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Background: Bullous pemphigoid (BP) is an autoimmune blistering disease lacking an FDA-approved therapy that disproportionately affects elderly patients with pruritic blisters. Biopsies of BP patients show granulocyte infiltration of lesional skin. The leukotriene B4 (LTB4) pathway is a key positive feedback loop in granulocyte recruitment into tissues. Here, we sought to determine if LTB4 pathway and tissue damage markers were associated with granulocyte invasion in BP. Methods: Lesional skin was analyzed by immunohistochemistry (IHC, N=4) for leukotriene A4 hydrolase (LTA4H), the rate-limiting enzyme in LTB4 synthesis, and the oxidizing enzyme myeloperoxidase.
Nonmelanoma skin cancers (NMSC), including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), are the most common cancers in the United States, with over 5.4 million cases diagnosed annually. Current therapeutic strategies and preventative measures have not been able to effectively manage this neoplasm. Therefore, better understanding of NMSC biology may provide novel mechanisms and targets for management of these cancers. Polo-like kinase 4 (PLK4) is a serine/threonine kinase, known to play a role in cell division by regulating centriole duplication.
To investigate if CTCL may be an antigen-driven process, we used the GLIPH algorithm to cluster TCRs from CTCL skin lesions into groups likely to recognize similar antigens across different individuals. We observed strong clustering of benign T cell TCR sequences. 30% of the top 10 benign T cell sequences in 227 CTCL patients clustered into shared specificity groups and 82% of these sequences fell into a single group, suggesting they may recognize a shared antigen. In contrast, only 7% of malignant clones and <1% of TCR sequences from normal skin donors clustered.
Since its discovery in normal skin, 5 cases of HPyV7-associated rashes have been reported. We present the clinical, viral, and immunologic findings from a renal transplant recipient with a pruritic, pink-grey, scaly eruption. Histopathology demonstrated the “peacock plumage” pattern characteristic of HPyV6/7-associated rashes and HPyV7 viral DNA was detected in affected skin. The eruption resolved after treatment with acitretin and reduction of mycophenolate mofetil dose. Skin biopsies revealed moderate infiltration of macrophages, Langerhans cells, and CD4+ T cells in pre-treatment skin, with notable CD8+ T cell infiltration evident only post-treatment.
The current clinical methods for the evaluation of lymphatic vessel function, important for the early diagnosis of several pathological conditions, in particular of post-surgical lymphedema, and for the evaluation of treatment efficacy, are based on complex and mainly qualitative imaging techniques. We established a simple strategy for the painless and quantitative assessment of cutaneous lymphatic function by developing a lymphatic-specific tracer formulation that consists of the clinically approved near-infrared fluorescent dye indocyanine green and the solubilizing surfactant Kolliphor HS15.
Primary melanomas >1 mm thickness are potentially curable by resection, but pose a risk of recurring metastatically. Despite molecular progress in many other cancers, prediction of melanoma recurrence is still based solely upon histopathologicial criteria. Because melanoma is an immunogenic tumor with a high mutational burden, we studied the predictive ability of T cell fraction (TCFr, % of nucleated cells that are T cells) and clonality measured by high throughput sequencing of the TCRB in 337 archival FFPE primary melanomas from patients (T2-T4: 1-2mm, 2-4mm and >4mm) followed up for at least 5 years.
Isotretinoin is the gold standard treatment for moderate to severe acne but its use is limited by its side effect profile. We need to accelerate drug discovery for moderate to severe acne. Drug-repurposing is one approach to accelerating drug discovery and those drugs that elicit a similar “signature” to isotretinoin may be beneficial as acne therapies. In order to generate “isotretinoin’s signature”, a complete understanding of the mechanisms by which isotretinoin improves acne in human patients is required.
Patients with Dermatomyositis (DM) have increased morbidity and mortality. Morbidity is due to multiple factors including muscle, skin, lung and joint disease, and increased rate of malignancy. DM patients also have decreased health-related quality of life (HRQOL) and increased psychiatric illness. The psychosocial toll that malignancy risk has on DM patients has been understudied and neglected. Our study includes adult patients with a recent DM diagnosis and no history of DM-associated malignancy.
Anal Squamous Cell Carcinoma (ASCC) is a rare, but deadly cutaneous malignancy for which chemoradiotherapy has remained the standard of care since 1974. Up to 90% of ASCC develops as a result of infection by high-risk human papilloma virus (HPV16 and 18). Immunotherapies including checkpoint inhibitors targeting PD-L1 are currently being explored as treatment options in advanced disease. Biomarkers indicative of altered metabolic states, like increased expression of the facilitative glucose transporter (GLUT1), have been used as prognostic indicators in other types of squamous cell cancers, but their role in ASCC remains unclear.
Decrease in mass and accumulation of damage are hallmarks of aging in all organs. Human dermis is primarily composed of densely-packed bundles of collagen fibrils, which contain mostly type I/type III collagens. We have quantitatively assessed age-related alterations of human dermal collagen fibrils from 60 healthy volunteers aged 20 to 92 years (mean age, 54 years), composed of 29 females and 31 males. Skin samples were obtained from sun-protected buttocks. During aging, collagen content is reduced and collagen fibril fragmentation increases, due to downregulation of type I (COLI) and type III (COLIII) procollagen and elevated matrix metalloproteinase-1 (MMP1) expression, respectively.
