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Defects in DNA repair pathways have been associated with an improved response to immune checkpoint inhibition (ICI). In particular, patients with the nucleotide excision repair (NER) defect disease Xeroderma pigmentosum (XP) responded impressively well to ICI treatment. Recently, in melanoma patients, pretherapeutic XP gene expression was predictive for anti-programmed cell death-1 (PD-1) ICI response. The underlying mechanisms of this finding are still to be revealed. Therefore, we used CRISPR/Cas9 to disrupt XPA in A375 melanoma cells. The resulting subclonal cell lines were investigated by Sanger sequencing. Based on their genetic sequence, candidates from XPA exon 1 and 2 were selected and further analyzed by immunoblotting, immunofluorescence, HCR and MTT assays. In XPA exon 1, we established a homozygous (c.19delG; p.A7Lfs*8) and a compound heterozygous (c.19delG/c.19_20insG; p.A7Lfs*8/p.A7Gfs*55) cell line. In XPA exon 2, we generated a compound heterozygous mutated cell line (c.206_208delTTG/c.208_209delGA; p.I69_D70delinsN/p.D70Hfs*31). The better performance of the homozygous than the heterozygous mutated exon 1 cells in DNA damage repair (HCR) and post-UV-C cell survival (MTT), was associated with the expression of a novel XPA protein variant. The results of our study serve as the fundamental basis for the investigation of the immunological consequences of XPA disruption in melanoma.

Introduction: Cold atmospheric plasma (CAP) has positive effects on wound healing and antimicrobial properties. However, an ongoing challenge is the development of specific modes of application for different clinical indications. Objectives: We investigated in a prospective pilot study the response and tolerability of a newly developed CAP wound dressing for the acute healing of split skin graft donor sites compared to conventional therapy. Methods: We applied both treatments to each patient (n = 10) for 7 days and measured 4 parameters of wound healing every other day (i.e., 1,440 measurements) using a hyperspectral imaging camera. Additionally, we evaluated the clinical appearance and pain levels reported by the patients. Results: The CAP wound dressing was superior to the control (p < 0.001) in the improvement of 3 wound parameters, that is, deep tissue oxygen saturation, hemoglobin distribution, and tissue water distribution. CAP was well tolerated, and pain levels were lower in CAP-treated wound areas. Conclusion: CAP wound dressing is a promising new tool for acute wound healing.

Purpose Uveal melanoma (UM) is an orphan cancer of high unmet medical need. Current patterns of care and surveillance remain unclear as they are situated in an interdisciplinary setting. Methods A questionnaire addressing the patterns of care and surveillance in the management of patients with uveal melanoma was distributed to 70 skin cancer centers in Austria, Germany and Switzerland. Frequency distributions of responses for each item of the questionnaire were calculated. Results 44 of 70 (62.9%) skin cancer centers completed the questionnaire. Thirty-nine hospitals were located in Germany (88.6%), three in Switzerland (6.8%) and two in Austria (4.5%). The majority (68.2%) represented university hospitals. Most patients with metastatic disease were treated in certified skin cancer centers (70.7%, 29/41). Besides, the majority of patients with UM were referred to the respective skin cancer center by ophthalmologists (87.2%, 34/39). Treatment and organization of follow-up of patients varied across the different centers. 35.1% (14/37) of the centers stated to not perform any screening measures. Conclusion Treatment patterns of patients with uveal melanoma in Germany, Austria and Switzerland remain extremely heterogeneous. A guideline for the treatment and surveillance is urgently needed.

Neben akuten Wunden durch Traumen oder chirurgische Eingriffe stellen chronische Wunden eine relativ grose, heterogene Erkrankungsgruppe dar. Dazu zahlen Beinulzera, bei denen die venose Genese die der arteriellen Genese deutlich ubertrifft, aber auch das diabetische Fussyndrom und Druckulzera. Aufgrund der Therapieresistenz v. a. chronischer Wunden werden dringend weitere, additiv wirksame Therapieoptionen benotigt. Die zusatzliche Behandlung mit kaltem Atmospharendruckplasma (KAP) stellt eine derartige innovative Option dar. Betrachtet wird die Wirkung von Kaltplasma auf die Heilung akuter und chronischer Wunden, und es wird der aktuelle Stand der Forschung aufgezeigt. Literatur zur Anwendung von KAP zur Wundbehandlung wurde gesichtet und als Ubersichtsarbeit zusammengefasst. Mit einer KAP-Behandlung konnen mehrere wundheilungsfordernde Effekte in einer Anwendung erzielt werden. Zum einen besitzt KAP eine starke und breite antimikrobielle Aktivitat auch gegen Biofilm. Zum anderen mediiert der Plasmacocktail, der aus reaktiven Stickstoff- und Sauerstoffspezies, UV und geladenen Teilchen (Stromfluss) besteht, gewebestimulierende und durchblutungsfordernde sowie antiinflammatorische Effekte. Eine deutliche Reduktion der Keimbesiedelung und eine schnellere Wundheilung konnten in kontrollierten Studien bereits klar nachgewiesen werden. Die mittlerweile umfassende Studienlandschaft mit strukturierten Fallberichten und randomisierten Fall-Kontroll-Studien lasst den Schluss zu, dass KAP zur Wundbehandlung sicher, effektiv und einfach einsetzbar ist. Die Anwendung von KAP zur Wundbehandlung hat vereinzelt bereits den Einzug in die klinische Routine gefunden.

Choosing the adequate systemic treatment for melanoma is driven by clinical parameters and personal preferences.Evaluation of the impact of disease and treatment on the daily life of patients receiving systemic therapy for melanoma.A German-wide, cross-sectional comparative study was conducted at 13 specialized skin cancer centres from 08/2020 to 03/2021. A questionnaire was distributed to assess patients' perception of disease and symptoms, the impact of their current treatment on quality of life (QOL) and activities, adverse events (AEs), therapeutic visits, as well as believe in and satisfaction with their current systemic melanoma treatment. Patient-reported outcomes (PROs) were rated on a continuous numerical rating scale or selected from a given list.Four hundred and fourteen patients with systemic melanoma therapy were included. 359 (87%) received immune checkpoint inhibition (ICI) and 55 (13%) targeted therapy (TT). About 1/3 of patients were adjuvantly treated, the remaining because of unresectable/metastatic melanoma. In subgroup analyses, only in the adjuvant setting, TT patients reported a significant decrease in their treatment associated QOL compared to patients with ICI (p = 0.02). Patients with TT were 1.9 times more likely to report AEs than patients with ICI, a difference being significant just for the adjuvant setting (p = 0.01). ICI treatment intervals differed significantly between adjuvant and unresectable/metastatic setting (p = 0.04), though all patients, regardless of their specific ICI drug, evaluated their treatment frequency as adequate. TT patients with dabrafenib/trametinib (n = 37) or encorafenib/binimetinib (n = 15) did not differ regarding the strain of daily pill intake. Patients older than 63 years rated various PROs better than younger patients.Patients evaluated their treatment mainly positively. ICI might be preferred over TT regarding QOL and patient-reported AEs in the adjuvant setting. Older melanoma patients appeared to be less impacted by their disease and more satisfied with their treatment.

BackgroundAssessment of immune-specific markers is a well-established approach for predicting the response to immune checkpoint inhibitors (ICIs). Promising candidates as ICI predictive biomarkers are the DNA damage response pathway genes. One of those pathways, which are mainly responsible for the repair of DNA damage caused by ultraviolet radiation, is the nucleotide excision repair (NER) pathway. Xeroderma pigmentosum (XP) is a hereditary disease caused by mutations of eight different genes of the NER pathway, or POLH, here together named the nine XP genes. Anecdotal evidence indicated that XP patients with melanoma or other skin tumors responded impressively well to anti-PD-1 ICIs. Hence, we analyzed the expression of the nine XP genes as prognostic and anti-PD-1 ICI predictive biomarkers in melanoma.MethodsWe assessed mRNA gene expression in the TCGA-SKCM dataset (n = 445) and two pooled clinical melanoma cohorts of anti-PD-1 ICI (n = 75). In TCGA-SKCM, we applied hierarchical clustering on XP genes to reveal clusters, further utilized as XP cluster scores. In addition, out of 18 predefined genes representative of a T cell inflamed tumor microenvironment, the TIS score was calculated. Besides these scores, the XP genes, immune-specific single genes (CD8A, CXCL9, CD274, and CXCL13) and tumor mutational burden (TMB) were cross-correlated. Survival analysis in TCGA-SKCM was conducted for the selected parameters. Lastly, the XP response prediction value was calculated for the two pooled anti-PD-1 cohorts by classification models.ResultsIn TCGA-SKCM, expression of the XP genes was divided into two clusters, inversely correlated with immune-specific markers. A higher ERCC3 expression was associated with improved survival, particularly in younger patients. The constructed models utilizing XP genes, and the XP cluster scores outperformed the immune-specific gene-based models in predicting response to anti-PD-1 ICI in the pooled clinical cohorts. However, the best prediction was achieved by combining the immune-specific gene CD274 with three XP genes from both clusters.ConclusionOur results suggest pre-therapeutic XP gene expression as a potential marker to improve the prediction of anti-PD-1 response in melanoma.

Background In recent studies, convolutional neural networks (CNNs) outperformed dermatologists in distinguishing dermoscopic images of melanoma and nevi. In these studies, dermatologists and artificial intelligence were considered as opponents. However, the combination of classifiers frequently yields superior results, both in machine learning and among humans. In this study, we investigated the potential benefit of combining human and artificial intelligence for skin cancer classification. Methods Using 11,444 dermoscopic images, which were divided into five diagnostic categories, novel deep learning techniques were used to train a single CNN. Then, both 112 dermatologists of 13 German university hospitals and the trained CNN independently classified a set of 300 biopsy-verified skin lesions into those five classes. Taking into account the certainty of the decisions, the two independently determined diagnoses were combined to a new classifier with the help of a gradient boosting method. The primary end-point of the study was the correct classification of the images into five designated categories, whereas the secondary end-point was the correct classification of lesions as either benign or malignant (binary classification). Findings Regarding the multiclass task, the combination of man and machine achieved an accuracy of 82.95%. This was 1.36% higher than the best of the two individual classifiers (81.59% achieved by the CNN). Owing to the class imbalance in the binary problem, sensitivity, but not accuracy, was examined and demonstrated to be superior (89%) to the best individual classifier (CNN with 86.1%). The specificity in the combined classifier decreased from 89.2% to 84%. However, at an equal sensitivity of 89%, the CNN achieved a specificity of only 81.5% Interpretation Our findings indicate that the combination of human and artificial intelligence achieves superior results over the independent results of both of these systems.

The prevalence of pathological skin-picking (PSP) has predominantly been studied in students and the community, but not yet in dermatological patients. However, those may be at increased risk of PSP because it is often triggered by the feel or look of the skin. Thus, its prevalence among patients with a physician-diagnosed dermatological disease remains to be determined.A consecutive series of 460 adult patients attending a dermatological university outpatient clinic was administered the 8-item Skin Picking Scale-Revised (SPS-R). They also reported demographic data and rated the severity of their skin disease. The dermatologist evaluating the patient provided his/her diagnosis.PSP as defined by SPS-R scores ≥7 was reported by 121 participants (26.3%). It was significantly more frequent in patients with atopic dermatitis (AD, OR = 3.23; 95% CI: 1.95-5.68) and psoriasis (OR = 1.64; 95% CI: 1.00-2.67), but less frequent in those with malignant epithelial skin tumors (OR = 0.10; 95% CI: 0.02-0.43). PSP was not associated with female gender or younger age.Our findings indicate that PSP affects about one in four patients with skin disease. In particular, individuals suffering from atopic dermatitis may represent a high-risk population for PSP deserving early recognition and adequate treatment.

Cold atmospheric pressure plasma (CAP) has antimicrobial and wound-healing properties. Patients affected by severe autosomal recessive dystrophic epidermolysis bullosa (RDEB) suffer from widespread, difficult-to-treat wounds, which require complex wound management.In a pilot project, we investigated over a period of 5 months the response and tolerability of a CAP wound therapy in a 21-year-old and a 28-year-old female patient with severe generalized RDEB and following cutaneous squamous cell cancer (cSSC) in the older patient.In both patients, diagnosis of RDEB was confirmed by molecular genetics. Individual- and patient-specific wound therapy was continued during the study period, and additionally CAP therapy with a dielectric barrier discharge (DBE) device was initiated. CAP treatment was performed for 90 s per wound and could be applied every day or every other day. Clinical evaluation included photographic documentation and regular interviews of patients and parents.CAP-treated wounds largely demonstrated improved wound healing and signs of a reduced bacterial contamination. Furthermore, CAP proved to prevent wound chronification. When applied on a polyester mesh, it was well-tolerated on most body sites.The introduction of CAP could improve the wound management of EB patients and should be evaluated in clinical studies. The effect of CAP on cSSC development should be particularly studied.HINTERGRUND: Kaltes Atmosphärendruckplasma (KAP) hat antimikrobielle und wundheilungsfördernde Eigenschaften. Betroffene der seltenen schweren rezessiven Epidermolysis bullosa (EB) dystrophica leiden an großflächigen, schwierig zu behandelnden Wunden, die eine komplexe Wundtherapie erfordern.In einem Pilotprojekt untersuchten wir über 5 Monate das Ansprechen und die Verträglichkeit einer KAP-Wundtherapie bei einer 21-jährigen und einer 28-jährigen Patientin mit schwerer rezessiver EB dystrophica sowie Zustand nach kutanen Plattenepithelkarzinomen (PEK) bei der älteren Patientin.Bei beiden Patientinnen wurde die Diagnose im Vorfeld molekulargenetisch bestätigt. Die individuelle, patientenspezifische Wundtherapie wurde fortgeführt und zusätzlich unterstützend ein DBE(„dielektrisch behinderte Entladung“)-basiertes KAP-Gerät eingesetzt. Die KAP-Behandlung betrug 90 s pro Wunde und konnte entweder täglich oder alle 2 Tage erfolgen. Die klinische Evaluation erfolgte mittels Fotodokumentation und durch regelmäßige Befragung der Patientinnen und Eltern.KAP-behandelte Wunden zeigten eine schnellere Heilungstendenz und Hinweise auf eine geringere bakterielle Besiedlung. Einer Chronifizierung der behandelten Wunden konnte vorgebeugt werden. Die KAP-Anwendung erfolgte nach vorheriger Auflage eines Polyestergitters auf die Wunden und wurde an den meisten Lokalisationen gut vertragen.Der Einsatz von KAP könnte die Wundtherapie bei EB-Patienten verbessern und sollte in klinischen Studien untersucht werden. Inwieweit KAP die Entwicklung von kutanen PEK verringern kann, ist dabei besonders zu evaluieren.

