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INTRODUCTION: Hemorrhage is a leading cause of death in trauma. Prehospital hemorrhage control techniques include tourniquet application for extremity wounds and direct compression; however, tourniquets are not effective in anatomic junctions, and direct compression is highly operator dependent. Balloon catheter compression has been employed previously in trauma care, but its use has been confined to the operating room and restricted to specific anatomic injuries. METHODS: In a single-center retrospective review, we describe a technique for balloon catheter compression for hemorrhage control that can be employed across the continuum of trauma care, from the prehospital setting to the trauma bay, the operating room, and postoperative period. RESULTS: Of 18,303 trauma patients in Venezuela, 45% of the 1757 patients with vascular injuries received Foley catheter compression for hemorrhage control. Of these catheters, the majority (75%) were placed in the emergency department, 5% in the prehospital setting, and 20% in the operating room. Over half (53.2%) of the balloon catheters were placed for hemorrhage control in non-compressible anatomic junctions. CONCLUSIONS: Foley catheter balloon compression is a useful addition to a provider's arsenal of hemorrhage control techniques, as it is effective in anatomic junctions, preserves collateral circulation through focused compression, and requires minimal active physical attention to maintain hemostasis.
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Pediatric high-grade glioma (pHGG) is an incurable central nervous system malignancy that is a leading cause of pediatric cancer death. While pHGG shares many similarities to adult glioma, it is increasingly recognized as a molecularly distinct, yet highly heterogeneous disease. In this study, we longitudinally profiled a molecularly diverse cohort of 16 pHGG patients before and after standard therapy through single-nucleus RNA and ATAC sequencing, whole-genome sequencing, and CODEX spatial proteomics to capture the evolution of the tumor microenvironment during progression following treatment. We found that the canonical neoplastic cell phenotypes of adult glioblastoma are insufficient to capture the range of tumor cell states in a pediatric cohort and observed differential tumor-myeloid interactions between malignant cell states. We identified key transcriptional regulators of pHGG cell states and did not observe the marked proneural to mesenchymal shift characteristic of adult glioblastoma. We showed that essential neuromodulators and the interferon response are upregulated post-therapy along with an increase in non-neoplastic oligodendrocytes. Through in vitro pharmacological perturbation, we demonstrated novel malignant cell-intrinsic targets. This multiomic atlas of longitudinal pHGG captures the key features of therapy response that support distinction from its adult counterpart and suggests therapeutic strategies which are targeted to pediatric gliomas.
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Iron oxide-copper-gold (IOCG) deposits are a globally important source of copper, gold and critical commodities. Despite their relevance, IOCG deposits remain an ill-defined clan, with a range of characteristics that has complicated development of the general genetic model. Here we focus on the Candelaria IOCG deposit in Chile and reveal that by using micro-textural and compositional variations in actinolite, a common alteration mineral found in many IOCG deposits, we can constrain the evolution of these systems. We demonstrate that Candelaria formed by the superposition of at least two pulses of mineralization with a late Cu-rich event overprinting and superimposed over an early, and probably higher temperature, iron oxide-apatite (IOA) mineralization event. These distinct pulses were likely caused by episodic injections of magmatic-hydrothermal fluids from crystallizing magmas at depth. Our data provide empirical evidence of grain-to-deposit scale compositional and potentially temperature changes in an IOCG system. The results support the use of actinolite chemistry as a novel approach to understand the formation of IOCG deposits and a potential tool for vectoring in exploration.
