Citations

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.

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.

Key PointsPhenotypic and genotypic profiling of MDM2 in DLBCL. MDM2 as a negative regulator of p53 tumor suppressor function.

Background The etiologies of ischemic stroke remain undetermined in 15% to 40% of patients. Apart from atrial fibrillation, other arrhythmias are less well‐characterized as risk factors. Premature cardiac contractions are known to confer long‐term cardiovascular risks, like myocardial infarction. Ischemic stroke as cardiovascular risk outcome remains a topic of interest. We examined the prospective relationships in the Atherosclerosis Risk in Communities ( ARIC ) study, to determine whether premature atrial ( PAC ) or ventricular ( PVC ) contractions are associated with increased risk for incident ischemic stroke. Methods and Results We analyzed 14 493 baseline stroke‐free middle‐aged individuals in the ARIC public‐use data. The presence of PAC or PVC at baseline was assessed from 2‐minute electrocardiogram. A physician‐panel confirmed and classified all stroke cases. Average follow‐up time was 13 years. Proportional hazards models assessed associations between premature contractions and incident stroke. PAC s and PVC s were identified in 717 (4.9%) and 793 (5.5%) participants, respectively. In all, 509(3.5%) participants developed ischemic stroke. The hazard ratio ( HR ) (95% confidence interval [ CI ]) associated with PVC was 1.77 (1.30, 2.41), attenuated to 1.25 (0.91, 1.71) after adjusting for baseline stroke risk factors. The interaction between PVC and baseline hypertension was marginally significant ( P =0.08). Among normotensives, having PVC s was associated with nearly 2‐fold increase in the rate of incident ischemic stroke ( HR 1.69; 95% CI 1.02, 2.78), adjusting for stroke risk factors. The adjusted risk of ischemic stroke associated with PAC s was 1.30 (95% CI 0.92, 1.83). Conclusions Presence of PVC s may indicate an increased risk of ischemic stroke, especially in normotensives. This risk approximates risk of stroke from being black, male, or obese in normotensives from this cohort.

Background and Purpose— Endovascular therapy has increasingly become the most common treatment for unruptured cerebral aneurysms in the United States. We evaluated a national, multi-hospital database to examine recent utilization trends and compare periprocedural outcomes between clipping and coiling treatments of unruptured aneurysms. Methods— The Premier Perspective database was used to identify patients hospitalized between 2006 to 2011 for unruptured cerebral aneurysm who underwent clipping or coiling therapy. A logistic propensity score was generated for each patient using relevant patient, procedure, and hospital variables, representing the probability of receiving clipping. Covariate balance was assessed using conditional logistic regression. Following propensity score adjustment using 1:1 matching methods, the risk of in-hospital mortality and morbidity was compared between clipping and coiling cohorts. Results— A total of 4899 unruptured aneurysm patients (1388 clipping, 3551 coiling) treated at 120 hospitals were identified. Following propensity score adjustment, clipping patients had a similar likelihood of in-hospital mortality (odds ratio [OR], 1.43; 95% confidence interval [CI], 0.49–4.44; P =0.47) but a significantly higher likelihood of unfavorable outcomes, including discharge to long-term care (OR, 4.78; 95% CI, 3.51–6.58; P <0.0001), ischemic complications (OR, 3.42; 95% CI, 2.39–4.99; P <0.0001), hemorrhagic complications (OR, 2.16; 95% CI, 1.33–3.57; P <0.0001), postoperative neurological complications (OR, 3.39; 95% CI, 2.25–5.22; P <0.0001), and ventriculostomy (OR, 2.10; 95% CI, 1.01–4.61; P =0.0320) compared with coiling patients. Conclusions— Among patients treated for unruptured intracranial aneurysms in a large sample of hospitals in the United States, clipping was associated with similar mortality risk but significantly higher periprocedural morbidity risk compared with coiling.

Background— A hub-and-spoke telestroke network is an effective way to extend quality acute stroke care to remote hospitals and to improve patient outcomes. This study assessed the cost-effectiveness of a telestroke network in the management of acute ischemic stroke from the perspectives of a network, a hub hospital, and a spoke hospital. Methods and Results— A model was developed to compare costs and effectiveness with and without a telestroke network over a 5-year time horizon. The model considered differences in rates of teleconsultations, intravenous thrombolysis, endovascular stroke therapies, and spoke-to-hub transfers. These inputs were estimated through the use of data from Georgia Health Sciences University and Mayo Clinic telestroke networks. A network model with 1 hub and 7 spokes predicted that 45 more patients would be treated with intravenous thrombolysis and 20 more with endovascular stroke therapies per year compared with no network, leading to an estimate of 6.11 more home discharges. Each year, a telestroke network was associated with $358 435 in cost savings; each spoke had $109 080 in cost savings, whereas the hub had positive costs of $405 121. However, cost sharing can be arranged so that each hospital could achieve an equal amount of cost savings ($44 804/y). Results were sensitive to the number of spokes, marginal treatment costs in spokes and rates of transfer, and endovascular stroke therapies. Conclusions— The results of this study suggest that a telestroke network may increase the number of patients discharged home and reduce the costs borne by the network hospitals. Hospitals should consider their available resources and the network features when deciding whether to join or set up a network.

