Delay Discounting is Associated with Treatment Response among Cocaine-Dependent Outpatients

Rationale—Delay discounting (DD) describes the rate at which reinforcers lose value as the temporal delay to their receipt increases. Steeper discounting has been positively associated with vulnerability to substance use disorders, including cocaine use disorders. Objectives—In the present study, we examined whether DD of hypothetical monetary reinforcers is associated with the duration of cocaine abstinence achieved among cocainedependent outpatients. Methods—Participants were 36 adults who were participating in a randomized controlled trial examining the efficacy of voucher-based contingency management (CM) using low-magnitude (N = 18) or high-magnitude (N = 18) voucher monetary values. Results—DD was associated with the number of continuous weeks of cocaine abstinence achieved, even after adjusting for treatment condition during the initial 12-week (t(33) = 2.48, p = .045) and entire recommended 24-week of treatment (t(33) = 2.40, p = .022). Participants who exhibited steeper discounting functions achieved shorter periods of abstinence in the Lowmagnitude voucher condition (12-week: t(16) = 2.48, p = .025; 24-week: t(16) = 2.68, p = .017), but not in the High-magnitude voucher condition (12-week: t(16) = 0.51, p = .618; 24-week: t(16) = 1.08, p = .298), although the interaction between DD and treatment condition was not significant (12-week: t(32) = −1.12, p = .271; 24-week: t(32) = −0.37, p = .712). Conclusions—These results provide further evidence on associations between DD and treatment response and extend those observations to a new clinical population (i.e., cocainedependent outpatients), while also suggesting that a more intensive intervention like the Highmagnitude CM condition may diminish this negative relationship between DD and treatment response

Initiation of Aspirin Therapy Modulates Angiogenic Protein Levels in Women with Breast Cancer Receiving Tamoxifen Therapy

Abstract Aspirin has a range of antineoplastic properties linked to inhibition of cyclooxygenase enzymes in tumor cells, platelet inhibition and to inhibition of angiogenesis. We undertook a prospective study to determine the influence of a 45‐day course of aspirin therapy on circulating and intraplatelet levels of selected proangiogenic (vascular endothelial growth factor [VEGF]) and antiangiogenic (thrombospondin‐1 [TSP‐1]) proteins, and platelet protein release in women diagnosed with breast cancer who were receiving tamoxifen therapy. Initiation of aspirin therapy increases serum and intraplatelet levels of TSP‐1 without a corresponding increase in VEGF levels. Following aspirin therapy, VEGF levels decreased (relative to pretreatment levels) while TSP‐1 returned to pretreatment levels. Plasma TSP‐1 and VEGF levels did not change on aspirin therapy. Aspirin use also decreased thrombin receptor mediated release of TSP‐1 and VEGF from platelets. The selective impact on platelet angiogenic protein content and release supports one mechanism by which aspirin can modify the angiogenic balance in women receiving tamoxifen therapy. Aspirin therapy appears to favor an overall antiangiogenic balance in women with breast cancer who are receiving tamoxifen therapy

Investigation of HNF-1B as a diagnostic biomarker for pancreatic ductal adenocarcinoma

Background: Diagnosing pancreatic ductal adenocarcinoma (PDAC) in the setting of metastasis with an unknown primary remains very challenging due to the lack of specific biomarkers. HNF-1B has been characterized as an important transcription factor for pancreatic development and was reported as a biomarker for clear cell subtype of PDAC. Methods: To investigate the diagnostic role of HNF-1B for PDAC, we used tissue microarray (TMA) and immunohistochemistry (IHC) to characterize HNF-1B expression in a large cohort of carcinomas, including 127 primary PDACs, 47 biliary adenocarcinomas, 17 metastatic PDACs, and 231 non-pancreaticobiliary carcinomas. Results: HNF-1B was expressed in 107 of 127 (84.3%) of PDACs, 13 of 15 (86.7%) of cholangiocarcinomas, 13 of 18 (72%) of ampullary carcinomas, and 13 of 14 (92.9%) of gallbladder adenocarcinomas. Notably, HNF-1B was expressed in 16 of 17 (94.1%) of metastatic PDACs. Among the non-pancreaticobiliary cancers, HNF-1B was expressed in ~ 77% clear cell carcinomas of the kidney and ovarian clear cell carcinomas. Gastroesophageal, lung, and prostate adenocarcinomas occasionally expressed HNF-1B in up to 37% cases. HNF-1B was completely negative in hepatocellular, colorectal, breast, and lung squamous cell carcinomas. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of HNF-1B for primary pancreaticobiliary carcinoma is 84, 68, 66, 85, and 75%, respectively. HNF-1B expression was not significantly associated with overall survival in patients with PDAC, but tumor size \u3e /=2 cm and high tumor grade were significantly associated with worse overall survival in multivariate analyses. Conclusions: HNF-1B may be used in surgical pathology to aid the diagnosis of metastatic pancreatic and biliary carcinoma with a panel of other markers to exclude lung, kidney, prostate, and Mullerian origins

Feasibility of automated pre-screening for lifestyle and behavioral health risk factors in primary care

