2,623 research outputs found
STK11 Prevents Invasion Through STAT3/5 and FAK Repression in Cutaneous Melanoma
Full text linkThe serine/threonine kinase 11 (STK11/LKB1) is a tumor suppressor involved in metabolism and cell motility. In BRAFV600E melanoma, STK11 is inactivated by ERK and RSK, preventing it from binding and activating AMPK and promoting melanoma cell proliferation. Although STK11 mutations occur in 5-10% of cutaneous melanoma, few functional studies have been performed. By knocking out STK11 with CRISPR/Cas9 in two human BRAF-mutant melanoma cell lines, we found that STK11-loss reduced the sensitivity to a BRAF inhibitor (BRAFi). More strikingly, STK11 loss led to an increased invasive phenotype in both 3-dimensional spheroids and in vivo zebrafish xenograft models. STK11 overexpression consistently reverted the invasive phenotype.
Interestingly, STK11 knockout increased invasion also in an NRAS-mutant melanoma cell line. Furthermore, while STK11 was expressed in primary human melanoma tumors, its expression significantly decreased in melanoma metastases especially in brain metastases. In the STK11-knockout cells we observed increased activating phosphorylation of STAT3/5 and FAK. Using inhibitors of STAT3/5 and FAK, we reverted the invasive phenotype in both BRAF and NRAS mutated cells. Our findings confirm an increased invasive phenotype upon STK11-inactivation in BRAF and NRAS-mutant cutaneous melanoma that can be targeted by STAT3/5 and FAK-inhibition
Long-term pegylated interferon-α and its potential in the treatment of melanoma
No full textReinhard Dummer, Joanna ManganaDepartment of Dermatology, University Hospital, Zürich, SwitzerlandAbstract: Conventional interferons including interferon-α (IFN-α) are cytokines used for years in the treatment of solid tumors and hematological malignancies. Their half-life is short. Pegylated forms of IFN-α present an improved pharmacokinetic profile that rendered them the preferred IFNs in hepatitis therapy. In the last decade, pegylated interferons (PegIFNs) have been investigated in melanoma patients. We review the scientific published literature on biology, pharmacokinetics, side effects and clinical applications of PegIFN-α in the treatment of stage III and IV melanoma. In the adjuvant setting, PegIFNα-2b has significant prolonged distant metastases free survival in patients with microscopic nodal involvement (stage TxN1aM0) and therefore is a promising treatment option in this patient population. In the palliative setting, monotherapy with PegIFNα-2α can induce complete remissions in a minority of stage IV melanoma patients. The combination of monochemotherapy is feasible and may result in lasting complete remissions. Ongoing research must focus on the identification of patients who mostly benefit, so that unnecessary toxicity would be avoided. Combining PegIFNs and chemotherapy or targeted agents deserves further exploration.Keywords: interferons, pegylated interferon-α, melanom
Pathogenesis of histiocytoses
No full textLangerhans cell histiocytosis (LCH) is a disease of unknown etiology showing clonal proliferation of Langerhans-like cells or their precursors [1, 16]. Pathologic LCH cells appear to be in an immature state of activation and/or differentiation [1]. They accumulate in peripheral tissue and express inflammatory cytokines resulting in their own recruitment and retention [21]. Moreover, activated CD40 ligand expressing T helper cells are found to be the predominant source of cytokines and growth factors in LCH lesions [3]. The “cytokine storm” seems to be further enhanced by the interaction of CD40 expressing LCH cells and CD40 ligand expressing T-cells [3]. High levels of granulocyte-macrophage colony-stimulating factor, tumor-necrosis factor alpha, interleukin-3, and other cytokines are potential chemoattractants for recruiting eosinophils, neutrophils, marcrophages, and CD34+ Langerhans cell precursors into the LCH lesion [3, 7]. These cytokines are known to contribute directly to the development of fibrosis, necrosis, and osteolysis [11]. They are also supposed to play a role in the presence of several other myeloid cell types; the multinucleated giant cell (MGC), amongst others, was found in LCH lesions [8]. MGCs are believed to play a major role in tissue destruction, as they are express osteoclast markers [8]. Remarkably, though various inflammatory cytokines are present in LCH lesions, LCH cells remain immature and do not maturate [3]. Lesional microenvironment seems to play a role in the maintenance of the phenotype of LCH cells [3]
