RESUMO
The increasing rates of drug misuse highlight the urgency of identifying improved therapeutics for treatment. Most drug-seeking behaviours that can be modelled in rodents utilize the repeated intravenous self-administration (SA) of drugs. Recent studies examining the mesolimbic pathway suggest that Kv7/KCNQ channels may contribute to the transition from recreational to chronic drug use. However, to date, all such studies used noncontingent, experimenter-delivered drug model systems, and the extent to which this effect generalizes to rats trained to self-administer drugs is not known. Here, we tested the ability of retigabine (ezogabine), a Kv7 channel opener, to regulate instrumental behaviour in male Sprague Dawley rats. We first validated the ability of retigabine to target experimenter-delivered cocaine in a conditioned place preference (CPP) assay and found that retigabine reduced the acquisition of place preference. Next, we trained rats for cocaine-SA under a fixed-ratio or progressive-ratio reinforcement schedule and found that retigabine pretreatment attenuated the SA of low to moderate doses of cocaine. This was not observed in parallel experiments, with rats self-administering sucrose, a natural reward. Compared with sucrose-SA, cocaine-SA was associated with reductions in the expression of the Kv7.5 subunit in the nucleus accumbens, without alterations in Kv7.2 and Kv7.3. Therefore, these studies reveal a reward-specific reduction in SA behaviour and support the notion that Kv7 is a potential therapeutic target for human psychiatric diseases with dysfunctional reward circuitry.
Assuntos
Carbamatos , Cocaína , Fenilenodiaminas , Ratos Sprague-Dawley , Autoadministração , Sacarose , Animais , Fenilenodiaminas/farmacologia , Fenilenodiaminas/administração & dosagem , Carbamatos/farmacologia , Carbamatos/administração & dosagem , Cocaína/farmacologia , Cocaína/administração & dosagem , Masculino , Ratos , Sacarose/administração & dosagem , Sacarose/farmacologia , Comportamento de Procura de Droga/efeitos dos fármacos , Canais de Potássio KCNQ/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Inibidores da Captação de Dopamina/farmacologia , Inibidores da Captação de Dopamina/administração & dosagemRESUMO
Antecedentes La satisfacción laboral, el burnout y la calidad de vida profesional de los fisioterapeutas es clave para mantener la calidad de los servicios prestados en los pacientes. Objetivos Describir la satisfacción laboral, el burnout y la calidad de vida profesional de los fisioterapeutas de Atención Hospitalaria de la Sanidad pública de Castilla y León (SACYL); identificar las diferencias existentes en la satisfacción laboral, el burnout y el nivel de calidad de vida profesional en los mismos; determinar la relación existente entre las tres variables. Materiales y métodos Se realizó un estudio descriptivo transversal, con muestreo de conveniencia, en fisioterapeutas de Castilla y León que trabajan en atención hospitalaria. Se recogieron datos de la satisfacción laboral (Font Roja), el burnout (Maslach Burnout Inventory) y la calidad de vida profesional (CVP-35) en su puesto de trabajo. Se llevó a cabo un análisis descriptivo y relacional de las variables analizadas. Resultados Participaron 72 fisioterapeutas, siendo 75% mujeres, con una media de edad de 42,8 ± 8,37 años. El nivel de burnout resultó medio-alto en las dimensiones de agotamiento emocional y despersonalización, bajo en realización personal y la satisfacción laboral baja (SMG = -0,04). Los valores de calidad de vida profesional alcanzan una puntuación de notable (7,15 ± 1,43). Conclusiones Los fisioterapeutas de atención hospitalaria del SACYL presentan una elevada motivación intrínseca, a pesar del escaso apoyo directivo que reciben. La mejora de ambas dimensiones conlleva un aumento de la satisfacción laboral y de la calidad de vida profesional, y un descenso de los niveles de burnout (especialmente en el agotamiento emocional y la despersonalización). (AU)
