bluuebunny/crossref_metadata_2025 huggingface dataset:
GhostRider
Authors: Liu Chang , Harris Austin , Maas Martin , Hicks Michael , Tiwari Mohit , Shi Elaine
Published: May 2015

This paper presents a new, co-designed compiler and architecture called GhostRider for supporting privacy preserving computation in the cloud. GhostRider ensures all programs satisfy a property called memory-trace obliviousness (MTO): Even an adversary that observes memory, bus traffic, and access times while the program executes can learn nothing about the program's sensitive inputs and outputs. One way to achieve MTO is to employ Oblivious RAM (ORAM), allocating all code and data in a single ORAM bank, and to also disable caches or fix the rate of memory traffic. This baseline approach can be inefficient, and so GhostRider's compiler uses a program analysis to do better, allocating data to non-oblivious, encrypted RAM (ERAM) and employing a scratchpad when doing so will not compromise MTO. The compiler can also allocate to multiple ORAM banks, which sometimes significantly reduces access times.We have formalized our approach and proved it enjoys MTO. Our FPGA-based hardware prototype and simulation results show that GhostRider significantly outperforms the baseline strategy.
GPU Concurrency
Authors: Alglave Jade , Batty Mark , Donaldson Alastair F. , Gopalakrishnan Ganesh , Ketema Jeroen , Poetzl Daniel , Sorensen Tyler , Wickerson John
Published: May 2015

Concurrency is pervasive and perplexing, particularly on graphics processing units (GPUs). Current specifications of languages and hardware are inconclusive; thus programmers often rely on folklore assumptions when writing software.

To remedy this state of affairs, we conducted a large empirical study of the concurrent behaviour of deployed GPUs. Armed with litmus tests (i.e. short concurrent programs), we questioned the assumptions in programming guides and vendor documentation about the guarantees provided by hardware. We developed a tool to generate thousands of litmus tests and run them under stressful workloads. We observed a litany of previously elusive weak behaviours, and exposed folklore beliefs about GPU programming---often supported by official tutorials---as false.

As a way forward, we propose a model of Nvidia GPU hardware, which correctly models every behaviour witnessed in our experiments. The model is a variant of SPARC Relaxed Memory Order (RMO), structured following the GPU concurrency hierarchy.
Dual Execution for On the Fly Fine Grained Execution Comparison
Authors: Kim Dohyeong , Kwon Yonghwi , Sumner William N. , Zhang Xiangyu , Xu Dongyan
Published: May 2015

Execution comparison has many applications in debugging, malware analysis, software feature identification, and intrusion detection. Existing comparison techniques have various limitations. Some can only compare at the system event level and require executions to take the same input. Some require storing instruction traces that are very space-consuming and have difficulty dealing with non-determinism. In this paper, we propose a novel dual execution technique that allows on-the-fly comparison at the instruction level. Only differences between the executions are recorded. It allows executions to proceed in a coupled mode such that they share the same input sequence with the same timing, reducing nondeterminism. It also allows them to proceed in a decoupled mode such that the user can interact with each one differently. Decoupled executions can be recoupled to share the same future inputs and facilitate further comparison. We have implemented a prototype and applied it to identifying functional components for reuse, comparative debugging with new GDB primitives, and understanding real world regression failures. Our results show that dual execution is a critical enabling technique for execution comparison.
Gastrin stimulates MMP-1 expression in gastric epithelial cells: putative role in gastric epithelial cell migration
Authors: Kumar J. Dinesh , Steele Islay , Moore Andrew R. , Murugesan Senthil V. , Rakonczay Zoltan , Venglovecz Viktoria , Pritchard D. Mark , Dimaline Rodney , Tiszlavicz Laszlo , Varro Andrea , Dockray Graham J.
Published: May 2015

The pyloric antral hormone gastrin plays a role in remodeling of the gastric epithelium, but the specific targets of gastrin that mediate these effects are poorly understood. Glandular epithelial cells of the gastric corpus express matrix metalloproteinase (MMP)-1, which is a potential determinant of tissue remodeling; some of these cells express the CCK-2 receptor at which gastrin acts. We have now examined the hypothesis that gastrin stimulates expression of MMP-1 in the stomach. We determined MMP-1 transcript abundance in gastric mucosal biopsies from Helicobacter pylori negative human subjects with normal gastric mucosal histology, who had a range of serum gastrin concentrations due in part to treatment with proton pump inhibitors (PPI). The effects of gastrin were studied on gastric epithelial AGS-GR cells using Western blot and migration assays. In human subjects with increased serum gastrin due to PPI usage, MMP-1 transcript abundance was increased 2-fold; there was also increased MMP-7 transcript abundance but not MMP-3. In Western blots, gastrin increased proMMP-1 abundance, as well that of a minor band corresponding to active MMP-1, in the media of AGS-GR cells, and the response was mediated by protein kinase C and p42/44 MAP kinase. There was also increased MMP-1 enzyme activity. Gastrin-stimulated AGS-GR cell migration in both scratch wound and Boyden chamber assays was inhibited by MMP-1 immunoneutralization. We conclude that MMP-1 expression is a target of gastrin implicated in mucosal remodeling.
Hyperhomocysteinemia inhibits satellite cell regenerative capacity through p38 alpha/beta MAPK signaling
Authors: Veeranki Sudhakar , Lominadze David , Tyagi Suresh C.
Published: May 2015

