by Keyword: resistance
Fonte M, Fontinha D, Moita D, Caño-Prades O, Avalos-Padilla Y, Fernàndez-Busquets X, Prudêncio M, Gomes P, Teixeira C, (2023). New 4-(N-cinnamoylbutyl)aminoacridines as potential multi-stage antiplasmodial leads European Journal Of Medicinal Chemistry 258, 115575
A novel family of 4-aminoacridine derivatives was obtained by linking this heteroaromatic core to different trans-cinnamic acids. The 4-(N-cinnamoylbutyl)aminoacridines obtained exhibited in vitro activity in the low- or sub-micromolar range against (i) hepatic stages of Plasmodium berghei, (ii) erythrocytic forms of Plasmodium falciparum, and (iii) early and mature gametocytes of Plasmodium falciparum. The most active compound, having a meta-fluorocinnamoyl group linked to the acridine core, was 20- and 120-fold more potent, respectively, against the hepatic and gametocyte stages of Plasmodium infection than the reference drug, primaquine. Moreover, no cytotoxicity towards mammalian and red blood cells at the concentrations tested was observed for any of the compounds under investigation. These novel conjugates represent promising leads for the development of new multi-target antiplasmodials.Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.
JTD Keywords: agents, analogs, antimalarial, artemisinin, blood-stage, cinnamic acid, gametocyte, hybrid, liver-stage, malaria, multi-target, plasmodium-falciparum, primaquine, quinacrine, resistance, Acridine, Antimalarial, Blood-stage, Cinnamic acid, Cinnamic acid-derivatives, Gametocyte, Hybrid, Liver-stage, Multi-target
Gholami S, Rezvani A, Vatanpour V, Khoshravesh SH, Llorens J, Engel E, Castaño O, Cortina JL, (2023). Chlorine resistance property improvement of polyamide reverse osmosis membranes through cross-linking degree increment Science Of The Total Environment 889, 164283
Highly permeable polyamide reverse osmosis (RO) membranes are desirable for reducing the energy burden and ensuring future water resources in arid and semiarid regions. One notable drawback of thin film composite (TFC) polyamide RO/NF membranes is the polyamide's sensitivity to degradation by free chlorine, the most used biocide in water purification trains. This investigation demonstrated a significant increase in the crosslinking-degree parameter by the m-phenylenediamine (MPD) chemical structure extending in the thin film nanocomposite (TFN) membrane without adding extra MPD monomers to enhance the chlorine resistance and performance. Membrane modification was carried out according to monomer ratio changes and Nanoparticle embedding into the PA layer approaches. A new class of TFN-RO membranes incorporating novel aromatic amine functionalized (AAF)-MWCNTs embedded into the polyamide (PA) layer was introduced. A purposeful strategy was carried out to use cyanuric chloride (2,4,6-trichloro-1,3,5-triazine) as an intermediate functional group in the AAF-MWCNTs. Thus, amidic nitrogen, connected to benzene rings and carbonyl groups, assembles a structure similar to the standard PA, consisting of MPD and trimesoyl chloride. The resulting AAF-MWCNTs were mixed in the aqueous phase during the interfacial polymerization to increase the susceptible positions to chlorine attack and improve the crosslinking degree in the PA network. The characterization and performance results of the membrane demonstrated an increase in ion selectivity and water flux, impressive stability of salt rejection after chlorine exposure, and improved antifouling performance. This purposeful modification resulted in overthrowing two tradeoffs; i) high crosslink density-water flux and ii) salt rejection-permeability. The modified membrane demonstrated ameliorative chlorine resistance relative to the pristine one, with twice the increase in crosslinking degree, more than four times the enhancement of the oxidation resistance, negligible reduction in the salt rejection (0.83 %), and only 5 L/m2.h flux loss following a rigorous static chlorine exposure of 500 ppm.h under acidic conditions. The excellent performance of new chlorine resistant TNF RO membranes fabricated via AAF-MWCNTs together with the facile membrane manufacturing process offered the possibility of postulating them in the desalination field, which could eventually help the current freshwater supply challenge.Copyright © 2023 Elsevier B.V. All rights reserved.
JTD Keywords: behavior, carbon nanotubes, desalination, interfacial polymerization, naclo resistance, nanocomposite, nanofiltration membrane, performance, polymerization, ro membranemodification, substrate, water, Antifouling, Desalination, Interfacial polymerization, Naclo resistance, Ro membrane modification, Thin-film composite
Farré R, Navajas D, (2023). Ventilation Mechanics Seminars In Respiratory And Critical Care Medicine 2023, 511-525
A fundamental task of the respiratory system is to operate as a mechanical gas pump ensuring that fresh air gets in close contact with the blood circulating through the lung capillaries to achieve O2 and CO2 exchange. To ventilate the lungs, the respiratory muscles provide the pressure required to overcome the viscoelastic mechanical load of the respiratory system. From a mechanical viewpoint, the most relevant respiratory system properties are the resistance of the airways (R aw), and the compliance of the lung tissue (C L) and chest wall (C CW). Both airflow and lung volume changes in spontaneous breathing and mechanical ventilation are determined by applying the fundamental mechanical laws to the relationships between the pressures inside the respiratory system (at the airway opening, alveolar, pleural, and muscular) and R aw, C L, and C CW. These relationships also are the basis of the different methods available to measure respiratory mechanics during spontaneous and artificial ventilation. Whereas a simple mechanical model (R aw, C L, and C CW) describes the basic understanding of ventilation mechanics, more complex concepts (nonlinearity, inhomogeneous ventilation, or viscoelasticity) should be employed to better describe and measure ventilation mechanics in patients.Thieme. All rights reserved.
JTD Keywords: airway-resistance, alveolar, compliance, dilution, elastance, flow, inhomogeneous ventilation, input impedance, lung-volume, mechanical ventilation, monitoring, pendelluft, pleural pressure, respiratory-distress-syndrome, viscoelasticity, Chest-wall mechanics, Resistance
Moreno D, Buxadera-Palomero J, Ginebra MP, Manero JM, Martin-Gómez H, Mas-Moruno C, Rodríguez D, (2023). Comparison of the Antibacterial Effect of Silver Nanoparticles and a Multifunctional Antimicrobial Peptide on Titanium Surface International Journal Of Molecular Sciences 24, 9739
Titanium implantation success may be compromised by Staphylococcus aureus surface colonization and posterior infection. To avoid this issue, different strategies have been investigated to promote an antibacterial character to titanium. In this work, two antibacterial agents (silver nanoparticles and a multifunctional antimicrobial peptide) were used to coat titanium surfaces. The modulation of the nanoparticle (≈32.1 ± 9.4 nm) density on titanium could be optimized, and a sequential functionalization with both agents was achieved through a two-step functionalization method by means of surface silanization. The antibacterial character of the coating agents was assessed individually as well as combined. The results have shown that a reduction in bacteria after 4 h of incubation can be achieved on all the coated surfaces. After 24 h of incubation, however, the individual antimicrobial peptide coating was more effective than the silver nanoparticles or their combination against Staphylococcus aureus. All tested coatings were non-cytotoxic for eukaryotic cells.
JTD Keywords: antimicrobial peptide, biomaterials, bone, coatings, performance, ph, resistance, silanization, silver nanoparticles, staphylococcus aureus, Antimicrobial peptide, Reduces bacterial adhesion, Silanization, Silver nanoparticles, Staphylococcus aureus, Titanium functionalization
González-Callejo P, Gener P, Díaz-Riascos ZV, Conti S, Cámara-Sánchez P, Riera R, Mancilla S, García-Gabilondo M, Peg V, Arango D, Rosell A, Labernadie A, Trepat X, Albertazzi L, Schwartz S, Seras-Franzoso J, Abasolo I, (2023). Extracellular vesicles secreted by triple-negative breast cancer stem cells trigger premetastatic niche remodeling and metastatic growth in the lungs International Journal Of Cancer 152, 2153-2165
Tumor secreted extracellular vesicles (EVs) are potent intercellular signaling platforms. They are responsible for the accommodation of the premetastatic niche (PMN) to support cancer cell engraftment and metastatic growth. However, complex cancer cell composition within the tumor increases also the heterogeneity among cancer secreted EVs subsets, a functional diversity that has been poorly explored. This phenomenon is particularly relevant in highly plastic and heterogenous triple-negative breast cancer (TNBC), in which a significant representation of malignant cancer stem cells (CSCs) is displayed. Herein, we selectively isolated and characterized EVs from CSC or differentiated cancer cells (DCC; EVsCSC and EVsDCC , respectively) from the MDA-MB-231 TNBC cell line. Our results showed that EVsCSC and EVsDCC contain distinct bioactive cargos and therefore elicit a differential effect on stromal cells in the TME. Specifically, EVsDCC activated secretory cancer associated fibroblasts (CAFs), triggering IL-6/IL-8 signaling and sustaining CSC phenotype maintenance. Complementarily, EVsCSC promoted the activation of α-SMA+ myofibroblastic CAFs subpopulations and increased the endothelial remodeling, enhancing the invasive potential of TNBC cells in vitro and in vivo. In addition, solely the EVsCSC mediated signaling prompted the transformation of healthy lungs into receptive niches able to support metastatic growth of breast cancer cells.© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