Background Job satisfaction, burnout and professional quality of life of physiotherapists is key to maintaining the quality of services provided to patients. Objectives To describe job satisfaction, burnout and professional quality of life of physiotherapists in hospital care in the public health system of Castilla y León (SACYL); to identify the existing differences in job satisfaction, burnout and the level of professional quality of life among them; to determine the relationship between the three variables. Materials and methods A cross-sectional descriptive study was carried out, with convenience sampling, in physiotherapists from Castilla y León working in hospital care. Data were collected on job satisfaction (Font Roja), burnout (Maslach Burnout Inventory) and professional quality of life (CVP-35) in the workplace. A descriptive and relational analysis of the variables analysed was carried out. Results Seventy-two physiotherapists participated, 75% of whom were women, with an average age of 42.8 ± 8.37 years. The level of burnout was medium-high in the dimensions of emotional exhaustion and depersonalisation, low in personal fulfilment and low in job satisfaction (SMG = −0.04). Professional quality of life values reach a score of remarkable (7.15 ± 1.43). Conclusions Hospital care physiotherapists of the SACYL present high intrinsic motivation, despite the low managerial support they receive. The improvement of both dimensions leads to an increase in job satisfaction and professional quality of life, and a decrease in burnout levels (especially in emotional exhaustion and depersonalisation). (AU)
Assuntos
Humanos , Fisioterapeutas , Satisfação no Emprego , Esgotamento Psicológico , Esgotamento Profissional , Qualidade de Vida , Estudos TransversaisRESUMO
Antecedentes La satisfacción laboral, el burnout y la calidad de vida profesional de los fisioterapeutas es clave para mantener la calidad de los servicios prestados en los pacientes. Objetivos Describir la satisfacción laboral, el burnout y la calidad de vida profesional de los fisioterapeutas de Atención Hospitalaria de la Sanidad pública de Castilla y León (SACYL); identificar las diferencias existentes en la satisfacción laboral, el burnout y el nivel de calidad de vida profesional en los mismos; determinar la relación existente entre las tres variables. Materiales y métodos Se realizó un estudio descriptivo transversal, con muestreo de conveniencia, en fisioterapeutas de Castilla y León que trabajan en atención hospitalaria. Se recogieron datos de la satisfacción laboral (Font Roja), el burnout (Maslach Burnout Inventory) y la calidad de vida profesional (CVP-35) en su puesto de trabajo. Se llevó a cabo un análisis descriptivo y relacional de las variables analizadas. Resultados Participaron 72 fisioterapeutas, siendo 75% mujeres, con una media de edad de 42,8 ± 8,37 años. El nivel de burnout resultó medio-alto en las dimensiones de agotamiento emocional y despersonalización, bajo en realización personal y la satisfacción laboral baja (SMG = -0,04). Los valores de calidad de vida profesional alcanzan una puntuación de notable (7,15 ± 1,43). Conclusiones Los fisioterapeutas de atención hospitalaria del SACYL presentan una elevada motivación intrínseca, a pesar del escaso apoyo directivo que reciben. La mejora de ambas dimensiones conlleva un aumento de la satisfacción laboral y de la calidad de vida profesional, y un descenso de los niveles de burnout (especialmente en el agotamiento emocional y la despersonalización). (AU)
