832 research outputs found
People
No full textAbstract
Keith T. Flaherty, MD; Richard M. Goldberg, MD; and Gustavo W. Leone, PhD, are featured.</jats:p
RG 1325-003-206 Delaware in World War II
No full textAmerican Women Voluntary Service raid protection class; Mrs. T. Muncy Keith points out salient features of the wardens map; A. H. Johnson; Ann Flaherty; Catherin
RG 1325-003-206 Delaware in World War II
No full textAmerican Women Voluntary Service raid protection class; Mrs. T. Muncy Keith points out salient features of the wardens map; A. H. Johnson; Ann Flaherty; Catherin
Rejection of benign melanocytic nevi by nevus-resident CD4(+) T cells
No full textMelanoma and melanocytic nevi harbor shared lineage-specific antigens and oncogenic mutations. Yet, the relationship between the immune system and melanocytic nevi is unclear. Using a patient-derived xenograft (PDX) model, we found that 81.8% of the transplanted nevi underwent spontaneous regression, while peripheral skin remained intact. Nevus-resident CD4(+) T helper 1 cells, which exhibited a massive clonal expansion to melanocyte-specific antigens, were responsible for nevus rejection. Boosting regulatory T cell suppressive function with low-dose exogenous human interleukin-2 injection or treatment with a human leukocyte antigen (HLA) class II-blocking antibody prevented nevus rejection. Notably, mice with rejected nevus PDXs were protected from melanoma tumor growth. We detected a parallel CD4(+) T cell-dominant immunity in clinically regressing melanocytic nevi. These findings reveal a mechanistic explanation for spontaneous nevus regression in humans and posit the activation of nevus-resident CD4(+) effector T cells as a novel strategy for melanoma immunoprevention and treatment.
Abstract IA05: Selective pressure by activated T cells identifies de novo and adaptive resistance mechanisms in melanoma
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Tumor Neoantigens and a Novel Hapten Vaccine Promote Immune Targeting of Wild-Type Tumor Lineage Antigens and Improve Response to Immune Checkpoint Blockade
No full textThe renaissance of immunotherapy, spurred on by the discovery of immune checkpoint inhibitors, has dramatically altered treatment of many different cancer types. Despite the ever-expanding clinical scope of immune checkpoint blockade, a majority of cancer patients still do not benefit from immunotherapy. Unraveling the mechanisms of response to immunotherapy and translating that understanding into new or improved therapies will be crucial steps toward extending the promise of immunotherapy to more patients.
One major factor correlated with positive response to immunotherapy is tumor neoantigen load. Additionally, in metastatic melanoma patients, the development of vitiligo is also associated with favorable response to immunotherapy. In chapter 2 of this thesis, we test the hypothesis that in melanoma patients treated with immune checkpoint blockade, a direct link exists between tumor neoantigens and vitiligo. Using carefully controlled murine models of melanoma, we demonstrate that in the context of immune checkpoint inhibition, tumor neoantigens promote epitope spreading and generate an autoimmune response against wild-type tumor lineage antigens.
Leveraging the knowledge gained in chapter 2, we developed a new therapeutic strategy using haptens to exogenously introduce “neo”-epitopes in tumors lacking neoantigens in order to improve response to immune checkpoint blockade in low neoantigen tumors. In chapter 3 of this thesis, we optimize a novel hapten vaccine that improves response to immune checkpoint blockade in mice with low neoantigen tumors. Furthermore, we show that the hapten vaccine recapitulates the epitope spreading and immune targeting of normal tumor lineage antigens induced by tumor neoantigens.
Over the course of testing various topical treatments for cancer immunotherapy, we identified a surprising hair-related phenotype. In chapter 4 of this thesis, we identify the treatment responsible for the phenotype and characterize the hair follicle biology underlying the phenotype. In addition, we connect the mechanism to recruitment of an immune cell population and explore novel topical treatment options.Biophysic
Geriatric Nursing Research Digest
No full textMeredith Wallace [Kazer] is a co-editor (with J. Fitzpatrick, T. Fulmer and E. Flaherty). In addition, Meredith Wallace [Kazer] is a contributing author, Exercise, Reminiscence, Parkinson’s Disease, Sleep, Introduction to Pathophysiological Issues in Aging, Introduction to Geriatric Emotional Health .
