British Journal of Dermatology最新文献

Background: Poor adherence to photoprotection in Xeroderma Pigmentosum (XP) increases morbidity and shortens lifespan due to skin cancers.

Objective: To test a highly personalised intervention (XPAND) to reduce the dose of ultraviolet radiation (UVR) reaching the face in adults with XP, designed using known psychosocial determinants of poor photoprotection.

Methods: A two-arm parallel group randomised controlled trial, including patients with sub-optimal photoprotection to receive XPAND or a delayed intervention control arm that received XPAND the following year. XPAND comprises seven one-to-one sessions targeting photoprotection barriers (e.g., misconceptions about UVR) supported by personalised text messages, activity sheets, and educational materials incorporating behaviour change techniques. The primary outcome, mean daily UVR dose-to-face across 21 days in June-July 2018, was calculated by combining UVR exposure at the wrist with a face photoprotection activity diary. Secondary outcomes were UVR dose-to-face across 21 days in August 2018, time spent outside, photoprotective measures used outside, mood, automaticity, confidence-to-photoprotect. Financial costs and quality-adjusted life years (QALYs) were calculated.

Results: 16 patients were randomised, 13 provided sufficient data for primary outcome analysis. The XPAND group (n=8) had lower mean daily UVR dose-to-face [0.03 SED (SD 0.02] compared to control (n=7) [0.36 SED (SD 0.16)] (adjusted difference=-0.25, p<0.001, Hedge's g=2.2). No significant between-group differences were observed in time spent outside, photoprotection outside, mood, or confidence. The delayed intervention control showed improvements in UVR dose-to-face (adjusted difference=-0.05, Hedge's g=-0.1) , time outside (adjusted difference=-69.9, Hedge's g=-0.28), and photoprotection (adjusted difference=-0.23, Hedge's g=0.45), after receiving XPAND. XPAND was associated with lower treatment costs (£-2642; 95% CI: -£8715 to £3873) and fewer QALYs (-0.0141; 95% CI: -0.0369 to 0.0028).

Conclusions: XPAND was associated with a lower UVR dose-to-face in XP patients and was cost-effective.

Background: Air pollution and genetic risk have been found to contribute to both onset and development of psoriasis. However, the extent to which genetic susceptibility modifies the effects of air pollutants on the risk of incident psoriasis remains unknown.

Objectives: Our study aimed to assess the association between joint exposure to multiple air pollutants and the risk of psoriasis and the modification by the genetic susceptibility.

Methods: This prospective study included 451,064 participants with complete air pollution data and free of psoriasis at baseline from the UK Biobank. All participants were enrolled from 2006 to 2010 and followed up to 2022. The air pollution score (APS) was calculated to assess the joint exposure to multiple air pollutants, including particulate matter (PM) with diameters ≤ 2.5 μm (PM2.5), between 2.5 and 10 μm (PM2.5-10), and ≤ 10 μm (PM10), as well as nitrogen dioxide (NO2) and nitrogen oxides (NOx). To evaluate the genetic risk, the polygenic risk score (PRS) for psoriasis was constructed. The Cox proportional hazard models were used to assess the association of air pollution and genetic susceptibility with the risk of psoriasis. Stratified analyses were conducted based on the individual characteristics.

Results: During a median follow-up of 13.79 years, 4414 psoriasis events were recorded. The hazard ratios (HRs) [95% confidence intervals (CIs)] for psoriasis were 1.036 (0.936-1.147), 1.091 (0.987-1.206), 1.159 (1.048-1.283), and 1.163 (1.052-1.286) in higher quintile groups compared with the lowest quintile of APS (P trend <0.05). When considering genetic susceptibility, participants with high PRS and high APS had the greatest risk of incident psoriasis [HR (95% CI): 1.962 (1.630-2.362)] than those with low PRS and low APS. The HRs (95% CIs) for PM2.5-10, NOx, PM2.5 absorbance, PM2.5, NO2, and PM10 in the group with high exposure level and genetic risk were 1.831 (1.537-2.181), 1.722 (1.431-2.073), 1.698 (1.416-2.037), 1.619 (1.353-1.938), 1.504 (1.252-1.806), and 1.425 (1.192-1.704), respectively.

