Citations

Immune checkpoint therapy with PD-1 blockade has emerged as an effective therapy for many advanced cancers; however, only a small fraction of patients achieve durable responses. To date, there is no validated blood-based means of predicting the response to PD-1 blockade. We report that Bim is a downstream signaling molecule of the PD-1 pathway, and its detection in T cells is significantly associated with expression of PD-1 and effector T cell markers. High levels of Bim in circulating tumor-reactive (PD-1 + CD11a hi CD8 + ) T cells were prognostic of poor survival in patients with metastatic melanoma who did not receive anti–PD-1 therapy and were also predictive of clinical benefit in patients with metastatic melanoma who were treated with anti–PD-1 therapy. Moreover, this circulating tumor-reactive T cell population significantly decreased after successful anti–PD-1 therapy. Our study supports a crucial role of Bim in both T cell activation and apoptosis as regulated by PD-1 and PD-L1 interactions in effector CD8 + T cells. Measurement of Bim levels in circulating T cells of patients with cancer may provide a less invasive strategy to predict and monitor responses to anti–PD-1 therapy, although future prospective analyses are needed to validate its utility.

ObjectiveTo determine effects of physical activity (PA) with diet‐induced weight loss on energy metabolism in adults with severe obesity.MethodsAdults with severe obesity (n = 11) were studied across 6 months of intervention, then compared with controls with less severe obesity (n = 7) or normal weight (n = 9). Indirect calorimetry measured energy metabolism during exercise and rest. Markers of muscle oxidation were determined by immunohistochemistry. Data were presented as medians.ResultsThe intervention induced 7% weight loss (P = 0.001) and increased vigorous PA by 24 min/wk (P = 0.02). During exercise, energy expenditure decreased, efficiency increased (P ≤ 0.03), and fatty acid oxidation (FAO) did not change. Succinate dehydrogenase increased (P = 0.001), but fiber type remained the same. Post‐intervention subjects’ resting metabolism remained similar to controls. Efficiency was lower in post‐intervention subjects compared with normal‐weight controls exercising at 25 W (P ≤ 0.002) and compared with all controls exercising at 60% VO2peak (P ≤ 0.019). Resting and exercise FAO of post‐intervention subjects remained similar to adults with less severe obesity. Succinate dehydrogenase and fiber type were similar across all body weight statuses.ConclusionsWhile metabolic adaptations to PA during weight loss occur in adults with severe obesity, FAO does not change. Resulting FAO during rest and exercise remains similar to adults with less severe obesity.

Abstract Antibody-directed chemotherapy (ADC) offers an advantage over conventional chemotherapy because it provides antibody-directed targeting, with resultant improvement in therapeutic efficacy and reduced toxicity. Despite extensive research, with notable exceptions, broad clinical application of ADC remains elusive; major hurdles include the instability of antibody–chemotherapy linkers and reduced tumor toxicity of the chemotherapy when bound to the antibody. To address these challenges, we have developed a platform technology that utilizes the nab-paclitaxel formulation of paclitaxel, Abraxane, in which hydrophobic paclitaxel is suspended in 130-nm albumin nanoparticles and thus made water-soluble. We have developed a method to noncovalently coat the Abraxane nanoparticle with recombinant mAbs (anti-VEGF, bevacizumab) and guide Abraxane delivery into tumors in a preclinical model of human A375 melanoma. Here, we define the binding characteristics of bevacizumab and Abraxane, demonstrate that the chemotherapy agent retains its cytotoxic effect, while the antibody maintains the ability to bind its ligand when the two are present in a single nanoparticle (AB160), and show that the nanoparticle yields improved antitumor efficacy in a preclinical human melanoma xenograft model. Further data suggest that numerous therapeutic monoclonal IgG1 antibodies may be utilized in this platform, which has implications for many solid and hematologic malignancies. Cancer Res; 76(13); 3954–64. ©2016 AACR.