JTD Keywords: chemoresistance, dormancy, drives, extracellular vesicles, invasion, plasticity, premetastatic niche, triple-negative breast cancer, tumor microenvironment, Cancer cell plasticity, Extracellular vesicles, Fibroblasts, Premetastatic niche, Triple-negative breast cancer, Tumor microenvironment
Palma-Florez S, López-Canosa A, Moralez-Zavala F, Castaño O, Kogan MJ, Samitier J, Lagunas A, Mir M, (2023). BBB-on-a-chip with integrated micro-TEER for permeability evaluation of multi-functionalized gold nanorods against Alzheimer's disease Journal Of Nanobiotechnology 21, 115
The lack of predictive models that mimic the blood-brain barrier (BBB) hinders the development of effective drugs for neurodegenerative diseases. Animal models behave differently from humans, are expensive and have ethical constraints. Organ-on-a-chip (OoC) platforms offer several advantages to resembling physiological and pathological conditions in a versatile, reproducible, and animal-free manner. In addition, OoC give us the possibility to incorporate sensors to determine cell culture features such as trans-endothelial electrical resistance (TEER). Here, we developed a BBB-on-a-chip (BBB-oC) platform with a TEER measurement system in close distance to the barrier used for the first time for the evaluation of the permeability performance of targeted gold nanorods for theranostics of Alzheimer's disease. GNR-PEG-Ang2/D1 is a therapeutic nanosystem previously developed by us consisting of gold nanorods (GNR) functionalized with polyethylene glycol (PEG), angiopep-2 peptide (Ang2) to overcome the BBB and the D1 peptide as beta amyloid fibrillation inhibitor, finally obtaining GNR-PEG-Ang2/D1 which showed to be useful for disaggregation of the amyloid in in vitro and in vivo models. In this work, we evaluated its cytotoxicity, permeability, and some indications of its impact on the brain endothelium by employing an animal-free device based on neurovascular human cells.In this work, we fabricated a BBB-oC with human astrocytes, pericytes and endothelial cells and a TEER measuring system (TEER-BBB-oC) integrated at a micrometric distance of the endothelial barrier. The characterization displayed a neurovascular network and the expression of tight junctions in the endothelium. We produced GNR-PEG-Ang2/D1 and determined its non-cytotoxic range (0.05-0.4 nM) for plated cells included in the BBB-oC and confirmed its harmless effect at the highest concentration (0.4 nM) in the microfluidic device. The permeability assays revealed that GNR-PEG-Ang2/D1 cross the BBB and this entry is facilitated by Ang2 peptide. Parallel to the permeability analysis of GNR-PEG-Ang2/D1, an interesting behavior of the TJs expression was observed after its administration probably related to the ligands on the nanoparticle surface.BBB-oC with a novel TEER integrated setup which allow a correct read-out and cell imaging monitoring was proven as a functional and throughput platform to evaluate the brain permeability performance of nanotherapeutics in a physiological environment with human cells, putting forward a viable alternative to animal experimentation.© 2023. The Author(s).
JTD Keywords: alzheimer disease (ad), cell-culture, cytotoxicity, endothelial-cells, gold nanoparticles, microfluidic platform, model, organ-on-a-chip (ooc), peptide, tight junction, trans-endothelial electrical resistance (teer), transport, Alzheimer disease (ad), Blood-brain barrier (bbb), Blood-brain-barrier, Blood–brain barrier (bbb), Gold nanoparticles, Organ-on-a-chip (ooc), Trans-endothelial electrical resistance (teer)
Sanmukh, Swapnil Ganesh, Admella, Joana, Moya-Andérico, Laura, Fehér, Tamás, Arévalo-Jaimes, Betsy Verónica, Blanco-Cabra, Núria, Torrents, Eduard, (2023). Accessing the In Vivo Efficiency of Clinically Isolated Phages against Uropathogenic and Invasive Biofilm-Forming Escherichia coli Strains for Phage Therapy Cells 12, 344
Escherichia coli is one of the most common members of the intestinal microbiota. Many of its strains are associated with various inflammatory infections, including urinary or gut infections, especially when displaying antibiotic resistance or in patients with suppressed immune systems. According to recent reports, the biofilm-forming potential of E. coli is a crucial factor for its increased resistance against antibiotics. To overcome the limitations of using antibiotics against resistant E. coli strains, the world is turning once more towards bacteriophage therapy, which is becoming a promising candidate amongst the current personalized approaches to target different bacterial infections. Although matured and persistent biofilms pose a serious challenge to phage therapy, they can still become an effective alternative to antibiotic treatment. Here, we assess the efficiency of clinically isolated phages in phage therapy against representative clinical uropathogenic and invasive biofilm-forming E. coli strains. Our results demonstrate that irrespective of host specificity, bacteriophages producing clear plaques with a high burst size, and exhibiting depolymerizing activity, are good candidates against biofilm-producing E. coli pathogens as verified from our in vitro and in vivo experiments using Galleria mellonella where survival was significantly increased for phage-therapy-treated larvae.
