Citations

Background: Prior reports on metabolic derangements observed in distance running frequently have small sample sizes, lack prerace laboratory measures, and report sodium as the sole measure. Hypothesis: Metabolic abnormalities—hyponatremia, hypokalemia, renal dysfunction, hemoconcentration—are frequent after completing a full or half marathon. Clinically significant changes occur in these laboratory values after race completion. Study Design: Observational, cross-sectional study. Methods: Consenting marathon and half marathon racers completed a survey as well as finger stick blood sampling on race day of the National Marathon to Fight Breast Cancer (Jacksonville, Florida, February 2008). Parallel blood measures were obtained before and after race completion (prerace, n = 161; postrace, n = 195). Results: The prevalence of prerace and postrace hyponatremia was 8 of 161 (5.0%) and 16 of 195 (8.2%), respectively. Hypokalemia was not present prerace but was present in 1 runner postrace (1 of 195). Renal dysfunction occurred prerace in 14 of 161 (8.7%) and postrace in 83 of 195 (42.6%). Among those with postrace renal dysfunction, 45.8% (38 of 83) were classified as moderate or severe. Hemoconcentration was present in 2 of 161 (1.2%) prerace and 6 of 195 (3.1%) postrace. The mean changes in laboratory values were (postrace minus prerace): sodium, 1.6 mmol/L; potassium, −0.2 mmol/L; blood urea nitrogen, 2.8 mg/dL; creatinine, 0.2 mg/dL; and hemoglobin, 0.3 g/dL for 149 pairs (except blood urea nitrogen, n = 147 pairs). Changes were significant for all comparisons ( P < 0.01) except potassium ( P = 0.08) and hemoglobin ( P = 0.01). Conclusions: Metabolic abnormalities are common among endurance racers, and they may be present prerace, including hyponatremia. The clinical significance of these findings is unknown. Clinical relevance: It is unclear which runners are at risk for developing clinically important metabolic derangements. Participating in prolonged endurance exercise appears to be safe in the majority of racers.

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 &lt; 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&lt;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 Background: Obesity has been linked to NHL risk in some studies, and may be stronger for obesity in early adulthood (ages 18-20). There has only been limited evaluation of physical activity and risk of NHL, particularly physical activity earlier in life. The purpose of this study was to evaluate the association of body mass index (BMI), physical activity (PA), and NHL risk during adulthood and at age 18. Methods: Self-reported anthropometrics and PA were collected in a clinic-based study of 954 newly diagnosed NHL cases and 1146 controls enrolled at the Mayo Clinic from 2002-2008. PA variables included duration and frequency of mild, moderate, and strenuous PA two years prior to case diagnosis or control selection, strenuous activity at age 18 (any vs. none), and height and weight at both time periods. An overall PA index was estimated by weighting the reported duration and frequency of each PA intensity by the average energy requirement (defined in METs) to obtain an average MET-minutes/week for each participant. BMI was calculated as weight (kg) divided by height (m) squared. Odds Ratios (OR), 95% confidence intervals (CI), and test for trend were estimated using unconditional logistic regression adjusted for the age, gender, and residence. Continuous variables were divided into quartiles according to the distribution among the controls; results are reported for the highest vs. lowest category or quartile unless otherwise specified. Results: The mean age at diagnosis/enrollment was 61 for both cases and controls; 47% and 43% of the cases and controls, respectively, were female. The most common NHL subtypes were CLL/SLL (32%), follicular lymphoma (FL; 26%), and diffuse large B-cell lymphoma (DLBCL; 21%). BMI 2 years prior to diagnosis was not associated with NHL risk (OR=1.21, p-trend=0.13), while there was a positive association with BMI at age 18 (OR=1.40, p-trend=0.001). There was no association of the PA index with risk (OR=0.91, p-trend=0.29). Furthermore, frequency of walking (OR=0.71, p-trend 0.43), mild (OR=1.30, p-trend=0.64), moderate (OR=0.99, p-trend=0.75), and strenuous (OR=0.77, p-trend=0.20) PA were not associated with NHL risk when evaluated individually. However, there was a suggestive weak inverse association between strenuous activity at age 18 and NHL risk (OR=0.85, 95% CI 0.71-1.05). On exploratory analysis, the association of BMI at age 18 with NHL risk was specific to DLBCL (OR=1.84, p-trend=0.002) and CLL/SLL (OR=1.25, p-trend=0.044) but not FL; all other results were similar across these subtypes. Conclusions: We did not observe an association between adult BMI and NHL risk; however a higher BMI in early adulthood was associated with NHL risk, consistent with limited prior reports. We found little evidence to support an association between PA in either early adulthood or later in life and NHL risk. 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 1833.

