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Background Psoriasis is considered an independent cardiovascular risk factor, evidentially driving atherosclerosis. However, little is known about changes in the microvasculature of non-lesional skin in psoriasis patients. This study systematically examined capillary pathologies in psoriasis patients by digital video nailfold capillaroscopy. Patients and methods Prospective study comparing nailfold capillaries of psoriasis patients with those of healthy controls. Nailfold capillaries were evaluated for 21 parameters and results were correlated with characteristics of patients and psoriatic disease, laboratory parameters, and measurements of carotid intima-media thickness. Results 77 psoriasis patients (24 patients with additional psoriatic arthritis) and 71 controls were well-matched for demographic features and for relevant confounding factors causing microangiopathy. In comparison with controls, psoriasis patients showed a significant loss of capillaries, capillary expansion with increased ramifications and tortuosity and capillary irregularities. Moreover, in psoriasis patients we found significantly elevated serum markers of inflammation and significantly increased intima-media-thickness measurements. We found no effect of disease duration nor disease activity on capillary changes. Conclusions Nailfold capillaries of psoriasis patients showed marked microvascular abnormalities accompanied by increased markers of systemic inflammation and atherosclerosis. Prospective cohort studies are needed to assess the role of nailfold capillaroscopy for predicting the cardiovascular risk of psoriasis patients.

HINTERGRUND UND ZIELE Systeme kunstlicher Intelligenz (durch "deep learning" faltende neuronale Netzwerke; engl. convolutional neural networks, CNN) erreichen inzwischen bei der Klassifikation von Hautlasionen vergleichbar gute Ergebnisse wie Dermatologen. Allerdings mussen die Limitationen solcher Systeme vor flachendeckendem klinischem Einsatz bekannt sein. Daher haben wir den Einfluss des "dunklen Rand-Artefakts" (engl. dark corner artefact; DCA) in dermatoskopischen Bildern auf die diagnostische Leistung eines CNN mit Marktzulassung zur Klassifikation von Hautlasionen untersucht. PATIENTEN UND METHODEN Ein Datensatz aus 233 Bildern von Hautlasionen (60 maligne und 173 benigne) ohne DCA (Kontrolle) wurde digital so modifiziert, dass kleine, mittlere oder grose DCA zu sehen waren. Alle 932 Bilder wurden dann mittels CNN mit Marktzulassung (Moleanalyzer-Pro® , FotoFinder Systems) auf Malignitatsscores hin analysiert. Das Spektrum reichte von 0-1; ein Score von > 0,5 wurde als maligne klassifiziert. ERGEBNISSE In der Kontrollserie ohne DCA erreichte das CNN eine Sensitivitat von 90,0 % (79,9 %-95,3 %), eine Spezifitat von 96,5 % (92,6 %-98,4 %) sowie eine Flache unter der Kurve (AUC, area under the curve) der "receiver operating characteristic" (ROC) von 0,961 (0,932-0,989). In den Datensatzen mit kleinen beziehungsweise mittleren DCA war die diagnostische Leistung vergleichbar. In den Bildersatzen mit grosen DCA wurden allerdings signifikant hohere Malignitatsscores erzielt. Dies fuhrte zu einer signifikant verminderten Spezifitat (87,9 % [82,2 %-91,9 %], P

The clinical differentiation of face and scalp lesions (FSLs) is challenging even for trained dermatologists. Studies comparing the diagnostic performance of a convolutional neural network (CNN) with dermatologists in FSL are lacking.A market-approved CNN (Moleanalyzer-Pro, FotoFinder Systems) was used for binary classifications of 100 dermoscopic images of FSL. The same lesions were used in a two-level reader study including 64 dermatologists (level I: dermoscopy only; level II: dermoscopy, clinical close-up images, textual information). Primary endpoints were the CNN's sensitivity and specificity in comparison with the dermatologists' management decisions in level II. Generalizability of the CNN results was tested by using four additional external data sets.The CNN's sensitivity, specificity and ROC AUC were 96.2% [87.0%-98.9%], 68.8% [54.7%-80.1%] and 0.929 [0.880-0.978], respectively. In level II, the dermatologists' management decisions showed a mean sensitivity of 84.2% [82.2%-86.2%] and specificity of 69.4% [66.0%-72.8%]. When fixing the CNN's specificity at the dermatologists' mean specificity (69.4%), the CNN's sensitivity (96.2% [87.0%-98.9%]) was significantly higher than that of dermatologists (84.2% [82.2%-86.2%]; p 0.001). Dermatologists of all training levels were outperformed by the CNN (all p 0.001). In confirmation, the CNN's accuracy (83.0%) was significantly higher than dermatologists' accuracies in level II management decisions (all p 0.001). The CNN's performance was largely confirmed in three additional external data sets but particularly showed a reduced specificity in one Australian data set including FSL on severely sun-damaged skin.When applied as an assistant system, the CNN's higher sensitivity at an equivalent specificity may result in an improved early detection of face and scalp skin cancers.

Background Deep learning convolutional neural networks (CNNs) show great potential for melanoma diagnosis. Melanoma thickness at diagnosis among others depends on melanoma localisation and subtype (e.g. advanced thickness in acrolentiginous or nodular melanomas). The question whether CNN may counterbalance physicians’ diagnostic difficulties in these melanomas has not been addressed. We aimed to investigate the diagnostic performance of a CNN with approval for the European market across different melanoma localisations and subtypes. Methods The current market version of a CNN (Moleanalyzer-Pro®, FotoFinder Systems GmbH, Bad Birnbach, Germany) was used for classifications (malignant/benign) in six dermoscopic image sets. Each set included 30 melanomas and 100 benign lesions of related localisations and morphology (set-SSM: superficial spreading melanomas and macular nevi; set-LMM: lentigo maligna melanomas and facial solar lentigines/seborrhoeic keratoses/nevi; set-NM: nodular melanomas and papillomatous/dermal/blue nevi; set-Mucosa: mucosal melanomas and mucosal melanoses/macules/nevi; set-AMskin: acrolentiginous melanomas and acral (congenital) nevi; set-AMnail: subungual melanomas and subungual (congenital) nevi/lentigines/ethnical type pigmentations). Results The CNN showed a high-level performance in set-SSM, set-NM and set-LMM (sensitivities >93.3%, specificities >65%, receiver operating characteristics-area under the curve [ROC-AUC] >0.926). In set-AMskin, the sensitivity was lower (83.3%) at a high specificity (91.0%) and ROC-AUC (0.928). A limited performance was found in set-mucosa (sensitivity 93.3%, specificity 38.0%, ROC-AUC 0.754) and set-AMnail (sensitivity 53.3%, specificity 68.0%, ROC-AUC 0.621). Conclusions The CNN may help to partly counterbalance reduced human accuracies. However, physicians need to be aware of the CNN's limited diagnostic performance in mucosal and subungual lesions. Improvements may be expected from additional training images of mucosal and subungual sites.

A prototypic pediatric cancer that frequently shows activation of RAS signaling is embryonal rhabdomyosarcoma (ERMS). ERMS also show aberrant Hedgehog (HH)/GLI signaling activity and can be driven by germline mutations in this pathway. We show, that in ERMS cell lines derived from sporadic tumors i.e. from tumors not caused by an inherited genetic variant, HH/GLI signaling plays a subordinate role, because oncogenic mutations in HRAS, KRAS, or NRAS (collectively named oncRAS) inhibit the main HH target GLI1 via the MEK/ERK-axis, but simultaneously increase proliferation and tumorigenicity. oncRAS also modulate expression of stem cell markers in an isoform- and context-dependent manner. In Hh-driven murine ERMS that are caused by a Patched mutation, oncHRAS and mainly oncKRAS accelerate tumor development, whereas oncNRAS induces a more differentiated phenotype. These features occur when the oncRAS mutations are induced at the ERMS precursor stage, but not when induced in already established tumors. Moreover, in contrast to what is seen in human cell lines, oncRAS mutations do not alter Hh signaling activity and marginally affect expression of stem cell markers. Together, all three oncRAS mutations seem to be advantageous for ERMS cell lines despite inhibition of HH signaling and isoform-specific modulation of stem cell markers. In contrast, oncRAS mutations do not inhibit Hh-signaling in Hh-driven ERMS. In this model, oncRAS mutations seem to be advantageous for specific ERMS populations that occur within a specific time window during ERMS development. In addition, this window may be different for individual oncRAS isoforms, at least in the mouse.

BACKGROUND AND OBJECTIVES Convolutional neural networks (CNN) have proven dermatologist-level performance in skin lesion classification. Prior to a broader clinical application, an assessment of limitations is crucial. Therefore, the influence of a dark tubular periphery in dermatoscopic images (also called dark corner artefact [DCA]) on the diagnostic performance of a market-approved CNN for skin lesion classification was investigated. PATIENTS AND METHODS A prospective image set of 233 skin lesions (60 malignant, 173 benign) without DCA (control-set) was modified to show small, medium or large DCA. All 932 images were analyzed by a market-approved CNN (Moleanalyzer-Pro® , FotoFinder Systems), providing malignancy scores (range 0-1) with the cut-off > 0.5 indicating malignancy. RESULTS In the control-set the CNN achieved a sensitivity of 90.0 % (79.9 % - 95.3 %), a specificity of 96.5 % (92.6 % - 98.4 %), and an area under the curve (AUC) of receiver operating characteristics (ROC) of 0.961 (0.932 - 0.989). Comparable diagnostic performance was observed in the DCAsmall-set and DCAmedium-set. Conversely, in the DCAlarge-set significantly increased malignancy scores triggered a significantly decreased specificity (87.9 % [82.2 % - 91.9 %], P

The CAPUA study was supported by FIS-FEDER/Spain grant numbers FIS-01/310, FIS-PI03-0365, and FIS-07-BI060604, FICYT/Asturias grant numbers FICYT PB02-67 and FICYT IB09-133, and the University Institute of Oncology (IUOPA), of the University of Oviedo and the Ciber de Epidemiologia y Salud Pública. CIBERESP, SPAIN (...), Ji, X., Mukherjee, S., Landi, M.T., Bosse, Y., Joubert, P., Zhu, D., Gorlov, I., Xiao, X., Han, Y., Gorlova, O., Hung, R.J., Brhane, Y., Carreras-Torres, R., Christiani, D.C., Caporaso, N., Johansson, M., Liu, G., Bojesen, S.E., Le Marchand, L., Albanes, D., Bickeböller, H., Aldrich, M.C., Bush, W.S., Tardon, A., Rennert, G., Chen, C., Byun, J., Dragnev, K.H., Field, J.K., Kiemeney, L.F., Lazarus, P., Zienolddiny, S., Lam, S., Schabath, M.B., Andrew, A.S., Bertazzi, P.A., Pesatori, A.C., Diao, N., Su, L., Song, L., Zhang, R., Leighl, N., Johansen, J.S., Mellemgaard, A., Saliba, W., Haiman, C., Wilkens, L., Fernandez-Somoano, A., Fernandez-Tardon, G., Heijden, E.H.F.M., Kim, J.H., Davies, M.P.A., Marcus, M.W., Brunnström, H., Manjer, J., Melander, O., Muller, D.C., Overvad, K., Trichopoulou, A., Tumino, R., Goodman, G.E., Cox, A., Taylor, F., Woll, P., Wichmann, E., Muley, T., Risch, A., Rosenberger, A., Grankvist, K., Johansson, M., Shepherd, F., Tsao, M.-S., Arnold, S.M., Haura, E.B., Bolca, C., Holcatova, I., Janout, V., Kontic, M., Lissowska, J., Mukeria, A., Ognjanovic, S., Orlowski, T.M., Scelo, G., Swiatkowska, B., Zaridze, D., Bakke, P., Skaug, V., Butler, L.M., Offit, K., Srinivasan, P., Bandlamudi, C., Hellmann, M.D., Solit, D.B., Robson, M.E., Rudin, C.M., Stadler, Z.K., Taylor, B.S., Berger, M.F., Houlston, R., McLaughlin, J., Stevens, V., Nickle, D.C., Obeidat, M., Timens, W., Artigas, M.S., Shete, S., Brenner, H., Chanock, S., Brennan, P., McKay, J.D., Amos, C.I.

The fatty acids (FAs) metabolism is suggested to play a pivotal role in the development of lung cancer, and we explored that by conducting a pathway-based analysis. We performed a meta-analysis of published datasets of six genome wide association studies (GWASs) from the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium, which included 12 160 cases with lung cancer and 16 838 cancer-free controls. A total of 30 722 single-nucleotide polymorphisms (SNPs) from 317 genes relevant to FA metabolic pathways were identified. An additional dataset fromthe Harvard Lung Cancer Study with 984 cases and 970 healthy controls was also added to the final meta-analysis. In the initial meta-analysis, 26 of 28 SNPs that passed false discovery rate multiple tests were mapped to the CYP4F3 gene. Among the 26 top ranked hits was a proxy SNP, CYP4F3 rs4646904 (P=8.65x10(-6), FDR = 0.018), which is suggested to change splicing pattern/efficiency and to be associated with gene expression levels. However, after adding data of rs4646904 from the Harvard GWAS, the significance in the combined analysis was reduced to P=3.52x10(-3) [odds ratio (OR) = 1.07, 95% confidence interval (95% CI) = 1.03-1.12]. Interestingly, the small Harvard dataset also pointed to the same direction of the association in subgroups of smokers (OR = 1.07) and contributed to a combined OR of 1.13 (95% CI = 1.06-1.20, P=6.70x10(-5)). The results suggest that a potentially functional SNP in CYP4F3 (rs4646904) may contribute to the etiology of lung cancer, especially in smokers. Additional mechanistic studies are warranted to unravel the potential biological significance of the finding.

Background Convolutional neural networks (CNNs) have shown a dermatologist-level performance in the classification of skin lesions. We aimed to deliver a head-to-head comparison of a conventional image analyser (CIA), which depends on segmentation and weighting of handcrafted features, to a CNN trained by deep learning. Methods Cross-sectional study using a real-world, prospectively acquired, dermoscopic dataset of 1981 skin lesions to compare the diagnostic performance of a market-approved CNN (Moleanalyzer-Pro™, developed in 2018) to a CIA (Moleanalyzer-3™/Dynamole™; developed in 2004, all FotoFinder Systems Inc, Germany). As a reference standard, we used histopathological diagnoses (n = 785) or, in non-excised benign lesions (n = 1196), expert consensus plus an uneventful follow-up by sequential digital dermoscopy for at least 2 years. Results A total of 281 malignant lesions and 1700 benign lesions from 435 patients (62.2% male, mean age: 52 years) were prospectively imaged. The CNN showed a sensitivity of 77.6% (95% confidence interval [CI]: [72.4%–82.1%]), specificity of 95.3% (95% CI: [94.2%–96.2%]), and receiver operating characteristic (ROC)-area under the curve (AUC) of 0.945 (95% CI: [0.930–0.961]). In contrast, the CIA achieved a sensitivity of 53.4% (95% CI: [47.5%–59.1%]), specificity of 86.6% (95% CI: [84.9%–88.1%]) and ROC-AUC of 0.738 (95% CI: [0.701–0.774]). The data set included melanomas originally diagnosed by dynamic changes during sequential digital dermoscopy (52 of 201, 20.6%), which reduced the sensitivities of both classifiers. Pairwise comparisons of sensitivities, specificities, and ROC-AUCs indicated a clear outperformance by the CNN (all p Conclusions The superior diagnostic performance of the CNN argues against a continued application of former CIAs as an aide to physicians’ clinical management decisions.

Convolutional neural networks (CNNs) efficiently differentiate skin lesions by image analysis. Studies comparing a market-approved CNN in a broad range of diagnoses to dermatologists working under less artificial conditions are lacking. One hundred cases of pigmented/non-pigmented skin cancers and benign lesions were used for a two-level reader study in 96 dermatologists (level I: dermoscopy only; level II: clinical close-up images, dermoscopy, and textual information). Additionally, dermoscopic images were classified by a CNN approved for the European market as a medical device (Moleanalyzer Pro, FotoFinder Systems, Bad Birnbach, Germany). Primary endpoints were the sensitivity and specificity of the CNN's dichotomous classification in comparison with the dermatologists' management decisions. Secondary endpoints included the dermatologists' diagnostic decisions, their performance according to their level of experience, and the CNN's area under the curve (AUC) of receiver operating characteristics (ROC). The CNN revealed a sensitivity, specificity, and ROC AUC with corresponding 95% confidence intervals (CI) of 95.0% (95% CI 83.5% to 98.6%), 76.7% (95% CI 64.6% to 85.6%), and 0.918 (95% CI 0.866-0.970), respectively. In level I, the dermatologists' management decisions showed a mean sensitivity and specificity of 89.0% (95% CI 87.4% to 90.6%) and 80.7% (95% CI 78.8% to 82.6%). With level II information, the sensitivity significantly improved to 94.1% (95% CI 93.1% to 95.1%; P < 0.001), while the specificity remained unchanged at 80.4% (95% CI 78.4% to 82.4%; P = 0.97). When fixing the CNN's specificity at the mean specificity of the dermatologists' management decision in level II (80.4%), the CNN's sensitivity was almost equal to that of human raters, at 95% (95% CI 83.5% to 98.6%) versus 94.1% (95% CI 93.1% to 95.1%); P = 0.1. In contrast, dermatologists were outperformed by the CNN in their level I management decisions and level I and II diagnostic decisions. More experienced dermatologists frequently surpassed the CNN's performance. Under less artificial conditions and in a broader spectrum of diagnoses, the CNN and most dermatologists performed on the same level. Dermatologists are trained to integrate information from a range of sources rendering comparative studies that are solely based on one single case image inadequate.

