A5070727750- Nonmelanoma Skin Cancer Studies
- Cutaneous Melanoma Detection and Management
- T-cell and B-cell Immunology
- Cutaneous lymphoproliferative disorders research
- Immune Response and Inflammation
- Immunotherapy and Immune Responses
- Cancer and Skin Lesions
- Systemic Lupus Erythematosus Research
- Immune Cell Function and Interaction
- Nail Diseases and Treatments
- Reconstructive Facial Surgery Techniques
- CAR-T cell therapy research
- Polyomavirus and related diseases
- Tumors and Oncological Cases
- Hedgehog Signaling Pathway Studies
- Monoclonal and Polyclonal Antibodies Research
- CRISPR and Genetic Engineering
- Augustinian Studies and Theology
- Single-cell and spatial transcriptomics
- Theology and Canon Law Studies
- Immunodeficiency and Autoimmune Disorders
- Molecular Biology Techniques and Applications
- Chemotherapy-related skin toxicity
- Biblical Studies and Interpretation
- Cancer Genomics and Diagnostics
Yale University
2016-2025
Pfizer (United States)
2021
Palo Alto University
2020
Stanford University
2020
Advanced Dermatology
2019
Previous studies (Leadbetter, E.A., I.R. Rifkin, A.H. Hohlbaum, B. Beaudette, M.J. Shlomchik, and A. Marshak-Rothstein. 2002. Nature. 416:603–607; Viglianti, G.A., C.M. Lau, T.M. Hanley, B.A. Miko, 2003. Immunity. 19:837–847) established the unique capacity of DNA DNA-associated autoantigens to activate autoreactive B cells via sequential engagement cell antigen receptor (BCR) Toll-like (TLR) 9. We demonstrate that this two-receptor paradigm can be extended BCR/TLR7 activation by RNA...
Somatically mutated high-affinity autoantibodies are a hallmark of some autoimmune diseases, including systemic lupus erythematosus. It has long been presumed that germinal centers (GCs) critical in autoantibody production, because they the only sites currently believed to sustain high rate somatic hypermutation. Contrary this idea, we found splenic autoreactive B cells MRL.Fas(lpr) mice proliferated and underwent active hypermutation at T zone-red pulp border rather than GCs. Our results...
Systemic autoimmune disease in humans and mice is characterized by loss of immunologic tolerance to a restricted set self-nuclear antigens. Autoantigens, such as double-stranded (ds) DNA the RNA-containing Smith antigen (Sm), may be selectively targeted systemic lupus erythematosus because their ability activate putative common receptor. Toll-like receptor 9 (TLR9), for CpG DNA, has been implicated activation autoreactive B cells vitro, but its role promoting autoantibody production vivo not...
Abstract Systemic lupus erythematosus is characterized by the production of autoantibodies against nucleic acid-associated Ags. We previously found that Tlr7 was required for anti-Sm and Tlr9 anti-chromatin autoantibodies. Yet, although deficiency ameliorated disease, exacerbated it. Despite mechanistic clinical implications this finding, it has yet to be elucidated. In study, we characterize MRL/lpr lupus-prone mice genetically deficient in Tlr7, Tlr9, both or Myd88 test whether function...
Type I IFNs play an important, yet poorly characterized, role in systemic lupus erythematosus. To better understand the interplay between type and activation of autoreactive B cells, we evaluated effect IFN receptor (IFNAR) deficiency murine cell responses to common TLR ligands. In comparison wild-type TLR7-stimulated IFNAR(-/-) cells proliferated significantly less well did not up-regulate costimulatory molecules. By contrast, IFNAR1(-/-) produce cytokines, but proliferate markers response...
Melanoma is among the most common malignant neoplasms in United States, with 91 270 cases estimated to be diagnosed 2018. Since 2012, Mohs micrographic surgery (MMS) has gained popularity treatment of melanoma situ. Although current guidelines for invasive without nodal metastases recommend wide margin excision (WME), use MMS this disease increased as well, particularly early stages. How survival outcomes after each procedure compare one another early-stage unknown date.To evaluate overall...
