Lung bioengineering: physical stimuli and stem/progenitor cell biology interplay towards biofabricating a functional organ

A current approach to obtain bioengineered lungs as a future alternative for transplantation is based on seeding stem cells on decellularized lung scaffolds. A fundamental question to be solved in this approach is how to drive stem cell differentiation onto the different lung cell phenotypes. Whereas the use of soluble factors as agents to modulate the fate of stem cells was established from an early stage of the research with this type of cells, it took longer to recognize that the physical microenvironment locally sensed by stem cells (e.g. substrate stiffness, 3D architecture, cyclic stretch, shear stress, air-liquid interface, oxygenation gradient) also contributes to their differentiation. The potential role played by physical stimuli would be particularly relevant in lung bioengineering since cells within the organ are physiologically subjected to two main stimuli required to facilitate efficient gas exchange: air ventilation and blood perfusion across the organ. The present review focuses on describing how the cell mechanical microenvironment can modulate stem cell differentiation and how these stimuli could be incorporated into lung bioreactors for optimizing organ bioengineering

Implantació d'un sistema de gestió EMAS a la UPC

Les organitzacions del coneixement, i en aquest cas la UPC (Universitat Politècnica de Catalunya), tenen un impacte negatiu sobre l’ambient a través de l’ús dels recursos naturals i la producció de residus i emissions. Però també poden tenir un fort impacte positiu indirecte, a través de l’educació formal, la recerca i l’aprenentatge permanent, lligat a la conscienciació i el despertar de les responsabilitats personals i professionals. La part més innovadora d’aquest projecte consisteix en afegir la consideració d’aquestes efectes positius indirectes dins de la recerca i les activitats docents, però també les altres activitats on la Universitat comunica coneixements. D’acord amb això, els processos clau d’una organització del coneixement que han de ser vetllats per un sistema de gestió ambiental són tres: • La educació formal, • la recerca i • la disseminació informal de coneixements Hem de recordar que la funció principal de tota Universitat és la educació formal dels seus estudiants, i exercir la màxima influència positiva sobre ells; és raonable acceptar que el futur comportament ambiental de la societat dependrà de l’educació que els seus dirigents han rebut a la universitat. Més genèricament, les directives per avaluar l’impacte ambiental, la reducció de la part negativa i crear o potenciar la seva part positiva ha de ser fàcilment transferible a qualsevol organització del coneixement. Per tant, és fonamental incloure dins d'un sistema de gestió ambiental per a la Universitat la quantificació de l'educació sobre la sostenibilitat, tant la que ofereix al seu estudiantat com la que realment arriben a interioritzar, juntament amb la sostenibilitat ambiental i la implicació de la recerca, i fins i tot la implicació personal i professional dels titulats. Per tant, els indicadors ambientals han d'abastar no només les mesures convencionals de la situació, el comportament (consum de recursos, la generació de residus, etc) i l'eficàcia del sistema, sinó també i sobretot, les mesures ambientals de la implicació de la recerca, l'educació i divulgació que la Universitat ofereix, així com les mesures de com aquesta l'educació és assimilada per l’estudiantat, i tinguda en compte tant en les seves circumstàncies actuals com futures, i en el seu comportament tant personal com professional. Actualment s’està portant a terme la última etapa de la implantació d’una adaptació del sistema de gestió EMAS al Campus de Manresa i al Campus del Baix Llobregat; on és vol observar la capacitat d’adaptació i la transferència del model. Uns dels objectius del projecte és explicar els avantatges de l’aplicació d’un sistema de gestió ambiental a la Universitat i les dificultats que aquesta implantació pot presentar, però també l’observació de la transició cap a una cultura en sostenibilitat, on la transparència, la participació i la reflexió cap a la comunitat i de totes les parts implicades han de ser la pedra angular.Peer Reviewe

Biomechanical Response of Lung Epithelial Cells to Iron Oxide and Titanium Dioxide Nanoparticles

Increasing evidence shows that lungs can be damaged by inhalation of nanoparticles (NPs) at environmental and occupational settings. Recent findings have associated the exposure to iron oxide (Fe2O3) and titanium dioxide (TiO2) - NPs widely used in biomedical and clinical research - with pulmonary oxidative stress and inflammation. Although changes on cellular mechanics could contribute to pulmonary inflammation, there is no information regarding the effects of Fe2O3 and TiO2 on alveolar epithelial cell biomechanics. The aim was to investigate the NPs-induced biomechanical effects in terms of cell stiffness and traction forces exerted by human alveolar epithelial cells. Cell Young's modulus (E) measured by atomic force microscopy in alveolar epithelial cells significantly decreased after exposure to Fe2O3 and TiO2 (∼28 and ∼25%, respectively) compared to control conditions. Moreover, both NPs induced a similar reduction in the traction forces exerted by the alveolar epithelial cells in comparison to the control conditions. Accordingly, immunofluorescence images revealed a reduction of actomyosin stress fibers in response to the exposure to NPs. However, no inflammatory response was detected. In conclusion, an acute exposure of epithelial pulmonary cells to Fe2O3 and TiO2 NPs, which was mild since it was non-cytotoxic and did not induce inflammation, modified cell biomechanical properties which could be translated into damage of the epithelial barrier integrity, suggesting that mild environmental inhalation of Fe2O3 and TiO2 NPs could not be innocuous

Intraductal Delivery Of Adenoviruses Targets Pancreatic Tumors In Transgenic Ela-myc Mice And Orthotopic Xenografts

Gene-based anticancer therapies delivered by adenoviruses are limited by the poor viral distribution into the tumor. In the current work we have explored the feasibility of targeting pancreatic tumors through a loco-regional route. We have taken advantage of the ductal network in the pancreas to retrogradelly inject adenoviruses through the common bile duct in two different mouse models of pancreatic carcinogenesis: The transgenic Ela-myc mice that develop mixed neoplasms displaying both acinar-like and duct-like neoplastic cells affecting the whole pancreas; and mice bearing PANC-1 and BxPC-3 orthotopic xenografts that constitute a model of localized human neoplastic tumors. We studied tumor targeting and the anticancer effects of newly thymidine kinase-engineered adenoviruses both in vitro and in vivo, and conducted comparative studies between intraductal or intravenous administration. Our data indicate that the intraductal delivery of adenovirus efficiently targets pancreatic tumors in the two mouse models. The in vivo application of AduPARTK(T) plus ganciclovir (GCV) treatment induced tumor regression in Ela-myc mice. Moreover, the intraductal injection of ICOVIR15-TKT oncolytic adenoviruses significantly improved mean survival of mice bearing PANC-1 and BxPC-3 pancreatic xenografts from 30 to 52 days and from 20 to 68 days respectively (p<0.0001) when combined with GCV. Of notice, both AduPARTK(T) and ICOVIR15-TKT antitumoral responses were stronger by ductal viral application than intravenously, in line with the 38-fold increase in pancreas transduction observed upon ductal administration. In summary our data show that cytotoxic adenoviruses retrogradelly injected to the pancreas can be a feasible approach to treat localized pancreatic tumors

Behavior of vascular resistance undergoing various pressure insufflation and perfusion on decellularized lungs

Bioengineering of functional lung tissue by using whole lung scaffolds has been proposed as a potential alternative for patients awaiting lung transplant. Previous studies have demonstrated that vascular resistance (Rv) could be altered to optimize the process of obtaining suitable lung scaffolds. Therefore, this work was aimed at determining how lung inflation (tracheal pressure) and perfusion (pulmonary arterial pressure) affect vascular resistance. This study was carried out using the lungs excised from 5 healthy male Sprague-Dawley rats. The trachea was cannulated and connected to a continuous positive airway pressure (CPAP) device to provide a tracheal pressure ranging from 0 to 15 cmH(2)O. The pulmonary artery was cannulated and connected to a controlled perfusion system with continuous pressure (gravimetric level) ranging from 5 to 30 cmH(2)O. Effective Rv was calculated by ratio of pulmonary artery pressure (P-PA) by pulmonary artery flow (V'(PA)). Rv in the decellularized lungs scaffolds decreased at increasing V'(PA), stabilizing at a pulmonary arterial pressure greater than 20 cmH(2)O. On the other hand, CPAP had no influence on vascular resistance in the lung scaffolds after being subjected to pulmonary artery pressure of 5 cmH(2)O. In conclusion, compared to positive airway pressure, arterial lung pressure markedly influences the mechanics of vascular resistance in decellularized lungs. (C) 2016 Elsevier Ltd. All rights reserved

Interrelations between Patients’ Clinicopathological Characteristics and Their Association with Response to Immunotherapy in a Real-World Cohort of NSCLC Patients

Biomarcadores; Eventos adversos relacionados con el sistema inmunitario; InmunoterapiaBiomarcadors; Esdeveniments adversos relacionats amb el sistema immunitari; ImmunoteràpiaBiomarkers; Immune related adverse events; ImmunotherapyImmune checkpoint inhibitors (ICIs) have transformed non-small cell lung cancer (NSCLC) treatment. Unfortunately, only some patients benefit from these therapies. Thus, certain clinicopathological characteristics of the patients have been proposed as biomarkers of ICIs response. We assembled a retrospective cohort of 262 NSCLC patients treated with ICIs, compiled relevant clinicopathological characteristics, and studied their associations with treatment outcome using Cox proportional-hazards survival models. Additionally, we investigated the interrelations between clinicopathological features and devised a method to create a compendium associated with ICIs response by selecting those that provide non-redundant information. In multivariate analyses, ECOG performance status (hazard ratio (HR) 1.37 (95% CI 1.11 to 1.68), p < 0.005), LDH (HR 1.24 (95% CI 1.03 to 1.48), p = 0.02)) and PD-L1 negativity were associated with decreased progression-free survival (PFS) (HR 1.92 (95% CI 1.03 to 3.58), p = 0.04), whereas presentation of immune-related adverse events (irAEs) (HR 0.35 (95% CI 0.22 to 0.55, p < 0.005) or females (HR 0.52 (95% CI 0.33 to 0.80, p < 0.005) had longer PFS. Additionally, numerous clinicopathological indicators were found to be interrelated. Thus, we searched for features that provide non-redundant information, and found the combination of LDH levels, irAEs, and gender to have a better association with ICIs treatment response (cross-validated c-index = 0.66). We concluded that several clinicopathological features showed prognostic value in our real-world cohort. However, some are interrelated, and compendiums of features should therefore consider these interactions. Joint assessment of LDH, irAEs, and gender may be a good prognostic compendium.None associated with this project

Batch-adaptive rejection threshold estimation with application to OCR post-processing

An OCR process is often followed by the application of a language model to find the best transformation of an OCR hypothesis into a string compatible with the constraints of the document, field or item under consideration. The cost of this transformation can be taken as a confidence value and compared to a threshold to decide if a string is accepted as correct or rejected in order to satisfy the need for bounding the error rate of the system. Widespread tools like ROC, precision-recall, or error-reject curves, are commonly used along with fixed thresholding in order to achieve that goal. However, those methodologies fail when a test sample has a confidence distribution that differs from the one of the sample used to train the system, which is a very frequent case in post-processed OCR strings (e.g., string batches showing particularly careful handwriting styles in contrast to free styles). In this paper, we propose an adaptive method for the automatic estimation of the rejection threshold that overcomes this drawback, allowing the operator to define an expected error rate within the set of accepted (non-rejected) strings of a complete batch of documents (as opposed to trying to establish or control the probability of error of a single string), regardless of its confidence distribution. The operator (expert) is assumed to know the error rate that can be acceptable to the user of the resulting data. The proposed system transforms that knowledge into a suitable rejection threshold. The approach is based on the estimation of an expected error vs. transformation cost distribution. First, a model predicting the probability of a cost to arise from an erroneously transcribed string is computed from a sample of supervised OCR hypotheses. Then, given a test sample, a cumulative error vs. cost curve is computed and used to automatically set the appropriate threshold that meets the user-defined error rate on the overall sample. The results of experiments on batches coming from different writing styles show very accurate error rate estimations where fixed thresholding clearly fails. An original procedure to generate distorted strings from a given language is also proposed and tested, which allows the use of the presented method in tasks where no real supervised OCR hypotheses are available to train the system.Navarro Cerdan, JR.; Arlandis Navarro, JF.; Llobet Azpitarte, R.; Perez-Cortes, J. (2015). Batch-adaptive rejection threshold estimation with application to OCR post-processing. Expert Systems with Applications. 42(21):8111-8122. doi:10.1016/j.eswa.2015.06.022S81118122422

Limb-girdle muscular dystrophy 1F is caused by a microdeletion in the transportin 3 gene

In 2001, we reported linkage of an autosomal dominant form of limb-girdle muscular dystrophy, limb-girdle muscular dystrophy 1F, to chromosome 7q32.1-32.2, but the identity of the mutant gene was elusive. Here, using a whole genome sequencing strategy, we identified the causative mutation of limb-girdle muscular dystrophy 1F, a heterozygous single nucleotide deletion (c.2771del) in the termination codon of transportin 3 (TNPO3). This gene is situated within the chromosomal region linked to the disease and encodes a nuclear membrane protein belonging to the importin beta family. TNPO3 transports serine/arginine-rich proteins into the nucleus, and has been identified as a key factor in the HIV-import process into the nucleus. The mutation is predicted to generate a 15-amino acid extension of the C-terminus of the protein, segregates with the clinical phenotype, and is absent in genomic sequence databases and a set of >200 control alleles. In skeletal muscle of affected individuals, expression of the mutant messenger RNA and histological abnormalities of nuclei and TNPO3 indicate altered TNPO3 function. Our results demonstrate that the TNPO3 mutation is the cause of limb-girdle muscular dystrophy 1F, expand our knowledge of the molecular basis of muscular dystrophies and bolster the importance of defects of nuclear envelope proteins as causes of inherited myopathies

Overview of Checkpoint Inhibitors Mechanism of Action: Role of Immune-Related Adverse Events and Their Treatment on Progression of Underlying Cancer

Corticosteroids; Efficacy; Immune checkpoint inhibitorsCorticosteroides; Eficacia; Inhibidores del punto de control inmunitarioCorticoides; Eficàcia; Inhibidors del punt de control immunitariIn recent years, immunotherapy-based regimens have been included into the treatment's algorithm of several cancer types. Programmed death-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) interact with their ligands found on the surface of antigen presenting cells (APC) or tumor cells (PD-L1/2 and CD80/86). Through these interactions, stimulatory or inhibitory signals are established. Immune checkpoint inhibitors (ICIs), block these interactions, and when administered not only as monotherapy but also as part of combination regimens, have shown to improve survival results in multiple advanced cancers leading to an increasing number of patients treated with ICI and, as a consequence, a rise in the number of patients developing immune-related adverse events (irAEs). Presence of irAEs has been associated with greater benefit from treatment, especially when blocking PD-L1. Recent data suggests that treatment benefit persists after discontinuation of ICIs due to a treatment related adverse event, regardless of the grade. Patients experiencing grade 3-4 irAEs are at risk of toxicity recurrence after reintroducing immunotherapy and therefore, the decision to resume the treatment is challenging. In these cases, a multidisciplinary approach is always needed and several factors should be considered. Management of severe toxicities may require systemic corticosteroids which can impact on T-cell function. Due to their immunosuppressive properties, it is necessary to deeper determine how corticosteroids influence responses. In terms of overall survival (OS), the use of steroids as therapy for irAEs seems not to reduce OS and several studies have reported durable responses in patients experiencing autoimmune toxicities treated with corticosteroids

Expression of TILs and Patterns of Gene Expression from Paired Samples of Malignant Pleural Mesothelioma (MPM) Patients

Gene expression; Immunotherapy; Malignant pleural mesotheliomaExpresión génica; Inmunoterapia; Mesotelioma pleural malignoExpressió gènica; Immunoteràpia; Mesotelioma pleural maligneMPM is an aggressive disease with an immunosuppressive tumor microenvironment, and interest in exploring immunotherapy in this disease has been increasing. In the first line of treatment, the combination of nivolumab and ipilimumab demonstrated an improvement in survival over chemotherapy. The presence of TILs has been recognized as a marker of antitumor immune response to chemotherapy in solid tumors. The aim of our study is to identify the effect of treatment on immune cells and the immune gene profile in MPM. We investigated the changes in expression of TILs in 10 human MPM paired tumor tissues using immunohistochemistry and gene expression analysis from paired untreated and treated samples. In this small series, we demonstrated that during the evolution of disease without any treatment there was an increase in the inflammatory component in tumor samples. After systemic treatment there was a decrease in the number of TILs. We observed that after systemic treatment or disease progression immune gene signatures were suppressed. Our integrated analysis of paired samples with immune profile and genomic changes on MPM suggested that during the evolution of the disease the immune system tends to switch, turning off with treatment.The study was partially funded by Project PREDICT-Meso (GEACC19003CED), funded by Fundación AECC