Book description: This is a key resource for evidence-based nursing care of the elderly. Written by leading experts in the forefront of the field, each entry describes the most significant research in a selected area and illuminates the relevance of this research to clinical practice. Among the to pics covered readers will find articles on health promotion and risk reduction, normalcy throughout the life span, issues in environments of care, geriatric emotional health, pathological conditions of aging, and neurobehavioral and cognitive changes of aging.https://digitalcommons.fairfield.edu/nursing-books/1049/thumbnail.jp
Memo from Hugh T. Fullerton, Assistant Adjutant General, August 26, 1942
No full textMemo sent from Captain Hugh T. Fullerton, Assistant Adjutant General, regarding the use of tourist sleeper accomodations for mass removal. The tourist sleeper accomodations were left up to the discretion of the U. S. Public Health Service.The War Relocation Authority (WRA), together with the Wartime Civil Control Administration (WCCA), the Civil Affairs Division (CAD) and the Office of the Commanding General (OFG) of the Western Defense Command (WDC) operated together to segregate and house some 110,000 men women and children from 1942 to 1945. The collection contains documents and photographs relating to the establishment and administrative workings of the (WDC), the (WRA) and the (WCCA) for the year 1942
Memo from Captain Hugh T. Fullerton, A. G. D., Assistant Adjutant General,
No full textA memo sent by Hugh T. Fullerton on behalf of Lieutenant General DeWitt with instructions for sector commanders and civilian agencies involved with mass removal. The memo was sent after the announcement of Public Proclamations Numbers 1 through 5 and gives an overview of the overall mass removal process.The War Relocation Authority (WRA), together with the Wartime Civil Control Administration (WCCA), the Civil Affairs Division (CAD) and the Office of the Commanding General (OFG) of the Western Defense Command (WDC) operated together to segregate and house some 110,000 men women and children from 1942 to 1945. The collection contains documents and photographs relating to the establishment and administrative workings of the (WDC), the (WRA) and the (WCCA) for the year 1942
Antitumor activity of BRAF inhibitor and IFN×alpha; Combination in BRAF-mutant melanoma
No full textBackground: BRAFV600E-mediated MAPK pathway activation is associated in melanoma cells with IFNAR1 downregulation. IFNAR1 regulates melanoma cell sensitivity to IFN×alpha;, a cytokine used for the adjuvant treatment of melanoma. These findings and the limited therapeutic efficacy of BRAF-I prompted us to examine whether the efficacy of IFN×alpha; therapy of BRAFV600E melanoma can be increased by its combination with BRAF-I.Methods: BRAF/NRAS genotype, ERK activation, IFNAR1, and HLA class I expression were tested in 60 primary melanomatumors from treatment-naive patients. The effect of BRAF-I on IFNAR1 expression was assessed in three melanoma cell lines and in four biopsies of BRAFV600E metastases. The antiproliferative, pro-apoptotic and immunomodulatory activity of BRAF-I and IFN×alpha; combination was tested in vitro and in vivo utilizing three melanoma cell lines, HLA class I-MA peptide complex-specific T-cells and immunodeficient mice (5 per group for survival and 10 per group for tumor growth inhibition). All statistical tests were two-sided. Differences were considered statistically significant when the P value was less than .05. Results: The IFNAR1 level was statistically significantly (P ×lt; .001) lower in BRAFV600E primary melanoma tumors than in BRAF wild-type tumors. IFNAR1 downregulation was reversed by BRAF-I treatment in the three melanoma cell lines (P ×le; .02) and in three out of four metastases. The IFNAR1 level in the melanoma tumors analyzed was increased as early as 10 to 14 days following the beginning of the treatment. These changes were associated with: 1) an increased susceptibility in vitro of melanoma cells to the antiproliferative (P ×le; .04), pro-apoptotic (P ×le; .009) and immunomodulatory activity, including upregulation of HLA class I antigen APM component (P ×le; .04) and MA expression as well as recognition by cognate T-cells (P ×lt; .001), of BRAF-I and IFN×alpha; combination and 2) an increased survival (P ×gt; .001) and inhibition of tumor growth of melanoma cells (P ×lt; .001) in vivo by BRAF-I and IFN×alpha; combination. Conclusions: The described results provide a strong rationale for the clinical trials implemented in BRAFV600E melanoma patients with BRAF-I and IFN×alpha; combination
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