstract Background: Colorectal cancer (CRC) in densely affected families without Lynch Syndrome may be due to mutations in undiscovered genetic loci. Familial linkage analyses have yielded disparate results; the use of exome sequencing in coding regions may identify novel segregating variants. Methods: We completed exome sequencing on 40 affected cases from 16 multicase pedigrees to identify novel loci. Variants shared among all sequenced cases within each family were identified and filtered to exclude common variants and single-nucleotide variants (SNV) predicted to be benign. Results: We identified 32 nonsense or splice-site SNVs, 375 missense SNVs, 1,394 synonymous or noncoding SNVs, and 50 indels in the 16 families. Of particular interest are two validated and replicated missense variants in CENPE and KIF23, which are both located within previously reported CRC linkage regions, on chromosomes 1 and 15, respectively. Conclusions: Whole-exome sequencing identified DNA variants in multiple genes. Additional sequencing of these genes in additional samples will further elucidate the role of variants in these regions in CRC susceptibility. Impact: Exome sequencing of familial CRC cases can identify novel rare variants that may influence disease risk. Cancer Epidemiol Biomarkers Prev; 22(7); 1239–51. ©2013 AACR.

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) enhance insulin sensitivity and glucose homeostasis in rodent models of insulin resistance. These beneficial effects have been linked with anti-inflammatory properties, but emerging data suggest that the mechanisms may also converge on mitochondria. We evaluated the influence of dietary n-3 PUFAs on mitochondrial physiology and muscle lipid metabolites in the context of high-fat diet (HFD) in mice. Mice were fed control diets (10% fat), HFD (60% fat), or HFD with fish oil (HFD+FO, 3.4% kcal from n-3 PUFAs) for 10 wk. Body mass and fat mass increased similarly in HFD and HFD+FO, but n-3 PUFAs attenuated the glucose intolerance that developed with HFD and increased expression of genes that regulate glucose metabolism in skeletal muscle. Despite similar muscle triglyceride levels in HFD and HFD+FO, long-chain acyl-CoAs and ceramides were lower in the presence of fish oil. Mitochondrial abundance and oxidative capacity were similarly increased in HFD and HFD+FO compared with controls. Hydrogen peroxide production was similarly elevated in HFD and HFD+FO in isolated mitochondria but not in permeabilized muscle fibers, likely due to increased activity and expression of catalase. These results support a hypothesis that n-3 PUFAs protect glucose tolerance, in part by preventing the accumulation of bioactive lipid mediators that interfere with insulin action. Furthermore, the respiratory function of skeletal muscle mitochondria does not appear to be a major factor in sphingolipid accumulation, glucose intolerance, or the protective effects of n-3 PUFAs.