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1.  The role of haplotype in 15q25.1 locus in lung cancer risk: results of scanning chromosome 15 
Carcinogenesis  2015;36(11):1275-1283.
Summary
The rs588765-rs16969968 haplotype modifies lung cancer risk more than effects from individual variations at rs16969968 or rs588765, and therefore may be a marker of genetic susceptibility to lung cancer even among never-smokers. This knowledge may facilitate our understanding of lung cancer etiology.
The role of haplotypes and the interaction of haplotypes and smoking in lung cancer risk have not been well characterized. We analyzed data from an Italian population-based, case–control study with 1815 lung cancer patients and 1959 healthy controls in discovery, and performed a validation using a case–control study with 2983 lung cancer patients and 3553 healthy controls of European ancestry for replication. Sliding window haplotype analysis within chromosome 15, evaluating 4722250 haplotypes and pair-wise haplotype analysis identified that CHRNA5 rs588765-rs16969968 was the most significant haplotype associated with lung cancer risk (omnibus P = 8.35×10−15 in discovery and 7.26×10−14 in replication), and improved the prediction of case status over that provided by the individual SNPs rs16969968 or rs588765 (likelihood ratio test P = 0.006 for rs16969968 and 3.83×10−14 for rs588765 in discovery, 0.009 for rs16969968 and 4.62×10−13 for rs588765 in replication, compared with rs588765-rs16969968). Compared with the wild-type homozygous diplotype, CA/CA homozygote exhibited an approximately 2-fold increase risk for lung cancer (OR = 2.12; 95% CI 1.46–3.07 in discovery, and OR = 2.01; 95% CI 1.51–2.67 in replication). Even among never-smokers, CA/CA homozygote showed an increased risk of lung cancer with borderline significance in discovery (adjusted OR = 1.75, 95% CI 0.96–3.19) and statistical significance in replication (adjusted OR = 2.10, 95% CI 1.12–3.96), compared with combined genotypes (CG/CG + CG/TG). Accordingly, rs588765-rs16969968 may be a genetic marker to lung cancer risk, even among never-smokers.
doi:10.1093/carcin/bgv118
PMCID: PMC4635666  PMID: 26282330
2.  Regulatory T cells are not a strong predictor of survival for patients with glioblastoma 
Neuro-Oncology  2015;17(6):801-809.
Background
Regulatory T cells (Tregs) are potentially prognostic indicators in patients with glioblastoma. If differences in frequency of Tregs in tumor or blood account for substantial variation in patient survival, then reliably measuring Tregs may enhance treatment selection and improve outcomes.
Methods
We measured Tregs and CD3+ T cells in tumors and blood from 25 patients with newly diagnosed glioblastoma. Tumor-infiltrating Tregs and CD3+ T cells, measured by quantitative DNA demethylation analysis (epigenetic qPCR) and by immunohistochemistry, and peripheral blood Treg proportions measured by flow cytometry were correlated with patient survival. Additionally, we analyzed data from The Cancer Genome Atlas (TCGA) to correlate the expression of Treg markers with patient survival and glioblastoma subtypes.
Results
Tregs, as measured in tumor tissue and peripheral blood, did not correlate with patient survival. Although there was a correlation between tumor-infiltrating Tregs expression by epigenetic qPCR and immunohistochemistry, epigenetic qPCR was more sensitive and specific. Using data from TCGA, mRNA expression of Forkhead box protein 3 (FoxP3) and Helios and FoxP3 methylation level did not predict survival. While the classical glioblastoma subtype corresponded to lower expression of Treg markers, these markers did not predict survival in any of the glioblastoma subtypes.
Conclusions
Although immunosuppression is a hallmark of glioblastoma, Tregs as measured in tissue by gene expression, immunohistochemistry, or demethylation and Tregs in peripheral blood measured by flow cytometry do not predict survival of patients. Quantitative DNA demethylation analysis provides an objective, sensitive, and specific way of identifying Tregs and CD3+ T cells in glioblastoma.
doi:10.1093/neuonc/nou363
PMCID: PMC4483125  PMID: 25618892
epigenetic qPCR; glioblastoma; immunotherapy; regulatory T cell; Tregs
3.  Portable, parallel 9-wavelength near-infrared spectral tomography (NIRST) system for efficient characterization of breast cancer within the clinical oncology infusion suite 
Biomedical Optics Express  2016;7(6):2186-2201.
A portable near-infrared spectral tomography (NIRST) system was developed with simultaneous frequency domain (FD) and continuous-wave (CW) optical measurements for efficient characterization of breast cancer in a clinical oncology setting. Simultaneous FD and CW recordings were implemented to speed up acquisition to 3 minutes for all 9 wavelengths, spanning a range from 661nm to 1064nm. An adjustable interface was designed to fit various breast sizes and shapes. Spatial images of oxy- and deoxy-hemoglobin, water, lipid, and scattering components were reconstructed using a 2D FEM approach. The system was tested on a group of 10 normal subjects, who were examined bilaterally and the recovered optical images were compared to radiographic breast density. Significantly higher total hemoglobin and water were estimated in the high density relative to low density groups. One patient with invasive ductal carcinoma was also examined and the cancer region was characterized as having a contrast ratio of 1.4 in total hemoglobin and 1.2 in water.
doi:10.1364/BOE.7.002186
PMCID: PMC4918575  PMID: 27375937
(170.0110) Imaging systems; (170.6960) Tomography; (120.3890) Medical optics instrumentation; (170.6510) Spectroscopy, tissue diagnostics
4.  Geospatial Association between Low Birth Weight and Arsenic in Groundwater in New Hampshire, USA 
Background
There is increasing evidence of the role of arsenic in the etiology of adverse human reproductive outcomes. Since drinking water can be a major source of arsenic to pregnant women, the effect of arsenic exposure through drinking water on human birth may be revealed by a geospatial association between arsenic concentration in groundwater and birth problems, particularly in a region where private wells substantially account for water supply, like New Hampshire, US.