BACKGROUND Deep learning convolutional neural networks (CNN) may assist physicians in the diagnosis of melanoma. The capacity of a CNN to differentiate melanomas from combined naevi, the latter representing well-known melanoma simulators, has not been investigated. OBJECTIVE To assess the diagnostic performance of a CNN when used to differentiate melanomas from combined naevi in comparison with dermatologists. METHODS In this study, a CNN with regulatory approval for the European market (Moleanalyzer-Pro, FotoFinder Systems GmbH, Bad Birnbach, Germany) was used. We attained a dichotomous classification (benign, malignant) in dermoscopic images of 36 combined naevi and 36 melanomas with a mean Breslow thickness of 1.3 mm. Primary outcome measures were the CNN's sensitivity, specificity and the diagnostic odds ratio (DOR) in comparison with 11 dermatologists with different levels of experience. RESULTS The CNN revealed a sensitivity, specificity and DOR of 97.1% (95% CI [82.7-99.6]), 78.8% (95% CI [62.8-89.1.3]) and 34 (95% CI [4.8-239]), respectively. Dermatologists showed a lower mean sensitivity, specificity and DOR of 90.6% (95% CI [84.1-94.7]; P = 0.092), 71.0% (95% CI [62.6-78.1]; P = 0.256) and 24 (95% CI [11.6-48.4]; P = 0.1114). Under the assumption that dermatologists use the CNN to verify their (initial) melanoma diagnosis, dermatologists achieve an increased specificity of 90.3% (95% CI [79.8-95.6]) at an almost unchanged sensitivity. The largest benefit was observed in 'beginners', who performed worst without CNN verification (DOR = 12) but best with CNN verification (DOR = 98). CONCLUSION The tested CNN more accurately classified combined naevi and melanomas in comparison with trained dermatologists. Their diagnostic performance could be improved if the CNN was used to confirm/overrule an initial melanoma diagnosis. Application of a CNN may therefore be of benefit to clinicians.

The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterations and tumorigenesis is triggered by complex networks of involved genes rather than independent actions. To explore the epistasis existing among oncogenesis-related genes in lung cancer development, we conducted pairwise genetic interaction analyses among 35,031 SNPs from 2027 oncogenesis-related genes. The genotypes from three independent genome-wide association studies including a total of 24,037 lung cancer patients and 20,401 healthy controls with Caucasian ancestry were analyzed in the study. Using a two-stage study design including discovery and replication studies, and stringent Bonferroni correction for multiple statistical analysis, we identified significant genetic interactions between SNPs in RGL1:RAD51B (OR=0.44, p value=3.27x10-11 in overall lung cancer and OR=0.41, p value=9.71x10-11 in non-small cell lung cancer), SYNE1:RNF43 (OR=0.73, p value=1.01x10-12 in adenocarcinoma) and FHIT:TSPAN8 (OR=1.82, p value=7.62x10-11 in squamous cell carcinoma) in our analysis. None of these genes have been identified from previous main effect association studies in lung cancer. Further eQTL gene expression analysis in lung tissues provided information supporting the functional role of the identified epistasis in lung tumorigenesis. Gene set enrichment analysis revealed potential pathways and gene networks underlying molecular mechanisms in overall lung cancer as well as histology subtypes development. Our results provide evidence that genetic interactions between oncogenesis-related genes play an important role in lung tumorigenesis and epistasis analysis, combined with functional annotation, provides a valuable tool for uncovering functional novel susceptibility genes that contribute to lung cancer development by interacting with other modifier genes.

Background Recent meta-analyses show that individuals with high risk variants in CHRNA5 on chromosome 15q25 are likely to develop lung cancer earlier than those with low-risk genotypes. The same high-risk genetic variants also predict nicotine dependence and delayed smoking cessation. It is unclear whether smoking cessation confers the same benefits in terms of lung cancer risk reduction for those who possess CHRNA5 risk variants versus those who do not. Methods Meta-analyses examined the association between smoking cessation and lung cancer risk in 15 studies of individuals with European ancestry who possessed varying rs16969968 genotypes (N = 12,690 ever smokers, including 6988 cases of lung cancer and 5702 controls) in the International Lung Cancer Consortium. Results Smoking cessation (former vs. current smokers) was associated with a lower likelihood of lung cancer (OR = 0.48, 95%CI = 0.30–0.75, p = 0.0015). Among lung cancer patients, smoking cessation was associated with a 7-year delay in median age of lung cancer diagnosis (HR = 0.68, 95%CI = 0.61–0.77, p = 4.9 ∗ 10–10). The CHRNA5 rs16969968 risk genotype (AA) was associated with increased risk and earlier diagnosis for lung cancer, but the beneficial effects of smoking cessation were very similar in those with and without the risk genotype. Conclusion We demonstrate that quitting smoking is highly beneficial in reducing lung cancer risks for smokers regardless of their CHRNA5 rs16969968 genetic risk status. Smokers with high-risk CHRNA5 genotypes, on average, can largely eliminate their elevated genetic risk for lung cancer by quitting smoking- cutting their risk of lung cancer in half and delaying its onset by 7 years for those who develop it. These results: 1) underscore the potential value of smoking cessation for all smokers, 2) suggest that CHRNA5 rs16969968 genotype affects lung cancer diagnosis through its effects on smoking, and 3) have potential value for framing preventive interventions for those who smoke., Highlights • CHRNA5 rs16969968 confers risk for earlier lung cancer diagnosis, but quitting produces benefit regardless of genotype. • Smokers can cut their risk of lung cancer in half and delay its onset by 7 years among those diagnosed. • Precision prevention allows clinicians to provide personalized health benefits of smoking cessation. This is a report on whether smoking cessation confers the same benefits in terms of lung cancer risk reduction for those who possess CHRNA5 risk variants versus those who do not. We determined that quitting smoking is highly beneficial in reducing lung cancer risk levels for smokers regardless of their CHRNA5 rs16969968 genetic risk status. Although CHRNA5 rs16969968 increases risk for earlier lung cancer by 4 years, quitting produces essentially the same benefit for smokers with either high or low genetic risks. Smokers can cut their risk of lung cancer in half and delay its onset by 7 years among those diagnosed. These results are important for smokers to prevent cancer. On average, smokers at all genetic risk levels can largely eliminate their elevated risk for lung cancer by quitting smoking.

Hintergrund und zielvorgaben Konfokale Laserscanmikroskopie (Reflectance confocal microscopy; RCM) kann eine nutzliche Methode fur die genaue, schnelle und nicht-invasive Diagnose fur vesikullobullose Hauterkrankungen (VSD) am Krankenbett sein. Das primare Ergebnis dieser Studie war eine deskriptive statistische Analyse von RCM-Merkmalen, die mit einer ausgewahlten Gruppe an VSD einhergehen. Patienten und methoden Monozentrische Beobachtungsstudie an einer Universitatsklinik fur Dermatologie. Vierzig Hautlasionen bei 24 Patienten mit bullosem Pemphigoid (BP), Infektion mit Varizella Zoster (VZI) oder allergischer Kontaktdermatitis (ACD) wurden ausgewertet. Ergebnisse Patienten mit BP, VZI und ACD wurden auf die Anwesenheit eines grosen Spektrums an RCM-Merkmalen hin untersucht, darunter die histopathologische Korrelation von Spongiose, Vesikel/Hautblasen, epidermaler Nekrose, pleomorphen, ballonierte Keratinozyten und entzundlichen Infiltraten. Die drei Erkrankungen zeigten spezifische Muster fur Auftreten dieser RCM-Merkmale. Wir identifizierten mit Hilfe einer multivariaten Regressionsanalyse einen Satz morphologischer Merkmale bei BP (Vesikel/Hautblasen an der dermoepidermalen Junktionszone, entzundliche Infiltrate in Hautblasen und basalen Epidermisschichten, Spongiose in basalen Epidermisschichten), VZI (Akantholyse im Stratum spinosum, epidermale Nekrose, pleomorphe, ballonierte Keratinozyten, multinukleare Riesenzellen) und ACD (Mikrovesikel, Spongiose und auffallige entzundliche Infiltrate im Stratum granulosum/spinosum). Schlussfolgerungen RCM scheint ein nutzliches Werkzeug bei der Analyse und der Unterscheidung einer ausgewahlten Gruppe von VSDs zu sein und bietet eine gute Korrelation mit histopathologischen Untersuchungsergebnissen.

SummaryBackground and objectives Reflectance confocal microscopy (RCM) may be a useful method for accurate, rapid, and noninvasive bedside diagnosis of vesiculobullous skin diseases (VSD). The main outcome measure of this study was a descriptive statistical analysis of RCM features associated with selected group of VSD. Patients and methods Single-center, observational study at a university-based dermatology department. Forty skin lesions in 24 patients with bullous pemphigoid (BP), varicella zoster virus infection (VZI), or allergic contact dermatitis (ACD) were assessed. Results Patients with BP, VZI, and ACD were assessed for the presence of a large spectrum of RCM features, among others including histopathological correlates for spongiosis, vesicles/blisters, epidermal necrosis, pleomorphic ballooned keratinocytes, and inflammatory infiltrate. The three conditions showed distinct patterns of occurrence with respect to these RCM features. Using a multivariate regression model, we identified sets of morphologic features in BP (vesicles/blisters at the dermoepidermal junction, inflammatory infiltrate within blisters and basal epidermal layers, spongiosis in basal epidermal layers), VZI (acantholysis in the stratum spinosum, epidermal necrosis, pleomorphic ballooned keratinocytes, multinucleated giant cells), and ACD (microvesicles, spongiosis, and prominent inflammatory infiltrate in the stratum granulosum/spinosum). Conclusions RCM seems to be a useful tool in the evaluation and differentiation of a selected group of VSD, and offers a good correlation with histopathological findings.

The CAPUA study was supported by FIS-FEDER/Spain grants FIS-01/310, FIS-PI03-0365, and FIS-07-BI060604; FICYT/Asturias grants FICYT PB02-67 and FICYT IB09-133; and the University Institute of Oncology (IUOPA) of the University of Oviedo and the Ciber de Epidemiologiay Salud Pública (CIBERESP), Spain. (...), Zhu, Y., Wei, Y., Zhang, R., Dong, X., Shen, S., Zhao, Y., Bai, J., Albanes, D., Caporaso, N.E., Landi, M.T., Zhu, B., Chanock, S.J., Gu, F., Lam, S., Tsao, M.-S., Shepherd, F.A., Tardon, A., Fernandez-Somoano, A., Fernandez-Tardon, G., Chen, C., Barnett, M.J., Doherty, J., Bojesen, S.E., Johansson, M., Brennan, P., McKay, J.D., Carreras-Torres, R., Muley, T., Risch, A., Wichmann, H.-E., Bickeboeller, H., Rosenberger, A., Rennert, G., Saliba, W., Arnold, S.M., Field, J.K., Davies, M.P.A., Marcus, M.W., Wu, X., Ye, Y., Le Marchand, L., Wilkens, L.R., Melander, O., Manjer, J., Brunnstrom, H., Hung, R.J., Liu, G., Brhane, Y., Kachuri, L., Andrew, A.S., Duell, E.J., Kiemeney, L.A., Van der Heijden, E.H.F.M., Haugen, A., Zienolddiny, S., Skaug, V., Grankvist, K., Johansson, M., Woll, P.J., Cox, A., Taylor, F., Teare, D.M., Lazarus, P., Schabath, M.B., Aldrich, M.C., Houlston, R.S., McLaughlin, J., Stevens, V.L., Shen, H., Hu, Z., Dai, J., Amos, C.I., Han, Y., Zhu, D., Goodman, G.E., Chen, F., Christiani, D.C.

Age dependent radiation sensitivity for DNA damage after in vitro blood exposure by computer tomography (CT) was investigated.Radiation biomarkers (dicentrics and gammaH2AX) in blood samples of newborns, children under five years and adults after sham exposure (0 mGy), low-dose (41 mGy) and high-dose (978 mGy) in vitro CT exposure were analyzed.Significantly higher levels of dicentric induction were found for the single and combined newborns/children group compared to adults, by a factor of 1.48 (95% CI 1.30-1.68), after exposure to 978 mGy. Although a significant dose response for damage induction and dose-dependent repair was found, the gammaH2AX assay did not show an age-dependent increase in DNA damage in newborns/children compared to adults. This was the case for the gammaH2AX levels after repair time intervals of 30 minutes and 24 hours, after correcting for the underlying background damage. For the low dose of 41 mGy, the power of the dicentric assay was also not sufficient to detect an age-dependent effect in the sample size investigated.A 1.5-fold increased level of dicentric aberrations is detected in newborns and children under five years after 1 Gy radiation exposure.

CAPUA study was supported by FIS-FEDER/Spain grant numbers FIS-01/310, FIS-PI03-0365, and FIS-07-BI060604, FICYT/Asturias grant numbers FICYT PB02-67 and FICYT IB09-133, and the University Institute of Oncology (IUOPA), of the University of Oviedo and the Ciber de Epidemiología y Salud Pública. CIBERESP, SPAIN (...), Ferreiro-Iglesias, A., Lesseur, C., McKay, J., Hung, R.J., Han, Y., Zong, X., Christiani, D., Johansson, M., Xiao, X., Li, Y., Qian, D.C., Ji, X., Liu, G., Caporaso, N., Scelo, G., Zaridze, D., Mukeriya, A., Kontic, M., Ognjanovic, S., Lissowska, J., Szołkowska, M., Swiatkowska, B., Janout, V., Holcatova, I., Bolca, C., Savic, M., Ognjanovic, M., Bojesen, S.E., Wu, X., Albanes, D., Aldrich, M.C., Tardon, A., Fernandez-Somoano, A., Fernandez-Tardon, G., Le Marchand, L., Rennert, G., Chen, C., Doherty, J., Goodman, G., Bickeböller, H., Wichmann, H.-E., Risch, A., Rosenberger, A., Shen, H., Dai, J., Field, J.K., Davies, M., Woll, P., Teare, M.D., Kiemeney, L.A., van der Heijden, E.H.F.M., Yuan, J.-M., Hong, Y.-C., Haugen, A., Zienolddiny, S., Lam, S., Tsao, M.-S., Johansson, M., Grankvist, K., Schabath, M.B., Andrew, A., Duell, E., Melander, O., Brunnström, H., Lazarus, P., Arnold, S., Slone, S., Byun, J., Kamal, A., Zhu, D., Landi, M.T., Amos, C.I., Brennan, P.

Item does not contain fulltext PURPOSE: Radon is a risk factor for lung cancer and uranium miners are more exposed than the general population. A genome-wide interaction analysis was carried out to identify genomic loci, genes or gene sets that modify the susceptibility to lung cancer given occupational exposure to the radioactive gas radon. METHODS: Samples from 28 studies provided by the International Lung Cancer Consortium were pooled with samples of former uranium miners collected by the German Federal Office of Radiation Protection. In total, 15,077 cases and 13,522 controls, all of European ancestries, comprising 463 uranium miners were compared. The DNA of all participants was genotyped with the OncoArray. We fitted single-marker and in multi-marker models and performed an exploratory gene-set analysis to detect cumulative enrichment of significance in sets of genes. RESULTS: We discovered a genome-wide significant interaction of the marker rs12440014 within the gene CHRNB4 (OR = 0.26, 95% CI 0.11-0.60, p = 0.0386 corrected for multiple testing). At least suggestive significant interaction of linkage disequilibrium blocks was observed at the chromosomal regions 18q21.23 (p = 1.2 x 10(-6)), 5q23.2 (p = 2.5 x 10(-6)), 1q21.3 (p = 3.2 x 10(-6)), 10p13 (p = 1.3 x 10(-5)) and 12p12.1 (p = 7.1 x 10(-5)). Genes belonging to the Gene Ontology term "DNA dealkylation involved in DNA repair" (GO:0006307; p = 0.0139) or the gene family HGNC:476 "microRNAs" (p = 0.0159) were enriched with LD-blockwise significance. CONCLUSION: The well-established association of the genomic region 15q25 to lung cancer might be influenced by exposure to radon among uranium miners. Furthermore, lung cancer susceptibility is related to the functional capability of DNA damage signaling via ubiquitination processes and repair of radiation-induced double-strand breaks by the single-strand annealing mechanism.

Non-small cell lung cancer is the most common type of lung cancer. Both environmental and genetic risk factors contribute to lung carcinogenesis. We conducted a genome-wide interaction analysis between single nucleotide polymorphisms (SNPs) and smoking status (never-versus ever-smokers) in a European-descent population. We adopted a two-step analysis strategy in the discovery stage: we first conducted a case-only interaction analysis to assess the relationship between SNPs and smoking behavior using 13 336 non-small cell lung cancer cases. Candidate SNPs with P-value

Recent genome-wide association studies (GWASs) have identified common genetic variants at 5p15.33, 6p21-6p22 and 15q25.1 associated with lung cancer risk. Several other genetic regions including variants of CHEK2 (22q12), TP53BP1 (15q15) and RAD52 (12p13) have been demonstrated to influence lung cancer risk in candidate- or pathway-based analyses. To identify novel risk variants for lung cancer, we performed a meta-analysis of 16 GWASs, totaling 14 900 cases and 29 485 controls of European descent. Our data provided increased support for previously identified risk loci at 5p15 (P = 7.2 × 10(-16)), 6p21 (P = 2.3 × 10(-14)) and 15q25 (P = 2.2 × 10(-63)). Furthermore, we demonstrated histology-specific effects for 5p15, 6p21 and 12p13 loci but not for the 15q25 region. Subgroup analysis also identified a novel disease locus for squamous cell carcinoma at 9p21 (CDKN2A/p16(INK4A)/p14(ARF)/CDKN2B/p15(INK4B)/ANRIL; rs1333040, P = 3.0 × 10(-7)) which was replicated in a series of 5415 Han Chinese (P = 0.03; combined analysis, P = 2.3 × 10(-8)). This large analysis provides additional evidence for the role of inherited genetic susceptibility to lung cancer and insight into biological differences in the development of the different histological types of lung cancer. peerReviewed

Cullin-RING ubiquitin ligases (CRLs) responsible for substrate specificity of ubiquitination and play a key role in cell-cycle control and DNA damage response. In this study, we assessed associations between 16,599 SNPs in 115 CRL genes and lung cancer risk by using summary data of six published genome-wide association studies (GWASs) of 12,160 cases and 16,838 cases of European ancestry. As a result, we identified three independent SNPs in DCAF4 (rs117781739, rs12587742 and rs2240980) associated with lung cancer risk (odds ratio = 0.91, 1.09 and 1.09, respectively; 95% confidence interval = 0.88-0.95, 1.05-1.14 and 1.05-1.13, respectively; and P = 3.99×10-6, 4.97×10-5 and 1.44×10-5, respectively) after multiple comparison correction by a false discovery rate

Konnen Sie echte von unechten Zwillingen unterscheiden? Diese Frage steht am Anfang der hier vorgestellten Unterrichtseinheit zum Grundprinzip des statistischen Testens. Dieses Thema ist unverzichtbarer Bestandteil jeder Einfuhrung in die Grundlagen der Statistik/Biometrie. Unser Ziel ist es, mit dieser Unterrichtseinheit den Teilnehmern das Thema anschaulich vorzustellen und ein grundlegendes Verstandnis statistischer Tests zu vermitteln. Die vorgestellte Veranstaltung ist sowohl fur eine Vorlesung als auch fur ein Seminar geeignet und dauert ungefahr 60 Minuten.

