INTRODUCTION: Precision medicine in psychiatry is still in its infancy. To establish patient-tailored treatment, adequate indicators predicting treatment response are required. Electroconvulsive therapy (ECT) is considered one of the most effective options for pharmacoresistant major depressive disorder (MDD), yet remission rates were reported to be below 50%. METHODS: Since epigenetics of the stress response system seem to play a role in MDD, we analyzed the DNA methylation (DNAm) of genes encoding the glucocorticoid receptor (NR3C1) and proopiomelanocortin (POMC) through Sanger Sequencing. For analysis, blood was taken before and after the first and last ECT from MDD patients (n=31), unmedicated depressed controls (UDC; n=19, baseline), and healthy controls (HC; n=20, baseline). RESULTS: Baseline DNAm in NR3C1 was significantly lower in UDCs compared to both other groups (UDC: 0.014(±0.002), ECT: 0.031(±0.001), HC: 0.024(±0.002); p<0.001), whereas regarding POMC, ECT patients had the highest DNAm levels (ECT: 0.252(±0.013), UDC: 0.156(±0.015), HC: 0.162(±0.014); p<0.001). NR3C1m and POMCm decreased after the first ECT (NR3C1: p<0.001; POMC: p=0.001), and responders were less methylated compared to non-responders in NR3C1(p<0.001). DISCUSSION: Our findings indicate that both genes might play a role in the chronification of depression and NR3C1 may be relevant for ECT response prediction.
Depressive Disorder, Major , Electroconvulsive Therapy , Humans , Depressive Disorder, Major/genetics , Depressive Disorder, Major/therapy , Pro-Opiomelanocortin/genetics , DNA Methylation/genetics , Epigenesis, Genetic , Treatment Outcome , Receptors, Glucocorticoid/genetics
BACKGROUND: Major depressive disorder (MDD) represents a serious global health concern. The urge for efficient MDD treatment strategies is presently hindered by the incomplete knowledge of its underlying pathomechanism. Despite recent progress (highlighting both genetics and the environment, and thus DNA methylation, to be relevant for its development), 30-50% of MDD patients still fail to reach remission with standard treatment approaches. Electroconvulsive therapy (ECT) is one of the most powerful options for the treatment of pharmacoresistant depression; nevertheless, ECT remission rates barely reach 50% in large-scale naturalistic population-based studies. To optimize MDD treatment strategies and enable personalized medicine in the long- term, prospective indicators of ECT response are thus in great need. Because recent target-driven analyses revealed DNA methylation baseline differences between ECT responder groups, we analyzed the DNA methylome of depressed ECT patients using next-generation sequencing. In this pilot study, we did not only aim to find novel targets for ECT response prediction but also to get a deeper insight into its possible mechanism of action. RESULTS: Longitudinal DNA methylation analysis of peripheral blood mononuclear cells isolated from a cohort of treatment-resistant MDD patients (n = 12; time points: before and after 1st and last ECT, respectively) using a TruSeq-Methyl Capture EPIC Kit for library preparation, led to the following results: (1) The global DNA methylation differed neither between the four measured time points nor between ECT responders (n = 8) and non-responders (n = 4). (2) Analyzing the DNA methylation variance for every probe (=1476812 single CpG sites) revealed eight novel candidate genes to be implicated in ECT response (protein-coding genes: RNF175, RNF213, TBC1D14, TMC5, WSCD1; genes encoding for putative long non-coding RNA transcripts: AC018685.2, AC098617.1, CLCN3P1). (3) In addition, DNA methylation of two CpG sites (located within AQP10 and TRERF1) was found to change during the treatment course. CONCLUSIONS: We suggest ten novel candidate genes to be implicated in either ECT response or its possible mechanism. Because of the small sample size of our pilot study, our findings must be regarded as preliminary.