Methods
We calculated town-level rates of preterm birth and term low birth weight (term LBW) for New Hampshire, using data for 1997-2009 and stratified by maternal age. We smoothed the rates using a locally-weighted averaging method to increase the statistical stability. The town-level groundwater arsenic values are from three GIS data layers generated by the US Geological Survey: probability of local groundwater arsenic concentration > 1 μg/L, probability > 5 μg/L, and probability > 10 μg/L. We calculated Pearson's correlation coefficients (r) between the reproductive outcomes (preterm birth and term LBW) and the arsenic values, at both state and county levels.
Results
For preterm birth, younger mothers (maternal age < 20) have a statewide r = 0.70 between the rates smoothed with a threshold = 2,000 births and the town mean arsenic level based on the data of probability > 10 μg/L; For older mothers, r = 0.19 when the smoothing threshold = 3,500; A majority of county level r values are positive based on the arsenic data of probability > 10 μg/L. For term LBW, younger mothers (maternal age < 25) have a statewide r = 0.44 between the rates smoothed with a threshold = 3,500 and town minimum arsenic level based on the data of probability > 1 μg/L; For older mothers, r = 0.14 when the rates are smoothed with a threshold = 1,000 births and also adjusted by town median household income in 1999, and the arsenic values are the town minimum based on probability > 10 μg/L. At the county level, for younger mothers positive r values prevail, but for older mothers it is a mix. For both birth problems, the several most populous counties - with 60-80% of the state's population and clustering at the southwest corner of the state – are largely consistent in having a positive r across different smoothing thresholds.
Conclusion
We found evident spatial associations between the two adverse human reproductive outcomes and groundwater arsenic in New Hampshire, US. However, the degree of associations and their sensitivity to different representations of arsenic level are variable. Generally, preterm birth has a stronger spatial association with groundwater arsenic than term LBW, suggesting an inconsistency in the impact of arsenic on the two reproductive outcomes. For both outcomes, younger maternal age has stronger spatial associations with groundwater arsenic.
doi:10.1007/s10653-014-9651-2
PMCID: PMC4425200  PMID: 25326895
preterm birth; low birth weight; arsenic; groundwater; locally-weighted averaging smoothing; New Hampshire
5.  Blocking CXCL9 Decreases HIV-1 Replication and Enhances the Activity of Prophylactic Antiretrovirals in Human Cervical Tissues 
Objectives:
The interferon-gamma–induced chemokine CXCL9 is expressed in a wide range of inflammatory conditions including those affecting the female genital tract. CXCL9 promotes immune cell recruitment, activation, and proliferation. The role of CXCL9 in modulating HIV-1 infection of cervicovaginal tissues, a main portal of viral entry, however, has not been established. We report a link between CXCL9 and HIV-1 replication in human cervical tissues and propose CXCL9 as a potential target to enhance the anti–HIV-1 activity of prophylactic antiretrovirals.
Design:
Using ex vivo infection of human cervical tissues as a model of mucosal HIV-1 acquisition, we described the effect of CXCL9 neutralization on HIV-1 gene expression and mucosal CD4+ T-cell activation. The anti-HIV-1 activity of tenofovir, the leading mucosal pre-exposure prophylactic microbicide, alone or in combination with CXCL9 neutralization was also studied.
Methods:
HIV-1 replication was evaluated by p24 ELISA. HIV-1 DNA and RNA, and CD4, CCR5, and CD38 transcription were evaluated by quantitative real-time polymerase chain reaction. Frequency of activated cervical CD4+ T cells was quantified using fluorescence-activated cell sorting.
Results:
Antibody blocking of CXCL9 reduced HIV-1 replication by decreasing mucosal CD4+ T-cell activation. CXCL9 neutralization in combination with suboptimal concentrations of tenofovir, possibly present in the cervicovaginal tissues of women using the drug inconsistently, demonstrated an earlier and greater decrease in HIV-1 replication compared with tissues treated with tenofovir alone.
Conclusions:
CXCL9 neutralization reduces HIV-1 replication and may be an effective target to enhance the efficacy of prophylactic antiretrovirals.
doi:10.1097/QAI.0000000000000891
PMCID: PMC4788559  PMID: 26545124
CXCL9; HIV-1 replication; cervical tissues; prophylactic microbicides
6.  MR-Guided Near-Infrared Spectral Tomography Increases Diagnostic Performance of Breast MRI 
Purpose
The purpose of this study was to determine the diagnostically most important molecular biomarkers quantified by magnetic resonance-guided (MR) near-infrared spectral tomography (NIRST) that distinguish malignant breast lesions from benign abnormalities when combined with outcomes from clinical breast MRI.
Experimental Design
The study was HIPAA compliant and approved by the Dartmouth Institutional Review Board, the NIH, the United States State Department, and Xijing Hospital. MR-guided NIRST evaluated hemoglobin, water, and lipid content in regions of interest defined by concurrent dynamic contrast-enhanced MRI (DCE-MRI) in the breast. MRI plus NIRST was performed in 44 subjects (median age, 46, age range, 20–81 years), 28 of whom had subsequent malignant pathologic diagnoses, and 16 had benign conditions. A subset of 30 subject examinations yielded optical data that met minimum sensitivity requirements to the suspicious lesion and were included in the analyses of diagnostic performance.
