BMI1 is a target gene of E2F-1 and is strongly expressed in primary neuroblastomas

The oncogene BMI1 encodes a polycomb group transcription factor that is required for embryonic development and self-renewal of stem cells. Despite these important functions little is known about the regulation of BMI1 expression. A cDNA microarray based search for target genes of E2F-1 in neuroblastoma cells expressing a 4-OHT-regulated E2F-1-ER fusion protein identified many hitherto unknown E2F-1 regulated genes. A total of 10% of these genes, including BMI1, encode proteins that function primarily in the regulation of gene expression. The BMI1 promoter contains a putative E2F binding site that was required for the activation of a BMI1 promoter-dependent reporter construct by E2F-1. Chromatin immunoprecipitation revealed 4-OHT-dependent binding of E2F-1-ER and binding of endogenous E2F-1 to the BMI1 promoter in tumor cells. We have previously shown activation of the oncogene MYCN by E2F. Thus, in neuroblastomas deregulated E2F-1 can activate two oncogenes, MYCN and BMI1 that are known to co-operate in tumor formation. Consistent with a role of Bmi1 in neuroblastoma tumorigenesis we found strong Bmi1 expression in primary neuroblastomas. Our results reveal a novel link between E2F and polycomb transcription factors and suggest a role of Bmi1 in neuroblastomas

A Report of Two Cases of Solid Facial Edema in Acne

Solid facial edema (SFE) is a rare complication of acne vulgaris. To examine the clinical features of acne patients with solid facial edema, and to give an overview on the outcome of previous topical and systemic treatments in the cases so far published.; We report two cases from Switzerland, both young men with initially papulopustular acne resistant to topical retinoids.; Both cases responded to oral isotretinoin, in one case combined with oral steroids. Our cases show a strikingly similar clinical appearance to the cases described by Connelly and Winkelmann in 1985 (Connelly MG, Winkelmann RK. Solid facial edema as a complication of acne vulgaris. Arch Dermatol. 1985;121(1):87), as well as to cases of Morbihan's disease that occurs as a rare complication of rosacea.; Even 30 years after, the cause of the edema remains unknown. In two of the original four cases, a potential triggering factor was identified such as facial trauma or insect bites; however, our two patients did not report such occurrencies. The rare cases of solid facial edema in both acne and rosacea might hold the key to understanding the specific inflammatory pattern that creates both persisting inflammation and disturbed fluid homeostasis which can occur as a slightly different presentation in dermatomyositis, angioedema, Heerfordt's syndrome and other conditions

Characterisation of IL‐1 family members in Sweet syndrome highlights the overexpression of IL‐1β and IL‐1R3 as possible therapeutic targets

Sweet syndrome (SS) as a prototypic neutrophilic dermatosis (NDs) shares certain clinical and histologic features with monogenic auto-inflammatory disorders in which interleukin (IL)-1 cytokine family members play an important role. This has led to the proposal that NDs are polygenic auto-inflammatory diseases and has fuelled research to further understand the role of IL-1 family members in the pathogenesis of NDs. The aim of this study was to characterise the expression of the IL-1 family members IL-1β, IL-36γ, IL-33 and IL-1R3 (IL-1RaP) in SS. The expression profile of IL-1β, IL-33, IL-36γ and their common co-receptor IL-1R3 was analysed by immunohistochemistry, in situ hybridisation and double immunofluorescence (IF) in healthy control skin (HC) and lesional skin samples of SS. Marked overexpression of IL-1β in the dermis of SS (p < 0.001), and a non-significant increase in dermal (p = 0.087) and epidermal (p = 0.345) IL-36γ expression compared to HC was observed. Significantly increased IL-1R3 expression within the dermal infiltrate of SS skin samples (p = 0.02) was also observed, whereas no difference in IL-33 expression was found between SS and HC (p = 0.7139). In situ hybridisation revealed a good correlation between gene expression levels and the above protein expression levels. Double IF identifies neutrophils and macrophages as the predominant sources of IL-1β. This study shows that IL-1β produced by macrophages and neutrophils and IL-1R3 are significantly overexpressed in SS, thereby indicating a potential pathogenic role for this cytokine and receptor in SS

The Nlrp3 inflammasome regulates acute graft-versus-host disease

The success of allogeneic hematopoietic cell transplantation is limited by acute graft-versus-host disease (GvHD), a severe complication accompanied by high mortality rates. Yet, the molecular mechanisms initiating this disease remain poorly defined. In this study, we show that, after conditioning therapy, intestinal commensal bacteria and the damage-associated molecular pattern uric acid contribute to Nlrp3 inflammasome-mediated IL-1β production and that gastrointestinal decontamination and uric acid depletion reduced GvHD severity. Early blockade of IL-1β or genetic deficiency of the IL-1 receptor in dendritic cells (DCs) and T cells improved survival. The Nlrp3 inflammasome components Nlrp3 and Asc, which are required for pro-IL-1β cleavage, were critical for the full manifestation of GvHD. In transplanted mice, IL-1β originated from multiple intestinal cell compartments and exerted its effects on DCs and T cells, the latter being preferentially skewed toward Th17. Compatible with these mouse data, increased levels of active caspase-1 and IL-1β were found in circulating leukocytes and intestinal GvHD lesions of patients. Thus, the identification of a crucial role for the Nlrp3 inflammasome sheds new light on the pathogenesis of GvHD and opens a potential new avenue for the targeted therapy of this severe complication