Abstract Purpose: This study uses spatially accurate image-guided tissue analysis to evaluate the correlation between Perfusion MRI (pMRI) and tissue microvascular density parameters as markers for tumor recurrence and treatment response in high-grade glioma (HGG). Methods: Following Institutional Review Board approval, we recruited previously treated (including chemo-radiation therapy) HGG patients undergoing surgical re-resection of new enhancing lesions on surveillance MRI. Preoperatively, we acquired pMRI and contrast-enhanced stereotactic T1-Weighted (T1W) MRI data sets. Intraoperatively, we recorded stereotactic locations of multiple biopsies based on T1W data sets that guided surgery. Following surgery, we coregistered pMRI and T1W data sets to calculate localized relative cerebral blood volume (rCBV) for each stereotactic specimen location. For each specimen, we performed 1) standard H&E staining to diagnose tumor recurrence or post-treatment radiation effect (PTRE); and 2) immunohistochemical analysis with CD34 to highlight tissue vessels. We analyzed CD-34 stained slides with Axiovision Automeasure 3.4 (Zeiss, Germany) to calculate both total microvessel number (MVN) and total microvessel area (MVA), each normalized to total slide specimen area (μm2). We calculated Pearson correlations to establish relationships between a) rCBV and MVN; and b) rCBV and MVA. We also performed t-test to compare MVN, MVA, and rCBV values between tumor and PTRE samples. A neuroradiologist performed all coregistration and pMRI calculations, and a neuropathologist analyzed all tissue specimens, without knowledge of corresponding data. A biostatistician performed all statistical comparisons. Results: In this preliminary study, we included 16 tissue specimens (from 8 subjects), each diagnosed as either tumor (n=7) or PTRE (n=9). We successfully calculated localized rCBV and determined both MVA and MVN for each specimen. The rCBV values showed highest correlation with total vessel area (MVA) (r=0.65, p=0.007) and slightly less correlation with vessel number (MVN) (r=0.52, p=0.04). Tumor showed significantly higher values than PTRE for all parameters: rCBV (1.87 + 0.82 versus 0.78 + 0.2, p=.002); MVA (0.22 + 0.03 versus 0.04 + 0.007, p=0.0001); and MVN (0.0068 + 0.001 versus. 0.0016 + 0.0006, p=0.0004). Conclusion: These preliminary results show the promise of Perfusion MRI to non-invasively estimate tissue microvessel density and distinguish tumor recurrence from treatment effects. The current study is ongoing to confirm results in a larger patient population. 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 3748.

Abstract Background: We had previously reported that the natural product chaetocin has potent and selective in vitro, ex vivo and in vivo anti-myeloma activity attributable to the imposition of cellular oxidative stress (ROS) in part mediated via competitive inhibition of the redox enzyme thioredoxin reductase. Having also observed chaetocin-induced cytotoxicity in solid tumor cell lines, we now extend prior work to characterize the effects of chaetocin in solid tumor cell lines and in human umbilical vein endothelial cells (HUVECs). Methods: The effects of chaetocin in solid tumor cell lines were assessed using colony forming assays, trypan blue exclusion assays, apoptosis and autophagy assays, electron microscopy, transcriptional profiling, and the National Cancer Institute 60 cell line screen. Results: Chaetocin demonstrated potent anti-cancer activity in all assessed solid tumor cell lines with IC50 values between 2-10 nM (24 h exposures, colony forming assays). While apoptosis was induced in a cell line-dependant fashion, it was not required for chaetocin-induced cytotoxicity, as ZVAD-fmk prevented apoptosis but not cell death. Markers of autophagy were not altered by chaetocin treatment. Interestingly, results form the NCI 60 cell line screen showed that hematological cell lines were generally more resistant to chaetocin than solid tumor lines despite our prior report indicating the activity of chaetocin in myeloma. Transcriptional profiling results were consistent with those anticipated from an agent producing cell death via imposition of cellular ROS, with heme oxidase-1 prominently induced along with other transcripts in pathways related to inflammatory response and cell death. Results from OxyBlot protein oxidation kit analyses (Millipore, Billerica, MA) confirmed a generalized increase in the carbonyl modification of proteins, a hallmark of cellular oxidative damage, in response to chaetocin treatment. Experiments using Rho0 mitochondrial inactive cells indicated that cellular ROS is induced by chaetocin independent of respiratory functional mitochondria. Chaetocin was also shown to block the interleukin-, fibroblast growth factor- or EGM2 media-induced proliferation of HUVEC cells at low-nanomolar concentrations. Conclusions: Chaetocin has wide-ranging antineoplastic activity across not only hematological, but also solid tumor, cell lines and displays evidence of antiangiogentic activity in HUVEC proliferation assays. Overall, chaetocin appears to be an attractive agent for further development as a candidate anti-cancer therapeutic in a variety of neoplasms. Supported in part by CA125750. 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 3571.