Background Factors associated with early vs. late diagnosis of cutaneous melanoma remain poorly understood. Objective To identify factors with a significant impact on melanoma thickness. Methods Patients with previous melanoma (n = 347, median age at diagnosis: 56.5 years, 44.7% female, 55.3% male) were recruited for this monocentre, non-randomized, observational study between April 2012 and March 2013. All patients were assessed by means of a structured interview and systematic clinical and dermoscopic full-body examination. Melanoma thickness in association with patients’ characteristics, risk indicators and patterns of diagnosis was submitted to statistical analyses. Results Univariate analyses revealed associations between a statistically significant lower Breslow thickness and participation in specialized dermoscopic screening programs, personal history of more than one previous melanoma, diagnostic examination with a dermatoscope, diagnostic examination by board certified dermatologist, high number of common and/or atypical nevi, younger age at time of diagnosis, higher level of education, or superficial spreading or lentigo maligna melanoma subtype (all P ≤ 0.01). In a multivariate regression analysis only three of these criteria: (i) participation in specialized screening programs (P

Lung cancer etiology is multifactorial, and growing evidence has indicated that long non-coding RNAs (lncRNAs) are important players in lung carcinogenesis. We performed a large-scale meta-analysis of 690,564 SNPs in 15,531 autosomal lncRNAs by using datasets from six previously published genome-wide association studies (GWASs) from the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium in populations of European ancestry. Previously unreported significant SNPs (P value −7) were further validated in two additional independent lung cancer GWAS datasets from Harvard University and deCODE. In the final meta-analysis of all eight GWAS datasets with 17,153 cases and 239,337 controls, a novel risk SNP rs114020893 in the lncRNA NEXN-AS1 region at 1p31.1 remained statistically significant (odds ratio = 1.17; 95% confidence interval = 1.11–1.24; P = 8.31 × 10−9). In further in silico analysis, rs114020893 was predicted to change the secondary structure of the lncRNA. Our finding indicates that SNP rs114020893 of NEXN-AS1 at 1p31.1 may contribute to lung cancer susceptibility.

Metabolism of nicotine by cytochrome P450 2A6 (CYP2A6) is a suspected determinant of smoking dose and, consequently, lung cancer risk. We conducted a genome-wide association study (GWAS) of CYP2A6 activity, as measured by the urinary ratio of trans-3′-hydroxycotinine and its glucuronide conjugate over cotinine (total 3HCOT/COT), among 2,239 smokers in the Multiethnic Cohort (MEC) study. We identified 248 CYP2A6 variants associated with CYP2A6 activity (P < 5 × 10−8). CYP2A6 activity was correlated (r = 0.32; P < 0.0001) with total nicotine equivalents (a measure of nicotine uptake). When we examined the effect of these variants on lung cancer risk in the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium GWAS dataset (13,479 cases and 43,218 controls), we found that the vast majority of these individual effects were directionally consistent and associated with an increased lung cancer risk. Two hundred and twenty-six of the 248 variants associated with CYP2A6 activity in the MEC were available in TRICL. Of them, 81% had directionally consistent risk estimates, and six were globally significantly associated with lung cancer. When conditioning on nine known functional variants and two deletions, the top two SNPs (rs56113850 in MEC and rs35755165 in TRICL) remained significantly associated with CYP2A6 activity in MEC and lung cancer in TRICL. The present data support the hypothesis that a greater CYP2A6 activity causes smokers to smoke more extensively and be exposed to higher levels of carcinogens, resulting in an increased risk for lung cancer. Although the variants identified in these studies may be used as risk prediction markers, the exact causal variants remain to be identified. Cancer Res; 76(19); 5768–76. ©2016 AACR.

Radiation sensitivity is assumed to be a cancer susceptibility factor due to impaired DNA damage signalling and repair. Relevant genetic factors may also determine the observed familial aggregation of early onset lung cancer. We investigated the heritability of radiation sensitivity in families of 177 Caucasian cases of early onset lung cancer. In total 798 individuals were characterized for their radiation-induced DNA damage response. DNA damage analysis was performed by alkaline comet assay before and after in vitro irradiation of isolated lymphocytes. The cells were exposed to a dose of 4 Gy and allowed to repair induced DNA-damage up to 60 minutes. The primary outcome parameter Olive Tail Moment was the basis for heritability estimates. Heritability was highest for basal damage (without irradiation) 70% (95%-CI: 51%–88%) and initial damage (directly after irradiation) 65% (95%-CI: 47%–83%) and decreased to 20%–48% for the residual damage after different repair times. Hence our study supports the hypothesis that genomic instability represented by the basal DNA damage as well as radiation induced and repaired damage is highly heritable. Genes influencing genome instability and DNA repair are therefore of major interest for the etiology of lung cancer in the young. The comet assay represents a proper tool to investigate heritability of the radiation sensitive phenotype. Our results are in good agreement with other mutagen sensitivity assays.

Background Sequential digital dermatoscopy identifies dynamic changes in melanocytic lesions. However, no algorithm exists that systematically weights dynamic changes regarding their association with melanoma. Objective We sought to identify relevant dynamic changes and to integrate these into a novel diagnostic algorithm. Methods During follow-up (mean 44.28 months) of 688 patients at high risk, 675 pigmented lesions with prospectively documented dynamic changes were excised. The association between specific changes and melanoma was assessed. Results We detected 61 melanomas (38 invasive, median thickness 0.42 mm) with dynamic changes. Multivariate logistic regression analyses revealed a significant association between the diagnosis of melanoma and 5 dynamic criteria. According to the observed odds ratios we defined two dynamic major criteria (2 points each: asymmetric-multifocal enlargement and architectural change) and 3 dynamic minor criteria (1 point each: focal increase in pigmentation, focal decrease in pigmentation, and overall decrease in pigmentation when not accompanied by a lighter pigmentation of the adjacent skin). The DynaMel score was generated by addition of dynamic and 7-point checklist scores with a threshold for excision of 3 or more points. Including information about dynamic changes increased the sensitivity of the 7-point checklist from 47.5% (29 of 61 melanomas detected) to 77.1% (47 of 61 melanomas detected). The specificity slightly decreased from 99.0% to 98.1%. Limitations Before broad application the DynaMel algorithm needs to be validated using data from a different prospective study. Conclusions The DynaMel algorithm integrates a scoring system for dynamic dermatoscopic changes into the 7-point checklist for dermatoscopy and thereby increased the sensitivity of melanoma detection.

Activation of the Hedgehog (Hh)-signaling pathway due to deficiency in the Hh receptor Patched1 (Ptch) is the pivotal defect leading to formation of basal cell carcinoma (BCC). Recent reports provided evidence of Ptch-dependent secretion of vitamin D3-related compound, which functions as an endogenous inhibitor of Hh signaling by repressing the activity of the signal transduction partner of Ptch, Smoothened (Smo). This suggests that Ptch-deficient tumor cells are devoid of this substance, which in turn results in activation of Hh-signaling. Here, we show that the application of the physiologically active form of vitamin D3, calcitriol, inhibits proliferation and growth of BCC of Ptch mutant mice in vitro and in vivo. This is accompanied by the activation of the vitamin D receptor (Vdr) and induction of BCC differentiation. In addition, calcitriol inhibits Hh signaling at the level of Smo in a Vdr-independent manner. The concomitant antiproliferative effects on BCC growth are stronger than those of the Hh-specific inhibitor cyclopamine, even though the latter more efficiently inhibits Hh signaling. Taken together, we show that exogenous supply of calcitriol controls the activity of 2 independent pathways, Hh and Vdr signaling, which are relevant to tumorigenesis and tumor treatment. These data suggest that calcitriol could be a therapeutic option in the treatment of BCC, the most common tumor in humans. Mol Cancer Ther; 10(11); 2179–88. ©2011 AACR.

Background Chronic venous leg ulcers (CVU) cause considerable burden of disease for the patients as well as enormous costs for health care systems. The pathophysiology of CVU is complex and not entirely understood. So far reliable pathogenic and/or prognostic parameters have not been identified. Objectives We studied the role of thrombophilia in patients referred to a University dermatology department for treatment of CVU. Patients and methods A cohort of 310 patients with active chronic venous leg ulcers (CEAP 6) was stratified into two comparably large groups according to the presence or absence of post-thrombotic syndrome (PTS+; PTS−) as determined using duplex scan and/or phlebography. In addition, several thrombophilia parameters were assessed. Results The prevalence of protein S deficiency and factor V Leiden mutation was significantly higher in PTS+ patients compared with the PTS− group. However, patients in both subgroups revealed high prevalences of thrombophilia (antithrombin deficiency, protein C deficiency, protein S deficiency, activated protein C resistance, factor V mutation or elevated homocysteine). Conclusion Based on these data, it is conceivable that thrombophilia contributes to the pathogenesis of CVU, possibly through induction of microcirculatory dysregulations.