Histopathological patterns indicative of distinct adverse drug reactions

Histologically, drug eruptions may present virtually all patterns of inflammation in the skin, including spongiotic, lichenoid and psoriasiform dermatitis as well as vasculitis or panniculitis. Drug reactions may mimic specific skin diseases such as lupus erythematosus, lichen planus or lymphoma. While a single drug may cause a wide range of reaction patterns, no reaction pattern is specific for a certain drug. Nevertheless, some reactions are quite characteristic for certain drugs as for example psoriasiform dermatitis for anti-TNF agents or folliculitis for epidermal growth factor receptor antagonists. Heightened awareness to the possible mimicry of other skin diseases as well as integration of clinical data is pivotal for the appropriate histological diagnosis of drug reactions in the skin. For practical reasons and in the aim of helping clinicians, the different drug reactions described in this chapter are classified according to the main histological reaction pattern present. Nevertheless, this classification may be somewhat artificial in some cases as drug reactions often reveal a coexistence of different reaction patterns

Basal Cell Carcinoma Mimicking Desmoplastic Trichoepithelioma: A Case with Correlation of Dermoscopy and Histology

Basal cell carcinoma (BCC) is the most common cancer in humans worldwide. Many highly specific dermoscopic criteria for BCC are well established in the literature. On the contrary, other malignant or benign skin tumors may mimic BCC by exhibiting similar or even the same dermoscopic features and therefore obscuring the diagnosis of BCC in certain situations. We herein report a case of BCC with dermoscopic features of both BCC and desmoplastic trichoepithelioma (DT). We would like to remind of the often neglected differential diagnosis of DT in a lesion with arborizing vessels and otherwise unusual dermoscopic presentation

Zur Gestaltung von Erziehungs-und Bildungspartnerschaften und ihre Bedeutung für den Abbau von Bildungsungleichheiten am Beispiel einer Kindertageseinrichtung in Sachsen

Der Inhalt der Bachelorarbeit befasst sich mit dem Thema Erziehungs- und Bildungspartnerschaften zwischen Eltern und pädagogischen Fachkräften am Beispiel einer Kindertageseinrichtung in Sachsen, unter dem Fokus der Herstellung von Chancengleichheit bezüglich der frühkindlichen Bildung. Es wird der Frage nachgegangen, welchen Einfluss die Gestaltung von Erziehungs- und Bildungspartnerschaften auf den Abbau von Bildungsungleichheiten hat

Clonality in sarcoidosis, granuloma annulare, and granulomatous mycosis fungoides

The histological discrimination of granulomatous cutaneous T-cell lymphomas (CTCLs) from reactive granulomatous disorders such as sarcoidosis and granuloma annulare (GA) may be difficult due to overlapping histological features. We analyzed the T-cell receptor gene rearrangement in sarcoidosis and GA to investigate the value of the detection of clonal T cells as an adjunctive diagnostic marker in the differentiation between sarcoidosis and GA versus granulomatous CTCLs. Rearrangement of T-cell receptor γ genes was examined by the use of automated high-resolution polymerase chain reaction fragment analysis in 35 cases of sarcoidosis and 15 cases of GA and compared with a series of 19 cases of granulomatous CTCLs. A monoclonal T-cell population was found in none of the cases of sarcoidosis and in 2 of 15 cases of GA (13%). In granulomatous CTCLs, a neoplastic T-cell clone was detected in 94%. Presence of clonal T cells argues in favour of a granulomatous CTCL, while a polyclonal T-cell population makes the presence of a sarcoidosis or a GA more likely. The analysis of T-cell clonality is a useful diagnostic adjunct in the differentiation between sarcoidosis and GA from granulomatous CTCLs

Cutaneous lymphomas: an update. Part 1: T-cell and natural killer/t-cell lymphomas and related conditions

Primary cutaneous T-cell lymphomas (CTCL) represent the majority of cutaneous lymphomas (CLs) and are a spectrum of diseases with a wide variety of clinical, histological, and phenotypic features and diverse biologic behavior. This review focuses on the observations on new variants of CTCL and recent developments in deciphering the pathogenetic mechanisms, which have implication for the nosologic concepts and future classification of CLs. Variants of mycosis fungoides (MF) such as the unilesional and the papular form have been characterized in more detail. Studies analyzed the expression of CD30 and PD-1 in MF and other forms of CTCL. New variants in the group of cutaneous CD30⁺ lymphoproliferative disorders include the epidermotropic CD8⁺ variant of lymphomatoid papulosis (type D) and angiocentric lymphomatoid papulosis (type E), which histologically mimic aggressive lymphomas, and therefore may be diagnostically challenging. Cutaneous proliferations of T cell-expressing markers of follicular helper T cells (PD-1, CXCL-13, and bcl-6) display a prognostically heterogeneous group. There is an increasing spectrum of CTCL with the expression of CD8 by tumor cells, including CD8⁺ MF, CD8⁺ forms of cutaneous CD30⁺ lymphoproliferative disorders, and CD8⁺ small/medium-sized lymphoproliferations, which are not included as distinct entities in the World Health Organization-European Organization for Research and Treatment of Cancer for CLs and the World Health Organization classification. Unusual presentations and incomplete phenotypes of blastic neoplasm of plasmacytoid dendritic cells are discussed. Clinicopathologic correlation is mandatory for the diagnosis of primary CLs. Analysis of genetic and epigenetic alterations in CLs revealed new diagnostic markers and putative targets for therapy of aggressive forms of CLs