Results
In the subset of 30 subject examinations meeting minimum optical data sensitivity criterion, the MR-guided NIRST separated malignant from benign lesions using total hemoglobin (HbT; P < 0.01) and tissue optical index (TOI; P < 0.001). Combined MRI plus TOI data caused one false positive and 1 false negative, and produced the best diagnostic performance, yielding an AUC of 0.95, sensitivity of 95%, specificity of 89%, positive predictive value of 95%, and negative predictive value of 89%, respectively.
Conclusions
MRI plus NIRST results correlated well with histopathologic diagnoses and could provide additional information to reduce the number of MRI-directed biopsies.
doi:10.1158/1078-0432.CCR-14-2546
PMCID: PMC4763338  PMID: 26019171
7.  Genetic polymorphisms modify bladder cancer recurrence and survival in a U.S. population-based prognostic study 
BJU international  2014;115(2):238-247.
Nearly half of bladder cancer patients experience recurrences. Reliable predictors of this recurrent phenotype are needed to guide surveillance and treatment.
Objective
To identify genetic variants that modify bladder cancer prognosis focusing on genes involved in major biological carcinogenesis processes (apoptosis, proliferation, DNA repair, hormone regulation, immune surveillance, and cellular metabolism).
Subjects and methods
We analyzed variant genotypes hypothesized to modify these processes in 563 urothelial-cell carcinoma cases enrolled in a population-based study of incident bladder cancer conducted in New Hampshire, U.S.A.
After diagnosis, cases were followed over time to ascertain recurrence and survival status, making this one of the first population-based studies with detailed prognosis data.
Cox proportional hazards regression was used to assess the relationship between SNPs and prognosis endpoints.
Results
Aldehyde dehydrogenase 2 (ALDH2) variants had shorter time to first bladder cancer recurrence (adjusted non-invasive HR 1.90 95%CI 1.29-2.78).
We observed longer survival among bladder cancer cases with non-invasive tumors associated with DNA repair XRCC4 heterozygous genotype compared with wildtype (adjusted HR 0.53 95%CI 0.38-0.74).
Time to recurrence was shorter for patients who had a variant allele in vascular cellular adhesion molecule 1 (VCAM1) and were treated with immunotherapy (P interaction <0.001).
Conclusion
Our analysis suggests candidate prognostic SNPs that could guide personalized bladder cancer surveillance and treatment.
doi:10.1111/bju.12641
PMCID: PMC4533837  PMID: 24666523
bladder cancer; polymorphism; prognosis; recurrence; survival; DNA repair; immune
8.  Predicting breast tumor response to neoadjuvant chemotherapy with Diffuse Optical Spectroscopic Tomography prior to treatment 
Purpose
Determine if pre-treatment biomarkers obtained from Diffuse Optical Spectroscopic Tomographic (DOST) imaging predict breast tumor response to Neoadjuvant Chemotherapy (NAC), which would have value to potentially eliminate delays in prescribing definitive local regional therapy that may occur from a standard complete 6–8 months course of NAC.
Experimental design
Nineteen patients undergoing NAC were imaged with DOST before, during and after treatment. The DOST images of total hemoglobin concentration (HbT), tissue oxygen saturation (StO2), and water (H2O) fraction at different time points have been used for testing the abilities of differentiating patients having pathologic complete response (pCR) vs. pathologic incomplete response (pIR).
Results
Significant differences (P-value<0.001, AUC=1.0) were found between pCR patients vs. pIR in outcome, based on the percentage change in tumor HbT within the first cycle of treatment. In addition, pre-treatment tumor HbT (Pre-TxHbT) relative to the contralateral breast was statistically significant (p-value=0.01, AUC=0.92) in differentiating pCR from pIR.
Conclusions
This is the first clinical evidence that DOST HbT may differentiate the two groups with predictive significance based on data acquired before NAC even begins. The study also demonstrates the potential of accelerating the validation of optimal NAC regimens through future randomized clinical trials by reducing the number of patients required and the length of time they need to be followed by using a validated imaging surrogate as an outcome measure.
doi:10.1158/1078-0432.CCR-14-1415
PMCID: PMC4254218  PMID: 25294916
Near Infrared; Optical tomography; chemotherapy response; breast cancer
9.  DPOAE level mapping for detecting noise-induced cochlear damage from short-duration music exposures 
Noise & Health  2015;17(78):263-272.
Distortion product otoacoustic emission (DPOAE) level mapping provides a comprehensive picture of cochlear responses over a range of DP frequencies and f2/f1 ratios. We hypothesized that individuals exposed to high-level sound would show changes detectable by DPOAE mapping, but not apparent on a standard DP-gram. Thirteen normal hearing subjects were studied before and after attending music concerts. Pure-tone audiometry (500-8,000 Hz), DP-grams (0.3-10 kHz) at 1.22 ratio, and DPOAE level maps were collected prior to, as soon as possible after, and the day after the concerts. All maps covered the range of 2,000-6,000 Hz in DP frequency and from 1.3 to -1.3 in ratio using equi-level primary tone stimuli. Changes in the pure-tone audiogram were significant (P ≤ 0.01) immediately after the concert at 1,000 Hz, 4,000 Hz, and 6,000 Hz. The DP-gram showed significant differences only at f2 = 4,066 (P = 0.01) and f2 = 4,348 (P = 0.04). The postconcert changes were readily apparent both visually and statistically (P ≤ 0.01) on the mean DP level maps, and remained statistically significantly different from baseline the day after noise exposure although no significant changes from baseline were seen on the DP-gram or audiogram the day after exposure. Although both the DP-gram and audiogram showed recovery by the next day, the average DPOAE level maps remained significantly different from baseline. The mapping data showed changes in the cochlea that were not detected from the DP-gram obtained at a single ratio. DPOAE level mapping provides comprehensive information on subtle cochlear responses, which may offer advantages for studying and tracking noise-induced hearing loss (NIHL).
doi:10.4103/1463-1741.165037
PMCID: PMC4900494  PMID: 26356368
Audiometry; distortion product otoacoustic emission (DPOAE) mapping; music-induced hearing loss; noise exposure; otoacoustic emissions
10.  Testing multiple hypotheses through IMP weighted FDR based on a genetic functional network with application to a new zebrafish transcriptome study 
BioData Mining  2015;8:17.
