First-line immunotherapy for lung cancer with MET exon 14 skipping and the relevance of TP53 mutations

Background The efficacy of checkpoint inhibitors for non-small cell lung cancer (NSCLC) with MET exon 14 skipping (METΔ14ex) remains controversial. Materials and methods 110 consecutive METΔ14ex NSCLC patients receiving first-line chemotherapy (CHT) and/or immunotherapy (IO) in 10 German centers between 2016–2022 were analyzed. Results Combined CHT-IO was given to 35/110 (32%) patients, IO alone to 43/110 (39%), and CHT to 32/110 (29%) upfront. Compared to CHT, CHT-IO showed longer progression-free survival (median PFS 6 vs. 2.5 months, p = 0.004), more objective responses (ORR 49% vs. 28%, p = 0.086) and numerically longer overall survival (OS 16 vs. 10 months, p = 0.240). For IO monotherapy, OS (14 vs. 16 months) and duration of response (26 vs. 22 months) were comparable to those of CHT-IO. Primary progressive disease (PD) was more frequent with IO compared to CHT-IO (13/43 vs. 3/35, p = 0.018), particularly for never-smokers (p = 0.041). Higher PD-L1 TPS were not associated with better IO outcomes, but TP53 mutated tumors showed numerically improved ORR (56% vs. 32%, p = 0.088) and PFS (6 vs. 3 months, p = 0.160), as well as longer OS in multivariable analysis (HR=0.54, p = 0.034) compared to their wild-type counterparts. Any second-line treatment was administered to 35/75 (47%) patients, with longer survival for capmatinib or tepotinib compared to crizotinib (PFS 10 vs. 3 months, p = 0.013; OS 16 vs. 13 months, p = 0.270). Conclusion CHT-IO is superior to CHT, and IO alone also effective for METΔ14ex NSCLC, especially in the presence of TP53 mutations and independent of PD-L1 expression, but never-smokers are at higher risk of primary PD

Pressure-Induced Conductivity in a Neutral Nonplanar Spin-Localized Radical

Souto, Manuel et al.There is a growing interest in the development of single-component molecular conductors based on neutral organic radicals that are mainly formed by delocalized planar radicals, such as phenalenyl or thiazolyl radicals. However, there are no examples of systems based on nonplanar and spin-localized C-centered radicals exhibiting electrical conductivity due to their large Coulomb energy (U) repulsion and narrow electronic bandwidth (W) that give rise to a Mott insulator behavior. Here we present a new type of nonplanar neutral radical conductor attained by linking a tetrathiafulvalene (TTF) donor unit to a neutral polychlorotriphenylmethyl radical (PTM) with the important feature that the TTF unit enhances the overlap between the radical molecules as a consequence of short intermolecular S···S interactions. This system becomes semiconducting upon the application of high pressure thanks to increased electronic bandwidth and charge reorganization opening the way to develop a new family of neutral radical conductors.This work was supported by the EU ITN iSwitch 642196 DGI grant (BeWell; CTQ2013-40480-R), the Networking Research Center on Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), and the Generalitat de Catalunya (grant 2014- SGR-17). This work has also been supported by MINECO through the projects CSD2007-00045, CTQ2012- 38599-C02- 02 and CTQ2013-48252-P. ICMAB acknowledges support from the Spanish Ministry of Economy and Competitiveness, through the “Severo Ochoa” Programme for Centres of Excellence in R&D (SEV- 2015-0496). M.S. is grateful to Spanish Ministerio de Educación, Cultura y Deporte for a FPU grant and he is enrolled in the Material Science Ph.D. program of UAB. D.B. is grateful to the EC ITN Nano2fun grant no607721. M.P.A. is grateful to the Spanish Ministerio de Educación, Cultura y Deporte for an FPU grant. M.P.A. and V.G.B. thank the project CTQ2015-67755-C2-1-R. H.O. Jeschke, M. Tomic and R. Valenti thank the Deutsche Forschungsgemeinschaft (DFG) for funding through grant SFB/TRR49 and Steve Winter for useful discussions. We thank Carlos Goḿ ez-Garcıá (Univ. Valencia) for SQUID measurements as well as Xavier Fontrodona (Univ. Girona) for X-ray diffraction measurements and Mercedes Taravillo (UCM) for the support provided during the high pressure Raman measurements.Peer reviewe

Microbial community dynamics in two-chambered microbial fuel cells : effect of different ion exchange membranes

BACKGROUND: The utilization of different kinds of ion exchange membrane is a common practice in bioelectrochemical systems such as two-chambered microbial fuel cells (MFCs). However, little is known about the effect of membrane materials on the anodic microbial community diversity.; RESULTS: The effect of two cationic and one anionic exchange membranes (Nafion N-117, Ultrex CMI-7000, and Ultrex AMI-7000) on the microbial community dynamics of Eubacteria and Archaea has been assessed in two-chambered MFCs. The experimental results indicated that the eubacterial community in the anodic chamber was not affected by the membrane materials, being predominantly populations of Bacteroidetes (Porphyromonadaceae) and -proteobacteria (Alcaligenaceae and Comamonadaceae). On the other hand, the archaeal counterpart appears to be highly dependent on the type of membrane used, as was evidenced by the selective enrichment of Methanosarcina sp. in the MFC equipped with the membrane Nafion N-117 which was the MFC that showed the highest current production.; CONCLUSIONS: The results obtained in the present study suggest that membrane materials affect archaeal diversity whereas both anodofilic eubacteria and methanogenic archaea populations could play an important role in the overall MFC process performance.Peer ReviewedPostprint (author’s final draft

PTX3 Intercepts Vascular Inflammation in Systemic Immune-Mediated Diseases

PTX3 is a prototypic soluble pattern recognition receptor, expressed at sites of inflammation and involved in regulation of the tissue homeostasis. PTX3 systemic levels increase in many (but not all) immune-mediated inflammatory conditions. Research on PTX3 as a biomarker has so far focused on single diseases. Here, we performed a multi-group comparative study with the aim of identifying clinical and pathophysiological phenotypes associated with PTX3 release. PTX3 concentration was measured by ELISA in the plasma of 366 subjects, including 96 patients with giant cell arteritis (GCA), 42 with Takayasu's arteritis (TA), 10 with polymyalgia rheumatica (PMR), 63 with ANCA-associated systemic small vessel vasculitides (AAV), 55 with systemic lupus erythematosus (SLE), 21 with rheumatoid arthritis (RA) and 79 healthy controls (HC). Patients with SLE, AAV, TA and GCA, but not patients with RA and PMR, had higher PTX3 levels than HC. PTX3 concentration correlated with disease activity, acute phase reactants and prednisone dose. It was higher in females, in patients with recent-onset disease and in those with previous or current active vasculitis at univariate analysis. Active small- or large- vessel vasculitis were the main independent variables influencing PTX3 levels at multivariate analysis. High levels of PTX3 in the blood can contribute to identify an increased risk of vascular involvement in patients with systemic immune-mediated diseases

Genome-wide protein QTL mapping identifies human plasma kallikrein as a post-translational regulator of serum uPAR levels

The soluble cleaved urokinase plasminogen activator receptor (scuPAR) is a circulating protein detected in multiple diseases, including various cancers, cardiovascular disease, and kidney disease, where elevated levels of scuPAR have been associated with worsening prognosis and increased disease aggressiveness. We aimed to identify novel genetic and biomolecular mechanisms regulating scuPAR levels. Elevated serum scuPAR levels were identified in asthma (n=514) and chronic obstructive pulmonary disease (COPD; n=219) cohorts when compared to controls (n=96). In these cohorts, a genome-wide association study of serum scuPAR levels identified a human plasma kallikrein gene (KLKB1) promoter polymorphism (rs4253238) associated with serum scuPAR levels in a control/asthma population (P=1.17×10−7), which was also observed in a COPD population (combined P=5.04×10−12). Using a fluorescent assay, we demonstrated that serum KLKB1 enzymatic activity was driven by rs4253238 and is inverse to scuPAR levels. Biochemical analysis identified that KLKB1 cleaves scuPAR and negates scuPAR's effects on primary human bronchial epithelial cells (HBECs) in vitro. Chymotrypsin was used as a proproteolytic control, while basal HBECs were used as a control to define scuPAR-driven effects. In summary, we reveal a novel post-translational regulatory mechanism for scuPAR using a hypothesis-free approach with implications for multiple human diseases

Phase I, multicenter, open-label study of intravenous VCN-01 oncolytic adenovirus with or without nab-paclitaxel plus gemcitabine in patients with advanced solid tumors

Background VCN-01 is an oncolytic adenovirus (Ad5 based) designed to replicate in cancer cells with dysfunctional RB1 pathway, express hyaluronidase to enhance virus intratumoral spread and facilitate chemotherapy and immune cells extravasation into the tumor. This phase I clinical trial was aimed to find the maximum tolerated dose/recommended phase II dose (RP2D) and dose-limiting toxicity (DLT) of the intravenous delivery of the replication-competent VCN-01 adenovirus in patients with advanced cancer. Methods Part I: patients with advanced refractory solid tumors received one single dose of VCN-01. Parts II and III: patients with pancreatic adenocarcinoma received VCN-01 (only in cycle 1) and nab-paclitaxel plus gemcitabine (VCN-concurrent on day 1 in Part II, and 7days before chemotherapy in Part III). Patients were required to have anti-Ad5 neutralizing antibody (NAbs) titers lower than 1/350 dilution. Pharmacokinetic and pharmacodynamic analyses were performed. Results 26% of the patients initially screened were excluded based on high NAbs levels. Sixteen and 12 patients were enrolled in Part I and II, respectively: RP2D were 1 x10(13) viral particles (vp)/patient (Part I), and 3.3x10(12) vp/patient (Part II). Fourteen patients were included in Part Ill: there were no DLTs and the RP2D was 1 x10(13) vp/patient. Observed DLTs were grade 4 aspartate aminotransferase increase in one patient (Part I, 1x10(13) vp), grade 4 febrile neutropenia in one patient and grade 5 thrombocytopenia plus enterocolitis in another patient (Part II, 1 x10(13) vp). In patients with pancreatic adenocarcinoma overall response rate were 50% (Part II) and 50% (Part III). VCN-01 viral genomes were detected in tumor tissue in five out of six biopsies (day 8). A second viral plasmatic peak and increased hyaluronidase serum levels suggested replication after intravenous injection in all patients. Increased levels of immune biomarkers (interferon- r,soluble lymphocyte activation ne-3, interleukin (IL)-6, IL-10) were found after VCN-01 administration. Conclusions Treatment with VCN-01 is feasible and has an acceptable safety. Encouraging biological and clinical activity was observed when administered in combination with nab-paditaxel plus gemcitabine to patients with pancreatic adenocarcinoma

Disordered microbial communities in asthmatic airways.

A rich microbial environment in infancy protects against asthma [1], [2] and infections precipitate asthma exacerbations [3]. We compared the airway microbiota at three levels in adult patients with asthma, the related condition of COPD, and controls. We also studied bronchial lavage from asthmatic children and controls.We identified 5,054 16S rRNA bacterial sequences from 43 subjects, detecting >70% of species present. The bronchial tree was not sterile, and contained a mean of 2,000 bacterial genomes per cm(2) surface sampled. Pathogenic Proteobacteria, particularly Haemophilus spp., were much more frequent in bronchi of adult asthmatics or patients with COPD than controls. We found similar highly significant increases in Proteobacteria in asthmatic children. Conversely, Bacteroidetes, particularly Prevotella spp., were more frequent in controls than adult or child asthmatics or COPD patients.The results show the bronchial tree to contain a characteristic microbiota, and suggest that this microbiota is disturbed in asthmatic airways

An integrated approach to better define the concept and functions of Urban Biosphere Reserves

The UNESCO-MAB Programme, and in particular the Biosphere Reserve Network, is described within the context of international strategies aimed at ecological sustainability in cities. An innovative acceptation of Biosphere Reserves for urban areas, based on the landscape ecology principle of the integration of natural, social, economic and cultural knowledge, is proposed. The interdisciplinary definition of structure and functions for Urban Biosphere Reserves envisages: (i) the inclusion of the whole metropolitan territory within the Reserve's boundaries; (ii) specific criteria for the delimitation of core areas and buffer zones in urban and periurban contexts; (iii) special focus on transition area requirements; (iv) the improvement in living conditions and a solution to the conflict between humans and the environment by enhancing and harmonizing the overall natural, economic, social and cultural qualities of cities; and (v) support for sustainable planning strategies on a local scale rather than the imposition of new conservation ties