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Musculoskeletal simulations can provide insights into the underlying mechanisms that govern animal locomotion. In this study, we describe the development of a new musculoskeletal model of the horse, and to our knowledge present the first fully muscle-driven, predictive simulations of equine locomotion. Our goal was to simulate a model that captures only the gross musculoskeletal structure of a horse, without specialized morphological features. We mostly present simulations acquired using feedforward control, without state feedback ("top-down control"). Without using kinematics or motion capture data as an input, we have simulated a variety of gaits that are commonly used by horses (walk, pace, trot, tölt, and collected gallop). We also found a selection of gaits that are not normally seen in horses (half bound, extended gallop, ambling). Due to the clinical relevance of the trot, we performed a tracking simulation that included empirical joint angle deviations in the cost function. To further demonstrate the flexibility of our model, we also present a simulation acquired using spinal feedback control, where muscle control signals are wholly determined by gait kinematics. Despite simplifications to the musculature, simulated footfalls and ground reaction forces followed empirical patterns. In the tracking simulation, kinematics improved with respect to the fully predictive simulations, and muscle activations showed a reasonable correspondence to electromyographic signals, although we did not predict any anticipatory firing of muscles. When sequentially increasing the target speed, our simulations spontaneously predicted walk-to-run transitions at the empirically determined speed. However, predicted stride lengths were too short over nearly the entire speed range unless explicitly prescribed in the controller, and we also did not recover spontaneous transitions to asymmetric gaits such as galloping. Taken together, our model performed adequately when simulating individual gaits, but our simulation workflow was not able to capture all aspects of gait selection. We point out certain aspects of our workflow that may have caused this, including anatomical simplifications and the use of massless Hill-type actuators. Our model is an extensible, generalized horse model, with considerable scope for adding anatomical complexity. This project is intended as a starting point for continual development of the model and code that we make available in extensible open-source formats. [ABSTRACT FROM AUTHOR]

Background Oral health is a key indicator of overall health, well-being, and quality of life. Several studies have provided new evidence about the role of oral diseases, specifically periodontitis, in generating risk for various forms of cancers, including lung, colorectal, and pancreatic cancers. Methods Incident lung cancer cases (n = 192) and matched controls (n = 192) were selected from participants of the CLUE I and CLUE II cohorts. Archived serum samples collected from participants in 1974 (in CLUE I) were analyzed using immunoblotting for immunoglobulin G (IgG) antibody levels to 13 bacteria of the periodontium. Associations between antibody levels and lung cancer were estimated using conditional logistic regression. Results Most of the periodontal bacterial antibodies measured were inversely associated with lung cancer risk; of these, 3 were statistically significant (Prevotella intermedia , Actinomyces naeslundii , and Veillonella parvula). A statistically significant positive association was observed for one of the Porphyromonas gingivalis strains after adjusting for P. intermedia. The sum of the logarithm of antibodies against the 13 measured bacteria was inversely associated with risk of lung cancer when the analysis was restricted to a longer follow-up (31-44 years after blood collection, highest vs lowest quartile: odds ratio = 0.26, 95% confidence interval = 0.08 to 0.84). Conclusions Findings from this study highlight the complexity of using serum IgG antibodies to periodontal bacteria to identify associations between oral pathogens and risk of lung cancer. The inverse associations observed for antibodies to periodontal bacteria suggest that these may represent markers of immunity that provide some advantage in reducing the development of lung cancer. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) is a highly prevalent human herpes virus that exerts a strong influence on immune repertoire which may influence cancer risk. We have tested whether CMV immunoglobulin G (IgG) serostatus is associated with immune cell proportions (n = 132 population controls), human papillomavirus (HPV) co-infection and head and neck cancer risk (n = 184 cancer cases and 188 controls) and patient survival. CMV status was not associated with the proportion of Natural Killer cells, B cells or the neutrophil-to-lymphocyte ratio. However, CD8+ T cells increased with increasing categories of IgG titers (P =1.7 × 10−10), and titers were inversely associated with the CD4:CD8 ratio (P = 5.6 × 10−5). Despite these differences in T cell proportions, CMV was not associated with HPV16 co-infection. CMV seropositivity was similar in cases (52%) and controls (47%) and was not associated with patient survival (hazard ratio [HR] 1.14, 95% confidence interval [CI]: 0.70 to 1.86). However, those patients with the highest titers had the worst survival (HR 1.91, 95% CI: 1.13 to 3.23). Tumor-based data from The Cancer Genome Atlas demonstrated that the presence of CMV transcripts was associated with worse patient survival (HR 1.79, 95% CI: 0.96 to 2.78). These findings confirm that a history of CMV infection alters T cell proportions, but this does not translate to HPV16 co-infection or head and neck cancer risk. Our data suggest that high titers and active CMV virus in the tumor environment may confer worse survival. [ABSTRACT FROM AUTHOR]

Background: Tumor-based classification of human glioma portends patient prognosis, but considerable unexplained survival variability remains. Host factors (eg, age) also strongly influence survival times, partly reflecting a compromised immune system. How blood epigenetic measures of immune characteristics and age augment molecular classifications in glioma survival has not been investigated. We assess the prognostic impact of immune cell fractions and epigenetic age in archived blood across glioma molecular subtypes for the first time.Methods: We evaluated immune cell fractions and epigenetic age in archived blood from the University of California San Francisco Adult Glioma Study, which included a training set of 197 patients with IDH-wild type, 1p19q intact, TERT wild type (IDH/1p19q/TERT-WT) glioma, an evaluation set of 350 patients with other subtypes of glioma, and 454 patients without glioma.Results: IDH/1p19q/TERT-WT patients had lower lymphocyte fractions (CD4+ T, CD8+ T, natural killer, and B cells) and higher neutrophil fractions than people without glioma. Recursive partitioning analysis delineated 4 statistically significantly different survival groups for patients with IDH/1p19q/TERT-WT based on an interaction between chronological age and 2 blood immune factors, CD4+ T cells, and neutrophils. Median overall survival ranged from 0.76 years (95% confidence interval = 0.55-0.99) for the worst survival group (n = 28) to 9.72 years (95% confidence interval = 6.18 to not available) for the best (n = 33). The recursive partitioning analysis also statistically significantly delineated 4 risk groups in patients with other glioma subtypes.Conclusions: The delineation of different survival groups in the training and evaluation sets based on an interaction between chronological age and blood immune characteristics suggests that common host immune factors among different glioma types may affect survival. The ability of DNA methylation-based markers of immune status to capture diverse, clinically relevant information may facilitate noninvasive, personalized patient evaluation in the neuro-oncology clinic. [ABSTRACT FROM AUTHOR]

