RESUMO
Measurement of respiratory impedance ([Formula: see text]) in intubated patients requires accurate compensation for pressure losses across the endotracheal tube (ETT). In this study, we compared time-domain (TD), frequency-domain (FD) and combined time-/frequency-domain (FT) methods for ETT compensation. We measured total impedance ([Formula: see text]) of a test lung in series with three different ETT sizes, as well as in three intubated porcine subjects. Pressure measurement at the distal end of the ETT was used to determine the true [Formula: see text]. For TD compensation, pressure distal to the ETT was obtained based on its resistive and inertial properties, and the corresponding [Formula: see text] was estimated. For FD compensation, impedance of the isolated ETT was obtained from oscillatory flow and pressure waveforms, and then subtracted from [Formula: see text]. For TF compensation, the nonlinear resistive properties of the ETT were subtracted from the proximal pressure measurement, from which the linear resistive and inertial ETT properties were removed in the frequency-domain to obtain [Formula: see text]. The relative root mean square error between the actual and estimated [Formula: see text] ([Formula: see text]) showed that TD compensation yielded the least accurate estimates of [Formula: see text] for the in vitro experiments, with small deviations observed at higher frequencies. The FD and TF compensations yielded estimates of [Formula: see text] with similar accuracies. For the porcine subjects, no significant differences were observed in [Formula: see text] across compensation methods. FD and TF compensation of the ETT may allow for accurate oscillometric estimates of [Formula: see text] in intubated subjects, while avoiding the difficulties associated with direct tracheal pressure measurement.
Assuntos
Intubação Intratraqueal , Traqueia , Animais , Impedância Elétrica , Humanos , Oscilometria , Taxa Respiratória , SuínosRESUMO
Metabolic reprogramming in pediatric diffuse midline glioma is driven by gene expression changes induced by the hallmark histone mutation H3K27M, which results in aberrantly permissive activation of oncogenic signaling pathways. Previous studies of diffuse midline glioma with altered H3K27 (DMG-H3K27a) have shown that the RAS pathway, specifically through its downstream kinase, extracellular-signal-related kinase 5 (ERK5), is critical for tumor growth. Further downstream effectors of ERK5 and their role in DMG-H3K27a metabolic reprogramming have not been explored. We establish that ERK5 is a critical regulator of cell proliferation and glycolysis in DMG-H3K27a. We demonstrate that ERK5 mediates glycolysis through activation of transcription factor MEF2A, which subsequently modulates expression of glycolytic enzyme PFKFB3. We show that in vitro and mouse models of DMG-H3K27a are sensitive to the loss of PFKFB3. Multi-targeted drug therapy against the ERK5-PFKFB3 axis, such as with small-molecule inhibitors, may represent a promising therapeutic approach in patients with pediatric diffuse midline glioma.
Assuntos
Glioma , Histonas , Animais , Criança , Humanos , Camundongos , MAP Quinases Reguladas por Sinal Extracelular , Glioma/genética , Glicólise , Histonas/genética , Fosfofrutoquinase-2 , Monoéster Fosfórico Hidrolases , Transdução de SinaisRESUMO
INTRODUCTION: During mechanical ventilation, cyclic recruitment and derecruitment (R/D) of alveoli result in focal points of heterogeneous stress throughout the lung. In the acutely injured lung, the rates at which alveoli can be recruited or derecruited may also be altered, requiring longer times at higher pressure levels to be recruited during inspiration, but shorter times at lower pressure levels to minimize collapse during exhalation. In this study, we used a computational model to simulate the effects of airway pressure release ventilation (APRV) on acinar recruitment, with varying inspiratory pressure levels and durations of exhalation. MATERIALS AND METHODS: The computational model consisted of a ventilator pressure source, a distensible breathing circuit, an endotracheal tube, and a porcine lung consisting of recruited and derecruited zones, as well as a transitional zone capable of intratidal R/D. Lung injury was simulated by modifying each acinus with an inflation-dependent surface tension. APRV was simulated for an inhalation duration (Thigh) of 4.0 seconds, inspiratory pressures (Phigh) of 28 and 40 cmH2O, and exhalation durations (Tlow) ranging from 0.2 to 1.5 seconds. RESULTS: Both sustained acinar recruitment and intratidal R/D within the subtree were consistently higher for Phigh of 40 cmH2O vs. 28 cmH2O, regardless of Tlow. Increasing Tlow was associated with decreasing sustained acinar recruitment, but increasing intratidal R/D, within the subtree. Increasing Tlow was associated with decreasing elastance of both the total respiratory system and transitional subtree of the model. CONCLUSIONS: Our computational model demonstrates the confounding effects of cyclic R/D, sustained recruitment, and parenchymal strain stiffening on estimates of total lung elastance during APRV. Increasing inspiratory pressures leads to not only more sustained recruitment of unstable acini but also more intratidal R/D. Our model indicates that higher inspiratory pressures should be used in conjunction with shorter exhalation times, to avoid increasing intratidal R/D.
Assuntos
Pressão Positiva Contínua nas Vias Aéreas , Pulmão , Animais , Suínos , Respiração Artificial/efeitos adversos , Complacência Pulmonar , Simulação por ComputadorRESUMO
Diffuse midline gliomas (DMGs) bearing driver mutations of histone 3 lysine 27 (H3K27M) are incurable brain tumors with unique epigenomes. Here, we generated a syngeneic H3K27M mouse model to study the amino acid metabolic dependencies of these tumors. H3K27M mutant cells were highly dependent on methionine. Interrogating the methionine cycle dependency through a short-interfering RNA screen identified the enzyme methionine adenosyltransferase 2A (MAT2A) as a critical vulnerability in these tumors. This vulnerability was not mediated through the canonical mechanism of MTAP deletion; instead, DMG cells have lower levels of MAT2A protein, which is mediated by negative feedback induced by the metabolite decarboxylated S-adenosyl methionine. Depletion of residual MAT2A induces global depletion of H3K36me3, a chromatin mark of transcriptional elongation perturbing oncogenic and developmental transcriptional programs. Moreover, methionine-restricted diets extended survival in multiple models of DMG in vivo. Collectively, our results suggest that MAT2A presents an exploitable therapeutic vulnerability in H3K27M gliomas.
Assuntos
Neoplasias Encefálicas , Glioma , Metionina Adenosiltransferase/metabolismo , Animais , Neoplasias Encefálicas/genética , Epigenoma , Glioma/genética , Histonas/genética , Metionina/genética , CamundongosRESUMO
INTRODUCTION: Mounting evidence suggest that macrophages play crucial roles in disease and tissue regeneration. However, despite much efforts during the past decade, our knowledge about the extent of macrophages' contribution to adult pancreatic regeneration after injury or during pancreatic disease progression is still limited. Nevertheless, it is generally accepted that some macrophage features that normally would contribute to healing and regeneration may be detrimental in pancreatic cancer. Altogether, the current literature contains conflicting reports on whether macrophages act as friends or foe in these conditions. METHODS AND RESULTS: In this review, we briefly review the origins of tissue resident and infiltrating macrophages and the importance of cellular crosstalking between macrophages and other resident cells in tissue regeneration. The primary objective of this review is to summarize our knowledge of the distinct roles of tissue resident and infiltrating macrophages, the impact of M1 and M2 macrophage phenotypes, and emerging evidence on macrophage crosstalking in pancreatic injury, regeneration, and disease. CONCLUSION: Macrophages are involved with various stages of pancreatic cancer development, pancreatitis, and diabetes. Elucidating their role in these conditions will aid the development of targeted therapeutic treatments.