JTD Keywords: antibiotic resistance, assay, bacteriophage, bacteriophages, biofilm-forming potential, infection, inflammatory infections, mechanisms, Galleria-mellonella, Intestinal microflora
Renau-Mínguez C, Herrero-Abadía P, Ruiz-Rodriguez P, Sentandreu V, Torrents E, Chiner-Oms Á, Torres-Puente M, Comas I, Julián E, Coscolla M, (2023). Genomic analysis of Mycobacterium brumae sustains its nonpathogenic and immunogenic phenotype Frontiers In Microbiology 13, 982679
Mycobacterium brumae is a rapid-growing, non-pathogenic Mycobacterium species, originally isolated from environmental and human samples in Barcelona, Spain. Mycobacterium brumae is not pathogenic and it's in vitro phenotype and immunogenic properties have been well characterized. However, the knowledge of its underlying genetic composition is still incomplete. In this study, we first describe the 4 Mb genome of the M. brumae type strain ATCC 51384T assembling PacBio reads, and second, we assess the low intraspecies variability by comparing the type strain with Illumina reads from three additional strains. Mycobacterium brumae genome is composed of a circular chromosome with a high GC content of 69.2% and containing 3,791 CDSs, 97 pseudogenes, one prophage and no CRISPR loci. Mycobacterium brumae has shown no pathogenic potential in in vivo experiments, and our genomic analysis confirms its phylogenetic position with other non-pathogenic and rapid growing mycobacteria. Accordingly, we determined the absence of virulence-related genes, such as ESX-1 locus and most PE/PPE genes, among others. Although the immunogenic potential of M. brumae was proved to be as high as Mycobacterium bovis BCG, the only mycobacteria licensed to treat cancer, the genomic content of M. tuberculosis T cell and B cell antigens in M. brumae genome is considerably lower than those antigens present in M. bovis BCG genome. Overall, this work provides relevant genomic data on one of the species of the mycobacterial genus with high therapeutic potential.Copyright © 2023 Renau-Mínguez, Herrero-Abadía, Ruiz-Rodriguez, Sentandreu, Torrents, Chiner-Oms, Torres-Puente, Comas, Julián and Coscolla.
JTD Keywords: antimicrobial susceptibility, bcg, identification, immunogenic, non-pathogenic, nontuberculous mycobacteria, resistance mechanisms, strain, therapeutic, Diversity, Immunogenic, Non-pathogenic, Nontuberculous mycobacteria, Therapeutic
Vukomanovic, M, Gazvoda, L, Kurtjak, M, Hrescak, J, Jaklic, B, Moya-Anderico, L, Cendra, MD, Torrents, E, (2022). Development of a ternary cyclodextrin-arginine-ciprofloxacin antimicrobial complex with enhanced stability Commun Biol 5, 1234
Designing useful functionalities in clinically validated, old antibiotics holds promise to provide the most economical solution for the global lack of effective antibiotics, as undoubtedly a serious health threat. Here we show that using the surface chemistry of the cyclodextrin (beta CD) cycle and arginine (arg) as a linker, provides more stable ternary antibiotic complex (beta CD-arg-cpx). In contrast to classical less stable inclusion complexes, which only modify antibiotic solubility, here-presented ternary complex is more stable and controls drug release. The components of the complex intensify interactions with bacterial membranes and increase the drug's availability inside bacterial cells, thereby improving its antimicrobial efficacy and safety profile. Multifunctional antibiotics, formulated as drug delivery systems per se, that take the drug to the site of action, maximize its efficacy, and provide optical detectability are envisaged as the future in fighting against infections. Their role as a tool against multiresistant strains remains as interesting challenge open for further research.; Ternary cyclodextrin- arginine- ciprofloxacin complexes show improved stability and increased efficacy against P. aeruginosa in Galleria mellonella worms.