The effects of various forms of ionising radiation are known to be mediated by interactions with cellular and molecular targets in irradiated and in some cases non-targeted tissue volumes. Despite major advances in advanced conformal delivery techniques, the probability of normal tissue complication (NTCP) remains the major dose-limiting factor in escalating total dose delivered during treatment. Potential strategies that have shown promise as novel delivery methods in achieving effective tumour control whilst sparing organs at risk involve the modulation of critical dose delivery parameters. This has led to the development of techniques using high dose spatial fractionation (GRID) and ultra-high dose rate (FLASH) which have translated to the clinic. The current review discusses the historical development and biological basis of GRID, microbeam and FLASH radiotherapy as advanced delivery modalities that have major potential for widespread implementation in the clinic in future years. [ABSTRACT FROM AUTHOR]

Background Early exposure to socioeconomic disadvantage is associated with obesity. Here we investigated how early, and conducted mediation analyses to identify behavioural factors in adulthood that could explain why. Methods Among 931 participants in the New England Family Study, we investigated the associations of family socioeconomic disadvantage measured before birth and at age 7 years with the following measures of adiposity in mid-adulthood (mean age = 44.4 years): body mass index (BMI), waist circumference and, among 400 participants, body composition from dual-energy X-ray absorption scans. Results In linear regressions adjusting for age, sex, race and childhood BMI Z-score, participants in the highest tertile of socioeconomic disadvantage at birth had 2.6 additional BMI units in adulthood [95% confidence interval (CI) = 1.26, 3.96], 5.62 cm waist circumference (95% CI = 2.69, 8.55), 0.73 kg of android fat mass (95% CI = 0.25, 1.21), and 7.65 higher Fat Mass Index (95% CI = 2.22, 13.09). Conditional on disadvantage at birth, socioeconomic disadvantage at age 7 years was not associated with adult adiposity. In mediation analyses, 10–20% of these associations were explained by educational attainment and 5–10% were explained by depressive symptoms. Conclusions Infancy may be a sensitive period for exposure to socioeconomic disadvantage, as exposure in the earliest years of life confers a larger risk for overall and central adiposity in mid-adulthood than exposure during childhood. Intervention on these two adult risk factors for adiposity would, if all model assumptions were satisfied, only remediate up to one-fifth of the excess adult adiposity among individuals born into socioeconomically disadvantaged households. [ABSTRACT FROM AUTHOR]

Background A short-course regimen of 3 months of weekly rifapentine and isoniazid (3HP) has recently been recommended by the World Health Organization as an alternative to at least 6 months of daily isoniazid (isoniazid preventive therapy [IPT]) for prevention of tuberculosis (TB). The contexts in which 3HP may be cost-effective compared to IPT among people living with human immunodeficiency virus are unknown. Methods We used a Markov state transition model to estimate the incremental cost-effectiveness of 3HP relative to IPT in high-burden settings, using a cohort of 1000 patients in a Ugandan HIV clinic as an emblematic scenario. Cost-effectiveness was expressed as 2017 US dollars per disability-adjusted life year (DALY) averted from a healthcare perspective over a 20-year time horizon. We explored the conditions under which 3HP would be considered cost-effective relative to IPT. Results Per 1000 individuals on antiretroviral therapy in the reference scenario, treatment with 3HP rather than IPT was estimated to avert 9 cases of TB and 1 death, costing $9402 per DALY averted relative to IPT. Cost-effectiveness depended strongly on the price of rifapentine, completion of 3HP, and prevalence of latent TB. At a willingness to pay of $1000 per DALY averted, 3HP is likely to be cost-effective relative to IPT only if the price of rifapentine can be greatly reduced (to approximately $20 per course) and high treatment completion (85%) can be achieved. Conclusions 3HP may be a cost-effective alternative to IPT in high-burden settings, but cost-effectiveness depends on the price of rifapentine, achievable completion rates, and local willingness to pay. [ABSTRACT FROM AUTHOR]

Background: Lung cancer is the deadliest cancer in developed countries but the etiology of lung cancer risk in never smokers (LCRINS) is largely unknown. We aim to assess the effects of alcohol consumption, in its different forms, on LCRINS. Methods: We pooled six multi-center case-control studies developed in the northwest of Spain. Cases and controls groups were composed of never smokers. We selected incident cases with anatomopathologically confirmed lung cancer diagnoses. All participants were personally interviewed. We performed two groups of statistical models, applying unconditional logistic regression with generalized additive models. One considered the effect of alcohol type consumption and the other considered the quantity of each alcoholic beverage consumed. Results: A total of 438 cases and 863 controls were included. Median age was 71 and 66, years, respectively. Adenocarcinoma was the predominant histological type, comprising 66% of all cases. We found that any type of wine consumption posed an OR of 2.20 OR 95%CI 1.12-4.35), and spirits consumption had an OR of 1.90 (95%CI 1.13-3.23). Beer consumption had an OR of 1.33 (95%CI 0.82-2.14). These results were similar when women were analyzed separately, but for men there was no apparent risk for any alcoholic beverage. The dose-response analysis for each alcoholic beverage revealed no clear pattern. Conclusions: Wine and spirits consumption might increase the risk of LCRINSs, particularly in females. These results have to be taken with caution given the limitations of the present study. [ABSTRACT FROM AUTHOR]

Established cardiac fibrosis (ECF) with symptomatic heart failure preserved ejection fraction represents an ever-increasing segment of the hypertensive population. The regression of ECF with attendant improvement in myocardial stiffness and symptomatic failure represents an unmet health care need. Is the regression of ECF in hypertensive heart disease feasible and will stiffness and symptomatic failure be improved? What is the cellular/molecular signaling involved in its regression? What incremental knowledge is needed to proceed effectively? These issues are addressed in this Review. [ABSTRACT FROM AUTHOR]

Death from chronic lung disease is increasing and chronic obstructive pulmonary disease has become the third leading cause of death in the United States in the past decade. Both chronic and acute lung diseases disproportionately affect elderly individuals, making it likely that these diseases will become more frequent and severe as the worldwide population ages. Chronic lung diseases are associated with substantial morbidity, frequently resulting in exercise limiting dyspnea, immobilization, and isolation. Therefore, effective strategies to prevent or treat lung disease are likely to increase healthspan as well as life span. This review summarizes the findings of a joint workshop sponsored by the NIA and NHLBI that brought together investigators focused on aging and lung biology. These investigators encouraged the use of genetic systems and aged animals in the study of lung disease and the development of integrative systems-based platforms that can dynamically incorporate data sets that describe the genomics, transcriptomics, epigenomics, metabolomics, and proteomics of the aging lung in health and disease. Further research was recommended to integrate benchmark biological hallmarks of aging in the lung with the pathobiology of acute and chronic lung diseases with divergent pathologies for which advanced age is the most important risk factor. [ABSTRACT FROM AUTHOR]

