Expression of Mucins in Different Entities of Salivary Gland Cancer: Highest Expression of Mucin-1 in Salivary Duct Carcinoma : Mucin-1 - highest expression in Salivary Duct Carcinoma.

Therapeutic options for advanced salivary gland cancer (SGC) are rare. Therefore, it was the aim of this study to investigate the extent and intensity of Mucin-1 (MUC1), Mucin-16 (MUC16), and Mucin-5AC (MUC5AC) as potential molecular targets using immunohistochemistry. The medical records of all patients who underwent primary surgery for salivary gland cancer with curative intent in a tertiary referral center between 1990 and 2018 were reviewed. Immunohistochemical staining for MUC1, MUC16, and MUC5AC was performed for all patients with sufficient formalin-fixed paraffin-embedded material, and a semi-quantitative combined score derived from the H-score for the cytoplasmatic, the membranous and the apical membrane was built for the most common entities of SGC. 107 patients with malignancies of the parotid (89.7%) and the submandibular gland (10.3%) were included. The most common entities were mucoepidermoid carcinoma (MuEp; n = 23), adenoid cystic carcinoma (AdCy; n = 22), and salivary duct carcinoma (SaDu; n = 21). The highest mean MUC1 combined score was found in SaDu with 223.6 (±91.7). The highest mean MUC16 combined score was found in MuEp with 177.0 (±110.0). The mean MUC5AC score was low across all entities. A higher MUC1 combined score was significantly associated with male gender (p = 0.03), lymph node metastasis (p < 0.01), lymphovascular invasion (p = 0.045), and extracapsular extension (p = 0.03). SaDu patients with MUC16 expression showed a significantly worse 5-year progression-free survival than those without MUC16 expression (p = 0.02). This is the first study to give a comprehensive overview of the expression of MUC1, MUC16, and MUC5AC in SGC. Since advanced SGCs lack therapeutic options in many cases, these results warrant in vitro research on therapeutic targets against MUC1 in SaDu cell lines and xenograft models.

Lesional activation of Tc 17 cells in Behçet disease and psoriasis supports HLA class I-mediated autoimmune responses.

BACKGROUND: Behçet disease (BD) presents with lymphocytic and neutrophilic vasculitis of unknown aetiology. HLA-B*51, the endoplasmic reticulum aminopeptidase 1 (ERAP1), and interleukin 23 receptor (IL23R)/IL12R are genetic risk factors. IL-23 regulates IL-17A, which controls the recruitment and activation of neutrophils. OBJECTIVES: To determine pathological changes in BD skin lesions related to the complex genetic predisposition. METHODS: We characterized the expression of IL-17A and IL-23A in various cell types by immunohistological double staining of sections from papulopustular skin lesions of acute attacks of BD and psoriasis vulgaris lesions, another HLA-class I-associated T-cell-mediated autoimmune disease in which excessive T-cell-derived IL-17A production promotes neutrophil activation. RESULTS: We found that in BD lesions, as in psoriasis, actively expanding CD8+ T cells were the predominant source of IL-17A. IL-17A+ CD8+ T (Tc 17) cells outnumbered infiltrating IL-17A+ CD4+ T cells. Unlike the epidermal localization of CD8+ T cells in psoriasis, Tc 17 cells in BD lesions mainly infiltrated the perivascular tissue and the blood vessel walls of dermis and subcutaneous tissue. They co-localised with a marked IL-23A expression by CD11c+ dendritic cells and CD68+ macrophages. IL-17A expression was associated with extensive recruitment of neutrophils around blood vessels that formed neutrophil extracellular traps (NETs). CONCLUSIONS: In BD, the genetic predisposition may mediate antigen-specific activation and differentiation of a Tc 17 response, possibly targeting endothelial (auto)antigens. Neutrophils recruited by IL-17A in this process may enhance tissue damage by extensive NET formation (NETosis). Thus, the IL-23/IL-17 axis presumably controls neutrophilic inflammation in BD vasculitis in the context of a predominant antigen-specific CD8+ T-cell response.

[Psoriasis in dupilumab-treated atopic dermatitis]. / Psoriasis bei Dupilumab-behandeltem atopischem Ekzem.

Dupilumab is a monoclonal antibody that binds to the common alpha chain of the IL­4 and IL-13 receptor and blocks the Th2 signaling pathway, which plays a key role in the development of atopic dermatitis. We report on the case of a 40-year-old man, who developed histologically confirmed psoriasis after 6 weeks of dupilumab therapy. The arbitrary, abrupt stopping of the unusual, not guideline-based oral steroid therapy, together with the blockade of the Th2 signaling pathway by dupilumab were apparently the relevant trigger factors for the newly developed psoriasis in our patient.

[CARs, CRS and neurotoxicity: severe complications after administration of immunotherapy : Essentials for intensivists]. / CAR, CRS und Neurotoxizität: schwere Komplikationen der Immuntherapie : Was der Intensivmediziner wissen muss.

BACKGROUND: The development of chimeric antigen receptor (CAR) T­cells has shown promising results in relapsed/refractory B­cell acute lymphoblastic leukemia/lymphoma (B-ALL) and diffuse large cell B­cell lymphoma. Complications, especially cytokine release syndrome (CRS) and CAR T­cell related encephalopathy syndrome (CRES), can be life threatening. The management of both plays a key role in CAR T­cell therapy. OBJECTIVES: Diagnosis, clinical presentation and development of complications in the treatment with CAR T­cells. MATERIALS AND METHODS: Summary of incidence, mortality and treatment of severe complications after administration of CAR T­cells referring to current studies and therapy recommendations. RESULTS: Complications after administration of CAR T­cells, especially CRS and CRES, can be life threatening. The timely identification of side effects and their appropriate treatment usually leads to complete recovery. CONCLUSIONS: Using a therapy algorithm in the treatment with CAR T­cells allows safe management of toxicities and can be helpful in recognizing them in time.

[Diagnosis and treatment of immune-related adverse events during checkpoint inhibitor therapy in intensive care medicine]. / Diagnostik und Therapie von immunvermittelten Nebenwirkungen durch Checkpointinhibitoren in der Intensivmedizin.

BACKGROUND: Due to the use of checkpoint inhibitors, intensive care units will be confronted with an increasing number of patients with immune-related adverse events. A broad spectrum of symptoms and potentially lethal consequences make diagnosis and treatment challenging. OBJECTIVES: Diagnosis and treatment of immune-related adverse events in the treatment with checkpoint inhibitors with a special focus on intensive care units. MATERIALS AND METHODS: Review of current publications about incidence, symptoms and treatment of adverse events after the use of checkpoint inhibitors relevant for intensive care medicine. RESULTS: Immune-related adverse events during therapy with checkpoint inhibitors are difficult to diagnose and present with various symptoms. Severe complications can often successfully be treated with early therapy. CONCLUSIONS: The early treatment of immune-related adverse events according to their severity is needed to prevent a potentially life-threatening course.

[Antifreeze poisoning : The case of a patient with repeated ethylene glycol poisoning]. / Intoxikation nach Frostschutzmittelaufnahme : Der Fall eines Patienten nach wiederholter Ethylenglykolintoxikation.

Ethylene glycol poisoning of incidental or suicidal intention can cause life-threatening metabolic acidosis, diverse secondary damage, and even lead to death. Beside hemodialysis effective therapy consists of the administration of fomepizole and ethanol. We describe a patient after repeated ethylene glycol poisoning with high anion gap metabolic acidosis and acute renal failure. Using hemodialysis, with dialysate containing a specific amount of ethanol, and intravenous ethanol administration we were able to prevent severe secondary organ damage.

Genetics and Crime: Integrating New Genomic Discoveries Into Psychological Research About Antisocial Behavior.

Drawing on psychological and sociological theories of crime causation, we tested the hypothesis that genetic risk for low educational attainment (assessed via a genome-wide polygenic score) is associated with criminal offending. We further tested hypotheses of how polygenic risk relates to the development of antisocial behavior from childhood through adulthood. Across the Dunedin and Environmental Risk (E-Risk) birth cohorts of individuals growing up 20 years and 20,000 kilometers apart, education polygenic scores predicted risk of a criminal record with modest effects. Polygenic risk manifested during primary schooling in lower cognitive abilities, lower self-control, academic difficulties, and truancy, and it was associated with a life-course-persistent pattern of antisocial behavior that onsets in childhood and persists into adulthood. Crime is central in the nature-nurture debate, and findings reported here demonstrate how molecular-genetic discoveries can be incorporated into established theories of antisocial behavior. They also suggest that improving school experiences might prevent genetic influences on crime from unfolding.

