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1.  Increased Prevalence of Metabolic Syndrome in Patients with Acne Inversa 
PLoS ONE  2012;7(2):e31810.
Background
Acne inversa (AI; also designated as Hidradenitis suppurativa) is a common chronic inflammatory skin disease, localized in the axillary, inguinal and perianal skin areas that causes painful, fistulating sinuses with malodorous purulence and scars. Several chronic inflammatory diseases are associated with the metabolic syndrome and its consequences including arteriosclerosis, coronary heart disease, myocardial infraction, and stroke. So far, the association of AI with systemic metabolic alterations is largely unexplored.
Methods and Findings
A hospital-based case-control study in 80 AI patients and 100 age- and sex-matched control participants was carried out. The prevalence of central obesity (odds ratio 5.88), hypertriglyceridemia (odds ratio 2.24), hypo-HDL-cholesterolemia (odds ratio 4.56), and hyperglycemia (odds ratio 4.09) in AI patients was significantly higher than in controls. Furthermore, the metabolic syndrome, previously defined as the presence of at least three of the five alterations listed above, was more common in those patients compared to controls (40.0% versus 13.0%; odds ratio 4.46, 95% confidence interval 2.02 to 9.96; P<0.001). AI patients with metabolic syndrome also had more pronounced metabolic alterations than controls with metabolic syndrome. Interestingly, there was no correlation between the severity or duration of the disease and the levels of respective parameters or the number of criteria defining the metabolic syndrome. Rather, the metabolic syndrome was observed in a disproportionately high percentage of young AI patients.
Conclusions
This study shows for the first time that AI patients have a high prevalence of the metabolic syndrome and all of its criteria. It further suggests that the inflammation present in AI patients does not have a major impact on the development of metabolic alterations. Instead, evidence is given for a role of metabolic alterations in the development of AI. We recommend monitoring of AI patients in order to correct their modifiable cardiovascular risk factors.
doi:10.1371/journal.pone.0031810
PMCID: PMC3281019  PMID: 22359634
2.  Genomic loss of the putative tumor suppressor gene E2A in human lymphoma 
The Journal of Experimental Medicine  2011;208(8):1585-1593.
Loss of E2A, observed in more than 70% of patients with Sézary syndrome, which is a subtype of T cell lymphoma, results in altered expression of genes potentially relevant to oncogenesis.
The transcription factor E2A is essential for lymphocyte development. In this study, we describe a recurrent E2A gene deletion in at least 70% of patients with Sézary syndrome (SS), a subtype of T cell lymphoma. Loss of E2A results in enhanced proliferation and cell cycle progression via derepression of the protooncogene MYC and the cell cycle regulator CDK6. Furthermore, by examining the gene expression profile of SS cells after restoration of E2A expression, we identify several E2A-regulated genes that interfere with oncogenic signaling pathways, including the Ras pathway. Several of these genes are down-regulated or lost in primary SS tumor cells. These data demonstrate a tumor suppressor function of E2A in human lymphoid cells and could help to develop new treatment strategies for human lymphomas with altered E2A activity.
doi:10.1084/jem.20101785
PMCID: PMC3149217  PMID: 21788410
3.  Willingness to Donate Human Samples for Establishing a Dermatology Research Biobank: Results of a Survey 
Biopreservation and Biobanking  2011;9(3):265-271.
There is a rising need for biomaterial in dermatological research with regard to both quality and quantity. Research biobanks as organized collections of biological material with associated personal and clinical data are of increasing importance. Besides technological/methodological and legal aspects, the willingness to donate samples by patients and healthy volunteers is a key success factor. To analyze the theoretical willingness to donate blood and skin samples, we developed and distributed a questionnaire. Six hundred nineteen questionnaires were returned and analyzed. The willingness to donate samples of blood (82.5%) and skin (58.7%) is high among the population analyzed and seems to be largely independent of any expense allowance. People working in the healthcare system, dermatological patients, and higher qualified individuals seem to be in particular willing to donate material. An adequate patient insurance as well as an extensive education about risks and benefits is requested. In summary, there is a high willingness to donate biological samples for dermatological research. This theoretical awareness fits well with our own experiences in establishing such a biobank.
doi:10.1089/bio.2011.0009
PMCID: PMC3178419  PMID: 21977242
4.  Influence of the Vehicle on the Penetration of Particles into Hair Follicles 
Pharmaceutics  2011;3(2):307-314.
Recently, it has been demonstrated that particulate substances penetrate preferentially into the hair follicles and that the penetration depth depends on the particle size. In the present study, the influence of the vehicle of the particulate substances on the penetration depth was investigated. Four different formulations (ethanolic suspension, aqueous suspension, ethanolic gel and aqueous gel) containing peptide-loaded particles of 1 μm in diameter were prepared and applied on porcine ear skin. After penetration, punch biopsies were taken and the penetration depths of the particles were investigated by laser scanning microscopy. The deepest penetration was achieved with the gel formulations demonstrating an influence of the vehicle on the penetration depth of particulate substances.
doi:10.3390/pharmaceutics3020307
PMCID: PMC3864236  PMID: 24310497
hair follicle; penetration; particle; vehicle; formulation
5.  CD56‐positive haematological neoplasms of the skin: a multicentre study of the Cutaneous Lymphoma Project Group of the European Organisation for Research and Treatment of Cancer 
Journal of Clinical Pathology  2006;60(9):981-989.
Background
Cutaneous lymphomas expressing CD56, a neural cell adhesion molecule, are characterised in most cases by a highly aggressive clinical course and a poor prognosis. However, prognostic subsets within the CD56+ group have been difficult to identify due to the lack of uniform clinicopathological and immunophenotypical criteria.
Methods
A multicentre study was conducted by the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer to define prognostic parameters and establish diagnostic and therapeutic guidelines for CD56+ haematological neoplasms presenting primarily in the skin.
Results
Four different subtypes of lymphoproliferations with CD56 expression were identified: (1) haematodermic neoplasm; (2) skin infiltration as the first manifestation of CD56+ acute myeloid leukaemia; (3) nasal‐type extranodal natural killer/T‐cell lymphoma; and (4) “classical” cases of cutaneous T‐cell lymphoma (CTCL) with co‐expression of the CD56 molecule. Patients in the first three groups had a poor outcome (93% died) with a median survival rate of 11 months (95% CI 2–72 months), whereas all patients with CD56+ CTCL were alive at the last follow‐up.
Conclusion
Results show that CD56+ cutaneous lymphoproliferative disorders, with the exception of CD56+ CTCL have a very poor prognosis. It is therefore clinically important to separate CD56+ CTCL from the remaining CD56+ haematological disorders.
doi:10.1136/jcp.2006.042135
PMCID: PMC1972425  PMID: 17018683
cutaneous lymphoma; CD56; extranodal NK/T‐cell lymphoma; haematodermic neoplasm; CD123
6.  Preferential Amplification of CD8 Effector-T Cells after Transcutaneous Application of an Inactivated Influenza Vaccine: A Randomized Phase I Trial 
PLoS ONE  2010;5(5):e10818.
Background
Current conventional vaccination approaches do not induce potent CD8 T-cell responses for fighting mostly variable viral diseases such as influenza, avian influenza viruses or HIV. Following our recent study on vaccine penetration by targeting of vaccine to human hair follicular ducts surrounded by Langerhans cells, we tested in the first randomized Phase-Ia trial based on hair follicle penetration (namely transcutaneous route) the induction of virus-specific CD8 T cell responses.
Methods and Findings
We chose the inactivated influenza vaccine – a conventional licensed tetanus/influenza (TETAGRIP®) vaccine – to compare the safety and immunogenicity of transcutaneous (TC) versus IM immunization in two randomized controlled, multi-center Phase I trials including 24 healthy-volunteers and 12 HIV-infected patients. Vaccination was performed by application of inactivated influenza vaccine according to a standard protocol allowing the opening of the hair duct for the TC route or needle-injection for the IM route. We demonstrated that the safety of the two routes was similar. We showed the superiority of TC application, but not the IM route, to induce a significant increase in influenza-specific CD8 cytokine-producing cells in healthy-volunteers and in HIV-infected patients. However, these routes did not differ significantly for the induction of influenza-specific CD4 responses, and neutralizing antibodies were induced only by the IM route. The CD8 cell response is thus the major immune response observed after TC vaccination.
Conclusions
This Phase Ia clinical trial (Manon05) testing an anti-influenza vaccine demonstrated that vaccines designed for antibody induction by the IM route, generate vaccine-specific CD8 T cells when administered transcutaneously. These results underline the necessity of adapting vaccination strategies to control complex infectious diseases when CD8 cellular responses are crucial. Our work opens up a key area for the development of preventive and therapeutic vaccines for diseases in which CD8 cells play a crucial role.
Trial Registration
Clinicaltrials.gov NCT00261001
doi:10.1371/journal.pone.0010818
PMCID: PMC2877091  PMID: 20520820
7.  Proteome-Based Analysis of Serologically Defined Tumor-Associated Antigens in Cutaneous Lymphoma 
PLoS ONE  2009;4(12):e8376.
Information on specificities of serological responses against tumor cells in cutaneous lymphoma patients is relatively restricted. To advance the knowledge of serological immune responses against and to assess the scope of tumor antigenicity of cutaneous lymphoma, 1- and 2-dimensional Western blot analyses with sera from patients were combined with proteomics-based protein identification. Testing sera from 87 cutaneous lymphoma patients by 1-dimensional Western blot analysis, 64 cases of seroreactivity against lymphoma cells were found. The positive responses were relatively weak, restricted to few antigens in each case, and heterogeneous. To identify the antigens, proteins of the mycosis fungoides cell line MyLa and primary tumor cells were separated by 2-dimensional gel electrophoresis, Western-blotted and probed with heterogeneous and autologous patient sera. The antigens were identified from silver-stained replica gels by MALDI-TOF mass spectrometry. 14 different antigens were assigned and identified with this proteome-serological approach. Only one, vimentin, had been reported before, the other 13 are new antigens for cutaneous lymphomas.
doi:10.1371/journal.pone.0008376
PMCID: PMC2793029  PMID: 20020065
9.  Proteome Serological Determination of Tumor-Associated Antigens in Melanoma 
PLoS ONE  2009;4(4):e5199.
Proteome serology may complement expression library-based approaches as strategy utilizing the patients' immune responses for the identification pathogenesis factors and potential targets for therapy and markers for diagnosis. Melanoma is a relatively immunogenic tumor and antigens recognized by melanoma-specific T cells have been extensively studied. The specificities of antibody responses to this malignancy have been analyzed to some extent by molecular genetic but not proteomics approaches. We screened sera of 94 melanoma patients for anti-melanoma reactivity and detected seropositivity in two-thirds of the patients with 2–6 antigens per case detected by 1D and an average of 2.3 per case by 2D Western blot analysis. For identification, antigen spots in Western blots were aligned with proteins in 2-DE and analyzed by mass spectrometry. 18 antigens were identified, 17 of which for the first time for melanoma. One of these antigens, galectin-3, has been related to various oncogenic processes including metastasis formation and invasiveness. Similarly, enolase has been found deregulated in different cancers. With at least 2 of 18 identified proteins implicated in oncogenic processes, the work confirms the potential of proteome-based antigen discovery to identify pathologically relevant proteins.
doi:10.1371/journal.pone.0005199
PMCID: PMC2667248  PMID: 19381273
10.  In vivo analysis of wound healing by optical methods 
The analysis of wound healing is important for the therapy control and for the development of drugs stimulating the healing process. Wounds cause damage to the skin barrier. A damaged stratum corneum leads to an increased water loss through the skin barrier. The standard measuring procedure for characterization of wound healing is the measurement of transepidermal water loss (TEWL). The disadvantage of this method is that it can be easily disturbed by the perspiration of the volunteers and by topically applied substances, for instance wound healing creams.
In the study presented, in vivo laser scanning microscopy and optical coherent tomography were compared concerning the application for their analysis of wound healing processes. The laser scanning microscopy allows the analysis of the healing process on a cellular level. The course of wound healing determined by laser scanning microscopy was correlated with numerical values, allowing the numerical characterization of the wound healing process.
PMCID: PMC2831523  PMID: 20204112
in vivo laser scanning microscopy; optical coherent tomography; transepidermal water loss; suction blister technique; wound healing analysis
11.  Water-filtered infrared-A (wIRA) can act as a penetration enhancer for topically applied substances 
Background: Water-filtered infrared-A (wIRA) irradiation has been shown to enhance penetration of clinically used topically applied substances in humans through investigation of functional effects of penetrated substances like vasoconstriction by cortisone.
Aim of the study: Investigation of the influence of wIRA irradiation on the dermatopharmacokinetics of topically applied substances by use of optical methods, especially to localize penetrating substances, in a prospective randomised controlled study in humans.
Methods: The penetration profiles of the hydrophilic dye fluorescein and the lipophilic dye curcumin in separate standard water-in-oil emulsions were determined on the inner forearm of test persons by tape stripping in combination with spectroscopic measurements. Additionally, the penetration was investigated in vivo by laser scanning microscopy. Transepidermal water loss, hydration of the epidermis, and surface temperature were determined. Three different procedures (modes A, B, C) were used in a randomised order on three separate days of investigation in each of 12 test persons. In mode A, the two dyes were applied on different skin areas without water-filtered infrared-A (wIRA) irradiation. In mode B, the skin surface was irradiated with wIRA over 30 min before application of the two dyes (Hydrosun® radiator type 501, 10 mm water cuvette, orange filter OG590, water-filtered spectrum: 590–1400 nm with dominant amount of wIRA). In mode C, the two dyes were applied and immediately afterwards the skin was irradiated with wIRA over 30 min. In all modes, tape stripping started 30 min after application of the formulations. Main variable of interest was the ratio of the amount of the dye in the deeper (second) 10% of the stratum corneum to the amount of the dye in the upper 10% of the stratum corneum.
Results: The penetration profiles of the hydrophilic fluorescein showed in case of pretreatment or treatment with wIRA (modes B and C) an increased penetration depth compared to the non-irradiated skin (mode A): The ratio of the amount of the dye in the deeper (second) 10% of the stratum corneum to the amount of the dye in the upper 10% of the stratum corneum showed medians and interquartile ranges for mode A of 0.017 (0.007/0.050), for mode B of 0.084 (0.021/0.106), for mode C of 0.104 (0.069/0.192) (difference between modes: p=0.0112, significant; comparison mode A with mode C: p<0.01, significant). In contrast to fluorescein, the lipophilic curcumin showed no differences in the penetration kinetics, in reference to whether the skin was irradiated with wIRA or not. These effects were confirmed by laser scanning microscopy. Water-filtered infrared-A irradiation increased the hydration of the stratum corneum: transepidermal water loss rose from approximately 8.8 g m-2 h-1 before wIRA irradiation to 14.2 g m-2 h-1 after wIRA irradiation and skin hydration rose from 67 to 87 relative units. Skin surface temperature increased from 32.8°C before wIRA to 36.4°C after wIRA irradiation.
Discussion: The better penetration of the hydrophilic dye fluorescein after or during skin irradiation (modes B and C) can be explained by increased hydration of the stratum corneum by irradiation with wIRA.
Conclusions: As most topically applied substances for the treatment of patients are mainly hydrophilic, wIRA can be used to improve the penetration of substances before or after application of substances – in the first case even of thermolabile substances – with a broad clinical relevance as a contact free alternative to an occlusive dressing.
PMCID: PMC2703260  PMID: 19675735
water-filtered infrared-A (wIRA); penetration; stratum corneum; skin barrier; penetration enhancer; dermatopharmacokinetics; dye; fluorescein; curcumin; tape stripping method; spectroscopy; laser scanning microscopy; transepidermal water loss (TEWL); hydration of the epidermis; corneometry; skin surface temperature; hydrophilic; lipophilic; occlusive dressing
12.  Identification of differentially expressed genes in cutaneous squamous cell carcinoma by microarray expression profiling 
Molecular Cancer  2006;5:30.
Background
Carcinogenesis is a multi-step process indicated by several genes up- or down-regulated during tumor progression. This study examined and identified differentially expressed genes in cutaneous squamous cell carcinoma (SCC).
Results
Three different biopsies of 5 immunosuppressed organ-transplanted recipients each normal skin (all were pooled), actinic keratosis (AK) (two were pooled), and invasive SCC and additionally 5 normal skin tissues from immunocompetent patients were analyzed. Thus, total RNA of 15 specimens were used for hybridization with Affymetrix HG-U133A microarray technology containing 22,283 genes. Data analyses were performed by prediction analysis of microarrays using nearest shrunken centroids with the threshold 3.5 and ANOVA analysis was independently performed in order to identify differentially expressed genes (p < 0.05). Verification of 13 up- or down-regulated genes was performed by quantitative real-time reverse transcription (RT)-PCR and genes were additionally confirmed by sequencing. Broad coherent patterns in normal skin vs. AK and SCC were observed for 118 genes.