Polymorphisms in microRNAs and their target sites can disrupt microRNA-dependent gene regulation, and have been associated with cancer susceptibility. However, genome-scale analyses of microRNA-related genetic variation in cancer are lacking. We tested the associations of ~40 000 common [minor allele frequency (MAF) ≥5%], microRNA-related single nucleotide polymorphisms (miR-SNPs), with risk of head and neck squamous cell carcinoma (HNSCC) in a discovery population, and validated selected loci in an independent population among a total of 2198 cases and 2180 controls. Joint analyses across the discovery and validation populations revealed six novel miR-SNP associations with risk of HNSCC. An upstream variant of MIR548H4 (rs7834169), replicated its association with overall HNSCC risk as well as risk of oral cavity cancer. Four other variants were specifically associated with oral cavity cancer risk (rs16914640, rs1134367, rs7306991 and rs1373756). 3UTR variant of HADH, rs221347 and rs4975616, located within known cancer risk locus 5p15.33, were specific to risk of laryngeal cancer. High confidence predicted microRNA binding sites were identified for CLEC2D, LOC37443, KDM8 and HADH overlapping rs16914640, rs7306991, rs1134367 and rs221347, respectively. Furthermore, we identified several microRNA interactions with KDM8 and HADH predicted to be disrupted by genetic variation at rs1134367 and rs221347. These results suggest microRNA-related genetic variation may contribute to the genetic susceptibility of HNSCC, and that more powerful evaluation of this class of genetic variation and their relationship with cancer risk is warranted. [ABSTRACT FROM AUTHOR]

Previous studies on smokeless tobacco use and head and neck cancer (HNC) have found inconsistent and often imprecise estimates, with limited control for cigarette smoking. Using pooled data from 11 US case-control studies (1981-2006) of oral, pharyngeal, and laryngeal cancers (6,772 cases and 8,375 controls) in the International Head and Neck Cancer Epidemiology (INHANCE) Consortium, we applied hierarchical logistic regression to estimate odds ratios and 95% confidence intervals for ever use, frequency of use, and duration of use of snuff and chewing tobacco separately for never and ever cigarette smokers. Ever use (versus never use) of snuff was strongly associated with HNC among never cigarette smokers (odds ratio (OR) = 1.71, 95% confidence interval (CI): 1.08, 2.70), particularly for oral cavity cancers (OR = 3.01, 95% CI: 1.63, 5.55). Although ever (versus never) tobacco chewing was weakly associated with HNC among never cigarette smokers (OR = 1.20, 95% CI: 0.81, 1.77), analyses restricted to cancers of the oral cavity showed a stronger association (OR = 1.81, 95% CI: 1.04, 3.17). Few or no associations between each type of smokeless tobacco and HNC were observed among ever cigarette smokers, possibly reflecting residual confounding by smoking. Smokeless tobacco use appears to be associated with HNC, especially oral cancers, with snuff being more strongly associated than chewing tobacco. [ABSTRACT FROM AUTHOR]

Polyomaviruses (PyV) are potentially tumorigenic in humans. However, limited data exist on the population seroprevalence of PyVs and individual characteristics that relate to seropositivity. Using multiplex serology, we determined the seroprevalence of 10 human PyVs (BK, JC, KI, WU, MCV, HPyV6, HPyV7, TSV, HPyV9, and HPyV10) among controls from a population-based skin cancer case-control study (n = 460) conducted in New Hampshire between 1993 and 1995. On a subset of participants (n = 194), methylation at CpG dinucleotides across the genome was measured in peripheral blood using the Illumina Infinium HumanMethylation27 BeadChip array (Illumina Inc., San Diego, California), from which lymphocyte subtype proportions were inferred. All participants were seropositive for at least 1 PyV, with seroprevalences ranging from 17.6% (HPyV9) to 99.1% (HPyV10). Seropositivity to JC, MCV, and HPyV7 increased with age. JC and TSV seropositivity were more common among men than among women. Smokers were more likely to be HPyV9-seropositive but MCV-seronegative, and HPyV7 seropositivity was associated with prolonged glucocorticoid use. Based on DNA methylation profiles, differences were observed in CD8-positive T- and B-cell proportions by BK, JC, and HPyV9 seropositivity. Our findings suggest that PyV seropositivity is common in the United States and varies by sociodemographic and biological characteristics, including those related to immune function. [ABSTRACT FROM AUTHOR]

Background: Adiposity is a risk factor for type 2 diabetes and cardiovascular disease, suggesting an important role for adipose tissue in the development of these conditions. The epigenetic underpinnings of adiposity are not well understood, and studies of DNA methylation in relation to adiposity have rarely focused on target adipose tissue. Objectives were to evaluate whether genome-wide DNA methylation profiles in subcutaneous adipose tissue and peripheral blood leukocytes are associated with measures of adiposity, including central fat mass, body fat distribution and body mass index.Methods: Participants were 106 men and women (mean age 47 years) from the New England Family Study. DNA methylation was evaluated using the Infinium HumanMethylation450K BeadChip. Adiposity phenotypes included dual-energy X-ray absorptiometry-assessed android fat mass, android:gynoid fat ratio and trunk:limb fat ratio, as well as body mass index.Results: Adipose tissue genome-wide DNA methylation profiles were associated with all four adiposity phenotypes, after adjusting for race, sex and current smoking (omnibus p-values <0.001). After further adjustment for adipose cell-mixture effects, associations with android fat mass, android:gynoid fat ratio, and trunk:limb fat ratio remained. In gene-specific analyses, adiposity phenotypes were associated with adipose tissue DNA methylation in several genes that are biologically relevant to the development of adiposity, such as AOC3, LIPE, SOD3, AQP7 and CETP. Blood DNA methylation profiles were not associated with adiposity, before or after adjustment for blood leukocyte cell mixture effects.Conclusion: Findings show that DNA methylation patterns in adipose tissue are associated with adiposity. [ABSTRACT FROM AUTHOR]

ABSTRACT Chronic stress and depression have adverse consequences on many organ systems, including the skeleton, but the mechanisms underlying stress-induced bone loss remain unclear. Here we demonstrate that neuropeptide Y (NPY), centrally and peripherally, plays a critical role in protecting against stress-induced bone loss. Mice lacking the anxiolytic factor NPY exhibit more anxious behavior and elevated corticosterone levels. Additionally, following a 6-week restraint, or cold-stress protocol, Npy-null mice exhibit three-fold greater bone loss compared to wild-type mice, owing to suppression of osteoblast activity. This stress-protective NPY pathway acts specifically through Y2 receptors. Centrally, Y2 receptors suppress corticotropin-releasing factor expression and inhibit activation of noradrenergic neurons in the paraventricular nucleus. In the periphery, they act to control noradrenaline release from sympathetic neurons. Specific deletion of arcuate Y2 receptors recapitulates the Npy-null stress response, coincident with elevated serum noradrenaline. Importantly, specific reintroduction of NPY solely in noradrenergic neurons of otherwise Npy-null mice blocks the increase in circulating noradrenaline and the stress-induced bone loss. Thus, NPY protects against excessive stress-induced bone loss, through Y2 receptor-mediated modulation of central and peripheral noradrenergic neurons. © 2014 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