AbstractBackgroundFamilial aggregation and segregation analysis studies have provided evidence of a genetic basis for esophageal adenocarcinoma (EAC) and its premalignant precursor, Barrett's esophagus (BE). We aim to demonstrate the utility of linkage analysis to identify the genomic regions that might contain the genetic variants that predispose individuals to this complex trait (BE and EAC).MethodsWe genotyped 144 individuals in 42 multiplex pedigrees chosen from 1000 singly ascertained BE/EAC pedigrees, and performed both model‐based and model‐free linkage analyses, using S.A.G.E. and other software. Segregation models were fitted, from the data on both the 42 pedigrees and the 1000 pedigrees, to determine parameters for performing model‐based linkage analysis. Model‐based and model‐free linkage analyses were conducted in two sets of pedigrees: the 42 pedigrees and a subset of 18 pedigrees with female affected members that are expected to be more genetically homogeneous. Genome‐wide associations were also tested in these families.ResultsLinkage analyses on the 42 pedigrees identified several regions consistently suggestive of linkage by different linkage analysis methods on chromosomes 2q31, 12q23, and 4p14. A linkage on 15q26 is the only consistent linkage region identified in the 18 female‐affected pedigrees, in which the linkage signal is higher than in the 42 pedigrees. Other tentative linkage signals are also reported.ConclusionOur linkage study of BE/EAC pedigrees identified linkage regions on chromosomes 2, 4, 12, and 15, with some reported associations located within our linkage peaks. Our linkage results can help prioritize association tests to delineate the genetic determinants underlying susceptibility to BE and EAC.

ABSTRACT Introduction The aim of this study was to test the clinimetric properties of the Comprehensive Cervical Dystonia Rating Scale. This is a modular scale with modifications of the Toronto Western Spasmodic Torticollis Rating Scale (composed of three subscales assessing motor severity, disability, and pain) now referred to as the revised Toronto Western Spasmodic Torticollis Scale‐2; a newly developed psychiatric screening instrument; and the Cervical Dystonia Impact Profile‐58 as a quality of life measure. Methods Ten dystonia experts rated subjects with cervical dystonia using the comprehensive scale. Clinimetric techniques assessed each module of the scale for reliability, item correlation, and factor structure. Results There were 208 cervical dystonia patients (73% women; age, 59 ± 10 years; duration, 15 ± 12 years). Internal consistency of the motor severity subscale was acceptable (Cronbach's alpha = 0.57). Item to total correlations showed that elimination of items with low correlations (<0.20) increased alpha to 0.71. Internal consistency estimates for the subscales for disability and pain were 0.88 and 0.95, respectively. The psychiatric screening scale had a Cronbach's alpha of 0.84 and satisfactory item to total correlations. When the subscales of the Toronto Western Spasmodic Torticollis Scale‐2 were combined with the psychiatric screening scale, Cronbach's alpha was 0.88, and construct validity assessment demonstrated four rational factors: motor; disability; pain; and psychiatric disorders. The Cervical Dystonia Impact Profile‐58 had an alpha of 0.98 and its construction was validated through a confirmatory factor analysis. Conclusions The modules of the Comprehensive Cervical Dystonia Rating Scale are internally consistent with a logical factor structure. © 2016 International Parkinson and Movement Disorder Society

Abstract Background: Barrett's esophagus is often asymptomatic and only a small portion of Barrett's esophagus patients are currently diagnosed and under surveillance. Therefore, it is important to develop risk prediction models to identify high-risk individuals with Barrett's esophagus. Familial aggregation of Barrett's esophagus and esophageal adenocarcinoma, and the increased risk of esophageal adenocarcinoma for individuals with a family history, raise the necessity of including genetic factors in the prediction model. Methods to determine risk prediction models using both risk covariates and ascertained family data are not well developed. Methods: We developed a Barrett's Esophagus Translational Research Network (BETRNet) risk prediction model from 787 singly ascertained Barrett's esophagus pedigrees and 92 multiplex Barrett's esophagus pedigrees, fitting a multivariate logistic model that incorporates family history and clinical risk factors. The eight risk factors, age, sex, education level, parental status, smoking, heartburn frequency, regurgitation frequency, and use of acid suppressant, were included in the model. The prediction accuracy was evaluated on the training dataset and an independent validation dataset of 643 multiplex Barrett's esophagus pedigrees. Results: Our results indicate family information helps to predict Barrett's esophagus risk, and predicting in families improves both prediction calibration and discrimination accuracy. Conclusions: Our model can predict Barrett's esophagus risk for anyone with family members known to have, or not have, had Barrett's esophagus. It can predict risk for unrelated individuals without knowing any relatives' information. Impact: Our prediction model will shed light on effectively identifying high-risk individuals for Barrett's esophagus screening and surveillance, consequently allowing intervention at an early stage, and reducing mortality from esophageal adenocarcinoma. Cancer Epidemiol Biomarkers Prev; 25(5); 727–35. ©2016 AACR.