JTD Keywords: Antibiotic-resistance, Beta-cyclodextrin, Dissolution, Drugs, Salts
Mughal, S, Lopez-Munoz, GA, Fernandez-Costa, JM, Cortes-Resendiz, A, De Chiara, F, Ramon-Azcon, J, (2022). Organs-on-Chips: Trends and Challenges in Advanced Systems Integration Advanced Materials Interfaces 9, 2201618
Organ-on-chip platforms combined with high-throughput sensing technology allow bridging gaps in information presented by 2D cultures modeled on static microphysiological systems. While these platforms do not aim to replicate whole organ systems with all physiological nuances, they try to mimic relevant structural, physiological, and functional features of organoids and tissues to best model disease and/or healthy states. The advent of this platform has not only challenged animal testing but has also presented the opportunity to acquire real-time, high-throughput data about the pathophysiology of disease progression by employing biosensors. Biosensors allow monitoring of the release of relevant biomarkers and metabolites as a result of physicochemical stress. It, therefore, helps conduct quick lead validation to achieve personalized medicine objectives. The organ-on-chip industry is currently embarking on an exponential growth trajectory. Multiple pharmaceutical and biotechnology companies are adopting this technology to enable quick patient-specific data acquisition at substantially low costs.
JTD Keywords: A-chip, Biosensor, Biosensors, Cancer, Cells, Culture, Disease models, Epithelial electrical-resistance, Hydrogel, Microfabrication, Microphysiological systems, Models, Niches, Organ-on-a-chips, Platform
El Hauadi K, Resina L, Zanuy D, Esteves T, Ferreira FC, Pérez-Madrigal MM, Alemán C, (2022). Dendritic Self-assembled Structures from Therapeutic Charged Pentapeptides Langmuir 38, 12905-12914
CRENKA [Cys-Arg-(NMe)Glu-Lys-Ala, where (NMe)Glu refers to N-methyl-Glu], an anti-cancer pentapeptide that induces prostate tumor necrosis and significant reduction in tumor growth, was engineered to increase the resistance to endogenous proteases of its parent peptide, CREKA (Cys-Arg-Glu-Lys-Ala). Considering their high tendency to aggregate, the self-assembly of CRENKA and CREKA into well-defined and ordered structures has been examined as a function of peptide concentration and pH. Spectroscopic studies and atomistic molecular dynamics simulations reveal significant differences between the secondary structures of CREKA and CRENKA. Thus, the restrictions imposed by the (NMe)Glu residue reduce the conformational variability of CRENKA with respect to CREKA, which significantly affects the formation of well-defined and ordered self-assembly morphologies. Aggregates with poorly defined morphology are obtained from solutions with low and moderate CREKA concentrations at pH 4, whereas well-defined dendritic microstructures with fractal geometry are obtained from CRENKA solutions with similar peptide concentrations at pH 4 and 7. The formation of dendritic structures is proposed to follow a two-step mechanism: (1) pseudo-spherical particles are pre-nucleated through a diffusion-limited aggregation process, pre-defining the dendritic geometry, and (2) such pre-nucleated structures coalesce by incorporating conformationally restrained CRENKA molecules from the solution to their surfaces, forming a continuous dendritic structure. Instead, no regular assembly is obtained from solutions with high peptide concentrations, as their dynamics is dominated by strong repulsive peptide-peptide electrostatic interactions, and from solutions at pH 10, in which the total peptide charge is zero. Overall, results demonstrate that dendritic structures are only obtained when the molecular charge of CRENKA, which is controlled through the pH, favors kinetics over thermodynamics during the self-assembly process.
JTD Keywords: aggregation, amphiphilic peptides, breast-cancer, cells, design, oxidative stress, resistance, strategy, Molecular-dynamics
Mir, M, Palma-Florez, S, Lagunas, A, Lopez-Martinez, MJ, Samitier, J, (2022). Biosensors Integration in Blood-Brain Barrier-on-a-Chip: Emerging Platform for Monitoring Neurodegenerative Diseases Acs Sensors 7, 1237-1247
Over the most recent decades, the development of new biological platforms to study disease progression and drug efficacy has been of great interest due to the high increase in the rate of neurodegenerative diseases (NDDs). Therefore, blood-brain barrier (BBB) as an organ-on-a-chip (OoC) platform to mimic brain-barrier performance could offer a deeper understanding of NDDs as well as a very valuable tool for drug permeability testing for new treatments. A very attractive improvement of BBB-oC technology is the integration of detection systems to provide continuous monitoring of biomarkers in real time and a fully automated analysis of drug permeably, rendering more efficient platforms for commercialization. In this Perspective, an overview of the main BBB-oC configurations is introduced and a critical vision of the BBB-oC platforms integrating electronic read out systems is detailed, indicating the strengths and weaknesses of current devices, proposing the great potential for biosensors integration in BBB-oC. In this direction, we name potential biomarkers to monitor the evolution of NDDs related to the BBB and/or drug cytotoxicity using biosensor technology in BBB-oC.