An ongoing loss of cardiomyocytes to apoptotic and necrotic cell death pathways contributes to the progressive nature of heart failure. The pathophysiological origins of necrotic cell loss relate to the neurohormonal activation that accompanies acute and chronic stressor states and which includes effector hormones of the adrenergic nervous system. Fifty years ago, Albrecht Fleckenstein and coworkers hypothesized the hyperadrenergic state, which accompanies such stressors, causes cardiomyocyte necrosis based on catecholamine-initiated excessive intracellular Ca2+ accumulation (EICA), and mitochondrial Ca2+ overloading in particular, in which the ensuing dysfunction and structural degeneration of these organelles leads to necrosis. In recent years, two downstream factors have been identified which, together with EICA, constitute a signal–transducer–effector pathway: (i) mitochondria-based induction of oxidative stress, in which the rate of reactive oxygen metabolite generation exceeds their rate of detoxification by endogenous antioxidant defences; and (ii) the opening of the mitochondrial inner membrane permeability transition pore (mPTP) followed by organellar swelling and degeneration. The pathogenesis of stress-related cardiomyopathy syndromes is likely related to this pathway. Other factors which can account for cytotoxicity in stressor states include: hypokalaemia; ionized hypocalcaemia and hypomagnesaemia with resultant elevations in parathyroid hormone serving as a potent mediator of EICA; and hypozincaemia with hyposelenaemia, which compromise antioxidant defences. Herein, we revisit the Fleckenstein hypothesis of EICA in leading to cardiomyocyte necrosis and the central role played by mitochondria. [ABSTRACT FROM PUBLISHER]

Background Although much is known about molecular and chromosomal characteristics that distinguish glioma histological subtypes, DNA methylation patterns of gliomas and their association with other tumor features such as mutation of isocitrate dehydrogenase (IDH) genes have only recently begun to be investigated. Methods DNA methylation of glioblastomas, astrocytomas, oligodendrogliomas, oligoastrocytomas, ependymomas, and pilocytic astrocytomas (n = 131) from the Brain Tumor Research Center at the University of California San Francisco, as well as nontumor brain tissues (n = 7), was assessed with the Illumina GoldenGate methylation array. Methylation data were subjected to recursively partitioned mixture modeling (RPMM) to derive methylation classes. Differential DNA methylation between tumor and nontumor was also assessed. The association between methylation class and IDH mutation (IDH1 and IDH2) was tested using univariate and multivariable analysis for tumors (n = 95) with available substrate for sequencing. Survival of glioma patients carrying mutant IDH (n = 57) was compared with patients carrying wild-type IDH (n = 38) using a multivariable Cox proportional hazards model and Kaplan–Meier analysis. All statistical tests were two-sided. Results We observed a statistically significant association between RPMM methylation class and glioma histological subtype (P < 2.2 × 10−16). Compared with nontumor brain tissues, across glioma tumor histological subtypes, the differential methylation ratios of CpG loci were statistically significantly different (permutation P < .0001). Methylation class was strongly associated with IDH mutation in gliomas (P = 3.0 × 10−16). Compared with glioma patients whose tumors harbored wild-type IDH, patients whose tumors harbored mutant IDH showed statistically significantly improved survival (hazard ratio of death = 0.27, 95% confidence interval = 0.10 to 0.72). Conclusion The homogeneity of methylation classes for gliomas with IDH mutation, despite their histological diversity, suggests that IDH mutation is associated with a distinct DNA methylation phenotype and an altered metabolic profile in glioma. [ABSTRACT FROM PUBLISHER]

Motivation: Patients with identical cancer diagnoses often progress differently. The disparity we see in disease progression and treatment response can be attributed to the idea that two histologically similar cancers may be completely different diseases on the molecular level. Methods for identifying cancer subtypes associated with patient survival have the capacity to be powerful instruments for understanding the biochemical processes that underlie disease progression as well as providing an initial step toward more personalized therapy for cancer patients. We propose a method called semi-supervised recursively partitioned mixture models (SS-RPMM) that utilizes array-based genetic and patient-level clinical data for finding cancer subtypes that are associated with patient survival.Results: In the proposed SS-RPMM, cancer subtypes are identified using a selected subset of genes that are associated with survival time. Since survival information is used in the gene selection step, this method is semi-supervised. Unlike other semi-supervised clustering classification methods, SS-RPMM does not require specification of the number of cancer subtypes, which is often unknown. In a simulation study, our proposed method compared favorably with other competing semi-supervised methods, including: semi-supervised clustering and supervised principal components analysis. Furthermore, an analysis of mesothelioma cancer data using SS-RPMM, revealed at least two distinct methylation profiles that are informative for survival.Availability: The analyses implemented in this article were carried out using R (http://www.r.project.org/).Contact: devin_koestler@brown.edu; e_andres_houseman@brown.eduSupplementary information: Supplementary data are available at Bioinformatics online. [ABSTRACT FROM PUBLISHER]

Background: Genome-wide association studies have identified three chromosomal regions at 15q25, 5p15, and 6p21 as being associated with the risk of lung cancer. To confirm these associations in independent studies and investigate heterogeneity of these associations within specific subgroups, we conducted a coordinated genotyping study within the International Lung Cancer Consortium based on independent studies that were not included in previous genome-wide association studies. [ABSTRACT FROM PUBLISHER]

Background: Sexual contact may be the means by which head and neck cancer patients are exposed to human papillomavirus (HPV).Methods: We undertook a pooled analysis of four population-based and four hospital-based case-control studies from the International Head and Neck Cancer Epidemiology (INHANCE) consortium, with participants from Argentina, Australia, Brazil, Canada, Cuba, India, Italy, Spain, Poland, Puerto Rico, Russia and the USA. The study included 5642 head and neck cancer cases and 6069 controls. We calculated odds ratios (ORs) of associations between cancer and specific sexual behaviours, including practice of oral sex, number of lifetime sexual partners and oral sex partners, age at sexual debut, a history of same-sex contact and a history of oral-anal contact. Findings were stratified by sex and disease subsite.Results: Cancer of the oropharynx was associated with having a history of six or more lifetime sexual partners [OR = 1.25, 95% confidence interval (CI) 1.01, 1.54] and four or more lifetime oral sex partners (OR = 2.25, 95% CI 1.42, 3.58). Cancer of the tonsil was associated with four or more lifetime oral sex partners (OR = 3.36, 95 % CI 1.32, 8.53), and, among men, with ever having oral sex (OR = 1.59, 95% CI 1.09, 2.33) and with an earlier age at sexual debut (OR = 2.36, 95% CI 1.37, 5.05). Cancer of the base of the tongue was associated with ever having oral sex among women (OR = 4.32, 95% CI 1.06, 17.6), having two sexual partners in comparison with only one (OR = 2.02, 95% CI 1.19, 3.46) and, among men, with a history of same-sex sexual contact (OR = 8.89, 95% CI 2.14, 36.8).Conclusions: Sexual behaviours are associated with cancer risk at the head and neck cancer subsites that have previously been associated with HPV infection. [ABSTRACT FROM AUTHOR]