AbstractBackgroundGastrointestinal (GI) and non‐GI disorders are associated with altered intestinal permeability, which can be measured in vivo by urinary excretion after oral lactulose and mannitol ingestion. Inadvertent dietary consumption of 12Carbon (12C, regular) mannitol in food or from other sources may interfere with the test's interpretation. 13Carbon (13C) constitutes 1% of carbon in nature and 13C mannitol is a stable isotope. Our aim was to determine the performance of 13C mannitol for measurement of intestinal permeability.MethodsTen healthy volunteers underwent intestinal permeability assay using coadministered 12C mannitol, 13C mannitol and lactulose, followed by timed urine collections. Urinary sugar concentrations were measured using tandem high performance liquid chromatography–mass spectrometry.Key resultsWe found that 13C mannitol can be distinguishable from 12C mannitol on tandem mass spectrometry. In addition, 13C mannitol had ~20‐fold lower baseline contamination compared to 12C mannitol. We describe here the 13C mannitol assay method for the measurement of intestinal permeability.Conclusions & InferencesIn conclusion, 13C mannitol is superior to 12C mannitol for measurement of intestinal permeability. It avoids issues with baseline contamination and erratic excretions during the testing period.

Background— Hypertensive pregnancy disorders have been associated with subjective cognitive complaints or brain white-matter lesions 5 to 10 years after the hypertensive pregnancy. The long-term effects of hypertensive pregnancies on brain structure and cognitive function remain unknown. Methods and Results— This study included 1279 women who participated in the Family Blood Pressure Project Genetic Epidemiology Network of Arteriopathy (GENOA) study. As part of the ancillary Genetics of Microangiopathic Brain Injury (GMBI) study, a neurocognitive battery was administered; 1075 also had a brain magnetic resonance imaging. A history of a hypertensive pregnancy disorder was obtained by a self-report using a validated questionnaire. Linear models fit with generalized estimating equations were used to assess the association between hypertensive pregnancy disorders and cognition, adjusting for age, race, education, body mass index, smoking, current hypertension, hypertension duration, and family history of hypertension. Regression models for the brain magnetic resonance imaging outcomes also were adjusted for total intracranial volume. Women with histories of hypertensive pregnancy disorders performed worse on all measures of processing speed (Digital Symbol Substitution Test [mean score, 41.2 versus 43.4; P =0.005], Trail Making Test Part A [mean seconds, 45.1 versus 42.2; P =0.035], and Stroop [mean score, 173.9 versus 181.0; P =0.002]) and had smaller brain volumes compared with women with histories of normotensive pregnancies (286 versus 297; P =0.023). Conclusions— Hypertensive pregnancy disorders are associated with worse performance on tests of processing speed and smaller brain volumes decades later. Population-based studies are needed to provide critical insight as to the contribution of hypertensive pregnancies to risk of cognitive decline and dementia.

ABSTRACT Protective antigen (PA)-specific antibody and cell-mediated immune (CMI) responses to annual and alternate booster schedules of anthrax vaccine adsorbed (AVA; BioThrax) were characterized in humans over 43 months. Study participants received 1 of 6 vaccination schedules: a 3-dose intramuscular (IM) priming series (0, 1, and 6 months) with a single booster at 42 months (4-IM); 3-dose IM priming with boosters at 18 and 42 months (5-IM); 3-dose IM priming with boosters at 12, 18, 30, and 42 months (7-IM); the 1970 licensed priming series of 6 doses (0, 0.5, 1, 6, 12, and 18 months) and two annual boosters (30 and 42 months) administered either subcutaneously (SQ) (8-SQ) or IM (8-IM); or saline placebo control at all eight time points. Antibody response profiles included serum anti-PA IgG levels, subclass distributions, avidity, and lethal toxin neutralization activity (TNA). CMI profiles included frequencies of gamma interferon (IFN-γ)- and interleukin 4 (IL-4)-secreting cells and memory B cells (MBCs), lymphocyte stimulation indices (SI), and induction of IFN-γ, IL-2, IL-4, IL-6, IL-1β, and tumor necrosis factor alpha (TNF-α) mRNA. All active schedules elicited high-avidity PA-specific IgG, TNA, MBCs, and T cell responses with a mixed Th1-Th2 profile and Th2 dominance. Anti-PA IgG and TNA were highly correlated (e.g., month 7, r 2 = 0.86, P < 0.0001, log 10 transformed) and declined in the absence of boosters. Boosters administered IM generated the highest antibody responses. Increasing time intervals between boosters generated antibody responses that were faster than and superior to those obtained with the final month 42 vaccination. CMI responses to the 3-dose IM priming remained elevated up to 43 months. (This study has been registered at ClinicalTrials.gov under registration no. NCT00119067.)