Chronic failure in maintenance and regeneration of skeletal muscles leads to lower muscle mass (sarcopenia), muscle weakness, and poor response to injury. Evidence suggests that aberrant p38 MAPK signaling undermines the repair process after injury in aged mice. Previous studies have shown that hyperhomocysteinemia (HHcy) has been associated with muscle weakness and lower than normal body weights. However, whether or not HHcy condition also compromises skeletal muscle regenerative capabilities is not clear. In the current study, we show that CBS−/+ mice, a model for HHcy condition, exhibited compromised regenerative function and cell proliferation upon injury. However, there was no significant difference in Pax7 expression levels in the satellite cells from CBS−/+ mouse skeletal muscles. Interestingly, the satellite cells from CBS−/+ mice not only exhibited diminished in vitro proliferative capabilities, but also there was heightened oxidative stress. In addition, there was enhanced p38 MAPK activation as well as p16 and p21 expression in the CBS−/+ mouse satellite cells. Moreover, the C2C12 myoblasts also exhibited higher p38 MAPK activation and p16 expression upon treatment with homocysteine in addition to enhanced ROS presence. Tissue engraftment potential and regeneration after injury were restored to some extent upon treatment with the p38-MAPK inhibitor, SB203580 , in the CBS−/+ mice. These results together suggest that HHcy-induced diminished satellite cell proliferation involves excessive oxidative stress and p38 MAPK signaling. Our study further proposes that HHcy is a potential risk factor for elderly frailty, and need to be considered as a therapeutic target while designing the alleviation interventions/postinjury rehabilitation measures for adults with HHcy.
Acute ascorbic acid ingestion increases skeletal muscle blood flow and oxygen consumption via local vasodilation during graded handgrip exercise in older adults
Authors: Richards Jennifer C. , Crecelius Anne R. , Larson Dennis G. , Dinenno Frank A.
Published: May 2015

Human aging is associated with reduced skeletal muscle perfusion during exercise, which may be a result of impaired endothelium-dependent dilation and/or attenuated ability to blunt sympathetically mediated vasoconstriction. Intra-arterial infusion of ascorbic acid (AA) increases nitric oxide-mediated vasodilation and forearm blood flow (FBF) during handgrip exercise in older adults, yet it remains unknown whether an acute oral dose can similarly improve FBF or enhance the ability to blunt sympathetic vasoconstriction during exercise. We hypothesized that 1) acute oral AA would improve FBF (Doppler ultrasound) and oxygen consumption (V̇o2) via local vasodilation during graded rhythmic handgrip exercise in older adults ( protocol 1), and 2) AA ingestion would not enhance sympatholysis in older adults during handgrip exercise ( protocol 2). In protocol 1 ( n = 8; 65 ± 3 yr), AA did not influence FBF or V̇o2 during rest or 5% maximal voluntary contraction (MVC) exercise, but increased FBF (199 ± 13 vs. 248 ± 16 ml/min and 343 ± 24 vs. 403 ± 33 ml/min; P < 0.05) and V̇o2 (26 ± 2 vs. 34 ± 3 ml/min and 43 ± 4 vs. 50 ± 5 ml/min; P < 0.05) at both 15 and 25% MVC, respectively. The increased FBF was due to elevations in forearm vascular conductance (FVC). In protocol 2 ( n = 10; 63 ± 2 yr), following AA, FBF was similarly elevated during 15% MVC (∼20%); however, vasoconstriction to reflex increases in sympathetic activity during −40 mmHg lower-body negative pressure at rest (ΔFVC: −16 ± 3 vs. −16 ± 2%) or during 15% MVC (ΔFVC: −12 ± 2 vs. −11 ± 4%) was unchanged. Our collective results indicate that acute oral ingestion of AA improves muscle blood flow and V̇o2 during exercise in older adults via local vasodilation.
Physiological response of cardiac tissue to bisphenol a: alterations in ventricular pressure and contractility
Authors: Posnack Nikki Gillum , Brooks Daina , Chandra Akhil , Jaimes Rafael , Sarvazyan Narine , Kay Matthew
Published: May 2015

Biomonitoring studies have indicated that humans are routinely exposed to bisphenol A (BPA), a chemical that is commonly used in the production of polycarbonate plastics and epoxy resins. Epidemiological studies have shown that BPA exposure in humans is associated with cardiovascular disease; however, the direct effects of BPA on cardiac physiology are largely unknown. Previously, we have shown that BPA exposure slows atrioventricular electrical conduction, decreases epicardial conduction velocity, and prolongs action potential duration in excised rat hearts. In the present study, we tested if BPA exposure also adversely affects cardiac contractile performance. We examined the impact of BPA exposure level, sex, and pacing rate on cardiac contractile function in excised rat hearts. Hearts were retrogradely perfused at constant pressure and exposed to 10−9-10−4 M BPA. Left ventricular developed pressure and contractility were measured during sinus rhythm and during pacing (5, 6.5, and 9 Hz). Ca2+ transients were imaged from whole hearts and from neonatal rat cardiomyocyte layers. During sinus rhythm in female hearts, BPA exposure decreased left ventricular developed pressure and inotropy in a dose-dependent manner. The reduced contractile performance was exacerbated at higher pacing rates. BPA-induced effects on contractile performance were also observed in male hearts, albeit to a lesser extent. Exposure to BPA altered Ca2+ handling within whole hearts (reduced diastolic and systolic Ca2+ transient potentiation) and neonatal cardiomyocytes (reduced Ca2+ transient amplitude and prolonged Ca2+ transient release time). In conclusion, BPA exposure significantly impaired cardiac performance in a dose-dependent manner, having a major negative impact upon electrical conduction, intracellular Ca2+ handing, and ventricular contractility.
Contribution of SRF, Elk-1, and myocardin to airway smooth muscle remodeling in heaves, an asthma-like disease of horses
Authors: Chevigny Mylène , Guérin-Montpetit Karine , Vargas Amandine , Lefebvre-Lavoie Josiane , Lavoie Jean-Pierre
Published: May 2015