The contribution of microRNAs (miRNAs) to carcinogenesis in many tumors, including head and neck squamous cell carcinomas (HNSCCs), is clear, but the etiology and clinical significance of their alteration remain important questions. Our previous work has identified four miRNAs as differentially expressed HNSCCs compared with non-diseased epithelia and showed that there is potential diagnostic utility in examining their expression. Here, we used quantitative real-time polymerase chain reaction to determine the relative expression of these miRNAs in a larger independent case series of HNSCC tumors (n = 169), examining associations of miRNA expression with exposures and clinical features associated with HNSCC. In multivariate analyses, expression of miR-375 was shown to increase with alcohol consumption (P = 0.002) and showed higher expression in tumors of pharyngeal and laryngeal origin compared with oral tumors (P < 0.05 and P < 0.01, respectively). Additionally, high miR-21 expression was associated with significantly decreased 5 year survival in patients (hazard ratio, 1.68; 95% CI: 1.04–2.77) in a model controlled for patient age, gender and tumor stage. Together, these data suggest that alterations in miRNA expression are related to exposures causal in head and neck cancer and may be useful biomarkers of patient outcome. [ABSTRACT FROM PUBLISHER]

Background: Cigarette smoking is a well-established risk factor for bladder cancer. The effects of smoking duration, intensity (cigarettes per day), and total exposure (pack-years); smoking cessation; exposure to environmental tobacco smoke; and changes in the composition of tobacco and cigarette design over time on risk of bladder cancer are unclear. [ABSTRACT FROM PUBLISHER]

Background: Human papillomavirus type 16 (HPV16) seropositivity and alcohol and tobacco use have been associated with risk of head and neck squamous cell carcinoma (HNSCC). However, it is less clear whether HPV16 influences HNSCC risk associated with alcohol and tobacco use.Methods: Incident cases of HNSCC diagnosed between December 1999 and December 2003 were identified from nine medical facilities in Greater Boston, MA. Control subjects were frequency matched to case subjects on age, sex, and town of residence. A total of 485 case subjects and 549 control subjects reported information on lifetime smoking and alcohol consumption and provided sera, which was used to determine presence of HPV16 antibodies. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of HNSCC risk by alcohol consumption (drinks per week: < 3, 3 to < 8, 8 to < 25, > or = 25) and smoking (pack-years: none, > 0 to < 20, 20 to < 45, > or = 45), adjusting for age, sex, race, education, and HPV16 serology. Polytomous logistic regression was used to estimate odds ratios and 95% confidence intervals for the association of HPV16 serology, alcohol consumption, and tobacco use in site-specific analyses. All statistical tests were two-sided.Results: The strongest risk factors by tumor site were smoking for laryngeal cancer, alcohol for cancer of the oral cavity, and HPV16 for pharyngeal cancer. For pharyngeal cancer, risk increased with increasing alcohol consumption (OR(> or = 25 versus < 3 drinks per week) = 5.1, 95% CI = 2.4 to 11.0) and smoking (OR(> or = 45 pack-years versus never smoker) = 6.9, 95% CI = 3.1 to 15.1) among HPV16-seronegative subjects but not among HPV16-seropositive subjects (P(interaction, HPV16 serology and alcohol) = .002; P(interaction, HPV16 serology and smoking) = .007). Among light drinkers or never smokers, HPV16 seropositivity was associated with a 30-fold increased risk of pharyngeal cancer.Conclusions: Alcohol or tobacco use does not further increase risk of HPV16-associated pharyngeal cancer. HNSCC risk associated with smoking, alcohol, and HPV16 differs by tumor site. [ABSTRACT FROM AUTHOR]

Background Human papillomavirus type 16 (HPV16) seropositivity and alcohol and tobacco use have been associated with risk of head and neck squamous cell carcinoma (HNSCC). However, it is less clear whether HPV16 influences HNSCC risk associated with alcohol and tobacco use. Methods Incident cases of HNSCC diagnosed between December 1999 and December 2003 were identified from nine medical facilities in Greater Boston, MA. Control subjects were frequency matched to case subjects on age, sex, and town of residence. A total of 485 case subjects and 549 control subjects reported information on lifetime smoking and alcohol consumption and provided sera, which was used to determine presence of HPV16 antibodies. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of HNSCC risk by alcohol consumption (drinks per week: <3, 3 to <8, 8 to <25, >25) and smoking (pack-years: none, >0 to <20, 20 to <45, ≥45), adjusting for age, sex, race, education, and HPV16 serology. Polytomous logistic regression was used to estimate odds ratios and 95% confidence intervals for the association of HPV16 serology, alcohol consumption, and tobacco use in site-specific analyses. All statistical tests were two-sided. Results The strongest risk factors by tumor site were smoking for laryngeal cancer, alcohol for cancer of the oral cavity, and HPV16 for pharyngeal cancer. For pharyngeal cancer, risk increased with increasing alcohol consumption (OR≥25 versus <3 drinks per week = 5.1, 95% Cl = 2.4 to 11.0) and smoking (OR≥45 pack-years versus never smoker = 6.9, 95% CI = 3.1 to 15.1) among HPV16-seronegative subjects but not among HPV16-seropositive subjects (Pinteraction, HPV16 serology and alcohol = .002; Pinteraction, HPV16 serology end smoking = .007). Among light drinkers or never smokers, HPV16 seropositivity was associated with a 30-fold increased risk of pharyngeal cancer. Conclusions Alcohol or tobacco use does not further increase risk of HPV16-associated pharyngeal cancer. HNSCC risk associated with smoking, alcohol, and HPV16 differs by tumor site. [ABSTRACT FROM AUTHOR]

Hypermethylation of tumor suppressor genes is central to the pathogenesis of human malignancy, yet this alteration's etiology remains unclear, and its clinical impact has not yet been studied using an approach that can yield directly generalizable results. Therefore, we sought to examine both of these issues in bladder cancer, seeking to understand the characteristics of epidemiologically well-defined patient tumors with differing levels of methylation silencing. We analyzed epigenetic silencing of 16 genes in a population-based incident case series of 331 bladder transitional cell carcinomas. We utilized a novel item response theory (IRT) model, to examine, in an unbiased fashion, the relationship of patient characteristics, carcinogen exposure history and tumor characteristics with the underlying propensity for gene hypermethylation. Age, male gender and current cigarette smoking were significantly positively associated with the methylation latent trait. Promoter hypermethylation as a latent trait significantly predicted both non-invasive/high-grade and invasive stage disease and was also significantly associated with survival, with each unit increase in the latent trait resulting in a 30% increase in the risk of death. This work, studying all stages and grades of incident bladder cancer, provides definitive evidence that carcinogen exposures play a critical role in selecting these alterations in tumorous clones and that epigenetic silencing is a strong and significant predictor of tumor stage and overall patient survival. Finally, our novel approach provides insight into the etiology of promoter hypermethylation, suggesting that selected, carcinogen-exposed individuals have a greater propensity for hypermethylation that is associated with more aggressive, fatal disease. [ABSTRACT FROM PUBLISHER]

