Citations

Increasing evidence indicates that cerebrovascular dysfunction plays a pathogenic role in Alzheimer's dementia (AD). Amyloid-β (Aβ), a peptide central to the pathogenesis of AD, has profound vascular effects mediated, for the most part, by reactive oxygen species produced by the enzyme NADPH oxidase. The mechanisms linking Aβ to NADPH oxidase-dependent vascular oxidative stress have not been identified, however. We report that the scavenger receptor CD36, a membrane glycoprotein that binds Aβ, is essential for the vascular oxidative stress and neurovascular dysfunction induced by Aβ 1–40 . Thus, topical application of Aβ 1–40 onto the somatosensory cortex attenuates the increase in cerebral blood flow elicited by neural activity or by endothelium-dependent vasodilators in WT mice but not in CD36-null mice (CD36 0/0 ). The cerebrovascular effects of infusion of Aβ 1–40 into cerebral arteries are not observed in mice pretreated with CD36 blocking antibodies or in CD36 0/0 mice. Furthermore, CD36 deficiency prevents the neurovascular dysfunction observed in transgenic mice overexpressing the Swedish mutation of the amyloid precursor protein Tg2576 despite elevated levels of brain Aβ 1–40 . CD36 is also required for the vascular oxidative stress induced by exogenous Aβ 1–40 or observed in Tg2576 mice. These observations establish CD36 as a key link between Aβ 1–40 and the NADPH oxidase-dependent vascular oxidative stress underlying the neurovascular dysfunction and suggest that CD36 is a potential therapeutical target to counteract the cerebrovascular dysfunction associated with Aβ.

Abstract Objective: To investigate the association of body mass index (BMI) and BMI change with change in prostate-specific antigen (PSA) level and to assess the possible roles of PSA hemodilution and prostate volume in explaining the obesity and PSA association. Methods: In 1990, a randomly selected cohort of Caucasian men, aged 40 to 79 years, from Olmsted County, Minnesota, completed questionnaires ascertaining demographic characteristics, current medical conditions, and medications biennially, with a subset undergoing blood draws and clinical examinations. Linear mixed models were used to predict annual changes and intercepts of individual changes in BMI, PSA, prostate volume, plasma volume, and PSA mass, adjusting for age in 545 men with at least 2 serial PSA, BMI, and prostate volume measurements. Results: Baseline BMI was inversely associated with the annual percent change in PSA, adjusting for age, baseline PSA, and prostate volume and for the rates of change in BMI and prostate volume (β = −0.003, 95% CI: −0.006 to −0.0003). Baseline obesity was positively associated with mean baseline levels and the rate of change in prostate volume (P = 0.002) and plasma volume (both P < 0.001) but was not associated with either the mean baseline values or the rate of change in PSA mass. Conclusions: Baseline obesity was associated with baseline PSA and prostate volume and with the rate of change in PSA over 15 years of follow-up. Impact: The inverse association of obesity with prostate cancer diagnosis may be at least partly due to detection bias, which is due to larger prostate volumes and PSA hemodilution in obese men. Cancer Epidemiol Biomarkers Prev; 20(3); 501–8. ©2011 AACR.