Myocyte hyperplasia and hypertrophy contribute to the increased mass of airway smooth muscle (ASM) in asthma. Serum-response factor (SRF) is a transcription factor that regulates myocyte differentiation in vitro in vascular and intestinal smooth muscles. When SRF is associated with phosphorylated (p)Elk-1, it promotes ASM proliferation while binding to myocardin (MYOCD) leading to the expression of contractile elements in these tissues. The objective of this study was therefore to characterize the expression of SRF, pElk-1, and MYOCD in ASM cells from central and peripheral airways in heaves, a spontaneously occurring asthma-like disease of horses, and in controls. Six horses with heaves and five aged-matched controls kept in the same environment were studied. Nuclear protein expression of SRF, pElk-1, and MYOCD was evaluated in peripheral airways and endobronchial biopsies obtained during disease remission and after 1 and 30 days of naturally occurring antigenic exposure using immunohistochemistry and immunofluorescence techniques. Nuclear expression of SRF ( P = 0.03, remission vs. 30 days) and MYOCD ( P = 0.05, controls vs. heaves at 30 days) increased in the peripheral airways of horses with heaves during disease exacerbation, while MYOCD ( P = 0.04, remission vs. 30 days) decreased in the central airways of control horses. No changes were observed in the expression of pElk-1 protein in either tissue. In conclusion, SRF and its cofactor MYOCD likely contribute to the hypertrophy of peripheral ASM observed in equine asthmatic airways, while the remodeling of the central airways is more static or involves different transcription factors.
Elevated sputum BPIFB1 levels in smokers with chronic obstructive pulmonary disease: a longitudinal study
Authors: Gao J. , Ohlmeier S. , Nieminen P. , Toljamo T. , Tiitinen S. , Kanerva T. , Bingle L. , Araujo B. , Rönty M. , Höyhtyä M. , Bingle C. D. , Mazur W. , Pulkkinen V.
Published: May 2015

A previous study involving a proteomic screen of induced sputum from smokers and patients with chronic obstructive pulmonary disease (COPD) demonstrated elevated levels of bactericidal/permeability-increasing fold-containing protein B1 (BPIFB1). The aim of the present study was to further evaluate the association of sputum BPIFB1 levels with smoking and longitudinal changes in lung function in smokers with COPD. Sputum BPIFB1 was characterized by two-dimensional gel electrophoresis and mass spectrometry. The expression of BPIFB1 in COPD was investigated by immunoblotting and immunohistochemistry using sputum and lung tissue samples. BPIFB1 levels were also assessed in induced sputum from nonsmokers ( n = 31), smokers ( n = 169), and patients with COPD ( n = 52) via an ELISA-based method. The longitudinal changes in lung function during the 4-year follow-up period were compared with the baseline sputum BPIFB1 levels. In lung tissue samples, BPIFB1 was localized to regions of goblet cell metaplasia. Secreted and glycosylated BPIFB1 was significantly elevated in the sputum of patients with COPD compared with that of smokers and nonsmokers. Sputum BPIFB1 levels correlated with pack-years and lung function as measured by forced expiratory volume in 1 s (FEV1) % predicted and FEV1/FVC (forced vital capacity) at baseline and after the 4-year follow-up in all participants. The changes in lung function over 4 years were significantly associated with BPIFB1 levels in current smokers with COPD. In conclusion, higher sputum concentrations of BPIFB1 were associated with changes of lung function over time, especially in current smokers with COPD. BPIFB1 may be involved in the pathogenesis of smoking-related lung diseases.
Ascorbic acid abrogates microparticle generation and vascular injuries associated with high-pressure exposure
Authors: Yang Ming , Bhopale Veena M. , Thom Stephen R.
Published: May 2015

We hypothesized that pathological changes associated with elevations in annexin V-positive microparticles (MPs) following high-pressure exposures can be abrogated by ascorbic acid in a murine model. Mice exposed for 2 h to 790-kPa air and killed at 2 or 13 h postdecompression exhibited over threefold elevations in circulating MPs, as well as subgroups bearing Ly6G, CD41, Ter119, CD31, and CD142 surface proteins. There was evidence of significant neutrophil activation, platelet-neutrophil interactions, and vascular injury to brain, omentum, psoas, and skeletal muscles assessed as leakage of high-molecular-weight dextran. Prophylactic ascorbic acid (500 mg/kg ip) administration prevented all postdecompression neutrophil changes and vascular injuries. Ascorbic acid administration immediately after decompression abrogated most changes, but evidence of vascular leakage in the brain and skeletal muscle at 13 h postdecompression persisted. No significant elevations in these parameters occurred after injection of ascorbic acid alone. The findings support the idea that MP production occurring with exposures to elevated gas pressure is an oxidative stress response and that antioxidants may offer protection from pathological effects associated with decompression.
Seasonal variation in natural abundance of2H and18O in urine samples from rural Nigeria
Authors: Harbison Justin E. , Dugas Lara R. , Brieger William , Tayo Bamidele O. , Alabi Tunrayo , Schoeller Dale A. , Luke Amy
Published: May 2015

