JAK3 as an emerging target for topical treatment of inflammatory skin diseases

The recent interest and elucidation of the JAK/STAT signaling pathway created new targets for the treatment of inflammatory skin diseases (ISDs). JAK inhibitors in oral and topical formulations have shown beneficial results in psoriasis and alopecia areata. Patients suffering from other ISDs might also benefit from JAK inhibition. Given the development of specific JAK inhibitors, the expression patterns of JAKs in different ISDs needs to be clarified. We aimed to analyze the expression of JAK/STAT family members in a set of prevalent ISDs: psoriasis, lichen planus (LP), cutaneous lupus erythematosus (CLE), atopic dermatitis (AD), pyoderma gangrenosum (PG) and alopecia areata (AA) versus healthy controls for (p) JAK1, (p) JAK2, (p) JAK3, (p) TYK2, pSTAT1, pSTAT2 and pSTAT3. The epidermis carried in all ISDs, except for CLE, a strong JAK3 signature. The dermal infiltrate showed a more diverse expression pattern. JAK1, JAK2 and JAK3 were significantly overexpressed in PG and AD suggesting the need for pan-JAK inhibitors. In contrast, psoriasis and LP showed only JAK1 and JAK3 upregulation, while AA and CLE were characterized by a single dermal JAK signal (pJAK3 and pJAK1, respectively). This indicates that the latter diseases may benefit from more targeted JAK inhibitors. Our in vitro keratinocyte psoriasis model displayed reversal of the psoriatic JAK profile following tofacitinib treatment. This direct interaction with keratinocytes may decrease the need for deep skin penetration of topical JAK inhibitors in order to exert its effects on dermal immune cells. In conclusion, these results point to the important contribution of the JAK/STAT pathway in several ISDs. Considering the epidermal JAK3 expression levels, great interest should go to the investigation of topical JAK3 inhibitors as therapeutic option of ISDs

Interpersonal problems and cognitive characteristics of interpersonal representations in Alexithymia: a study using a self-report and interview-based measure of Alexithymia

In this study, associations between alexithymia, interpersonal problems, and cognitive-structural aspects of internal interpersonal representations were examined. Alexithymia was measured using the Toronto Structured Interview for Alexithymia (TSIA) and the 20-item Toronto Alexithymia Scale (TAS-20). To measure interpersonal problems, the dominance and affiliation dimension scores of the Inventory of Interpersonal Problems were used, and cognitive-structural characteristics of interpersonal representations were measured using the Social Cognition and Object Relations Scale (SCORS). As hypothesized, alexithymia was related to cold and withdrawn, but not to dominant or submissive, interpersonal functioning. In terms of the SCORS, alexithymia was negatively related to complexity of interpersonal representations, both in TAT and in interview narratives, indicating a link between alexithymia and mentalization. However, alexithymia was related only to the dimension of social causality when this dimension was scored on TAT narratives. Overall, the TSIA provides the most consistent and stable results after controlling for negative affectivity

Is the uptake, engagement, and effectiveness of exclusively mobile interventions for the promotion of weight-related behaviors equal for all? A systematic review

Mobile health interventions are promising behavior change tools. However, there is a concern that they may benefit some populations less than others and thus widen inequalities in health. This systematic review investigated differences in uptake of, engagement with, and effectiveness of mobile interventions for weight-related behaviors (i.e., diet, physical activity, and sedentary behavior) based on a range of inequality indicators including age, gender, race/ethnicity, and socioeconomic status. The protocol was registered on PROSPERO (CRD42020192473). Six databases (CINAHL, EMBASE, ProQuest, PsycINFO, Pubmed, and Web of Science) were searched from inception to July 2021. Publications were eligible for inclusion if they reported the results of an exclusively mobile intervention and examined outcomes by at least one inequality indicator. Sixteen publications reporting on 13 studies were included with most reporting on multiple behaviors and inequality indicators. Uptake was investigated in one study with no differences reported by the inequality indicators studied. Studies investigating engagement (n = 7) reported differences by age (n = 1), gender (n = 3), ethnicity (n = 2), and education (n = 2), while those investigating effectiveness (n = 9) reported differences by age (n = 3), gender (n = 5), education (n = 2), occupation (n = 1), and geographical location (n = 1). Given the limited number of studies and their inconsistent findings, evidence of the presence of a digital divide in mobile interventions targeting weight-related behaviors is inconclusive. Therefore, we recommend that inequality indicators are specifically addressed, analyzed, and reported when evaluating mobile interventions

