[T-cell immune responses in chronic inflammatory diseases of the nasal mucosa]. / T-Zell-Immunreaktionen bei chronisch entzündlichen Erkrankungen der nasalen Schleimhäute.

Acute rhinosinusitis and chronic rhinosinusitis are inflammatory diseases of the mucosal membranes due to mislead immunological reactions to aeroallergens. T­cells are divided into different groups based on their cytokine secretion: T­helper type 1 (Th1) and type 2 (Th2) cells. The allergic immune response is caused by activation of specific Th2 cells. With specific immunotherapy, the mislead hyperactivated "allergic" immune response is reduced to a reaction within the normal range. The inflammatory forms of chronic rhinosinusitis are called endotypes, and, in the future, could enable a targeted, pathomechanistic therapy. These endotype-based treatment approaches target specific signaling pathways that have already shown good effects for chronic rhinosinusitis with nasal polyps using monoclonal antibodies. However, so far, only selected patients with non-rhinologic indications, off-label treatments, or in clinical trials have benefited from these treatments.

[Histamine receptors in chronic inflammatory diseases of the nose and paranasal sinuses]. / Histaminrezeptoren bei chronisch-entzündlichen Erkrankungen der Nase und Nasennebenhöhlen.

BACKGROUND: Release of histamine from mast cells and basophils in inflammatory diseases of the nose and paranasal sinuses has been demonstrated in allergic and non-allergic processes. METHODS: A selective literature search was conducted in PubMed and Medline, and publications in German-language journals were additionally analyzed. RESULTS: The histamine receptors H1-H4 play a role in otorhinolaryngologic inflammatory diseases. To date, the histamine receptor subtype 4 (H4R), which is functionally expressed by immune cells in chronic inflammatory diseases, has received little attention. Stimulation of H4R influences the release of cytokines and chemokines as well as the migration behavior of immune cells. In animal models blockade of H4R reduced inflammation symptoms and pruritus. CONCLUSIONS: H4R plays a key role in the pathogenesis of chronic inflammatory diseases and may represent an interesting future therapeutic target.

Nanomaterial-microbe cross-talk: physicochemical principles and (patho)biological consequences.

The applications of nanoparticles (NPs) are increasing exponentially in consumer products, biotechnology and biomedicine, and humans, as well as the environment, are increasingly being exposed to NPs. Analogously, various (pathogenic) microorganisms are present at all the major exposure and entry sites for NPs in the human body as well as in environmental habitats. However, the field has just started to explore the complex interplay between NPs and microbes and the (patho)biological consequences. Based on recent insights, herein, we critically reviewed the available knowledge about the interaction of NPs with microbes and the analytical investigations including the latest intravital imaging tools. We have commented on how the NPs' characteristics influence complex formation with microorganisms, presented the underlying physicochemical forces, and provided examples of how this knowledge can be used to rationally control the NP-microbe interaction. We concluded by discussing the role of the biomolecule corona in NP-microbe crosstalk and speculated the impact of NP-microbe complex formation on the (patho)biological outcome and fate of microbial pathogens. The presented insights will not only support the field in engineering NPs with improved anti-microbial activity but also stimulate research on the biomedical and toxicological relevance of nanomaterial-microbiome complex formation for the anthropocene in general.

[Staging of oropharyngeal carcinomas : New TNM classification as a challenge for head and neck cancer centers]. / Staging von Oropharynxkarzinomen : Neue TNM-Klassifikation als Herausforderung für Kopf-Hals-Tumorzentren.

BACKGROUND: The TNM (tumor, nodes, metastasis) classification is updated periodically according to the literature and international recommendations. With the 8th edition, notable changes have been developed especially with regard to oropharyngeal cancer. MATERIALS AND METHODS: The modifications as well as the practicability of the classification for staging of oropharyngeal cancers are demonstrated on the basis of cases from the tumor database. RESULTS: The latest edition of the TNM classification realizes requirements to differentiate between human papilloma virus (HPV) positive and HPV-negative tumors during staging. Furthermore, the prognostic relevance of extranodal extension of lymph node metastases was integrated into the classification. While downstaging is performed regarding N category and Union Internationale Contre le Cancer (UICC) stage in many p16-positive tumors, for p16-negative tumors, extranodal spread mostly leads to a notable upstaging. Due to limited specificity of the p16 immunostaining, the relevance of false positive results has to be underlined. Missing integration of smoking behavior, limited standardization of the extranodal extension examination technique, as well as high demands on the documentation quality should be kept in mind. CONCLUSION: Clinical trials will have to show whether deescalation strategies regarding p16-positive carcinomas are supported by the changes made in the TNM staging system. A prospective multicenter study should examine the universal applicability, the appropriateness for all sublocations, as well as the prognostic significance of the current edition.

Soluble CD163 and soluble mannose receptor predict survival and decompensation in patients with liver cirrhosis, and correlate with gut permeability and bacterial translocation.

BACKGROUND: Activated hepatic macrophages play a key role in inflammation and fibrosis progression in chronic liver disease. AIM: To assess the prognostic value of soluble (s)CD163 and mannose receptor (sMR) in cirrhotic patients and explore associations with markers of intestinal permeability (lactulose-mannitol ratio, diamine oxidase), bacterial translocation (endotoxin, lipopolysaccharide-binding protein) and markers of systemic immune activation (interleukin-6, interleukin-8, sCD14). METHODS: We prospectively investigated 101 cirrhotic patients (Child-Pugh class A: n = 72, Child-Pugh classes B and C: n = 29) and 31 healthy controls. Patients were observed for a median follow-up of 37 months. RESULTS: Median plasma levels of sCD163 and soluble mannose receptor were significantly elevated in cirrhotic patients (P < .001) and increased with disease severity (sCD163 in healthy controls = 1.3, Child-Pugh class A = 4.2, Child-Pugh classes B and C = 8.4 mg/L; sMR in healthy controls = 15.8, Child-Pugh class A = 36.5, Child-Pugh classes B and C = 66.3 µg/dL). A total of 21 patients died during the observation period. Patients with sCD163 levels above 5.9 mg/L showed significantly reduced survival (survival rate after 36 months: 71% versus 98%, P < .001). Patients with soluble mannose receptor levels above 45.5 µg/dL developed significantly more complications of cirrhosis within 12 months (73% versus 9%, P < .001). Furthermore, both variables correlated with the lactulose-mannitol ratio, diamine oxidase, lipopolysaccharide and interleukin-8. CONCLUSION: Our data demonstrate the prognostic value of sCD163 in predicting long-term survival in patients with liver cirrhosis and identify soluble mannose receptor as a prognostic marker for occurrence of cirrhosis-associated complications. The correlation between gut barrier dysfunction and activation of macrophages points towards a link between them.

HDAC1 and HDAC2 integrate the expression of p53 mutants in pancreatic cancer.

Mutation of p53 is a frequent genetic lesion in pancreatic cancer being an unmet clinical challenge. Mutants of p53 have lost the tumour-suppressive functions of wild type p53. In addition, p53 mutants exert tumour-promoting functions, qualifying them as important therapeutic targets. Here, we show that the class I histone deacetylases HDAC1 and HDAC2 contribute to maintain the expression of p53 mutants in human and genetically defined murine pancreatic cancer cells. Our data reveal that the inhibition of these HDACs with small molecule HDAC inhibitors (HDACi), as well as the specific genetic elimination of HDAC1 and HDAC2, reduce the expression of mutant p53 mRNA and protein levels. We further show that HDAC1, HDAC2 and MYC directly bind to the TP53 gene and that MYC recruitment drops upon HDAC inhibitor treatment. Therefore, our results illustrate a previously unrecognized class I HDAC-dependent control of the TP53 gene and provide evidence for a contribution of MYC. A combined approach targeting HDAC1/HDAC2 and MYC may present a novel and molecularly defined strategy to target mutant p53 in pancreatic cancer.

Randomised clinical trial: the effects of a multispecies probiotic vs. placebo on innate immune function, bacterial translocation and gut permeability in patients with cirrhosis.

BACKGROUND: Probiotics may correct intestinal dysbiosis and proinflammatory conditions in patients with liver cirrhosis. AIM: To test the effects of a multispecies probiotic on innate immune function, bacterial translocation and gut permeability. METHODS: In a randomised, double blind, placebo-controlled study, stable cirrhotic out-patients either received a daily dose of a probiotic powder containing eight different bacterial strains (Ecologic Barrier, Winclove, Amsterdam, The Netherlands) (n = 44) or a placebo (n = 36) for 6 months and were followed up for another 6 months. RESULTS: We found a significant but subclinical increase in neutrophil resting burst (2.6-3.2%, P = 0.0134) and neopterin levels (7.7-8.4 nmol/L, P = 0.001) with probiotics but not with placebo. Probiotic supplementation did not have a significant influence on neutrophil phagocytosis, endotoxin load, gut permeability or inflammatory markers. Ten severe infections occurred in total; one during intervention in the placebo group, and five and four after the intervention has ended in the probiotic and placebo group, respectively. Liver function showed some improvement with probiotics but not with placebo. CONCLUSIONS: Probiotic supplementation significantly increased serum neopterin levels and the production of reactive oxygen species by neutrophils. These findings might explain the beneficial effects of probiotics on immune function. Furthermore, probiotic supplementation may be a well-tolerated method to maintain or even improve liver function in stable cirrhosis. However, its influence on gut barrier function and bacterial translocation in cirrhotic patients is minimal.

Taspase1: a 'misunderstood' protease with translational cancer relevance.

Proteolysis is not only a critical requirement for life, but the executing enzymes also play important roles in numerous pathological conditions, including cancer. Therefore, targeting proteases is clearly relevant for improving cancer patient care. However, to effectively control proteases, a profound knowledge of their mechanistic function as well as their regulation and downstream signalling in health and disease is required. The highly conserved protease Threonine Aspartase1 (Taspase1) is overexpressed in numerous liquid and solid malignancies and was characterized as a 'non-oncogene addiction' protease. Although Taspase1 was shown to cleave various regulatory proteins in humans as well as leukaemia provoking mixed lineage leukaemia fusions, our knowledge on its detailed functions and the underlying mechanisms contributing to cancer is still incomplete. Despite superficial similarity to type 2 asparaginases as well as Ntn proteases, such as the proteasome, Taspase1-related research so far gives us the picture of a unique protease exhibiting special features. Moreover, neither effective genetic nor chemical inhibitors for this enzyme are available so far, thus hampering not only to further dissect Taspase1's pathobiological functions but also precluding the assessment of its clinical impact. Based on recent insights, we here critically review the current knowledge of Taspase1's structure-function relationship and its mechanistic relevance for tumorigenesis obtained from in vitro and in vivo cancer models. We provide a comprehensive overview of tumour entities for which Taspase1 might be of predictive and therapeutic value, and present the respective experimental evidence. To stimulate progress in the field, a comprehensive overview of Taspase1 targeting approaches is presented, including coverage of Taspase1-related patents. We conclude by discussing future inhibition strategies and relevant challenges, which need to be resolved by the field.

The nanoparticle biomolecule corona: lessons learned - challenge accepted?

Besides the wide use of engineered nanomaterials (NMs) in technical products, their applications are not only increasing in biotechnology and biomedicine, but also in the environmental field. While the physico-chemical properties and behaviour of NMs can be characterized accurately under idealized conditions, this is no longer the case in complex physiological or natural environments. Herein, proteins and other biomolecules rapidly bind to NMs, forming a protein/biomolecule corona that critically affects the NMs' (patho)biological and technical identities. As the corona impacts the in vitro and/or in vivo NM applications in humans and ecosystems, a mechanistic understanding of its relevance and of the biophysical forces regulating corona formation is mandatory. Based on recent insights, we here critically review and present an updated concept of corona formation and evolution. We comment on how corona signatures may be linked to effects at the nano-bio interface in physiological and environmental systems. In order to comprehensively analyse corona profiles and to mechanistically understand the coronas' biological/ecological impact, we present a tiered multidisciplinary approach. To stimulate progress in this field, we introduce the potential impact of the corona for NM-microbiome-(human)host interactions and the novel concept of 'nanologicals', i.e., the nanomaterial-specific targeting of molecular machines. We conclude by discussing the relevant challenges that still need to be resolved in this field.