Abstract Preclinical investigations have identified insulin-like growth factor (IGF) signaling as a key mechanism for cancer growth and resistance to clinically useful therapies in multiple tumor types including breast cancer. Thus, agents targeting and blocking IGF signaling have promise in the treatment of solid tumors. To identify possible mechanisms of resistance to blocking the IGF pathway, we generated a cell line that was resistant to the IGF-1R/InsR benzimidazole inhibitors, BMS-554417 and BMS-536924, and compared expression profiles of the parental and resistant cells lines using Affymetrix GeneChip Human Genome U133 arrays. Compared with MCF-7 cells, breast cancer resistance protein (BCRP) expression was increased 9-fold in MCF-7R4, which was confirmed by immunoblotting and was highly statistically significant (P = 7.13E-09). BCRP was also upregulated in an independently derived resistant cell line, MCF-7 924R. MCF-7R4 cells had significantly lower intracellular accumulation of BMS-536924 compared with MCF-7 cells. Expression of BCRP in MCF-7 cells was sufficient to reduce sensitivity to BMS-536924. Furthermore, knockdown of BCRP in MCF-7R4 cells resensitized cells to BMS-536924. Four cell lines selected for resistance to the pyrrolotriazine IGF-1R/InsR inhibitor, BMS-754807, did not have upregulation of BCRP. These data suggest that benzimidazole IGF-1R/InsR inhibitors may select for upregulation and be effluxed by the ATP-binding cassette transporter, BCRP, contributing to resistance. However, pyrrolotriazine IGF-1R/InsR inhibitors do not appear to be affected by this resistance mechanism. Mol Cancer Ther; 10(1); 117–25. ©2011 AACR.

Brown fat is specialized for energy expenditure and has therefore been proposed to function as a defense against obesity. Despite recent advances in delineating the transcriptional regulation of brown adipocyte differentiation, cellular lineage specification and developmental cues specifying brown-fat cell fate remain poorly understood. In this study, we identify and isolate a subpopulation of adipogenic progenitors (Sca-1 + /CD45 − /Mac1 − ; referred to as Sca-1 + progenitor cells, ScaPCs) residing in murine brown fat, white fat, and skeletal muscle. ScaPCs derived from different tissues possess unique molecular expression signatures and adipogenic capacities. Importantly, although the ScaPCs from interscapular brown adipose tissue (BAT) are constitutively committed brown-fat progenitors, Sca-1 + cells from skeletal muscle and subcutaneous white fat are highly inducible to differentiate into brown-like adipocytes upon stimulation with bone morphogenetic protein 7 (BMP7). Consistent with these findings, human preadipocytes isolated from subcutaneous white fat also exhibit the greatest inducible capacity to become brown adipocytes compared with cells isolated from mesenteric or omental white fat. When muscle-resident ScaPCs are re-engrafted into skeletal muscle of syngeneic mice, BMP7-treated ScaPCs efficiently develop into adipose tissue with brown fat-specific characteristics. Importantly, ScaPCs from obesity-resistant mice exhibit markedly higher thermogenic capacity compared with cells isolated from obesity-prone mice. These data establish the molecular characteristics of tissue-resident adipose progenitors and demonstrate a dynamic interplay between these progenitors and inductive signals that act in concert to specify brown adipocyte development.

AbstractVorinostat, an oral histone deacetylase inhibitor with antitumor activity, is in clinical trials for hematologic and solid tumors that metastasize and compromise bone structure. Consequently, there is a requirement to establish the effects of vorinostat on tumor growth within bone. Breast (MDA-231) and prostate (PC3) cancer cells were injected into tibias of SCID/NCr mice and the effects of vorinostat on tumor growth and osteolytic disease were assessed by radiography, micro-computed tomography, and histologic and molecular analyses. Vorinostat-treated and control mice without tumors were also examined. Tumor growth in bone was reduced ∼33% by vorinostat with inhibited osteolysis in the first few weeks of the experiment. However, osteolysis became more severe in both the vehicle and vorinostat-treated groups. Vorinostat increased the expression of tumor-derived factors promoting bone resorption, including PTHrP, IL-8, and osteopontin. After 4 weeks of vorinostat therapy, the non–tumor-bearing contralateral femurs and limbs from vorinostat-treated tumor-free SCID mice showed significant bone loss (50% volume density of controls). Thus, our studies indicate that vorinostat effectively inhibits tumor growth in bone, but has a negative systemic effect reducing normal trabecular bone mass. Vorinostat treatment reduces tumor growth in bone and accompanying osteolytic disease as a result of decreased tumor burden in bone. However, vorinostat can promote osteopenia throughout the skeleton independent of tumor cell activity. Mol Cancer Ther; 9(12); 3210–20. ©2010 AACR.