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Introduction: Bladder cancer is a common neoplasia of the urinary tract that holds the highest cost of lifelong treatment per patient, highlighting the need for a continuous search for new therapies for the disease. Current bladder cancer models are either imperfect in their ability to translate results to clinical practice (mouse models), or rare and not inducible (canine models). Swine models are an attractive alternative to model the disease due to their similarities with humans on several levels. The Oncopig Cancer Model has been shown to develop tumors that closely resemble human tumors. However, urothelial carcinoma has not yet been studied in this platform. Methods: We aimed to develop novel Oncopig bladder cancer cell line (BCCL) and investigate whether these urothelial swine cells mimic human bladder cancer cell line (5637 and T24) treatment-responses to cisplatin, doxorubicin, and gemcitabine in vitro. Results: Results demonstrated consistent treatment responses between Oncopig and human cells in most concentrations tested (p>0.05). Overall, Oncopig cells were more predictive of T24 than 5637 cell therapeutic responses. Microarray analysis also demonstrated similar alterations in expression of apoptotic (GADD45B and TP53INP1) and cytoskeleton-related genes (ZMYM6 and RND1) following gemcitabine exposure between 5637 (human) and Oncopig BCCL cells, indicating apoptosis may be triggered through similar signaling pathways. Molecular docking results indicated that swine and humans had similar Dg values between the chemotherapeutics and their target proteins. Discussion: Taken together, these results suggest the Oncopig could be an attractive animal to model urothelial carcinoma due to similarities in in vitro therapeutic responses compared to human cells.
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OBJECTIVE: Evaluate injury trends in Brazilian Jiu Jitsu (BJJ) participation by presenting to U.S. emergency departments over a 10-year period and formulate an injury profile. METHODS: The U.S. Consumer Product Safety Commission's (CPSC) National Electronic Injury Surveillance System (NEISS) database was queried for martial arts related injuries from 1 January 2012 to 31 December 2021. Codes and narratives were examined to compile data for patients sustaining BJJ-related injuries. RESULTS: From 1 January 2012 to 31 December 2021 there were 7,722 (NE = 282,315) ED-diagnosed martial arts related injuries with 911 (NE = 36,023) BJJ-related injuries identified. Regression analysis demonstrated an increasing trend in the annual incidence of Brazilian Jiu Jitsu injuries presenting to the ED (R2 = 0.934; SE = 2.069: p < .0001). Average age was 25.68 years of age (range 4-83). The most common injury diagnoses were sprains/strains and other/not listed at 27.68% and 26.39%. The most commonly injured body parts were the upper trunk, and the shoulder comprising 13.66% and 12.14% of injured body parts, respectively. The most commonly fractured region was toes, at 14.15% of all fractures. The most common dislocations occurred at the shoulder and knee, at 32.49% and 28.45% of dislocations, respectively. The most common mechanisms of injury specifically identified were indeterminate contact between players, fall onto ground, or fall onto another player comprising 18.62% and 17.17%, of injuries, respectively. CONCLUSION: There was an increasing trend of BJJ-related injuries presenting to U.S. Emergency Departments. The most common diagnoses and body parts injured were sprains/strains and upper trunk and shoulder, respectively. The most commonly fractured and dislocated regions were toes and shoulder, respectively. The most common mechanisms of injury were indeterminate contact or falling. This study provides novel information concerning trends in injury and injury profiles for Brazilian Jiu Jitsu related injuries.