The doubly labeled water (DLW) method is used to measure free-living energy expenditure in humans. Inherent to this technique is the assumption that natural abundances of stable isotopes2H and18O in body water remain constant over the course of the measurement period and after elimination of the loading dose of DLW will return to the same predose level. To determine variability in the natural abundances of2H and18O in humans living in a region with seasonal shifts in rain patterns and sources of drinking water, over the course of 12 mo we collected weekly urine samples from four individuals living in southwest Nigeria as well as samples of their drinking water. From ongoing regional studies of hypertension, obesity, and energy expenditure, we estimated average water turnover rate, urine volumes, and sodium and potassium excretion. Results suggest that2H and18O in urine, mean concentrations of urinary sodium and potassium, urine volume, and total body turnover differed significantly from dry to rainy season. Additionally, seasonal weather variables (mean monthly maximum temperatures, total monthly rainfall, and minimum relative humidity) were all significantly associated with natural abundances in urine. No seasonal difference was observed in drinking water samples. Findings suggest that natural abundances in urine may not remain constant as assumed, and studies incorporating DLW measurements across the transition of seasons should interpret results with caution unless appropriate doses of the tracers are used.
Heart failure with preserved ejection fraction: Defining the function of ROS and NO
Authors: Zuo Li , Chuang Chia-Chen , Hemmelgarn Benjamin T. , Best Thomas M.
Published: May 2015

The understanding of complex molecular mechanisms underlying heart failure (HF) is constantly under revision. Recent research has paid much attention to understanding the growing number of patients that exhibit HF symptoms yet have an ejection fraction similar to a normal phenotype. Termed heart failure with preserved ejection fraction (HFpEF), this novel hypothesis traces its roots to a proinflammatory state initiated in part by the existence of comorbidities that create a favorable environment for the production of reactive oxygen species (ROS). Triggering a cascade that involves reduced nitric oxide (NO) availability, elevated ROS levels in the coronary endothelium eventually contribute to hypertrophy and increased resting tension in cardiomyocytes. Improved understanding of the molecular pathways associated with HFpEF has led to studies that concentrate on reducing ROS production in the heart, boosting NO availability, and increasing exercise capacity for HFpEF patients. This review will explore the latest research into the role of ROS and NO in the progression of HFpEF, as well as discuss the encouraging results of numerous therapeutic studies.
Secalonic Acid-D Represses HIF1α/VEGF-Mediated Angiogenesis by Regulating the Akt/mTOR/p70S6K Signaling Cascade
Authors: Guru Santosh Kumar , Pathania Anup Singh , Kumar Suresh , Ramesh Deshidi , Kumar Manjeet , Rana Satiander , Kumar Ajay , Malik Fayaz , Sharma P.R. , Chandan B.K. , Jaglan Sundeep , Sharma J.P. , Shah Bhahwal Ali , Tasduq Sheikh Abdullah , Lattoo Surrinder K. , Faruk Abdul , Saxena A.K. , Vishwakarma R.A. , Bhushan Shashi
Published: May 2015

Tumor angiogenesis is a validated target for therapeutic intervention, but agents that are more disease selective are needed. Here, we report the isolation of secalonic acid-D (SAD), a mycotoxin from a novel source that exhibits potent antiangiogenic antitumor activity. SAD inhibited multiple HIF1α/VEGF-arbitrated angiogenesis dynamics as scored in human umbilical vascular endothelial cells and human MCF-7 breast tumor xenografts. Similarly, SAD suppressed VEGF-induced microvessel sprouting from rat aortic ring and blood vessel formation in the Matrigel plug assay in C57/BL6J mice. Under normoxic or hypoxic conditions, SAD inhibited cell survival through the Akt/mTOR/p70S6K pathway, with attendant effects on key proangiogenesis factors, including HIF1α, VEGFR, and MMP-2/MMP-9. These effects were reversed by cotreatment with the Akt inhibitors perifosine and GSK69069 or by the addition of neutralizing VEGF antibodies. The apoptotic properties of SAD were determined to be both extrinsic and intrinsic in nature, whereas the cell-cycle inhibitory effects were mediated by altering the level of key G1–S transition-phase proteins. In experimental mouse models of breast cancer, SAD dosing produced no apparent toxicities (either orally or intraperitoneal) at levels that yielded antitumor effects. Taken together, our findings offered a preclinical validation and mechanistic definition of the antiangiogenic activity of a novel mycotoxin, with potential application as a cancer-selective therapeutic agent. Cancer Res; 75(14); 2886–96. ©2015 AACR.
Blocking Tumor Necrosis Factor α Enhances CD8 T-cell–Dependent Immunity in Experimental Melanoma
Authors: Bertrand Florie , Rochotte Julia , Colacios Céline , Montfort Anne , Tilkin-Mariamé Anne-Françoise , Touriol Christian , Rochaix Philippe , Lajoie-Mazenc Isabelle , Andrieu-Abadie Nathalie , Levade Thierry , Benoist Hervé , Ségui Bruno
Published: May 2015

TNF plays a dual, still enigmatic role in melanoma, either acting as a cytotoxic cytokine or favoring a tumorigenic inflammatory microenvironment. Herein, the tumor growth of melanoma cell lines expressing major histocompatibility complex class I molecules at high levels (MHC-Ihigh) was dramatically impaired in TNF-deficient mice, and this was associated with enhanced tumor-infiltrating CD8+ T lymphocytes. Immunodepletion of CD8 T cells fully restored melanoma growth in TNF−/− mice. Systemic administration of Etanercept inhibited MHC-Ihigh melanoma growth in immunocompetent but not in immunodeficient (IFNγ−/−, nude, or CD8−/−) mice. MHC-Ihigh melanoma growth was also reduced in mice lacking TNF-R1, but not TNF-R2. TNF−/− and TNF-R1−/− mice as well as Etanercept-treated WT mice displayed enhanced intratumor content of high endothelial venules surrounded by high CD8+ T-cell density. Adoptive transfer of activated TNF-R1–deficient or –proficient CD8+ T cells in CD8-deficient mice bearing B16K1 tumors demonstrated that TNF-R1 deficiency facilitates the accumulation of live CD8+ T cells into the tumors. Moreover, in vitro experiments indicated that TNF triggered activated CD8+ T cell death in a TNF-R1–dependent manner, likely limiting the accumulation of tumor-infiltrating CD8+ T cells in TNF/TNF-R1–proficient animals. Collectively, our observations indicate that TNF-R1–dependent TNF signaling impairs tumor-infiltrating CD8+ T-cell accumulation and may serve as a putative target to favor CD8+ T-cell–dependent immune response in melanoma. Cancer Res; 75(13); 2619–28. ©2015 AACR.
NKX3.1 Suppresses TMPRSS2–ERG Gene Rearrangement and Mediates Repair of Androgen Receptor–Induced DNA Damage
Authors: Bowen Cai , Zheng Tian , Gelmann Edward P.
Published: May 2015

TMPRSS2 gene rearrangements occur at DNA breaks formed during androgen receptor–mediated transcription and activate expression of ETS transcription factors at the early stages of more than half of prostate cancers. NKX3.1, a prostate tumor suppressor that accelerates the DNA repair response, binds to androgen receptor at the ERG gene breakpoint and inhibits both the juxtaposition of the TMPRSS2 and ERG gene loci and also their recombination. NKX3.1 acts by accelerating DNA repair after androgen-induced transcriptional activation. NKX3.1 influences the recruitment of proteins that promote homology-directed DNA repair. Loss of NKX3.1 favors recruitment to the ERG gene breakpoint of proteins that promote error-prone nonhomologous end-joining. Analysis of prostate cancer tissues showed that the presence of a TMPRSS2–ERG rearrangement was highly correlated with lower levels of NKX3.1 expression consistent with the role of NKX3.1 as a suppressor of the pathogenic gene rearrangement. Cancer Res; 75(13); 2686–98. ©2015 AACR.
Mendelian Randomization Study of Body Mass Index and Colorectal Cancer Risk
Authors: Thrift Aaron P. , Gong Jian , Peters Ulrike , Chang-Claude Jenny , Rudolph Anja , Slattery Martha L. , Chan Andrew T. , Locke Adam E. , Kahali Bratati , Justice Anne E. , Pers Tune H. , Gallinger Steven , Hayes Richard B. , Baron John A. , Caan Bette J. , Ogino Shuji , Berndt Sonja I. , Chanock Stephen J. , Casey Graham , Haile Robert W. , Du Mengmeng , Harrison Tabitha A. , Thornquist Mark , Duggan David J. , Le Marchand Loïc , Lindor Noralane M. , Seminara Daniela , Song Mingyang , Wu Kana , Thibodeau Stephen N. , Cotterchio Michelle , Win Aung Ko , Jenkins Mark A. , Hopper John L. , Ulrich Cornelia M. , Potter John D. , Newcomb Polly A. , Hoffmeister Michael , Brenner Hermann , White Emily , Hsu Li , Campbell Peter T.
Published: May 2015

Background: High body mass index (BMI) is consistently linked to increased risk of colorectal cancer for men, whereas the association is less clear for women. As risk estimates from observational studies may be biased and/or confounded, we conducted a Mendelian randomization study to estimate the causal association between BMI and colorectal cancer.

Methods: We used data from 10,226 colorectal cancer cases and 10,286 controls of European ancestry. The Mendelian randomization analysis used a weighted genetic risk score, derived from 77 genome-wide association study–identified variants associated with higher BMI, as an instrumental variable (IV). We compared the IV odds ratio (IV-OR) with the OR obtained using a conventional covariate-adjusted analysis.

Results: Individuals carrying greater numbers of BMI-increasing alleles had higher colorectal cancer risk [per weighted allele OR, 1.31; 95% confidence interval (CI), 1.10–1.57]. Our IV estimation results support the hypothesis that genetically influenced BMI is directly associated with risk for colorectal cancer (IV-OR per 5 kg/m2, 1.50; 95% CI, 1.13–2.01). In the sex-specific IV analyses higher BMI was associated with higher risk of colorectal cancer among women (IV-OR per 5 kg/m2, 1.82; 95% CI, 1.26–2.61). For men, genetically influenced BMI was not associated with colorectal cancer (IV-OR per 5 kg/m2, 1.18; 95% CI, 0.73–1.92).