In genome-wide studies, hundreds of thousands of hypothesis tests are performed simultaneously. Bonferroni correction and False Discovery Rate (FDR) can effectively control type I error but often yield a high false negative rate. We aim to develop a more powerful method to detect differentially expressed genes. We present a Weighted False Discovery Rate (WFDR) method that incorporate biological knowledge from genetic networks. We first identify weights using Integrative Multi-species Prediction (IMP) and then apply the weights in WFDR to identify differentially expressed genes through an IMP-WFDR algorithm. We performed a gene expression experiment to identify zebrafish genes that change expression in the presence of arsenic during a systemic Pseudomonas aeruginosa infection. Zebrafish were exposed to arsenic at 10 parts per billion and/or infected with P. aeruginosa. Appropriate controls were included. We then applied IMP-WFDR during the analysis of differentially expressed genes. We compared the mRNA expression for each group and found over 200 differentially expressed genes and several enriched pathways including defense response pathways, arsenic response pathways, and the Notch signaling pathway.
doi:10.1186/s13040-015-0050-8
PMCID: PMC4474579  PMID: 26097506
False discovery rate; Family-wise error rate; Genomic studies; Data integration
11.  Development and validation of an ex vivo electron paramagnetic resonance fingernail biodosimetric method 
Radiation Protection Dosimetry  2014;159(1-4):172-181.
There is an imperative need to develop methods that can rapidly and accurately determine individual exposure to radiation for screening (triage) populations and guiding medical treatment in an emergency response to a large-scale radiological/nuclear event. To this end, a number of methods that rely on dose-dependent chemical and/or physical alterations in biomaterials or biological responses are in various stages of development. One such method, ex vivo electron paramagnetic resonance (EPR) nail dosimetry using human nail clippings, is a physical biodosimetry technique that takes advantage of a stable radiation-induced signal (RIS) in the keratin matrix of fingernails and toenails. This dosimetry method has the advantages of ubiquitous availability of the dosimetric material, easy and non-invasive sampling, and the potential for immediate and rapid dose assessment. The major challenge for ex vivo EPR nail dosimetry is the overlap of mechanically induced signals and the RIS. The difficulties of analysing the mixed EPR spectra of a clipped irradiated nail were addressed in the work described here. The following key factors lead to successful spectral analysis and dose assessment in ex vivo EPR nail dosimetry: (1) obtaining a thorough understanding of the chemical nature, the decay behaviour, and the microwave power dependence of the EPR signals, as well as the influence of variation in temperature, humidity, water content, and O2 level; (2) control of the variability among individual samples to achieve consistent shape and kinetics of the EPR spectra; (3) use of correlations between the multiple spectral components; and (4) use of optimised modelling and fitting of the EPR spectra to improve the accuracy and precision of the dose estimates derived from the nail spectra. In the work described here, two large clipped nail datasets were used to test the procedures and the spectral fitting model of the results obtained with it. A 15-donor nail set with 90 nail samples from 15 donors was used to validate the sample handling and spectral analysis methods that have been developed but without the interference of a native background signal. Good consistency has been obtained between the actual RIS and the estimated RIS computed from spectral analysis. In addition to the success in RIS estimation, a linear dose response has also been achieved for all individuals in this study, where the radiation dose ranges from 0 to 6 Gy. A second 16-donor nail set with 96 nail samples was used to test the spectral fitting model where the background signal was included during the fitting of the clipped nail spectra data. Although the dose response for the estimated and actual RIS calculated in both donor nail sets was similar, there was an increased variability in the RIS values that was likely due to the variability in the background signal between donors. Although the current methods of sample handling and spectral analysis show good potential for estimating the RIS in the EPR spectra of nail clippings, there is a remaining degree of variability in the RIS estimate that needs to be addressed; this should be achieved by identifying and accounting for demographic sources of variability in the background nail signal and the composition of the nail matrix.
doi:10.1093/rpd/ncu129
PMCID: PMC4095917  PMID: 24803513
12.  Role of a Genetic Variant on the 15q25.1 Lung Cancer Susceptibility Locus in Smoking-Associated Nasopharyngeal Carcinoma 
PLoS ONE  2014;9(10):e109036.
Background
The 15q25.1 lung cancer susceptibility locus, containing CHRNA5, could modify lung cancer susceptibility and multiple smoking related phenotypes. However, no studies have investigated the association between CHRNA5 rs3841324, which has been proven to have the highest association with CHRNA5 mRNA expression, and the risk of other smoking-associated cancers, except lung cancer. In the current study we examined the association between rs3841324 and susceptibility to smoking-associated nasopharyngeal carcinoma (NPC).
Methods
In this case-control study we genotyped the CHRNA5 rs3841324 polymorphism with 400 NPC cases and 491 healthy controls who were Han Chinese and frequency-matched by age (±5 years), gender, and alcohol consumption. Univariate and multivariate logistic regression analyses were used to calculate the odds ratio (OR) and 95% confidence intervals (95% CI).