Conclusion
The majority of identified differentially expressed genes in cutaneous SCC were previously not described.
doi:10.1186/1476-4598-5-30
PMCID: PMC1569867  PMID: 16893473
13.  The monoclonal antibody SM5-1 recognizes a fibronectin variant which is widely expressed in melanoma 
Background
Previously we have generated the monoclonal antibody SM5-1 by using a subtractive immunization protocol of human melanoma. This antibody exhibits a high sensitivity for primary melanomas of 99% (248/250 tested) and for metastatic melanoma of 96% (146/151 tested) in paraffin embedded sections. This reactivity is superior to the one obtained by HMB-45, anti-MelanA or anti-Tyrosinase and is comparable to anti-S100. However, as compared to anti-S100, the antibody SM5-1 is highly specific for melanocytic lesions since 40 different neoplasms were found to be negative for SM5-1 by immunohistochemistry. The antigen recognized by SM5-1 is unknown.
Methods
In order to characterize the antigen recognized by mAb SM5-1, a cDNA library was constructed from the metastatic human melanoma cell line SMMUpos in the Uni-ZAP lambda phage and screened by mAb SM5-1. The cDNA clones identified by this approach were then sequenced and subsequently analyzed.
Results
Sequence analysis of nine independent overlapping clones (length 3100–5600 bp) represent fibronectin cDNA including the ED-A, but not the ED-B region which are produced by alternative splicing. The 89aa splicing variant of the IIICS region was found in 8/9 clones and the 120aa splicing variant in 1/9 clones, both of which are included in the CS1 region of fibronectin being involved in melanoma cell adhesion and spreading.
Conclusion
The molecule recognized by SM5-1 is a melanoma associated FN variant expressed by virtually all primary and metastatic melanomas and may play an important role in melanoma formation and progression. This antibody is therefore not only of value in immunohistochemistry, but potentially also for diagnostic imaging and immunotherapy.
doi:10.1186/1471-2407-6-8
PMCID: PMC1351261  PMID: 16405722
14.  Long-term therapy of interferon-alpha induced pulmonary arterial hypertension with different PDE-5 inhibitors: a case report 
background
Interferon alpha2 is widely used in hepatitis and high-risk melanoma. Interferon-induced pulmonary arterial hypertension as a side effect is rare.
Case presentation
We describe a melanoma patient who developed severe pulmonary arterial hypertension 30 months after initiation of adjuvant interferon alpha2b therapy. Discontinuation of interferon did not improve pulmonary arterial hypertension. This patient could be treated successfully with phosphodiesterase-5 inhibitor therapy.
Conclusion
This is only the 5th case of interferon-induced pulmonary arterial hypertension and the first documented case where pulmonary arterial hypertension was not reversible after termination of interferon alpha2 therapy. If interferon alpha2 treated patients develop respiratory symptoms, pulmonary arterial hypertension should be considered in the differential diagnosis. For these patients phosphodiesterase-5 inhibitors, e.g. sildenafil or vardenafil, could be an effective therapeutic approach.
doi:10.1186/1476-7120-3-26
PMCID: PMC1208925  PMID: 16138923
pulmonary arterial hypertension; PAH; PDE-5 inhibitor; interferon-alpha
15.  Identification of sample-specific sequences in mammalian cDNA and genomic DNA by the novel ligation-mediated subtraction (Limes) 
Nucleic Acids Research  2001;29(4):e20.
The representational difference analysis (RDA) and other subtraction techniques are used to enrich sample-specific sequences by elimination of ubiquitous sequences existing in both the sample of interest (tester) and the subtraction partner (driver). While applying the RDA to genomic DNA of cutaneous lymphoma cells in order to identify tumor relevant alterations, we predominantly isolated repetitive sequences and artificial repeat-mediated fusion products of otherwise independent PCR fragments (PCR hybrids). Since these products severely interfered with the isolation of tester-specific fragments, we developed a considerably more robust and efficient approach, termed ligation-mediated subtraction (Limes). In first applications of Limes, genomic sequences and/or transcripts of genes involved in the regulation of transcription, such as transforming growth factor β stimulated clone 22 related gene (TSC-22R), cell death and cytokine production (caspase-1) or antigen presentation (HLA class II sequences), were found to be completely absent in a cutaneous lymphoma line. On the assumption that mutations in tumor-relevant genes can affect their transcription pattern, a protocol was developed and successfully applied that allows the identification of such sequences. Due to these results, Limes may substitute/supplement other subtraction/comparison techniques such as RDA or DNA microarray techniques in a variety of different research fields.
PMCID: PMC29627  PMID: 11160940

Results 1-15 (15)