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Traumatismos en Atletas , Fracturas Óseas , Luxaciones Articulares , Artes Marciales , Esguinces y Distensiones , Humanos , Preescolar , Niño , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Traumatismos en Atletas/epidemiología , Brasil/epidemiología , Artes Marciales/lesiones , Servicio de Urgencia en Hospital , Fracturas Óseas/epidemiologíaRESUMEN
PURPOSE: This article, the first in a 2-part review, aims to reinforce current literature on the pathophysiology of cardiac arrhythmias and various evidence-based treatment approaches and clinical considerations in the acute care setting. Part 1 of this series focuses on atrial arrhythmias. SUMMARY: Arrhythmias are prevalent throughout the world and a common presenting condition in the emergency department (ED) setting. Atrial fibrillation (AF) is the most common arrhythmia worldwide and expected to increase in prevalence. Treatment approaches have evolved over time with advances in catheter-directed ablation. Based on historic trials, heart rate control has been the long-standing accepted outpatient treatment modality for AF, but the use of antiarrhythmics is often still indicated for AF in the acute setting, and ED pharmacists should be prepared and poised to help in AF management. Other atrial arrhythmias include atrial flutter (AFL), atrioventricular nodal reentry tachycardia (AVNRT), and atrioventricular reentrant tachycardia (AVRT), which warrant distinction due to their unique pathophysiology and because each requires a different approach to utilization of antiarrhythmics. Atrial arrhythmias are typically associated with greater hemodynamic stability than ventricular arrhythmias but still require nuanced management according to patient subset and risk factors. Since antiarrhythmics can also be proarrhythmic, they may destabilize the patient due to adverse effects, many of which are the focus of black-box label warnings that can be overreaching and limit treatment options. Electrical cardioversion for atrial arrhythmias is generally successful and, depending on the setting and/or hemodynamics, often indicated. CONCLUSION: Atrial arrhythmias arise from a variety of mechanisms, and appropriate treatment depends on various factors. A firm understanding of physiological and pharmacological concepts serves as a foundation for exploring evidence supporting agents, indications, and adverse effects in order to provide appropriate care for patients.
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Fibrilación Atrial , Aleteo Atrial , Taquicardia por Reentrada en el Nodo Atrioventricular , Taquicardia Supraventricular , Humanos , Adulto , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/terapia , Fibrilación Atrial/complicaciones , Taquicardia Supraventricular/terapia , Aleteo Atrial/diagnóstico , Aleteo Atrial/terapia , Taquicardia por Reentrada en el Nodo Atrioventricular/complicaciones , Taquicardia por Reentrada en el Nodo Atrioventricular/cirugía , Antiarrítmicos/uso terapéuticoRESUMEN
A critical question is whether agroecology can promote climate change mitigation and adaptation outcomes without compromising food security. We assessed the outcomes of smallholder agricultural systems and practices in low- and middle-income countries (LMICs) against 35 mitigation, adaptation, and yield indicators by reviewing 50 articles with 77 cases of agroecological treatments relative to a baseline of conventional practices. Crop yields were higher for 63% of cases reporting yields. Crop diversity, income diversity, net income, reduced income variability, nutrient regulation, and reduced pest infestation, indicators of adaptative capacity, were associated with 70% or more of cases. Limited information on climate change mitigation, such as greenhouse gas emissions and carbon sequestration impacts, was available. Overall, the evidence indicates that use of organic nutrient sources, diversifying systems with legumes and integrated pest management lead to climate change adaptation in multiple contexts. Landscape mosaics, biological control (e.g., enhancement of beneficial organisms) and field sanitation measures do not yet have sufficient evidence based on this review. Widespread adoption of agroecological practices and system transformations shows promise to contribute to climate change services and food security in LMICs. Gaps in adaptation and mitigation strategies and areas for policy and research interventions are finally discussed.
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Cambio Climático , Gases de Efecto Invernadero , Agricultura , Adaptación Fisiológica , NutrientesRESUMEN
Deforestation threatens the integrity of the Amazon biome and the ecosystem services it provides, including greenhouse gas mitigation. Forest-to-pasture conversion has been shown to alter the flux of methane gas (CH4 ) in Amazonian soils, driving a switch from acting as a sink to a source of atmospheric CH4 . This study aimed to better understand this phenomenon by investigating soil microbial metagenomes, focusing on the taxonomic and functional structure of methane-cycling communities. Metagenomic data from forest and pasture soils were combined with measurements of in situ CH4 fluxes and soil edaphic factors and analysed using multivariate statistical approaches. We found a significantly higher abundance and diversity of methanogens in pasture soils. As inferred by co-occurrence networks, these microorganisms seem to be less interconnected within the soil microbiota in pasture soils. Metabolic traits were also different between land uses, with increased hydrogenotrophic and methylotrophic pathways of methanogenesis in pasture soils. Land-use change also induced shifts in taxonomic and functional traits of methanotrophs, with bacteria harbouring genes encoding the soluble form of methane monooxygenase enzyme (sMMO) depleted in pasture soils. Redundancy analysis and multimodel inference revealed that the shift in methane-cycling communities was associated with high pH, organic matter, soil porosity and micronutrients in pasture soils. These results comprehensively characterize the effect of forest-to-pasture conversion on the microbial communities driving the methane-cycling microorganisms in the Amazon rainforest, which will contribute to the efforts to preserve this important biome.