Background Job satisfaction, burnout and professional quality of life of physiotherapists is key to maintaining the quality of services provided to patients. Objectives To describe job satisfaction, burnout and professional quality of life of physiotherapists in hospital care in the public health system of Castilla y León (SACYL); to identify the existing differences in job satisfaction, burnout and the level of professional quality of life among them; to determine the relationship between the three variables. Materials and methods A cross-sectional descriptive study was carried out, with convenience sampling, in physiotherapists from Castilla y León working in hospital care. Data were collected on job satisfaction (Font Roja), burnout (Maslach Burnout Inventory) and professional quality of life (CVP-35) in the workplace. A descriptive and relational analysis of the variables analysed was carried out. Results Seventy-two physiotherapists participated, 75% of whom were women, with an average age of 42.8 ± 8.37 years. The level of burnout was medium-high in the dimensions of emotional exhaustion and depersonalisation, low in personal fulfilment and low in job satisfaction (SMG = −0.04). Professional quality of life values reach a score of remarkable (7.15 ± 1.43). Conclusions Hospital care physiotherapists of the SACYL present high intrinsic motivation, despite the low managerial support they receive. The improvement of both dimensions leads to an increase in job satisfaction and professional quality of life, and a decrease in burnout levels (especially in emotional exhaustion and depersonalisation). (AU)
Assuntos
Humanos , Fisioterapeutas , Satisfação no Emprego , Esgotamento Psicológico , Esgotamento Profissional , Qualidade de Vida , Estudos TransversaisRESUMO
Introduction: We reported increased spleen tyrosine kinase (SYK) expression in kidney biopsies of patients with IgA nephropathy (IgAN) and that inhibition of SYK reduces inflammatory cytokines production from IgA stimulated mesangial cells. Methods: This study was a double-blind, randomized, placebo-controlled phase 2 trial of fostamatinib (an oral SYK inhibitor) in 76 patients with IgAN. Patients were randomized to receive placebo, fostamatinib at 100 mg or 150 mg twice daily for 24 weeks on top of maximum tolerated dose of renin-angiotensin system inhibitors. The primary end point was reduction of proteinuria. Secondary end points included change from baseline in estimated glomerular filtration rate (eGFR) and kidney histology. Results: Although we could not detect significant reduction in proteinuria with fostamatinib overall, in a predetermined subgroup analysis, there was a trend for dose-dependent reduction in median proteinuria (from baseline to 24 weeks by 14%, 27%, and 36% in the placebo, fostamatinib 100 mg, and 150 mg groups, respectively) in patients with baseline urinary protein-to-creatinine ratios (UPCR) more than 1000 mg/g. Kidney function (eGFR) remained stable in all groups. Fostamatinib was well-tolerated. Side effects included diarrhea, hypertension, and increased liver enzymes. Thirty-nine patients underwent repeat biopsy showing reductions in SYK staining associated with therapy at low dose (-1.5 vs. 1.7 SYK+ cells/glomerulus in the placebo group, P < 0.05). Conclusions: There was a trend toward reduction in proteinuria with fostamatinib in a predefined analysis of high risk patients with IgAN despite maximal care, as defined by baseline UPCR greater than 1000 mg/g. Further study may be warranted.
RESUMO
Dimethyl fumarate 1 is approved for the treatment of multiple sclerosis but is also associated with off-target activation of the niacin receptor. By using a tetrazolone or triazolone bioisostere approach to the fumarate and vinyl sulfone series of Nrf2 activators, we have optimized the electrophilicity of the double bond to tune the on-target Nrf2 activation with PK properties to achieve efficacy in animal models of multiple sclerosis. The study linked highly potent, highly electrophilic molecules to low plasma stability and, subsequently, limited efficacy. By contrast, a sulfonylvinyltriazolone 17 retains on-target potency but shows much weaker electrophilic potential. As a consequence, in vivo high exposures of 17 are obtained, resulting in efficacy in the EAE model similar to that observed for DMF. 17 (R079) is Ames negative, is not cytotoxic to cells, and shows little inhibition of either the niacin receptor or a panel of off-target receptors.
RESUMO
Endothelial dysfunction is an early event in coronary microvascular disease. Integrin-linked kinase (ILK) prevents endothelial nitric oxide synthase (eNOS) uncoupling and, thus, endothelial dysfunction. However, the specific role of endothelial ILK in cardiac function remains to be fully elucidated. We hypothesised that endothelial ILK plays a crucial role in maintaining coronary microvascular function and contractile performance in the heart. We generated an endothelial cell-specific ILK conditional knock-out mouse (ecILK cKO) and investigated cardiovascular function. Coronary endothelial ILK deletion significantly impaired cardiac function: ejection fraction, fractional shortening and cardiac output decreased, whilst left ventricle diastolic internal diameter decreased and E/A and E/E' ratios increased, indicating not only systolic but also diastolic dysfunction. The functional data correlated with extensive extracellular matrix remodelling and perivascular fibrosis, indicative of adverse cardiac remodelling. Mice with endothelial ILK deletion suffered early ischaemic-like events with ST elevation and transient increases in cardiac troponins, which correlated with fibrotic remodelling. In addition, ecILK cKO mice exhibited many features of coronary microvascular disease: reduced cardiac perfusion, impaired coronary flow reserve and arterial remodelling with patent epicardial coronary arteries. Moreover, endothelial ILK deletion induced a moderate increase in blood pressure, but the antihypertensive drug Losartan did not affect microvascular remodelling whilst only partially ameliorated fibrotic remodelling. The plasma miRNA profile reveals endothelial-to-mesenchymal transition (endMT) as an upregulated pathway in endothelial ILK conditional KO mice. Our results show that endothelial cells in the microvasculature in endothelial ILK conditional KO mice underwent endMT. Moreover, endothelial cells isolated from these mice and ILK-silenced human microvascular endothelial cells underwent endMT, indicating that decreased endothelial ILK contributes directly to this endothelial phenotype shift. Our results identify ILK as a crucial regulator of microvascular endothelial homeostasis. Endothelial ILK prevents microvascular dysfunction and cardiac remodelling, contributing to the maintenance of the endothelial cell phenotype.
Assuntos
Células Endoteliais , Isquemia Miocárdica , Humanos , Animais , Camundongos , Células Endoteliais/patologia , Transdução de Sinais , Remodelação Ventricular , Isquemia Miocárdica/patologia , Vasos Coronários , FibroseRESUMO
The increasing rates of drug misuse highlight the urgency of identifying improved therapeutics for treatment. Most drug-seeking behaviors that can be modeled in rodents utilize the repeated intravenous self-administration (SA) of drugs. Recent studies examining the mesolimbic pathway suggest that K v 7/KCNQ channels may contribute in the transition from recreational to chronic drug use. However, to date, all such studies used noncontingent, experimenter-delivered drug model systems, and the extent to which this effect generalizes to rats trained to self-administer drug is not known. Here, we tested the ability of retigabine (ezogabine), a K v 7 channel opener, to regulate instrumental behavior in male Sprague Dawley rats. We first validated the ability of retigabine to target experimenter-delivered cocaine in a CPP assay and found that retigabine reduced the acquisition of place preference. Next, we trained rats for cocaine-SA under a fixed-ratio or progressive-ratio reinforcement schedule and found that retigabine-pretreatment attenuated the self-administration of low to moderate doses of cocaine. This was not observed in parallel experiments, with rats self-administering sucrose, a natural reward. Compared to sucrose-SA, cocaine-SA was associated with reductions in the expression of the K v 7.5 subunit in the nucleus accumbens, without alterations in K v 7.2 and K v 7.3. Therefore, these studies reveal a reward specific reduction in SA behavior considered relevant for the study of long-term compulsive-like behavior and supports the notion that K v 7 is a potential therapeutic target for human psychiatric diseases with dysfunctional reward circuitry.
RESUMO
Considering pure quantum states, entanglement concentration is the procedure where, from N copies of a partially entangled state, a single state with higher entanglement can be obtained. Obtaining a maximally entangled state is possible for N=1. However, the associated success probability can be extremely low when increasing the system's dimensionality. In this work, we study two methods to achieve a probabilistic entanglement concentration for bipartite quantum systems with a large dimensionality for N=1, regarding a reasonably good probability of success at the expense of having a non-maximal entanglement. Firstly, we define an efficiency function Q considering a tradeoff between the amount of entanglement (quantified by the I-Concurrence) of the final state after the concentration procedure and its success probability, which leads to solving a quadratic optimization problem. We found an analytical solution, ensuring that an optimal scheme for entanglement concentration can always be found in terms of Q. Finally, a second method was explored, which is based on fixing the success probability and searching for the maximum amount of entanglement attainable. Both ways resemble the Procrustean method applied to a subset of the most significant Schmidt coefficients but obtaining non-maximally entangled states.
RESUMO
Leishmaniasis is a neglected disease caused by flagellated parasites of the Leishmania genus affecting more than 10 million people worldwide. Current treatments for leishmaniasis involve the administration of poorly tolerated drugs with toxic side effects in patients. There is an imperative necessity for novel compounds to treat this disease. One of the most used strategies in the search for different antiparasitic compounds is the screening of purified plant molecules. The diterpenes 12-hydroxy-11,14-diketo-6,8,12-abietatrien-19,20-olide (HABTO) and 5-epi-icetexone (ICTX) isolated from Salvia cuspidata were shown to be effective against Leishmania amazonensis in vitro and in vivo. They displayed an antiproliferative effect against L. amazonensis promastigotes. They also induce an increase in ROS levels and affect the mitochondrial activity of parasites. HABTO and ICTX in an in vivo model of cutaneous leishmaniasis decrease footpad swelling, parasite load, and splenic index. Moreover, they induce significant reduction in the O.D. of total anti-Leishmania IgG and IgG1 subtype antibody responses against L. amazonensis compared to the PBS group but maintain high levels of IgG2a. This suggests that in HABTO- or ICTX-treated mice, there is a slowdown in the progression of the disease. These terpenes could be considered as possible novel antileishmanial agents against L. amazonensis and thus treat cutaneous leishmaniasis.
Assuntos
Antiprotozoários , Leishmania mexicana , Leishmania , Leishmaniose Cutânea , Salvia , Animais , Camundongos , Antiparasitários/farmacologia , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Leishmaniose Cutânea/tratamento farmacológico , Camundongos Endogâmicos BALB C , Terpenos/farmacologiaRESUMO
OBJECTIVE: Syk is a cytoplasmic protein tyrosine kinase that plays a role in signaling via B cell and Fc receptors (FcR). FcR engagement and signaling via Syk is thought to be important in antineutrophil cytoplasm antibody (ANCA) IgG-mediated neutrophil activation. This study was undertaken to investigate the role of Syk in ANCA-induced myeloid cell activation and vasculitis pathogenesis. METHODS: Phosphorylation of Syk in myeloid cells from healthy controls and ANCA-associated vasculitis (AAV) patients was analyzed using flow cytometry. The effect of Syk inhibition on myeloperoxidase (MPO)-ANCA IgG activation of cells was investigated using functional assays (interleukin-8 and reactive oxygen species production) and targeted gene analysis with NanoString. Total and phosphorylated Syk at sites of tissue inflammation in patients with AAV was assessed using immunohistochemistry and RNAscope in situ hybridization. RESULTS: We identified increased phosphorylated Syk at critical activatory tyrosine residues in blood neutrophils and monocytes from patients with active AAV compared to patients with disease in remission or healthy controls. Syk was phosphorylated in vitro following MPO-ANCA IgG stimulation, and Syk inhibition was able to prevent ANCA-mediated cellular responses. Using targeted gene expression analysis, we identified up-regulation of FcR- and Syk-dependent signaling pathways following MPO-ANCA IgG stimulation. Finally, we showed that Syk is expressed and phosphorylated in tissue leukocytes at sites of organ inflammation in AAV. CONCLUSION: These findings indicate that Syk plays a critical role in MPO-ANCA IgG-induced myeloid cell responses and that Syk is activated in circulating immune cells and tissue immune cells in AAV; therefore, Syk inhibition may be a potential therapeutic option.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Anticorpos Anticitoplasma de Neutrófilos , Humanos , Inflamação , Receptores Fc , Imunoglobulina G , Imunidade Inata , Peroxidase , Quinase SykRESUMO
Janus kinases (JAK) play a critical role in JAK/signal transducer and activator of transcription (STAT) signaling pathways that mediate immune response and cell growth. From high-throughput screening (HTS) hit to lead optimization, a series of pyrimidine compounds has been discovered as potent JAK1 inhibitors with selectivity over JAK2. Cell-based assays were used as primary screening methods for evaluating potency and selectivity, the results were further assessed and confirmed by biochemical and additional cellular assays for lead molecules. Also discussed is the unique correlation between a trifluomethyl group and CYP3A4 inhibition in the presence of NADPH, the activity of which was successfully decreased with the reduction of fluoro-atoms, increasing IC50 from 0.5 µM to >10 µM. The development of novel and scalable synthetic routes for amino-phenyl intermediates was essential for the discovery of late-stage lead molecules, including clinical candidate R507 (33). In preclinical studies, 33 exhibited great efficacy in mouse studies by inhibiting IFNγ expression induced by IL-2 and in a rat collagen-induced arthritis disease model.
RESUMO
The problem of non-orthogonal state discrimination underlies crucial quantum information tasks, such as cryptography and computing protocols. Therefore, it is decisive to find optimal scenarios for discrimination among quantum states. We experimentally investigate the strategy for the optimal discrimination of two non-orthogonal states considering a fixed rate of inconclusive outcomes (FRIO). The main advantage of the FRIO strategy is to interpolate between unambiguous and minimum error discrimination by solely adjusting the rate of inconclusive outcomes. We present a versatile experimental scheme that performs the optimal FRIO measurement for any pair of generated non-orthogonal states with arbitrary a priori probabilities and any fixed rate of inconclusive outcomes. Considering different values of the free parameters in the FRIO protocol, we implement it upon qubit states encoded in the polarization mode of single photons generated in the spontaneous parametric down-conversion process. Moreover, we resort to a newfangled double-path Sagnac interferometer to perform a three-outcome non-projective measurement required for the discrimination task, showing excellent agreement with the theoretical prediction. This experiment provides a practical toolbox for a wide range of quantum state discrimination strategies using the FRIO scheme, which can significantly benefit quantum information applications and fundamental studies in quantum theory.
RESUMO
Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in transduction of IL-1R/TLR signaling which is responsible for innate immune response. From HTS campaign, bicyclic-pyrimidine compounds have been identified as potent IRAK4 inhibitors, exhibiting good potency in both IRAK4 biochemical and LPS induced IL-23 inhibition cell-based assays. The SAR efforts were focused on further improving on-target potency, reducing PAD activities of HTS hit molecule and improving in vivo PK profiles of early lead compounds. When different aromatic rings were fused to the pyrimidine core, and with various substituents at 2- or 4-position of the pyrimidine, the impact on potency and PK properties were observed and are discussed. Selected compounds were further evaluated in IL-1ß induced IL-6 inhibition acute animal model and rodent arthritis disease model, of which compounds 33 and 39 showed good efficacy in both studies.