JTD Keywords: biosensors, blood−brain barrier (bbb), neurodegenerative diseases (ndds), organ-on-a-chip (ooc), Bbb, Biosensors, Blood-brain barrier (bbb), Electrical-resistance, Electrochemical biosensors, Endothelial-cells, In-vitro model, Matrix metalloproteinases, Mechanisms, Neurodegenerative diseases (ndds), Organ-on-a-chip (ooc), Permeability, Stress, Transendothelial electrical resistance (teer), Transepithelial, Transepithelial/transendothelial electrical resistance (teer), Transport
Rätze, Max AK., Koorman, Thijs, Sijnesael, Thijmen, Bassey-Archibong, Blessing, van de Ven, Robert, Enserink, Lotte, Visser, Daan, Jaksani, Sridevi, Viciano, Ignacio, Bakker, Elvira RM., Richard, François, Tutt, Andrew, O’Leary, Lynda, Fitzpatrick, Amanda, Roca-Cusachs, Pere, van Diest, Paul J., Desmedt, Christine, Daniel, Juliet M., Isacke, Clare M., Derksen, Patrick WB., (2022). Loss of E-cadherin leads to Id2-dependent inhibition of cell cycle progression in metastatic lobular breast cancer Oncogene 41, 2932-2944
Invasive lobular breast carcinoma (ILC) is characterized by proliferative indolence and long-term latency relapses. This study aimed to identify how disseminating ILC cells control the balance between quiescence and cell cycle re-entry. In the absence of anchorage, ILC cells undergo a sustained cell cycle arrest in G0/G1 while maintaining viability. From the genes that are upregulated in anchorage independent ILC cells, we selected Inhibitor of DNA binding 2 (Id2), a mediator of cell cycle progression. Using loss-of-function experiments, we demonstrate that Id2 is essential for anchorage independent survival (anoikis resistance) in vitro and lung colonization in mice. Importantly, we find that under anchorage independent conditions, E-cadherin loss promotes expression of Id2 in multiple mouse and (organotypic) human models of ILC, an event that is caused by a direct p120-catenin/Kaiso-dependent transcriptional de-repression of the canonical Kaiso binding sequence TCCTGCNA. Conversely, stable inducible restoration of E-cadherin expression in the ILC cell line SUM44PE inhibits Id2 expression and anoikis resistance. We show evidence that Id2 accumulates in the cytosol, where it induces a sustained and CDK4/6-dependent G0/G1 cell cycle arrest through interaction with hypo-phosphorylated Rb. Finally, we find that Id2 is indeed enriched in ILC when compared to other breast cancers, and confirm cytosolic Id2 protein expression in primary ILC samples. In sum, we have linked mutational inactivation of E-cadherin to direct inhibition of cell cycle progression. Our work indicates that loss of E-cadherin and subsequent expression of Id2 drive indolence and dissemination of ILC. As such, E-cadherin and Id2 are promising candidates to stratify low and intermediate grade invasive breast cancers for the use of clinical cell cycle intervention drugs.
JTD Keywords: anoikis resistance, carcinoma, d1, differentiation, gene-expression, growth, id2, proliferation, repression, Mammary epithelial-cells
Montero, J, Haq, R, (2022). Adapted to Survive: Targeting Cancer Cells with BH3 Mimetics Cancer Discovery 12, 1217-1232
A hallmark of cancer is cell death evasion, underlying suboptimal responses to chemotherapy, targeted agents, and immunotherapies. The approval of the anti apoptotic BCL2 antagonist venetoclax has fi nally validated the potential of targeting apoptotic pathways in patients with cancer. Nevertheless, pharmacologic modulators of cell death have shown markedly varied responses in preclinical and clinical studies. Here, we review emerging concepts in the use of this class of therapies. Building on these observations, we propose that treatment-induced changes in apoptotic dependency, rather than pretreatment dependencies, will need to be recognized and targeted to realize the precise deployment of these new pharmacologic agents. Signifi cance: Targeting antiapoptotic family members has proven effi cacious and tolerable in some cancers, but responses are infrequent, particularly for patients with solid tumors. Biomarkers to aid patient selection have been lacking. Precision functional approaches that overcome adaptive resistance to these compounds could drive durable responses to chemotherapy, targeted therapy, and immunotherapies.
