Pepducins as a potential treatment strategy for asthma and COPD.

Current therapies to treat asthma and other airway diseases primarily include anti-inflammatory agents and bronchodilators. Anti-inflammatory agents target trafficking and resident immunocytes and structural cells, while bronchodilators act to prevent or reverse shortening of airway smooth muscle (ASM), the pivotal tissue regulating bronchomotor tone. Advances in our understanding of the biology of G protein-coupled receptors (GPCRs) and biased agonism offers unique opportunities to modulate GPCR function that include the use of pepducins and allosteric modulators. Recent evidence suggests that small molecule inhibitors of Gα q as well as pepducins targeting G q -coupled receptors can broadly inhibit contractile agonist-induced ASM function. Given these advances, new therapeutic approaches can be leveraged to diminish the global rise in morbidity and mortality associated with asthma and chronic obstructive pulmonary disease

Shotgun and targeted MS analyses pinpoint the zampanolide-tubulin interacting site

Comunicaciones a congreso

Síntesis de ectomicorrizas entre Cistus sp. y las especies del complejo Boletus edulis

En los jarales resultantes de la reiteración de incendios forestales en el oeste de Castilla y León (León, Salamanca y Zamora) es habitual la presencia de fructificaciones de Boletus edulis Bull. La recolección de estos hongos micorrícicos comestibles en los jarales dominados exclusivamente por Cistus ladanifer, supone una oportunidad económica alternativa a los usos tradicionales para zonas con bajos ingresos procedentes del monte. El objetivo de éste trabajo es la obtención de ectomicorrizas de las especies del complejo B. edulis con Cistus sp. bajo condiciones controladas, y las descripciones anatómicas detalladas de las mismas. La identificación de los aislados fúngicos de Boletus aereus Bull., B. edulis, B. reticulatus Schaeff. y B. pinophilus Pilát & Dermek fue confirmada por métodos moleculares. Se han obtenido ectomicorrizas de Boletus aereus, B. edulis y B. reticulatus con Cistus albidus L. y C. ladanifer en condiciones de síntesis en cultivo puro, en un substrato de turbavermiculita estéril y solución nutritiva. Las ectomicorrizas formadas se describieron siguiendo los caracteres anatómicos y morfológicos habituales. Las tres ectomicorrizas son muy similares, de color blanco, con ramificación monopodial-pinnada, manto formado por tres capas plectenquimatosas y con rizomorfos de tipo boletoide

Comprehensive characterization of molecular interactions based on nanomechanics

Molecular interaction is a key concept in our understanding of the biological mechanisms of life. Two physical properties change when one molecular partner binds to another. Firstly, the masses combine and secondly, the structure of at least one binding partner is altered, mechanically transducing the binding into subsequent biological reactions. Here we present a nanomechanical micro-array technique for bio-medical research, which not only monitors the binding of effector molecules to their target but also the subsequent effect on a biological system in vitro. This label-free and real-time method directly and simultaneously tracks mass and nanomechanical changes at the sensor interface using micro-cantilever technology. To prove the concept we measured lipid vesicle (approximately 748*10(6) Da) adsorption on the sensor interface followed by subsequent binding of the bee venom peptide melittin (2840 Da) to the vesicles. The results show the high dynamic range of the instrument and that measuring the mass and structural changes simultaneously allow a comprehensive discussion of molecular interactions

Value of EUS in Determining Curative Resectability in Reference to CT and FDG-PET: The Optimal Sequence in Preoperative Staging of Esophageal Cancer?

Background: The separate value of endoscopic ultrasonography (EUS), multidetector computed tomography (CT), and18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in the optimal sequence in staging esophageal cancer has not been investigated adequately. Methods: The staging records of 216 consecutive operable patients with esophageal cancer were reviewed blindly. Different staging strategies were analyzed, and the likelihood ratio (LR) of each module was calculated conditionally on individual patient characteristics. A logistic regression approach was used to determine the most favorable staging strategy. Results: Initial EUS results were not significantly related to the LRs of initial CT and FDG-PET results. The positive LR (LR+) of EUS-fine-needle aspiration (FNA) was 4, irrespective of CT and FDG-PET outcomes. The LR+ of FDG-PET varied from 13 (negative CT) to 6 (positive CT). The LR+ of CT ranged from 3-4 (negative FDG-PET) to 2-3 (positive FDG-PET). Age, histology, and tumor length had no significant impact on the LRs of the three diagnostic tests. Conclusions: This study argues in favor of PET/CT rather than EUS as a predictor of curative resectability in esophageal cancer. EUS does not correspond with either CT or FDG-PET. LRs of FDG-PET were substantially different between subgroups of negative and positive CT results and vice versa

A novel patient-derived tumorgraft model with TRAF1-ALK anaplastic large-cell lymphoma translocation.

Although anaplastic large-cell lymphomas (ALCL) carrying anaplastic lymphoma kinase (ALK) have a relatively good prognosis, aggressive forms exist. We have identified a novel translocation, causing the fusion of the TRAF1 and ALK genes, in one patient who presented with a leukemic ALK+ ALCL (ALCL-11). To uncover the mechanisms leading to high-grade ALCL, we developed a human patient-derived tumorgraft (hPDT) line. Molecular characterization of primary and PDT cells demonstrated the activation of ALK and nuclear factor kB (NFkB) pathways. Genomic studies of ALCL-11 showed the TP53 loss and the in vivo subclonal expansion of lymphoma cells, lacking PRDM1/Blimp1 and carrying c-MYC gene amplification. The treatment with proteasome inhibitors of TRAF1-ALK cells led to the downregulation of p50/p52 and lymphoma growth inhibition. Moreover, a NFkB gene set classifier stratified ALCL in distinct subsets with different clinical outcome. Although a selective ALK inhibitor (CEP28122) resulted in a significant clinical response of hPDT mice, nevertheless the disease could not be eradicated. These data indicate that the activation of NFkB signaling contributes to the neoplastic phenotype of TRAF1-ALK ALCL. ALCL hPDTs are invaluable tools to validate the role of druggable molecules, predict therapeutic responses and implement patient specific therapies

CD28null CD4 T-cell expansions in autoimmune disease suggest a link with cytomegalovirus infection

Immunosenescence is thought to contribute to the increase of autoimmune diseases in older people. Immunosenescence is often associated with the presence of an expanded population of CD4 T cells lacking expression of CD28 (CD28null). These highly cytotoxic CD4 T cells were isolated from disease-affected tissues in patients with rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, or other chronic inflammatory diseases and their numbers appeared to be linked to disease severity. However, we recently demonstrated that the common herpes virus, cytomegalovirus (CMV), not ageing, is the major driver of this subset of cytotoxic T cells. In this review, we discuss how CMV might potentiate and exacerbate autoimmune disease through the expansion of CD28null CD4 T cells

Effects of recycled aggregate growth substrate on green roof vegetation development: a six year experiment

Green roofs have the potential to address several of the environmental problems associated with urbanisation, and can be used as mitigation for habitats lost at ground level. Brown roofs (a type of green roof) can be used to mitigate for the loss of brownfield habitat, but the best way of designing these habitats remains unclear. This paper reports an experiment to test the effects of different types of recycled aggregate on the development of vegetation assemblages on brown roof mesocosms. Five recycled aggregates were tested: (1) crushed brick, (2) crushed demolition aggregate, (3) solid municipal waste incinerator bottom ash aggregate, (4) a 1:1 mix of 1 and 2, and (5) a 1:1 mix of 3 and 2. Each was seeded with a wildflower mix that also included some Sedum acre and vegetation development was studied over a six-year period. Species richness, assemblage character, number of plants able to seed, and plant biomass were measured. Drought disturbance was the key factor controlling changes in plant assemblage, but effects varied with substrate treatment. All treatments supported a similar plant biomass, but treatments with a high proportion of crushed brick in the growth substrate supported richer assemblages, with more species able to seed, and a smaller amount of Sedum acre. Crushed brick, or recycled aggregates with a high proportion of crushed brick, are recommended as good growth substrate materials for encouraging brown roof plant diversity. This investigation demonstrates the importance of multi-year studies of green roof development for the generation of robust findings

Congenital Pyriform Sinus Fistula: Systematic Review and Proposal for Treatment Using a Novel Endoscopic Approach

The pyriform sinus fistula (PSF) is a congenital developmental defect of the third or fourth branchial pouch. It presents as acute inflammatory swelling of the neck with recurrent deep neck abscesses, recurrent neck cystic lesions or suppurative thyroiditis. The literature reports various surgical approaches to treat this condition in children. A systematic review of the literature related to management protocols for PSF was conducted and we report a case exemplifying treatment in our department. Traditionally, treatment for PSF has been open surgery; however, in the last few decades, the minimally invasive transoral endoscopic approach has gained in importance, demonstrating long-term outcomes comparable to open surgery and with lower morbidity, and it has now become the first-choice treatment. We further describe a case of PSF treated by a transoral endoscopic approach with electric cauterization, fibrin glue obliteration of the fistula and Polydimethylsiloxane (Vox-Implants®, Bioplasty, Geleen, The Netherlands) submucosal injection. According to the authors, application of Vox-Implants® injection, in addition to standard techniques, may be helpful to reduce fistula recurrence rate after surgery