Assuntos
Quinases Associadas a Receptores de Interleucina-1 , Pirimidinas , Animais , Imunidade Inata , Pirimidinas/farmacologia , Transdução de SinaisRESUMO
IRAK4 kinase plays a key role in TLR/IL-1R signaling pathways that regulate innate immune responses, and if uncontrolled, it is responsible for various inflammatory disorders. By high-throughput screening (HTS) and hit-to-lead optimization, compounds with a 5-aryl-2,4-diaminopyrimidine core structure have been identified as potent IRAK4 inhibitors. A cocrystal structure of IRAK4 protein with an early lead molecule helped with understanding the structure-activity relationship and the design of the new compounds. Initial HTS hits from this series of compounds were also found to inhibit TAK1 kinase, which would cause liver toxicity and potentially bone marrow failure. Optimization of this series resulted in improved selectivity over TAK1 kinase. The TAK1 selectivity was found to be closely associated with different sizes and types of substituents at the 5-position of the pyrimidine. The impact of other pyrimidine substituents on the potency and selectivity was also explored. A few representative compounds were evaluated in IL-1ß-induced IL-6 inhibition animal model studies and showed modest efficacy.
RESUMO
Antibody mediated rejection is a major cause of renal allograft loss. Circulating preformed donor specific antibodies (DSA) can result as a consequence of blood transfusion, pregnancy or prior transplantation. Current treatment strategies are limited due to partial or transient efficacy, adverse side-effects or patient unsuitability. Previous in vivo studies exploring autoimmune diseases have shown that spleen tyrosine kinase (SYK) signalling is involved in the development of pathogenic autoantibody. The role of SYK in allogenic antibody production is unknown, and we investigated this in a rodent model of sensitization, established by the transfusion of F344 whole blood into LEW rats. Two-week treatment of sensitized rats with selective SYK inhibitor fostamatinib strongly blocked circulating DSA production without affecting overall total immunoglobulin levels, and inhibition was sustained up to 5 weeks post-completion of the treatment regimen. Fostamatinib treatment did not affect mature B cell subset or plasma cell levels, which remained similar between non-treated controls, vehicle treated and fostamatinib treated animals. Our data indicate fostamatinib may provide an alternative therapeutic option for patients who are at risk of sensitization following blood transfusion while awaiting renal transplant.
Assuntos
Transplante de Rim , Animais , Anticorpos , Rejeição de Enxerto , Humanos , Transplante de Rim/efeitos adversos , Oxazinas/farmacologia , Oxazinas/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Ratos , Ratos Endogâmicos F344 , Quinase Syk , Doadores de TecidosRESUMO
Leukemia stem cells (LSCs) in chronic myeloid leukemia (CML) are quiescent, insensitive to BCR-ABL1 tyrosine kinase inhibitors (TKIs) and responsible for CML relapse. Therefore, eradicating quiescent CML LSCs is a major goal in CML therapy. Here, using a G0 marker (G0M), we narrow down CML LSCs as G0M- and CD27- double positive cells among the conventional CML LSCs. Whole transcriptome analysis reveals NF-κB activation via inflammatory signals in imatinib-insensitive quiescent CML LSCs. Blocking NF-κB signals by inhibitors of interleukin-1 receptor-associated kinase 1/4 (IRAK1/4 inhibitors) together with imatinib eliminates mouse and human CML LSCs. Intriguingly, IRAK1/4 inhibitors attenuate PD-L1 expression on CML LSCs, and blocking PD-L1 together with imatinib also effectively eliminates CML LSCs in the presence of T cell immunity. Thus, IRAK1/4 inhibitors can eliminate CML LSCs through inhibiting NF-κB activity and reducing PD-L1 expression. Collectively, the combination of TKIs and IRAK1/4 inhibitors is an attractive strategy to achieve a radical cure of CML.