Patatin-like phospholipase 3 (rs738409) gene polymorphism is associated with increased liver enzymes in obese adolescents and metabolic syndrome in all ages.

BACKGROUND: Obesity is associated with non-alcoholic fatty liver disease (NAFLD), and the patatin-like phospholipase 3 (PNPLA3) rs738409 (Ile148Met, C>G) gene polymorphism is one of the most important genetic determinants of NAFLD. Carriers have been reported to better respond to lifestyle modification. AIM: To investigate the effect of rs738409 on overweight/obese adolescents and adults with and without metabolic syndrome (MetS). METHODS: Two hundred and eighty-eight overweight/obese and 209 normal weight participants of the STYJOBS/EDECTA cohort (NCT00482924) were analysed for PNPLA3 genotypes. RESULTS: Compared to overweight/obese without MetS, in overweight/obese study participants with MetS, the presence of the G allele (148Met) was significantly higher (CC: 5.0% vs. 9.2%, Spearman's correlation, 0.12; P = 0.038). Persons with CG (heterozygote for the risk allele) and with GG (homozygote for the risk allele) genotypes showed significantly higher ALT levels than those with CC genotypes. Even young individuals aged below 20 years had significantly increased ALT levels if they were homozygote with the G allele. CONCLUSIONS: The PNPLA3 rs738409 polymorphism is associated already in youths with increased ALT, and is more frequent in obese with MetS of all ages. Hence, overweight/obese rs738409 carriers should be identified early in life and treated with a rigorous life style intervention.

Physicochemical characterization of nanoparticles and their behavior in the biological environment.

Whilst the physical and chemical properties of nanoparticles in the gas or idealized solvent phase can nowadays be characterized with sufficient accuracy, this is no longer the case for particles in the presence of a complex biological environment. Interactions between nanoparticles and biomolecules are highly complex on a molecular scale. The detailed characterization of nanoparticles under these conditions and the mechanistic knowledge of their molecular interactions with the biological world is, however, needed for any solid conclusions with regards to the relationship between the biological behavior of such particles and their physicochemical properties. In the present article we discuss some of the challenges with characterization and behavior of nanoparticles that are associated with their presence in chemically complex biological environments. Our focus is on the stability of colloids as well as on the formation and characteristics of protein coronae that have recently been shown to significantly modify the properties of pristine particles. Finally, we discuss the perspectives that may be expected from an improved understanding of nanoparticles in biological media.

Polymorphisms of interferon-λ4 and IL28B - effects on treatment response to interferon/ribavirin in patients with chronic hepatitis C.

BACKGROUND: The IL28B genotype in rs12979860 predicts success of peginterferon/ribavirin (PEG/RBV) therapy in patients with chronic hepatitis C (CHC). Recently, a dinucleotide frame shift variant in ss469415590 (TT or ΔG) was described, which generates the novel interferon lambda 4 protein (IFNL4). IFNL4 ss469415590 (ΔG) allele carriers have an impaired clearance of HCV infection and response to IFN-α therapy. In this study, we compared the role of IFNL4 polymorphism with the two commonly used IL28B SNPs rs12979860 and rs8099917 on response to PEG/RBV in patients with CHC. AIM: To compare the role of IFNL4 polymorphism with the two commonly used IL28B SNPs rs12979860 and rs8099917 on response to PEG/RBV in patients with CHC. METHODS: A total of 754 PEG/RBV patients treated (male/female = 484/270; Caucasians: 98.8%; mean age: 42.8 [CI 95%: 42.0-43.6] y; genotype (GT)1: n = 435, GT2: n = 23, GT3: n = 185, GT4: n = 114) were investigated. Liver fibrosis was assessed by liver biopsy in 456 patients. Single nucleotide polymorphisms (SNPs) in ss469415590, rs12979860 and rs8099917 were analysed by RT-PCR system. RESULTS: Of the patients, 12.9% (n = 97) had the ss469415590 ΔG/ΔG genotype (IFNL4), 51.3% (n = 387) were heterozygous (TT/ΔG) and 35.8% (n = 270) had TT/TT. IFNL4 polymorphism was independently associated with SVR in GT1 (OR: 2.539, CI 95%: 1.629-3.021, P < 0.001) and GT4 (OR: 12.573, CI 95%: 3.427-46.133, P < 0.001), but not in GT3 (OR: 1.514, CI 95%: 0.933-2.458, P = 0.093). IFNL4 correlated strongly with rs12979860 (ρ = 0.988, P < 0.001), but only moderately with rs8099917 (ρ = 0.598, P < 0.001). CONCLUSIONS: These findings underscore the role of IFNL4 for treatment response in patients with CHC genotypes 1 and 4. However, due to its strong correlation with rs12979860 in IL28B, there is no benefit in additional testing for IFNL4 for treatment prediction in Caucasian patients. By contrast, IFNL4 improves prediction of response to interferon-based therapies, if SNP rs8099917 is used.

SIAH proteins: critical roles in leukemogenesis.

The delicate balance between the synthesis and the degradation of proteins ensures cellular homeostasis. Proteases act in an irreversible manner and therefore have to be strictly regulated. The ubiquitin-proteasome system (UPS) is a major pathway for the proteolytic degradation of cellular proteins. As dysregulation of the UPS is observed in most cancers including leukemia, the UPS is a valid target for therapeutic intervention strategies. Ubiquitin-ligases selectively bind substrates to target them for poly-ubiquitinylation and proteasomal degradation. Therefore, pharmacological modulation of these proteins could allow a specific level of control. Increasing evidence accumulates that ubiquitin-ligases termed mammalian seven in absentia homologs (SIAHs) are not only critical for the pathogenesis of solid tumors but also for leukemogenesis. However, the relevance and therapeutic potential of SIAH-dependent processes has not been fully elucidated. Here, we summarize functions of SIAH ubiquitin-ligases in leukemias, how they select leukemia-relevant substrates for proteasomal degradation, and how the expression and activity of SIAH1 and SIAH2 can be modulated in vivo. We also discuss that epigenetic drugs belonging to the group of histone deacetylase inhibitors induce SIAH-dependent proteasomal degradation to accelerate the turnover of leukemogenic proteins. In addition, our review highlights potential areas for future research on SIAH proteins.

Monitoring nanoparticle induced cell death in H441 cells using field-effect transistors.

In this work we propose the use of field-effect transistors (FETs) to examine the reaction of individual tumor cells to treatment with cell death inducing nanoparticles for future use in cancer therapy.For our analysis the human cancer cell line H441 (a human lung adenocarcinoma epithelial cell line) was cultivated on fibronectin coated FETs and treated with various concentrations of silicon nanoparticles. The cell line was cultivated under standard conditions. The reactions of the cells to the nanoparticles were analyzed via transfer function measurements, microscopic examination and standard MTT viability assays. Microscopic examination showed a clear change of morphology to round cells, which accompanies detachment from the surface of the substrate. Cell detachment could also be observed as a signal shift in the transfer function.The results of our study indicate the applicability of FETs for cancer research and analyzing pharmacological effects of new compounds. In addition our results implicate the usefulness of silicon nanoparticle based compounds in cancer therapy.

The influence of probiotic supplementation on gut permeability in patients with metabolic syndrome: an open label, randomized pilot study.

BACKGROUND/OBJECTIVES: Obesity and metabolic disorders are linked to inflammation via gut microbiota and/or gut permeability. Gut-derived endotoxin triggers inflammation leading to metabolic syndrome (MetS) and contributing to oxidative stress. We intended to investigate the effect of Lactobacillus casei Shirota on gut permeability, presence of endotoxin and neutrophil function in MetS. SUBJECTS/METHODS: Patients with MetS were randomized to receive 3 × 6.5 × 109 CFU L. casei Shirota (probiotic group) or not for 3 months. Gut permeability was assessed by a differential sugar absorption method and by determination of diaminooxidase serum levels, endotoxin by an adapted limulus amoebocyte lysate assay, neutrophil function and toll-like receptor (TLR) expression by flow cytometry and ELISA was used to detect lipopolysaccharide-binding protein (LBP) and soluble CD14 (sCD14) levels. RESULTS: Twenty-eight patients and 10 healthy controls were included. Gut permeability was significantly increased in MetS compared with controls but did not differ between patient groups. None of the patients were positive for endotoxin. LBP and sCD14 levels were not significantly different from healthy controls. High-sensitive C-reactive protein and LBP levels slightly but significantly increased after 3 months within the probiotics group. Neutrophil function and TLR expression did not differ from healthy controls or within the patient groups. CONCLUSIONS: Gut permeability of MetS patients was increased significantly compared with healthy controls. L. casei Shirota administration in the MetS patients did not have any influence on any parameter tested possibly due to too-short study duration or underdosing of L. casei Shirota.