Abstract: Congestive heart failure (CHF) is more than a failing heart and salt-avid state. Also present is a systemic illness which features oxidative stress in diverse tissues, a proinflammatory phenotype, and a wasting of soft tissue and bone. Reactive oxygen and nitrogen species contribute to this illness and the progressive nature of CHF. Aldosteronism, an integral component of the neurohormonal profile found in CHF, plays a permissive role in leading to an altered redox state. Because of augmented urinary and fecal excretion of Ca2+ and Mg2+ and consequent decline in plasma-ionized [Ca2+]o and [Mg2+]o that accompanies aldosteronism, parathyroid glands release parathyroid hormone (PTH) in an attempt to restore Ca2+ and Mg2+ homeostasis; this includes bone resorption. However, PTH-mediated intracellular Ca2+ overloading, considered a Ca2+ paradox, leads to oxidative stress. This can be prevented by: spironolactone, an aldosterone receptor antagonist that rescues urinary and fecal cation losses; parathyroidectomy; amlodipine, a Ca2+ channel blocker; N-acetylcysteine, an antioxidant. In addition to the role played by aldosteronism in the appearance of secondary hyperparathyroidism is the chronic use of a loop diuretic, which further enhances urinary Ca2+ and Mg2+ excretion, and reduced Ca2+ stores associated with hypovitaminosis D. This broader perspective of CHF and the ever increasing clinical relevance of divalent cations and oxidative stress raise the question of their potential management with macro- and micronutrients. An emerging body of evidence suggests the nutritional management of CHF offers an approach that will be complementary to today''s pharmaceutical-based strategies. [Copyright &y& Elsevier]

Study results of single nucleotide polymorphisms (SNPs) and cancer susceptibility are often conflicting, possibly because of the analytic challenges of testing for multiple genetic and environmental risk factors using traditional analytic tools. We investigated the relationship between DNA repair gene SNPs, smoking, and bladder cancer susceptibility in 355 cases and 559 controls enrolled in a population-based study of bladder cancer in the US. Our multifaceted analytical approach included logistic regression, multifactor dimensionality reduction, and hierarchical interaction graphs for the analysis of gene–gene and gene–environment interactions followed by linkage disequilibrium and haplotype analysis. Overall, we did not find an association between any single DNA repair gene SNP and bladder cancer risk. We did find a marginally significant elevated risk of the XPD codon 751 homozygote variant among never smokers [adjusted odds ratio (OR) 2.5, 95% confidence interval (CI) 1.0–6.2]. In addition, the XRCC1 194 variant allele was associated with a reduced bladder cancer risk among heavy smokers [adjusted OR 0.4, 95% CI 0.2–0.9)]. The best predictors of bladder cancer included the XPD codon 751 and 312 SNPs along with smoking. Interpretation of this multifactor model revealed that the relationship between the XPD SNPs and bladder cancer is mostly non-additive while the effect of smoking is mostly additive. Since the two XPD SNPs are in significant linkage disequilibrium (D′ = 0.52, P = 0.0001), we estimated XPD haplotypes. Individuals with variant XPD haplotypes were more susceptible to bladder cancer [e.g. adjusted OR 2.5, 95% CI 1.7–3.6] and the effect was magnified when smoking was considered. These results support the hypothesis that common polymorphisms in DNA repair genes modify bladder cancer risk and emphasize the need for a multifaceted statistical approach to identify gene–gene and gene–environment interactions. [ABSTRACT FROM AUTHOR]

Tobacco smoking, certain occupational exposures, and exposure to inorganic arsenic in drinking water have been associated with the occurrence of bladder cancer. However, in these tumors the exposure-associated pattern of somatic alterations in genes in the causal pathway for disease has been poorly characterized. In particular, the mechanism by which arsenic induces bladder cancer and the effects of lower environmental levels of exposure remain uncertain. Animal and in-vitro studies have suggested that arsenic and other exposures may act through epigenetic mechanisms. We, therefore, examined, in a population-based study of human bladder cancer, the relationship between epigenetic silencing of three tumor suppressor genes, p16INK4A, RASSF1A and PRSS3, and exposure to both tobacco and arsenic in bladder cancer. Promoter methylation of each of these genes occurred in ∼30% of bladder cancers, and both RASSF1A and PRSS3 promoter methylation were associated with advanced tumor stage (P < 0.001 and P < 0.04, respectively). Arsenic exposure, measured as toenail arsenic, was associated with RASSF1A (P < 0.02) and PRSS3 (P < 0.1) but not p16INK4A promoter methylation, in models adjusted for stage and other factors. Cigarette smoking was associated with a >2-fold increased risk of promoter methylation of the p16INK4A gene only, with greater risk seen in patients with exposures more recent to disease diagnosis. These results, from human bladder tumors, add to the body of animal and in vitro evidence that suggests a role in epigenetic alterations for bladder carcinogens. [ABSTRACT FROM AUTHOR]

ERCC2 and ERCC1 are important in DNA nucleotide excision repair and lie on chromosome 19q13.3 near a putative glioma suppressor region. We genotyped constitutive variants ERCC1 C8092A and ERCC2 K751Q and R156R in approximately 450 adults with glioma and 500 controls from two independent population-based series, uniformly reviewed patients' tumors to determine histopathologic category, and determined a variety of tumor markers among astrocytic tumors. Odds ratios (ORs) for glioblastoma for those carrying two ERCC1 A alleles versus none or one were 1.67 in series 1 and 1.64 in series 2, which yielded a combined OR of 1.67(95% CI, 0.93-3.02; P = 0.09), adjusted for age, gender, ethnicity, and series. Odds ratios for the ERCC2 variants were not consistently elevated or reduced for the two series in all cases versus controls. However, among whites, for those with ERCC2 K751Q genotype QQ versus QK/KK, the OR for nonglioblastoma histologies versus controls was 1.82 (95% CI, 0.97-3.44; P = 0.06). Also, among whites, glioma patients were significantly more likely than controls to be homozygous for variants in both ERCC1 C8092A and ERCC2 K751Q (OR, 3.2; 95% CI, 1.1-9.3). Given the numbers of comparisons made, these findings could be due to chance. However, the results might warrant clarification in additional series in conjunction with the nearby putative glioma suppressor genes (GLTSCR1 and GLTSCR2). [ABSTRACT FROM AUTHOR]