The COMET assay is recognized as a rapid and sensitive method in quantifying radiation induced DNA damage. We investigated the distorting influence of endogenous, assay-inherent factors onto base (single cell level) and primary outcome measures (experimental/slide level), such as olive tail moment (OTM) and percentage DNA in the tail (%tail-DNA). From 2003 to 2008, we performed the assay on lymphocytes isolated from the blood samples of 355 lung cancer patients, 170 controls, and 610 relatives, as well as one single reference individual, repeated 170 times. In total, the data from 10,016 single experiments containing around 1,750,000 cells have been included in this study. This is the first time that the endogenous variability of the COMET assay has been validated systematically on such a huge data set over a 5 year period. Assuming that the reference sample reflects assay specific white noise, we estimated a proportion of 7-95% of the variability of the outcome measures due to assay variation (white noise) depending on parameter, exposure level, and study group. The proportion of white noise was largest for the initial radiation damage. The specific endogenous factors considered attribute to 14.8% of the total variability in the primary outcome measurements of the OTM and 6.9% of the %tail-DNA. OTM turns out to be a sensitive parameter to detect variation, but is also more susceptible to disturbance caused by endogenous factors than %tail-DNA. To reduce the experimental variability in COMET assays, we recommend a highly standardized operation protocol as well as inspecting and/or adjusting the primary outcome measures according to endogenous factors before calculating secondary outcome measures, e.g. DNA repair capacity (DRC) or testing statistical inference. A human reference (HR) sample is also useful to inspect homogeneity in the temporal progression of long lasting investigations, but not for calibrating primary outcome measurements.

Chronic venous leg ulcers are common and cause considerable burden of disease for affected patients with significant costs for health care systems worldwide. The complex pathophysiology of chronic venous leg ulcers is still not entirely understood. In addition, reliable pathogenic and/or prognostic parameters are not known. Published data suggest that patients with chronic venous leg ulcers reveal congenital or acquired thrombophilia. We examined the serum Lipoprotein (a) [Lp(a)] level, a proatherogenic and prothrombotic risk factor, in patients with chronic venous leg ulcers (n=210, stratified into patients with postthrombotic syndrome or without) and in a healthy control group (n=341). Forty-two percent of all patients, compared with 20% of healthy controls, revealed significantly increased Lp(a) serum concentrations above 0.3 g/L. Furthermore, 49% without postthrombotic syndrome but only 35% with postthrombotic syndrome showed increased Lp(a) levels. The increase of Lp(a) level was significantly different between all three groups (p

The Commission Internationale de l’Eclairage (CIE) L\*a\*b* three-dimensional coordinates suggest strong correlations between the data of a* (red–green axis) and b* (blue–yellow axis), as both are located on the same plane in the model and should therefore show a strong dependency. In order to assess the veridicality of colour determinations, the null hypothesis of no significant changes in CIE-a\*/b\* coherences of dental colours following a colour or lightness change induced by external dental bleaching was tested. Values from 231 extracted anterior teeth were assessed using the digital photographic CIELAB recalculation method. Teeth were then assigned to three groups ( n = 77) with contrasting baseline CIE-L* values. Group A served as the control with no alteration in dental colour. The specimens in the two other groups were altered in colour or lightness employing treatment with either 15 per cent carbamide peroxide (group B) or 38 per cent hydrogen peroxide (group C). Pearson’s pairwise correlation coefficient of CIE-L*; a*, CIE-L*; b*, and CIE-a*; b* were calculated for assessments at baseline (T0) and after 2 (T1), 4 (T2), 12 (T3), and 24 (T4) weeks. The correlations of a* and b* from T0 to T4, in relation to group A, were stable, with coefficients of 0.78→0.65→0.65→0.69→0.67. Bleaching-induced colour and lightness changes did not have a significant influence on the a\*/b\* coherences assessed. A distinctly weaker and inverse relationship was observed between L* and a* values and between L* and b* values in the groups, with correlation coefficients ranging from −0.54 to −0.12. Colour coherences detected at specific points in time were in agreement with theoretical CIE colour coherences. In order to compare the methodology of different colour analyses, the analysis of correlations between CIE-a* and -b* values is advocated as an additional routine test in future CIELAB studies.

By pure endpoint diagnosis of the disease, the risk of developing schizophrenia has been repeatedly associated with specific variants of the neuregulin1 (NRG1) gene. However, the role of NRG1 in the etiology of schizophrenia has remained unclear. Since Nrg1 serves vital functions in early brain development of mice, we hypothesized that human NRG1 alleles codetermine developmentally influenced readouts of the disease: age of onset and positive symptom severity. We analyzed 1,071 comprehensively phenotyped schizophrenic/schizoaffective patients, diagnosed according to DSM-IV-TR, from the GRAS (Gottingen Research Association for Schizophrenia) Data Collection for genetic variability in the Icelandic region of risk in the NRG1 gene. For the case-control analysis part of the study, we included 1,056 healthy individuals with comparable ethnicity. The phenotype-based genetic association study (PGAS) was performed on the GRAS sample. Instead of a risk constellation, we detected that several haplotypic variants of NRG1 were, unexpectedly, less frequent in the schizophrenic than in the control sample (mean OR = 0.78, range between 0.68 and 0.85). In the PGAS we found that these “protective” NRG1 variants are specifically underrepresented in subgroups of schizophrenic subjects with early age of onset and high positive symptom load. The GRAS Data Collection as a prerequisite for PGAS has enabled us to associate protective NRG1 genotypes with later onset and milder course of schizophrenia. © 2011 Wiley-Liss, Inc.

The retrospectively developed 7-point checklist is one of the most applicable dermatoscopic algorithms for clinical use. However, until today no prospective data on the diagnostic performance of this algorithm were reported.Our aim was to assess the sensitivity, specificity, and diagnostic accuracy of the 7-point checklist in the setting of a prospective long-term study.Patients at increased melanoma risk (n = 688) were screened at regular intervals by naked-eye examination, the dermatoscopic 7-point checklist, and digital dermatoscopy follow-up (10-year study interval).We detected 127 melanomas including 50 melanomas in situ. The mean Breslow thickness of invasive melanomas was 0.57 mm. A total of 79 melanomas displayed the 7-point checklist melanoma threshold of 3 or more points (62% sensitivity, compared with 78%-95% in retrospective settings). In all, 48 melanomas scored fewer than 3 points and were excised because of complementary information (eg, lesional history, dynamic changes detected by digital dermatoscopy). The specificity of the 7-point checklist was 97% (compared with 65%-87% in retrospective settings). Regression patterns, atypical vascular patterns, and radial streaming were associated with the highest relative risk for melanoma (odds ratio 3.26, 95% confidence interval 2.05-5.16; odds ratio 3.04, 95% confidence interval 1.70-5.46; odds ratio 2.91, 95% confidence interval 1.64-5.15; P.0003, respectively). Melanomas thicker than 0.5 mm exhibited significantly more regression patterns and atypical vascular patterns (P.02). The malignant versus benign ratio for all excised lesions was 1:8.6 (127 melanomas, 1092 nonmelanomas).Calculation of the specificity was a limitation. True negative lesions were defined by a score less than 3 points and either the histopathological diagnosis of nonmelanoma or the absence of dynamic changes during digital dermatoscopy follow-up (nonexcised, nonsuspicious, no change).The 7-point checklist for dermatoscopy was less sensitive but highly specific in this prospective clinical setting. Complementary information clearly increased the sensitivity. Regression patterns or radial streaming in nevi of patients at high risk should raise a higher melanoma suspicion than might be concluded from retrospective studies.