The VEGF/VEGF-R axis in sporadic vestibular schwannomas correlates with irradiation and disease recurrence.

BACKGROUND/AIMS: The molecular mechanisms downstream of mutated neurofibromatosis type 2 (NF2) gene resulting in the growth and development of vestibular schwannoma (VS) are controversial. Several lines of evidence suggest the involvement of the vascular endothelial growth factor (VEGF) pathway in VS development. Given that recent studies of VEGF blockade in patients with NF2-associated VS showed positive effects on VS growth control, we initiated this comprehensive study of the VEGF pathway in sporadic VS. METHODS: A tissue microarray analysis of 182 sporadic VS was conducted. The expression of VEGF and its receptors as well as the proliferative activity of the tumors were quantified. The expression data were correlated to tumor volumes and diameters as well as to tumor recurrence and previous irradiation. RESULTS: All studied tumors expressed VEGF and its receptors. Proliferative activity was related to the growth characteristics of the tumors. Moreover, we found significantly higher VEGF levels in recurrent tumors (p = 0.0387) and in preoperatively irradiated tumors (p = 0.0213). CONCLUSION: Our data suggest a relevant role of the VEGF pathway in VS growth and therapy outcome. Therefore, targeting this pathway using antiangiogenic compounds might be beneficial for patients with sporadic VS, especially those with recurrent or irradiated tumors.

[Interferon α therapy in patients with chronic hepatitis C infection: biopsychosocial consequences]. / Interferon α bei Patienten mit chronischer Hepatitis C : Biopsychosoziale Auswirkungen.

BACKGROUND: Interferon α (IFN-alpha) is widely used in the treatment of viral infections, including hepatitis C. Unfortunately depression is a common side effect of IFN-alpha therapy. The presence of depressive symptoms is important because they have an adverse effect on the course of the illness and reduce the quality of life and the treatment adherence. The current prospective study examines the effects of IFN-alpha on the development of depressive disorders, on cognitive functioning and on quality of life. METHOD: A total of 25 patients with chronic hepatitis C infection were investigated. All patients were treated in the Department of Gastroenterology and Hepatology, University of Medicine of Graz, Austria. Psychometric observer rating and self-rating scales were administered 1 month and 3 months after the beginning of the antiviral treatment to evaluate depressive symptoms [Beck Depression Inventory (BDI); Hamilton Depression Scale]. The data on life satisfaction before therapy and health-related quality of life were obtained from the Fragebogen zur Lebenszufriedenheit (FLZ) and the SF-36 (Health Status Questionnaire). Cognitive function was based on the SKT (Syndrom Kurztest). All patients completed the Social Support Questionnaire (SSS), a multidimensional self-report measure of social support. RESULTS: Three months after the initial IFN-alpha administration in the whole sample significant impairments in health-related quality of life were found in the health-related domains "physical functioning", "role physical", "role emotional", "social functioning" and "vitality". The whole sample showed cognitive impairments. No changes in social support were recorded. Three months after the first INF-alpha administration, 48% (n=12) of the sample suffered from moderate clinical depression. In comparison to patients without pathological affective findings, patients with INF-alpha-induced clinical depression showed decreased life satisfaction before the initial antiviral therapy. Impairments in health-related quality of life (SF-36) were found in the sample with clinical depression in the health-related domains "general health", "social functioning", "role emotional", "vitality" and "mental health". CONCLUSION: Hepatitis C is associated with an increased prevalence of psychiatric disorders, particularly depression. INF-alpha patients having low levels of life satisfaction in the domains "self-concept" (skills, appearance, self-confidence, vitality …), "employment" and "physical health and constitution" seem to face a major risk of depression.