Abstract Mitochondria have been implicated in carcinogenesis because of their central role in apoptosis, free radical production, and cellular energy metabolism. Although studies have identified somatic mitochondrial DNA mutations in ovarian cancers, little attention has been directed to the possible role of germline mitochondrial variants in mitochondrial dysfunction and subsequent ovarian cancer development. Through an ongoing epithelial ovarian cancer genome-wide association study of 1,856 invasive cases (59% with serous carcinomas) and 1,912 controls (frequency-matched on age, race, and study site), we genotyped 138 SNPs tagging variation in the maternally-inherited mitochondrial genome (mtDNA) to evaluate the hypothesis that single nucleotide polymorphisms (SNPs) in mtDNA are associated with ovarian cancer risk. All subjects were non-Hispanic, non-Jewish Caucasians, and were genotyped with the Illumina 610-quad Beadchip. Samples and SNPs with call rates less than 95% were excluded. Subjects with ambiguous gender, unresolved identical genotypes, and less than 80% European ancestry were excluded. For each SNP, logistic regression was used to estimate odds ratios (OR) and corresponding 95% confidence intervals (CI) between carriers of the minor versus major maternally-inherited allele and case status. Subgroup analysis was conducted to estimate allele-specific risks between serous-only cases and controls. Haplotype analysis was performed for regions containing statistically significant SNPs (p<0.05). Two rare SNPs, C16329T in the displacement loop gene (MT-D-loop) (OR: 6.72, 95%CI: 1.5-29.8, p=0.004; minor allele frequency (MAF)=0.001) and C15905T in the tRNA threonine gene (MT-TT) (OR: 1.60, 95%CI: 1.1-2.3, p=0.009; MAF=0.027), were associated with increased ovarian cancer risk; whereas T6777C in the cytochrome c oxidase subunit 1 gene (MT-CO1) (OR: 0.68, 95%CI: 0.51-0.91, p=0.009; MAF=0.063) was associated with decreased risk. All three SNPs remained statistically significant after adjustment for multiple comparisons within the mitochondrial SNPs using permutation testing. C16329T and T6777C were also significantly associated among cases with serous histology, with ORs (95% CIs) of 6.13 (1.2-29.6) and 0.61 (0.43-0.87), respectively. Haplotype analysis for each of the three regions investigated revealed significant haplotype-disease associations; however, findings suggest that the respective associations were driven by the most significant SNP(s) listed above. This is the first large-scale epidemiologic study to provide evidence that SNPs in mitochondrial genes may be novel risk factors for ovarian cancer. Future investigation of additional mitochondrial variants (i.e. nuclear-encoded mitochondrial proteins) is necessary to more comprehensively investigate this association. Furthermore, replication of the most promising SNPs in a larger population is warranted to validate these findings. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2835.

Abstract Colon cancer is the result of a multi-step process involving the accumulation of genetic and epigenetic alterations leading to the transformation of normal colon epithelium to adenocarcinoma. Identification of characteristic genetic alterations is of critical importance to increase our understanding of the transformation process. We focused our analysis on the most common molecular sub-type of colon cancers, microsatellite stable (MSS) and CpG island methylator phenotype (CIMP)-negative, to identify characteristic copy number alteration (CNA) events and associated gene expression profiles using high-resolution genome-wide microarrays. DNA and RNA were extracted from 41 fresh-frozen paired colon tumors and adjacent normal tissue collected by the Colon Cancer Family Registry. Genomic profiles, such as CNAs and loss of heterozygosity (LOH), were identified with the Affymetrix Genome-Wide Human SNP 6.0 array for both tumor and adjacent normal tissue. Gene expression profiles of tumors and adjacent normal tissue were identified with the Affymetrix GeneChip Human Exon 1.0 ST array. Partek Genomics Suite software was used for analysis and data integration. We identified recurrent (>25%) CNAs in several chromosomal regions: gain in 1q, 7p, 7q, 8q, 13q, 20p, 20q, Xp, Xq and loss in 5q, 8p, 14q, 16p, 17p, 18p, and 18q. In addition, based on the allele information from the SNP arrays, we found a subset of these recurrent CNAs were associated with LOH. Preliminary results from the integration of CNA and gene expression data in tumors indicate that a subset of these recurrent CNAs is associated with the disruption of gene expression. For example, we observed recurrent copy number gain in 8q24.21, the genomic region containing the c-MYC gene, and associated up-regulation of c-MYC gene expression in tumors compared to adjacent normal tissue. In another example, recurrent copy number loss at 5q22.2 was associated with down-regulation of APC gene expression; loss of function of this tumor suppressor is associated with both hereditary and sporadic colon cancer. This genome-wide characterization of both genomic alterations and gene expression may help identify key genes and pathways that are disrupted in this common molecular subtype of colon cancer. We will present detailed results from this integrated and comprehensive genetic profiling of MSS and CIMP-negative colon cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2145.