Basal cell carcinoma (BCC) is the most common skin tumor in humans. Although BCCs rarely metastasize, they can cause significant morbidity due to local aggressiveness. Approximately 20% of BCCs show signs of spontaneous regression. The understanding of molecular events mediating spontaneous regression has the potential to reduce morbidity of BCC and, potentially, other tumors, if translated into tumor therapies. We show that BCCs induced in conditional Ptchflox/floxERT2+/− knockout mice regress with time and show a more differentiated phenotype. Differentiation is accompanied by Wnt5a expression in the tumor stroma, which is first detectable at the fully developed tumor stage. Coculture experiments revealed that Wnt5a is upregulated in tumor-adjacent macrophages by soluble signals derived from BCC cells. In turn, Wnt5a induces the expression of the differentiation marker K10 in tumor cells, which is mediated by Wnt/Ca2+ signaling in a CaMKII-dependent manner. These data support a role of stromal Wnt5a in BCC differentiation and regression, which may have important implications for development of new treatment strategies for this tumor. Taken together, our results establish BCC as an easily accessible model of tumor regression. The regression of BCC despite sustained Hedgehog signaling activity seems to be mediated by tumor-stromal interactions via Wnt5a signaling. Cancer Res; 70(7); 2739–48

Based on their role for the induction of T-cell responses, dendritic cells (DCs) are popular candidates in cancer vaccine development. We established a novel single-step intracellular delivery of peptide/poly(I:C) complexes for antigen loading and Toll-like receptor-3 (TLR3)-mediated maturation of human DCs using a cell-penetrating peptide (tat49–57: RKKRRQRRR) as delivery vector. Towards this end, a cationic tat-sequence was fused with an antigenic, major histocompatibility complex (MHC) class I-binding melanoma epitope (Melan-A/Mart-1 sequence: ELAGIGILTV) and then mixed with negatively charged poly(I:C) dsRNA to form peptide/nucleic acid complexes. Flow cytometry and confocal laser scanning microscopy confirmed intracellular localization of TLR3 in monocyte-derived immature DCs (iDCs). Peptide/poly(I:C) complexes were readily internalized by iDCs without negatively affecting cell viability. They induced DC maturation and secretion of bioactive interleukin (IL)-12p70. When peptide/poly(I:C) complex-loaded DCs were used for autologous T cell stimulation, epitope-specific interferon-gamma secretion was quantitatively superior in comparison to peptide-loaded DCs matured by a cytokine cocktail, as detected by enzyme-linked immunospot assays. Thus, complexes of cationic antigenic peptides and poly(I:C) might be of great utility for a TLR3-mediated DC maturation and intracellular peptide targeting in a single step. Resulting DCs induce a strong expansion/activation of antigen-specific T cells in the context of an IL-12p70 secretion.

Three genetic loci for lung cancer risk have been identified by genome-wide association studies (GWAS), but inherited susceptibility to specific histologic types of lung cancer is not well established. We conducted a GWAS of lung cancer and its major histologic types, genotyping 515,922 single-nucleotide polymorphisms (SNPs) in 5739 lung cancer cases and 5848 controls from one population-based case-control study and three cohort studies. Results were combined with summary data from ten additional studies, for a total of 13,300 cases and 19,666 controls of European descent. Four studies also provided histology data for replication, resulting in 3333 adenocarcinomas (AD), 2589 squamous cell carcinomas (SQ), and 1418 small cell carcinomas (SC). In analyses by histology, rs2736100 (TERT), on chromosome 5p15.33, was associated with risk of adenocarcinoma (odds ratio [OR] = 1.23, 95% confidence interval [CI] = 1.13–1.33, p = 3.02 × 10−7), but not with other histologic types (OR = 1.01, p = 0.84 and OR = 1.00, p = 0.93 for SQ and SC, respectively). This finding was confirmed in each replication study and overall meta-analysis (OR = 1.24, 95% CI = 1.17–1.31, p = 3.74 × 10−14 for AD; OR = 0.99, p = 0.69 and OR = 0.97, p = 0.48 for SQ and SC, respectively). Other previously reported association signals on 15q25 and 6p21 were also refined, but no additional loci reached genome-wide significance. In conclusion, a lung cancer GWAS identified a distinct hereditary contribution to adenocarcinoma.

OBJECTIVES The efficacy of temozolomide (TMZ) or dacarbazine (DTIC) in melanoma treatment depends on low O-6-methylguanine-DNA-methyltransferase (MGMT) repair and on high mismatch repair. The aim of this study was to identify individual host markers for hematologic side effects and the treatment efficacy of TMZ or DTIC in melanoma treatment. METHODS Fifty-one Caucasian patients with metastasized melanoma were recruited. In each patient, the mRNA expression of MGMT and two essential mismatch repair genes, MLH1 and MSH2, was measured in peripheral blood. The coding gene regions, including splice sites, were sequenced to identify genetic variants, and the promoter methylation status of the genes was determined. RESULTS Both constitutively low and high mRNA expression of MGMT, MLH1, and MSH2 were significantly associated with reduced hematologic side effects (P = 0.008-0.020), but did not correlate with treatment efficacy. We identified five variants in the MGMT gene, 13 variants in MLH1, and seven variants in MSH2, including five novel genetic variants in MLH1. Variations of the hosts' gene expression of MGMT, MLH1, and MSH2 did not result from promoter methylation. Of note, one variant in MSH2 (rs2303428) was associated with increased hematologic side effects and showed a tendency for better treatment response. CONCLUSION Our results indicate that either low or high host expression of MGMT, MLH1, and MSH2 may serve as a marker for reduced hematologic side effects of TMZ or DTIC, but not for treatment efficacy in melanoma. The genetic variant rs2303428 (MSH2) might serve as a predictive marker for hematologic side effects and treatment response.

Phenotypes of liver disease due to chronic hepatitis C virus (HCV) infection show a wide range of variations in terms of histological manifestations and the clinical outcome. Sensing of viral double-stranded RNA (dsRNA) by Toll-like receptor 3 (TLR3) is likely involved in early pathogen detection and the host response to viral infection. This study analyzed epidemiological and clinical data from a total of 137 patients with chronic HCV infection with regard to two polymorphic positions within the TLR3 gene: rs5743305 (T/A) is located within the promoter region and might affect transcriptional activity, rs3775291 (C/T) is a non-synonymous single nucleotide polymorphism (SNP) located within exon 4 and the variant receptor has been shown to be functionally impaired. TLR3 promoter and the exon 4 variations were not found to be associated with TLR3 gene expression in peripheral blood mononuclear cells (PBMCs). In the liver, however, a tendency of higher TLR3 gene expression was found for exon 4 TT genotypes. Both variations were not found to be associated with clinical parameters of chronic disease. On the other hand, an analysis of the TLR3 exon 4 genotype distribution with respect to HCV subtype revealed an absence of TT genotype among HCV subtype 1a infected individuals. This study thus failed to reveal any association of the two SNPs under investigation with clinical parameters of chronic hepatitis C. However, data argue for a functional relevance of the exon 4 SNP in terms of conferring a different susceptibility towards HCV subtype infection.

Cytochrome P450 (CYP) enzymes, involved in metabolism of tobacco carcinogens, are also involved in estrogen metabolism and many are regulated by estrogens. These genes may thus be of relevance to gender-specific differences in lung cancer risk, particularly in early-onset lung cancer, where a high proportion of women is observed. We conducted a case-control study to investigate genetic polymorphisms in cytochromes that might modify the risk of developing early-onset lung cancer. In total, 638 Caucasian patients under the age of 51 with primary lung cancer and 1300 cancer-free control individuals, matched by age and sex, were included in this analysis. Thirteen polymorphisms in the CYP1A1, CYP1B1, CYP2A13, CYP3A4 and CYP3A5 genes were analyzed. No significant association was found for any of the analyzed polymorphisms and lung cancer risk overall. However, among women, a significantly increased risk of early-onset lung cancer was observed for carriers of the minor allele of CYP1B1 SNP rs1056836 [odds ratio (OR) 1.97; 95% confidence interval (CI) 1.32-2.94; P < 0.001]. Also, a non-significant increase in lung cancer risk was observed in the group of women carriers of the minor allele of CYP2A13 SNP rs1709084 (OR 1.64; 95% CI 1.00-2.70; P = 0.05). The effect of these two polymorphisms was shown to be modified by smoking. Haplotype analysis was performed for CYP1B1 and CYP2A13. No differences between cases and controls were observed for both genes (P = 0.63 and P = 0.42 for CYP1B1 and CYP2A13, respectively). Our results suggest that the CYP1B1 and the CYP2A13 genotypes may contribute to individual susceptibility to early-onset lung cancer in women.

Objectives Deletion polymorphisms of Glutathione-S-transferase (GST) M1 and T1 are considered risk factors for various diseases. However, most previous studies only distinguished “null” and “non-null” genotypes. Our aim was to develop a reliable, high-throughput GSTM1/T1 genotyping method able to determine allele copy numbers. Design and methods We developed a multiplex real time PCR method to distinguish between heterozygous (1/0) and homozygous (1/1) GSTM1 and GSTT1 genotypes. The principle of relative quantification was applied and an expectation–maximisation (EM) algorithm was developed to assign one of 3 possible genotypes: 1/1, 1/0 or 0/0 for each of the two genes. Results 1320 Caucasians were genotyped using the newly developed method. The observed genotype distributions did not deviate from the expected and were in Hardy–Weinberg equilibrium. GSTM1 duplication was detected in one sample. Conclusion This new semiquantitative genotyping method is a sensitive and promising tool for large-scale molecular epidemiological and clinical studies.

