The Global Guidelines in Dermatology Mapping Project (GUIDEMAP) assesses the methodological quality of clinical practice guidelines (CPGs) for high-burden skin diseases. This review focuses on... Show moreThe Global Guidelines in Dermatology Mapping Project (GUIDEMAP) assesses the methodological quality of clinical practice guidelines (CPGs) for high-burden skin diseases. This review focuses on contact dermatitis. We searched MEDLINE, Embase, PubMed, Web of Science, Cochrane Library, Emcare, Epistemonikos, PsycINFO and Academic Search Premier for CPGs published between 1 November 2018 and 1 November 2023. Prespecified guideline resources were hand searched. Two authors independently undertook screening, data extraction and quality assessments. Instruments used were the Appraisal of Guidelines for Research and Evaluation (AGREE) II Reporting Checklist, the U.S. Institute of Medicine's (IOM) criteria of trustworthiness, The Agency for Healthcare Research and Quality's National Guideline Clearinghouse Extent Adherence to Trustworthy Standards (NEATS) Instrument and Lenzer's Red Flags. Twenty five CPGs were included, exhibiting heterogeneity in both the topics they addressed and their methodological quality. Whereas the CPGs on management of hand eczema from Denmark, Europe and the Netherlands scored best, most CPGs fell short of being clear, unbiased, trustworthy and evidence-based. Disclosure of conflicts of interest scored well, and areas needing improvement include ‘strength and wording of recommendations’, ‘applicability’, ‘updating’ and ‘external review’. Adhering to AGREE II and Grading of Recommendations, Assessment, Development and Evaluations (GRADE) enhances methodological quality. Show less
Scheuplein, M.; Vermeulen, S.; van Harmelen, A.L.; Alink, L. 2023
It is estimated that up to 25% of all children growing up worldwide experience child maltreatment, making it a global emergency with substantial individual and public health consequences. This... Show moreIt is estimated that up to 25% of all children growing up worldwide experience child maltreatment, making it a global emergency with substantial individual and public health consequences. This chapter addresses one of the most societally pervasive consequences of child maltreatment which is known as the "cycle of victimization." This concept depicts the increased risk of maltreated individuals to victimize others later in life, both within and outside the family environment. To understand the architecture of this victimization cycle, the chapter further sheds light on neurocognitive mechanisms aiding different forms of victimization and the buffering role of social support that could help break the cycle of victimization. Advancing our understanding of these complex and interrelated mechanisms will ultimately facilitate the design and implementation of more targeted early treatments and (preventive) interventions and support a move toward a safer society. Show less
PurposeBRCA-deficient breast cancers (BC) are highly sensitive to platinum-based chemotherapy and PARP inhibitors due to their deficiency in the homologous recombination (HR) pathway. However, HR... Show morePurposeBRCA-deficient breast cancers (BC) are highly sensitive to platinum-based chemotherapy and PARP inhibitors due to their deficiency in the homologous recombination (HR) pathway. However, HR deficiency (HRD) extends beyond BRCA-associated BC, highlighting the need for a sensitive method to enrich for HRD tumors in an alternative way. A promising approach is the use of functional HRD tests which evaluate the HR capability of tumor cells by measuring RAD51 protein accumulation at DNA damage sites. This study aims to evaluate the performance of a functional RAD51-based HRD test for the identification of HRD BC.MethodsThe functional HR status of 63 diagnostic formalin-fixed paraffin-embedded (FFPE) BC samples was determined by applying the RAD51-FFPE test. Samples were screened for the presence of (epi)genetic defects in HR and matching tumor samples were analyzed with the RECAP test, which requires ex vivo irradiated fresh tumor tissue on the premise that the HRD status as determined by the RECAP test faithfully represented the functional HR status.ResultsThe RAD51-FFPE test identified 23 (37%) of the tumors as HRD, including three tumors with pathogenic variants in BRCA1/2. The RAD51-FFPE test showed a sensitivity of 88% and a specificity of 76% in determining the HR-class as defined by the RECAP test.ConclusionGiven its high sensitivity and compatibility with FFPE samples, the RAD51-FFPE test holds great potential to enrich for HRD tumors, including those associated with BRCA-deficiency. This potential extends to situations where DNA-based testing may be challenging or not easily accessible in routine clinical practice. This is particularly important considering the potential implications for treatment decisions and patient stratification. Show less