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Microbiota , Suelo , Suelo/química , Metano/metabolismo , Bosques , Genes Bacterianos , Microbiota/genética , Microbiología del SueloRESUMEN
The Amazon rainforest is a biodiversity hotspot and large terrestrial carbon sink threatened by agricultural conversion. Rainforest-to-pasture conversion stimulates the release of methane, a potent greenhouse gas. The biotic methane cycle is driven by microorganisms; therefore, this study focused on active methane-cycling microorganisms and their functions across land-use types. We collected intact soil cores from three land use types (primary rainforest, pasture, and secondary rainforest) of two geographically distinct areas of the Brazilian Amazon (Santarém, Pará and Ariquemes, Rondônia) and performed DNA stable-isotope probing coupled with metagenomics to identify the active methanotrophs and methanogens. At both locations, we observed a significant change in the composition of the isotope-labeled methane-cycling microbial community across land use types, specifically an increase in the abundance and diversity of active methanogens in pastures. We conclude that a significant increase in the abundance and activity of methanogens in pasture soils could drive increased soil methane emissions. Furthermore, we found that secondary rainforests had decreased methanogenic activity similar to primary rainforests, and thus a potential to recover as methane sinks, making it conceivable for forest restoration to offset greenhouse gas emissions in the tropics. These findings are critical for informing land management practices and global tropical rainforest conservation.
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Bosque Lluvioso , Suelo , Brasil , Metano , Microbiología del SueloRESUMEN
Amazonian rainforest is undergoing increasing rates of deforestation, driven primarily by cattle pasture expansion. Forest-to-pasture conversion has been associated with increases in soil methane (CH4) emission. To better understand the drivers of this change, we measured soil CH4 flux, environmental conditions, and belowground microbial community structure across primary forests, cattle pastures, and secondary forests in two Amazonian regions. We show that pasture soils emit high levels of CH4 (mean: 3454.6 ± 9482.3 µg CH4 m-2 d-1), consistent with previous reports, while forest soils on average emit CH4 at modest rates (mean: 9.8 ± 120.5 µg CH4 m-2 d-1), but often act as CH4 sinks. We report that secondary forest soils tend to consume CH4 (mean: -10.2 ± 35.7 µg CH4 m-2 d-1), demonstrating that pasture CH4 emissions can be reversed. We apply a novel computational approach to identify microbial community attributes associated with flux independent of soil chemistry. While this revealed taxa known to produce or consume CH4 directly (i.e. methanogens and methanotrophs, respectively), the vast majority of identified taxa are not known to cycle CH4. Each land use type had a unique subset of taxa associated with CH4 flux, suggesting that land use change alters CH4 cycling through shifts in microbial community composition. Taken together, we show that microbial composition is crucial for understanding the observed CH4 dynamics and that microorganisms provide explanatory power that cannot be captured by environmental variables.
