Artifizielle UV-Exposition und Vitamin D-Status : Systematisches Review mit Metaanalyse zu möglichen Einflussfaktoren

Ziel der Arbeit war es, den aktuellen Wissensstand zur Relevanz bestimmter Einflussgrößen (Bestrahlungsdosis (in Standard Erythem Dosis (SED)), Fläche des bestrahlten Hautareals, Bestrahlungsdauer, Fraktionierung der Bestrahlungsdosis, Baseline 25(OH)D3-Serumwert, Alter, Geschlecht) auf die UV-induzierte kutane Vitamin D-Synthese herauszuarbeiten. Dazu führten wir in Übereinstimmung mit den Richtlinien von Preferred Reporting Items for Systema-tic Reviews and Meta-analyses (PRISMA) und Meta-analysis of Observational studies in Epidemiolo-gy (MOOSE) eine Literaturrecherche (MEDLINE 01/1960-07/2016) mit dem Ziel eines syste-matischen Reviews mit Metaanalyse durch. Um eine ausreichende Standardisierung zu ge-währleisten, konzentrierten wir unsere Analyse auf die Exposition mit artifiziellen Bestrah-lungssystemen. Zur Beurteilung der Auswirkungen auf die kutane Vitamin D-Synthese, wur-den Veränderungen im Vitamin D-Status (25(OH)D3-Serumkonzentration) betrachtet. Die Literaturrecherche fand unter Verwendung folgender Suchbegriffe statt: UV, UV radiation, UVB, ultraviolet, ultraviolet radiation, SED, Standard Erythem Dose, vitamin D, vitamin D3, vitamin D increase, 25(OH)D3, 25-Hydroxyvitamin D, 25-Hydroxycholecalciferol. In unserer Primäranalyse konnten 1099 Studien identifiziert werden, von denen unter Berücksichtigung von Ein- und Ausschlusskriterien 15 Studien in die Metaanalyse eingeflossen sind. Es konnte herausgefunden werden, dass nach Bestrahlung des gesamten Körpers (100% Kör-peroberfläche) mit 1 SED und einem Baselinewert von 50 nmol/l, der erwartete 25(OH)D3-Anstieg 15,87 nmol/l beträgt. In einer Meta-Regression untersuchten wir welche Faktoren für die Heterogenität zwischen den Studien verantwortlich sind. Im Gegensatz zur Fläche der bestrahlten Körperoberfläche (p = 0,334) hatte die Gesamtdosis (p < 0,0001) und der 25(OH)D3-Baselinewert (p < 0,005) einen signifikanten Einfluss auf den 25(OH)D3-Anstieg. Dabei führt ein höherer 25(OH)D3-Baselinewert zu einem geringeren 25(OH)D3-Zuwachs nach Bestrahlung. Unsere Ergebnisse sprechen dafür, dass eine Einzelbestrahlung zwischen 0,75 und 3 SED die höchste Effektivität bezüglich UV-vermittelter Vitamin D-Synthese auf-weist. Weiterhin konnte die Halbwertszeit von 25(OH)D3 auf 2 Monaten geschätzt werden. Unsere Ergebnisse sollten beim Einsatz von artifiziellen Bestrahlungssystemen zur Optimie-rung des Vitamin D-Status berücksichtigt werden.Background: Vitamin D deficiency is a worldwide health problem. Under most living condi-tions in Europe and North America up to 90% of the body’s requirement of vitamin D have to be fulfilled by the UVB-induced cutaneous synthesis of this prohormone. As a consequence, it is of high scientific interest, to determine the impact of various factors on UVB-induced cutaneous vitamin D production, measured as serum 25(OH)D3 concentration. Objective: It was the aim of this systematic review and meta-analysis to investigate our present scientific knowledge on this topic. Additionally, the half-life of 25(OH)D3 was estimated. Method: A systematic literature search was conducted using MEDLINE and cross-referenced studies to investigate the impact of exposure to artificial UV-sources on vitamin D status. Relevant pa-rameters included the 25(OH)D3 serum level before and after exposure, time of exposure, the UV source and dose (in standard erythema dose (SED)). Summary mean differences and 95% confidence intervals (95% CI) were derived from random-effects meta-analysis to account for possible heterogeneity across studies. Furthermore, meta-regression was conducted to account for dose (in SED), 25(OH)D3 baseline level and exposed body surface area (BSA). Results & Conclusion: We found 15 papers published in the past 7 years. Results from meta-regression suggest a statistically significant impact of dose and baseline 25(OH)D3 level on increase of 25(OH)D3-level (p < 0,01). The mean 25(OH)D3-increase per SED was estimated to be 0,19 nmol/l (95% CI: 0,11; 0,26). Exposed BSA was not statistically significant associated with the increase of 25(OH)D3. In conclusion, our study indicates, that single doses between 0,75 and 3 SED result in the highest increase in serum 25(OH)D3 per dose unit (SED). Exposure with higher single doses of UVB resulted in less pronounced increase in serum 25(OH)D3 per dose unit. The exposure should be fragmented to several units with a lower dose, instead of one single exposure with a higher dose. The increase in 25(OH)D3 serum concentration was not proportional to the amount of exposed BSA. Partial exposure of the BSA resulted in relatively higher increase of 25(OH)D3 serum concentration per ΔH / SED / 1% BSA as compared to the whole body. E.g. exposure of face and hands resulted leads to an 8-fold higher increase in ΔH / SED / 1% BSA as compared to whole body irradiation. Beside we found out, that the baseline 25(OH)D3 level is crucial. The lower the baseline, the higher the 25(OH)D3 augmen-tation after irradiation. The 25(OH)D3 level decreases per nmol/l by 0,39 nmol/l on average. The half-life of 25(OH)D3 can be assumed to be about two months