JTD Keywords: Anti-apoptotic mcl-1, Bcl-x-l, Bim expression, Chemotherapy sensitivity, Combination strategies, Family proteins, Multiple-myeloma, Oblimersen sodium, Phase-i, Venetoclax resistance
Alcon C, Martín F, Prada E, Mora J, Soriano A, Guillén G, Gallego S, Roma J, Samitier J, Villanueva A, Montero J, (2022). MEK and MCL-1 sequential inhibition synergize to enhance rhabdomyosarcoma treatment Cell Death Discov 8, 172
Targeted agents have emerged as promising molecules for cancer treatment, but most of them fail to achieve complete tumor regression or attain durable remissions due to tumor adaptations. We used dynamic BH3 profiling to identify targeted agents effectiveness and anti-apoptotic adaptations upon targeted treatment in rhabdomyosarcoma. We focused on studying the use of BH3 mimetics to specifically inhibit pro-survival BCL-2 family proteins, overwhelm resistance to therapy and prevent relapse. We observed that the MEK1/2 inhibitor trametinib rapidly depleted the pro-apoptotic protein NOXA, thus increasing MCL-1 availability. Indeed, we found that the MCL-1 inhibitor S63845 synergistically enhanced trametinib cytotoxicity in rhabdomyosarcoma cells in vitro and in vivo. In conclusion, our findings indicate that the combination of a BH3 mimetic targeting MCL-1 with trametinib improves efficiency on rhabdomyosarcoma by blocking tumor adaptation to treatment.
JTD Keywords: apoptosis, bcl-2, combination, expression, pathway, resistance, survival, therapy, tumors, Histone deacetylase inhibitor
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, e0097821
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.
JTD 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
Arque, X, Torres, MDT, Patino, T, Boaro, A, Sanchez, S, de la Fuente-Nunez, C, (2022). Autonomous Treatment of Bacterial Infections in Vivo Using Antimicrobial Micro- and Nanomotors Acs Nano 16, 7547-7558
The increasing resistance of bacteria to existing antibiotics constitutes a major public health threat globally. Most current antibiotic treatments are hindered by poor delivery to the infection site, leading to undesired off-target effects and drug resistance development and spread. Here, we describe micro- and nanomotors that effectively and autonomously deliver antibiotic payloads to the target area. The active motion and antimicrobial activity of the silica-based robots are driven by catalysis of the enzyme urease and antimicrobial peptides, respectively. These antimicrobial motors show micromolar bactericidal activity in vitro against different Gram-positive and Gram-negative pathogenic bacterial strains and act by rapidly depolarizing their membrane. Finally, they demonstrated autonomous anti-infective efficacy in vivo in a clinically relevant abscess infection mouse model. In summary, our motors combine navigation, catalytic conversion, and bactericidal capacity to deliver antimicrobial payloads to specific infection sites. This technology represents a much-needed tool to direct therapeutics to their target to help combat drug-resistant infections.
JTD Keywords: antibiotic-resistance, antimicrobial peptides, autonomous treatment, bacterial infection, delivery, ll-37, nanomotors, nanoparticles, peptide, self-propulsion, tissue, vitro, wasp venom, Antibiotic-resistance, Antimicrobial peptides, Autonomous treatment, Bacterial infection, Delivery, Ll-37, Mesoporous silica nanoparticles, Nanomotors, Nanoparticles, Peptide, Self-propulsion, Tissue, Vitro, Wasp venom
Farre, R, Rodriguez-Lazaro, MA, Gozal, D, Trias, G, Solana, G, Navajas, D, Otero, J, (2022). Simple low-cost construction and calibration of accurate pneumotachographs for monitoring mechanical ventilation in low-resource settings Frontiers Of Medicine 9, 938949
Assessing tidal volume during mechanical ventilation is critical to improving gas exchange while avoiding ventilator-induced lung injury. Conventional flow and volume measurements are usually carried out by built-in pneumotachographs in the ventilator or by stand-alone flowmeters. Such flow/volume measurement devices are expensive and thus usually unaffordable in low-resource settings. Here, we aimed to design and test low-cost and technically-simple calibration and assembly pneumotachographs. The proposed pneumotachographs are made by manual perforation of a plate with a domestic drill. Their pressure-volume relationship is characterized by a quadratic equation with parameters that can be tailored by the number and diameter of the perforations. We show that the calibration parameters of the pneumotachographs can be measured through two maneuvers with a conventional resuscitation bag and by assessing the maneuver volumes with a cheap and straightforward water displacement setting. We assessed the performance of the simplified low-cost pneumotachographs to measure flow/volume during mechanical ventilation as carried out under typical conditions in low-resource settings, i.e., lacking gold standard expensive devices. Under realistic mechanical ventilation settings (pressure- and volume-control; 200-600 mL), inspiratory tidal volume was accurately measured (errors of 2.1% on average and <4% in the worst case). In conclusion, a simple, low-cost procedure facilitates the construction of affordable and accurate pneumotachographs for monitoring mechanical ventilation in low- and middle-income countries.