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Metano , Suelo , Animales , Brasil , Bovinos , Bosques , Microbiología del SueloRESUMEN
Approximately 90% of bladder carcinomas are of the urothelial carcinoma type, which are characterized by high rates of recurrence and predisposition to progress to invasive tumors, representing one of the most costly neoplasms for health systems. Intravesical chemotherapy is a standard for the treatment of non-invasive bladder cancer. However, chemotherapy is usually aggressive and cytotoxic, which increases the death rates caused by cancer. Heterocyclic compounds which exhibit favorable pharmacokinetic and pharmacodynamic properties may enhance drug affinity for a target protein by targeting the treatment. Thus, this work presents the synthesis, characterization, and in vitro biological evaluation of new antioxidant (inhibition of lipid peroxidation, scavenging of free radical DPPH, and thiol peroxidase-like activity) and antiproliferative chalcogenobiotin derivatives and tests them against bladder carcinoma 5637 cells. A prominent response was obtained for the selected compounds, with tellurium biotin derivatives displaying effective antioxidant and antiproliferative activity. The effective compounds also demonstrated no toxicity in in vitro or in vivo studies.
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Antineoplásicos/farmacología , Antioxidantes/farmacología , Calcógenos/farmacología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Vejiga Urinaria/efectos de los fármacos , Antineoplásicos/síntesis química , Antineoplásicos/química , Antioxidantes/síntesis química , Antioxidantes/química , Compuestos de Bifenilo/antagonistas & inhibidores , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Calcógenos/síntesis química , Calcógenos/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Peroxidación de Lípido/efectos de los fármacos , Estructura Molecular , Picratos/antagonistas & inhibidores , Relación Estructura-Actividad , Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
In the present study, the antitumoral properties of a series of 7-chloroquinoline-1,2,3-triazoyl-carboxamides (QTCA) were investigated by analyzing their cytotoxic activities against human bladder cells (5637; grade II carcinoma). In addition, their effects on cell viability, cell cycle arrest mechanisms, apoptosis induction, in silico molecular docking, and detection of pro-apoptotic and anti-apoptotic proteins were evaluated. The cytotoxicity assay identified major dose- and time-dependent cytotoxic effects in 5637 cells after they were exposed to treatment with QTCA, only minimal effects were observed on normal cells. A live/dead assay confirmed that significant cell death, arrest in the G0/G1 phase and apoptosis were associated with treatment by 1-(7-Chloroquinolin-4-yl)-5-methyl-N-phenyl-1H-1,2,3-triazole-4-carboxamide (QTCA-1) and 1-(7-Chloroquinolin-4-yl)-N-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide (QTCA-4). The in silico results indicated that these compounds acted through different mechanisms for the induction of cell cycle arrest and apoptosis. Western blotting confirmed the binding of the QTCAs to pro- and anti-apoptotic proteins. In conclusion, QTCA-1 and QTCA-4 are promising candidates for inducing cytotoxicity, cell cycle arrest, and apoptosis in human bladder cancer cells.
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Amidas/farmacología , Quinolinas/farmacología , Triazoles/farmacología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Humanos , Simulación del Acoplamiento Molecular , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Neoplasias de la Vejiga Urinaria/metabolismoRESUMEN
Melanoma is the most aggressive form of skin cancer, with a high mortality rate and with 96,480 new cases expected in 2019 in the USS. BRAFV600E, the most common driver mutation, is found in around 50% of melanomas, contributing to tumor growth, angiogenesis, and metastatic progression. Dacarbazine (DTIC), an alkylate agent, was the first chemotherapeutic agent approved by the US Food and Drug Administration (FDA) used as a standard treatment. Since then, immunotherapies have been approved for metastatic melanoma (MM) including ipilimumab and pembrolizumab checkpoint inhibitors that help decrease the risk of progression. Moreover, Mycobacterium bovis Bacillus Calmette-Guerin (BCG) serves as an adjuvant therapy that induces the recruitment of natural killer NK, CD4+, and CD8+ T cells and contributes to antitumor immunity. BCG can be administered in combination with chemotherapeutic and immunotherapeutic agents and can be genetically manipulated to produce recombinant BCG (rBCG) strains that express heterologous proteins or overexpress immunogenic proteins, increasing the immune response and improving patient survival. In this review, we highlight several studies utilizing rBCG immunotherapy for MM in combination with other therapeutic agents.