The genetic basis for most patients with pustular skin disease remains elusive.

BACKGROUND: Rare variants in the genes IL36RN, CARD14 and AP1S3 have been identified to cause or contribute to pustular skin diseases, primarily generalized pustular psoriasis (GPP). OBJECTIVES: To better understand the disease relevance of these genes, we screened our cohorts of patients with pustular skin diseases [primarily GPP and palmoplantar pustular psoriasis (PPP)] for coding changes in these three genes. Carriers of single heterozygous IL36RN mutations were screened for a second mutation in IL36RN. METHODS: Coding exons of IL36RN, CARD14 and AP1S3 were sequenced in 67 patients - 61 with GPP, two with acute generalized exanthematous pustulosis and four with acrodermatitis continua of Hallopeau. We screened IL36RN and AP1S3 for intragenic copy-number variants and 258 patients with PPP for coding changes in AP1S3. Eleven heterozygous IL36RN mutations carriers were analysed for a second noncoding IL36RN mutation. Genotype-phenotype correlations in carriers/noncarriers of IL36RN mutations were assessed within the GPP cohort. RESULTS: The majority of patients (GPP, 64%) did not carry rare variants in any of the three genes. Biallelic and monoallelic IL36RN mutations were identified in 15 and five patients with GPP, respectively. Noncoding rare IL36RN variants were not identified in heterozygous carriers. The only significant genotype-phenotype correlation observed for IL36RN mutation carriers was early age at disease onset. Additional rare CARD14 or AP1S3 variants were identified in 15% of IL36RN mutation carriers. CONCLUSIONS: The identification of IL36RN mutation carriers harbouring additional rare variants in CARD14 or AP1S3 indicates a more complex mode of inheritance of pustular psoriasis. Our results suggest that, in heterozygous IL36RN mutation carriers, there are additional disease-causing genetic factors outside IL36RN.

The role of IL-23 and the IL-23/TH 17 immune axis in the pathogenesis and treatment of psoriasis.

Psoriasis is a chronic, immune-mediated disease affecting more than 100 million people worldwide and up to 2.2% of the UK population. The aetiology of psoriasis is thought to originate from an interplay of genetic, environmental, infectious and lifestyle factors. The manner in which genetic and environmental factors interact to contribute to the molecular disease mechanisms has remained elusive. However, the interleukin 23 (IL-23)/T-helper 17 (TH 17) immune axis has been identified as a major immune pathway in psoriasis disease pathogenesis. Central to this pathway is the cytokine IL-23, a heterodimer composed of a p40 subunit also found in IL-12 and a p19 subunit exclusive to IL-23. IL-23 is important for maintaining TH 17 responses, and levels of IL-23 are elevated in psoriatic skin compared with non-lesional skin. A number of agents that specifically inhibit IL-23p19 are currently in development for the treatment of moderate-to-severe plaque psoriasis, with recent clinical trials demonstrating efficacy with a good safety and tolerability profile. These data support the role of this cytokine in the pathogenesis of psoriasis. A better understanding of the IL-23/TH 17 immune axis is vital and will promote the development of additional targets for psoriasis and other inflammatory diseases that share similar genetic aetiology and pathogenetic pathways.

[Autoimmune reactions in psoriasis : Spotlight]. / Autoimmunreaktionen bei Psoriasis : Spotlight.

BACKGROUND: Psoriasis is a human leukocyte antigen (HLA)-associated T­cell-mediated disorder. OBJECTIVES: The role of the main psoriasis risk allele HLA-C*06:02 in disease manifestation and the mechanisms which activate the pathogenic T­cell response in the skin of psoriasis patients remained elusive. MATERIALS AND METHODS: Key to the immune pathogenesis of psoriasis was the analysis of the specificity of the infiltrating lesional psoriatic CD8(+) T cells RESULTS AND CONCLUSION: Analyses of the lesional psoriatic T­cell reactivity demonstrate that psoriasis is an autoimmune disease. It is based on an autoimmune response against melanocytes which is preferentially mediated by HLA-C*06:02 through autoantigen presentation. Here we discuss the mechanisms of this autoimmune response in the context of the polygenic psoriatic predisposition.