Conclusions: High BMI was associated with increased colorectal cancer risk for women. Whether abdominal obesity, rather than overall obesity, is a more important risk factor for men requires further investigation.

Impact: Overall, conventional epidemiologic and Mendelian randomization studies suggest a strong association between obesity and the risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 24(7); 1024–31. ©2015 AACR.
Prediagnostic Physical Activity and Colorectal Cancer Survival: Overall and Stratified by Tumor Characteristics
Authors: Hardikar Sheetal , Newcomb Polly A. , Campbell Peter T. , Win Aung Ko , Lindor Noralane M. , Buchanan Daniel D. , Makar Karen W. , Jenkins Mark A. , Potter John D. , Phipps Amanda I.
Published: May 2015

Background: Physical activity is associated with a lower incidence of colorectal cancer; however, the relationship of physical activity with colorectal cancer survival is not yet clear. We evaluated the association between prediagnostic physical activity and colorectal cancer survival, overall and accounting for tumor markers associated with colorectal cancer survival: BRAF and KRAS mutation status and microsatellite instability (MSI) status.

Methods: Participants were 20- to 74-year-old colorectal cancer patients diagnosed between 1998 and 2007 from the population-based Seattle Colon Cancer Family Registry (S-CCFR). Self-reported physical activity in the years preceding colorectal cancer diagnosis was summarized as average metabolic equivalent task hours per week (MET-h/wk; n = 1,309). Somatic BRAF and KRAS mutations and MSI status were evaluated on a subset of patients (n = 1043). Cox regression was used to estimate HRs and 95% confidence intervals (CI) for overall and disease-specific survival after adjusting for relevant confounders. Stratified analyses were conducted across categories of BRAF, KRAS, and MSI, as well as tumor stage and site.

Results: Higher prediagnostic recreational physical activity was associated with significantly more favorable overall survival (HR for highest vs. lowest category, 0.70; 95% CI, 0.52–0.96); associations were similar for colorectal cancer–specific survival. Results consistently indicated a favorable association with physical activity across strata defined by tumor characteristics.

Conclusion: Individuals who were physically active before colorectal cancer diagnosis experienced better survival than those who were inactive or minimally active.

Impact: Our results support existing physical activity recommendations for colorectal cancer patients and suggest that the beneficial effect of activity is not specific to a particular molecular phenotype of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 24(7); 1130–7. ©2015 AACR.
Lung Cancer in the Era of Precision Medicine
Authors: Politi Katerina , Herbst Roy S.
Published: May 2015

The past decade has been transformative for lung cancer patients, physicians, and scientists. The discovery of EGFR mutations that confer sensitivity to tyrosine kinase inhibitors in lung adenocarcinomas in 2004 heralded the beginning of the era of precision medicine for lung cancer. Indeed, it precipitated concerted efforts by many investigators to define molecular subgroups of lung cancer, characterize the genomic landscape of lung cancer subtypes, identify novel therapeutic targets, and define mechanisms of sensitivity and resistance to targeted therapies. The fruits of these efforts are visible every day now in lung cancer clinics: Patients receive molecular testing to determine whether their tumor harbors an actionable mutation, new and improved targeted therapies that can overcome resistance to first-generation drugs are in clinical trials, and drugs targeting the immune system are showing activity in patients. This extraordinary promise is tempered by the sobering fact that even the newest treatments for metastatic disease are rarely curative and are effective only in a small fraction of all patients. Ongoing and future efforts to find new vulnerabilities of lung cancers, unravel the complexity of drug resistance, increase the efficacy of immunotherapies, and perform biomarker-driven clinical trials are necessary to improve outcomes for patients with lung cancer. Clin Cancer Res; 21(10); 2213–20. ©2015 AACR.

See all articles in this CCR Focus section, “Progress in Lung Cancer.”
Squamous Cell Lung Cancer: From Tumor Genomics to Cancer Therapeutics
Authors: Gandara David R. , Hammerman Peter S. , Sos Martin L. , Lara Primo N. , Hirsch Fred R.
Published: May 2015

Squamous cell lung cancer (SCC) represents an area of unmet need in lung cancer research. For the past several years, therapeutic progress in SCC has lagged behind the now more common non–small cell lung cancer histologic subtype of adenocarcinoma. However, recent efforts to define the complex biology underlying SCC have begun to bear fruit in a multitude of ways, including characterization of previously unknown genomic and signaling pathways, delineation of new, potentially actionable molecular targets, and subsequent development of a large number of agents directed against unique SCC-associated molecular abnormalities. For the first time, SCC-specific prognostic gene signatures and predictive biomarkers of new therapeutic agents are emerging. In addition, recent and ongoing clinical trials, including the Lung-MAP master protocol, have been designed to facilitate approval of targeted therapy–biomarker combinations. In this comprehensive review, we describe the current status of SCC therapeutics, recent advances in the understanding of SCC biology and prognostic gene signatures, and the development of innovative new clinical trials, all of which offer new hope for patients with advanced SCC. Clin Cancer Res; 21(10); 2236–43. ©2015 AACR.