Topically applied lipid- and surfactant-based nanoparticles in the treatment of skin disorders

Introduction: In the treatment of dermatological disorders, topical drug administration is a mainstay. However, nanoparticle-based carrier systems could improve and expand the current therapeutic range via localized delivery of active ingredients. Areas covered: This review gives a detailed description of lipid-and surfactant-based drug delivery systems which have been explored for topical drug administration. To guide researchers in their choice of delivery system, an informative decision tree is included. Moreover, this review provides a complete overview of the topical or transdermal drug products, currently on the market or under clinical investigation, delivered via the discussed carriers, in the treatment of skin disorders. Expert opinion: Conventional liposomes are still popular in the domain of topical or transdermal drug delivery and dominate the market landscape. However, several other carriers, such as exosomes and niosomes, are being explored which offer distinct advantages over liposomes and should therefore not be disregarded when selecting a proper drug delivery system

In vitro psoriasis models with focus on reconstructed skin models as promising tools in psoriasis research

Psoriasis is a complex chronic immune-mediated inflammatory cutaneous disease associated with the development of inflammatory plaques on the skin. Studies proved that the disease results from a deregulated interplay between skin keratinocytes, immune cells and the environment leading to a persisting inflammatory process modulated by pro-inflammatory cytokines and activation of T cells. However, a major hindrance to study the pathogenesis of psoriasis more in depth and subsequent development of novel therapies is the lack of suitable pre-clinical models mimicking the complex phenotype of this skin disorder. Recent advances in and optimization of three-dimensional skin equivalent models have made them attractive and promising alternatives to the simplistic monolayer cultures, immunological different invivo models and scarce ex vivo skin explants. Moreover, human skin equivalents are increasing in complexity level to match human biology as closely as possible. Here, we critically review the different types of three-dimensional skin models of psoriasis with relevance to their application potential and advantages over other models. This will guide researchers in choosing the most suitable psoriasis skin model for therapeutic drug testing (including gene therapy via siRNA molecules), or to examine biological features contributing to the pathology of psoriasis. However, the addition of T cells (as recently applied to a de-epidermized dermis-based psoriatic skin model) or other immune cells would make them even more attractive models and broaden their application potential. Eventually, the ultimate goal would be to substitute animal models by three-dimensional psoriatic skin models in the pre-clinical phases of anti-psoriasis candidate drugs

The assessment of the social cognition and object relations scale on TAT and interview data

This study examines the reliability and convergent validity of 2 versions of the Social Cognition and Object Relations Scale (SCORS), one for use with Thematic Apperception Test narratives (SCORS-TAT; Westen, 1990) and one for use with clinical interview data (SCORS-CDI; Westen, Barends, Leigh, Mendel, & Silbert, 1990 ). Four SCORS dimensions were evaluated. Data were collected in a psychiatric sample (N = 74). Results show that although interrater reliability was good for all dimensions, internal consistency was low, especially for the affective dimensions. Structural equation modeling, in which a model with 2 factors (i.e., SCORS-TAT and SCORS-CDI) and 4 dimensions each was tested, indicated low convergence between corresponding dimensions of SCORS-TAT and SCORS-CDI. Correlational analyses suggested that this was due to a strong method factor. Regression analyses, however, revealed that the presence of a personality disorder operated as a moderator for convergence between corresponding cognitive-structural dimensions

The combined bone forming capacity of human periosteal derived cells and calcium phosphates.

