Explore the vast range of titles available.

Oncogenes derived from the neurotrophin receptor tropomyosin-related kinase TrkA act as drivers in sub-populations of a wide-range of human cancers. This, combined with a recent report that both adult and childhood cancers driven by novel oncogenic TrkA chimeric-fusions exhibit profound, long-lived therapeutic responses to the Trk inhibitor Larotrectinib, highlights the need to improve clinical detection of TrkA oncogene-driven cancers in order to maximise this novel therapeutic potential. Cancers potentially driven by TrkA oncogenes include a proportion of paediatric neuroblastomas (NBs) that express the alternative TrkA splice variant TrkAIII, which exhibits exon 6, 7 and 9 skipping and oncogenic-activity that depends upon deletion of the extracellular D4 Ig-like domain. In contrast to fully spliced TrkA, which exhibits tumour suppressor activity in NB and associates with good prognosis, TrkAIII associates with advanced stage metastatic disease, post therapeutic relapse and worse prognosis, induces malignant transformation of NIH-3T3 cells and exhibits oncogenic activity in NB models. TrkAIII induction in NB cells is stress-regulated by conditions that mimic hypoxia or perturbate the ER with potential to change TrkA tumour-suppressing signals into oncogenic TrkAIII signals within the stressful tumour microenvironment. In contrast to cell surface TrkA, TrkAIII re-localises to intracellular pre-Golgi membranes, centrosomes and mitochondria, within which it exhibits spontaneous ligand-independent activation, triggering a variety of mechanisms that promote tumorigenicity and malignant behaviour, which impact the majority of cancer hallmarks. In this review, we present updates on TrkAIII detection and association with human malignancies, the multiple ways TrkAIII exerts oncogenic activity and potential therapeutic approaches for TrkAIII expressing cancers, with particular reference to NB.

Post-therapeutic relapse, poor survival rates and increasing incidence justify the search for novel therapeutic targets and strategies in cutaneous malignant melanoma (CMM). Within this context, a potential oncogenic role for TrkA in CMM is suggested by reports of NTRK1 amplification, enhanced TrkA expression and intracellular TrkA activation associated with poor prognosis. TrkA, however, exhibits tumour-suppressing properties in melanoma cell lines and has recently been reported not to be associated with CMM progression. To better understand these contradictions, we present the first analysis of potential oncogenic alternative TrkA mRNA splicing, associated with TrkA immunoreactivity, in CMMs, and compare the behaviour of fully spliced TrkA and the alternative TrkAIII splice variant in BRAF(V600E)-mutated A375 melanoma cells. Alternative TrkA splicing in CMMs was associated with unfolded protein response (UPR) activation. Of the several alternative TrkA mRNA splice variants detected, TrkAIII was the only variant with an open reading frame and, therefore, oncogenic potential. TrkAIII expression was more frequent in metastatic CMMs, predominated over fully spliced TrkA mRNA expression in ≈50% and was invariably linked to intracellular phosphorylated TrkA immunoreactivity. Phosphorylated TrkA species resembling TrkAIII were also detected in metastatic CMM extracts. In A375 cells, reductive stress induced UPR activation and promoted TrkAIII expression and, in transient transfectants, promoted TrkAIII and Akt phosphorylation, enhancing resistance to reductive stress-induced death, which was prevented by lestaurtinib and entrectinib. In contrast, fully spliced TrkA was dysfunctional in A375 cells. The data identify fully spliced TrkA dysfunction as a novel mechanism for reducing melanoma suppression, support a causal relationship between reductive stress, UPR activation, alternative TrkAIII splicing and TrkAIII activation and characterise a targetable oncogenic pro-survival role for TrkAIII in CMM.

Psoriasis is a dermatological disorder whose clinical manifestations have attracted the interest of physicians since ancient times. Hippocrates of Cos in the 5th century B.C. and later Galen in the 1st century A.D. were the first to refer to skin lesions characterized by scales and itching. In the 19th century, dermatology progressed, gaining scientific autonomy and leading to improvements both in the clinical study of psoriasis and in the search for new treatment methodologies. The dermatological schools established in this century, located in London, Paris, and Vienna, dedicated themselves to studying skin diseases, adopting unique methodological approaches and creating dermatological nomenclature. The English school focused on the objective description of lesions, while the French school was the first to approach the study of evolutionary processes, formulating theories not always based on experimental methods. Finally, the Austrian school based its research entirely on the study of diseases through the use of instruments and laboratory tests. Representatives of all three schools played a crucial role in the scientific progress of dermatology, leading to the subsequent evolution and improvement of therapies, which gradually replaced the use of ancient remedies and archaic administration methods. The treatments promoted by the different 19th-century European dermatologists reflected both their scientific thinking and the medical beliefs of the time. For this reason, the following historical-medical reconstruction of the evolution of psoriasis therapies in the 19th century can contribute to enriching the studies of dermatology.

Knowledge regarding differences in care for psoriatic patients is limited. The aim of this study was to investigate factors influencing prescription of systemic treatments for patients with psoriasis with a special focus on socioeconomic factors. This was a non-interventional, cross-sectional study, conducted in 18 Italian University and/or hospital centers with psoriasis-specialized units. Questionnaires evaluating demographic and socioeconomic characteristics were administered to participants. Overall, 1880 consecutive patients affected by mild-to-severe psoriasis were recruited. Univariate and multivariable logistic regression analyses of systemic therapy prescription, with a special focus on biologics, accounting for the above mentioned characteristics were performed. Our analysis showed that all analyzed patients' characteristics were significantly associated with biological therapy compared to non-biological systemic one. Particularly, women were less likely to receive biologics than men (OR = 0.66; 95% CI, 0.57-0.77). Elderly patients ([greater than or equal to]65 years) and subjects with a BMI [greater than or equal to]30 had lower odds to receive biologics respect to adults ([greater than or equal to]35-64 years) (OR = 0.33; 95% CI, 0.25-0.40), and subjects with BMI[greater than or equal to]25<30 (OR = 0.64; 95% CI, 0.53-0.77), respectively. Northern and Southern patients were both less likely to receive biologics than Central patients (OR = 0.75; 95% CI, 0.63-0.89, and OR = 0.56; 95% CI,0.47-0.68, respectively). Lower economic profile and never reading books were both associated with decreased odds of receiving biological therapy. This study shows that sex, age, comorbidities, and socioeconomic characteristics influence the prescription of systemic treatments in psoriasis, highlighting that there are still unmet needs influencing the therapeutic decision-making process that have to be addressed.

The idea of psoriatic disease continuum has been progressively prompted based on the advances of the knowledge about the pathogenic steps underpinning the occurrence of psoriasis (PSO) and psoriatic arthritis (PSA). To evaluate biomolecules (inflammatory cytokines, inflammatory chemokines, cell adhesion and cellular mediators) in naïve patients with PSO, PSA with PSO, and PSA sine PSO. To stratify the results considering the presence of psoriatic nail involvement, extensive skin disease and obesity evaluating all involved patients. By multiplex technology, 20 serum biomolecules were assessed with the inclusion of pro-inflammatory cytokines (GM-CSF, IFN-γ, IL-1α, IL-1β, IL-6, IL-8, IL-12p70, IL-17A, IL-23, TNF), anti-inflammatory cytokines (IFN-α, IL-4, IL-10, IL-13), inflammatory chemokines (IP-10, MCP-1, MIP-1α, MIP-1β), cell adhesion and cellular mediators (ICAM-1, E-selectin, P-selectin). The assessment of possible statistical differences between the means of the three groups was performed by One-Way ANOVA. In addition, by non-parametric T-tests, we stratified the results according to selected clinical characteristics (psoriatic nail involvement, PASI ≥ 10, BMI ≥ 30). In 80 assessed naïve patients, patients with PSO showed significant increases of E-selectin (p=0.021) and IL-8 (0.041) than other groups. In patients with PSA with PSO, significant higher levels of ICAM-1 were observed (p=0.009) than other groups. We did not observe further differences comparing pro-inflammatory and anti-inflammatory cytokines, inflammatory chemokines, and cell adhesion and cellular mediators in patients with PSO, PSA with PSO, and PSA sine PSO. Patients with psoriatic onychopathy showed significant increased levels of ICAM-1 (p=0.010) and IP-10 (0.030) than others. In patients with PASI ≥ 10, significantly enhanced values of IL-8 (p=0.004), TNF (p=0.013), E-selectin (p=0.004), MIP-1α (p=0.003), and MIP-1β (p=0.039). In patients with BMI ≥ 30, significantly higher levels of E-selectin were pointed out (p=0.035) than others. Our findings may suggest that a similar cytokine profile may characterize naïve patients with PSO, PSA with PSO, and PSA sine PSO, reinforcing the concept of psoriatic disease continuum. However, some differences may be also shown, underlying possible pathogenic differences and leading to the clinical heterogeneity of these patients.

Several immune-related markers have been implicated in basal cell carcinoma (BCC) pathogenesis. The BCC inflammatory infiltrate is dominated by Th2 cytokines, suggesting a specific state of immunosuppression. In contrast, regressing BCC are characterized by a Th1 immune response with IFN-γ promoting a tumor suppressive activity. IL-23/Th17-related cytokines, as interleukin (IL)-17, IL-23 and IL-22, play a significant role in cutaneous inflammatory diseases, but their involvement in skin carcinogenesis is controversial and is poorly investigated in BCC. In this study we investigated the expression of IFN-γ, IL-17, IL-23 and IL-22 cytokines in BCC at the protein and mRNA level and their modulation during imiquimod (IMQ) treatment or photodynamic therapy (PDT). IFN-γ, IL-17, IL-23 and IL-22 levels were evaluated by immunohistochemistry and quantitative Real Time PCR in 41 histopathologically-proven BCCs (28 superficial and 13 nodular) from 39 patients. All BCC samples were analyzed at baseline and 19 of 41 also during medical treatment (9 with IMQ 5% cream and 10 with MAL-PDT). Association between cytokines expression and clinico-pathological variables was evaluated. Higher levels of IFN-γ, IL-17, IL-23 and IL-22 were found in BCCs, mainly in the peritumoral infiltrate, compared to normal skin, with the expression being correlated to the severity of the inflammatory infiltrate. IFN-γ production was higher in superficial BCCs compared to nodular BCCs, while IL-17 was increased in nodular BCCs. A significant correlation was found between IFN-γ and IL-17 expression with both cytokines expressed by CD4+ and CD8+ T-cells. An increase of all cytokines occurred during the inflammatory phase induced by IMQ and at the early time point of PDT treatment, with significant evidence for IFN-γ, IL-23, and IL-22. Our results confirm the role of IFN-γ and support the involvement of IL-23/Th17-related cytokines in BCC pathogenesis and in the inflammatory response during IMQ and MAL-PDT treatments.