See all articles in this CCR Focus section, “Progress in Lung Cancer.”
MEK Inhibitor PD-0325901 Overcomes Resistance to PI3K/mTOR Inhibitor PF-5212384 and Potentiates Antitumor Effects in Human Head and Neck Squamous Cell Carcinoma
Authors: Mohan Suresh , Vander Broek Robert , Shah Sujay , Eytan Danielle F. , Pierce Matthew L. , Carlson Sophie G. , Coupar Jamie F. , Zhang Jialing , Cheng Hui , Chen Zhong , Van Waes Carter
Published: May 2015

Purpose: Head and neck squamous cell carcinomas exhibit variable sensitivity to inhibitors of the PI3K/mTOR pathway, an important target of genomic alterations in this cancer type. The mitogen-activated protein kinase kinase (MEK)/ERK/activator protein 1 (AP-1) and nuclear factor-κB (NF-κB) pathways are also frequently co-activated, but their roles in resistance mechanisms to PI3K/mTOR inhibitors and as therapeutic targets in head and neck squamous cell carcinoma (HNSCC) are not well defined.

Experimental Design: We determined the IC50s of dual PI3K/mTOR inhibitor PF-05212384 (PF-384) by XTT assays in 14 HNSCC lines with PI3K/Akt/mTOR cascade alterations. In two resistant models, we further characterized the molecular, cellular, and in vivo attributes and effects of combining PF-384 with MEK inhibitor PD-0325901 (PD-901).

Results: PF-384 IC50s varied between 0.75 and 133 nmol/L in 14 HNSCC lines with overexpression or mutations of PIK3CA, and sensitivity correlated with increased phospho-AKT(T308/S473). In resistant UMSCC-1 and -46 models, PF-384 increased G0-/G1-phase accumulation but weakly induced sub-G0 cell death. PF-384 inhibited direct targets of PI3K/mTOR, but incompletely attenuated co-activated ERK and UMSCC-1 xenograft growth in vivo. PD-901 strongly inhibited MEK/ERK targets, and the combination of PF-384 and PD-901 inhibited downstream NF-κB and AP-1 transactivation, and IL8 and VEGF production in vitro. PD-901 potently inhibited tumor growth alone and with PF384, enhanced antiproliferative, apoptotic, and anti-angiogenesis activity in vivo.

Conclusions: PI3K/mTOR inhibitor PF-384 exhibits variable activity in a panel of HNSCC cell lines with differing PIK3CA expression and mutation status. MEK inhibitor PD-901 overcomes resistance and enhances antitumor effects observed with PF-384 in vivo. Clin Cancer Res; 21(17); 3946–56. ©2015 AACR.
Aromatase Inhibitor–Mediated Downregulation of INrf2 (Keap1) Leads to Increased Nrf2 and Resistance in Breast Cancer
Authors: Khatri Raju , Shah Preeti , Guha Rupa , Rassool Feyruz V. , Tomkinson Alan E. , Brodie Angela , Jaiswal Anil K.
Published: May 2015

Aromatase inhibitors are effective drugs that reduce or eliminate hormone-sensitive breast cancer. However, despite their efficacy, resistance to these drugs can occur in some patients. The INrf2 (Keap1):Nrf2 complex serves as a sensor of drug/radiation-induced oxidative/electrophilic stress. INrf2 constitutively suppresses Nrf2 by functioning as an adapter protein for the Cul3/Rbx1-mediated ubiquitination/degradation of Nrf2. Upon stress, Nrf2 dissociates from INrf2, is stabilized, translocates to the nucleus, and coordinately induces a battery of cytoprotective gene expression. Current studies investigated the role of Nrf2 in aromatase inhibitor resistance. RT-PCR and immunoblot assays showed that aromatase inhibitor–resistant breast cancer LTLTCa and AnaR cells express lower INrf2 and higher Nrf2 protein levels, as compared with drug-sensitive MCF-7Ca and AC1 cells, respectively. The increase in Nrf2 was due to lower ubiquitination/degradation of Nrf2 in aromatase inhibitor–resistant cells. Higher Nrf2-mediated levels of biotransformation enzymes, drug transporters, and antiapoptotic proteins contributed to reduced efficacy of drugs and aversion to apoptosis that led to drug resistance. shRNA inhibition of Nrf2 in LTLTCa (LTLTCa-Nrf2KD) cells reduced resistance and sensitized cells to aromatase inhibitor exemestane. Interestingly, LTLTCa-Nrf2KD cells also showed reduced levels of aldehyde dehydrogenase, a marker of tumor-initiating cells and significantly decreased mammosphere formation, as compared with LTLTCa-Vector control cells. The results together suggest that persistent aromatase inhibitor treatment downregulated INrf2 leading to higher expression of Nrf2 and Nrf2-regulated cytoprotective proteins that resulted in increased aromatase inhibitor drug resistance. These findings provide a rationale for the development of Nrf2 inhibitors to overcome resistance and increase efficacy of aromatase inhibitors. Mol Cancer Ther; 14(7); 1728–37. ©2015 AACR.
Abstract A05: Secondary consent to research use of biospecimens among men
Authors: Drake Bettina F. , MacMillan William , Haslag-Minoff Jennifer , Kaphingst Kimberly
Published: May 2015

Background: Research conducted with stored biospecimens has substantial societal benefits. Equally important is the use of the samples for research unplanned at the time of consent for biospecimen collection; however, willingness to allow samples to be used for future research may vary by sociodemographic backgrounds. Much of the literature on secondary research use of biospecimens is conducted among women and therefore, little is known about male willingness to consent to secondary research use of biospecimens.