JTD Keywords: calibration, flow measurement, low- and middle-income countries, mechanical ventilation, pneumotachograph, Calibration, Flow, Flow measurement, Low- and middle-income countries, Lung injury, Mechanical ventilation, Pneumotachograph, Pressure-drop, Resistance, Tidal volume
Molina-Fernandez, R, Picon-Pages, P, Barranco-Almohalla, A, Crepin, G, Herrera-Fernandez, V, Garcia-Elias, A, Fanlo-Ucar, H, Fernandez-Busquets, X, Garcia-Ojalvo, J, Oliva, B, Munoz, FJ, (2022). Differential regulation of insulin signalling by monomeric and oligomeric amyloid beta-peptide Brain Commun 4, fcac243
Alzheimer's disease and Type 2 diabetes are pathological processes associated to ageing. Moreover, there are evidences supporting a mechanistic link between Alzheimer's disease and insulin resistance (one of the first hallmarks of Type 2 diabetes). Regarding Alzheimer's disease, amyloid beta-peptide aggregation into beta-sheets is the main hallmark of Alzheimer's disease. At monomeric state, amyloid beta-peptide is not toxic but its function in brain, if any, is unknown. Here we show, by in silico study, that monomeric amyloid beta-peptide 1-40 shares the tertiary structure with insulin and is thereby able to bind and activate insulin receptor. We validated this prediction experimentally by treating human neuroblastoma cells with increasing concentrations of monomeric amyloid. beta-peptide 1-40. Our results confirm that monomeric amyloid beta-peptide 1-40 activates insulin receptor autophosphorylation, triggering downstream enzyme phosphorylarions and the glucose Transporter 4 translocation to the membrane. On the other hand, neuronal insulin resistance is known to be associated to Alzheimer's disease since early stages. We thus modelled the docking of oligomeric amyloid peptide 1-40 to insulin receptor. We found that oligomeric amyloid. beta-peptide 1-40 blocks insulin receptor, impairing its activation. It was confirmed in vitro by observing the lack of insulin receptor autophosphorylation, and also the impairment of insulin-induced intracellular enzyme activations and the glucose Transporter 4 translocation to the membrane. By biological system analysis, we have carried out a mathematical model recapitulating the process that turns amyloid beta-peptide binding to insulin receptor from the physiological to the pathophysiological regime. Our results suggest that monomeric amyloid beta-peptide 1-40 contributes to mimic insulin effects in the brain, which could be good when neurons have an extra requirement of energy beside the well-known protective effects on insulin intracellular signalling, while its accumulation and subsequent oligomerization blocks the insulin receptor producing insulin resistance and compromising neuronal metabolism and protective pathways.
JTD Keywords: akt, alzheimer’s disease, amyloid β-peptide, insulin, A-beta, Aggregation, Akt, Alzheimer's disease, Alzheimers-disease, Amyloid beta-peptide, Brain, Design, Insulin, Insulin resistance, Precursor protein, Protein-protein docking, Receptor, Resistance, Site
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.
JTD 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, 695225
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.
JTD 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
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, 62
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.
JTD Keywords: cells, model, resistance, shear, technology, In-vitro
Cendra MdM, Torrents E, (2021). Pseudomonas aeruginosa biofilms and their partners in crime Biotechnology Advances 49, 107734
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.
JTD 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
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.
JTD 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
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, 124
© 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.
JTD Keywords: antibiotic resistance, bacteriophages, Antibiotic resistance, Bacteriophages, Endolysin
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, 34-48
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.
JTD 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
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, 112274
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.
JTD Keywords: drug repurposing, inflammation, macrophage, nrf2, Apoptosis, Breast-cancer, Drug repurposing, Expression, Inflammation, Macrophage, Nrf2, Resistance, Sex-differences, Tamoxifen, Tumor-associated macrophages
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.
JTD 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 Î±-up or a Î²-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.
JTD 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.
JTD 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.
JTD 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 10cmH
JTD 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.
JTD 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.
JTD 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.
JTD 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.
JTD 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.
JTD Keywords: Resistance