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OBJECTIVE: To assess the household secondary infection risk (SIR) of B.1.1.7 (Alpha) and non-Alpha lineages of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among children. STUDY DESIGN: During January to April 2021, we prospectively followed households with a SARS-CoV-2 infection. We collected questionnaires, serial nasopharyngeal swabs for reverse transcription polymerase chain reaction testing and whole genome sequencing, and serial blood samples for serology testing. We calculated SIRs by primary case age (pediatric vs adult), household contact age, and viral lineage. We evaluated risk factors associated with transmission and described symptom profiles among children. RESULTS: Among 36 households with pediatric primary cases, 21 (58%) had secondary infections. Among 91 households with adult primary cases, 51 (56%) had secondary infections. SIRs among pediatric and adult primary cases were 45% and 54%, respectively (OR, 0.79; 95% CI, 0.41-1.54). SIRs among pediatric primary cases with Alpha and non-Alpha lineage were 55% and 46%, respectively (OR, 1.52; 95% CI, 0.51-4.53). SIRs among pediatric and adult household contacts were 55% and 49%, respectively (OR, 1.01; 95% CI, 0.68-1.50). Among pediatric contacts, no significant differences in the odds of acquiring infection by demographic or household characteristics were observed. CONCLUSIONS: Household transmission of SARS-CoV-2 from children and adult primary cases to household members was frequent. The risk of secondary infection was similar among child and adult household contacts. Among children, household transmission of SARS-CoV-2 and the risk of secondary infection was not influenced by lineage. Continued mitigation strategies (eg, masking, physical distancing, vaccination) are needed to protect at-risk groups regardless of virus lineage circulating in communities.
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COVID-19 , SARS-CoV-2 , Adulto , COVID-19/epidemiologia , California , Criança , Colorado/epidemiologia , HumanosRESUMO
BACKGROUND: Worsened stroke outcomes with hypertension comorbidity are insensitive to blood pressure-lowering therapies. In an experimental stroke model with comorbid hypertension, we investigated causal roles of ang II (angiotensin II)-mediated stimulation of the brain WNK (with no lysine [K] kinases)-SPAK (STE20/SPS1-related proline/alanine-rich kinase)-NKCC1 (Na-K-Cl cotransporter) complex in worsened outcomes. METHODS: Saline- or ang II-infused C57BL/6J male mice underwent stroke induced by permanent occlusion of the distal branches of the middle cerebral artery. Mice were randomly assigned to receive either vehicle dimethyl sulfoxide/PBS (2 mL/kg body weight/day, IP), a novel SPAK inhibitor, 5-chloro-N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxybenzamide (ZT-1a' 5 mg/kg per day, IP) or a NF-κB (nuclear factor-κB) inhibitor TAT-NBD (transactivator of transcription-NEMO-binding domain' 20 mg/kg per day, IP). Activation of brain NF-κB and WNK-SPAK-NKCC1 cascade as well as ischemic stroke outcomes were examined. RESULTS: Stroke triggered a 2- to 5-fold increase of WNK (isoforms 1, 2, 4), SPAK/OSR1 (oxidative stress-responsive kinase 1), and NKCC1 protein in the ang II-infused hypertensive mouse brains at 24 hours after stroke, which was associated with increased nuclear translocation of phospho-NF-κB protein in the cortical neurons (a Pearson correlation r of 0.77, P<0.005). The upregulation of WNK-SPAK-NKCC1 cascade proteins resulted from increased NF-κB recruitment on Wnk1, Wnk2, Wnk4, Spak, and Nkcc1 gene promoters and was attenuated by NF-κB inhibitor TAT-NBD. Poststroke administration of SPAK inhibitor ZT-1a significantly reduced WNK-SPAK-NKCC1 complex activation, brain lesion size, and neurological function deficits in the ang II-hypertensive mice without affecting blood pressure and cerebral blood flow. CONCLUSIONS: The ang II-induced stimulation of NF-κB transcriptional activity upregulates brain WNK-SPAK-NKCC1 cascade and contributes to worsened ischemic stroke outcomes, illustrating the brain WNK-SPAK-NKCC1 complex as a therapeutic target for stroke with comorbid hypertension.