TP53 is well-recognized as a mutational target in cancers and common variation in the TP53 gene has been investigated as potentially contributing to cancer susceptibility. The codon 72 polymorphism has been proposed to alter the phenotype of TP53 mutations, and TP53 mutations have been reported to occur preferentially on the arginine allele. Using a consecutive case series of non-small cell lung cancer we have investigated whether TP53 mutations occur preferentially on the arginine or proline allele, and whether the combination of mutation and allelism confers differences in the clinical phenotype. The overall prevalence of TP53 mutation was 26% (76/293). The majority of mutations occurred on the arginine allele (51/60, 85%), and there was corresponding strong selection for loss of the proline allele [87% of loss of heterozygosity (LOH) events were loss of proline]. However, there was no statistically significant difference in the prevalence of mutation by constitutional genotype and among heterozygotes with LOH, TP53 mutation prevalence did not differ by the codon 72 polymorphism (48% on arginine versus 40% on proline). Importantly, patient survival did significantly differ: those patients having a TP53 mutation on the proline allele had the worst survival outcomes (hazards ratio = 2.6, P < 0.03). Further, this phenotype was limited to those patients with advanced disease, where mutation on the proline allele was associated with a significantly worse outcome compared with those without mutation or with mutation on the arginine allele (P  <  0.001). Our data suggest that there are selective pressures for loss of the TP53 proline allele in non-small cell lung cancer. Further, the combination of mutation with the codon 72 proline variant predicts poorer patient survival, particularly in a disease that has progressed outside the lung, a finding that warrants further investigation. [ABSTRACT FROM AUTHOR]

SEMA3B has been implicated as important for neuronal development and as a tumor suppressor in lung cancer. A single nucleotide alteration of this gene leads to the amino acid substitution T415I, and functionally, this variant protein has a reduced ability to act as a tumor suppressor. The prevalence of this variant in populations is unclear and its role in inherited lung cancer susceptibility has not been tested. Utilizing casecontrol studies of head and neck squamous cell carcinoma in a Caucasian population and of lung cancer in African-American and Latino-American populations, we determined both the prevalence of this polymorphic variant and its association with the case status of these patients. The variant Ile allele occurs at an allele frequency of 0.18 in African-American and 0.39 in Latino-American control subjects but not in Caucasian subjects. In analyses controlling for ethnicity and known lung cancer risk factors, a significant association was observed between case status and possession of the variant allele (OR 0.71, 95% CI 0.510.99). In stratified analysis, both Latino-Americans (OR 0.56, 95% CI 0.321.01) and African-Americans (OR 0.75, 95% CI 0.501.13) also showed a reduced risk of disease associated with the variant Ile allele. Possessing either the heterozygous or homozygous variant genotype confers a >40% reduced relative risk of lung cancer in Latino Americans controlling for other lung cancer risk factors. This study points to the need for further examination of this gene and its variant in lung cancer and other diseases. [ABSTRACT FROM AUTHOR]

Inorganic arsenic is a known human carcinogen, yet its mechanism of action remains poorly understood. Epidemiological data suggest that arsenic exposure interacts with UV radiation exposure to increase the risk of skin cancer. Studies have suggested that arsenic is able to impair DNA repair enzymes and alter the repair of UV‐induced DNA damage. Here we have tested the hypothesis that arsenite [As(III)] and UV interact synergistically to enhance mutagenesis. TK6 human lymphoblastoid cells that are functionally heterozygous at the thymidine kinase (TK) locus were pre‐exposed to As(III) alone and in combination with UV. Our data suggest that As(III) is mutagenic only at high doses at the TK locus. As(III) enhanced UV mutagenesis in a more than additive fashion. To investigate the mechanism underlying this synergy we assessed the removal of UV‐induced dimers in TK6 cells using the T4 endonuclease‐incorporated Comet assay. Pre‐treatment with As(III) specifically inhibited the repair of UV‐induced pyrimidine dimer‐related DNA damage. Taken together, these data suggest that pre‐treatment of human cells with arsenic impairs the nucleotide excision repair pathway and leads to enhanced UV mutagenesis. [ABSTRACT FROM AUTHOR]

The INK4 locus has two promoters and encodes two unique proteins that share exons in different reading frames, p16INK4a and p14ARF. The p16INK4a protein, by inhibiting cyclin-dependent kinase, down regulates Rb-E2F and leads to cell cycle arrest in the G1 phase. The p14ARF protein interacts with the MDM2 protein, neutralizing MDM2-mediated degradation of p53. Since p53/Rb genes are not altered in malignant mesothelioma, additional components of these pathways, such as p16INK4a and p14ARF, are candidates for inactivation. In this study, we have examined p16INK4a and p14ARF alterations (gene deletion, mutation and promoter methylation) in 45 primary malignant mesothelioma specimens. Fourteen patients (31%) had altered p16; four tumors had a methylated promoter region (8.8%), 10 tumors showed p16 to be deleted (22.2%), and one tumor had a point mutation (2%). We did not find any instances of methylation in the p14ARF 5′-CpG island. Patients whose tumors had p16 deletion were significantly younger than those with methylation, and, in the patients whose lungs were studied for the prevalence of asbestos fibers, those with any p16 alteration had lower fiber counts than those with no p16 alteration. Hence, p16 gene alteration is relatively common in malignant mesothelioma, while p14ARF is rarely, if ever, methylated. Our data suggest that deletion of p16 occurs in a relatively susceptible subset of the population. [ABSTRACT FROM PUBLISHER]

Background: Cigarette smoking is associated with a twofold increased risk of pancreatic cancer. We conducted a population-based case-control study in six San Francisco Bay area counties from 1994 to 2001 to investigate associations between polymorphisms in genes for two carcinogen-metabolizing enzymes (cytochrome P450 1A1 [CYP1A1] and glutathione S-transferase [GST]), smoking, and adenocarcinoma of the exocrine pancreas.Methods: We used polymerase chain reaction-based methods to analyze blood samples obtained from 309 case subjects and 964 control subjects to determine their genotypes for three CYP1A1 polymorphisms (m1, m2, and m4) and for homozygous deletions of two GST genes, GSTM1 and GSTT1. Control subjects were frequency matched to case subjects by age and sex. All statistical tests were two-sided.Results: None of the genetic polymorphisms themselves affected the risk of pancreatic cancer among Caucasian study participants. However, we observed an interaction between GSTT1-null genotype and cigarette smoking among Caucasians that was more prominent among women than among men. Relative to never smokers with the GSTT1-present genotype, the age-adjusted odds ratios (ORs) of pancreatic cancer for heavy smokers with the GSTT1-null genotype were 5.0 (95% confidence interval [CI] = 1.8 to 14.5) for women and 3.2 (95% CI = 1.3 to 8.1) for men; for heavy smokers with the GSTT1-present genotype they were 2.0 (95% CI = 1.0 to 4.0) for women and 2.1 (95% CI = 1.1 to 3.9) for men. ORs for pancreatic cancer among heavy smokers with both GSTT1-null and GSTM1-null genotypes were similar in magnitude to those among heavy smokers with the GSTT1-null genotype alone. There was no evidence of an interaction between CYP1A1 polymorphisms and smoking.Conclusions: The combination of heavy smoking and a deletion polymorphism in GSTT1 is associated with an increased risk of pancreatic cancer among Caucasians, with the associations possibly stronger in women than in men. [ABSTRACT FROM AUTHOR]

