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Lauritsen JP , Haks MC , Lefebvre JM , Kappes DJ , Wiest DL , Chen X , Arciero CA , Godwin AK , Barsevick AM , Whitmer K , Nail LM , Beck SL , Dudley WN , Weiner LM , Treat J
Role of the transcription factor Th-POK in CD4:CD8 lineage commitment.
Immunol Rev. 2006 Feb Feb Feb Jan Jan-Feb Oct;209(2) :237-52.
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Abstract
PG - 237-52 AB - The molecular basis of CD4:CD8 lineage commitment, in particular the mechanism by which the precise correlation between lineage choice and T-cell receptor (TCR) specificity toward class I or II major histocompatibility complex is achieved, remains controversial. Both stochastic/selective and instructive models in various forms have been proposed to explain this correlation. The two main experimental approaches previously employed to elucidate this process have focused on the beginning and end of the process, i.e. the influence of TCR signaling and the alternate transcriptional control of the CD4 and CD8 loci during commitment. The recent finding that the transcription factor Th-POK is necessary and sufficient for CD4 commitment has now provided a direct entry point for studying the intracellular pathways that govern lineage commitment. Here, we review data leading to the identification and characterization of this factor and discuss the implications of these studies in the context of current models of lineage commitment. AD - Fox Chase Cancer Center, Philadelphia, PA, USA. FAU - Kappes, Dietmar J AU - Kappes DJ FAU - He, Xi AU - He X FAU - He, Xiao AU - He X LA - eng PT - Journal Article PL - Denmark TA - Immunol Rev JT - Immunological reviews. JID - 7702118 SB - IM Recent insights into the signals that control alphabeta/gammadelta-lineage fate BRCA1-associated complexes: new targets to overcome breast cancer radiation resistance Symptom cluster research: conceptual, design, measurement, and analysis issues Fully human therapeutic monoclonal antibodies Incorporating novel agents with gemcitabine-based treatment of NSCLC. PG - S8-9 AB - First-line treatment with a two-drug combination chemotherapy regimen comprising of a platinum-based agent with a third-generation agent has been the accepted standard of care in most countries for the treatment of advanced non-small-cell lung cancer (NSCLC). Previously, the addition of a third agent to standard chemotherapy regimens has failed to improve survival in the majority of randomized trials that have been conducted. However, recent findings suggest that the addition of the novel targeted agent bevacizumab to a standard paclitaxel/carboplatin regimen significantly improves survival. The addition of novel agents to gemcitabine-based regimens is therefore a logical approach to improving the treatment of advanced NSCLC. Several trials of gemcitabine-based regimens with bevacizumab are ongoing. During thymopoiesis, two major types of mature T cells are generated that can be distinguished by the clonotypic subunits contained within their T-cell receptor (TCR) complexes: alphabeta T cells and gammadelta T cells. Although there is no consensus as to the exact developmental stage where alphabeta and gammadelta T-cell lineages diverge, gammadelta T cells and precursors to the alphabeta T-cell lineage (bearing the pre-TCR) are thought to be derived from a common CD4(-)CD8(-) double-negative precursor. The role of the TCR in alphabeta/gammadelta lineage commitment has been controversial, in particular whether different TCR isotypes intrinsically favor adoption of the corresponding lineage. Recent evidence supports a signal strength model of lineage commitment, whereby stronger signals promote gammadelta development and weaker signals promote adoption of the alphabeta fate, irrespective of the TCR isotype from which the signals originate. Moreover, differences in the amplitude of activation of the extracellular signal-regulated kinase- mitogen-activated protein kinase-early growth response pathway appear to play a critical role. These findings will be placed in context of previous analyses in an effort to more precisely define the signals that control T-lineage fate during thymocyte development. Since BRCA1 was cloned a decade ago, significant progress has been made in defining its biochemical and biological functions, as well as its role in breast and ovarian cancers. BRCA1 has been implicated in many cellular processes, including DNA repair, cell cycle checkpoint control, protein ubiquitination and chromatin remodeling. This review examines the role(s) of BRCA1 in mediating these cellular processes, and discusses its potential involvement in the resistance of breast cancer to radiation-based therapies. Finally, the possibility that BRCA1-associated proteins may serve as new targets for breast cancer radiation therapy is explored. The activation or inactivation of these BRCA1-associated proteins may modify both the risk of developing cancers in BRCA1 mutation carriers and the efficacy of breast cancer therapy, including radiation. AD - Department of Medical Oncology, Fox Chase Cancer Center, PA 19111-2409, USA. xiaowei.chen@fccc.edu Cancer patients may experience multiple concurrent symptoms caused by the cancer, cancer treatment, or their combination. The complex relationships between and among symptoms, as well as the clinical antecedents and consequences, have not been well described. This paper examines the literature on cancer symptom clusters focusing on the conceptualization, design, measurement, and analytic issues. The investigation of symptom clustering is in an early stage of testing empirically whether the characteristics defined in the conceptual definition can be observed in cancer patients. Decisions related to study design include sample selection, the timing of symptom measures, and the characteristics of symptom interventions. For self-report symptom measures, decisions include symptom dimensions to evaluate, methods of scaling symptoms, and the time frame of responses. Analytic decisions may focus on the application of factor analysis, cluster analysis, and path models. Studying the complex symptoms of oncology patients will yield increased understanding of the patterns of association, interaction, and synergy of symptoms that produce specific clinical outcomes. It will also provide a scientific basis and new directions for clinical assessment and intervention. AD - Fox Chase Cancer Center (A.M.B.), Cheltenham, Pennsylvania; University of Cincinnati (K.W.), Cincinnati, Ohio; Oregon Health & Science University (L.M.N.), Portland, Oregon; and University of Utah (S.L.B., W.N.D.), Salt Lake City, Utah, USA. Monoclonal antibody (mAb) therapy has been facilitated by a number of technologic advances over the past 30 years. Whereas hybridoma development of murine mAbs was requisite for the development of mAbs as drugs, the inherent immunogenicity of rodent sequences in humans has presented obstacles to the clinical application of mAbs. Sensitization to mAb therapeutics poses significant risk to the patient and may blunt the efficacy of these therapies. The advent of chimeric antibodies lessened but did not eliminate the rodent content of mAbs; thus, immunogenicity remained a concern. Further elimination of rodent sequences enabled the production of humanized mAbs, followed by current technology using phage display and, finally, transgenic mice technology, which allows for the generation of fully human therapeutic mAbs. The reduced immunogenicity of this new generation of mAbs is expected to enhance efficacy, safety, and ease of use. In addition to providing replacements for existing mAb drugs, new technologies have greatly facilitated the optimization and modification of mAbs, opening numerous therapeutic avenues. AD - Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA. Louis.Weiner@fccc.edu
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