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BACKGROUND: Aortic valve stenosis is a sexually dimorphic disease, with women often presenting with sustained fibrosis and men with more extensive calcification. However, the intracellular molecular mechanisms that drive these clinically important sex differences remain underexplored. METHODS: Hydrogel biomaterials were designed to recapitulate key aspects of the valve tissue microenvironment and to serve as a culture platform for sex-specific valvular interstitial cells (VICs; precursors to profibrotic myofibroblasts). The hydrogel culture system was used to interrogate intracellular pathways involved in sex-dependent VIC-to-myofibroblast activation and deactivation. RNA sequencing was used to define pathways involved in driving sex-dependent activation. Interventions with small molecule inhibitors and siRNA transfections were performed to provide mechanistic insight into sex-specific cellular responses to microenvironmental cues, including matrix stiffness and exogenously delivered biochemical factors. RESULTS: In both healthy porcine and human aortic valves, female leaflets had higher baseline activation of the myofibroblast marker α-smooth muscle actin compared with male leaflets. When isolated and cultured, female porcine and human VICs had higher levels of basal α-smooth muscle actin stress fibers that further increased in response to the hydrogel matrix stiffness, both of which were higher than in male VICs. A transcriptomic analysis of male and female porcine VICs revealed Rho-associated protein kinase signaling as a potential driver of this sex-dependent myofibroblast activation. Furthermore, we found that genes that escape X-chromosome inactivation such as BMX and STS (encoding for Bmx nonreceptor tyrosine kinase and steroid sulfatase, respectively) partially regulate the elevated female myofibroblast activation through Rho-associated protein kinase signaling. This finding was confirmed by treating male and female VICs with endothelin-1 and plasminogen activator inhibitor-1, factors that are secreted by endothelial cells and known to drive myofibroblast activation through Rho-associated protein kinase signaling. CONCLUSIONS: Together, in vivo and in vitro results confirm sex dependencies in myofibroblast activation pathways and implicate genes that escape X-chromosome inactivation in regulating sex differences in myofibroblast activation and subsequent aortic valve stenosis progression. Our results underscore the importance of considering sex as a biological variable to understand the molecular mechanisms of aortic valve stenosis and to help guide sex-based precision therapies.
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Válvula Aórtica/citología , Expresión Génica , Genes Ligados a X , Miofibroblastos/metabolismo , Inactivación del Cromosoma X , Actinas/genética , Actinas/metabolismo , Animales , Estenosis de la Válvula Aórtica/etiología , Estenosis de la Válvula Aórtica/metabolismo , Estenosis de la Válvula Aórtica/patología , Biomarcadores , Células Cultivadas , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Inmunohistoquímica , Masculino , Miofibroblastos/efectos de los fármacos , Factores Sexuales , Transducción de Señal , Porcinos , TranscriptomaRESUMEN
Purpose: This study aims to minimize monitor units (MUs) of intensity-modulated treatments in the Monaco treatment planning system while preserving plan quality by optimizing the "Minimum Segment Width" (MSW) and "Fluence Smoothing" parameters. Materials and Methods: We retrospectively analyzed 30 prostate, 30 gynecological, 15 breast cancer, 10 head and neck tumor, 11 radiosurgery, and 10 hypo-fractionated plans. Original prostate plans employed "Fluence Smoothing" = Off and were reoptimized with Low, Medium, and High settings. The remaining pathologies initially used MSW = 0.5 cm and were reoptimized with MSW = 1.0 cm. Plan quality, including total MU, delivery time, and dosimetric constraints, was statistically analyzed with a paired t-test. Results: Prostate plans exhibited the highest MU variation when changing "Fluence Smoothing" from Off to High (average ΔMU = -5.1%; P < 0.001). However, a High setting may increase overall MU when MSW = 0.5 cm. Gynecological plans changed substantially when MSW increased from 0.5 cm to 1.0 cm (average ΔMU = -29%; P < 0.001). Organs at risk sparing and planning target volumes remained within 1.2% differences. Replanning other pathologies with MSW = 1.0 cm affected breast and head and neck tumor plans (average ΔMU = -168.38, average Δt = -11.74 s, and average ΔMU = -256.56, average Δt = -15.05 s, respectively; all with P < 0.004). Radiosurgery and hypofractioned highly modulated plans did not yield statistically significant results. Conclusions: In breast, pelvis, head and neck, and prostate plans, starting with MSW = 1.0 cm optimally reduces MU and treatment time without compromising plan quality. MSW has a greater impact on MU than the "Fluence Smoothing" parameter. Plans with high modulation might present divergent behavior, requiring a case-specific analysis with MSW values higher than 0.5 cm.
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INTRODUCTION: In response to the evolution of the coronavirus disease 2019 (COVID-19) pandemic, the admission protocol for the temporary COVID-19 hospital in Mexico City has been updated to hospitalize patients preemptively with an oxygen saturation (SpO2) of >90%. METHODS: This prospective, observational, single-center study compared the progression and outcomes of patients who were preemptively hospitalized versus those who were hospitalized based on an SpO2 ⩽90%. We recorded patient demographics, clinical characteristics, COVID-19 symptoms, and oxygen requirement at admission. We calculated the risk of disease progression and the benefit of preemptive hospitalization, stratified by CALL Score: age, lymphocyte count, and lactate dehydrogenase (<8 and ⩾8) at admission. RESULTS: Preemptive hospitalization significantly reduced the requirement for oxygen therapy (odds ratio 0.45, 95% confidence interval 0.31-0.66), admission to the intensive care unit (ICU) (0.37, 0.23-0.60), requirement for invasive mechanical ventilation (IMV) (0.40, 0.25-0.64), and mortality (0.22, 0.10-0.50). Stratification by CALL score at admission showed that the benefit of preemptive hospitalization remained significant for patients requiring oxygen therapy (0.51, 0.31-0.83), admission to the ICU (0.48, 0.27-0.86), and IMV (0.51, 0.28-0.92). Mortality risk remained significantly reduced (0.19, 0.07-0.48). CONCLUSION: Preemptive hospitalization reduced the rate of disease progression and may be beneficial for improving COVID-19 patient outcomes.