Background: Recently, convolutional neural networks (CNNs) systematically outperformed dermatologists in distinguishing dermoscopic melanoma and nevi images. However, such a binary classification does not reflect the clinical reality of skin cancer screenings in which multiple diagnoses need to be taken into account. Methods: Using 11,444 dermoscopic images, which covered dermatologic diagnoses comprising the majority of commonly pigmented skin lesions commonly faced in skin cancer screenings, a CNN was trained through novel deep learning techniques. A test set of 300 biopsy-verified images was used to compare the classifier's performance with that of 112 dermatologists from 13 German university hospitals. The primary end-point was the correct classification of the different lesions into benign and malignant. The secondary end-point was the correct classification of the images into one of the five diagnostic categories. Findings: Sensitivity and specificity of dermatologists for the primary end-point were 74.4% (95% confidence interval [CI]: 67.0–81.8%) and 59.8% (95% CI: 49.8–69.8%), respectively. At equal sensitivity, the algorithm achieved a specificity of 91.3% (95% CI: 85.5–97.1%). For the secondary end-point, the mean sensitivity and specificity of the dermatologists were at 56.5% (95% CI: 42.8–70.2%) and 89.2% (95% CI: 85.0–93.3%), respectively. At equal sensitivity, the algorithm achieved a specificity of 98.8%. Two-sided McNemar tests revealed significance for the primary end-point (p < 0.001). For the secondary end-point, outperformance (p < 0.001) was achieved except for basal cell carcinoma (on-par performance). Interpretation: Our findings show that automated classification of dermoscopic melanoma and nevi images is extendable to a multiclass classification problem, thus better reflecting clinical differential diagnoses, while still outperforming dermatologists at a significant level (p < 0.001).

Background: The outcome of patients with macroscopic stage III melanoma is poor. Neoadjuvant treatment with ipilimumab plus nivolumab at the standard dosing schedule induced pathological responses in a high proportion of patients in two small independent early-phase trials, and no patients with a pathological response have relapsed after a median follow up of 32 months. However, toxicity of the standard ipilimumab plus nivolumab dosing schedule was high, preventing its broader clinical use. The aim of the OpACIN-neo trial was to identify a dosing schedule of ipilimumab plus nivolumab that is less toxic but equally effective. Methods: OpACIN-neo is a multicentre, open-label, phase 2, randomised, controlled trial. Eligible patients were aged at least 18 years, had a WHO performance status of 0–1, had resectable stage III melanoma involving lymph nodes only, and measurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1. Patients were enrolled from three medical centres in Australia, Sweden, and the Netherlands, and were randomly assigned (1:1:1), stratified by site, to one of three neoadjuvant dosing schedules: group A, two cycles of ipilimumab 3 mg/kg plus nivolumab 1 mg/kg once every 3 weeks intravenously; group B, two cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg once every 3 weeks intravenously; or group C, two cycles of ipilimumab 3 mg/kg once every 3 weeks directly followed by two cycles of nivolumab 3 mg/kg once every 2 weeks intravenously. The investigators, site staff, and patients were aware of the treatment assignment during the study participation. Pathologists were masked to treatment allocation and all other data. The primary endpoints were the proportion of patients with grade 3–4 immune-related toxicity within the first 12 weeks and the proportion of patients achieving a radiological objective response and pathological response at 6 weeks. Analyses were done in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02977052, and is ongoing with an additional extension cohort and to complete survival analysis. Findings: Between Nov 24, 2016 and June 28, 2018, 105 patients were screened for eligibility, of whom 89 (85%) eligible patients were enrolled and randomly assigned to one of the three groups. Three patients were excluded after randomisation because they were found to be ineligible, and 86 received at least one dose of study drug; 30 patients in group A, 30 in group B, and 26 in group C (accrual to this group was closed early upon advice of the Data Safety Monitoring Board on June 4, 2018 because of severe adverse events). Within the first 12 weeks, grade 3–4 immune-related adverse events were observed in 12 (40%) of 30 patients in group A, six (20%) of 30 in group B, and 13 (50%) of 26 in group C. The difference in grade 3–4 toxicity between group B and A was -20% (95% CI -46 to 6; p = 0·158) and between group C and group A was 10% (-20 to 40; p = 0·591). The most common grade 3–4 adverse events were elevated liver enzymes in group A (six [20%)]) and colitis in group C (five [19%]); in group B, none of the grade 3–4 adverse events were seen in more than one patient. One patient (in group A) died 9·5 months after the start of treatment due to the consequences of late-onset immune-related encephalitis, which was possibly treatment-related. 19 (63% [95% CI 44–80]) of 30 patients in group A, 17 (57% [37–75]) of 30 in group B, and nine (35% [17–56]) of 26 in group C achieved a radiological objective response, while pathological responses occurred in 24 (80% [61–92]) patients in group A, 23 (77% [58–90]) in group B, and 17 (65% [44–83]) in group C. Interpretation: OpACIN-neo identified a tolerable neoadjuvant dosing schedule (group B: two cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg) that induces a pathological response in a high proportion of patients and might be suitable for broader clinical use. When more mature data confirm these early observations, this schedule should be tested in randomised phase 3 studies versus adjuvant therapies, which are the current standard-of-care systemic therapy for patients with stage III melanoma. Funding: Bristol-Myers Squibb.

