Budesonide and Formoterol Reduce Early Innate Anti-Viral Immune Responses In Vitro

Asthma is a chronic inflammatory airways disease in which respiratory viral infections frequently trigger exacerbations. Current treatment of asthma with combinations of inhaled corticosteroids and long acting beta2 agonists improves asthma control and reduces exacerbations but what impact this might have on innate anti-viral immunity is unclear. We investigated the in vitro effects of asthma drugs on innate anti-viral immunity. Peripheral blood mononuclear cells (PBMC) from healthy and asthmatic donors were cultured for 24 hours with the Toll-like receptor 7 agonist, imiquimod, or rhinovirus 16 (RV16) in the presence of budesonide and/or formoterol. Production of proinflammatory cytokines and expression of anti-viral intracellular signalling molecules were measured by ELISA and RT-PCR respectively. In PBMC from healthy donors, budesonide alone inhibited IP-10 and IL-6 production induced by imiquimod in a concentration-dependent manner and the degree of inhibition was amplified when budesonide and formoterol were used in combination. Formoterol alone had little effect on these parameters, except at high concentrations (10−6 M) when IL-6 production increased. In RV16 stimulated PBMC, the combination of budesonide and formoterol inhibited IFNα and IP-10 production in asthmatic as well as healthy donors. Combination of budesonide and formoterol also inhibited RV16-stimulated expression of the type I IFN induced genes myxovirus protein A and 2′, 5′ oligoadenylate synthetise. Notably, RV16 stimulated lower levels of type Myxovirus A and oligoadenylate synthase in PBMC of asthmatics than control donors. These in vitro studies demonstrate that combinations of drugs commonly used in asthma therapy inhibit both early pro-inflammatory cytokines and key aspects of the type I IFN pathway. These findings suggest that budesonide and formoterol curtail excessive inflammation induced by rhinovirus infections in patients with asthma, but whether this inhibits viral clearance in vivo remains to be determined

Proteostasis Dysregulation in Pancreatic Cancer

The most common form of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), has a dismal 5-year survival rate of less than 5%. Radical surgical resection, in combination with adjuvant chemotherapy, provides the best option for long-term patient survival. However, only approximately 20% of patients are resectable at the time of diagnosis, due to locally advanced or metastatic disease. There is an urgent need for the identification of new, specific, and more sensitive biomarkers for diagnosis, prognosis, and prediction to improve the treatment options for pancreatic cancer patients. Dysregulation of proteostasis is linked to many pathophysiological conditions, including various types of cancer. In this review, we report on findings relating to the main cellular protein degradation systems, the ubiquitin-proteasome system (UPS) and autophagy, in pancreatic cancer. The expression of several components of the proteolytic network, including E3 ubiquitinligases and deubiquitinating enzymes, are dysregulated in PDAC, which accounts for approximately 90% of all pancreatic malignancies. In the future, a deeper understanding of the emerging role of proteostasis in pancreatic cancer has the potential to provide clinically relevant biomarkers and new strategies for combinatorial therapeutic options to better help treat the patients.Peer reviewe

Towards the development of a Decision Support System (DSS) for building renovation: Domain Mapping Matrix (DMM) for sustainability renovation criteria and renovation approaches

Future building renovation concerns more holistic perspectives related to the sustainability seen in a wider range of objectives/criteria facilitated by the renovation scenarios. In this regard, based on the studies upon existing sustainability evaluation and assessment tools carried out in previous research works, a characteristic diagram including a value map for evaluating a holistic sustainable retrofitting was developed. Further, in present paper, by reviewing the relevant literature, looking into recent European renovation research projects, the Danish SIGMA database, and investigation of a real case, a comprehensive list of renovation approaches (i.e. insulation technologies, windows replacement etc.) were classified in 26 categories. Using empirical information, this paper expands the Domain Mapping Matrix (DMM) between the recently developed criteria (18 criteria including 118 sub-criteria) and renovation approaches (26 categories including 139 alternatives). The aim is to consider how is the dependency between renovation approaches while they meet different criteria or sub-criteria, and vice versa, regarding to the selection of the criteria versus application of some possible renovation approaches. Developing Decision Support Systems (DSS) for generation of sustainable building renovation scenarios is ultimately an intricate, challenging task. The increasing complexity of decision problems regarding to the fulfilment of sustainability objectives/criteria, the growing number of subjects involved and keen competition between conflicting costs and interests make decisions-making difficult. Developing a DMM enhances the required insight for the development of an operational system for architecture of decision-makings. It has a strong effect to deal with existing complexity regarding to the large number of renovation approaches and various sustainability objectives/criteria. Added to this, the DMM can be used for understanding and tracking of the value (or added value) regarding to the other criteria (i.e. spatial quality) while the focus is on optimization of some common criteria i.e., improvement of energy efficiency or reduction of investment cost