Vermeulen, S.; Scheuplein, M.; Harmelen, A.L. van; Alink, L.R.A. 2023
Cancer risk after ionizing radiation (IR) is assumed to be linear with the dose; however, for low doses, definite evidence is lacking. Here, using temporal multi-omic systems analyses after a low ... Show moreCancer risk after ionizing radiation (IR) is assumed to be linear with the dose; however, for low doses, definite evidence is lacking. Here, using temporal multi-omic systems analyses after a low (LD; 0.1 Gy) or a high (HD; 1 Gy) dose of X-rays, we show that, although the DNA damage response (DDR) displayed dose proportionality, many other molecular and cellular responses did not. Phosphoproteomics uncovered a novel mode of phospho-signaling via S12-PPP1R7, and large-scale dephosphorylation events that regulate mitotic exit control in undamaged cells and the G2/M checkpoint upon IR in a dose-dependent manner. The phosphoproteomics of irradiated DNA double-strand breaks (DSBs) repair-deficient cells unveiled extended phospho-signaling duration in either a dose-dependent (DDR signaling) or independent (mTOR-ERK-MAPK signaling) manner without affecting signal magnitude. Nascent transcriptomics revealed the transcriptional activation of genes involved in NRF2-regulated antioxidant defense, redox-sensitive ERK-MAPK signaling, glycolysis and mitochondrial function after LD, suggesting a prominent role for reactive oxygen species (ROS) in molecular and cellular responses to LD exposure, whereas DDR genes were prominently activated after HD. However, how and to what extent the observed dose-dependent differences in molecular and cellular responses may impact cancer development remain unclear, as the induction of chromosomal damage was found to be dose-proportional (10-200 mGy). Show less
Background Clinical practice guidelines (CPGs) are essential in delivering optimum healthcare, such as for atopic dermatitis (AD), a highly prevalent skin disease. Although many CPGs are available... Show moreBackground Clinical practice guidelines (CPGs) are essential in delivering optimum healthcare, such as for atopic dermatitis (AD), a highly prevalent skin disease. Although many CPGs are available for AD, their quality has not been critically appraised.Objectives To identify CPGs on AD worldwide and to assess with validated instruments whether those CPGs are clear, unbiased, trustworthy and evidence based (CUTE).Methods We searched MEDLINE, Embase, PubMed, Web of Science, Cochrane Library, Emcare, Epistemonikos, PsycINFO and Academic Search Premier for CPGs on AD published between 1 April 2016 and 1 April 2021. Additionally we hand searched prespecified guideline resources. Screening, data extraction and quality assessment of eligible guidelines were independently carried out by two authors. Instruments used for quality assessment were the AGREE II Reporting Checklist, the US Institute of Medicine (IOM) criteria of trustworthiness and Lenzer's Red Flags.Results Forty CPGs were included, mostly from countries with a high sociodemographic index. The reporting quality varied enormously. Three CPGs scored 'excellent' on all AGREE II domains and three scored 'poor' on all domains. We found no association between AGREE II scores and a country's gross domestic product. One CPG fully met all nine IOM criteria and two fully met eight. Three CPGs had no red flags. 'Applicability' and 'rigour of development' were the lowest scoring AGREE II domains; 'external review', 'updating procedures' and 'rating strength of recommendations' were the IOM criteria least met; and most red flags were for 'limited or no involvement of methodological expertise' and 'no external review'. Management of conflicts of interest (COIs) appeared challenging. When constructs of the instruments overlapped, they showed high concordance, strengthening our conclusions.Conclusions Overall, many CPGs are not sufficiently clear, unbiased, trustworthy or evidence based (CUTE) and lack applicability. Therefore improvement is warranted, for which using the AGREE II instrument is recommended. Some improvements can be easily accomplished through robust reporting. Others, such as transparency, applicability, evidence foundation and managing COIs, might require more effort. Show less