A number of genes have been implicated in the pathogenesis of BCC in addition to the Hedgehog pathway, which is known to drive the initiation of this tumour. We performed in-depth analysis of 13 BCC-related genes ( CSMD1, CSMD2, DPH3 promote r, PTCH1, SMO, GLI1, NOTCH1, NOTCH2, TP53, ITIH2, DPP10, STEAP4, TERT promoter) in 57 BCC lesions (26 superficial and 31 nodular) from 55 patients and their corresponding blood samples. PTCH1 and TP53 mutations were found in 71.9% and 45.6% of BCCs, respectively. A high mutation rate was also detected in CSMD1 (63.2%), NOTCH1 (43.8%) and DPP10 (35.1%), and frequent non-coding mutations were identified in TERT (57.9%) and DPH3 promoter (49.1%). CSMD1 mutations significantly co-occurred with TP53 changes ( p  = 0.002). A significant association was observed between the superficial type of BCC and PTCH1 ( p  = 0.018) and NOTCH1 ( p  = 0.020) mutations. In addition, PTCH1 mutations were significantly associated with intermittent sun exposure ( p  = 0.046) and the occurrence of single lesions ( p  = 0.021), while NOTCH1 mutations were more frequent in BCCs located on the trunk compared to the head/neck and extremities ( p  = 0.001). In conclusion, we provide further insights into the molecular alterations underlying the tumorigenic mechanism of superficial and nodular BCCs with a view towards novel rationale-based therapeutic strategies.

The involvement of the neurotrophin network in pathological skin conditions, such as psoriasis or squamous cancer, by their common neurotrophin receptor CD271 has become recently evident. Depending on the specific ligand and co-receptor interacting with it, CD271 mediates various cellular responses in keratinocytes. In vitro analysis shows that it is implicated in the transition from human interfollicular keratinocyte stem cells to transient amplifying cells. However, no in vivo models are available to dissect the complexity of these mechanisms, including the effect on the inflammatory response. Here, we develop and characterize two novel mouse models, the CD271cKO and the CD271ciKO, where CD271 is conditionally absent in keratinocytes during development or after topical induction, respectively. By histology, functional assay, transcriptomics and molecular analysis, we identified substantial skin changes correlated to CD271 deletion, including epidermal hyperproliferation, “activated” keratinocyte signature, and a delayed in the differentiation process, mostly linked to PI3K/Akt and mitogenic pathways-dependent processes. KO keratinocyte displays upregulation of Ki67, PCNA, KRT5, KRT6, and ERK phosphorylation, as well as major expression of IL1α, Cxcl15, and TGFβ. KO skin resemble dysplastic skin conditions, including the recruitment of immune cells, particularly T cells, macrophages, and neutrophils, and release of inflammatory cytokines involved in TNF, JAK/Stat, IL17, and PI3k/Akt signaling pathways. Overall, our data defines CD271 as a crucial regulator of skin homeostasis. Therefore, our models represent an exceptionally useful tool for the characterization of skin pathophysiology linked to CD271 and possibly for developing appropriate therapies.

Introduction: An increased risk of developing vitiligo has recently been described in patients with atopic dermatitis (AD). Vitiligo and AD can be associated because of shared pathogenetic pathways, including alterations in the Janus kinases/signal transducer and activator of transcription (JAK/STAT) signaling, suggesting JAK inhibitors as a promising new therapeutic approach in vitiligo. Case Presentation: We describe a 25-year-old woman diagnosed with AD since childhood and subsequent onset of slowly progressive vitiligo at the age of 16. Systemic therapy with JAK1 inhibitor upadacitinib 15 mg daily was started, after a medical and laboratory evaluation to exclude pregnancy and other contraindications. Progressive improvement of AD was observed after the first weeks of treatment with clinical remission at week 16. At the same time, clear improvement of vitiligo was observed with an almost complete remission achieved at week 28 of treatment. Conclusion: The remission of both AD and vitiligo achieved with upadacitinib monotherapy supports the therapeutic utility of inhibition of JAK 1 signaling in these patients.