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Vacuna BCG/administración & dosificación , Vacuna BCG/inmunología , Factores Inmunológicos/administración & dosificación , Inmunoterapia/métodos , Melanoma/terapia , Terapia Combinada/métodos , Humanos , Metástasis de la Neoplasia/terapiaRESUMEN
The global incidence of cancer is rising rapidly and continues to be one of the leading causes of death in the world. Melanoma deserves special attention since it represents one of the fastest growing types of cancer, with advanced metastatic forms presenting high mortality rates due to the development of drug resistance. The aim of this review is to evaluate how the screening of drugs and compounds for melanoma has been performed over the last seven decades. Thus, we performed literature searches to identify melanoma drug screening methods commonly used by research groups during this timeframe. In vitro and in vivo tests are essential for the development of new drugs; however, incorporation of in silico analyses increases the possibility of finding more suitable candidates for subsequent tests. In silico techniques, such as molecular docking, represent an important and necessary first step in the screening process. However, these techniques have not been widely used by research groups to date. Our research has shown that the vast majority of research groups still perform in vitro and in vivo tests, with emphasis on the use of in vitro enzymatic tests on melanoma cell lines such as SKMEL and in vivo tests using the B16 mouse model. We believe that the union of these three approaches (in silico, in vitro, and in vivo) is essential for improving the discovery and development of new molecules with potential antimelanoma action. This workflow would provide greater confidence and safety for preclinical trials, which will translate to more successful clinical trials and improve the translatability of new melanoma treatments into clinical practice while minimizing the unnecessary use of laboratory animals under the principles of the 3R's.
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Síndrome de Down/genética , Polimorfismo de Nucleótido Simple , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , California/epidemiología , California/etnología , Estudios de Casos y Controles , Niño , Preescolar , Cromosomas Humanos Par 21/genética , Síndrome de Down/complicaciones , Síndrome de Down/etnología , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Guatemala/epidemiología , Guatemala/etnología , Haplotipos , Hispánicos o Latinos , Humanos , Lactante , Recién Nacido , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/etnología , Análisis de Componente Principal , Factores de Riesgo , Regulador Transcripcional ERG/genéticaRESUMEN
BACKGROUND: There is wide variability of transfusion practices for children with hemorrhagic injuries across trauma centers. We are planning a multicenter, randomized clinical trial evaluating tranexamic acid in children with hemorrhage. Standardization of transfusion practices across sites is important to minimize confounding. Therefore, we sought to generate consensus-based transfusion guidelines for the trial. METHODS: We used a modified Delphi process utilizing a multi-site, multi-disciplinary panel of experts to develop our transfusion guidelines. A survey of 23 clinical categories on various aspects of transfusion practices was developed and distributed via SurveyMonkey®. Statements were graded on a 5-point Likert scale ("Strongly agree" to "This intervention may be harmful"). Statements were accepted if ≥ 80% of the panelists rated the statement as "Strongly agree" or "Agree". After each round, the responses were calculated and the results included on subsequent rounds. RESULTS: 35 panelists from four pediatric trauma centers participated in the study, including 11 (31%) pediatric EM physicians, 8 (23%) pediatric trauma surgeons, 5 (14%) transfusionists, 5 (14%) pediatric anesthesiologists, and 6 (17%) pediatric critical care physicians (range of 8 to 10 from each clinical site). Four survey iterations were performed. In total 176 statements were rated and 39 were accepted by criteria across all 23 categories. An rational algorithm for transfusion in trauma was then developed. CONCLUSIONS: We successfully developed transfusion guidelines for various aspects of the management of children with hemorrhagic injuries using a modified Delphi process with broad interdisciplinary participation. We anticipate implementation of these guidelines will help minimize heterogeneity of transfusion practices across clinical sites for the upcoming clinical trial evaluating tranexamic acid in children with hemorrhage.