Patched (Ptch) heterozygous mice develop medulloblastoma (MB) and rhabdomyosarcoma (RMS) resembling the corresponding human tumors. We have previously shown that epigenetic silencing of the intact Ptch allele contributes to tumor formation in this model. Here, we investigated whether targeting of epigenetic silencing mechanisms could be useful in the treatment of Ptch-associated cancers. A reduction of endogenous DNA methyltransferase1 (Dnmt1) activity significantly reduced tumor incidence in heterozygous Ptch knockout mice. A combined treatment with the Dnmt inhibitor 5-aza-2′deoxycytidine (5-aza-dC) and the histone deacetlyase (HDAC) inhibitor valproic acid (VPA) efficiently prevented MB and RMS formation, whereas monotherapies with either drug were less effective. Wild-type Ptch expression was efficiently reactivated in tumors by 5-aza-dC/VPA combination therapy. This was associated with reduced methylation of the Ptch promoter and induction of histone hyperacetylation suggesting inhibition of HDACs in vivo. However, the treatment was not effective in clinically overt, advanced stage tumors. This is a first in vivo demonstration that targeting of Dnmt and HDAC activities is highly effective in preventing formation of Ptch-associated tumors. The results suggest a novel clinical strategy for consolidation therapy of corresponding tumors in humans after completion of conventional treatment. Our data also suggest that epigenetic therapy may be less effective in treating advanced stages of tumors, at least in this tumor model. [Cancer Res 2009;69(3):887–95]

Endothelin is the most potent endogenous vasoconstrictor and is involved in several vascular disorders such as arterial hypertension. Its intense interaction with other vasoactive hormone systems revealed the consideration about the endothelin gene as an interesting candidate for influencing the development of essential hypertension and hypertensive endorgan damage. The purpose of this study was to investigate the role of endothelin-1 Lys198Asn polymorphism in patients with severe arterial hypertension as well as associated endorgan damages.In 400 hypertensive patients and 150 normotensive controls we examined the endothelin-1 Lys198Asn polymorphism by DNA sequencing and patients were divided according to their genotype (GG, GT, and TT). Moreover, the frequency of endothelin-1 Lys198Asn polymorphism was investigated with respect to the prevalence of several actual or historical endorgan damages (renal disorder, coronary artery disease, vascular events, vascular damage, and congestive heart failure) in hypertensive patients.Genotype distribution for endothelin-1 Lys198Asn polymorphism was 57.3% (GG), 41.3% (GT), and 1.43% (TT) in normotensive individuals; and in hypertensive individuals was 54.75% (GG), 43% (GT) and 2.25% (TT). Genotype distribution was unaffected in patients with severe hypertension, renal disorder, vascular events, vascular damage, and congestive heart failure. We, however, found a significant difference in hypertensive individuals with coronary artery disease and TT genotype (P=0.004).Homozygous TT carrier contributes to a higher prevalence of coronary artery disease, especially for three-vessel disease in hypertensive individuals. Thus, the polymorphism at position 198 could serve as a possibility to differentiate high-risk subgroups in the heterogeneous population of hypertensive patients.

Ataxia-telangiectasia (A-T) is an autosomal recessive disease characterized by neurological and immunological symptoms, radiosensitivity, and cancer predisposition. Heterozygous carriers of risk mutations in the A-T gene are predisposed to epithelial cancers. We initiated a study to elucidate the frequency and clinical relevance of ATM gene mutations in lung cancer patients of the young (LUCY) and compared the results with population-based control subjects from southwest Germany (KORA=Cooperative Health Research in the Region of Augsburg).In this study, the clinical relevance of ATM gene mutations (S707P; 1066-6T--G; 2250G--A, 7630A--C, E1978X, R2443X, 3801delG, S49C, and D2625EA2626P, L1420F, P1045R) in 183 young lung cancer patients (50 years) is evaluated. The control population was comprised of 200 cancer-free subjects from the KORA study.A total of 25 heterozygous carriers of ATM in the LUCY, respectively; 32 heterozygotes in the KORA group were identified. The observed allele frequencies in the LUCY cases were within the range detected for the control subjects (KORA). Multiple analyses of lung cancer patients who carried at least one risk allele of the ATM did not show significantly elevated or reduced risks.In this study, 16% of the German control subjects had ATM variants. ATM variants were detected in about 14% of the lung cancer patients and did not differ significantly from the control subjects. In comparison to young lung cancer patients, ATM gene mutations had no detectable relevant modifying effect on lung cancer risk.

Objective: To find genetic markers of the individual cytochrome P450 (CYP)3A expression. Methods: A large collection of liver samples phenotyped for CYP3A expression and activity was genotyped for CYP3A variants. Data were analyzed for associations between CYP3A phenotypes and genotypes, and for evidence of recent selection. Results: We report associations between the hepatic CYP3A4 protein expression level, as well as its enzymatic activity, measured as verapamil N-dealkylation, and genetic polymorphisms from two regions within the CYP3A gene cluster. One region is defined by several variants, mostly located within CYP3A7, the other by a single nucleotide polymorphism in intron 7 of CYP3A4. The effects of these single nucleotide polymorphisms are sex-dependent. For example, female carriers of T alleles of the single nucleotide polymorphism rs4646437C>T in CYP3A4 intron 7 have, respectively, 5.1-fold and 2.7-fold higher expression and activity compared with male T-carriers, but only 2.2-fold and 1.4-fold higher expression and activity compared with males of genotype CC. A regression analysis indicates that the impact of these single nucleotide polymorphisms in men goes beyond the previously reported sex effect. The rs4646437C undergoes positive selection in Caucasians, as evidenced by its relative extended haplotype homozygosity value located within the uppermost percentile of a genome-wide test set of haplotypes in the same 5% frequency bin. Conclusions: Our findings reconcile the apparent contradiction between the evidence for the influence of the individual genetic makeup on CYP3A4 expression and activity suggested by clinical studies, and the failure to identify the responsible gene variants.

Results from genome-wide association studies (GWAS) have indicated that strong single-gene effects are the exception, not the rule, for most diseases. We assessed the joint effects of germline genetic variations through a pathway-based approach that considers the tissue-specific contexts of GWAS findings. From GWAS meta-analyses of lung cancer (12 160 cases/16 838 controls), breast cancer (15 748 cases/18 084 controls) and prostate cancer (14 160 cases/12 724 controls) in individuals of European ancestry, we determined the tissue-specific interaction networks of proteins expressed from genes that are likely to be affected by disease-associated variants. Reactome pathways exhibiting enrichment of proteins from each network were compared across the cancers. Our results show that pathways associated with all three cancers tend to be broad cellular processes required for growth and survival. Significant examples include the nerve growth factor (P = 7.86 × 10(-33)), epidermal growth factor (P = 1.18 × 10(-31)) and fibroblast growth factor (P = 2.47 × 10(-31)) signaling pathways. However, within these shared pathways, the genes that influence risk largely differ by cancer. Pathways found to be unique for a single cancer focus on more specific cellular functions, such as interleukin signaling in lung cancer (P = 1.69 × 10(-15)), apoptosis initiation by Bad in breast cancer (P = 3.14 × 10(-9)) and cellular responses to hypoxia in prostate cancer (P = 2.14 × 10(-9)). We present the largest comparative cross-cancer pathway analysis of GWAS to date. Our approach can also be applied to the study of inherited mechanisms underlying risk across multiple diseases in general.

Large-scale genome-wide association studies (GWAS) have likely uncovered all common variants at the GWAS significance level. Additional variants within the suggestive range (0.0001> P > 5×10(-8)) are, however, still of interest for identifying causal associations. This analysis aimed to apply novel variant prioritization approaches to identify additional lung cancer variants that may not reach the GWAS level. Effects were combined across studies with a total of 33456 controls and 6756 adenocarcinoma (AC; 13 studies), 5061 squamous cell carcinoma (SCC; 12 studies) and 2216 small cell lung cancer cases (9 studies). Based on prior information such as variant physical properties and functional significance, we applied stratified false discovery rates, hierarchical modeling and Bayesian false discovery probabilities for variant prioritization. We conducted a fine mapping analysis as validation of our methods by examining top-ranking novel variants in six independent populations with a total of 3128 cases and 2966 controls. Three novel loci in the suggestive range were identified based on our Bayesian framework analyses: KCNIP4 at 4p15.2 (rs6448050, P = 4.6×10(-7)) and MTMR2 at 11q21 (rs10501831, P = 3.1×10(-6)) with SCC, as well as GAREM at 18q12.1 (rs11662168, P = 3.4×10(-7)) with AC. Use of our prioritization methods validated two of the top three loci associated with SCC (P = 1.05×10(-4) for KCNIP4, represented by rs9799795) and AC (P = 2.16×10(-4) for GAREM, represented by rs3786309) in the independent fine mapping populations. This study highlights the utility of using prior functional data for sequence variants in prioritization analyses to search for robust signals in the suggestive range.

We analyzed the value of digital epiluminescence microscopy (DELM) for the long-term follow-up of atypical nevi. Patients (n=530) were prospectively categorized into defined melanoma risk groups and followed by clinical and epiluminescence microscopy (ELM) examinations. Atypical nevi (n=7001) were additionally followed by DELM. During follow-up (median 32.2 months), we detected 53 melanomas among 637 excised lesions (8.3% overall chance of success). The chance of success for melanoma detection among lesions suspicious by ELM criteria was increased to 17% when additional DELM-documented changes were present. Moreover, 18 of the 53 melanomas were exclusively identified by DELM-documented changes, indicating that DELM increased the sensitivity of the ELM analysis by identifying additional melanomas. However, for lesions exclusively excised due to DELM changes, the chance of success was lower than for ELM (5.2 vs 11.8%). Excisions due to mere DELM changes detected 66.7% of melanomas in familial atypical mole and multiple melanoma (FAMMM) and 32.5% of melanomas in atypical mole syndrome (AMS) patients. We conclude that DELM is a valuable tool for the long-term follow-up of atypical nevi, especially in the high-risk groups of FAMMM and AMS patients. Randomized controlled trials are needed to validate the data from this clinical trial.