TRAIL Deficient Mice Are Protected from Sugen/Hypoxia Induced Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a progressive lung disease diagnosed by an increase in pulmonary arterial blood pressure that is driven by a progressive vascular remodelling of small pulmonary arterioles. We have previously reported that tumor necrosis factor apoptosis-inducing ligand (TRAIL) protein expression is increased in pulmonary vascular lesions and pulmonary artery smooth muscle cells (PASMC) of patients with idiopathic PAH. The addition of recombinant TRAIL induces the proliferation and migration of PASMCs in vitro. TRAIL is required for hypoxia-induced pulmonary hypertension in mice, and blockade of TRAIL prevents and reduces disease development in other rodent models of PAH. Due to the availability of knockout and transgenic mice, murine models of disease are key to further advances in understanding the complex and heterogeneous pathogenesis of PAH. However, murine models vary in their disease severity, and are often criticized for lacking the proliferative pulmonary vascular lesions characteristic of PAH. The murine Sugen-hypoxic (SuHx) mouse model has recently been reported to have a more severe PAH phenotype consisting advanced pulmonary vascular remodelling. We therefore aimed to determine whether TRAIL was also required for the development of PAH in this model. C57BL/6 and TRAIL−/− mice were exposed to normoxia, Sugen5416 alone, hypoxia or both Sugen5416 and hypoxia (SuHx). We report here that SuHx treated C57BL/6 mice developed more severe PAH than hypoxia alone, and that TRAIL−/− mice were protected from disease development. These data further emphasise the importance of this pathway and support the use of the SuHx mouse model for investigating the importance of potential mediators in PAH pathogenesis

Increased expression of 5-hydroxytryptamine(2A/B) receptors in idiopathic pulmonary fibrosis: a rationale for therapeutic intervention

Background Idiopathic pulmonary fibrosis (IPF) has a poor prognosis and limited responsiveness to available treatments. It is characterised by epithelial cell injury, fibroblast activation and proliferation and extracellular matrix deposition. Serotonin (5-hydroxytryptamine; 5-HT) induces fibroblast proliferation via the 5-HTR2A and 5-HTR2B receptors, but its pathophysiological role in IPF remains unclear. A study was undertaken to determine the expression of 5-HT receptors in IPF and experimental lung fibrosis and to investigate the effects of therapeutic inhibition of 5-HTR2A/B signalling on lung fibrosis in vivo and in vitro. Methods and results Quantitative RT-PCR showed that the expression of 5-HTR1A/B and 5-HTR2B was significantly increased in the lungs of patients with IPF (n = 12) and in those with non-specific interstitial pneumonia (NSIP, n = 6) compared with transplant donors (n = 12). The expression of 5-HTR2A was increased specifically in IPF lungs but not in NSIP lungs. While 5-HTR2A protein largely localised to fibroblasts, 5-HTR2B localised to the epithelium. To assess the effects of 5HTR(2A/B) inhibition on fibrogenesis in vivo, mice were subjected to bleomycin-induced lung fibrosis and treated with the 5-HTR2A/B antagonist terguride (or vehicle) in a therapeutic approach (days 14-28 after bleomycin). Terguride-treated mice had significantly improved lung function and histology and decreased collagen content compared with vehicle-treated mice. Functional in vitro studies showed that terguride is a potent inhibitor of transforming growth factor beta(1)- or WNT3a-induced collagen production. Conclusion The studies revealed an increased expression of 5-HTR2A specifically in IPF. Blockade of 5-HTR2A/B signalling by terguride reversed lung fibrosis and is thus a promising therapeutic approach for IPF

Developing an Industrial IoT Platform – Trade-off between Horizontal and Vertical Approaches

Demands for a digitalized, connected, and smart production provide a fertile ground for industrial Internet-of-Things (IIoT) platforms to arise within the manufacturing industry (e.g., Siemens Mind Sphere, AXOOM Smart Enterprise, FORCAM FORCE). Nevertheless, many companies struggle to successfully kick-off platform ecosystems. Information Systems (IS) literature is of limited help, because insights on managing platform ecosystems are mostly derived from successful examples in the business-to-consumer (B2C) context. To better understand the challenging situation of companies in the emerging IIoT environment, we conducted an in-depth case study at a prospective platform provider. Insights gained through interviews and engagement in the field uncovered a tension between a horizontal platform strategy and vertical integrated solutions as a central challenge for companies aiming to launch an IIoT-platform in the market. By conceptualizing this trade-off, its causes along with related benefits and challenges, we add to existing literature on platform governance and launch strategies

Are serial CA 19-9 kinetics helpful in predicting survival in patients with advanced or metastatic pancreatic cancer treated with gemcitabine and cisplatin?

Background: Serial kinetics of serum CA 19-9 levels have been reported to reflect response and survival in patients with pancreatic cancer undergoing surgery, radiotherapy, and chemotherapy. We prospectively studied serial kinetics of serum CA 19-9 levels of patients with locally advanced or metastatic disease treated with gemcitabine and cisplatin. Patients and Methods: Enrolled in the study were 87 patients (female/male = 26/61; stage III/IV disease = 24/63). Patients received gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 plus cisplatin 50 mg/m(2) on days 1 and 15, every 4 weeks. Serum samples were collected at the onset of chemotherapy and before the start of a new treatment cycle (day 28). Results: 77 of 87 patients (88.5%) with initially elevated CA 19-9 levels were included for evaluation. According to imaging criteria, 4 (5.2%) achieved a complete remission and 11 (14.3%) achieved partial remission, yielding an overall response rate of 19.5%. 43 (55.8%) patients were CA 19-9 responders, defined by greater than or equal to50% decrease in CA 19-9 serum levels within 2 months after treatment initiation. Except for one, all patients who had responded by imaging criteria (n = 14) fulfilled the criterion of a CA 19-9 responder. Despite being characterized as non-responders by CT-imaging criteria (stable/progressive disease), 29 patients were classified as CA 19-9 responders (positive predictive value 32.5%). Independent of the response evaluation by CT, CA 19-9 responders survived significantly longer than CA 19-9 non-responders (295 d; 95% CI: 285-445 vs. 174 d; 95% CI: 134-198; p = 0.022). Conclusion: CA 19-9 kinetics in serum serve as an early and reliable indicator of response and help to predict survival in patients with advanced pancreatic cancer receiving effective treatment with gemcitabine and cisplatin

Systematische Erfassung von Nebenwirkungen ambulanter Verhaltenstherapie

Psychotherapie ist ein integraler Bestandteil der Behandlung psychischer Störungen. Anders als in anderen Disziplinen der Medizin sind den Nebenwirkungen von Psychotherapie bisher nur wenig Aufmerksamkeit geschenkt worden. Im Zuge dieser Publikationspromotion wurde eine Definition von Psychotherapienebenwirkungen entwickelt und ein Instrument (UE-ATR-Checkliste) zu deren Untersuchung eingeführt. In einer Untersuchung an 100 Psychotherapeuten in Ausbildung (VT) und ihren Behandlungsfällen wurde systematisch nach dem Erfahrungsstand der Ausbildungsteilnehmer gefragt und die Qualität, Quantität sowie der Schweregrad und die Dauer von Nebenwirkungen in ihren Behandlungsfällen mit Hilfe eines halbstandardisierten Interviews erfasst. Es zeigte sich, dass die Therapeuten in Ausbildung mit einer hohen Auftretensrate von Nebenwirkungen rechnen, wenngleich ein positiver Bias vorliegt, was die eigenen Behandlungen betrifft. Bei 100 Behandlungsfällen zeigten sich in 43 % der Fälle Nebenwirkungen, die zu meist Stunden oder Tage dauerten und in mehr als der Hälfte leicht bis mittleren Schweregrades waren. Die Ergebnisse der Studie legen nahe, dass eine systematische Überwachung der Behandlungen sinnvoll sein kann und dem Thema der Psychotherapienebenwirkungen im Rahmen der Ausbildung mehr Raum geschenkt werden sollte.Psychotherapy is an important tool in the treatment of mental disorders. Different from other disciplines in the healthcare system psychotherapy´s potential to cause side effects is not well known and has not drawn much attention in the research community. Aim of the publication based dissertation thesis was to develop a definition and instrument (UE-ATR checklist) to conduct systematic research on psychotherapy side effects in a naturalistic setting. 100 therapists in training conducting CBT participated in the study. With a semi-structured interview based on the UE-ATR checklist therapists were asked about their experiences with and expectations of side effects and reported on 100 of their cases. The checklist allowed to identify several side effects, their severity and duration. Results show that therapists in training expect side effects to occur in about every second case, but they show a positive bias concerning their own work. Utilizing the UE-ATR-checklist side effects were reported in 43 % of cases. Most of them were of mild to moderate impact and lasted for hours to days. The results suggest that a systematic monitoring of SEs is necessary and possible and that information about side effects should be part of the training of therapists

Riociguat: Mode of action and clinical development in pulmonary hypertension

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are progressive and debilitating diseases characterized by gradual obstruction of the pulmonary vasculature, leading to elevated pulmonary artery pressure and increased pulmonary vascular resistance. If untreated, they can result in death due to right heart failure. Riociguat is a novel soluble guanylate cyclase (sGC) stimulator that is approved for the treatment of PAH and CTEPH. Here we describe in detail the role of the nitric oxide-sGC-cyclic guanosine monophosphate (cGMP) signaling pathway in the pathogenesis of PAH and CTEPH, and the mode of action of riociguat. We also review the preclinical data associated with the development of riociguat, along with the efficacy and safety data of riociguat from initial clinical trials and the pivotal Phase III randomized clinical trials in PAH and CTEPH