Upadacitinib (upa), an oral, once-daily, selective Janus Kinase 1 (JAK1) inhibitor, was investigated for the treatment of atopic dermatitis (AD) in a phase 2 study in 167 adults with moderate-to-severe AD randomized to upa 7.5mg, 15mg, and 30mg (n=42 per group) or placebo (n=41). Mean % improvements from baseline to 16 wk in Eczema Area and Severity Index (EASI: 39.4%/61.7%/74.4% vs 23%, P<0.05/<0.001/<0.001) and pruritus NRS (39.6%/48.0%/68.9% vs 9.7%, P<0.01/<0.001/<0.001) were significantly greater for 7.5/15/30mg upa vs placebo.
Discoid lupus erythematosus (DLE) presents initially as erythematous papules and plaques that later progress to hyperpigmented and hypopigmented plaques with central scarring. The immunopathology of different stages of DLE is not well characterized. We previously found increased CD8+ T cells in early DLE skin and more CD20+ B cells in later DLE skin. To follow up on these findings, we compared helper T (Th) cell subpopulations in early (inflammatory), mid (inflammatory with scarring) and late (scaring) DLE skin.
The circulating tumor DNA is being evaluated for clinical use. We previously reported a high cell-free DNA (cfDNA) in patients with cutaneous T-cell lymphoma (CTCL). We and others recently identified/confirmed multiple gene mutations and copy number variations (CNVs) in CTCL patients. The aim of this work was to assess common/rare gene mutations and CNVs in cfDNA of CTCL patients. The cfDNA was extracted from sera of 37 CTCL patients, with 11 paired genomic DNA (gDNA). The CNVs for CDKN2A, STAT5B, TP53, ARID1A, and MYC were assessed by droplet digital PCR.
Recessive dystrophic epidermolysis bullosa (RDEB) is a life-threatening disease caused by mutations in COL7A1 coding for type VII collagen (C7), the major component of anchoring fibrils (AFs). About 30% of COL7A1 mutations are nonsense and generate premature termination codons. Previously, we showed that gentamicin therapy by topical application or intradermal injection generated new, functional C7 and AFs in RDEB patients. Although effective, topical administration of gentamicin to the entire skin surface area could be cumbersome and would not treat mucocutaneous sites.
Dermatomyositis (DM) is associated with malignancy, particularly at and shortly after the diagnosis. While consensus guidelines have not been developed, cancer screening is generally recommended following the diagnosis of DM. Conventional cancer screening (CCS) often includes measurement of tumor markers, a CT of the chest/abdomen/pelvis, mammogram, cervical cytology, endoscopy and transvaginal ultrasound. Annual whole-body PET/CT is an alternative for cancer screening in DM. Here, we aim to better understand the indirect costs associated with CCS and assess the degree of burden CCS poses to patients compared to annual whole-body PET/CT.
Nonsurgical therapies for the treatment of keratinocyte-derived carcinomas are limited by systemic toxicities, adverse effects, and incomplete resolution. In response, we explored novel formulations of biodegradable nanoparticles (NPs) capable of encapsulating camptothecin (CPT) for the local nonsurgical treatment of squamous cell carcinoma (SCC) in mice. We have previously shown that biodegradable poly(lactic acid)-hyperbranched polyglycerol (PLA-HPG) NPs enhance drug delivery, solubility, and bioavailability within solid tumors.
Bullous pemphigoid (BP) is an autoimmune blistering disease. One of the most bothersome symptoms of BP is severe itch, which greatly impacts patients’ quality of life. Thus, a primary objective of BP treatment includes reducing itch. However, managing itch in BP is difficult due to the fact that little is known about its mechanisms. In this study, we examined skin biopsy specimens from 24 patients with BP (ages, 32–90 years old; male vs female, 12 vs 12) and from 6 healthy volunteers, assessing innervation patterns and immune cells through performing immunohistochemistry of putative neural factors and cytokines known to be involved in itch.
Contact with poison ivy, poison oak and poison sumac is the leading cause of plant-related allergic contact dermatitis (PRACD) in the United States, with a range of 10 to 50 million affected per year. Additionally, while PRACD is rather common, dermatological access across Pennsylvania is limited. The purpose of this study is to evaluate the burden of PRACD on the health care system and propose an intervention to address the gaps in access to dermatological services for management. For this project we used the Truven MarketScan Database and examined Pennsylvania level data from 2014 to 2016 and national level data from 2016 using ICD-9 and ICD-10 diagnosis codes to identify office visits.
Whole biopsy studies with RNA sequencing or gene arrays elucidated the immune pathways characterizing atopic dermatitis/AD, leading to development of targeted therapeutics. However, single-cell gene profiling is key for identifying rare populations and cell-specific AD biomarkers. To classify cell types and assess transcriptomic changes in lesional/LS and non-lesional/NL skin of AD patients (n=5) versus controls (n=7), we performed single-cell RNA-seq with 10x Genomics. We isolated 23,124, 7,035, and 10,433 cells from healthy, NL, and LS skin, respectively, capturing major cutaneous cell types.
Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma, a non-Hodgkin’s lymphoma of skin-tropic T lymphocytes. Topical steroids and other skin-directed treatments often improve but do not cure CTCL skin lesions. We report here that low-dose radiation therapy (LDRT, 8 Gy) induced durable remissions of treated lesions. We hypothesized that treatment with LDRT may eradicate the malignant T cell clone within the treated site. To address this, we examined pre- and post-treatment biopsies from 20 lesional skin samples of 18 MF patients who received either 8 Gy LDRT (n=16) or topical steroids (n=4) with high-throughput T-cell receptor sequencing (HTS) of the TCRB gene to identify, quantify, and follow the malignant T cell clone.