DNA Methylation , Depressive Disorder, Major/therapy , Electroconvulsive Therapy/methods , Adult , Aged , Female , Humans , Longitudinal Studies , Male , Middle Aged , Pilot Projects , Treatment Outcome , Young Adult
Daylight photodynamic therapy (DL-PDT) is an effective and convenient treatment for multiple actinic keratosis (AKs). There are limited tools to evaluate the outcome of AK treatment. Recently, the actinic keratosis area and severity index (AKASI) has been proposed as a quantitative tool for assessing AK severity. To investigate patient satisfaction and efficacy of DL-PDT for severe AKs and to validate AKASI scoring as a quantitative tool for assessing the outcome of DL-PDT treatment. In this prospective single-centre study, we analysed the results of patients treated with one or two cycles of DL-PDT for severe AKs in the facial or scalp area. Forty patients (37 male and three female) with a mean age of 74 years (range: 56-87 years) were included and received either one (n = 20) or two (n = 20) cycles of DL-PDT. At baseline, most patients (95%) had 20 or more lesions. Patients treated with one cycle of DL-PDT showed a mean AKASI reduction of 45.5% (p < 0.001). Patients eligible for two cycles of DL-PDT demonstrated a mean AKASI reduction of 23.7% (p < 0.05) after one and 48.2% (p < 0.001) after two cycles. Patients participating in this study were either very satisfied (67.5%) or satisfied (32.5%). Almost all patients (97.5%) would recommend DL-PDT to other patients. DL-PDT is a well-tolerated, safe and efficient treatment option for field cancerisation in the facial and scalp area with high patient satisfaction. AKASI scoring has proven useful as a quantitative tool for assessing the outcome of DL-PDT treatment.
Aminolevulinic Acid/administration & dosage , Facial Dermatoses/drug therapy , Keratosis, Actinic/drug therapy , Photochemotherapy/methods , Scalp Dermatoses/drug therapy , Sunscreening Agents/administration & dosage , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Prospective Studies , Severity of Illness Index
BACKGROUND: Cutaneous sarcomas are rare and characterized by pathogenetic heterogeneity. Knowledge about local infiltration patterns and recurrence rates may be useful in improving patient care and outcomes. The objective of the present study was to compare these two characteristics in sarcomas that had been treated using the identical surgical procedure. PATIENTS AND METHODS: Between 2006-2010, 84 patients with various types of sarcoma underwent surgery followed by three-dimensional histology. Tumor entities included dermatofibrosarcoma protuberans (DFSP, 54 patients), leiomyosarcoma (ten patients), rhabdomyosarcoma (one patient), angiosarcoma (seven patients) as well as atypical fibroxanthoma (AFX, three patients) and cutaneous undifferentiated pleomorphic sarcoma (UPS, nine patients). Median follow-up was four years (range: 2-6 years). RESULTS: Local recurrence rates among patients with primary DFSP were 2.2 %. All patients undergoing re-excision were subsequently tumor free. Patients with leiomyosarcoma, rhabdomyosarcoma, AFX, and cutaneous UPS experienced no local recurrence; however, one individual developed in-transit metastasis (UPS) (8.3 %). Three patients with angiosarcoma developed local recurrence (43 %), two of whom remained tumor free following re-excision. Two angiosarcoma patients died from distant metastases (29 %). Both DFSP and especially angiosarcoma lesions exhibited extensive subclinical growth. CONCLUSIONS: Recurrence rates of cutaneous sarcomas following three-dimensional histology are low. Local recurrences are readily manageable by re-excision. Angiosarcoma is characterized by extensive superficial growth, aggressive biological behavior, and predominantly hematogenous spread.
Dermatofibrosarcoma , Hemangiosarcoma , Histiocytoma, Malignant Fibrous , Sarcoma , Skin Neoplasms , Dermatofibrosarcoma/diagnosis , Dermatofibrosarcoma/surgery , Hemangiosarcoma/diagnosis , Hemangiosarcoma/therapy , Histiocytoma, Malignant Fibrous/diagnosis , Histiocytoma, Malignant Fibrous/surgery , Humans , Neoplasm Recurrence, Local , Sarcoma/surgery , Skin Neoplasms/diagnosis , Skin Neoplasms/surgery
HINTERGRUND: Nach Tumoroperationen erfolgt ein Defektverschluss mit den für den individuellen Fall optimalen chirurgischen Methoden. Besonders im Kopf-Hals--Bereich ist das Ergebnis sehr wichtig. Ziel der retrospektiven Studie war es, Rekonstruktionsmethoden von Defekten entsprechend Alter, Lokalisation und Größe nach funktionellen und ästhetischen Gesichtspunkten zu vergleichen. PATIENTEN UND METHODIK: Die betroffenen Patienten wurden mittels Fragebögen angeschrieben. 1827 Patienten (Alter von 18 bis 92 Jahren, Median: 56 Jahre) beurteilten postoperative Probleme, ästhetisches sowie funktionelles Ergebnis und das Gesamtresultat. Aus der Patientenakte wurden Größe und Lokalisation des Defektes sowie die Art des Verschlusses dokumentiert. ERGEBNISSE: Die Dehnungslappenplastik erhielt bezüglich des Gesamtresultats mit einer sehr guten oder guten Bewertung (86 %) das beste Ergebnis. Lappenplastiken und Hauttransplantate wurden schlechter beurteilt. Postoperative Beschwerden traten signifikant häufiger nach lokalen Lappenplastiken auf. Die Sichtbarkeit der Narbe wurde von älteren Patienten bei allen Defektgrößen (< 150 mm2 , 150-300 mm2 , > 300 mm2 ) geringer beurteilt als von jüngeren. Narben in der zentralen Gesichtspartie wurden als sichtbarer wahrgenommen. Geschlecht und Rauchen hatten keinen Einfluss. SCHLUSSFOLGERUNGEN: Narben in zentralen Gesichtsregionen werden stärker wahrgenommen. Ältere Patienten beurteilten die Narbenbildung insgesamt als unauffälliger. Dehnungslappenplastiken, auch unter Wundrandspannung, führen zu sehr guten Ergebnissen und einer hohen Patientenzufriedenheit.