Assuntos
Quinases Associadas a Receptores de Interleucina-1/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mieloide/tratamento farmacológico , Células-Tronco Neoplásicas/metabolismo , Animais , Antineoplásicos/farmacologia , Doença Crônica , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Mesilato de Imatinib/farmacologia , Inibidores de Checkpoint Imunológico/farmacologia , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/farmacologiaRESUMO
In optical communications, space-division multiplexing is a promising strategy to augment the fiber network capacity. It relies on modern fiber designs that support the propagation of multiple spatial modes. One of these fibers, the ring-core fiber (RCF), is able to propagate modes that carry orbital angular momentum (OAM), and has been shown to enhance not only classical but also quantum communication systems. Typically, the RCF spatial modes are used as orthogonal transmission channels for data streams that are coupled into the fiber using different free space beams. Free space beams commonly used are Laguerre-Gaussian (LG) and perfect vortex (PV) beams. Here, we study the optimal conditions to multiplex information into ring-core fibers in this scheme. We study the beam coupling efficiency using the overlap between free space beams and RCF bound beams and determine which are the most relevant LG beams to be considered and how their coupling efficiency can be maximized by properly adjusting the beam width with respect to the fiber parameters. Our results show that the coupling efficiency depends upon the OAM value and that this can limit the achievable transmission rates in SDM systems. In this regard, we find optimal coupling configurations for LG beams based on the RCF fiber and beam parameters. Further, we study the PV beam that allows for nearly perfect coupling efficiencies for all spatial modes supported by these fibers. PV beams present higher coupling efficiencies than LG beams and negligible dependence on the OAM value, thus offering an attractive solution to multiplex high counts of OAM channels from free space into a ring-core fiber using a single coupling configuration.
RESUMO
Restaurant delivery services have gained in popularity among college students; however, students participating in the Supplemental Nutrition Assistance Program (SNAP) are not allowed to redeem their benefits via restaurant delivery services. This mixed-methods head-to-head crossover trial assessed whether college students experiencing marginal food security prefer benefits via a grocery store gift card (as a proxy for traditional SNAP benefits) or via a restaurant delivery service gift card of equivalent value, and which type of benefit is more effective at improving food security status. Thirty college students experiencing marginal food security were recruited to receive $80 in cash equivalent benefits to spend over a two-month period in the form of grocery store gift cards and restaurant delivery service gift cards. Participants completed surveys and interviews to measure their food security status and share their experiences with each benefit type. After four months of benefits, 48.3% of participants improved their food security status. However, neither type of benefit was statistically better at improving food security status. Most participants preferred grocery store benefits (89.7%) over restaurant delivery service benefits (10.3%). However, more research is needed to explore whether allowing SNAP recipients to redeem their benefits with restaurant delivery services is a viable mechanism to address food challenges among college students experiencing marginal food security.
Assuntos
Assistência Alimentar , Restaurantes , Estudos de Viabilidade , Segurança Alimentar , Abastecimento de Alimentos , Humanos , Pobreza , Estudantes , SupermercadosRESUMO
INTRODUCTION: Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor. Aryl hydrocarbon receptor interacting protein (AIP) in one of AHR ligands. The aim of this study is to analyze the prognostic influence of AIP in pancreatic carcinoma. MATERIAL AND METHODS: Retrospective case series with immunohistochemical analysis of AIP. We have estimated a multivariate Cox's model for the outcome (progression free and overall survival). RESULTS: 204 patients were included in the study. As expected prognosis was poor and 67.8% died of disease. As for AIP 9.8% of the cases showed nuclear staining of the epithelial tumor cells and 59.4% a cytoplasmic one. Stroma was stained in 53.1% of the cases. Univariate survival analysis revealed a significantly worse prognosis of patients with cytoplasmic AIP expression (stroma and epithelium), but nuclear expression was associated to a better prognosis. In the multivariate analysis stromal AIP expression was an independent prognosticator of progression free survival, together with pT stage, histological grade and history of diabetes. DISCUSSION: AIP Is a conserved cochaperone protein binding to many proteins. AIP has been proposed as a potential tumor suppressor gene. To date, no study has analyzed the immunohistochemical expression of AIP in pancreatic carcinoma. Our results indicate that both epithelial and stromal cytoplasmic expression of AIP is associated to bad prognosis, while nuclear translocation seems to improve prognosis. CONCLUSION: Although we must deepen into the complex signaling pathways underlying this potential association, our results open a way to inhibiting AHR as a potential target against pancreatic carcinoma.