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Hipertensão , AVC Isquêmico , Acidente Vascular Cerebral , Animais , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B , Proteínas Serina-Treonina Quinases , Membro 2 da Família 12 de Carreador de Soluto/genética , Membro 2 da Família 12 de Carreador de Soluto/metabolismo , Acidente Vascular Cerebral/patologiaRESUMO
Superoxide dismutase 2 (SOD2) catalyzes the dismutation of superoxide to hydrogen peroxide in mitochondria, limiting mitochondrial damage. The SOD2 amino acid valine-to-alanine substitution at position 16 (V16A) in the mitochondrial leader sequence is a common genetic variant among patients with sickle cell disease (SCD). However, little is known about the cardiovascular consequences of SOD2V16A in SCD patients or its impact on endothelial cell function. Here, we show SOD2V16A associates with increased tricuspid regurgitant velocity (TRV), systolic blood pressure, right ventricle area at systole, and declined 6-minute walk distance in 410 SCD patients. Plasma lactate dehydrogenase, a marker of oxidative stress and hemolysis, significantly associated with higher TRV. To define the impact of SOD2V16A in the endothelium, we introduced the SOD2V16A variant into endothelial cells. SOD2V16A increases hydrogen peroxide and mitochondrial reactive oxygen species (ROS) production compared with controls. Unexpectedly, the increased ROS was not due to SOD2V16A mislocalization but was associated with mitochondrial complex IV and a concomitant decrease in basal respiration and complex IV activity. In sum, SOD2V16A is a novel clinical biomarker of cardiovascular dysfunction in SCD patients through its ability to decrease mitochondrial complex IV activity and amplify ROS production in the endothelium.
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Anemia Falciforme , Células Endoteliais , Anemia Falciforme/complicações , Anemia Falciforme/genética , Anemia Falciforme/metabolismo , Células Endoteliais/metabolismo , Humanos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismoRESUMO
INTRODUCTION: Core muscle injuries (CMI) are common in every sport. To minimize lost playing time, providers apply various nonsurgical treatments, including platelet-rich plasma, corticosteroids, ultrasound (US)-guided percutaneous tenotomy, and prolotherapy. Limited data exist with regard to their effectiveness. We chose to review a cohort of consecutive professional and collegiate athletes who sustained CMI at various points within their seasons and underwent a combination of US-guided percutaneous needle "tenotomy" and corticosteroid injections to complete the remainder of their seasons. METHODS: Twenty-five consecutive collegiate or professional athletes with CMI involving the rectus abdominis-adductor aponeurotic plate were included in this retrospective study. Athletes with concomitant symptomatic hip femoroacetabular impingement were included in the study. The primary outcome measure was whether athletes completed their seasons. Secondary measures were weeks played after the procedures (delay until surgery), need for repeat procedures, and outcomes after eventual surgery. Postoperative performance was assessed via interviews at 6 wk and 6 months postoperatively. RESULTS: Twenty-one of 25 (84%) athletes completed their seasons. On average, athletes returned to play 3 d (range, 1-9 d) after the procedures. Surgical repair was delayed a mean of 18 wk (range, 2-44 wk). Seven athletes had concomitant symptomatic femoroacetabular impingement and six underwent combined hip arthroscopy and core muscle repairs. Among 17 patients who eventually had core muscle surgery alone (no hip surgery), 82% (14 of 17) reported performing at their preinjury level at 6 wk. At 6 months, 96% of postop athletes (22 of 23) reported performing at their preinjury level. CONCLUSIONS: Temporizing CMI with US-guided percutaneous tenotomy and corticosteroid injections is effective in allowing continued sport participation among high-level athletes and does not negatively affect postoperative outcomes.
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Traumatismos Abdominais/terapia , Corticosteroides/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Traumatismos em Atletas/terapia , Reto do Abdome/lesões , Tenotomia/métodos , Ultrassonografia de Intervenção/métodos , Traumatismos Abdominais/diagnóstico por imagem , Corticosteroides/uso terapêutico , Adulto , Anti-Inflamatórios/uso terapêutico , Traumatismos em Atletas/diagnóstico por imagem , Desempenho Atlético , Terapia Combinada , Feminino , Seguimentos , Humanos , Injeções Intramusculares , Masculino , Estudos Retrospectivos , Volta ao Esporte , Tempo para o Tratamento , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVES: To evaluate whether Patient-Reported Outcomes Measurement Information System (PROMIS) pediatric patient-reported outcome (PRO) measures can serve as valid endpoints in a clinical trial of a chronic pediatric illness. STUDY DESIGN: We evaluated the responsiveness of PROMIS pediatric measures collected through the Clinical Outcomes of Methotrexate Binary Therapy in Practice (COMBINE) trial, a multicenter, randomized, double-blind, placebo-controlled, pragmatic clinical trial in pediatric patients with Crohn's disease (CD). We examined the relationships between changes in PROMIS pediatric measures and changes in disease activity by evaluating PRO score changes among patients who did and patients who did not experience improvement in disease activity. RESULTS: Participants included 266 children and adolescents with CD from a total of 35 institutions. Over the course of follow-up, participants showed improvement in most PRO domains, with the largest effect sizes observed for the clinically improved group. Patients who maintained steroid-free remission showed significantly lower PRO scores for the Pain Interference, Fatigue, and inflammatory bowel disease (IBD) Symptoms domains and higher scores for the Positive Affect domain. CONCLUSIONS: This study demonstrates the responsiveness of the PROMIS pediatric measures of Fatigue and Pain Interference as study endpoints in a large, multicenter pragmatic trial in pediatric CD, extending a growing body of research supporting the use of PROMIS pediatric measures as reliable PRO endpoints for clinical trials.
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Doença de Crohn , Adolescente , Criança , Doença de Crohn/tratamento farmacológico , Fadiga , Humanos , Sistemas de Informação , Dor , Medidas de Resultados Relatados pelo Paciente , Qualidade de VidaRESUMO
INTRODUCTION: The effect of platelet-rich plasma (PRP) treatment on recovery in acute hamstring injuries is controversial. Previous study results are inconsistent, and a standardized therapeutic approach has not been established yet. PURPOSE: To assess the treatment effect using a combination of hematoma aspiration and muscle strain PRP injection in partial hamstring muscle tears (grade 2 strains) in athletes. METHODS: Magnetic resonance imaging of athletes with grade 2 hamstring strains were reviewed from 2013 to 2018. From 2013 to 2015, athletes were treated conservatively, and from 2016 to 2018, with a combination of ultrasound-guided hematoma aspiration and PRP muscle strain injection. The outcome, including return-to-play (in days) and recurrence rate, was compared retrospectively between both groups (conservative vs aspiration/PRP) using ANOVA and Fisher's exact test. There was no significant difference in age, type of sport, and muscle involvement (including injury grade/location, hamstring muscle type, and length/cross-sectional area of the strain). RESULTS: Fifty-five athletes (28 treated conservatively, 27 with hematoma aspiration/PRP injection) were included. Average return-to-play time (mean) was 32.4 d in the conservative group and 23.5 d in the aspiration/PRP group (P < 0.001). Recurrence rate of the hamstring strain was 28.6% (8/28) in the conservative treatment group and less than 4% (1/27) in the aspiration/PRP group (P = 0.025). CONCLUSIONS: Athletes with grade 2 hamstring strains treated with a combination of hematoma aspiration and PRP injection had a significantly shorter return-to-play and a lower recurrence rate compared with athletes receiving conservative treatment.