Infarct scar, a requisite to the rebuilding of necrotic myocardium following myocardial infarction (MI), has long been considered inert. Earlier morphologic studies suggested healing at the infarct site was complete within 6–8 weeks following MI and resultant scar tissue, albeit necessary, was acellular and simply fibrillar collagen. Utilizing molecular and cellular biologic technologies, recent studies indicate otherwise. Infarct scar is composed of phenotypically transformed fibroblast-like cells, termed myofibroblasts (myoFb) because they express alpha-smooth muscle actin (α-SMA) and these microfilaments confer contractile behavior in response to various peptides and amines. These cells are nourished by a neovasculature and are persistent at the MI site, where they are metabolically active expressing components requisite to angiotensin (Ang) peptide generation, including converting enzyme, receptors for AngII and transforming growth factor (TGF)-β1. They continue to elaborate fibrillar type I collagen. Their generation of these peptides contribute to ongoing scar tissue collagen turnover and to fibrous tissue formation of noninfarcted myocardium. Infarct scar contraction accounts for its thinning and its tonus may contribute to abnormal ventricular chamber stiffness with diastolic dysfunction. Infarct scar is a dynamic tissue: cellular, vascularized, metabolically active and contractile. Pharmacologic interventions with angiotensin converting enzyme inhibitor or AT1 receptor antagonist has proven effective in attenuating scar tissue metabolic activity and minimizing adverse accumulation of fibrous tissue in noninfarcted myocardium. [ABSTRACT FROM PUBLISHER]

Polymorphisms in several DNA repair genes have recently been identified, but little is known about their phenotypic significance. To determine whether variation in DNA repair genes is related to host DNA damage, we studied the association between polymorphisms in XRCC1 (codon 399) and ERCC2 (codon 751) and two markers of DNA damage, sister chromatid exchange (SCE) frequencies (n = 76) and polyphenol DNA adducts (n = 61). SCE frequencies were determined using a modified fluorescence–Giemsa method and polyphenol DNA adducts were determined using a P1-enhanced 32P-post-labeling procedure. XRCC1 and ERCC2 genotypes were identified using PCR–RFLP. Mean SCE frequencies among current smokers who were homozygous carriers of the 399Gln allele in XRCC1 were greater than those in 399Arg/Arg current smokers. We also observed a possible gene-dosage effect for XRCC1 399Gln and detectable DNA adducts, and significantly more adducts among older subjects who were carriers of the 399Gln allele than in younger subjects with the 399Arg/Arg genotype. The polymorphism in ERCC2 was unrelated to SCE frequency or DNA adduct level. Our results suggest that carriers of the polymorphic XRCC1 399Gln allele may be at greater risk for tobacco- and age-related DNA damage. [ABSTRACT FROM PUBLISHER]

Focuses on a study that evaluated the relationship of the enzymes glutathione S-transferase mu 1 (GSTM1) and theta 1 (GSTT1) gene polymorphism and breast cancer risk. Contribution of environmental carcinogens on breast cancer; Methodology; Results and discussion.

Background: DNA adducts formed as a consequence of exposure to tobacco smoke may be involved in carcinogenesis, and their presence may indicate a high risk of lung cancer. To determine whether DNA adducts can be used as a "dosimeter" for cancer risk, we measured the adduct levels in nontumorous lung tissue and blood mononuclear cells from patients with lung cancer, and we collected data from the patients on their history of smoking.Methods: We used the 32P-postlabeling assay to measure aromatic hydrophobic DNA adducts in nontumorous lung tissue from 143 patients and in blood mononuclear cells from 54 of these patients. From the smoking histories, we identified exposure variables associated with increased DNA adduct levels by use of multivariate analyses with negative binomial regression models. RESULTS/ CONCLUSIONS: We found statistically significant interactions for variables of current and former smoking and for other smoking variables (e.g., pack-years [number of packs smoked per day x years of smoking] or years smoked), indicating that the impact of smoking variables on DNA adduct levels may be different in current and former smokers. Consequently, our analyses indicate that models for current and former smokers should be considered separately. In current smokers, recent smoking intensity (cigarettes smoked per day) was the most important variable. In former smokers, age at smoking initiation was inversely associated with DNA adduct levels. A highly statistically significant correlation (r=.77 [Spearman's correlation]; two sided P<.001) was observed between DNA adduct levels in blood mononuclear cells and lung tissue.Implications: Our results in former smokers suggest that smoking during adolescence may produce physiologic changes that lead to increased DNA adduct persistence or that young smokers may be markedly susceptible to DNA adduct formation and have higher adduct burdens after they quit smoking than those who started smoking later in life. [ABSTRACT FROM AUTHOR]

Objective: Fetal cardiac development includes rapid formation of a three-dimensional collagen network, composed mainly of type I and III fibrillar collagens. Collagen fibrils have been found in cardiac jelly at very early stages of cardiac development and are thought to have structural and functional properties. In adult rat cardiac tissue, angiotensin II (AngII) via AT1 receptor binding and AngII-regulated expression of transforming growth factor beta-1 (TGF-β1) each upregulate collagen transcription. AT1 and AT2 receptor subtypes are developmentally regulated; both have been localized in fetal tissue where the AT2 receptor is considered a determinant of morphogenesis. We sought to determine whether blockade of either receptor would result in attenuation of collagen mRNA expression and fibrillar collagen accumulation and alter TGF-β1 mRNA expression in the developing fetal heart examined at birth. Methods: Pregnant rats were treated either with an AT1 receptor antagonist losartan or an AT2 receptor antagonist PD123319 and compared with untreated age-matched controls. Offspring were studied within 24 h of birth. Type I and type III collagen mRNA expression, as well as TGF-β1 mRNA expression, were examined by in situ hybridization. Collagen concentration was determined spectrophotometrically by picrosirius red staining and type I and III collagens were detected by immunoblotting. Results: We found: (1) comparable birth weights in control and PD123319-treated animals, but reduced body weight in newborn losartan-treated animals; (2) compared to untreated animals, type I collagen and TGF-β1 mRNA expression in cardiac tissue were each equally reduced in both losartan and PD123319-treated animals; (3) increased type III collagen mRNA expression in both PD123319- and losartan-treated groups; and (4) a significant decrease in total soluble cardiac collagen concentration in both losartan and PD123319-treated groups, confirmed by attenuated immunoreactivity of type I and III collagens in whole heart extracts by Western blotting. Conclusions: The results of these pharmacologic interventions suggest AngII receptors are expressed in cardiac tissue during gestation, where both AT1 and AT2 receptors are involved in the regulation of type I and III collagen expression and structural protein accumulation. These effects appear to be mediated, in part, by attenuated cardiac TGF-β1 levels. The marked decrease in newborn cardiac collagen content has yet undefined functional consequences. [ABSTRACT FROM PUBLISHER]