Results
We found that individuals with CHRNA5 rs3841324 combined variant genotypes (ins/del+del/del) had a >1.5-fold elevated risk for NPC than those with the ins/ins genotype (adjusted OR = 1.52; 95% CI, 1.16–2.00), especially among ever smokers (adjusted OR = 2.07; 95% CI, 1.23–3.48). The combined variant genotypes acted jointly with cigarette smoking to contribute to a 4.35-fold increased NPC risk (adjusted OR = 4.35; 95% CI, 2.57–7.38). There was a dose-response relationship between deletion alleles and NPC susceptibility (trend test, P = 0.011).
Conclusions
Our results suggest that genetic variants on the 15q25.1 lung cancer susceptibility locus may influence susceptibility to NPC, particularly for smoking-associated NPC. Such work may be helpful to facilitate an understanding of the etiology of smoking-associated cancers and improve prevention efforts.
doi:10.1371/journal.pone.0109036
PMCID: PMC4203692  PMID: 25329654
13.  Cutaneous alpha, beta and gamma human papillomaviruses in relation to squamous cell carcinoma of the skin: a population-based study 
Human papillomavirus (HPV) infection is common worldwide and, in immunodeficient populations, may contribute to the pathogenesis of keratinocyte cancers, particularly squamous cell carcinomas (SCC). However, their role in SCC in the general population is less clear. We conducted a comprehensive analysis to investigate the independent effects of seropositivity for cutaneous alpha, beta and gamma HPV types on risk of SCC, and a meta-analysis of the available literature. In a population-based case-control study from New Hampshire, USA (n=1408), histologically-confirmed SCC cases and controls were tested for L1 antibodies to alpha, beta and gamma cutaneous HPV types 2–5, 7–10, 15, 17, 20, 23, 24, 27b, 36, 38, 48–50, 57, 65, 75–77, 88, 92, 95, 96, 101, 103, and 107 using multiplex serology. An increasing risk of SCC with number of beta HPVs to which an individual tested positive was observed even among those seronegative for gamma types (P for trend = 0.016) with an odds ratio of 1.95 (95% confidence interval (CI) = 1.07–3.56) for four or more beta types positive. In a meta-analysis of six case-control studies, increased SCC risks in relation to beta HPV seropositivity were found across studies, (meta odds ratio = 1.45, CI = 1.27–1.66). While the prevalence of gamma HPVs assayed was somewhat higher among SCC cases than controls, the association was only weakly evident among those seronegative for beta HPVs. Overall, the association between cutaneous HPVs and skin cancers appears to be specific to SCC and to genus beta HPVs in a general US population.
doi:10.1002/ijc.28176
PMCID: PMC3713187  PMID: 23536363
human papillomavirus; squamous cell carcinoma; population-based; case-control; meta-analysis
14.  Diverse convergent evidence in the genetic analysis of complex disease: coordinating omic, informatic, and experimental evidence to better identify and validate risk factors 
BioData Mining  2014;7:10.
In omic research, such as genome wide association studies, researchers seek to repeat their results in other datasets to reduce false positive findings and thus provide evidence for the existence of true associations. Unfortunately this standard validation approach cannot completely eliminate false positive conclusions, and it can also mask many true associations that might otherwise advance our understanding of pathology. These issues beg the question: How can we increase the amount of knowledge gained from high throughput genetic data? To address this challenge, we present an approach that complements standard statistical validation methods by drawing attention to both potential false negative and false positive conclusions, as well as providing broad information for directing future research. The Diverse Convergent Evidence approach (DiCE) we propose integrates information from multiple sources (omics, informatics, and laboratory experiments) to estimate the strength of the available corroborating evidence supporting a given association. This process is designed to yield an evidence metric that has utility when etiologic heterogeneity, variable risk factor frequencies, and a variety of observational data imperfections might lead to false conclusions. We provide proof of principle examples in which DiCE identified strong evidence for associations that have established biological importance, when standard validation methods alone did not provide support. If used as an adjunct to standard validation methods this approach can leverage multiple distinct data types to improve genetic risk factor discovery/validation, promote effective science communication, and guide future research directions.
doi:10.1186/1756-0381-7-10
PMCID: PMC4112852  PMID: 25071867
Replication; Validation; Complex disease; Heterogeneity; GWAS; Omics; Type 2 error; Type 1 error; False negatives; False positives
15.  Non Melanoma Skin Cancer and Subsequent Cancer Risk 
PLoS ONE  2014;9(6):e99674.
Introduction
Several studies have shown an increased risk of cancer after non melanoma skin cancers (NMSC) but the individual risk factors underlying this risk have not been elucidated, especially in relation to sun exposure and skin sensitivity to sunlight.
Purpose
The aim of this study was to examine the individual risk factors associated with the development of subsequent cancers after non melanoma skin cancer.
Methods
Participants in the population-based New Hampshire Skin Cancer Study provided detailed risk factor data, and subsequent cancers were identified via linkage with the state cancer registry. Deaths were identified via state and national death records. A Cox proportional hazard model was used to estimate risk of subsequent malignancies in NMSC patients versus controls and to assess the potential confounding effects of multiple risk factors on this risk.
Results
Among 3584 participants, risk of a subsequent cancer (other than NMSC) was higher after basal cell carcinoma (BCC) (adjusted HR 1.40 [95% CI 1.15, 1.71]) than squamous cell carcinoma (SCC) (adjusted HR 1.18 [95% CI 0.95, 1.46]) compared to controls (adjusted for age, sex and current cigarette smoking). After SCC, risk was higher among those diagnosed before age 60 (HR 1.96 [95% CI 1.24, 3.12]). An over 3-fold risk of melanoma after SCC (HR 3.62; 95% CI 1.85, 7.11) and BCC (HR 3.28; 95% CI 1.66, 6.51) was observed, even after further adjustment for sun exposure-related factors and family history of skin cancer. In men, prostate cancer incidence was higher after BCC compared to controls (HR 1.64; 95% CI 1.10, 2.46).