Anti-PD-1 targeted immunotherapies have revolutionized the treatment of advanced melanoma and other tumor entities, and long disease-free intervals have been reported in responding patients. However, a considerable number of patients still progress rapidly after the start of anti-PD-1 antibodies. Here, we document two patients, 78 and 85-year old, who suffered from advanced BRAF-V600 wild-type melanoma and received pembrolizumab 2 mg/kg every 3 weeks as the first systemic treatment. After only one, respectively, two infusions of pembrolizumab, both patients developed melanuria and diffuse melanosis cutis (DMC) on sun-exposed areas of their skin. Both also had liver metastases, which have been reported to be associated with DMC before. Pembrolizumab was stopped because of rapid tumor progression and both patients died within 2 months after manifestation of DMC. We conclude that DMC is a condition that may be a negative predictor of response to anti-PD-1 treatment. With respect to the very short survival, which is even shorter than that reported after conventional therapies, it needs to be evaluated whether immunotherapy may be a (relative) contraindication in DMC patients when another treatment option, that is targeted therapy, is available.

Background Increasing knowledge of cancer genomes has triggered the development of specific targeted inhibitors, thus providing a valuable therapeutic pool. Methods In this report, the authors analyze the presence of targetable alterations in 136 tumor samples from 92 patients with melanoma using a comprehensive approach based on targeted DNA sequencing and supported by RNA and protein analysis. Three topics of high clinical relevance are addressed: the identification of rare, activating alterations; the detection of patient-specific, co-occurring single nucleotide variants (SNVs) and copy number variations (CNVs) in parallel pathways; and the presence of cancer-relevant germline mutations. Results The analysis of patient-matched blood and tumor samples was done with a custom-designed gene panel that was enriched for genes from clinically targetable pathways. To detect alterations with high therapeutic relevance for patients with unknown driver mutations, genes that are untypical for melanoma also were included. Among all patients, CNVs were identified in one-third of samples and contained amplifications of druggable kinases, such as CDK4, ERBB2, and KIT. Considering SNVs and CNVs, 60% of patients with metastases exhibited co-occurring activations of at least 2 pathways, thus providing a rationale for individualized combination therapies. Unexpectedly, 9% of patients carry potentially protumorigenic germline mutations frequently affecting receptor tyrosine kinases. Remarkably two-thirds of BRAF/NRAS wild-type melanomas harbor activating mutations or CNVs in receptor tyrosine kinases. Conclusions The results indicate that the integrated analysis of SNVs, CNVs, and germline mutations reveals new druggable targets for combination tumor therapy.

