Background: In recent studies, convolutional neural networks (CNNs) outperformed dermatologists in distinguishing dermoscopic images of melanoma and nevi. In these studies, dermatologists and artificial intelligence were considered as opponents. However, the combination of classifiers frequently yields superior results, both in machine learning and among humans. In this study, we investigated the potential benefit of combining human and artificial intelligence for skin cancer classification. Methods: Using 11,444 dermoscopic images, which were divided into five diagnostic categories, novel deep learning techniques were used to train a single CNN. Then, both 112 dermatologists of 13 German university hospitals and the trained CNN independently classified a set of 300
Objective. To define the phenotype and function of CD4؉,CD25؉ regulatory T cells (Treg) in patients with cutaneous lupus erythematosus (CLE), a heterogeneous autoimmune disease characterized primarily by inflammatory skin lesions.Methods. The number of Treg in skin specimens obtained from patients with various subtypes of CLE was investigated by immunohistochemical analysis, using anti-Foxp3 and anti-CD4 monoclonal antibodies. Furthermore, characterization of peripheral blood CD4؉,CD25؉ Treg from normal healthy donors and patients with CLE was carried out by flow cytometry, analyzing the expression of Foxp3 and Treg subpopulations. We also purified CD4؉,CD25 high Treg obtained from patients with CLE and tested the sensitivity of these cells to CD95L-mediated apoptosis.Results. Quantitative analysis of CD4؉ T cells in skin lesions from patients with CLE revealed that the number was similar to that in lesions from patients with other chronic inflammatory diseases, but the number of Foxp3؉ Treg in CLE was significantly reduced. There was no correlation between disease subtype and the frequency of Foxp3؉ Treg in the skin of patients with CLE. In peripheral blood, no significant differences were observed in the number and phenotype of CD4؉,CD25؉ Treg or in the sensitivity to apoptosis of CD4؉,CD25 high Treg derived from patients with CLE and those derived from normal healthy donors.Conclusion. These data suggest that an organspecific abnormality of Treg in the skin underscores the importance of analyzing Treg in the affected tissue. Such a local process might give insight into the pathogenic mechanisms of CLE and differs from a global peripheral dysfunction as reported for patients with a systemic manifestation of the disease.
Aberrant signaling of the nuclear facotr (NF-KB) pathway has been identified as a mediator of survival and apoptosis resistance in leukemias and lymphomas. Here, we report that cell death of cutaneous T-cell lymphoma cell lines induced by inhibition of the NF-KB pathway is independent of caspases or classic death receptors. We found that free intracellular iron and reactive oxygen species (ROS) are the main mediators of this cell death. Antioxidants such as N-Acetyl-L-cysteine and glutathione or the iron chelator desferrioxamine effectively block cell death in cutaneous T-cell lymphoma cell lines or primary T cells from Sézary patients. We show that inhibition of constitutively active NF-KB causes down-regulation of ferritin heavy chain (FHC) that leads to an increase of free intracellular iron, which, in turn, induces massive generation of ROS. Furthermore, direct down-regulation of FHC by siRNA caused a ROS-dependent cell death. Finally, high concentrations of ROS induce cell death of malignant T cells. In contrast, T cells isolated from healthy donors do not display down-regulation of FHC and, therefore, do not show an increase in iron and cell death upon NF-KB inhibition. In addition, in a murine T-cell lymphoma model, we show that inhibition of NF-KB and subsequent down-regulation of FHC significantly delays tumor growth in vivo. Thus, our results promote FHC as a potential target for effective therapy in lymphomas with aberrant NF-KB signaling. [Cancer Res 2009;69(6):2365-74]
A number of different histological and immunophenotypical criteria are required to differentiate between SS and EIDs.