In ultraviolet (UV) radiation-exposed skin, mutations fuel clonal cell growth. The relationship between UV exposure and the accumulation of (CMs) correlation CMs skin cancer risk are largely unexplored. We characterized 450 individual-matched sun-exposed (SE) non-SE (NE) normal human samples. number relative contribution were significantly different SE NE areas. Furthermore, we identified hotspots in
Abstract Autoreactive B cells are activated by DNA, chromatin, or chromatin-containing immune complexes (ICs) through a mechanism dependent on dual engagement of the BCR and TLR9. We examined contribution endogenous DNA sequence elements to this process. can determine both recognition fragments containing CpG islands, natural source unmethylated dinucleotides, promote activation DNA-reactive derived from transgenic mice as well present in normal repertoire. ICs these island potent ligands...
Abstract Nucleic acid–reactive B cells frequently arise in the bone marrow but are tolerized by mechanisms including receptor editing, functional anergy, and/or deletion. TLR9, a sensor of endosomal dsDNA, both promotes and regulates systemic autoimmunity vivo, precise nature its apparently contradictory roles remained unclear. In this study, using 3H9 anti-DNA BCR transgene autoimmune-prone MRL.Faslpr mouse model lupus erythematosus, we identify stages at which TLR9 contributes to...
<ns4:p>Cutaneous squamous cell carcinoma (SCC) is among the most common cancers in humans, and many patients with SCC will develop multiple tumors within their lifetime. The field cancerization concept, originally proposed over 60 years ago, hypothesized that primary may arise simultaneously coexist subclinical precursor lesions a defined field. Genetic sequencing of has identified what be earliest clonal proliferations development confirmed skin mediated by ultraviolet radiation. For SCCs...
There is a paucity of evidence to guide physicians regarding prevention strategies for cutaneous squamous cell carcinoma (CSCC) in solid organ transplant recipients (SOTRs).To examine the development and results Delphi process initiated identify consensus-based medical management recommendations CSCC SOTRs.Dermatologists with more than 5 years' experience treating SOTRs were invited participate. A novel actinic damage skin cancer index (AD-SCI), consisting 6 ordinal stages corresponding an...
Cutaneous squamous cell carcinoma (cSCC) incidence and deaths continue to rise, underscoring the need for improved cSCC prevention. Elimination of actinic keratosis (AK) precursor lesions is a major strategy prevent cSCC. Topical calcipotriol 5-fluorouracil (5-FU) have been shown eliminate AKs reduce risk development, but mechanism was undefined. In this issue JCI, Oka et al. demonstrate that type 2 immunity necessary sufficient elimination premalignant keratinocytes Paired biopsies from AK...
Increasing evidence suggests that the excessive accumulation of apoptotic or necrotic cellular debris may contribute to pathology systemic autoimmune disease. HMGB1 is a nuclear DNA-associated protein, which can be released from dying cells thereby triggering inflammatory processes. We have previously shown IgG2a-reactive B cell receptor (BCR) transgenic AM14 proliferate in response endogenous chromatin immune complexes (ICs), form anti-nucleosome antibody PL2-3 and debris, TLR9-dependent...
The AM14 rheumatoid factor (RF) transgenic (Tg) mouse has been valuable for studying how self-reactive B cells are regulated beyond central tolerance, because they remain ignorant in normal mice. B-cell activation can be studied on autoimmune-prone strains or by inducing with IgG2a anti-chromatin antibodies (Abs). Despite the utility of conventional Ig-Tg mice, site-directed (sd-Tg) mice provide a more physiological model responses, allowing class switch and somatic hypermutation. We report...
Synthetic oligonucleotides containing CpG motifs have been shown to induce proliferation, differentiation, and cytokine production in B cells, macrophages, dendritic cells through a TLR9-dependent mechanism. A class (CpG-A) (CpG-B) display distinct physical properties. CpG-A, but not CpG-B, can multimerize form exceedingly large lattices. CpG-A cannot effectively activate does plasmacytoid produce high levels of IFNalpha, while CpG-B is potent cell mitogen. In this study, we report that...
Mohs micrographic surgery (MMS) is a promising treatment modality for melanoma in situ (MIS). However, variations surgical technique limit the generalizability of existing data and may impede future study MMS clinical trials.
<h3>Importance</h3> Early-stage melanoma, among the most common cancers in US, is typically treated with wide local excision. However, recent advances immunohistochemistry have led to an increasing number of these cases being excised via Mohs micrographic surgery (MMS). Although studies resections for other reported that facility-level factors are associated patient outcomes, it not yet established how may affect outcomes patients surgery. <h3>Objective</h3> To evaluate association treatment...