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Transfusión Sanguínea/métodos , Hemorragia , Ácido Tranexámico/uso terapéutico , Heridas y Lesiones/complicaciones , Antifibrinolíticos/uso terapéutico , Niño , Consenso , Técnica Delphi , Hemorragia/etiología , Hemorragia/terapia , Humanos , Pediatría/métodos , Pediatría/normas , Guías de Práctica Clínica como Asunto , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
CuA is a binuclear copper site acting as electron entry port in terminal heme-copper oxidases. In the oxidized form, CuA is a mixed valence pair whose electronic structure can be described using a potential energy surface with two minima, σu* and πu, that are variably populated at room temperature. We report that mutations in the first and second coordination spheres of the binuclear metallocofactor can be combined in an additive manner to tune the energy gap and, thus, the relative populations of the two lowest-lying states. A series of designed mutants span σu*/πu energy gaps ranging from 900 to 13 cm-1. The smallest gap corresponds to a variant with an effectively degenerate ground state. All engineered sites preserve the mixed-valence character of this metal center and the electron transfer functionality. An increase of the Cu-Cu distance less than 0.06 Å modifies the σu*/πu energy gap by almost 2 orders of magnitude, with longer distances eliciting a larger population of the πu state. This scenario offers a stark contrast to synthetic systems, as model compounds require a lengthening of 0.5 Å in the Cu-Cu distance to stabilize the πu state. These findings show that the tight control of the protein environment allows drastic perturbations in the electronic structure of CuA sites with minor geometric changes.
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Proteínas Bacterianas/química , Complejos de Coordinación/química , Cobre/química , Grupo Citocromo b/química , Complejo IV de Transporte de Electrones/química , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Proteínas Bacterianas/genética , Grupo Citocromo b/genética , Complejo IV de Transporte de Electrones/genética , Electrones , Estructura Molecular , Ingeniería de Proteínas , Subunidades de Proteína/química , Alineación de Secuencia , Termodinámica , Thermus thermophilus/enzimologíaRESUMEN
OBJECTIVE The authors of this study found that, given the latency period required for arteriovenous malformation (AVM) obliteration after stereotactic radiosurgery (SRS), a study with limited follow-up cannot assess the benefit of SRS for unruptured AVMs. METHODS The authors reviewed their institutional experience with "ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous Malformations)-eligible" AVMs treated with SRS between 1987 and 2016, with the primary outcome defined as stroke (ischemic or hemorrhagic) or death (AVM related or AVM unrelated). Patients with at least 3 years of follow-up in addition to those who experienced stroke or died during the latency period were included. Secondary outcome measures included obliteration rates, patients with new seizure disorders, and those with new focal deficits without stroke. RESULTS Of 233 patients included in this study, 32 had a stroke or died after SRS over the mean 8.4-year follow-up (14%). Utilizing the 10% stroke or death rate at a mean 2.8-year follow-up for untreated AVMs in ARUBA, the rate in the authors' study is significantly lower than that anticipated at the 8.4-year follow-up for an untreated cohort (14% vs 30%, p = 0.0003). Notwithstanding obliteration, in this study, annualized rates of hemorrhage and stroke or death after 3 years following SRS were 0.4% and 0.8%, respectively. The overall obliteration rate was 72%; new seizure disorders, temporary new focal deficits without stroke, and permanent new focal deficits without stroke occurred in 2% of patients each. CONCLUSIONS After a sensible follow-up period exceeding the latency period, there is a lower rate of stroke/death for patients with treated, unruptured AVMs with SRS than for patients with untreated AVMs.