Chemokine Receptor Expression Pattern Correlates to Progression of Conjunctival Melanocytic Lesions

Purpose: Chemokines play a role in the progression and metastatic spread of both cutaneous and uveal melanomas. The aim of this study was to examine the prognostic value of expression of chemokine receptors CCR7, CXCR4, and CCR10 in conjunctival melanocytic lesions. Methods: In total, 44 conjunctival nevi, 21 cases of primary acquired melanosis (PAM) with atypia and 35 conjunctival melanomas, were included. After immunohistochemical staining for CCR7, CXCR4, and CCR10 the immunoreactive score (IRS) was determined. The findings were correlated for association with melanoma and development of metastasis. For mechanistic evaluation, we used a mouse melanoma metastasis model using two human conjunctival melanoma cell lines, CM2005.1 and CRMM1. Results: All tested chemokines showed a significantly higher expression in conjunctival melanoma than conjunctival nevi. There was a statistically significant difference between the IRS in nevi and PAM with atypia for nuclear IRS in CCR10 (P = 0.03) and both nuclear and cytoplasmic IRS in CXCR4 (P < 0.01 and P = 0.03, respectively); this was also true evaluating the groups PAM with atypia and melanoma all together (P < 0.01). Furthermore, a trend for lower IRS was seen in cases of melanoma without metastasis, with a suggestive pattern of a higher IRS in cases that did develop metastases, supported for CXCR4 using the mouse melanoma metastasis model. Conclusions: Expression of specific chemokines changes during the progression and metastatic spread of conjunctival melanocytic lesions. Differential chemokine profiles may hold prognostic value for patients with conjunctival melanomas and might be considered as a therapeutic target

Smad7 in T cells drives T helper 1 responses in multiple sclerosis and experimental autoimmune encephalomyelitis

Autoreactive CD4+ T lymphocytes play a vital role in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Since the discovery of T helper 17 cells, there is an ongoing debate whether T helper 1, T helper 17 or both subtypes of T lymphocytes are important for the initiation of autoimmune neuroinflammation. We examined peripheral blood CD4+ cells from patients with active and stable relapsing–remitting multiple sclerosis, and used mice with conditional deletion or over-expression of the transforming growth factor-β inhibitor Smad7, to delineate the role of Smad7 in T cell differentiation and autoimmune neuroinflammation. We found that Smad7 is up-regulated in peripheral CD4+ cells from patients with multiple sclerosis during relapse but not remission, and that expression of Smad7 strongly correlates with T-bet, a transcription factor defining T helper 1 responses. Concordantly, mice with transgenic over-expression of Smad7 in T cells developed an enhanced disease course during experimental autoimmune encephalomyelitis, accompanied by elevated infiltration of inflammatory cells and T helper 1 responses in the central nervous system. On the contrary, mice with a T cell-specific deletion of Smad7 had reduced disease and central nervous system inflammation. Lack of Smad7 in T cells blunted T cell proliferation and T helper 1 responses in the periphery but left T helper 17 responses unaltered. Furthermore, frequencies of regulatory T cells were increased in the central nervous system of mice with a T cell-specific deletion and reduced in mice with a T cell-specific over-expression of Smad7. Downstream effects of transforming growth factor-β on in vitro differentiation of naïve T cells to T helper 1, T helper 17 and regulatory T cell phenotypes were enhanced in T cells lacking Smad7. Finally, Smad7 was induced during T helper 1 differentiation and inhibited during T helper 17 differentiation. Taken together, the level of Smad7 in T cells determines T helper 1 polarization and regulates inflammatory cellular responses. Since a Smad7 deletion in T cells leads to immunosuppression, Smad7 may be a potential new therapeutic target in multiple sclerosis

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10-8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses.

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

Monitoring quality and coverage of harm reduction services for people who use drugs: a consensus study.

BACKGROUND AND AIMS: Despite advances in our knowledge of effective services for people who use drugs over the last decades globally, coverage remains poor in most countries, while quality is often unknown. This paper aims to discuss the historical development of successful epidemiological indicators and to present a framework for extending them with additional indicators of coverage and quality of harm reduction services, for monitoring and evaluation at international, national or subnational levels. The ultimate aim is to improve these services in order to reduce health and social problems among people who use drugs, such as human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infection, crime and legal problems, overdose (death) and other morbidity and mortality. METHODS AND RESULTS: The framework was developed collaboratively using consensus methods involving nominal group meetings, review of existing quality standards, repeated email commenting rounds and qualitative analysis of opinions/experiences from a broad range of professionals/experts, including members of civil society and organisations representing people who use drugs. Twelve priority candidate indicators are proposed for opioid agonist therapy (OAT), needle and syringe programmes (NSP) and generic cross-cutting aspects of harm reduction (and potentially other drug) services. Under the specific OAT indicators, priority indicators included 'coverage', 'waiting list time', 'dosage' and 'availability in prisons'. For the specific NSP indicators, the priority indicators included 'coverage', 'number of needles/syringes distributed/collected', 'provision of other drug use paraphernalia' and 'availability in prisons'. Among the generic or cross-cutting indicators the priority indicators were 'infectious diseases counselling and care', 'take away naloxone', 'information on safe use/sex' and 'condoms'. We discuss conditions for the successful development of the suggested indicators and constraints (e.g. funding, ideology). We propose conducting a pilot study to test the feasibility and applicability of the proposed indicators before their scaling up and routine implementation, to evaluate their effectiveness in comparing service coverage and quality across countries. CONCLUSIONS: The establishment of an improved set of validated and internationally agreed upon best practice indicators for monitoring harm reduction service will provide a structural basis for public health and epidemiological studies and support evidence and human rights-based health policies, services and interventions

Author Correction: A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-23162-4

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Abstract Introduction Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects