In seasonally breeding vertebrates, changes in day length induce categorically distinct behavioral and reproductive phenotypes via thyroid hormone-dependent mechanisms. Winter photoperiods inhibit ...reproductive neuroendocrine function but cannot sustain this inhibition beyond 6 mo, ensuring vernal reproductive recrudescence. This genomic plasticity suggests a role for epigenetics in the establishment of seasonal reproductive phenotypes. Here, we report that DNA methylation of the proximal promoter for the type III deiodinase (dio3) gene in the hamster hypothalamus is reversible and critical for photoperiodic time measurement. Short photoperiods and winter-like melatonin inhibited hypothalamic DNA methyltransferase expression and reduced dio3 promoter DNA methylation, which up-regulated dio3 expression and induced gonadal regression. Hypermethylation attenuated reproductive responses to short photoperiods. Vernal refractoriness to short photoperiods reestablished summer-like methylation of the dio3 promoter, dio3 expression, and reproductive competence, revealing a dynamic and reversible mechanism of DNA methylation in the mammalian brain that plays a central role in physiological orientation in time.
While genetic mutation is a hallmark of cancer, many cancers also acquire epigenetic alterations during tumorigenesis including aberrant DNA hypermethylation of tumor suppressors, as well as changes ...in chromatin modifications as caused by genetic mutations of the chromatin-modifying machinery. However, the extent of epigenetic alterations in cancer cells has not been fully characterized. Here, we describe complete methylome maps at single nucleotide resolution of a low-passage breast cancer cell line and primary human mammary epithelial cells. We find widespread DNA hypomethylation in the cancer cell, primarily at partially methylated domains (PMDs) in normal breast cells. Unexpectedly, genes within these regions are largely silenced in cancer cells. The loss of DNA methylation in these regions is accompanied by formation of repressive chromatin, with a significant fraction displaying allelic DNA methylation where one allele is DNA methylated while the other allele is occupied by histone modifications H3K9me3 or H3K27me3. Our results show a mutually exclusive relationship between DNA methylation and H3K9me3 or H3K27me3. These results suggest that global DNA hypomethylation in breast cancer is tightly linked to the formation of repressive chromatin domains and gene silencing, thus identifying a potential epigenetic pathway for gene regulation in cancer cells.
Veterans face a range of challenges as they transition out of the military and into civilian life. For some, this period of transition is characterized by loss of identity, loss of daily structure, ...loss of community, and confusion about where they fit within society. If not attended to, problems associated with the military‐to‐civilian transition can lead to significant functional impairment. Yet, little is known about how psychotherapy can support this period of adjustment that every veteran will face. This article presents a case study of a veteran struggling to adjust to the civilian world following his service in the military. Critical areas of assessment, conceptualization, and intervention are explicated to help inform best practices for mental health providers working with veterans.
Immunotherapy directed against private tumor neo-antigens derived from non-synonymous somatic mutations is a promising strategy of personalized cancer immunotherapy. However, feasibility in low ...mutational load tumor types remains unknown. Comprehensive and deep analysis of circulating and tumor-infiltrating lymphocytes (TILs) for neo-epitope specific CD8
T cells has allowed prompt identification of oligoclonal and polyfunctional such cells from most immunotherapy-naive patients with advanced epithelial ovarian cancer studied. Neo-epitope recognition is discordant between circulating T cells and TILs, and is more likely to be found among TILs, which display higher functional avidity and unique TCRs with higher predicted affinity than their blood counterparts. Our results imply that identification of neo-epitope specific CD8
T cells is achievable even in tumors with relatively low number of somatic mutations, and neo-epitope validation in TILs extends opportunities for mutanome-based personalized immunotherapies to such tumors.
Mass spectrometry (MS) is the state-of-the-art methodology for capturing the breadth and depth of the immunopeptidome across human leukocyte antigen (HLA) allotypes and cell types. The majority of ...studies in the immunopeptidomics field are discovery driven. Hence, data-dependent tandem MS (MS/MS) acquisition (DDA) is widely used, as it generates high-quality references of peptide fingerprints. However, DDA suffers from the stochastic selection of abundant ions that impairs sensitivity and reproducibility. In contrast, in data-independent acquisition (DIA), the systematic fragmentation and acquisition of all fragment ions within given isolation m/z windows yield a comprehensive map for a given sample. However, many DIA approaches commonly require generating comprehensive DDA-based spectrum libraries, which can become impractical for studying noncanonical and personalized neoantigens. Because the amount of HLA peptides eluted from biological samples such as small tissue biopsies is typically not sufficient for acquiring both meaningful DDA data necessary for generating comprehensive spectral libraries and DIA MS measurements, the implementation of DIA in the immunopeptidomics translational research domain has remained limited. We implemented a DIA immunopeptidomics workflow and assessed its sensitivity and accuracy by matching DIA data against libraries with growing complexity—from sample-specific libraries to libraries combining 2 to 40 different immunopeptidomics samples. Analyzing DIA immunopeptidomics data against a complex multi-HLA spectral library resulted in a two-fold increase in peptide identification compared with sample-specific library and in a three-fold increase compared with DDA measurements, yet with no detrimental effect on the specificity. Furthermore, we demonstrated the implementation of DIA for sensitive personalized neoantigen discovery through the analysis of DIA data with predicted MS/MS spectra of clinically relevant HLA ligands. We conclude that a comprehensive multi-HLA library for DIA approach in combination with MS/MS prediction is highly advantageous for clinical immunopeptidomics, especially when low amounts of biological samples are available.
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•So far, DIA in the immunopeptidomics translational research has been limited.•DIA immunopeptidomics data were analyzed against a complex multi-HLA spectral library.•This resulted in improved sensitivity with no detrimental effect on the specificity.•We implemented DIA for clinical antigen discovery combined with predicted MS/MS spectra.
The implementation of DIA in the immunopeptidomics translational research domain has remained limited because the amount of HLA peptides eluted from clinical samples is typically not sufficient for acquiring both meaningful DDA data for generating comprehensive spectral libraries and DIA MS measurements. We implemented a DIA immunopeptidomics workflow and assessed its sensitivity and accuracy with libraries of growing complexity and multi-HLA libraries. In addition, we demonstrated the analysis of DIA data with predicted MS/MS spectra of clinically relevant HLA ligands.
The concept of recovery has become an increasingly common framework for organizing mental health care, thus many psychologists find themselves working in settings that espouse a recovery orientation ...to service delivery. However, the concepts of recovery and recovery-oriented services are complex and have many definitions and psychologists struggle to know whether or not the psychotherapy they provide is aligned with recovery-oriented care. This article provides practical recommendations on how to integrate recovery into the common processes of psychotherapy that cut across all theoretical orientations or particular treatment approaches. Specifically, this article details the process of building a therapeutic bond, conceptualizing a client's problems and goals, implementing a treatment plan, and discharge planning, all from a recovery-oriented perspective. A case demonstration and analysis is presented to illustrate the recovery-oriented psychotherapy process described in this article.
Impact Statement
Recovery is an increasingly common treatment philosophy guiding best practices within mental health care systems. However, psychologists may be uncertain about how to best integrate recovery into their psychotherapy practice. This article provides practical guidance to psychologists and other mental health providers, about how to deliver recovery-oriented psychotherapy.
Systematic studies evaluating clinical benefit of tumor genomic profiling are lacking. We conducted a prospective study in 250 patients with select solid tumors at the Cleveland Clinic. Eligibility ...required histopathologic diagnosis, age of 18 years or older, Eastern Cooperative Oncology Group performance status 0-2, and written informed consent. Tumors were sequenced using FoundationOne (Cambridge, MA). Results were reviewed at the Cleveland Clinic Genomics Tumor Board. Outcomes included feasibility and clinical impact. Colorectal (25%), breast (18%), lung (13%), and pancreatobiliary (13%) cancers were the most common diagnoses. Median time from consent to result was 25 days (range = 3-140). Of 223 evaluable samples, 49% (n = 109) of patients were recommended a specific therapy, but only 11% (n = 24) received such therapy: 12 on clinical trials, nine off-label, three on-label. Lack of clinical trial access (n = 49) and clinical deterioration (n = 29) were the most common reasons for nonrecommendation/nonreceipt of genomics-driven therapy.
Veterans living with mental health conditions have ambitious career goals and want support to find employment that meets their interests and preferences. Despite calls from researchers to “invest” ...and “commit” to career development research and practice for individuals living with psychiatric conditions, we still do not have empirically tested models for facilitating career development among individuals with mental health conditions, especially veterans. This qualitative study investigates the career development needs and recommended intervention strategies of veterans living with mental health conditions. Vocational counselors from the Veterans Health Administration (VHA) and veterans receiving vocational rehabilitation services (N = 13) participated in semi-structured focus groups. Findings illuminate the tasks, barriers, interventions, implementation strategies, and transitional work context that hinder and support career development of veterans with mental health conditions. Findings offer theoretical and applied guidance to researchers and counselors regarding career development of veterans living with mental health conditions.
Genome-wide analysis of cancer/testis gene expression Hofmann, Oliver; Caballero, Otavia L; Stevenson, Brian J ...
Proceedings of the National Academy of Sciences - PNAS,
12/2008, Letnik:
105, Številka:
51
Journal Article
Recenzirano
Odprti dostop
Cancer/Testis (CT) genes, normally expressed in germ line cells but also activated in a wide range of cancer types, often encode antigens that are immunogenic in cancer patients, and present ...potential for use as biomarkers and targets for immunotherapy. Using multiple in silico gene expression analysis technologies, including twice the number of expressed sequence tags used in previous studies, we have performed a comprehensive genome-wide survey of expression for a set of 153 previously described CT genes in normal and cancer expression libraries. We find that although they are generally highly expressed in testis, these genes exhibit heterogeneous gene expression profiles, allowing their classification into testis-restricted (39), testis/brain-restricted (14), and a testis-selective (85) group of genes that show additional expression in somatic tissues. The chromosomal distribution of these genes confirmed the previously observed dominance of X chromosome location, with CT-X genes being significantly more testis-restricted than non-X CT. Applying this core classification in a genome-wide survey we identified >30 CT candidate genes; 3 of them, PEPP-2, OTOA, and AKAP4, were confirmed as testis-restricted or testis-selective using RT-PCR, with variable expression frequencies observed in a panel of cancer cell lines. Our classification provides an objective ranking for potential CT genes, which is useful in guiding further identification and characterization of these potentially important diagnostic and therapeutic targets.
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