Conclusions
Our population-based study indicates an increased cancer risk after NMSC that cannot be fully explained by known cancer risk factors.
doi:10.1371/journal.pone.0099674
PMCID: PMC4061037  PMID: 24937304
16.  TRIMODALITY THERAPY FOR STAGE II-III CARCINOMA OF THE ESOPHAGUS: A DOSE-RANGING STUDY OF CONCURRENT CAPECITABINE, DOCETAXEL, AND THORACIC RADIOTHERAPY 
PURPOSE
This dose escalation study was performed to determine the recommended phase II dose of oral capecitabine to be delivered concurrently with thoracic radiation therapy and weekly docetaxel in patients with locally advanced esophageal carcinoma.
METHODS
Patients with operable stage II or III esophageal carcinoma were staged by endoscopic ultrasonography (EUS) and CT. Two cycles of docetaxel (80 mg/m2) and carboplatin (target area under the concentration curve 6 mg*min/mL) were delivered over 6 weeks. This was followed by concurrent weekly docetaxel (15 mg/m2), thoracic radiotherapy (50.4 Gy in 28 fractions), and increasing doses of capecitabine (500 mg to 3500 mg) given prior to each fraction of radiotherapy. Following re-staging, responding patients continued to esophagectomy within 4–8 weeks of completing chemoradiotherapy.
RESULTS
Forty-four patients (pts) were enrolled and 40 were evaluable for the dose-ranging component of concurrent chemoradiotherapy. EUS stages at enrollment were T3N1 (29 pts), T3N0 (4 pts), T2N1 (6 pts), and T4N0 (1 pts). The maximum tolerated dose of capecitabine was 3500 mg. Thirty-six patients had surgery; 83% had R0 resection and 17% had complete pathological response. Median overall survival was 23.5 months, with 34% and 27% alive at three and five years.
CONCLUSION
The recommended phase II dose of capecitabine is 3500 mg when given concurrently with 50.4 Gy of thoracic radiotherapy in 28 fractions and weekly docetaxel. This trimodality therapy for operable locally advanced esophageal carcinoma was very well-tolerated and remarkably active. This regimen holds promise for treatment of esophageal carcinoma and warrants further investigation.
doi:10.1097/JTO.0b013e3182829bf3
PMCID: PMC3600150  PMID: 23370365
17.  Assessment of the Changes in 9L and C6 Glioma pO2 by EPR Oximetry as a Prognostic Indicator of Differential Response to Radiotherapy 
Radiation research  2013;179(3):343-351.
Tumor hypoxia impedes the outcome of radiotherapy. As the extent of hypoxia in solid tumors varies during the course of radiotherapy, methods that can provide repeated assessment of tumor pO2 such as EPR oximetry may enhance the efficacy of radiotherapy by scheduling irradiations when the tumors are oxygenated. The repeated measurements of tumor pO2 may also identify responders, and thereby facilitate the design of better treatment plans for nonresponding tumors. We have investigated the temporal changes in the ectopic 9L and C6 glioma pO2 irradiated with single radiation doses less than 10 Gy by EPR oximetry. The 9L and C6 tumors were hypoxic with pO2 of approximately 5–9 mmHg. The pO2 of C6 tumors increased significantly with irradiation of 4.8–9.3 Gy. However, no change in the 9L tumor pO2 was observed. The irradiation of the oxygenated C6 tumors with a second dose of 4.8 Gy resulted in a significant delay in growth compared to hypoxic and 2 Gy × 5 treatment groups. The C6 tumors with an increase in pO2 of greater than 50% from the baseline of irradiation with 4.8 Gy (responders) had a significant tumor growth delay compared to nonresponders. These results indicate that the ectopic 9L and C6 tumors responded differently to radiotherapy. We propose that the repeated measurement of the oxygen levels in the tumors during radiotherapy can be used to identify responders and to design tumor oxygen guided treatment plans to improve the outcome.
doi:10.1667/RR2811.1
PMCID: PMC3633145  PMID: 23391148
18.  RESPECT-PTSD: Re-Engineering Systems for the Primary Care Treatment of PTSD, A Randomized Controlled Trial 
ABSTRACT
BACKGROUND
Although collaborative care is effective for treating depression and other mental disorders in primary care, there have been no randomized trials of collaborative care specifically for patients with Posttraumatic stress disorder (PTSD).
OBJECTIVE
To compare a collaborative approach, the Three Component Model (3CM), with usual care for treating PTSD in primary care.
DESIGN
The study was a two-arm, parallel randomized clinical trial. PTSD patients were recruited from five primary care clinics at four Veterans Affairs healthcare facilities and randomized to receive usual care or usual care plus 3CM. Blinded assessors collected data at baseline and 3-month and 6-month follow-up.
PARTICIPANTS
Participants were 195 Veterans. Their average age was 45 years, 91% were male, 58% were white, 40% served in Iraq or Afghanistan, and 42% served in Vietnam.
INTERVENTION
All participants received usual care. Participants assigned to 3CM also received telephone care management. Care managers received supervision from a psychiatrist.
MAIN MEASURES
PTSD symptom severity was the primary outcome. Depression, functioning, perceived quality of care, utilization, and costs were secondary outcomes.
KEY RESULTS
There were no differences between 3CM and usual care in symptoms or functioning. Participants assigned to 3CM were more likely to have a mental health visit, fill an antidepressant prescription, and have adequate antidepressant refills. 3CM participants also had more mental health visits and higher outpatient pharmacy costs.
