Atopy and related clinical symptoms among Swiss medical students from 2007 to 2015

Abstract Background Atopic allergy is a widespread disease with increasing prevalence in the second half of the twentieth century and is most often associated with clinical symptoms, like rhinoconjunctivitis, asthma or eczema. This study explored the prevalence of atopy and polysensitization in nine cohorts of Swiss medical students during the period of 2007–2015. Furthermore, the self-reported allergic symptoms, such as rhinoconjunctivitis, asthma and eczema, among students with and without atopy were assessed. Methods Each cohort was assessed in the third study year. Students underwent an ImmunoCAP rapid test, a qualitative point-of-care test, and completed an anonymous questionnaire on age, gender and clinical symptoms including rhinoconjunctivitis, asthma and eczema. Statistical analyses assessed the overall prevalence of atopy in each group and estimated the average annual increase using a linear mixed model. We examined the frequency of occurrence of polysensitization and differences of reported symptoms among students with and without atopy. Results Data of 1513 students (mean age 22.4–23.3 years across cohorts) in nine cohorts (median cohort size 215 interquartile range IQR 193–222) were available for analysis. Test results consistent with atopy were present in 39.9% of students. Average increase of atopy over the 9 years of observation was 2.25% (95% CI 0.18–4.31%; p = 0.037). Main drivers for this increase were the ubiquitously available allergens, house dust mite, timothy grass and birch pollen. Atopy and polysensitization were more pronounced in male students: Polysensitization also increased in the observation period. The clinical symptoms, rhinoconjunctivitis, asthma and eczema were reported by 463 (76.7%) atopic and by 141 (15.5%) non-atopic students. Conclusions We observed a slight increase of atopy and polysensitization within 9 years of observation in Swiss medical students. The most frequent sensitization occurred with allergens with the highest chance of exposure. Rhinoconjunctivitis, asthma and eczema are a symptom complex associated with atopy but also found in non-atopic students. Trial registration retrospectively registered by the Cantonal Ethics Committee Zurich on 22.01.2016; Nr: 08-201

Relationship Between Rhinitis, Asthma, and Eczema and the Presence of Sensitization in Young Swiss Adults

Background: Rhinitis is a very common disease with allergies being the most frequent causative factor. It can co-occur together with asthma and eczema in atopic as well as in nonatopic patients. Objectives: To assess the prevalence of allergic sensitization within patient groups with rhinitis in consideration of the co-occurring disorders of asthma and eczema. Methods: Students of the third year of medical school completed an anonymous questionnaire on age, gender, and clinical symptoms, such as seasonal rhinitis, perennial rhinitis, asthma, and eczema, and underwent an ImmunoCAP Rapid test. We calculated the prevalence of sensitization within subgroups of patients reporting allergic disorders, such as rhinitis, asthma, and eczema. Results: Questionnaires and ImmunoCAP Rapid tests of 1513 medical students were analyzed. The participants' self-reported presence of seasonal/perennial rhinitis, asthma, and eczema was compared to the presence of sensitization. Data of 1467 subjects could be analyzed. Seasonal rhinitis was the most common symptom, followed by eczema, asthma, and perennial rhinitis. The participants were differentiated into 16 subgroups according to the combined clinical manifestations of the different symptoms and association to sensitization within subgroups. The prevalence of sensitization ranged from 18% in subjects reporting only eczema without any other symptom to 100% in those reporting to have asthma, seasonal/perennial rhinitis, and eczema together. In subjects reporting no sign or symptom at all, the prevalence of sensitization was 19%. Seasonal rhinitis was the strongest single predictor for sensitization with the highest proportion of sensitized participants in all symptom combinations (67%-100%), followed by perennial rhinitis (31%-100%), asthma (30%-100%), and eczema (18%-100%). Conclusion: Rhinitis most often is associated with allergen sensitization, and the probability of sensitization is substantially enhanced by co-occurrence of asthma. A careful assessment of clinical signs and symptoms is important and enables the selection of patients in whom targeted diagnostic analysis and therapy is appropriate.Trial registration: retrospectively registered by the Cantonal Ethics Committee Zurich on 22.01.2016; Nr: 08-2016

A high-content EMT screen identifies multiple receptor tyrosine kinase inhibitors with activity on TGFβ receptor

An epithelial to mesenchymal transition (EMT) enables epithelial tumor cells to break out of the primary tumor mass and to metastasize. Understanding the molecular mechanisms driving EMT in more detail will provide important tools to interfere with the metastatic process. To identify pharmacological modulators and druggable targets of EMT, we have established a novel multi-parameter, high-content, microscopy-based assay and screened chemical compounds with activities against known targets. Out of 3423 compounds, we have identified 19 drugs that block transforming growth factor beta (TGFβ)-induced EMT in normal murine mammary gland epithelial cells (NMuMG). The active compounds include inhibitors against TGFβ receptors (TGFBR), Rho-associated protein kinases (ROCK), myosin II, SRC kinase and uridine analogues. Among the EMT-repressing compounds, we identified a group of inhibitors targeting multiple receptor tyrosine kinases, and biochemical profiling of these multi-kinase inhibitors reveals TGFBR as a thus far unknown target of their inhibitory spectrum. These findings demonstrate the feasibility of a multi-parameter, high-content microscopy screen to identify modulators and druggable targets of EMT. Moreover, the newly discovered "off-target" effects of several receptor tyrosine kinase inhibitors have important consequences for in vitro and in vivo studies and might beneficially contribute to the therapeutic effects observed in vivo

Relationship Between Rhinitis, Asthma, and Eczema and the Presence of Sensitization in Young Swiss Adults

Background Rhinitis is a very common disease with allergies being the most frequent causative factor. It can co-occur together with asthma and eczema in atopic as well as in nonatopic patients. Objectives To assess the prevalence of allergic sensitization within patient groups with rhinitis in consideration of the co-occurring disorders of asthma and eczema. Methods Students of the third year of medical school completed an anonymous questionnaire on age, gender, and clinical symptoms, such as seasonal rhinitis, perennial rhinitis, asthma, and eczema, and underwent an ImmunoCAP Rapid test. We calculated the prevalence of sensitization within subgroups of patients reporting allergic disorders, such as rhinitis, asthma, and eczema. Results Questionnaires and ImmunoCAP Rapid tests of 1513 medical students were analyzed. The participants’ self-reported presence of seasonal/perennial rhinitis, asthma, and eczema was compared to the presence of sensitization. Data of 1467 subjects could be analyzed. Seasonal rhinitis was the most common symptom, followed by eczema, asthma, and perennial rhinitis. The participants were differentiated into 16 subgroups according to the combined clinical manifestations of the different symptoms and association to sensitization within subgroups. The prevalence of sensitization ranged from 18% in subjects reporting only eczema without any other symptom to 100% in those reporting to have asthma, seasonal/perennial rhinitis, and eczema together. In subjects reporting no sign or symptom at all, the prevalence of sensitization was 19%. Seasonal rhinitis was the strongest single predictor for sensitization with the highest proportion of sensitized participants in all symptom combinations (67%–100%), followed by perennial rhinitis (31%–100%), asthma (30%–100%), and eczema (18%–100%). Conclusion Rhinitis most often is associated with allergen sensitization, and the probability of sensitization is substantially enhanced by co-occurrence of asthma. A careful assessment of clinical signs and symptoms is important and enables the selection of patients in whom targeted diagnostic analysis and therapy is appropriate. Trial registration: retrospectively registered by the Cantonal Ethics Committee Zurich on 22.01.2016; Nr: 08-2016

Antivascular Therapy for Multidrug-Resistant Ovarian Tumors by Macitentan, a Dual Endothelin Receptor Antagonist1

Endothelin receptors (ETRs) are often overexpressed in ovarian tumors, which can be resistant to conventional therapies. Thus, we investigated whether blockage of the ETR pathways using the dual ETR antagonist macitentan combined with taxol or cisplatinum can produce therapy for orthotopically growing multidrug-resistant (MDR) human ovarian carcinoma. In several studies, nude mice were injected in the peritoneal cavity with HeyA8-MDR human ovarian cancer cells. Ten days later, mice were randomized to receive vehicle (saline), macitentan (oral, daily), taxol (intraperitoneal, weekly), cisplatinum (intraperitoneal, weekly), macitentan plus taxol, or macitentan plus cisplatinum. Moribund mice were killed, and tumors were collected, weighed, and prepared for immunohistochemical analysis. The HeyA8-MDR tumors did not respond to taxol, cisplatinum, or macitentan administered as single agents. In contrast, combination therapy with macitentan and taxol or macitentan and cisplatinum significantly decreased the tumor incidence and weight and significantly increased the survival of mice and their general condition. Multiple immunohistochemical analyses revealed that treatment with macitentan and macitentan plus taxol or cisplatinum inhibited the phosphorylation of ETRs, decreased the levels of pVEGFR2, pAkt, and pMAPK in tumor cells after 2 weeks of treatment and induced a first wave of apoptosis in tumor-associated endothelial cells followed by apoptosis in surrounding tumor cells. Our study shows that ovarian cancer cells, which express the endothelin axis and are multidrug resistant, are exquisitely sensitive to treatment with a dual ET antagonist and can be resensitized to both taxol and cisplatinum. This combined therapy led to a significant reduction in tumor weight

Macitentan (ACT-064992), a Tissue-Targeting Endothelin Receptor Antagonist, Enhances Therapeutic Efficacy of Paclitaxel by Modulating Survival Pathways in Orthotopic Models of Metastatic Human Ovarian Cancer

Potential treatments for ovarian cancers that have become resistant to standard chemotherapies include modulators of tumor cell survival, such as endothelin receptor (ETR) antagonist. We investigated the therapeutic efficacy of the dual ETR antagonist, macitentan, on human ovarian cancer cells, SKOV3ip1 and IGROV1, growing orthotopically in nude mice. Mice with established disease were treated with vehicle (control), paclitaxel (weekly, intraperitoneal injections), macitentan (daily oral administrations), or a combination of paclitaxel and macitentan. Treatment with paclitaxel decreased tumor weight and volume of ascites. Combination therapy with macitentan and paclitaxel reduced tumor incidence and further reduced tumor weight and volume of ascites when compared with paclitaxel alone. Macitentan alone occasionally reduced tumor weight but alone had no effect on tumor incidence or ascites. Immunohistochemical analyses revealed that treatment with macitentan and macitentan plus paclitaxel inhibited the phosphorylation of ETRs and suppressed the survival pathways of tumor cells by decreasing the levels of pVEGFR2, pAkt, and pMAPK. The dose of macitentan necessary for inhibition of phosphorylation correlated with the dose required to increase antitumor efficacy of paclitaxel. Treatment with macitentan enhanced the cytotoxicity mediated by paclitaxel as measured by the degree of apoptosis in tumor cells and tumor-associated endothelial cells. Collectively, these results show that administration of macitentan in combination with paclitaxel prevents the progression of ovarian cancer in the peritoneal cavity of nude mice in part by inhibiting survival pathways of both tumor cells and tumor-associated endothelial cells