Cutaneous T-cell lymphomas (CTCLs) are malignancies of skin-homing lymphoid cells, which have so far not been investigated thoroughly for common oncogenic mutations. We screened 90 biopsy specimens from CTCL patients (41 mycosis fungoides, 36 Sé zary syndrome, and 13 non-mycosis fungoides/Sé zary syndrome CTCL) for somatic mutations using OncoMap technology. We detected oncogenic mutations for the RAS pathway in 4 of 90 samples. One mycosis fungoides and one pleomorphic CTCL harbored a KRAS G13D mutation; one Séz-ary syndrome and one CD30 ؉ CTCL harbored a NRAS Q61K amino acid change. All mutations were found in stage IV patients (4 of 42) who showed significantly decreased overall survival compared with stage IV patients without mutations (P ؍ .04). In addition, we detected a NRAS Q61K IntroductionCutaneous T-cell lymphomas (CTCLs) are rare malignancies of skin-homing T lymphocytes. Curative modalities have thus far proven elusive. CTCL microarray studies have revealed natural clusters in association with prognosis. 1 Array-based comparative genomic hybridization (CGH) combined with gene expression profiling identified highly recurrent chromosomal alterations both in mycosis fungoides (MF) and Sézary syndrome (SS) patient specimens. 2,3 For example, FASTK and SKAP1 gene loci showed recurrent gains, and these genes also exhibited increased expression, whereas RB1 and DLEU tumor suppressor genes displayed diminished expression associated with loss. In another study, recurrent deletion of tumor suppressor genes BCL7A, SMAC/ DIABLO, and RHOF in MF was observed. 4 Genomic patterns characteristic of MF differ markedly from SS. 5 This might implicate discriminative molecular pathogenesis and different therapeutic requirements.The RAS-RAF-MEK-ERK signaling pathway regulates cell responses to environmental stimuli and plays a crucial role in many cancers. 6 Thus, RAF and MEK are attractive therapeutic targets. 7,8 RAS is a small guanine-nucleotide binding protein that is attached to the inner side of the plasma membrane. Activation of RAS causes RAF recruitment and activation by phosphorylation. Activated RAF kinase phosphorylates and activates MEK, which phosphorylates ERK. Three RAS (KRAS, NRAS, and HRAS), 3 RAF (ARAF, BRAF, and CRAF), 2 MEK (MEK1 and MEK2), and 2 ERK (ERK1 and ERK2) isoforms compose the "canonical" mitogen-activated protein kinase pathway. Somatic mutations that are found in many cancers, including colon carcinoma, melanoma, or pancreatic cancer, occur almost exclusively in BRAF, KRAS, or NRAS isoforms. 9-11 Typical mutations affect glycine 12 (G12), glycine 13 (G13), or glutamine 61 (Q61) and keep RAS in an activated form. The RAS pathway regulates survival, proliferation, senescence, and differentiation. However, in tumor cells, mutated (oncogenic) RAS preferentially promotes survival and proliferation. Thus, RAF and MEK kinases serve as suitable drug targets. RAF is targeted by inhibitors in preclinical or clinical development, including, for example, RAF265 and PLX4720. 12,13 However, target...
Cutaneous T-cell lymphoma (CTCL) has been suggested by in vitro experiments to represent a malignant CD4+ T-cell proliferation with a regulatory T-cell (Treg) phenotype (CD4+CD25+FOXP3+). We investigated percentages of FOXP3+ and CD25+ cells in the blood of 15 Sézary, 14 mycosis fungoides (MF), and 10 psoriasis (Pso) patients and 20 normal healthy donors (NHDs). We found similar numbers of FOXP3+ cells in MF (10.4% of blood CD4+ cells) and Pso (11.1%) patients and NHDs (9.8%). In 8 of 15 (53%) Sézary patients, significantly reduced percentages of FOXP3+ cells were seen in blood (2.9%) and skin (10.4%). Interestingly, 6 of 15 (40%) Sézary patients showed significantly increased percentages of FOXP3+ cells (39.7% (blood), 20.3% (skin)); however, these cells did not express CD25. In these latter patients, clone-specific TCR-Vbeta-chain antibodies were used to demonstrate that these FOXP3+CD25- cells were monoclonal CTCL tumor cells. FOXP3+CD25- CTCL tumor cells showed a highly demethylated status of the foxp3 gene locus similar to Treg cells, and they were functionally able to suppress IL-2 mRNA induction in TCR-stimulated conventional T cells. Thus, FOXP3+CD25- CTCL tumor cells with functional features of Treg cells define a subgroup of Sézary patients who might carry a different prognosis and might require differential treatment.
Signal transduction to nuclear factor-kappa B (NF-κB) involves multiple kinases and phosphorylated target proteins, but little is known about signal termination by dephosphorylation. By RNAi screening, we have identified protein phosphatase 4 regulatory subunit 1 (PP4R1) as a negative regulator of NF-κB activity in T lymphocytes. PP4R1 formed part of a distinct PP4 holoenzyme and bridged the inhibitor of NF-κB kinase (IKK) complex and the phosphatase PP4c, thereby directing PP4c activity to dephosphorylate and inactivate the IKK complex. PP4R1 expression was triggered upon activation and proliferation of primary human T lymphocytes and deficiency for PP4R1 caused sustained and increased IKK activity, T cell hyperactivation, and aberrant NF-κB signaling in NF-κB-addicted T cell lymphomas. Collectively, our results unravel PP4R1 as a previously unknown activation-associated negative regulator of IKK activity in lymphocytes whose downregulation promotes oncogenic NF-κB signaling in a subgroup of T cell lymphomas.
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