Abstract Rationale: Given recent success in delivering interferon-beta (IFNβ) using replication incompetent adenovirus in patients with malignant pleural effusions, we hypothesized that vectors that could replicate (inducing oncolysis) and express IFNβ at high level would be more effective. Both vaccinia virus (VV) and vesicular stomatitis (VSV) expressing mouse IFNβ have been constructed in a manner to improve their safety and efficacy as oncolytic vectors. In this study, we evaluated these two oncolytic vectors in different murine thoracic cancer models for clinical translation. Experimental procedures: We compared the efficacy of VVIFNβ and VSVIFNβ to kill 3 mouse lung cancer and 4 mouse mesothelioma lines in vitro over a 5 day-period assessing cell viability by MTT assay. The amount of IFNβ produced by these two vectors were measured with ELISA. The viral replication in infected mice was assessed by measuring viral titers in both immunocompetent and immunodeficient mice bearing an IFN-non-responsive AB12 tumor, following intratumoral injection of either vector at 108 pfu/mouse. To assess their anti-tumor activity, the two vectors were also given at 108 pfu/mouse intratumorally in mice bearing two lung cancer tumors on their flanks. Results: The replication of VSVIFNβ and its killing ability was limited in some of the tumor lines. This appeared to be due to an intact IFN response pathway. In contrast, VVIFNβ was able to kill all of the tumor lines. In culture, VSV replicates faster than VV, which resulted in faster cell killing (in susceptible cell lines), but with less IFNβ production. The amount of IFNβ production by VVIFNβ was comparable with AdIFNβ over a 5 day period. VVIFNβ-infected immunodeficient mice showed minimal or no toxicity when given virus intravenously, while all 5 mice infected with VSVIFNβ developed neurotoxicity within a week. In the TC-1 lung cancer model, VVIFNβ caused tumor regression, while VSVIFNβ and AdIFNβ were completely ineffective. In a second model using LKRM2, all 3 viral vectors were equivalent. The anti-tumor effect of VVIFNβ was shown to be mainly CD8 dependant, as depletion of CD8 with antibody dampened the tumor growth inhibition from 48% to 20%. Conclusions: Overall, VVIFNβ appears to be a better oncolytic vector than VSVIFNβ for a number of reasons: 1) it is safer, 2) it is able to replicate in vitro and in vivo in almost every cell line tested, 3) it induces longer and larger IFNβ production, and 4) it can potentially be given intravenously. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1513.

The current criteria for classification of Alzheimer's disease (AD) have deficiencies that limit drug development, research, and practice. The current standard for the clinical diagnosis of AD, the National Institute of Neurological and Communicative Disorders and Stroke (now known as the National Institute of Neurological Disorders and Stroke), and the Alzheimer's Disease and Related Disorders Association (now known as the Alzheimer's Association) criteria, are nearly 25 years old and have not been revised to incorporate advances in the epidemiology and genetics of AD, studies of clinicopathologic correlations and recent studies of potential diagnostic biomarkers. In a very real sense our ability to diagnose AD with a very high level of certainty has outpaced our current diagnostic criteria. The Alzheimer's Association Research Roundtable convened a meeting in April 2009 to discuss new data and technologies that could, with further development, enable improvements in the clinical diagnosis of AD, especially in its earliest and mildest stages. This meeting reviewed the current standards for detecting and defining the clinical presentation of AD and discussed areas that could contribute to earlier and more accurate definitive clinical diagnosis. These included clinical, neuropsychological, and other performance‐based assessments, genetic contributions, and biochemical and neuroimaging biomarkers that could reflect AD pathology and lead to better ascertainment of AD, mild cognitive impairment, and presymptomatic AD.