Current knowledge suggests that the periosteum, a fibrous tissue which covers the surface of all bones, contains a population of progenitor cells which mediate the repair of bone defects. In an effort to optimise the utilisation of this source of cells for bone engineering, herein we describe the rational selection of calcium phosphate (CaP) containing materials, based on biomaterial properties, and evaluation of their combined bone forming capacity. Five different commercially available orthopaedic 3D matrices composed of CaP particles in an open collagen network (NuOss, CopiOs, Bio-Oss((R)), Collagraft and Vitoss((R))) were evaluated in vitro and in vivo with human periosteal derived cells (hPDCs). It was found that the cell-material combinations behaved quite differently in vivo, despite apparent in vitro similarities in gene expression profiles. Bone formation was highest within the NuOss/hPDC implant at 13.03%, which also contained the highest incidence of bone marrow formation. The bone formed in this implant was chimeric with approximately 65% originating from implanted cells. Upon analysis of human specific gene expression, although it was found that predominantly osteogenic differentiation was observed within NuOss/hPDC implants, a lesser induction of chondrogenic genes was also observed. The formation of a cartilage intermediate was confirmed by histology. Additionally the NuOss/hPDC implant integrated into the mouse environment with apparent active scaffold resorption. This study demonstrates the importance of matching a cell support/biological matrix with a cell type and subsequently has outlined parameters which can be used for the rational selection of biomaterials for bone engineering

Is the uptake, engagement, and effectiveness of exclusively mobile interventions for the promotion of weight-related behaviors equal for all? A systematic review.

Funder: Hull York Medical School; Id: http://dx.doi.org/10.13039/100017819Mobile health interventions are promising behavior change tools. However, there is a concern that they may benefit some populations less than others and thus widen inequalities in health. This systematic review investigated differences in uptake of, engagement with, and effectiveness of mobile interventions for weight-related behaviors (i.e., diet, physical activity, and sedentary behavior) based on a range of inequality indicators including age, gender, race/ethnicity, and socioeconomic status. The protocol was registered on PROSPERO (CRD42020192473). Six databases (CINAHL, EMBASE, ProQuest, PsycINFO, Pubmed, and Web of Science) were searched from inception to July 2021. Publications were eligible for inclusion if they reported the results of an exclusively mobile intervention and examined outcomes by at least one inequality indicator. Sixteen publications reporting on 13 studies were included with most reporting on multiple behaviors and inequality indicators. Uptake was investigated in one study with no differences reported by the inequality indicators studied. Studies investigating engagement (n = 7) reported differences by age (n = 1), gender (n = 3), ethnicity (n = 2), and education (n = 2), while those investigating effectiveness (n = 9) reported differences by age (n = 3), gender (n = 5), education (n = 2), occupation (n = 1), and geographical location (n = 1). Given the limited number of studies and their inconsistent findings, evidence of the presence of a digital divide in mobile interventions targeting weight-related behaviors is inconclusive. Therefore, we recommend that inequality indicators are specifically addressed, analyzed, and reported when evaluating mobile interventions

Targeted silencing of DEFB4 in a bioengineered skin-humanized mouse model for psoriasis: development of siRNA SECosome-based novel therapies

Psoriasis is a complex inflammatory skin disease that presents a wide variety of clinical manifestations. Human β defensin-2 (hBD-2) is highly up-regulated in psoriatic lesions and has been defined as a biomarker for disease activity. We explored the potential benefits of targeting hBD-2 by topical application of DEFB4-siRNA-containing SECosomes in a bioengineered skin-humanized mouse model for psoriasis. A significant improvement in the psoriatic phenotype was observed by histological examination, with a normalization of the skin architecture and a reduction in the number and size of blood vessels in the dermal compartment. Treatment leads to the recovery of transglutaminase activity, filaggrin expression and stratum corneum appearance to the levels similar to those found in normal regenerated human skin. The availability of a reliable skin-humanized mouse model for psoriasis in conjunction with the use of the SECosome technology may provide a valuable preclinical tool for identifying potential therapeutic targets for this disease