Background: Screening of primary care patients for unhealthy behaviors and mental health issues is recommended by numerous governing bodies internationally, yet evidence suggests that provider-initiated screening is not routine practice. The objective of this study was to implement systematic pre-screening of primary care patients for common preventive health issues on a large scale. Methods: Patients registered for non-acute visits to one of 40 primary care providers from eight clinics in an Academic Medical Center health care network in the United States from May, 2012 to May, 2014 were contacted one- to three-days prior to their visit. Patients were invited to complete a questionnaire using an Interactive Voice Response (IVR) system. Six items assessed pain, smoking, alcohol use, physical activity, concern about weight, and mood. Results: The acceptance rate among eligible patients reached by phone was 65.6 %, of which 95.5 % completed the IVR-Screen (N = 8,490; mean age 57; 57 % female). Sample demographics were representative of the overall primary care population from which participants were drawn on gender, race, and insurance status, but participants were slightly older and more likely to be married. Eighty-seven percent of patients screened positive on at least one item, and 59 % endorsed multiple problems. The majority of respondents (64.2 %) reported being never or only somewhat physically active. Weight concern was reported by 43.9 % of respondents, 36.4 % met criteria for unhealthy alcohol use, 23.4 % reported current pain, 19.6 % reported low mood, and 9.4 % reported smoking. Conclusions: The percent endorsement for each behavioral health concern was generally consistent with studies of screening using other methods, and contrasts starkly with the reported low rates of screening and intervention for such concerns in typical PC practice. Results support the feasibility of IVR-based, large-scale pre-appointment behavioral health/ lifestyle risk factor screening of primary care patients. Pre-screening in this population facilitated participation in a controlled trial of brief treatment for unhealthy drinking, and also could be valuable clinically because it allows for case identification and management during routine care

Response to reduced nicotine content cigarettes among smokers differing in tobacco dependence severity

This study examines whether tobacco dependence severity moderates the acute effects of reducing nicotine content in cigarettes on the addiction potential of smoking, craving/withdrawal, or smoking topography. Participants (N = 169) were daily smokers with mild, moderate, or high tobacco-dependence severity using the Heaviness of Smoking Index. Following brief abstinence, participants smoked research cigarettes varying in nicotine content (0.4, 2.4, 5.2, 15.8 mg nicotine/g tobacco) in a within-subject design. Results were analyzed using repeated measures analysis of co-variance. No main effects of dependence severity or interactions with nicotine dose were noted in relative reinforcing effects in concurrent choice testing or subjective effects on the modified Cigarette Evaluation Questionnaire. Demand for smoking in the Cigarette Purchase Task was greater among more dependent smokers, but reducing nicotine content decreased demand independent of dependence severity. Dependence severity did not significantly alter response to reduced nicotine content cigarettes on the Minnesota Tobacco Withdrawal Scale nor Questionnaire of Smoking Urges-brief (QSU) Factor-2 scale; dependence severity and dose interacted significantly on the QSU-brief Factor-1 scale, with reductions dependent on dose among highly but not mildly or moderately dependent smokers. Dependence severity and dose interacted significantly on only one of six measures of smoking topography (i.e., maximum flow rate), which increased as dose increased among mildly and moderately but not highly dependent smokers. These results suggest that dependence severity has no moderating influence on the ability of reduced nicotine content cigarettes to lower the addiction potential of smoking, and minimal effects on relief from craving/withdrawal or smoking topography

Effect of albiglutide on cardiovascular outcomes in older adults: a post hoc analysis of a randomized controlled trial

Aim: To analyse the effects of albiglutide, a glucagon‐like peptide 1 receptor agonist, on cardiovascular outcomes in older adults aged ≥65 years with type 2 diabetes and cardiovascular disease who participated in the Harmony Outcomes trial (NCT02465515). Materials and methods: We conducted a post hoc analysis of the primary endpoint of the Harmony Outcomes trial—time to first occurrence of a major adverse cardiovascular event—in subgroups of participants aged <65 and ≥65 years and <75 and ≥75 years at baseline. Hazard ratios and 95% confidence intervals (CIs) were generated using Cox proportional hazards regression. Results: The analysis population included 9462 Harmony Outcomes participants, including 4748 patients ≥65 and 1140 patients ≥75 years at baseline. Hazard ratios for the prevention of major adverse cardiovascular events were 0.66 (95% CI, 0.53‐0.82) in persons <65 and 0.86 (95% CI, 0.71‐1.04) in those ≥65 years (age interaction p = .07), and 0.78 (95% CI, 0.67‐0.91) in <75 and 0.70 (95% CI, 0.48‐1.01) in ≥75 year age groups (interaction p = .6). When analysed as a continuous variable, age did not modify the effect of albiglutide on the primary endpoint. Conclusions: This post hoc analysis adds to the body of literature showing that glucagon‐like peptide 1 receptor agonists added to standard type 2 diabetes therapy safely reduce the incidence of cardiovascular events in older adults with established cardiovascular disease. In this analysis, the risk‐benefit profile was similar between younger and older age groups treated with albiglutide

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment