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Hüttener, Mário, Hergueta, Jon, Bernabeu, Manuel, Prieto, Alejandro, Aznar, Sonia, Merino, Susana, Tomás, Joan, Juárez, Antonio, (2022). Roles of Proteins Containing Immunoglobulin-Like Domains in the Conjugation of Bacterial Plasmids Msphere 7,

Transmission of a plasmid from one bacterial cell to another, in several instances, underlies the dissemination of antimicrobial resistance (AMR) genes. The process requires well-characterized enzymatic machinery that facilitates cell-to-cell contact and the transfer of the plasmid.

Keywords: antimicrobial resistance, bacterial ig-like proteins, bacterial lg-like proteins, chromosomal genes, identification, inca/c, mutational analysis, plasmid conjugation, products, r-factors, resistance plasmids, salmonella-enterica, sequence, Antimicrobial resistance, Bacterial ig-like proteins, Escherichia-coli, Plasmid conjugation


Pepe, G, Sfogliarini, C, Rizzello, L, Battaglia, G, Pinna, C, Rovati, G, Ciana, P, Brunialti, E, Mornata, F, Maggi, A, Locati, M, Vegeto, E, (2021). ER alpha-independent NRF2-mediated immunoregulatory activity of tamoxifen Biomedicine & Pharmacotherapy 144,

Sex differences in immune-mediated diseases are linked to the activity of estrogens on innate immunity cells, including macrophages. Tamoxifen (TAM) is a selective estrogen receptor modulator (SERM) used in estrogen receptor-alpha (ER alpha)-dependent breast cancers and off-target indications such as infections, although the immune activity of TAM and its active metabolite, 4-OH tamoxifen (4HT), is poorly characterized. Here, we aimed at investigating the endocrine and immune activity of these SERMs in macrophages. Using primary cultures of female mouse macrophages, we analyzed the expression of immune mediators and activation of effector functions in competition experiments with SERMs and 17 beta-estradiol (E2) or the bacterial endotoxin LPS. We observed that 4HT and TAM induce estrogen antagonist effects when used at nanomolar concentrations, while pharmacological concentrations that are reached by TAM in clinical settings regulate the expression of VEGF alpha and other immune activation genes by ER alpha- and G protein-coupled receptor 1 (GPER1)-independent mechanisms that involve NRF2 through PI3K/Akt-dependent mechanisms. Importantly, we observed that SERMs potentiate cell phagocytosis and modify the effects of LPS on the expression of inflammatory cytokines, such as TNF alpha and IL1 beta, with an overall increase in cell inflammatory phenotype, further sustained by potentiation of IL1 beta secretion through caspase-1 activation.

Keywords: drug repurposing, inflammation, macrophage, nrf2, Apoptosis, Breast-cancer, Drug repurposing, Expression, Inflammation, Macrophage, Nrf2, Resistance, Sex-differences, Tamoxifen, Tumor-associated macrophages


Castillo-Escario, Yolanda, Kumru, Hatice, Ferrer-Lluis, Ignasi, Vidal, Joan, Jané, Raimon, (2021). Detection of Sleep-Disordered Breathing in Patients with Spinal Cord Injury Using a Smartphone SENSORS 21,

Patients with spinal cord injury (SCI) have an increased risk of sleep-disordered breathing (SDB), which can lead to serious comorbidities and impact patients’ recovery and quality of life. However, sleep tests are rarely performed on SCI patients, given their multiple health needs and the cost and complexity of diagnostic equipment. The objective of this study was to use a novel smartphone system as a simple non-invasive tool to monitor SDB in SCI patients. We recorded pulse oximetry, acoustic, and accelerometer data using a smartphone during overnight tests in 19 SCI patients and 19 able-bodied controls. Then, we analyzed these signals with automatic algorithms to detect desaturation, apnea, and hypopnea events and monitor sleep position. The apnea–hypopnea index (AHI) was significantly higher in SCI patients than controls (25 ± 15 vs. 9 ± 7, p < 0.001). We found that 63% of SCI patients had moderate-to-severe SDB (AHI ? 15) in contrast to 21% of control subjects. Most SCI patients slept predominantly in supine position, but an increased occurrence of events in supine position was only observed for eight patients. This study highlights the problem of SDB in SCI and provides simple cost-effective sleep monitoring tools to facilitate the detection, understanding, and management of SDB in SCI patients.

Keywords: apnea syndrome, biomedical signal processing, individuals, mhealth, monitoring, nasal resistance, people, position, prevalence, questionnaire, sample, sleep apnea, sleep position, sleep-disordered breathing, smartphone, time, Apnea-hypopnea indices, Biomedical signal processing, Biomedical signals processing, Cost effectiveness, Diagnosis, Mhealth, Monitoring, Noninvasive medical procedures, Oximeters, Oxygen-saturation, Patient rehabilitation, Simple++, Sleep apnea, Sleep position, Sleep research, Sleep-disordered breathing, Smart phones, Smartphone, Smartphones, Spinal cord injury, Spinal cord injury patients


Manzano-Muñoz A, Alcon C, Menéndez P, Ramírez M, Seyfried F, Debatin KM, Meyer LH, Samitier J, Montero J, (2021). MCL-1 Inhibition Overcomes Anti-apoptotic Adaptation to Targeted Therapies in B-Cell Precursor Acute Lymphoblastic Leukemia Frontiers In Cell And Developmental Biology 9,

Multiple targeted therapies are currently explored for pediatric and young adult B-cell precursor acute lymphoblastic leukemia (BCP-ALL) treatment. However, this new armamentarium of therapies faces an old problem: choosing the right treatment for each patient. The lack of predictive biomarkers is particularly worrying for pediatric patients since it impairs the implementation of new treatments in the clinic. In this study, we used the functional assay dynamic BH3 profiling (DBP) to evaluate two new treatments for BCP-ALL that could improve clinical outcome, especially for relapsed patients. We found that the MEK inhibitor trametinib and the multi-target tyrosine kinase inhibitor sunitinib exquisitely increased apoptotic priming in an NRAS-mutant and in a KMT2A-rearranged cell line presenting a high expression of FLT3, respectively. Following these observations, we sought to study potential adaptations to these treatments. Indeed, we identified with DBP anti-apoptotic changes in the BCL-2 family after treatment, particularly involving MCL-1 – a pro-survival strategy previously observed in adult cancers. To overcome this adaptation, we employed the BH3 mimetic S63845, a specific MCL-1 inhibitor, and evaluated its sequential addition to both kinase inhibitors to overcome resistance. We observed that the metronomic combination of both drugs with S63845 was synergistic and showed an increased efficacy compared to single agents. Similar observations were made in BCP-ALL KMT2A-rearranged PDX cells in response to sunitinib, showing an analogous DBP profile to the SEM cell line. These findings demonstrate that rational sequences of targeted agents with BH3 mimetics, now extensively explored in clinical trials, may improve treatment effectiveness by overcoming anti-apoptotic adaptations in BCP-ALL.

Keywords: apoptosis, bh3 mimetics, cancer, dependence, increases, kinase inhibition, pediatric leukemia, precision medicine, resistance, sensitivity, targeted therapies, tumor-cells, venetoclax, Apoptosis, Bcl-2 family proteins, Bh3 mimetics, Pediatric leukemia, Resistance, Targeted therapies


Alcon C, Gómez Tejeda Zañudo J, Albert R, Wagle N, Scaltriti M, Letai A, Samitier J, Montero J, (2021). ER+ Breast Cancer Strongly Depends on MCL-1 and BCL-xL Anti-Apoptotic Proteins Cells 10,

Breast cancer is the most frequent type of cancer and the major cause of mortality in women. The rapid development of various therapeutic options has led to the improvement of treatment outcomes; nevertheless, one-third of estrogen receptor (ER)-positive patients relapse due to cancer cell acquired resistance. Here, we use dynamic BH3 profiling (DBP), a functional predictive assay that measures net changes in apoptotic priming, to find new effective treatments for ER+ breast cancer. We observed anti-apoptotic adaptations upon treatment that pointed to metronomic therapeutic combinations to enhance cytotoxicity and avoid resistance. Indeed, we found that the anti-apoptotic proteins BCL-xL and MCL-1 are crucial for ER+ breast cancer cells resistance to therapy, as they exert a dual inhibition of the pro-apoptotic protein BIM and compensate for each other. In addition, we identified the AKT inhibitor ipatasertib and two BH3 mimetics targeting these anti-apoptotic proteins, S63845 and A-1331852, as new potential therapies for this type of cancer. Therefore, we postulate the sequential inhibition of both proteins using BH3 mimetics as a new treatment option for refractory and relapsed ER+ breast cancer tumors.

Keywords: apoptosis, bh3 mimetics, cell-line, chemotherapy, classification, dbp, death, er+ breast cancer, fulvestrant, her2, inhibitor, kinase, pik3ca, priming, resistance, targeted therapies, Apoptosis, Bh3 mimetics, Dbp, Endocrine therapy, Er plus breast cancer, Er+ breast cancer, Priming, Resistance, Targeted therapies


Blanco-Cabra N, López-Martínez MJ, Arévalo-Jaimes BV, Martin-Gómez MT, Samitier J, Torrents E, (2021). A new BiofilmChip device for testing biofilm formation and antibiotic susceptibility Npj Biofilms And Microbiomes 7,

Currently, three major circumstances threaten the management of bacterial infections: increasing antimicrobial resistance, expansion of chronic biofilm-associated infections, and lack of an appropriate approach to treat them. To date, the development of accelerated drug susceptibility testing of biofilms and of new antibiofouling systems has not been achieved despite the availability of different methodologies. There is a need for easy-to-use methods of testing the antibiotic susceptibility of bacteria that form biofilms and for screening new possible antibiofilm strategies. Herein, we present a microfluidic platform with an integrated interdigitated sensor (BiofilmChip). This new device allows an irreversible and homogeneous attachment of bacterial cells of clinical origin, even directly from clinical specimens, and the biofilms grown can be monitored by confocal microscopy or electrical impedance spectroscopy. The device proved to be suitable to study polymicrobial communities, as well as to measure the effect of antimicrobials on biofilms without introducing disturbances due to manipulation, thus better mimicking real-life clinical situations. Our results demonstrate that BiofilmChip is a straightforward tool for antimicrobial biofilm susceptibility testing that could be easily implemented in routine clinical laboratories.

Keywords: cells, model, resistance, shear, technology, In-vitro


Watt, AC, Cejas, P, DeCristo, MJ, Metzger, O, Lam, EYN, Qiu, XT, BrinJones, H, Kesten, N, Coulson, R, Font-Tello, A, Lim, K, Vadhi, R, Daniels, VW, Montero, J, Taing, L, Meyer, CA, Gilan, O, Bell, CC, Korthauer, KD, Giambartolomei, C, Pasaniuc, B, Seo, JH, Freedman, ML, Ma, CT, Ellis, MJ, Krop, I, Winer, E, Letai, A, Brown, M, Dawson, MA, Long, HW, Zhao, JJ, Goel, S, (2021). CDK4/6 inhibition reprograms the breast cancer enhancer landscape by stimulating AP-1 transcriptional activity Nature Cancer 2, 34-+

Goel and colleagues show that CDK4/6 inhibition induces global chromatin changes mediated by AP-1 factors, which mediate key biological and clinical effects in breast cancer. Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) were designed to induce cancer cell cycle arrest. Recent studies have suggested that these agents also exert other effects, influencing cancer cell immunogenicity, apoptotic responses and differentiation. Using cell-based and mouse models of breast cancer together with clinical specimens, we show that CDK4/6 inhibitors induce remodeling of cancer cell chromatin characterized by widespread enhancer activation, and that this explains many of these effects. The newly activated enhancers include classical super-enhancers that drive luminal differentiation and apoptotic evasion, as well as a set of enhancers overlying endogenous retroviral elements that are enriched for proximity to interferon-driven genes. Mechanistically, CDK4/6 inhibition increases the level of several activator protein-1 transcription factor proteins, which are in turn implicated in the activity of many of the new enhancers. Our findings offer insights into CDK4/6 pathway biology and should inform the future development of CDK4/6 inhibitors.

Keywords: Abemaciclib, Androgen receptor, Animal experiment, Animal model, Animal tissue, Apoptosis, Article, Breast cancer, C-jun, Cancer cell, Carcinoembryonic antigen related cell adhesion molecule 1, Caspase 3, Cell cycle arrest, Cells, Chromatin, Chromatin immunoprecipitation, Controlled study, Cyclin dependent kinase 4, Cyclin dependent kinase 6, Dna damage, Epidermal growth factor receptor 2, Estrogen receptor, Female, Flow cytometry, Fulvestrant, Hla drb1 antigen, Human, Human cell, Immunoblotting, Immunogenicity, Immunoprecipitation, Interferon, Luciferase assay, Mcf-7 cell line, Mda-mb-231 cell line, Microarray analysis, Morphogenesis, Mouse, Nonhuman, Palbociclib, Protein, Protein expression, Rb, Resistance, Rna polymerase ii, Rna sequence, Selective-inhibition, Senescence, Short tandem repeat, Signal transduction, Tamoxifen, Transcription elongation, Transcription factor, Transcription factor ap 1, Transcriptome, Tumor biopsy, Tumor differentiation, Tumor spheroid, Tumor xenograft, Vinculin, Whole exome sequencing


Cendra MdM, Torrents E, (2021). Pseudomonas aeruginosa biofilms and their partners in crime BIOTECHNOLOGY ADVANCES 49,

Pseudomonas aeruginosa biofilms and the capacity of the bacterium to coexist and interact with a broad range of microorganisms have a substantial clinical impact. This review focuses on the main traits of P. aeruginosa biofilms, such as the structural composition and regulatory networks involved, placing particular emphasis on the clinical challenges they represent in terms of antimicrobial susceptibility and biofilm infection clearance. Furthermore, the ability of P. aeruginosa to grow together with other microorganisms is a significant pathogenic attribute with clinical relevance; hence, the main microbial interactions of Pseudomonas are especially highlighted and detailed throughout this review. This article also explores the infections caused by single and polymicrobial biofilms of P. aeruginosa and the current models used to recreate them under laboratory conditions. Finally, the antimicrobial and antibiofilm strategies developed against P. aeruginosa mono and multispecies biofilms are detailed at the end of this review.

Keywords: aeruginosa models, antibiotic-resistance, antimicrobials, bacterial biofilms, biofilms, c-di-gmp, chronic infections, enterococcus-faecalis, extracellular dna, in-vitro, lectin pa-iil, p, p. aeruginosa models, polymicrobial, polymicrobial interactions, staphylococcus-aureus, Antimicrobials, Biofilms, Chronic infections, P. aeruginosa models, Polymicrobial, Pseudomonas aeruginosa, Urinary-tract-infection


Abdelrahman F, Easwaran M, Daramola OI, Ragab S, Lynch S, Oduselu TJ, Khan FM, Ayobami A, Adnan F, Torrents E, Sanmukh S, El-Shibiny A, (2021). Phage-encoded endolysins Antibiotics 10, 1-31

© 2021 by the authors. Licensee MDPI, Basel, Switzerland. Due to the global emergence of antibiotic resistance, there has been an increase in research surrounding endolysins as an alternative therapeutic. Endolysins are phage-encoded enzymes, utilized by mature phage virions to hydrolyze the cell wall from within. There is significant evidence that proves the ability of endolysins to degrade the peptidoglycan externally without the assistance of phage. Thus, their incorporation in therapeutic strategies has opened new options for therapeutic application against bacterial infections in the human and veterinary sectors, as well as within the agricultural and biotechnology sectors. While endolysins show promising results within the laboratory, it is important to document their resistance, safety, and immunogenicity for in-vivo application. This review aims to provide new insights into the synergy between endolysins and antibiotics, as well as the formulation of endolysins. Thus, it provides crucial information for clinical trials involving endolysins.

Keywords: antibiotic resistance, bacteriophages, Antibiotic resistance, Bacteriophages, Endolysin


Montero, Joan, Gstalder, Cécile, Kim, Daniel J., Sadowicz, Dorota, Miles, Wayne, Manos, Michael, Cidado, Justin R., Paul Secrist, J., Tron, Adriana E., Flaherty, Keith, Stephen Hodi, F., Yoon, Charles H., Letai, Anthony, Fisher, David E., Haq, Rizwan, (2019). Destabilization of NOXA mRNA as a common resistance mechanism to targeted therapies Nature Communications 10, (1), 5157

Most targeted cancer therapies fail to achieve complete tumor regressions or attain durable remissions. To understand why these treatments fail to induce robust cytotoxic responses despite appropriately targeting oncogenic drivers, here we systematically interrogated the dependence of cancer cells on the BCL-2 family of apoptotic proteins after drug treatment. We observe that multiple targeted therapies, including BRAF or EGFR inhibitors, rapidly deplete the pro-apoptotic factor NOXA, thus creating a dependence on the anti-apoptotic protein MCL-1. This adaptation requires a pathway leading to destabilization of the NOXA mRNA transcript. We find that interruption of this mechanism of anti-apoptotic adaptive resistance dramatically increases cytotoxic responses in cell lines and a murine melanoma model. These results identify NOXA mRNA destabilization/MCL-1 adaptation as a non-genomic mechanism that limits apoptotic responses, suggesting that sequencing of MCL-1 inhibitors with targeted therapies could overcome such widespread and clinically important resistance.

Keywords: Cancer therapeutic resistance, Melanoma, Targeted therapies


Aragonès, A. C., Aravena, D., Cerdá, J. I., Acís-Castillo, Z., Li, H., Real, J. A., Sanz, F., Hihath, J., Ruiz, E., Díez-Pérez, I., (2016). Large conductance switching in a single-molecule device through room temperature spin-dependent transport Nano Letters 16, (1), 218-226

Controlling the spin of electrons in nanoscale electronic devices is one of the most promising topics aiming at developing devices with rapid and high density information storage capabilities. The interface magnetism or spinterface resulting from the interaction between a magnetic molecule and a metal surface, or vice versa, has become a key ingredient in creating nanoscale molecular devices with novel functionalities. Here, we present a single-molecule wire that displays large (>10000%) conductance switching by controlling the spin-dependent transport under ambient conditions (room temperature in a liquid cell). The molecular wire is built by trapping individual spin crossover FeII complexes between one Au electrode and one ferromagnetic Ni electrode in an organic liquid medium. Large changes in the single-molecule conductance (>100-fold) are measured when the electrons flow from the Au electrode to either an α-up or a β-down spin-polarized Ni electrode. Our calculations show that the current flowing through such an interface appears to be strongly spin-polarized, thus resulting in the observed switching of the single-molecule wire conductance. The observation of such a high spin-dependent conductance switching in a single-molecule wire opens up a new door for the design and control of spin-polarized transport in nanoscale molecular devices at room temperature.

Keywords: Density functional calculations, Magnetoresistance, Single-molecule junctions, Spin orbit coupling, Spin-crossover complexes, Spinterface, STM break-junction


Tassinari, E., Aznar, S., Urcola, I., Prieto, A., Hüttener, M., Juárez, A., (2016). The incC sequence is required for R27 plasmid stability Frontiers in Microbiology 7, (6), Article 629

IncHI plasmids account for multiple antimicrobial resistance in Salmonella and other enterobacterial genera. These plasmids are generally very stable in their bacterial hosts. R27 is the archetype of IncHI1 plasmids. A high percentage of the R27-encoded open reading frames (ORFs) (66.7%) do not show similarity to any known ORFs. We performed a deletion analysis of all non-essential R27 DNA sequences to search for hitherto non-identified plasmid functions that might be required for plasmid stability. We report the identification of a short DNA sequence (incC) that is essential for R27 stability. That region contains several repeats (incC repeats), belongs to one of the three-plasmid replicons (R27 FIA-like) and is targeted by the R27 E protein. Deletion of the incC sequence drastically reduces R27 stability both in Escherichia coli and in Salmonella, the effect being more pronounced in this latter species. Interfering with incC-E protein interaction must lead to a reduced IncHI1 plasmid stability, and may represent a new approach to combat antimicrobial resistance.

Keywords: Antimicrobial resistance, E protein, IncC, IncHI1 plasmids, Plasmid R27, Plasmid stability


Farré, R., Navajas, D., (2016). Forced oscillation: A poorly exploited tool for simply assessing respiratory function in children Respirology , 21, (6), 982-983

da Palma, R. K., Nonaka, P. N., Campillo, N., Uriarte, J. J., Urbano, J. J., Navajas, D., Farré, R., Oliveira, L. V. F., (2016). Behavior of vascular resistance undergoing various pressure insufflation and perfusion on decellularized lungs Journal of Biomechanics 49, (7), 1230-1232

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 15cmH2O. The pulmonary artery was cannulated and connected to a controlled perfusion system with continuous pressure (gravimetric level) ranging from 5 to 30cmH2O. 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 20cmH2O. On the other hand, CPAP had no influence on vascular resistance in the lung scaffolds after being subjected to pulmonary artery pressure of 5cmH2O. In conclusion, compared to positive airway pressure, arterial lung pressure markedly influences the mechanics of vascular resistance in decellularized lungs.

Keywords: Decellularized lung, Scaffolds, Vascular resistance


da Palma, R. K., Campillo, N., Uriarte, J. J., Oliveira, L. V. F., Navajas, D., Farré, R., (2015). Pressure- and flow-controlled media perfusion differently modify vascular mechanics in lung decellularization Journal of the Mechanical Behavior of Biomedical Materials , 49, 69-79

Organ biofabrication is a potential future alternative for obtaining viable organs for transplantation. Achieving intact scaffolds to be recellularized is a key step in lung bioengineering. Perfusion of decellularizing media through the pulmonary artery has shown to be effective. How vascular perfusion pressure and flow vary throughout lung decellularization, which is not well known, is important for optimizing the process (minimizing time) while ensuring scaffold integrity (no barotrauma). This work was aimed at characterizing the pressure/flow relationship at the pulmonary vasculature and at how effective vascular resistance depends on pressure- and flow-controlled variables when applying different methods of media perfusion for lung decellularization. Lungs from 43 healthy mice (C57BL/6; 7-8 weeks old) were investigated. After excision and tracheal cannulation, lungs were inflated at 10cmH2O airway pressure and subjected to conventional decellularization with a solution of 1% sodium dodecyl sulfate (SDS). Pressure (PPA) and flow (V'PA) at the pulmonary artery were continuously measured. Decellularization media was perfused through the pulmonary artery: (a) at constant PPA=20cmH2O or (b) at constant V'PA=0.5 and 0.2ml/min. Effective vascular resistance was computed as Rv=PPA/V'PA. Rv (in cmH2O/(ml/min)); mean±SE) considerably varied throughout lung decellularization, particularly for pressure-controlled perfusion (from 29.1±3.0 in baseline to a maximum of 664.1±164.3 (p<0.05), as compared with flow-controlled perfusion (from 49.9±3.3 and 79.5±5.1 in baseline to a maximum of 114.4±13.9 and 211.7±70.5 (p<0.05, both), for V'PA of 0.5 and 0.2ml/min respectively. Most of the media infused to the pulmonary artery throughout decellularization circulated to the airways compartment across the alveolar-capillary membrane. This study shows that monitoring perfusion mechanics throughout decellularization provides information relevant for optimizing the process time while ensuring that vascular pressure is kept within a safety range to preserve the organ scaffold integrity.

Keywords: Acellular lung, Fluid mechanics, Lung bioengineering, Lung scaffold, Organ biofabrication, Tissue engineering, Vascular resistance


Uriarte, J. J., Nonaka, P. N., Campillo, N., Palma, R. K., Melo, E., de Oliveira, L. V. F., Navajas, D., Farré, R., (2014). Mechanical properties of acellular mouse lungs after sterilization by gamma irradiation Journal of the Mechanical Behavior of Biomedical Materials , 40, 168-177

Lung bioengineering using decellularized organ scaffolds is a potential alternative for lung transplantation. Clinical application will require donor scaffold sterilization. As gamma-irradiation is a conventional method for sterilizing tissue preparations for clinical application, the aim of this study was to evaluate the effects of lung scaffold sterilization by gamma irradiation on the mechanical properties of the acellular lung when subjected to the artificial ventilation maneuvers typical within bioreactors. Twenty-six mouse lungs were decellularized by a sodium dodecyl sulfate detergent protocol. Eight lungs were used as controls and 18 of them were submitted to a 31kGy gamma irradiation sterilization process (9 kept frozen in dry ice and 9 at room temperature). Mechanical properties of acellular lungs were measured before and after irradiation. Lung resistance (RL) and elastance (EL) were computed by linear regression fitting of recorded signals during mechanical ventilation (tracheal pressure, flow and volume). Static (Est) and dynamic (Edyn) elastances were obtained by the end-inspiratory occlusion method. After irradiation lungs presented higher values of resistance and elastance than before irradiation: RL increased by 41.1% (room temperature irradiation) and 32.8% (frozen irradiation) and EL increased by 41.8% (room temperature irradiation) and 31.8% (frozen irradiation). Similar increases were induced by irradiation in Est and Edyn. Scanning electron microscopy showed slight structural changes after irradiation, particularly those kept frozen. Sterilization by gamma irradiation at a conventional dose to ensure sterilization modifies acellular lung mechanics, with potential implications for lung bioengineering.

Keywords: Gamma irradiation, Lung bioengineering, Lung decellularization, Organ scaffold, Pulmonary mechanics, Decellularization, Gamma irradiation, Mouse lung, Pulmonary mechanics, dodecyl sulfate sodium, animal tissue, Article, artificial ventilation, bioengineering, bioreactor, compliance (physical), controlled study, freezing, gamma irradiation, lung, lung mechanics, lung resistance, male, mouse, nonhuman, room temperature, scanning electron microscopy, tissue scaffold, trachea pressure


Nonaka, P. N., Uriarte, J. J., Campillo, N., Melo, E., Navajas, D., Farré, R., Oliveira, L. V. F., (2014). Mechanical properties of mouse lungs along organ decellularization by sodium dodecyl sulfate Respiratory Physiology & Neurobiology , 200, 1-5

Lung decellularization is based on the use of physical, chemical, or enzymatic methods to break down the integrity of the cells followed by a treatment to extract the cellular material from the lung scaffold. The aim of this study was to characterize the mechanical changes throughout the different steps of lung decellularization process. Four lungs from mice (C57BL/6) were decellularized by using a conventional protocol based on sodium dodecyl sulfate. Lungs resistance (RL) and elastance (EL) were measured along decellularization steps and were computed by linear regression fitting of tracheal pressure, flow, and volume during mechanical ventilation. Transients differences found were more distinct in an intermediate step after the lungs were rinsed with deionized water and treated with 1% SDS, whereupon the percentage of variation reached approximately 80% for resistance values and 30% for elastance values. In conclusion, although a variation in extracellular matrix stiffness was observed during the decellularization process, this variation can be considered negligible overall because the resistance and elastance returned to basal values at the final decellularization step.

Keywords: Lung bioengineering, Lung decellularization, Organ scaffold, dodecyl sulfate sodium, animal tissue, article, artificial ventilation, compliance (physical), controlled study, enzyme chemistry, extracellular matrix, female, flow, lung, lung decellularization, lung pressure, lung resistance, mouse, nonhuman, positive end expiratory pressure, priority journal, rigidity, tissue engineering, trachea pressure


Farre, R., Montserrat, J. M., Navajas, D., (2008). Assessment of upper airway mechanics during sleep Respiratory Physiology & Neurobiology , 163, (1-3), 74-81

Obstructive sleep apnea, which is the most prevalent sleep breathing disorder, is characterized by recurrent episodes of upper airway collapse and reopening. However, the mechanical properties of the upper airway are not directly measured in routine polysomnography because only qualitative sensors (thermistors for flow and thoraco-abdominal bands for pressure) are used. This review focuses on two techniques that quantify upper airway obstruction during sleep. A Starling model of collapsible conduit allows us to interpret the mechanics of the upper airway by means of two parameters: the critical pressure (Pcrit) and the upstream resistance (Rup). A simple technique to measure Pcrit and Rup involves the application of different levels of continuous positive airway pressure (CPAP) during sleep. The forced oscillation technique is another non-invasive procedure for quantifying upper airway impedance during the breathing cycle in sleep studies. The latest developments in these two methods allow them to be easily applied on a routine basis in order to more fully characterize upper airway mechanics in patients with sleep breathing disorders.

Keywords: Obstructive sleep apnea, Upper airway, Airway resistance, Critical pressure, Respiratory impedance


Morgenstern, C., Jané, R., Schwaibold, M., Randerath, W., (2008). Automatic classification of inspiratory flow limitation assessed non-invasively during sleep IEEE Engineering in Medicine and Biology Society Conference Proceedings 30th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (ed. IEEE), IEEE (Vancouver, Canada) 1-8, 1132-1135

Detection of inspiratory flow limitation (IFL) is being recognized of increasing importance in order to diagnose pathologies related to sleep disordered breathing. Currently, IFL is usually identified with the help of invasive esophageal pressure measurement, still considered the gold-standard reference to assess respiratory effort. But the invasiveness of esophageal pressure measurement and its impact on sleep discourages its use in clinical routine. In this study, a new non-invasive automatic system is proposed for objective IFL classification. First, an automatic annotation system for IFL based on pressure/flow relationship was developed. Then, classifiers (Support Vector Machines and adaboost classifiers) were trained with these gold-standard references in order to objectively classify breaths non-invasively, solely based on the breaths' flow contours. The new non-invasive automatic classification system seems to be promising, as it achieved a sensitivity of 0.92 and a specificity of 0.89, outperforming prior classification results obtained by human experts.

Keywords: Upper airway-resistance


Morgenstern, C., Jané, R., Schwaibold, M., Randerath, W., (2008). Characterization of inspiratory flow limitation during sleep with an exponential model IEEE Engineering in Medicine and Biology Society Conference Proceedings 30th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (ed. IEEE), IEEE (Vancouver, Canada) 1-8, 2439-2442

Assessing incidence and severity of inspiratory flow limitation (TFL) is of importance for patients suffering of sleep disordered breathing (SDB) in order to diagnose a spectrum of different pathologies. In this study a new exponential equation is proposed to characterize the pressure/flow relationship of IFL and non-TFL breaths. Classical and alternative criteria are applied on the model's predictions in order to assess TFL, and its outcome is compared to the outcome of other models. The newly proposed exponential model seems to be promising, as it outperforms other models by achieving a global average sensitivity of 93% and specificity of 91%, and the lowest mean square error when estimating resistance at peak pressure. Additional statistical tests were performed on the exponential model's coefficients in order to determine if a coefficient based classification is possible.

Keywords: Resistance