Cytotoxic T lymphocyte responses against melanocytes and melanoma

<p>Abstract</p> <p>Background</p> <p>Vitiligo is a common toxicity associated with immunotherapy for melanoma. Cytotoxic T lymphocytes (CTLs) against melanoma commonly target melanoma-associated antigens (MAAs) which are also expressed by melanocytes. To uncouple vitiligo from melanoma destruction, it is important to understand if CTLs can respond against melanoma and melanocytes at different levels.</p> <p>Methods</p> <p>To understand the dichotomous role of MAA-specific CTL, we characterized the functional reactivities of established CTL clones directed to MAAs against melanoma and melanocyte cell lines.</p> <p>Results</p> <p>CTL clones generated from melanoma patients were capable of eliciting MHC-restricted, MAA-specific lysis against melanocyte cell lines as well as melanoma cells. Among the tested HLA-A*0201-restricted CTL clones, melanocytes evoked equal to slightly higher degranulation and cytolytic responses as compared to melanoma cells. Moreover, MAA-specific T cells from vaccinated patients responded directly ex vivo to melanoma and melanocytes. Melanoma cells express slightly higher levels of MART-1 and gp100 than melanocytes as measured by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and immunohistochemistry.</p> <p>Conclusions</p> <p>Our data suggest that CTLs respond to melanoma and melanocytes equally in vitro and directly ex vivo.</p

Quantitative, Architectural Analysis of Immune Cell Subsets in Tumor-Draining Lymph Nodes from Breast Cancer Patients and Healthy Lymph Nodes

Background: To date, pathological examination of specimens remains largely qualitative. Quantitative measures of tissue spatial features are generally not captured. To gain additional mechanistic and prognostic insights, a need for quantitative architectural analysis arises in studying immune cell-cancer interactions within the tumor microenvironment and tumor-draining lymph nodes (TDLNs). Methodology/Principal Findings: We present a novel, quantitative image analysis approach incorporating 1) multi-color tissue staining, 2) high-resolution, automated whole-section imaging, 3) custom image analysis software that identifies cell types and locations, and 4) spatial statistical analysis. As a proof of concept, we applied this approach to study the architectural patterns of T and B cells within tumor-draining lymph nodes from breast cancer patients versus healthy lymph nodes. We found that the spatial grouping patterns of T and B cells differed between healthy and breast cancer lymph nodes, and this could be attributed to the lack of B cell localization in the extrafollicular region of the TDLNs. Conclusions/Significance: Our integrative approach has made quantitative analysis of complex visual data possible. Our results highlight spatial alterations of immune cells within lymph nodes from breast cancer patients as an independent variable from numerical changes. This opens up new areas of investigations in research and medicine. Future application of this approach will lead to a better understanding of immune changes in the tumor microenvironment and TDLNs, and how they affect clinical outcome

Effects of supervision on tax compliance:Evidence from a field experiment in Austria

We conduct a field experiment on tax compliance, focusing on newly founded firms. As a novelty the effect of tax authorities’ supervision on timely tax payments is examined. Interestingly, results show no positive overall effect of close supervision on tax compliance

Pooled Analysis of Alcohol Dehydrogenase Genotypes and Head and Neck Cancer: A HuGE Review

Possession of the fast metabolizing alleles for alcohol dehydrogenase (ADH), ADH1B*2 and ADH1C*1, and the null allele for aldehyde dehydrogenase (ALDH), ALDH2*2, results in increased acetylaldehyde levels and is hypothesized to increase the risk of head and neck cancer. To examine this association, the authors undertook a Human Genome Epidemiology review on these three genes and a pooled analysis of published studies on ADH1C. The majority of Asians had the fast ADH1B*2 and ADH1C*1 alleles, while the majority of Caucasians had the slow ADH1B*1/1 and ADH1C*1/2 genotypes. The ALDH2*2 null allele was frequently observed among Asians, though it was rarely observed in other populations. In a pooled analysis of data from seven case-control studies with a total of 1,325 cases and 1,760 controls, an increased risk of head and neck cancer was not observed for the ADH1C*1/2 genotype (odds ratio = 1.00, 95% confidence interval: 0.81, 1.23) or the ADH1C*1/1 genotype (odds ratio = 1.14, 95% confidence interval: 0.92, 1.41). Increased relative risks of head and neck cancer were reported for the ADH1B*1/1 and ALDH2*1/2 genotypes in several studies. Recommendations for future studies include larger sample sizes and incorporation of relevant ADH and ALDH genes simultaneously, as well as other genes. These considerations suggest the potential for the organization of a consortium of investigators conducting studies in this fiel