Methods: This study analyzed the future research consent questions from a prostate cancer biorepository study (N=1,932). The prostate cancer biorepository study enrolled men after a prostate cancer diagnosis but before treatment to collect serum and tissue for analyses on genetic, dietary and clinical risk factors for prostate cancer recurrence and mortality. On the consent form, men were asked three separate questions regarding participation in future studies: 1) May we use the materials collected in this study to analyze other factors? 2) May we share your information with other investigators at our institution without any protected health information? 3) May we share your information with other investigators at our university with protected health information? We analyzed each of these questions separately to determine significant predictors for consent to each of these questions. Predictors assessed included race, age, education, marital status, employment status, smoking history, family history of prostate cancer, stage of cancer, and grade of cancer.

Results: 99.33% consented to the secondary use of other factors; 98.39% consented to the secondary use with other investigators without any identifying information; and 68.88% consented to the secondary use with other investigators with identifying information. Race was the only significant predictor for each of the three questions. African-American men were significantly less likely to agree to the secondary use to analyze other factors (Chi sq=8.38, p=0.0152); to share samples without protected health information (Chi sq=29.79, p<0.0001); or to share samples with protected health information (Chi sq=12.85, p=0.0016).

Conclusion: There is a general willingness to consent to secondary research use of biospecimens among men. However, African-American men remain less likely to consent to secondary research use than men of other racial backgrounds. Racial differences in willingness to consent affect whether data generated from biorepositories are applicable to African American men.

Citation Format: Bettina F. Drake, William MacMillan, Jennifer Haslag-Minoff, Kimberly Kaphingst. Secondary consent to research use of biospecimens among men. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr A05. doi:10.1158/1538-7755.DISP13-A05
Abstract A29: Community and academic partnership to prevent breast cancer: Experience from the Community Outreach and Preventive Services Core of a P20 Center
Authors: Rahman Saleh M.M. , Harris Cynthia M. , Mitchell Miaisha , Soliman Karam F.A
Published: May 2015

Background: The Florida A&M University Center of Excellence for Cancer Research, Training and Community Service has developed a historical partnership with Leon and Gadsden, an urban and a rural County respectively, to eliminate cancer disparities through the Community Outreach and Preventive Services (COPS) Core. This partnership also aims at developing, implementing and evaluating theory-driven, culturally sensitive outreach intervention to increase breast cancer screening among underserved population.

Methods: The partnerships accomplish these goals by creating community-university coalition building through CBPR, social marketing campaign, disease prevention, training, and education. Key elements in this partnership are trust, reciprocity, power-sharing in decision making, open communication, and conflict resolution. Five strategies namely ‘Know Thyself’, ‘All the King's Men’, ‘Bonfire of Vanities’, ‘The Wonderful Wizard of Oz’ and ‘The Beautiful and the Damned’ (©Rahman) were used in the CBPR process. An evaluation plan and feedback mechanism was established based on Tuchman's model on stages in decision making such as forming, storming, norming and performing to identify strengths and weaknesses and to adopt specific strategies for improvement.

Results: Two local universities, seven community-based organizations, local health departments, the regional hospital, local chapters of national organizations and media channels are included in this partnership. Fifteen meetings as well as five community events were held and a total of 65 women were recruited for screening mammograms in the past seven months.

Conclusion: Preliminary evaluation indicates trustworthy partnership among stakeholders, successful initial recruitment and social marketing campaign. However, strategic improvements are needed for sustainable partnership to reduce cancer disparities.

Citation Format: Saleh M.M. Rahman, Cynthia M. Harris, Miaisha Mitchell, Karam F.A Soliman. Community and academic partnership to prevent breast cancer: Experience from the Community Outreach and Preventive Services Core of a P20 Center. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr A29. doi:10.1158/1538-7755.DISP13-A29
Abstract A38: High levels of breast cancer mortality: Social determinants of health impact rural African American women and how they conceptualize health in the Arkansas Delta
Authors: Greer-Williams Nancy J. , Enoch Kimberely S. , Starlard-Davenport Athena , Booth Brandon , Kieber-Emmons Thomas , Sarto Gloria E. , Henry-Tillman Ronda
Published: May 2015

We know that certain components including demographics, cultural background, lifestyle choices and lack of access to health care contribute strongly to health disparities in rural regions of the United States. This paper explores perceptions of health, the environment, and the relationships between them that impact breast cancer mortality in the Arkansas Delta. The social-ecological model provides a conceptual approach to relate social determinates to health disparities. This exploratory study blended a community-based, qualitative approach with ecological theory. Our objective was to identify potential social determinants of health which impact these women's ability to seek medical advice or engage in breast cancer prevention in a timely manner. Methods: Qualitative data were gathered with (n=79) women, ranging in age from 18 to 84, who were residents of 3 rural Arkansas Delta communities. Respondents poignantly described issues that affect health disparities in their communities. Conclusions: The study identified potential social determinants of health, at multiple ecological levels, among African American women in three communities in the Arkansas Delta. The social determinants identified had the ability to impact a variety of health behaviors and health outcomes. Our findings show the value of qualitative approaches for exploring the complexities of rural breast cancer mortality.

Citation Format: Nancy J. Greer-Williams, Kimberely S. Enoch, Athena Starlard-Davenport, Brandon Booth, Thomas Kieber-Emmons, Gloria E. Sarto, Ronda Henry-Tillman. High levels of breast cancer mortality: Social determinants of health impact rural African American women and how they conceptualize health in the Arkansas Delta. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr A38. doi:10.1158/1538-7755.DISP13-A38