Matrix stiffening and β1 integrin drive subtype-specific fibroblast accumulation in lung cancer

©2014 AACR. The crucial role of tumor-associated fibroblasts (TAF) in cancer progression is now clear in non-small cell lung cancer (NSCLC). However, therapies against TAFs are limited due to a lack of understanding in the subtype-specific mechanisms underlying their accumulation. Here, the mechanical (i.e., matrix rigidity) and soluble mitogenic cues that drive the accumulation of TAFs from major NSCLC subtypes: adenocarcinoma (ADC) and squamous cell carcinoma (SCC) were dissected. Fibroblasts were cultured on substrata engineered to exhibit normal- or tumor-like stiffnesses at different serumconcentrations, and critical regulatory processes were elucidated. In control fibroblasts from nonmalignant tissue, matrix stiffening alone increased fibroblast accumulation, and this mechanical effect was dominant or comparable with that of soluble growth factors up to 0.5% serum. The stimulatory cues ofmatrix rigidity were driven by β1 integrin mechanosensing through FAK (pY397), and were associated with a posttranscriptionally driven rise in β1 integrin expression. The latter mechano-regulatory circuit was also observed in TAFs but in a subtype-specific fashion, because SCC-TAFs exhibited higher FAK (pY397), β1 expression, and ERK1/2 (pT202/Y204) than ADC-TAFs. Moreover, matrix stiffening induced a larger TAF accumulation in SCC-TAFs (>50%) compared with ADC-TAFs (10%-20%). In contrast, SCC-TAFs were largely serum desensitized, whereas ADC-TAFs responded to high serum concentration only. These findings provide the first evidence of subtype-specific regulation of NSCLC-TAF accumulation. Furthermore, these data support that therapies aiming to restore normal lung elasticity and/or β1 integrin-dependent mechano regulation may be effective against SCC-TAFs, whereas inhibiting stromal growth factor signaling may be effective against ADC-TAFs. Implications: This study reveals distinct mechanisms underlying the abnormal accumulation of tumor-supporting fibroblasts in two major subtypes of lung cancer, which will assist the development of personalized therapies against these cells.Ministerio de Economía y Competitividad (SAF2009-13243 and PI13/02368, to J. Alcaraz; PS09/01377, to N. Reguart; SAF2012-34916, to F. Rodríguez-Pascual), AECC (10/103; to N. Reguart and J. Alcaraz), SEPAR (2009-853; to N. Reguart), and predoctoral fellowships from the Fundacio Cellex (to M. Puig),Ministerio de Educación (to A. Giménez), CONACYT (to R. Lugo), and COLCIENCIAS (to A. Velasquez).Peer Reviewe

Reducció de micro-aturades en encaixadora del sector alimentació

[ES] L’estudi i posada en marxa del projecte per a reduir les microaturades en encaixadora serveix per comprovar la necessitat d’un sistema de millora continua en l’entorn competitiu actual i els beneficis del TPM a nivell productiu, organitzatiu i humà. Basant-se sobretot en una bona comunicació i en la implicació de la plantilla, el TPM aconsegueix coordinar tots els departaments de l’empresa (Producció, manteniment, I+D, Qualitat, Planificació, Logística, Compres, Recursos humans, ...) per portar a terme la consecució dels objectius comuns. Recolzant-se amb les diferents tipus de ferramentes de les que disposa el TPM i la metodologia Kaizen (Gantt, Pareto, 5W, etc...) i l’estadística s’ha pogut arribar a resultats força interessants i esperançadors en la reducció de microaturades, (4% de temps total de producció), podent exportar a més les millores a altres màquines similars que s’encontren en l’empresa.[EN] The study and set up of the project of packing machine’s micro-stoppages reduction serves to check the need of a system of continuous improvement in the current competitive environment and the profits of the TPM to productive level, organisational and human. Basing in a good communication and in the implication of the staff, the TPM achieves to coordinate all the departments of the company (Production, Maintenance, R&D, Quality, Planning, Logistical, Purchasing, Human Resources, ...) To carry out the achievement of the common aims. Leaning in the different types of tools of which have the TPM and the methodology Kaizen (Gantt, Pareto, 5W, etc...) and the statistics has been able to arrive to results very interesting and hopeful in the reduction of micro-stoppages (4% of total time of production), being able to export besides the improvements to other similar machines that find in the company.Alcaraz I Boronat, J. (2018). Reducció de micro-aturades en encaixadora del sector alimentació. http://hdl.handle.net/10251/112645TFG

Ionic partition and transport in multi-ionic channels: A Molecular Dynamics Simulation study of the OmpF bacterial porin

We performed all-atom molecular dynamics simulations studying the partition of ions and the ionic current through the bacterial porin OmpF and two selected mutants. The study is motivated by new interesting experimental findings concerning their selectivity and conductance behaviour at neutral pH. The mutations considered here are designed to study the effect of removal of negative charges present in the constriction zone of the wild type OmpF channel (which contains on one side a cluster with three positive residues and on the other side two negatively charged residues). Our results show that these mutations induce an exclusion of cations from the constriction zone of the channel, substantially reducing the flow of cations. In fact, the partition of ions inside the mutant channels is strongly inhomogeneous, with regions containing excess of cations and regions containing excess of anions. Interestingly, the overall number of cations inside the channel is larger than the number of anions in the two mutants, as in the OmpF wild type channel. We found that the differences in ionic charge inside these channels are justified by the differences in electric charge between the wild type OmpF and the mutants, following an electroneutral balance

Nintedanib selectively inhibits the activation and tumour-promoting effects of fibroblasts from lung adenocarcinoma patients

Background: Nintedanib is a clinically approved multikinase receptor inhibitor to treat non-small cell lung cancer with adenocarcinoma (ADC) histology in combination with docetaxel, based on the clinical benefits reported on ADC but not on squamous cell carcinoma (SCC), which are the two most common histologic lung cancer subtypes.Methods: We examined the potential role of tumour-associated fibroblasts (TAFs) in the differential effects of nintedanib in ADC and SCC. Because TAFs are largely quiescent and activated in histologic sections, we focused on the antifibrotic effects of nintedanib on TAFs stimulated with the potent fibroblast activator TGF-beta 1, which is upregulated in lung cancer.Results: Nintedanib dose-dependently inhibited the TGF-beta 1-induced expression of a panel of pro-fibrotic activation markers in both ADC-TAFs and control fibroblasts derived from uninvolved lung parenchyma, whereas such inhibition was very modest in SCC-TAFs. Remarkably, nintedanib abrogated the stimulation of growth and invasion in a panel of carcinoma cell lines induced by secreted factors from activated TAFs in ADC but not SCC, thereby supporting that TGF-beta signalling and aberrant TAF-carcinoma cross-talk is regulated by different mechanisms in ADC and SCC.Conclusions: These results reveal that nintedanib is an effective inhibitor of fibrosis and its associated tumour-promoting effects in ADC, and that the poor antifibrotic response of SCC-TAFs to nintedanib may contribute to the differential clinical benefit observed in both subtypes. Our findings also support that preclinical models based on carcinoma-TAF interactions may help defining the mechanisms of the poor antifibrotic response of SCC-TAFs to nintedanib and testing new combined therapies to further expand the therapeutic effects of this drug in solid tumours

A Quickly Deployed and UAS-Based Logistics Network for Delivery of Critical Medical Goods during Healthcare System Stress Periods: A Real Use Case in Valencia (Spain)

[EN] On the one hand, Unmanned Aircraft Systems (UASs) have experienced great applicability surge in the recent years, arising as a promising technology with a wide field of use. On the other hand, healthcare, a critical system in modern society, is subject to a heavy and unexpected pressure in the case of situations such as the COVID-19 pandemic. This article aims to leverage the flexibility of UASs as complementary support for healthcare logistic systems when under high-stress conditions, via quick deployment of an air delivery network. We have defined a logistics network model and created three scenarios based on the model and current needs in Valencia (Spain). Flight tests have been performed in these scenarios, which include urban areas and controlled airspace. Operations complied with requirements derived from the application of Specific Operations Risk Assessment (SORA) methodology, recently adopted by the European Aviation Safety Agency (EASA). Flights were successful, being able to swiftly deliver medical goods without requiring any dedicated infrastructure. However, a moderate number of contingencies took place during the tests, mainly related to control link quality and Air Traffic Management (ATM) integration, forcing the use of dedicated procedures to cope with them. Although additional development is required to ensure the safety of large-scale automated operations, the use of UASs as part of logistic networks is a feasible means to support existing structures, especially in situations in dire need.This research was funded by Generalitat Valenciana (DECRETO 63/2020) and Universitat Politecnica de Valencia (PAID-01-18). The APC was funded by Universitat Politecnica de Valencia.Quintanilla García, I.; Vera-Vélez, N.; Alcaraz Martínez, P.; Vidal Ull, J.; Fernández Gallo, B. (2021). A Quickly Deployed and UAS-Based Logistics Network for Delivery of Critical Medical Goods during Healthcare System Stress Periods: A Real Use Case in Valencia (Spain). Drones. 5(1):1-14. https://doi.org/10.3390/drones50100131145

Dysregulated collagen homeostasis by matrix stiffening and TGF-β1 in fibroblasts from idiopathic pulmonary fibrosis patients: role of FAK/Akt

Idiopathic pulmonary fibrosis (IPF) is an aggressive disease in which normal lung parenchyma is replaced by a stiff dysfunctional scar rich in activated fibroblasts and collagen-I. We examined how the mechanochemical pro-fibrotic microenvironment provided by matrix stiffening and TGF-β1 cooperates in the transcriptional control of collagen homeostasis in normal and fibrotic conditions. For this purpose we cultured fibroblasts from IPF patients or control donors on hydrogels with tunable elasticity, including 3D collagen-I gels and 2D polyacrylamide (PAA) gels. We found that TGF-β1 consistently increased COL1A1 while decreasing MMP1 mRNA levels in hydrogels exhibiting pre-fibrotic or fibrotic-like rigidities concomitantly with an enhanced activation of the FAK/Akt pathway, whereas FAK depletion was sufficient to abrogate these effects. We also demonstrate a synergy between matrix stiffening and TGF-β1 that was positive for COL1A1 and negative for MMP1. Remarkably, the COL1A1 expression upregulation elicited by TGF-β1 alone or synergistically with matrix stiffening were higher in IPF-fibroblasts compared to control fibroblasts in association with larger FAK and Akt activities in the former cells. These findings provide new insights on how matrix stiffening and TGF-β1 cooperate to elicit excessive collagen-I deposition in IPF, and support a major role of the FAK/Akt pathway in this cooperation

Validated methodology for quantifying infestation levels of dreissenid mussels in environmental DNA (eDNA) samples

The zebra mussel (Dreissena polymorpha Pallas, 1771) and the quagga mussel (D. rostriformis Deshayes, 1838) are successful invasive bivalves with substantial ecological and economic impacts in freshwater systems once they become established. Since their eradication is extremely difficult, their detection at an early stage is crucial to prevent spread. In this study, we optimized and validated a qPCR detection method based on the histone H2B gene to quantify combined infestation levels of zebra and quagga mussels in environmental DNA samples. Our results show specific dreissenid DNA present in filtered water samples for which microscopic diagnostic identification for larvae failed. Monitoring a large number of locations for invasive dreissenid species based on a highly specific environmental DNA qPCR assay may prove to be an essential tool for management and control plans focused on prevention of establishment of dreissenid mussels in new locations.info:eu-repo/semantics/publishedVersio

Accessible charts are part of the equation of accessible papers: a heuristic evaluation of the highest impact LIS Journals

Purpose Statistical charts are an essential source of information in academic papers. Charts have an important role in conveying, clarifying and simplifying the research results provided by the authors, but they present some accessibility barriers for people with low vision. This article aims to evaluate the accessibility of the statistical charts published in the library and information science (LIS) journals with the greatest impact factor. Design/methodology/approach A list of heuristic indicators developed by the authors has been used to assess the accessibility of statistical charts for people with low vision. The heuristics have been applied to a sample of charts from 2019 issues of ten LIS journals with the highest impact factor according to the ranking of the JCR. Findings The current practices of image submission do not follow the basic recommended guidelines on accessibility like color contrast or the use of textual alternatives. On the 2 other hand, some incongruities between the technical suggestions of image submission and their application in analyzed charts also emerged. The main problems identified are: poor text alternatives, insufficient contrast ratio between adjacent colors, and the inexistence of customization options. Authoring tools do not help authors to fulfill these requirements. Research limitations The sample is not very extensive; nonetheless, it is representative of common practices and the most frequent accessibility problems in this context. Social implications The heuristics proposed are a good starting point to generate guidelines for authors when preparing their papers for publication and to guide journal publishers in creating accessible documents. Low vision users, a highly prevalent condition, will benefit from the improvements. Originality/value The results of this research provide key insights into low vision accessibility barriers, not considered in previous literature and can be a starting point for their solution.This research has been done in the framework of the PhD Programme in Engineering and Information Technology of the Universitat de Lleida (UdL). This work has been partially supported by the Spanish project PID2019-105093GB-I00 (MINECO/FEDER, UE) and CERCA Programme/Generalitat de Catalunya

Paralelización del problema de satisfacción de restricciones utilizando arco consistencia

El problema de satisfacción de restricciones se utiliza en varios campos de la informática: Inteligencia Artificial, planificación de recursos, etc., y se considera NP-completo. A causa de la complejidad computacional de este problema es necesario utilizar buenas heurísticas y paralelismo para reducir el tiempo de cómputo. En este proyecto se realizarán varias implementaciones paralelas para maximizar el uso del hardware disponible y reducir el tiempo de resolución del problema.In some fields related to Computer Science the Constraint Satisfaction problem is used, in exemple: Artificial Intelligence, resource planing, etcetera, and this problem is NP-complete. Because of it's computational complexity there is a need to use good heuristics and paralelism to reduce the time to solve it. In this project some parallel implementations will be performed to maximize the use of the available hardware and minimize the time needed to solve this problem.El problema de satisfacció de restriccions s'utilitza en diferents camps de la informàtica: Intel·ligència Artificial, planificació de recursos, etc., i es considera NP-complet. A causa de la complexitat computacional d'aquest problema es necessari emprar bones heurístiques i paral·lelisme per reduir el temps de còmput. En aquest projecte es realitzaran varies implementacions paral·leles per a maximitzar l'ús del hardware disponible i reduir el temps de resolució del problema