6 research outputs found

    An Atypical Presentation of a Rare Disease

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    A 76-year-old white woman presented for evaluation of asymptomatic skin lesions on her right shin, right buttock, and left arm. All lesions initially underwent slow growth and plateaued and then remained stable in size. A complete review of systems revealed normal results. She had 3 well-demarcated erythematous round plaques ranging from 1.5 to 3 cm, all with a central depression, yellow hue, and prominent telangiectasias (Figs 1 and 2). An excisional biopsy was performed. Histologically, there were palisading granulomas within the papillary and reticular dermis, predominantly composed of a histiocytic cell population with multiple large giant cells (S100-; Fig 3)

    c-Src/Cav1-dependent activation of the EGFR by Dsg2.

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    The desmosomal cadherin, desmoglein 2 (Dsg2), is deregulated in a variety of human cancers including those of the skin. When ectopically expressed in the epidermis of transgenic mice, Dsg2 activates multiple mitogenic signaling pathways and increases susceptibility to tumorigenesis. However, the molecular mechanism responsible for Dsg2-mediated cellular signaling is poorly understood. Here we show overexpression as well as co-localization of Dsg2 and EGFR in cutaneous SCCs in vivo. Using HaCaT keratinocytes, knockdown of Dsg2 decreases EGFR expression and abrogates the activation of EGFR, c-Src and Stat3, but not Erk1/2 or Akt, in response to EGF ligand stimulation. To determine whether Dsg2 mediates signaling through lipid microdomains, sucrose density fractionation illustrated that Dsg2 is recruited to and displaces Cav1, EGFR and c-Src from light density lipid raft fractions. STED imaging confirmed that the presence of Dsg2 disperses Cav1 from the cell-cell borders. Perturbation of lipid rafts with the cholesterol-chelating agent MβCD also shifts Cav1, c-Src and EGFR out of the rafts and activates signaling pathways. Functionally, overexpression of Dsg2 in human SCC A431 cells enhances EGFR activation and increases cell proliferation and migration through a c-Src and EGFR dependent manner. In summary, our data suggest that Dsg2 stimulates cell growth and migration by positively regulating EGFR level and signaling through a c-Src and Cav1-dependent mechanism using lipid rafts as signal modulatory platforms

    Enhancement of cutaneous wound healing by Dsg2 augmentation of uPAR secretion

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    In addition to playing a role in adhesion, desmoglein 2 (Dsg2) is an important regulator of growth and survival signaling pathways, cell proliferation, migration and invasion, and oncogenesis. While low-level Dsg2 expression is observed in basal keratinocytes and is downregulated in non-healing venous ulcers, overexpression has been observed in both melanomas and non-melanoma malignancies. Here, we show that transgenic mice overexpressing Dsg2 in basal keratinocytes primed the activation of mitogenic pathways, but did not induce dramatic epidermal changes or susceptibility to chemical-induced tumor development. Interestingly, acceleration of full-thickness wound closure and increased wound-adjacent keratinocyte proliferation was observed in these mice. As epidermal cytokines and their receptors play critical roles in wound healing, Dsg2-induced secretome alterations were assessed with an antibody profiler array and revealed increased release and proteolytic processing of the urokinase-type plasminogen activator receptor (uPAR). Dsg2 induced uPAR expression in the skin of transgenic compared to wild-type mice. Wound healing further enhanced uPAR in both epidermis and dermis with concomitant increase in the pro-healing laminin-332, a major component of the basement membrane zone, in transgenic mice. This study demonstrates that Dsg2 induces epidermal activation of various signaling cascades and accelerates cutaneous wound healing, in part, through uPAR-related signaling cascades

    A Survey of Empirical Results on Program Slicing

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    International audienceBACKGROUND:Patients with peripheral artery disease have an increased risk of cardiovascular morbidity and mortality. Antiplatelet agents are widely used to reduce these complications.METHODS:This was a multicentre, double-blind, randomised placebo-controlled trial for which patients were recruited at 602 hospitals, clinics, or community practices from 33 countries across six continents. Eligible patients had a history of peripheral artery disease of the lower extremities (previous peripheral bypass surgery or angioplasty, limb or foot amputation, intermittent claudication with objective evidence of peripheral artery disease), of the carotid arteries (previous carotid artery revascularisation or asymptomatic carotid artery stenosis of at least 50%), or coronary artery disease with an ankle-brachial index of less than 0·90. After a 30-day run-in period, patients were randomly assigned (1:1:1) to receive oral rivaroxaban (2·5 mg twice a day) plus aspirin (100 mg once a day), rivaroxaban twice a day (5 mg with aspirin placebo once a day), or to aspirin once a day (100 mg and rivaroxaban placebo twice a day). Randomisation was computer generated. Each treatment group was double dummy, and the patient, investigators, and central study staff were masked to treatment allocation. The primary outcome was cardiovascular death, myocardial infarction or stroke; the primary peripheral artery disease outcome was major adverse limb events including major amputation. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants.FINDINGS:Between March 12, 2013, and May 10, 2016, we enrolled 7470 patients with peripheral artery disease from 558 centres. The combination of rivaroxaban plus aspirin compared with aspirin alone reduced the composite endpoint of cardiovascular death, myocardial infarction, or stroke (126 [5%] of 2492 vs 174 [7%] of 2504; hazard ratio [HR] 0·72, 95% CI 0·57-0·90, p=0·0047), and major adverse limb events including major amputation (32 [1%] vs 60 [2%]; HR 0·54 95% CI 0·35-0·82, p=0·0037). Rivaroxaban 5 mg twice a day compared with aspirin alone did not significantly reduce the composite endpoint (149 [6%] of 2474 vs 174 [7%] of 2504; HR 0·86, 95% CI 0·69-1·08, p=0·19), but reduced major adverse limb events including major amputation (40 [2%] vs 60 [2%]; HR 0·67, 95% CI 0·45-1·00, p=0·05). The median duration of treatment was 21 months. The use of the rivaroxaban plus aspirin combination increased major bleeding compared with the aspirin alone group (77 [3%] of 2492 vs 48 [2%] of 2504; HR 1·61, 95% CI 1·12-2·31, p=0·0089), which was mainly gastrointestinal. Similarly, major bleeding occurred in 79 (3%) of 2474 patients with rivaroxaban 5 mg, and in 48 (2%) of 2504 in the aspirin alone group (HR 1·68, 95% CI 1·17-2·40; p=0·0043).INTERPRETATION:Low-dose rivaroxaban taken twice a day plus aspirin once a day reduced major adverse cardiovascular and limb events when compared with aspirin alone. Although major bleeding was increased, fatal or critical organ bleeding was not. This combination therapy represents an important advance in the management of patients with peripheral artery disease. Rivaroxaban alone did not significantly reduce major adverse cardiovascular events compared with asprin alone, but reduced major adverse limb events and increased major bleeding
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