Natural and Orthogonal Interaction framework for modeling gene-environment interactions with application to lung cancer

Objectives: We aimed at extending the Natural and Orthogonal Interaction (NOIA) framework, developed for modeling gene-gene interactions in the analysis of quantitative traits, to allow for reduced genetic models, dichotomous traits, and gene-environment interactions. We evaluate the performance of the NOIA statistical models using simulated data and lung cancer data. Methods: The NOIA statistical models are developed for additive, dominant, and recessive genetic models as well as for a binary environmental exposure. Using the Kronecker product rule, a NOIA statistical model is built to model gene-environment interactions. By treating the genotypic values as the logarithm of odds, the NOIA statistical models are extended to the analysis of case-control data. Results: Our simulations showed that power for testing associations while allowing for interaction using the NOIA statistical model is much higher than using functional models for most of the scenarios we simulated. When applied to lung cancer data, much smaller p values were obtained using the NOIA statistical model for either the main effects or the SNP-smoking interactions for some of the SNPs tested. Conclusion: The NOIA statistical models are usually more powerful than the functional models in detecting main effects and interaction effects for both quantitative traits and binary traits. Copyright (C) 2012 S. Karger AG, Base

Mapping degree in Banach spaces and spectral theory

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46287/1/209_2005_Article_BF01187933.pd

The temporal pattern of respiratory and heart disease mortality in response to air pollution.

Short-term changes in ambient particulate matter with aerodynamic diameters < 10 micro m (PM10) have been associated with short-term fluctuations in mortality or morbidity in many studies. In this study, we tested whether those deaths are just advanced by a few days or weeks using a multicity hierarchical modeling approach for all-cause, respiratory, and cardiovascular deaths, for all ages and stratifying by age groups, within the APHEA-2 (Air Pollution and Health: A European Approach) project. We fit a Poisson regression and used an unconstrained distributed lag to model the effect of PM10 exposure on deaths up to 40 days after the exposure. In baseline models using PM10 the day of and day before the death, we found that the overall PM10 effect (per 10 micro g/m3) was 0.74% [95% confidence interval (95% CI), -0.17 to 1.66] for respiratory deaths and 0.69% (95% CI, 0.31-1.08) for cardiovascular deaths. In unrestricted distributed lag models, the effect estimates increased to 4.2% (95% CI, 1.08-7.42) for respiratory deaths and to 1.97% (95% CI, 1.38-2.55) for cardiovascular deaths. Our study confirms that most of the effect of air pollution is not simply advanced by a few weeks and that effects persist for more than a month after exposure. The effect size estimate for PM10 doubles when we considered longer-term effects for all deaths and for cardiovascular deaths and becomes five times higher for respiratory deaths. We found similar effects when stratifying by age groups. These larger effects are important for risk assessment

Metastatic breast carcinoma mimicking a sebaceous gland neoplasm: a case report

<p>Abstract</p> <p>Introduction</p> <p>Breast cancer is common in women and its metastases involve the skin in approximately one quarter of patients. Accordingly, metastatic breast cancer shown to be cutaneous through histology must be distinguished from a wide variety of other neoplasms as well as the diverse morphologic variants of breast cancer itself.</p> <p>Case presentation</p> <p>We report the case of a 61-year-old Caucasian woman with cutaneous metastases of a bilateral ductal breast carcinoma that in histopathological examination mimicked an adnexal neoplasm with sebaceous differentiation.</p> <p>Conclusion</p> <p>Against the background of metastatic breast carcinoma, dermatopathological considerations of sebaceous differentiation of skin lesions are presented and discussed focusing on the rare differential diagnosis of sebaceous carcinoma of the breast.</p