CONCLUSIONS
Results suggest the need for careful examination of the way that collaborative care models are implemented for treating PTSD, and for additional supports to encourage primary care providers to manage PTSD.
doi:10.1007/s11606-012-2166-6
PMCID: PMC3539037  PMID: 22865017
posttraumatic stress disorder; integrated primary care; veterans; randomized clinical trials; treatment
19.  Bone Marrow Transplant for Multiple Myeloma: Impact of Distance From the Transplant Center 
Purpose
This study investigated the impact of prognostic variables, including the distance a patient lives from a transplant center, on the outcome of autologous hematopoietic stem cell transplantation (ASCT) for multiple myeloma.
Methods
This retrospective analysis included 77 myeloma patients who received an ASCT at Dartmouth Hitchcock Medical Center between 1996 and 2009, 70 of whom were treated between 2002 and 2009. Using linear regression and univariate analysis, we examined the impact of distance from the transplant center on survival. Kaplan-Meier curves identified overall and event-free survival. An association between distance from the transplant center and survival was examined using Cox regression analysis, while adjusting for patient-, disease-, and treatment-related variables.
Results
Increasing distance from the transplant center correlated with improved overall survival (P=.004), but had no impact on disease-free survival (P=.26).
Conclusions
These results suggest that the distance from a transplant center should not be a barrier to ASCT for eligible patients with multiple myeloma.
PMCID: PMC3855803  PMID: 22398804
Thrombotic; thrombocytopenia; purpura; ADAMTS13; microangiopathic; hemolytic
20.  Prevalence of Venous Thromboembolism in Patients With Secondary Polycythemia 
To investigate an association between secondary polycythemia and venous thromboembolism (VTE) risk, we performed a case–control study to compare the prevalence of VTE in participants with secondary polycythemia due to chronic obstructive pulmonary disease (COPD; N = 86) to that in age- and sex-matched controls with COPD without secondary polycythemia (N = 86). Although there was a significant difference in mean hematocrit between cases and controls (53.5% vs 43.6%, respectively; P < .005), we identified no difference in the number of total or idiopathic VTE events in the 2 groups. Patients with VTE, however, had a significantly higher body mass index than patients without VTE. Our findings suggest that secondary polycythemia alone may not be a significant risk factor for VTE but that VTE risk in this population may be related to known risk factors such as obesity. The role of phlebotomy for VTE risk reduction secondary polycythemia is therefore questionable.
doi:10.1177/1076029612460425
PMCID: PMC3831025  PMID: 23007895
polycythemia; venous thromboembolism; phlebotomy; obesity
21.  Use of MRI in Preoperative Planning for Women with Newly Diagnosed DCIS: Risk or Benefit? 
Annals of surgical oncology  2012;19(10):10.1245/s10434-012-2548-3.
Background
The role of magnetic resonance imaging (MRI) in preoperative planning for women diagnosed with breast cancer remains controversial. The risks and benefits in women with newly diagnosed ductal carcinoma in situ (DCIS) are largely unknown.
Patients and Methods
Retrospective chart review comparing women treated for DCIS who did and did not undergo MRI for preoperative planning. End points included number of additional biopsies prompted by MRI, surgical reexcision rates, weight of excisions, mastectomy rates, and conversion to mastectomy after attempted breast conservation.
Results
218 patients met study criteria. Sixty-four patients did not undergo preoperative MRI, and 154 patients did. There was no statistically significant difference (P = not significant, NS) in reexcision rates between the 34.1 % (42/ 123) of women who did and 20/51 (39.2 %) women who did not undergo MRI. Despite use of preoperative MRI, 11/123 women (8.9 %) were converted to mastectomy due to positive margins compared with 4/51 (7.8 %) in the women who did not undergo MRI (P = NS). In women undergoing MRI, average weight of excision at definitive surgery was 49.5 g, while in women who did not undergo MRI, average weight of excision at definitive surgery was 48.7 g.
Conclusions
Our data show that MRI does not significantly decrease reexcision rates or conversion to mastectomy after attempted breast-conservation surgery. Based on our findings, we do not believe preoperative MRI adds benefit to the care of this patient population. Prospective trials are necessary to further investigate the risks and benefits of preoperative MRI in women with DCIS.
doi:10.1245/s10434-012-2548-3
PMCID: PMC3809001  PMID: 22911365
22.  Diagnostic cellular abnormalities in neoplastic and non-neoplastic lesions of the epidermis: a morphological and statistical study 
Journal of cutaneous pathology  2013;40(4):10.1111/cup.12090.
Background
Distinguishing cellular abnormalities in reactive and malignant lesions is challenging. We compared the incidence and severity of cytological abnormalities in malignant/premalignant and benign epidermal lesions.
Methods
One hundred fifty-two biopsies representing 69 malignant/premalignant squamous lesions and 83 benign conditions were studied. Cytological features, including nuclear hyperchromasia, nuclear overlap (crowding), irregular nuclei, high nuclear/cytoplasmic (N/C) ratio, conspicuous nucleoli, delicate inconspicuous nucleoli, clumped chromatin, pleomorphic parakeratosis, normal and abnormal mitotic figures and necrotic keratinocytes, were evaluated and graded. Statistical analysis was performed.
Results
Irregular nuclei, increased N/C ratio, conspicuous single prominent nucleoli, nuclear overlap (crowding), pleomorphic parakeratosis, nuclear hyperchromasia, necrotic keratinocytes, normal and abnormal mitotic figures and coarse chromatin were seen more frequently in malignant neoplasms (p < 0.05). Abnormal mitotic figures, although uncommon (20.3%), were only noted in the malignant/premalignant group. Certain cytological features were common among both malignant and benign lesions, suggesting that they are of little value.