Abstract In a randomized trial of therapy for FMS-like tyrosine kinase-3 (FLT3) mutant acute myeloid leukemia in first relapse, 224 patients received chemotherapy alone or followed by 80 mg of the FLT3 inhibitor lestaurtinib twice daily. Endpoints included complete remission or complete remission with incomplete platelet recovery (CR/CRp), overall survival, safety, and tolerability. Correlative studies included pharmacokinetics and analysis of in vivo FLT3 inhibition. There were 29 patients with CR/CRp in the lestaurtinib arm and 23 in the control arm (26% vs 21%; P = .35), and no difference in overall survival between the 2 arms. There was evidence of toxicity in the lestaurtinib-treated patients, particularly those with plasma levels in excess of 20μM. In the lestaurtinib arm, FLT3 inhibition was highly correlated with remission rate, but target inhibition on day 15 was achieved in only 58% of patients receiving lestaurtinib. Given that such a small proportion of patients on this trial achieved sustained FLT3 inhibition in vivo, any conclusions regarding the efficacy of combining FLT3 inhibition with chemotherapy are limited. Overall, lestaurtinib treatment after chemotherapy did not increase response rates or prolong survival of patients with FLT3 mutant acute myeloid leukemia in first relapse. This study is registered at www.clinicaltrials.gov as #NCT00079482.

Introduction: Telemedicine options for symptom assessment include both telephonic means (call centers) and Internet sites. Although symptom assessment call centers have been available for decades, symptom assessment over the Internet is relatively new. It is not well known what types of symptoms Internet users are seeking assessment for and whether extant telephone triage algorithms would be applicable to Internet users. Methods: Symptom assessments on a heavily used Internet site ( MayoClinic.com ) were compared with symptom calls to a U.S. call center (Ask Mayo Clinic). Results: Internet users sought symptom assessments about adult symptoms 13 times more often than children's symptoms. In contrast, over the telephone, adult symptoms were addressed 2.1 times more frequently than children's symptoms. Despite the differences in frequencies of adult and child symptom assessments, users of the Internet and telephone callers asked about specific symptoms with similar relative frequencies. Analysis of 20 adult symptom types shared by the Web and call center revealed that by excluding only 2 assessments (nasal symptoms and leg pain) the remaining 18 showed a significant correlation in counts of use ( r 2 = 0.68, p < 0.001 for linear trend). Conclusions: Internet users have symptoms assessed in similar proportions to callers, with a few exceptions. Compared with callers, Web users are much more likely looking for information about adult symptoms. Callers are proportionally asking more about acute symptoms, whereas Internet users appear more interested in symptom assessment of chronic conditions.

ObjectiveThe harvest of some microvascular free flaps for head and neck reconstruction entails tedious and time‐consuming dissection of multiple perforating vessels and/or muscular attachments. The objective of this study is to investigate the use of ultrasonic shears as a means to decrease operative time and increase surgical efficiency in the harvest of microvascular free flaps.Study DesignProspective cohort study.SettingTertiary referral center.Subjects and MethodsA prospective study of all people undergoing fibula (FFF) or anterolateral thigh (ALT) free flap reconstruction of head and neck defects was conducted from October 1, 2005, through December 30, 2009.ResultsThere were 69 FFF and 39 ALT free flaps performed by a single surgeon during the study period. Ultrasonic shears were used in 53 (76.8%) FFF and 26 (80.6%) ALT free flaps, whereas traditional dissection techniques were used in 16 (23.2%) FFF and 13 (19.4%) ALT free flaps. The use of ultrasonic shears significantly decreased the harvest time of FFF and ALT free flaps an average of 14.5 and 16.3 minutes, respectively. The average cost savings associated with the use of ultrasonic shears was $492 for FFF and $543 for ALT free flaps compared to traditional dissections techniques. Similar rates of complications were observed when ultrasonic shears were used compared to traditional techniques.ConclusionsThe use of ultrasonic shears in the harvest of microvascular free flaps decreases operative time, leading to significantly decreased costs without an increased risk of complications compared to traditional dissection techniques.