Rosacea is a chronic inflammatory dermatosis mainly affecting the cheeks, nose, chin, and forehead. Rosacea is characterized by recurrent episodes of flushing or transient erythema, persistent... Show moreRosacea is a chronic inflammatory dermatosis mainly affecting the cheeks, nose, chin, and forehead. Rosacea is characterized by recurrent episodes of flushing or transient erythema, persistent erythema, phymatous changes, papules, pustules, and telangiectasia. The eyes may also be involved. Due to rosacea affecting the face, it has a profound negative impact on quality of life, self-esteem, and well-being. In addition to general skin care, there are several approved treatment options available for addressing these features, both topical and systemic. For some features, intense pulse light, laser, and surgery are of value. Recent advances in fundamental scientific research have underscored the roles of the innate and adaptive immune systems as well as neurovascular dysregulation underlying the spectrum of clinical features of rosacea. Endogenous and exogenous stimuli may initiate and aggravate several pathways in patients with rosacea. This review covers the new phenotype-based diagnosis and classification system reflecting pathophysiology, and new and emerging treatment options and approaches. We address new topical and systemic formulations, as well as recent evidence on treatment combinations. In addition, ongoing studies investigating novel therapeutic interventions will be summarized. Show less
We previously found that surface topographies induce the expression of the Scxa gene, encoding Scleraxis in tenocytes. Because Scxa is a TGF-beta responsive gene, we investigated the link between... Show moreWe previously found that surface topographies induce the expression of the Scxa gene, encoding Scleraxis in tenocytes. Because Scxa is a TGF-beta responsive gene, we investigated the link between mechanotransduction and TGF-beta signaling. We discovered that mesenchymal stem cells exposed to both micro-topographies and TGF-beta 2 display synergistic induction of SMAD phosphorylation and transcription of the TGF-beta target genes SCX, alpha-SMA, and SOX9. Pharmacological perturbations revealed that Rho/ROCK/SRF signaling is required for this synergistic response. We further found an activation of the early response genes SRF and EGR1 during the early adaptation phase on micro-topographies, which coincided with higher expression of the TGF-beta type II receptor gene. Of interest, PKC activators Prostratin and Ingenol-3, known for inducing actin reorganization and activation of serum response elements, were able to mimic the topography-induced TGF-beta response. These findings provide novel insights into the convergence of mechanobiology and TGF-beta signaling, which can lead to improved culture protocols and therapeutic applications. Show less
The sensitivity to PARP inhibitors (PARPi) is related to tumor-specific defects in homologous recombination (HR) and extends beyond BRCA1/2-related deficiencies. A robust method to identify HR... Show moreThe sensitivity to PARP inhibitors (PARPi) is related to tumor-specific defects in homologous recombination (HR) and extends beyond BRCA1/2-related deficiencies. A robust method to identify HR-deficient (HRD) carcinomas is therefore of utmost clinical importance. In this study, we evaluated the use of a functional test (the RECAP test) for the identification of HRD ovarian carcinomas. Forty-nine epithelial ovarian carcinomas (EOC) were analyzed by the RECAP test. Thirty-nine of these tumors were of the high-grade serous (HGSOC) histologic subtype. Ten out of these 39 HGSOC specimens showed HRD (26%), whereas ovarian carcinomas of other histologic subtypes (n = 10) were all HR-proficient (HRP). Eight out of 9 sequenced HRD tumors showed pathogenic BRCA1/2 variants or BRCA1 promoter hypermethylation. This study shows that the RECAP test is a reliable and rapid test to identify functional deficiencies in HR and a good alternative to DNA-based HRD tests.Recent studies have shown that the efficacy of PARP inhibitors in epithelial ovarian carcinoma (EOC) is related to tumor-specific defects in homologous recombination (HR) and extends beyond BRCA1/2 deficient EOC. A robust method with which to identify HR-deficient (HRD) carcinomas is therefore of utmost clinical importance. In this study, we investigated the proficiency of a functional HR assay based on the detection of RAD51 foci, the REcombination CAPacity (RECAP) test, in identifying HRD tumors in a cohort of prospectively collected epithelial ovarian carcinomas (EOCs). Of the 39 high-grade serous ovarian carcinomas (HGSOC), the RECAP test detected 26% (10/39) to be HRD, whereas ovarian carcinomas of other histologic subtypes (n = 10) were all HR-proficient (HRP). Of the HRD tumors that could be sequenced, 8/9 showed pathogenic BRCA1/2 variants or BRCA1 promoter hypermethylation, indicating that the RECAP test reliably identifies HRD, including but not limited to tumors related to BRCA1/2 deficiency. Furthermore, we found a trend towards better overall survival (OS) of HGSOC patients with RECAP-identified HRD tumors compared to patients with HRP tumors. This study shows that the RECAP test is an attractive alternative to DNA-based HRD tests, and further development of a clinical grade RECAP test is clearly warranted. Show less
Leuning, D.G.; Beijer, N.R.M.; Fosse, N.A. du; Vermeulen, S.; Lievers, E.; Kooten, C. van; ... ; Boer, J. de 2018