BACKGROUND: Defect coverage following tumor excision requires a case-by-case decision as regards the optimal reconstruction technique. In the head and neck region in particular, the cosmetic outcome is of major importance. The objective of the present study was to compare various reconstruction methods in terms of their functional and aesthetic outcome based on patient age, defect size and site. PATIENTS AND METHODS: Overall, 1,827 patients (age: 18-92 years, median age: 56 years) were contacted. Using a standardized questionnaire, they were asked to assess postoperative complications, cosmetic and functional outcome, and the overall result of the surgical procedure. In addition, patient records were used to collect data on defect size and site as well as the type of surgical procedure employed. RESULTS: Rated as very good or good (86 %), defect closure by advancement flaps received the highest scores in terms of overall result. Other flaps and skin grafts were rated less favorably. Postoperative complications were significantly more common after local flaps. Irrespective of defect size (< 150 mm2 , 150-300 mm2 , > 300 mm2 ), older patients considered the visibility of the scar to be less prominent than younger individuals. Scars in the central facial region were perceived to be more visible. Gender and smoking habits had no impact on the results of the survey. CONCLUSIONS: Scars in the central facial region were perceived to be more prominent. Overall, older individuals considered their scars to be less conspicuous. Even though they are initially associated with greater tension, advancement flaps resulted in very good aesthetic and functional results and a high level of patient satisfaction.
Facial Neoplasms/surgery , Patient Satisfaction , Plastic Surgery Procedures/methods , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Cicatrix/psychology , Esthetics , Facial Neoplasms/psychology , Female , Humans , Male , Middle Aged , Postoperative Complications/psychology , Plastic Surgery Procedures/psychology , Surgical Flaps/transplantation , Surveys and Questionnaires , Tumor Burden , Wound Healing , Young Adult
BACKGROUND: Bullous pemphigoid (BP) is the most common autoimmune blistering disease of the skin requiring skin and serum tests for a precise diagnosis. OBJECTIVES: We analysed the sensitivity and specificity of BP-relevant parameters and the value of autoantibody titres during follow-up of BP patients. MATERIALS & METHODS: In a retrospective single-centre study, we included 200 consecutive patients with BP and 400 non-BP patients, and evaluated the test results of patients' serum and skin. In addition, we followed patients' autoantibody titres and clinical characteristics. RESULTS: BP180-ELISA revealed the highest sensitivity (85.0%; specificity: 93.9%), while BP230-ELISA demonstrated the lowest sensitivity (55.5%; specificity: 92.9%). Direct and indirect immunofluorescence showed comparable results for sensitivity (77.2%/72.7%) and specificity (94.9%/93.7%). The sensitivity for skin histology was 76.3% (specificity: 81.3%). Longitudinal analysis showed significant changes in autoantibody titres. CONCLUSIONS: BP diagnostics should include serum tests for BP autoantibodies and skin immunofluorescence. Skin histology is supportive for diagnosis. Autoantibody titres are markers for disease activity.
Autoantigens/analysis , Dystonin/analysis , Non-Fibrillar Collagens/analysis , Pemphigoid, Bullous/immunology , Aged , Enzyme-Linked Immunosorbent Assay , Eosinophils/cytology , Female , Fluorescent Antibody Technique, Direct , Fluorescent Antibody Technique, Indirect , Humans , Leukocyte Count , Male , Pemphigoid, Bullous/diagnosis , Retrospective Studies , Sensitivity and Specificity , Collagen Type XVII
BACKGROUND: Psoriasis is an inflammatory skin disease with aberrant keratinocyte proliferation, presumably as a result of immune cell activation. Th17 cytokines like IL-17A and IL-22 are critically implicated in epidermal thickening, altered keratinocyte differentiation and production of innate factors such as antimicrobial peptides. Psoriasis treatment options include modern targeted therapies using anti-cytokine antibodies and traditional non-targeted treatments like anthralin (dithranol). While the mode of action of anti-cytokine antibodies is defined, the effects of topical anthralin on psoriatic skin are not fully understood. OBJECTIVE: This study aims to unravel the direct effects of anthralin on keratinocyte proliferation, differentiation and production of psoriasis-associated factors. METHODS: We tested the effects of anthralin on cell proliferation, cytokeratin expression and changes in the expression of antimicrobial peptides using primary keratinocytes and 3D psoriasis tissue models with and without stimulation of the psoriasis-promoting cytokines IL-17A and IL-22. Moreover, we compared the findings derived from monolayer and multilayer cultures to data derived from lesional skin of patients with psoriasis before and under treatment with anthralin. RESULTS: Our study shows that anthralin directly induces cell apoptosis in vitro in monolayer cultures but not in 3D psoriasis tissue models treated with IL-17A and IL-22. Yet, keratinocyte proliferation as determined by Ki-67 staining is impaired by anthralin in vivo. In lesional skin but not in 3D psoriasis tissue models anthralin rapidly normalizes cytokeratin (CK)16 expression. Furthermore, anthralin directly inhibits DEFB4 expression in vitro and in vivo, while other antimicrobial peptides and cytokines studied like IL-6 and IL-8 are regulated differently in vitro and in vivo. CONCLUSIONS: Our results show that anthralin directly regulates DEFB4A expression. However, its beneficial effects on psoriasis cannot be explained by direct effects on keratinocyte differentiation or cytokine expression.
Anthralin/pharmacology , Dermatologic Agents/pharmacology , Keratin-16/metabolism , Keratinocytes/drug effects , Psoriasis/drug therapy , beta-Defensins/metabolism , Administration, Cutaneous , Anthralin/therapeutic use , Apoptosis/drug effects , Biopsy , Cell Differentiation/drug effects , Cell Proliferation/drug effects , Cells, Cultured , Dermatologic Agents/therapeutic use , Fluorescent Antibody Technique , Humans , Interleukin-17/metabolism , Interleukin-6/metabolism , Interleukin-8/metabolism , Interleukins/metabolism , Keratin-10/metabolism , Keratin-5/metabolism , Keratinocytes/metabolism , Ki-67 Antigen/metabolism , Psoriasis/pathology , Skin/cytology , Skin/drug effects , Skin/pathology , Tissue Culture Techniques/methods , Interleukin-22
Rhinophyma is a deforming soft tissue hyperplasia of the nose and surgical removal represents the treatment of choice. Comprehensive data on surgical therapy and the impact of rhinophyma on patient quality of life are lacking. Patients who received surgery for rhinophyma between 2006 and 2015 were retrospectively evaluated for postoperative complications, clinical outcome, recurrence of rhinophyma, and the impact of rhinophyma on daily life. A total of 143 patients were treated with superficial tumour decortication by scalpel under tumescent anaesthesia. Outcomes were determined by clinical review, clinical files, and a patient questionnaire. Of 143 patients, 70 answered the questionnaire and were included in this study with a mean follow-up time of 54 months. Cosmetic results were evaluated as very good or good in 77% of patients. The majority of patients (87%) were very satisfied or satisfied with the postoperative result. Surgical treatment of rhinophyma improved patients' quality of life in 67% of patients. Recurrence of rhinophyma was detected in 38% of patients. Surgery is an effective therapy for rhinophyma with excellent outcome.
Quality of Life , Rhinophyma/surgery , Adult , Aged , Aged, 80 and over , Esthetics , Female , Humans , Male , Middle Aged , Patient Satisfaction , Postoperative Complications , Recurrence , Retrospective Studies , Surveys and Questionnaires
HINTERGRUND UND ZIEL: Die intraläsionale Gabe von Anti-CD20-Antikörpern (Rituximab) wurde als effektive Therapieoption für Patienten mit niedrig malignen primär kutanen B-Zell-Lymphomen beschrieben. Bis heute wurden allerdings keine Parameter identifiziert, welche reproduzierbar ein gutes klinisches Ansprechen dieser Therapie vorhersagen. Ziel dieser Studie ist, sowohl das klinische Ansprechen und die unerwünschten Nebenwirkungen als auch die Patientenwahrnehmung hinsichtlich intraläsionaler Injektionen von anti-CD20-Antikörpern zur Behandlung indolenter primär kutaner B-Zell-Lymphome im Vergleich mit anderen Therapien zu evaluieren. PATIENTEN UND METHODIK: Elf Patienten mit einem primär kutanen B-Zell-Lymphom, namentlich primär kutanes Keimzentrumslymphom (n = 9) und primär kutanes Marginalzonenlymphom (n = 2), welche mittels intraläsionalem Anti-CD20-Antikörper behandelt wurden, wurden retrospektiv evaluiert hinsichtlich der Ansprechrate und unerwünschter Nebenwirkungen sowie in Bezug auf deren Selbsteinschätzung dieser und anderer Therapien des primär kutanen B-Zell-Lymphoms. ERGEBNISSE: Patienten, deren primär kutanes B-Zell-Lymphom mittels intraläsionaler Gabe von Anti-CD20-Antikörper behandelt wurde, zeigten ein komplettes oder partielles Ansprechen in 45 % beziehungsweise 27 % aller Patienten. Speziell Patienten mit grippeähnlichen Symptomen nach erfolgter Injektion zeigten ein gutes Ansprechen. Die Mehrheit der Patienten empfand die Therapie mit Rituximab als die beste Therapie im Vergleich zu anderen Therapien wie beispielsweise chirurgische Exzision oder Radiotherapie. FAZIT: Intraläsionales Rituximab ist eine effektive Therapie mit hoher Patientenzufriedenheit. Starke therapiebedingte Nebenwirkungen wie Fieber, Schüttelfrost und Kopfschmerzen nach Gabe von Rituximab könnten als Indikator für gute Wirksamkeit dienen.
The nutritional curcumin (CUR) is beneficial in cell-mediated autoimmune diseases. The molecular mechanisms underlying this food-mediated silencing of inflammatory immune responses are poorly understood. By investigating antigen-specific immune responses we found that dietary CUR impairs the differentiation of Th1/Th17 cells in vivo during encephalomyelitis and instead promoted Th2 cells. In contrast, feeding CUR had no inhibitory effect on ovalbumin-induced airway inflammation. Mechanistically, we found that CUR induces an anti-inflammatory phenotype in dendritic cells (DC) with enhanced STAT3 phosphorylation and suppressed expression of Il12b and Il23a. On the molecular level CUR readily induced NRF2-sensitive heme oxygenase 1 (HO-1) mRNA and protein in LPS-activated DC. HO-1 enhanced STAT3 phosphorylation, which enriched to Il12b and Il23a loci and negatively regulated their transcription. These findings demonstrate the underlying mechanism through which a nutritional can interfere with the immune response. CUR silences IL-23/Th17-mediated pathology by enhancing HO-1/STAT3 interaction in DC.
Autoimmune Diseases/drug therapy , Curcumin/administration & dosage , Heme Oxygenase-1/genetics , Inflammation/drug therapy , Interleukin-23/genetics , Membrane Proteins/genetics , STAT3 Transcription Factor/genetics , Animals , Autoimmune Diseases/genetics , Autoimmune Diseases/pathology , Dendritic Cells/drug effects , Encephalomyelitis, Autoimmune, Experimental , Immunity, Cellular/drug effects , Inflammation/chemically induced , Inflammation/genetics , Inflammation/pathology , Mice , Ovalbumin/toxicity , Phosphorylation , Th17 Cells/drug effects , Th2 Cells/drug effects , Th2 Cells/immunology
BACKGROUND AND OBJECTIVES: Intralesional injection of anti-CD20 antibody (rituximab) has been described as effective therapeutic option for patients with indolent primary cutaneous B-cell lymphoma (PCBL). To date, no parameters that reproducibly predict favorable clinical outcome of this treatment have been identified. The study aims to evaluate the clinical response and adverse effects as well as patients' self-perception of intralesional injection of anti-CD20 antibody for treatment of indolent PCBL compared to other treatment modalities. PATIENTS AND METHODS: Eleven patients with PCBL, namely primary cutaneous follicle center lymphoma (n = 9) and primary cutaneous marginal zone lymphoma (n = 2), treated with intralesional anti-CD20 antibody were retrospectively evaluated for response rate and adverse events as well as their self-perception of anti-CD20 antibody therapy and other therapies of PCBL. RESULTS: Patients treated with intralesional anti-CD20 antibody for PCBL showed complete response or partial response in 45 % or 27 % of patients, respectively. Particularly, patients with marked flu-like symptoms after intralesional injection of rituximab responded very well to rituximab. The majority of patients considered rituximab as best therapy compared to other therapies such as excision or radiotherapy. CONCLUSIONS: Intralesional rituximab is an effective therapy with high patient satisfaction. Strong therapy induced side effects of fever, chills and headache after administration of rituximab might be used as indicator for favorable response.
Gastrointestinal Diseases/chemically induced , Gastrointestinal Diseases/diagnosis , Headache/chemically induced , Lymphoma, B-Cell/drug therapy , Rituximab/administration & dosage , Rituximab/adverse effects , Skin Neoplasms/drug therapy , Adult , Aged , Chills/chemically induced , Chills/diagnosis , Chills/prevention & control , Female , Gastrointestinal Diseases/prevention & control , Headache/diagnosis , Headache/prevention & control , Humans , Injections, Intralesional , Lymphoma, B-Cell/immunology , Male , Middle Aged , Neoplasm Grading , Skin Neoplasms/immunology , Statistics as Topic , Treatment Outcome
Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is an important adaptor protein for inflammasome activation, mediating the secretion of protumorigenic innate cytokines. However, ASC is also known to trigger apoptosis in tumor cells, acting as a tumor-suppressor gene, which is lost in several human cancers. The aim of this study was to evaluate the clinical significance of ASC in human cutaneous squamous cell carcinoma (SCC). Initially, ASC expression was immunohistochemically evaluated in non-metastic and metastatic SCC. While ASC expression does not correlate with metastatic potential, it correlates with the degree of dedifferentiation. Using methylation specific PCR we were able to demonstrate ASC silencing by promotor specific methylation and impaired inflammasome function in methylated cell lines, linking epigenetic modifications to innate immune activation in keratinocytes. Interestingly, upon ASC restoration by treatment with demethylating agents, we were able to restore AIM2 and NLRP3 activation. In summary, loss of ASC driven tumor development is counterbalanced in the identical cell by the inhibition of pro-tumorigenic inflammation in the tumor cell itself.
Carcinoma, Squamous Cell/genetics , Cytoskeletal Proteins/genetics , Gene Silencing , Skin Neoplasms/genetics , Aged , CARD Signaling Adaptor Proteins , Carcinoma, Squamous Cell/pathology , Cell Differentiation , Cell Line, Tumor , DNA Methylation , Female , Humans , Inflammasomes/metabolism , Male , Neoplasm Metastasis , Promoter Regions, Genetic , Skin Neoplasms/pathology
T helper (Th) cells producing interleukin (IL)-17, IL-22, and tumor necrosis factor (TNF) form the key T cell population driving psoriasis pathogenesis. They orchestrate the inflammation in the skin that results in the proliferation of keratinocytes and endothelial cells. Besides Th17 cells, other immune cells that are capable of producing IL-17-associated cytokines participate in psoriatic inflammation. Recent advances in psoriasis research improved our understanding of the cellular and molecular players that are involved in Th17 pathology and inflammatory pathways in the skin. The inflammation-driving actions of TNF in psoriasis are already well known and antibodies against TNF are successful in the treatment of Th17-mediated psoriatic skin inflammation. A further key cytokine with potent IL-17-/IL-22-promoting properties is IL-23. Therapeutics directly neutralizing IL-23 or IL-17 itself are now extending the therapeutic spectrum of antipsoriatic agents and further developments are on the way. The enormous progress in psoriasis research allows us to control this Th17-mediated inflammatory skin disease in many patients.
The protease activity of the paracaspase mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1) plays an important role in antigen receptor-mediated lymphocyte activation by controlling the activity of the transcription factor nuclear factor-κB and is thus essential for the expression of inflammatory target genes. MALT1 is not only present in cells of the hematopoietic lineage, but is ubiquitously expressed. Here we report that stimulation with zymosan or Staphylococcus aureus induced MALT1 protease activity in human primary keratinocytes. Inhibition of the Src family of kinases or novel protein kinase C isoforms as well as silencing of CARMA2 or BCL10 interfered with activation of MALT1 protease. Silencing or inhibition of MALT1 protease strongly decreased the expression of important inflammatory genes such as TNFα, IL-17C, CXCL8 and HBD-2. MALT1-inhibited cells were unable to mount an antimicrobial response upon zymosan stimulation or phorbolester/ionomycin treatment, demonstrating a central role of MALT1 protease activity in keratinocyte immunity and suggesting MALT1 as a potential target in inflammatory skin diseases.
Caspases/metabolism , Inflammation/genetics , Keratinocytes/cytology , Neoplasm Proteins/metabolism , Zymosan/chemistry , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Anti-Infective Agents/chemistry , B-Cell CLL-Lymphoma 10 Protein , CARD Signaling Adaptor Proteins/genetics , CARD Signaling Adaptor Proteins/metabolism , Caspases/genetics , Gene Expression Profiling , Gene Silencing , Guanylate Cyclase/genetics , Guanylate Cyclase/metabolism , Humans , Interleukin-17/genetics , Interleukin-17/metabolism , Interleukin-8/genetics , Interleukin-8/metabolism , Keratinocytes/drug effects , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein , NF-kappa B p50 Subunit/genetics , NF-kappa B p50 Subunit/metabolism , Neoplasm Proteins/genetics , Oligonucleotide Array Sequence Analysis , Protein Isoforms , Protein Kinase C/metabolism , Staphylococcus aureus , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism , beta-Defensins/genetics , beta-Defensins/metabolism , src-Family Kinases/metabolism
BACKGROUND: Restless legs syndrome (RLS) is characterized by unpleasant sensations in the legs and an uncontrollable urge to move them in order to gain relief. Higher frequencies of RLS have been reported in systemic lupus, multiple sclerosis, rheumatoid arthritis and atopic dermatitis. OBJECTIVES: Since the disease-related stress present in psoriasis is similar to the stress of those diseases, we aimed to study the frequency of RLS in a German cohort of patients with psoriasis. METHODS: 300 patients with psoriasis and 300 healthy controls were evaluated for RLS symptoms in this study. RESULTS: While 17% (n = 51) of patients with psoriasis reported symptoms of RLS, only 4% (n = 12) of individuals without psoriasis suffered from RLS symptoms (95% confidence interval: 0.08 - 0.18, p<0.01). In patients with psoriasis and RLS the average RLS score was 16.0 ± 9.2 whereas individuals with RLS in the control group had an average RLS score of 13.5 ± 7.1. CONCLUSIONS: Our findings indicate an increased frequency of RLS in patients with psoriasis, suggesting screening patients with psoriasis for the presence of RLS as a well-treatable co-morbidity.
Psoriasis/epidemiology , Psoriasis/psychology , Quality of Life , Restless Legs Syndrome/epidemiology , Restless Legs Syndrome/psychology , Adult , Comorbidity , Female , Germany/epidemiology , Humans , Male , Middle Aged , Severity of Illness Index , Surveys and Questionnaires
It has recently been demonstrated that memory B cells can reenter and reengage germinal center (GC) reactions, opening the possibility that multi-hit lymphomagenesis gradually occurs throughout life during successive immunological challenges. Here, we investigated this scenario in follicular lymphoma (FL), an indolent GC-derived malignancy. We developed a mouse model that recapitulates the FL hallmark t(14;18) translocation, which results in constitutive activation of antiapoptotic protein B cell lymphoma 2 (BCL2) in a subset of B cells, and applied a combination of molecular and immunofluorescence approaches to track normal and t(14;18)(+) memory B cells in human and BCL2-overexpressing B cells in murine lymphoid tissues. BCL2-overexpressing B cells required multiple GC transits before acquiring FL-associated developmental arrest and presenting as GC B cells with constitutive activation-induced cytidine deaminase (AID) mutator activity. Moreover, multiple reentries into the GC were necessary for the progression to advanced precursor stages of FL. Together, our results demonstrate that protracted subversion of immune dynamics contributes to early dissemination and progression of t(14;18)(+) precursors and shapes the systemic presentation of FL patients.
B-Lymphocyte Subsets/metabolism , Cell Movement , Gene Expression Regulation, Neoplastic , Lymphoma, Follicular/metabolism , Neoplasms, Experimental/metabolism , Proto-Oncogene Proteins c-bcl-2/biosynthesis , Animals , B-Lymphocyte Subsets/pathology , Cytidine Deaminase/genetics , Cytidine Deaminase/metabolism , Female , Humans , Lymphoma, Follicular/genetics , Lymphoma, Follicular/pathology , Male , Mice , Mice, Transgenic , Neoplasms, Experimental/genetics , Neoplasms, Experimental/pathology , Proto-Oncogene Proteins c-bcl-2/genetics
BACKGROUND: The continuous evaluation of the edges of a tumor by means of three-dimensional (3D) histology often appears complicated and require the surgeon and dermatopathologist to work together closely. We present clear rules that allow communication between all parties involved and then verify their application in daily routine. METHODS: Tissue processing, interpretation of results, as well as communication between the surgeon and the dermatopathologist are based on an algorithm with the aid of exact times and embedding cassettes, which allow precise topographic orientation. We evaluated the use of this method in daily clinic practice, taking into account 947 operated basal cell carcinomas in regard to the development of recurrent tumors. RESULTS: At a median follow-up of 47 months, 10 of the 947 operated basal cell carcinomas (1.1 %) recurred. Sclerodermiform basal cell carcinomas and basal cell carcinomas which could not be curatively resected (R0 resection) during the initial surgery showed a significantly higher recurrence rate (p < 0.05 and p < 0.001). CONCLUSIONS: Standardized rules for dealing with excised tissue allow an effective application of 3D histology in daily clinical practice. 3D histology results in low recurrence rates. Sclerodermiform basal cell carcinomas which could not be curatively resected (R0 resection) were identified as a risk group for the development of recurrent tumors.
Biopsy/standards , Carcinoma, Basal Cell/pathology , Dermoscopy/standards , Imaging, Three-Dimensional/standards , Skin Neoplasms/pathology , Specimen Handling/standards , Aged , Algorithms , Female , Germany , Humans , Male , Microscopy/standards , Practice Guidelines as Topic , Reproducibility of Results , Sensitivity and Specificity
The pathogenesis of follicular lymphoma is a multi-hit process progressing over many years through the accumulation of numerous genetic alterations. Besides the hallmark t(14;18), it is still unclear which other oncogenic hits contribute to the early steps of transformation and in which precursor stages these occur. To address this issue, we performed high-resolution comparative genomic hybridization microarrays on laser-capture micro-dissected cases of follicular lymphoma in situ (n=4), partial involvement by follicular lymphoma (n=4), and duodenal follicular lymphoma (n=4), assumed to represent, potentially, the earliest stages in the evolution of follicular lymphoma. Cases of reactive follicular hyperplasia (n=2), uninvolved areas from follicular lymphoma in situ lymph nodes, follicular lymphoma grade 1-2 (n=5) and follicular lymphoma grade 3A (n=5) were used as controls. Surprisingly, alterations involving several relevant (onco)genes were found in all entities, but at significantly lower proportions than in overt follicular lymphoma. While the number of alterations clearly assigns all these entities as precursors, the pattern of partial involvement by follicular lymphoma alterations was quantitatively and qualitatively closer to that of follicular lymphoma, indicating significant selective pressure in line with its faster rate of progression. Among the most notable alterations, we observed and validated deletions of 1p36 and gains of the 7p and 12q chromosomes and related oncogenes, which include some of the most recurrent oncogenic alterations in overt follicular lymphoma (TNFRSF14, EZH2, MLL2). By further delineating distinctive and hierarchical molecular and genetic features of early follicular lymphoma entities, our analysis underlines the importance of applying appropriate criteria for the differential diagnosis. It also provides a first set of candidates likely to be involved in the cascade of hits that pave the path of the various progression phases to follicular lymphoma development.
Cell Transformation, Neoplastic/genetics , Lymphoma, Follicular/genetics , Lymphoma, Follicular/pathology , Carcinoma in Situ/genetics , Carcinoma in Situ/pathology , Comparative Genomic Hybridization , Disease Progression , Genomic Instability , Germinal Center/pathology , Humans , Neoplasm Grading , Neoplasm Staging
