Primary cutaneous malignancies in the Northern Cape Province of South Africa: A retrospective histopathological review

Background. Excessive sun exposure and a high prevalence of HIV increase skin cancer risk in South Africa (SA).Objective. To describe the nature and extent of skin cancers presenting in the public and private health sectors of the Northern Cape Province of SA.Methods. A retrospective analysis of histologically confirmed new primary cutaneous malignancies from 1 January 2008 to 31 December 2012 was conducted using public and private health sector databases. Types, quantity and distribution of common invasive malignancies by population group, age, gender, anatomical site and health sector were explored. One-year cumulative incidence was calculated and logistic regression models were used to analyse incidence and melanoma thickness trends.Results. A total of 4 270 biopsies (13 cutaneous malignancies) were identified. The commonest was squamous cell carcinoma (SCC), followed by basal cell carcinoma, Kaposi’s sarcoma (KS), cutaneous malignant melanoma (CMM) and basosquamous carcinoma, in descending order. The odds of a white male developing SCC increased by 8% each year (odds ratio (OR) 1.08, 95% confidence interval (CI) 1.01 - 1.15; p=0.022), while the odds of a black male developing SCC and KS decreased by 9% (OR 0.91, 95% CI 0.84 - 0.99; p=0.033) and 18% (OR 0.82, 95% CI 0.70 - 0.97; p=0.022), respectively, each year. SCC and CMM were diagnosed at more advanced stages in the public than in the private healthcare sector. CMM is being detected earlier, as indicated by low-stage depth increasing by 72% annually (OR 1.72, 95% CI 1.04 - 3.01; p=0.042).Conclusions. Results suggest that reported skin cancer patterns are changing. There is a need for further research and equitable appropriation of financial resources and effort towards developing primary skin cancer prevention initiatives in SA

Radical-induced purine lesion formation is dependent on DNA helical topology

AbstractHerein we report the quantification of purine lesions arising from gamma-radiation sourced hydroxyl radicals (HO•) on tertiary dsDNA helical forms of supercoiled (SC), open circular (OC), and linear (L) conformation, along with single-stranded folded and non-folded sequences of guanine-rich DNA in selected G-quadruplex structures. We identify that DNA helical topology and folding plays major, and unexpected, roles in the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) and 8-oxo-7,8-dihydro-2'-deoxyadenosine (8-oxo-dA), along with tandem-type purine lesions 5′,8-cyclo-2′-deoxyguanosine (5′,8-cdG) and 5′,8-cyclo-2′-deoxyadenosine (5′,8-cdA). SC, OC, and L dsDNA conformers together with folded and non-folded G-quadruplexes d[TGGGGT]4 (TG4T), d[AGGG(TTAGGG)3] (Tel22), and the mutated tel24 d[TTGGG(TTAGGG)3A] (mutTel24) were exposed to HO• radicals and purine lesions were then quantified via stable isotope dilution LC-MS/MS analysis. Purine oxidation in dsDNA follows L > OC ≫ SC indicating ..

A novel DLX3-PKC integrated signaling network drives keratinocyte differentiation

Epidermal homeostasis relies on a well-defined transcriptional control of keratinocyte proliferation and differentiation, which is critical to prevent skin diseases such as atopic dermatitis, psoriasis or cancer. We have recently shown that the homeobox transcription factor DLX3 and the tumor suppressor p53 co-regulate cell cycle-related signaling and that this mechanism is functionally involved in cutaneous squamous cell carcinoma development. Here we show that DLX3 expression and its downstream signaling depend on protein kinase C alpha (PKC alpha) activity in skin. We found that following 12-O-tetradecanoyl-phorbol-13-acetate (TPA) topical treatment, DLX3 expression is significantly upregulated in the epidermis and keratinocytes from mice overexpressing PKC alpha by transgenic targeting (K5-PKC alpha), resulting in cell cycle block and terminal differentiation. Epidermis lacking DLX3 (DLX3cKO), which is linked to the development of a DLX3-dependent epidermal hyperplasia with hyperkeratosis and dermal leukocyte recruitment, displays enhanced PKC alpha activation, suggesting a feedback regulation of DLX3 and PKC alpha. Of particular significance, transcriptional activation of epidermal barrier, antimicrobial peptide and cytokine genes is significantly increased in DLX3cKO skin and further increased by TPA-dependent PKC activation. Furthermore, when inhibiting PKC activity, we show that epidermal thickness, keratinocyte proliferation and inflammatory cell infiltration are reduced and the PKC-DLX3-dependent gene expression signature is normalized. Independently of PKC, DLX3 expression specifically modulates regulatory networks such as Wnt signaling, phosphatase activity and cell adhesion. Chromatin immunoprecipitation sequencing analysis of primary suprabasal keratinocytes showed binding of DLX3 to the proximal promoter regions of genes associated with cell cycle regulation, and of structural proteins and transcription factors involved in epidermal differentiation. These results indicate that Dlx3 potentially regulates a set of crucial genes necessary during the epidermal differentiation process. Altogether, we demonstrate the existence of a robust DLX3-PKC alpha signaling pathway in keratinocytes that is crucial to epidermal differentiation control and cutaneous homeostasis

The effectiveness of psychological interventions delivered in routine practice: systematic review and meta-analysis

This review presents a comprehensive evaluation of the effectiveness of routinely delivered psychological therapies across inpatient, outpatient and University-based clinics. This was a pre-registered systematic-review of studies meeting pre-specified inclusion criteria (CRD42020175235). Eligible studies were searched in three databases: MEDLINE, CINAHL and PsycInfo. Pre–post treatment (uncontrolled) effect sizes were calculated and pooled using random effects meta-analysis to generate effectiveness benchmarks. Moderator analyses were used to examine sources of heterogeneity in effect sizes. Overall, 252 studies (k = 298 samples) were identified, of which 223 (k = 263 samples) provided sufficient data for inclusion in meta-analysis. Results showed large pre–post treatment effects for depression [d = 0.96, (CI 0.88–1.04), p ≤ 0.001, k = 122], anxiety [d = 0.8 (CI 0.71–0.9), p ≤ 0.001, k = 69], and other outcomes [d = 1.01 (CI 0.93–1.09), p ≤ 0.001, k = 158]. This review provides support for the effectiveness of routinely delivered psychological therapy. Effectiveness benchmarks are supplied to support service evaluations across multiple settings

Types and mechanisms of idiographic change during guided self‐help for anxiety

Objectives To compare idiographic change during two formats of guided self-help (GSH); cognitive-behavioural therapy guided self-help (CBT-GSH) and cognitive analytic therapy guided self-help (CAT-GSH). Design Qualitative inductive thematic analysis. Methods Semi-structured interviews with N = 17 participants with a reliable change outcome on the GAD-7 after completing GSH for anxiety. Changes were categorised and themes extracted. Results No differences between CAT-GSH and CBT-GSH were found regarding types of change reported. The five overarching themes found were personal qualities of success, enlightenment through understanding, specific tools and techniques, changes to relationships and tailoring support. Four themes maximally differentiated between the two different types of GSH; CAT-GSH enabled relational insight and change whilst CBT-GSH enabled better understanding of anxiety, new coping techniques and supportive relationships. Conclusions Both common and model-specific factors contribute to patient change during GSH. Whilst all forms of GSH are grounded in the psychoeducational approach, separate theoretical foundations and associated methods facilitate different types of ideographic change