Objective— Endothelial cell (EC) inflammatory status is critical to many vascular diseases. Emerging data demonstrate that mutations of Krüppel-like factor-11 (KLF11), a gene coding maturity-onset diabetes mellitus of the young type 7 ( MODY7 ), contribute to the development of neonatal diabetes mellitus. However, the function of KLF11 in the cardiovascular system still remains to be uncovered. In this study, we aimed to investigate the role of KLF11 in vascular endothelial inflammation. Methods and Results— KLF11 is highly expressed in vascular ECs and induced by proinflammatory stimuli. Adenovirus-mediated KLF11 overexpression inhibits expression of tumor necrosis factors-α–induced adhesion molecules. Moreover, small interfering RNA–mediated KLF11 knockdown augments the proinflammatory status in ECs. KLF11 inhibits promoter activity of adhesion molecules induced by tumor necrosis factor-α and nuclear factor-κB p65 overexpression. Mechanistically, KLF11 potently inhibits nuclear factor-κB signaling pathway via physical interaction with p65. Furthermore, KLF11 knockdown results in increased binding of p65 to vascular cell adhesion molecule-1 and E-selectin promoters. At the whole organism level, KLF11 −/− mice exhibit a significant increase in leukocyte recruitment to ECs after lipopolysaccharide administration. Conclusion— Taken together, our data demonstrate for the first time that KLF11 is a suppressor of EC inflammatory activation, suggesting that KLF11 constitutes a novel potential molecular target for inhibition of vascular inflammatory diseases.

Abstract High throughput sequencing technologies open up a new dimension in cancer genomics by enabling the characterization of cancer genomes at base-pair resolution. To date, the majority of large-scale genomics projects rely on fresh-frozen biospecimens in their studies, which are difficult to obtain and often lack long-term clinical data. Unlike fresh-frozen samples, archived formalin-fixed paraffin-embedded (FFPE) tissues are more readily accessible, and are often associated with known clinical outcomes and more complete clinical annotations. However, sequencing library preparation methods need to be further optimized with regard to applicability to FFPE samples. To test whether next-generation sequencing technologies could overcome previously reported artifacts associated with formalin fixation and report accurate sequencing results, we compared whole-genome and targeted enrichment DNA sequencing data obtained from five FFPE tumor samples for which matching frozen tissues were available. We successfully generated sequencing libraries using 1 µg of genomic DNA as input material and a modified TruSeq™ sample preparation protocol. We designed a custom enrichment pool targeting exons from 215 cancer-related genes and utilized this pool to pull-down and sequence approximately 1.3 Mb region of the genome with an average 400x coverage depth to test if deep sequencing would improve validation of tumor-specific somatic mutations. We used the Illumina sequence analysis pipeline and the Windows-based second generation DNA sequencing software NextGENe® to analyze the data and identify sequence variations that are different from the human reference genome. CNV detection was overall higher among FFPE samples compared with fresh-frozen samples, demonstrating that tissue processing impacts sequencing data quality. We obtained good concordance in variant calls between matched FFPE and fresh-frozen samples. Discordant variant calls were mainly due to low depth of coverage in the regions where variant calls were made. Improvements to DNA sequencing methods for archived samples will significantly enhance cancer research and will result in more reliable prediction of individual cancer therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3179. doi:1538-7445.AM2012-3179

Abstract MicroRNAs (miRNAs) play an important role in a variety of physiological processes as well as pathophysiological processes, including cancinogenesis. This study was to identify a distinct miRNA expression signature for cervical intraepithelial neoplasia (CIN) and to reveal individual miRNAs that may be involved in the development of cervical carcinoma. Expression profiling using quantitative real-time RT-PCR of 202 miRNAs was performed on micro-dissected high-grade CIN (CIN 2/3) tissues as compared to normal cervical epithelium. The expression of 12 miRNAs including miR-518a, miR-34b, miR-34c, miR-20b, miR-338, miR-9, miR-512-5p, miR-424, miR-345, miR-10a, miR-193b and miR-203 were significantly different between high-grade CIN and normal epithelium. This miRNA signature was further validated by an independent set of high-grade CIN tissue. The same characteristic signature can also be used to distinguish cervical squamous cell carcinoma (SCC) from normal controls. Target prediction analysis revealed that these dysregulated miRNAs control the apoptosis signaling pathway and cell cycle regulation. These findings contribute to understanding of the pathogenesis of cervical carcinoma at the molecular level. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5047. doi:1538-7445.AM2012-5047

Abstract BACKGROUND: Mammographic percent dense area, the percent ratio of dense to total breast area in a mammogram, is one of the strongest measures of a woman's risk of breast cancer. However, systematic differences have been observed between readers and mammography technologies (film and digital) that could cause clinically inconsistent associations with risk. The purpose of this study was to evaluate inter- and intra-reproducibility of percent dense area between readers and between film and digital technologies. METHODS: One hundred digitized film mammograms were randomly selected with 25 films in each of quartile of percent density and read by two readers at two different sites (Mayo Clinic and UCSF). The readers had extensive experience and were also jointly trained at university of Toronto using Cumulus software. After training, all films were read twice with at least one year between duplicate readings. The Mayo clinic reading used Cumulus while UCSF used custom semiautomatic software to estimate total and dense tissue area. In addition, digitized films and unprocessed full field digital mammograms of the same women were assessed by one reader. The time between the film and digital acquisitions ranged from nine to twenty-four months. Interclass correlation coefficient (ICC) was calculated for each comparison. RESULTS: The intra- and inter-observer ICCs, consistency for film images, were 0.96 (UCSF) and 0.97 (Mayo), and 0.96 (UCSF vs. Mayo). We found ICC between film and digital mammograms for percent dense area was 0.88. The digital mammogram had 9% significantly higher total breast area and 5% significantly lower percent density area compared to film. CONCLUSIONS: Similarly trained readers had a high reproducibility regardless of the software used. Our results suggest centralized reader training should enable pooling of film breast density results from different clinics. However, pooling film and digital results would need careful calibration due to lower measured percent dense areas than on film. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-08-03.