Conclusions: Long-term exposure to various air pollutants is positively associated with an increased risk of incident psoriasis, particularly in individuals with high genetic risk. More comprehensive measures are needed to reduce the air pollution levels for better prevention of psoriasis.

Background: Cutaneous leiomyosarcoma (cLMS) is a rare soft tissue neoplasm, showing smooth muscle differentiation, that arises from the mesenchymal cells of the dermis. To-date, genetic investigation of these tumours has involved studies with small sample sizes and limited analyses that identified recurrent somatic mutations in RB1 and TP53, copy number gain of MYCOD and IGF1R, and copy number loss of PTEN.

Objectives: To better understand the molecular pathogenesis of cLMS, we comprehensively explored the mutational landscape of these rare tumours to identify candidate driver events.

Methods: In this retrospective, multi-institutional study, we performed whole-exome sequencing and RNA sequencing on 38 cases of cLMS.

Results: TP53 and RB1 were identified as significantly mutated, thus, represent validated driver genes of cLMS. COSMIC mutational signatures SBS7a/b and DBS1 were recurrent, thus, ultraviolet light exposure may be an aetiological factor driving cLMS. Analysis of significantly recurrent somatic copy number alterations, which represent candidate driver events, found focal (<10Mb) deletions encompassing TP53 and KDM6B, and amplifications encompassing ZMYM2, MYOCD, MAP2K4 and NCOR1. A larger (24 Mb) recurrent deletion encompassing CYLD was also identified as significant. Significantly recurrent broad copy number alterations, involving at least half of a chromosome arm, included deletions of 6p/q, 10p/q, 11q, 12q, 13q and 16p/q, and amplification of 15q. Notably PTEN is located on 10q, RB1 on 13q and IGFR1 on 15q. Fusion gene analysis identified recurrent CRTC1/3::MAML2 fusions, as well as many novel fusions in individual samples.

Conclusions: Our analysis of the largest number of cLMS cases to-date highlights the importance of large cohort sizes and the exploration beyond small targeted gene panels when performing molecular analyses, as it allowed a comprehensive exploration of the mutational landscape of these tumours and identification of novel candidate driver events. It also uniquely afforded the opportunity to compare the molecular phenotype of cLMS with LMS of other tissue types, such as uterine and soft tissue LMS. Given that molecular profiling has resulted in the development of novel targeted treatment approaches for uterine and soft tissue LMS, our study now allows the same opportunities to become available for patients with cLMS.

Background: Keloid is a dermal fibrotic disorder characterised by excessive extracellular matrix production by fibroblasts. Despite the significance of mechanostimulation in fibrotic diseases, its association with keloid pathophysiology or treatment remains unexplored.

Objective: We investigated the role of mechanical force in keloid formation and elucidated the significance of Rho-associated coiled-coil-containing kinase 1 (ROCK1) as a mechanoresponsive target for keloid treatment.

Methods: Patient-derived keloid fibroblasts (KFs) were subjected to cyclic stretching ranging from 0 to 20% elongation using a cell-stretching system. We observed the inhibitory effects of the ROCK1 inhibitor Y27632 on KFs and keloid formation. Validation was performed using keloid xenograft severe combined immune-deficient (SCID) mouse model.

Results: ROCK1 was overexpressed in KFs isolated from patients. Cyclic stretching induced fibroblast proliferation and actin polymerisation by activating Rho/ROCK1 signalling. Treatment with Y27632 downregulated fibrotic markers, reduced the migration capacity of KFs, and induced extensive actin cytoskeleton remodelling. In keloid xenograft SCID mouse model, Y27632 effectively suppressed keloid formation, mitigating inflammation and fibrosis.

Conclusions: The ROCK1 inhibitor Y27632 is a promising molecule for keloid treatment, exerting its effects through actin cytoskeleton remodelling and nuclear inhibition of fibrotic markers in keloid pathogenesis.