As the atmospheric system is characterized by highly complex interactions between a large number of physical variables, it is a challenging task for researchers to break up the complicated structures into a few significant modes of variability. An innovative technique, called Non-negative Matrix Factorization (NMF), developed to provide a reduced-dimensional representation of large-scale non-negative data and to extract underlying features, is introduced as a tool for meteorological applications. The method is used to decompose space-time meteorological fields into spatial patterns and associated time indices in order to advance our knowledge of dominant atmospheric processes. For the Northern Hemisphere the 500 hPa geopotential field together with sea level pressure (SLP) are analysed using an up-to-date NMF algorithm as well as a helpful method of NMF initialization based on Singular Value Decomposition (SVD). Several NMF patterns correspond to the variations identified by traditional EOF analysis, such as the East Atlantic and the Pacific/North American Pattern. For the North Atlantic Oscillation the NMF identifies sub-patterns: The positive phase is associated with systems of pressure variation over the Pacific Ocean and the Arctic, respectively, the negative phase resembles the EOF pattern. As the NMF patterns not only represent variability, like EOF patterns, but also are fractions of the total observed values, we demonstrate for a location near Nikolski, Alaska, the temporal development of the geopotential as a superposition of NMF-factors. Copyright © 2009 Royal Meteorological Society

Objective: Growth factor gene therapy represents one current approach in the therapy of myocardial ischemia. We assessed the in vitro and in vivo expression of naked plasmid DNA aiming at preservation of function in a chronically ischemic myocardial model. Methods: In vitro: Primary cardiac fibroblasts were transfected with plasmids encoding enhanced green fluorescent protein, human VEGF 121 , human FGF-2, or porcine MCP-1. Protein synthesis was assessed microscopically, by ELISA, Western blotting, or intracellular immunofluorescence. In vivo: A LAD stenosis was created in healthy pigs. One week later, segmental myocardial shortening (SMS) and systemic hemodynamics (left ventricular stroke work index, LVSWI, time derivative of left ventricular pressure, dp/dt max ) were assessed at baseline. Afterwards, the ischemic area received either intramyocardial injections of naked cytokine plasmid DNA or vector only, or was left untreated. One myocardial sample taken 1 h after plasmid injection was subjected to RT-PCR and PCR. After 3 months, cardiac function was re-examined. Results: In vitro: Transfection of cardiac fibroblasts resulted in high gene expression for several days. In vivo: Plasmid-specific DNA and mRNA were found 1 h after plasmid injection (n = 1). After 3 months, VEGF, FGF-2, and vector rendered better results of regional contractility at rest and of LVSWI. However, only VEGF and FGF-2 were effective with regard to regional contractility under dobutamine stress and to left ventricular contractility. Conclusion: In conclusion, intramyocardial injection of naked plasmid DNA encoding VEGF 121 or FGF-2 improved myocardial function in chronic ischemia in more aspects than vector only and was superior to untreated ischemia or MCP-1. This strategy can be considered a successful tool for growth factor stimulated preservation of function in chronic myocardial ischemia.

There are many factors determining the concentration of volatile organic compounds (VOCs) in indoor air. On the basis of 601 population-based measurements we develop an explicit exposure model that includes factors, such as renovation, furniture, flat size, smoking, and education level of the occupants. As a novel method for the evaluation of concentrations of indoor air pollutants we use quantile regression, which has the advantages of robustness against non-Gaussian distributions (and outliers) and can adjust for unbalanced frequencies of observations. The applied bi- and multivariate quantile regressions provide (1) the VOC burden that is representative for the population of Leipzig, Germany, and (2) an inter-comparison of the effects of the studied factors and their levels. As a result, we find strong evidence for factors of general impact on most VOC components, such as the season, flooring, the type of the room, and the size of the apartment. Other impact factors are very specific to the VOC components. For example, wooden flooring (parquet) and new furniture increase the concentration of terpenes as well as the modifying factors high education and sampling in the child's room. Smokers ventilate their flats in an extent that in general reduces the VOC concentrations, except for benzene (contained in tobacco smoke), which is still higher in smoking than in non-smoking flats. Very often dampness is associated with an increased VOC burden in indoor air. An investigation of mixtures emphasises a high burden of co-occurring terpenes in very small and very large apartments.