Treatment of psoriasis with etanercept: the typical patient profile.

The chronic nature of psoriasis means that patients often require lifetime treatment. Over this time, treatment frequently has to be adapted to meet variable demands resulting from changes in life course and life events. Biological drugs used to treat psoriasis vary in their dosing regimens, convenience and flexibility. Dermatologists need to understand which biologic agent is best suited for each individual patient. A wealth of evidence supports the safe and effective use of etanercept, which offers a rapid and sustained response, flexibility of dosing, maintenance of response after dose reduction or interruption, and efficacy against non-skin manifestations such as psoriatic arthritis. An expert panel met to agree the typical patient profile of a psoriasis patient treated with etanercept, the main benefits of etanercept in psoriasis, and the patient group most likely to benefit from its use. They agreed that flexibility of dosing, the potential to individualize therapy by stopping and starting treatment while maintaining efficacy, and the possibility of cost saving through the use of flexible treatment regimens were important benefits supporting the use of etanercept in many patients with psoriasis.

[Psoriasis migrans : Erythema migrans as Koebner phenomenon in psoriasis]. / Psoriasis migrans : Erythema migrans als Köbner-Phänomen bei Psoriasis.

Psoriasis is a chronic inflammatory disorder of the epidermis, which can be induced by systemic factors, such as streptococci infections or drugs. In addition, psoriasis can be caused by a local cutaneus trauma, known as Koebner phenomenon. Here, we describe a woman with psoriasis in remission, who developed a new psoriatic lesion due to a cutaneous infection with Borrelia burgdorferi. After causal therapy with doxycycline, the erythema migrans and psoriasis lesions disappeared.

DNA origami based Au-Ag-core-shell nanoparticle dimers with single-molecule SERS sensitivity.

DNA origami nanostructures are a versatile tool to arrange metal nanostructures and other chemical entities with nanometer precision. In this way gold nanoparticle dimers with defined distance can be constructed, which can be exploited as novel substrates for surface enhanced Raman scattering (SERS). We have optimized the size, composition and arrangement of Au/Ag nanoparticles to create intense SERS hot spots, with Raman enhancement up to 10(10), which is sufficient to detect single molecules by Raman scattering. This is demonstrated using single dye molecules (TAMRA and Cy3) placed into the center of the nanoparticle dimers. In conjunction with the DNA origami nanostructures novel SERS substrates are created, which can in the future be applied to the SERS analysis of more complex biomolecular targets, whose position and conformation within the SERS hot spot can be precisely controlled.

A patient-centred approach to biological treatment decision making for psoriasis: an expert consensus.

BACKGROUND: Each individual psoriasis patient has different expectations and goals for biological treatment, which may differ from those of the clinician. As such, a patient-centred approach to treatment goals remains an unmet need in psoriasis. OBJECTIVE: The aim of this study was to review available data on patients' and physicians' decision criteria and expectations of biological treatment for moderate-to-severe psoriasis with the aim of developing a core set of questions for clinicians to ask patients routinely to understand what is important to them and thus better align physicians' and patients' expectations of treatment with biologics and its outcomes. METHODS: A literature search was conducted to identify key themes and data gaps. Aspects of treatment relevant when choosing a biological agent for an individual patient were identified and compared to an existing validated instrument. A series of questions aimed at helping the physician to identify the particular aspects of treatment that are recognised as important to individual psoriasis patients was developed. RESULTS: Key findings of the literature search were grouped under themes of adherence, decision-making, quality of life, patient/physician goals, communication, patient-reported outcomes, satisfaction and patient benefit index. Several aspects of treatment were identified as being relevant when choosing a biological agent for an individual patient. The questionnaire is devised in two parts. The first part asks questions about patients' experience of psoriasis and satisfaction with previous treatments. The second part aims to identify the treatment attributes patients consider to be important and may as such affect their preference for a particular biological treatment. The questionnaire results will allow the physician to understand the key factors that can be influenced by biological drug choice that are of importance to the patient. This information can be used be the physician in clinical decision making. CONCLUSION: The questionnaire has been developed to provide a new tool to better understand and align patients' and physicians' preferences and goals for biological treatment of psoriasis.