Non-self-discrimination as a driving concept in the identification of an immunodominant HMW-MAA epitopic peptide sequence by autoantibodies from melanoma cancer patients
No full textWe analyzed the sera of patients with melanoma to define the human humoral autoantibody profile towards HMW-MAA. Computational proteome scanning using the non-self-discrimination principle as a guide led to the individuation of the low-similarity HMW-MAA781-789RATVWMLRL peptide fragment as an immunodominant B-cell epitope. Linear B-cell determinant individuation was experimentally validated by dot blot immunoassay and NMR spectroscopy analysis. Regulation of physiologic self-reactivity by the non-self-discrimination principle is discussed
Epidemiology of histocytoses
No full textLangerhans cell histiocytisis (LCH) is the most common of the histiocytic disorders [39]. It represents a spectrum of several clinical entities chracterized by a disorder of antigenpresenting dendritic cells of the immune system. Its epidemiology is poorly understood and based mainly on a few international and regional studies of defined populations [34]. The overall incidence rate varies from 2.6 to 8.9 children per million per year [1, 19, 34, 36]. Children of any age can be affected, however the peak age of presentation, in children, is between the ages of one and three [34]. LCH is also diagnosed in adults [37] but only a few reports are available describing LCH patients with onset during adulthood [3]. Some studies reveal a greater prevalence of LCH among male children [19]. On the other hand, in adults, a preponderance of females is documented with onset as late as the ninth decade of life [26]. Dissemitaned LCH is described to present most frequently in the first year of life [19]. Congenital self-healing LCH is an uncommon form of LCH, which is usually present at birth or in the neonatal period [23]
Lymph Node Metastases from Non-Melanoma Skin Cancer of the Head and Neck
Full text linkNon-melanoma skin cancer (NMSC) represents the most common malignancy in the world, comprising exceedingly common lesions such as basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) and rare lesions such as Merkel cell carcinoma. Risk factors are widely recognized and include ultraviolet (UV) light exposure, radiation exposure, immunosuppression, and many others. As a whole, survival and functional outcomes are favorable, but each histopathological subtype of NMSC behaves differently. Treatment regimens for the primary site usually include wide surgical excision and neck dissection in cases of clinically involved metastatic lymph nodes. The elective management of draining nodal basins, however, is a contested topic. Nearly all subtypes, excluding BCC, have a significant risk of lymphatic metastases, and have been studied with regard to sentinel lymph node biopsy (SLNB) and elective neck dissection. To date, no studies have definitively established a true single standard of care, as exists for melanoma, for any of the NMSCs. As a result, the authors have sought to summarize the current literature and identify indications and management options for the management of the cervical lymphatics for each major subtype of NMSC. Further research remains critically necessary in order to develop complete treatment algorithms
Cutaneous lymphoma
No full textCutaneous lymphomas, like other lymphomas, are systemic diseases by definition. Therefore, surgery has limited indications. However, primary cutaneous B-cell lymphomas (CBCL), such as follicle center lymphomas and large cell primary cutaneous CD30+ T-cell lymphomas, may present as a single nodule in the skin. In these cases, because investigation on tumor material is necessary, an excision biopsy might be a good alternative to an incisional biopsy. In the case of surgical treatment of a nodule in primary cutaneous lymphomas, a safety margin of at least 1 cm should be applied, although there are no supporting clinical trails
Ein generalisiertes additives Modell (GAM) für die Prognose beim malignen Stage-1-Melanom
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