Conclusion
In the setting of an atypical cutaneous squamous proliferation, nuclear irregularity, increased N/C ratio, conspicuous nucleoli, crowding and hyperchromasia are the most useful indicators of malignancy. In contrast, mitotic figures, necrotic cells and coarse chromatin are less useful. The presence of abnormal mitotic figures is very helpful when present; however, their overall rarity limits their utility.
doi:10.1111/cup.12090
PMCID: PMC3809146  PMID: 23398548
atypical features; cutaneous squamous cell carcinoma; non-melanoma skin cancer; squamous cell carcinomas
23.  Increased Rates of Long-Term Complications after MammoSite Brachytherapy Compared with Whole Breast Radiation Therapy 
Journal of the American College of Surgeons  2013;217(3):10.1016/j.jamcollsurg.2013.03.028.
BACKGROUND
Due to its short duration of therapy and low rates of local recurrence, women undergoing breast conservation are increasingly opting for partial breast irradiation with the MammoSite (Cytyc/Hologic) catheter. In early follow-up studies, few complications were reported. Few data, however, exist regarding longer-term complications. We compared the long-term local toxicities of MammoSite partial breast irradiation with those resulting from whole breast radiation.
STUDY DESIGN
This was a retrospective study performed in a single academic medical center. All patients who underwent breast-conserving surgery between 2003 and 2008, who met institutional criteria for brachytherapy, were included. We compared women treated with MammoSite with patients treated with whole breast radiation therapy (WBRT). Endpoints included incidence of palpable masses at the lumpectomy site, telangiectasias, and local recurrence.
RESULTS
Seventy-one MammoSite patients and 245 WBRT patients were well matched with regard to clinical characteristics. Median follow-up was 4 years. A palpable mass developed at the site of lumpectomy in 27% of the MammoSite patients compared with 7% of the WBRT patients (p < 0.0001). Telangiectasias developed more frequently in the MammoSite group than in the WBRT group (24% vs 4%, p < 0.001). Forty-two percent of patients treated with MammoSite developed a palpable mass, telangectasia, or both.
CONCLUSIONS
Palpable masses and telangiectasias are frequent long-term complications after MammoSite brachytherapy and occur at a significantly higher rate after MammoSite brachytherapy than after WBRT. This increased rate of long-term local toxicity should be considered when counseling women on options for adjuvant radiation therapy after breast-conserving surgery.
doi:10.1016/j.jamcollsurg.2013.03.028
PMCID: PMC3808115  PMID: 23830216
24.  Effect of calcium supplementation on fracture risk: a double-blind randomized controlled trial1, 2, 3 
Background
The effect of supplementation with calcium alone on risk fractures in a healthy population is not clear.
Objective
The objective was to determine whether 4 y of calcium supplementation would reduce the fracture risk during treatment and subsequent follow-up in a randomized placebo-controlled trial.
Design
The participants were aged <80 y at study entry (mean age: 61 y), were generally healthy, and had a recent diagnosis of colorectal adenoma. A total of 930 participants (72% men; mean age: 61 y) were randomly assigned to receive 4 y of treatment with 3 g CaCO3 (1200 mg elemental Ca) daily or placebo and were followed for a mean of 10.8 y. The primary outcomes of this analysis were all fractures and minimal trauma fractures (caused by a fall from standing height or lower while sitting, standing, or walking).
Results
There were 46 fractures (15 from minimal trauma) in 464 participants in the calcium group and 54 (29 from minimal trauma) in 466 participants in the placebo group. The overall risk of fracture differed significantly between groups during the treatment phase [hazard ratio (HR): 0.28; 95% CI: 0.09, 0.85], but not during the subsequent posttreatment follow-up (HR: 1.10; 95% CI: 0.71, 1.69). Minimal trauma fractures were also less frequent in the calcium group during treatment (HR: 0; 95% CI: 0, 0.50).
Conclusion
Calcium supplementation reduced the risk of all fractures and of minimal trauma fractures among healthy individuals. The benefit appeared to dissipate after treatment was stopped.
PMCID: PMC3773875  PMID: 18541589
25.  Immune Response in Patients With Newly Diagnosed Glioblastoma Multiforme Treated With Intranodal Autologous Tumor Lysate-dendritic Cell Vaccination After Radiation Chemotherapy 
Summary
Patients with glioblastoma multiforme (GBM) are profoundly immunosuppressed and may benefit from restoration of an antitumor immune response in combination with conventional radiation therapy and temozolomide (TMZ). The optimal strategies to evaluate clinically relevant immune responses to treatment have yet to be determined. The primary objective of our study was to determine immunologic response to cervical intranodal vaccination with autologous tumor lysate-loaded dendritic cells (DCs) in patients with GBM after radiation therapy and TMZ. We used a novel hierarchical clustering analysis of immune parameters measured before and after vaccination. Secondary objectives were to assess treatment feasibility and to correlate immune response with progression-free survival (PFS) and overall survival. Ten eligible patients received vaccination. Tumor-specific cytotoxic T-cell response measured after vaccination was enhanced for the precursor frequency of CD4+ T and CD4+ interferon γ-producing cells. Hierarchical clustering analysis of multiple functional outcomes discerned 2 groups of patients according to their immune response, and additionally showed that patients in the top quintile for at least one immune function parameter had improved survival. There were no serious adverse events related to DC vaccination. All patients were alive at 6 months after diagnosis and the 6-month PFS was 90%. The median PFS was 9.5 months and overall survival was 28 months. In patients with GBM, immune therapy with DC vaccination after radiation and TMZ resulted in tumor-specific immune responses that were associated with prolonged survival. Our data suggest that DC vaccination in combination with radiation and chemotherapy in patients with GBM is feasible, safe, and may induce tumor-specific immune responses.
doi:10.1097/CJI.0b013e318215e300
PMCID: PMC3766324  PMID: 21499132
dendritic cells; glioblastoma; vaccine; immune response

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