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Malformaciones Arteriovenosas Intracraneales/cirugía , Procedimientos Neuroquirúrgicos , Radiocirugia , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Malformaciones Arteriovenosas Intracraneales/complicaciones , Malformaciones Arteriovenosas Intracraneales/mortalidad , Hemorragias Intracraneales/epidemiología , Hemorragias Intracraneales/etiología , Hemorragias Intracraneales/mortalidad , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , Convulsiones/etiología , Accidente Cerebrovascular/etiología , Resultado del TratamientoRESUMEN
The screening of potential therapeutic compounds using phenotypic drug discovery (PDD) is being embraced once again by researchers and pharmaceutical companies as an approach to enhance the development of new effective therapeutics. Before the genomics and molecular biology era and the consecutive emergence of targeted-drug discovery approaches, PDD was the most common platform used for drug discovery. PDD, also known as phenotypic screening, consists of screening potential compounds in either in vitro cellular or in vivo animal models to identify compounds resulting in a desirable phenotypic change. Using this approach, the biological targets of the compounds are not taken into consideration. Suitable animal models are crucial for the continued validation and discovery of new drugs, as compounds displaying promising results in phenotypic in vitro cell-based and in vivo small animal model screenings often fail in clinical trials. Indeed, this is mainly a result of differential anatomy, physiology, metabolism, immunology, and genetics between humans and currently used pre-clinical small animal models. In contrast, pigs are more predictive of therapeutic treatment outcomes in humans than rodents. In addition, pigs provide an ideal platform to study cancer due to their similarities with humans at the anatomical, physiological, metabolic, and genetic levels. Here we provide a mini-review on the reemergence of PDD in drug development, highlighting the potential of porcine cancer models for improving pre-clinical drug discovery and testing. We also present precision medicine based genetically defined swine cancer models developed to date and their potential as biomedical models.
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In plant-animal mutualisms, how an animal forages often determines how much benefit its plant partner receives. In many animals, foraging behaviour changes in response to foraging gene expression or activation of the cGMP-dependent protein kinase (PKG) that foraging encodes. Here, we show that this highly conserved molecular mechanism affects the outcome of a plant-animal mutualism. We studied the two PKG genes of Allomerus octoarticulatus, an Amazonian ant that defends the ant-plant Cordia nodosa against herbivores. Some ant colonies are better 'bodyguards' than others. Working in the field in Peru, we found that colonies fed with a PKG activator recruited more workers to attack herbivores than control colonies. This resulted in less herbivore damage. PKG gene expression in ant workers correlated with whether an ant colony discovered an herbivore and how much damage herbivores inflicted on leaves in a complex way; natural variation in expression levels of the two genes had significant interaction effects on ant behaviour and herbivory. Our results suggest a molecular basis for ant protection of plants in this mutualism.
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Hormigas/genética , Cordia , Proteínas Quinasas Dependientes de GMP Cíclico/genética , Herbivoria , Simbiosis , Animales , Hormigas/enzimología , Genes de Insecto , PerúRESUMEN
BACKGROUND: Sinonasal bitter taste receptors (T2Rs) contribute to upper airway innate immunity and correlate with chronic rhinosinusitis (CRS) clinical outcomes. A subset of T2Rs expressed on sinonasal solitary chemosensory cells (SCCs) are activated by denatonium, resulting in a calcium-mediated secretion of bactericidal antimicrobial peptides (AMPs) in neighboring ciliated epithelial cells. We hypothesized that there is patient variability in the amount of bacterial killing induced by different concentrations of denatonium and that the differences correlate with CRS clinical outcomes. METHODS: Bacterial growth inhibition was quantified after mixing bacteria with airway surface liquid (ASL) collected from denatonium-stimulated sinonasal air-liquid interface (ALI) cultures. Patient ASL bacterial killing at 0.1 mM denatonium and baseline characteristics and sinus surgery outcomes were compared between these populations. RESULTS: There is variability in the degree of denatonium-induced bacterial killing between patients. In CRS with nasal polyps (CRSwNP), patients with increased bacterial killing after stimulation with low levels of denatonium undergo significantly more functional endoscopic sinus surgeries (FESSs) (p = 0.037) and have worse 6-month post-FESS 22-item Sino-Nasal Outcome Test (SNOT-22) scores (p = 0.012). CONCLUSION: Bacterial killing after stimulation with low levels of denatonium correlates with number of prior FESS and postoperative SNOT-22 scores in CRSwNP. Some symptoms of CRS in patients with hyperresponsiveness to low levels of denatonium may be due to increased airway immune activity or inherent disease severity.
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Cilios/metabolismo , Pólipos Nasales/inmunología , Infecciones por Pseudomonas/inmunología , Pseudomonas aeruginosa/fisiología , Compuestos de Amonio Cuaternario/metabolismo , Rinitis/inmunología , Sinusitis/inmunología , Péptidos Catiónicos Antimicrobianos/metabolismo , Bacteriólisis , Señalización del Calcio , Procesos de Crecimiento Celular , Células Cultivadas , Enfermedad Crónica , Cilios/patología , Progresión de la Enfermedad , Endoscopía , Femenino , Humanos , Inmunidad Innata , Masculino , Pólipos Nasales/microbiología , Rinitis/microbiología , Sinusitis/microbiología , Resultado del TratamientoRESUMEN
Recently, liquid crystalline elastomers (LCEs) have been proposed as active substrates for cell culture due to their potential to attach and orient cells, and impose dynamic mechanical signals through the application of external stimuli. In this report, the preparation of anisotropic and oriented nematic magnetic-sensitized LCEs with iron oxide nanoparticles, and the evaluation of the effect of particle addition at low concentrations on the resultant structural, thermal, thermo-mechanical, and mechanical properties is presented. Phase transformations produced by heating in alternating magnetic fields were investigated in LCEs in contact with air, water, and a common liquid cell culture medium was also evaluated. The inclusion of nanoparticles into the elastomers displaced the nematic-to-isotropic phase transition, without affecting the nematic structure as evidenced by similar values of the order parameter, while reducing the maximum thermomechanical deformations. Remote and reversible deformations of the magnetic LCEs were achieved through the application of alternating magnetic fields, which induces the nematic-isotropic phase transition through nanoparticle heat generation. Formulation parameters can be modified to allow for remote actuation at values closer to the human physiological temperature range and within the range of deformations that can affect the cellular behavior of fibroblasts. Finally, a collagen surface treatment was performed to improve compatibility with NIH-3T3 fibroblast cultures, which enabled the attachment and proliferation of fibroblasts on substrates with and without magnetic particles under quiescent conditions. The LCEs developed in this work, which are able to deform and experience stress changes by remote contact-less magnetic stimulation, may allow for further studies on the effect of substrate morphology changes and dynamic mechanical properties during in vitro cell culture.
Asunto(s)
Elastómeros/química , Cristales Líquidos/química , Nanocompuestos/química , Animales , Adhesión Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Compuestos Férricos/química , Nanopartículas de Magnetita/química , Nanopartículas de Magnetita/toxicidad , Ratones , Microscopía Confocal , Células 3T3 NIH , Nanocompuestos/toxicidad , TemperaturaRESUMEN
Members of the phylum Acidobacteria are among the most abundant soil bacteria on Earth, but little is known about their response to environmental changes. We asked how the relative abundance and biogeographic patterning of this phylum and its subgroups responded to forest-to-pasture conversion in soils of the western Brazilian Amazon. Pyrosequencing of 16S rRNA genes was employed to assess the abundance and composition of the Acidobacteria community across 54 soil samples taken using a spatially nested sampling scheme at the landscape level. Numerically, Acidobacteria represented 20% of the total bacterial community in forest soils and 11% in pasture soils. Overall, 15 different Acidobacteria subgroups of the current 26 subgroups were detected, with Acidobacteria subgroups 1, 3, 5, and 6 accounting together for 87% of the total Acidobacteria community in forest soils and 75% in pasture soils. Concomitant with changes in soil chemistry after forest-to-pasture conversion-particularly an increase in properties linked to soil acidity and nutrient availability-we observed an increase in the relative abundances of Acidobacteria subgroups 4, 10, 17, and 18, and a decrease in the relative abundances of other Acidobacteria subgroups in pasture relative to forest soils. The composition of the total Acidobacteria community as well as the most abundant Acidobacteria subgroups (1, 3, 5, and 6) was significantly more similar in composition across space in pasture soils than in forest soils. These results suggest that preponderant responses of Acidobacteria subgroups, especially subgroups 1, 3, 4, 5, and 6, to forest-to-pasture conversion effects in soils could be used to define management-indicators of agricultural practices in the Amazon Basin. These acidobacterial responses are at least in part through alterations on acidity- and nutrient-related properties of the Amazon soils.