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Traumatismos em Atletas/terapia , Músculos Isquiossurais/lesões , Hematoma/terapia , Paracentese/métodos , Plasma Rico em Plaquetas , Volta ao Esporte , Adolescente , Adulto , Humanos , Estudos Retrospectivos , Adulto JovemRESUMO
OBJECTIVE: The mainstay of treatment for patients with malignant pleural disease is fluid drainage and systemic therapy. A tumor-specific oncolytic virus or T-cell-activating interleukin-2 immunotherapy may provide an opportunity for local control. We previously developed a vaccinia virus-expressing interleukin-2, an oncolytic virus that mediated tumor regression in preclinical peritoneal tumor models with expansion of tumor-infiltrating lymphocytes. We evaluated the antitumor efficacy and immune modulatory effects of vaccinia virus-expressing interleukin-2 in malignant pleural disease. METHODS: A murine model of malignant pleural disease was established with percutaneous intrapleural deposition of the Lewis lung carcinoma cell line and monitored with bioluminescent imaging. After intrapleural or systemic administration of vaccinia viruses (vaccinia virus yellow fluorescent protein control, vaccinia virus-expressing interleukin-2), systemic anti-programmed cell death-1 antibody, or combination therapy (vaccinia virus-expressing interleukin-2 and anti-programmed cell death-1), tumor mass, immune cell infiltration, T-cell receptor diversity, and survival were assessed. RESULTS: Intrapleural vaccinia virus resulted in significant tumor regression compared with phosphate-buffered saline control (P < .05). Inclusion of the interleukin-2 transgene further increased intratumoral CD8+ T cells (P < .01) and programmed cell death-1 expression on CD8+ tumor-infiltrating lymphocytes (P < .001). Intrapleural vaccinia virus-expressing interleukin-2 was superior to systemic vaccinia virus-expressing interleukin-2, with reduced tumor burden (P < .0001) and improved survival (P < .05). Intrapleural vaccinia virus-expressing interleukin-2 alone or combined treatment with systemic anti-programmed cell death-1 reduced tumor burden (P < .01), improved survival (P < .01), and increased intratumoral αß T-cell receptor diversity (P < .05) compared with systemic anti-programmed cell death-1 monotherapy. CONCLUSIONS: Intrapleural vaccinia virus-expressing interleukin-2 reduced tumor burden and enhanced survival in a murine malignant pleural disease model. Increased CD8+ tumor-infiltrating lymphocytes and αß T-cell receptor diversity are associated with enhanced response. Clinical trials will enable assessment of intrapleural vaccinia virus-expressing interleukin-2 therapy in patients with malignant pleural disease.
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Interleucina-2/metabolismo , Neoplasias Pulmonares/imunologia , Terapia Viral Oncolítica , Receptores de Antígenos de Linfócitos T/metabolismo , Animais , Linfócitos T CD8-Positivos/metabolismo , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Receptor de Morte Celular Programada 1/metabolismo , Vaccinia virusRESUMO
Magnetite is the main constituent of iron oxide-apatite (IOA) deposits, which are a globally important source of Fe and other elements such as P and REE, critical for modern technologies. Geochemical studies of magnetite from IOA deposits have provided key insights into the ore-forming processes and source of mineralizing fluids. However, to date, only qualitative estimations have been obtained for one of the key controlling physico-chemical parameters, i.e., the temperature of magnetite formation. Here we reconstruct the thermal evolution of Andean IOA deposits by using magnetite thermometry. Our study comprised a > 3000 point geochemical dataset of magnetite from several IOA deposits within the Early Cretaceous Chilean Iron Belt, as well as from the Pliocene El Laco IOA deposit in the Chilean Altiplano. Thermometry data reveal that the deposits formed under a wide range of temperatures, from purely magmatic (~ 1000 to 800 °C), to late magmatic or magmatic-hydrothermal (~ 800 to 600 °C), to purely hydrothermal (< 600 °C) conditions. Magnetite cooling trends are consistent with genetic models invoking a combined igneous and magmatic-hydrothermal origin that involve Fe-rich fluids sourced from intermediate silicate magmas. The data demonstrate the potential of magnetite thermometry to better constrain the thermal evolution of IOA systems worldwide, and help refine the geological models used to find new resources.
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The arterial resistance vasculature modulates blood pressure and flow to match oxygen delivery to tissue metabolic demand. As such, resistance arteries and arterioles have evolved a series of highly orchestrated cell-cell communication mechanisms between endothelial cells and vascular smooth muscle cells to regulate vascular tone. In response to neurohormonal agonists, release of several intracellular molecules, including nitric oxide, evokes changes in vascular tone. We and others have uncovered novel redox switches in the walls of resistance arteries that govern nitric oxide compartmentalization and diffusion. In this review, we discuss our current understanding of redox switches controlling nitric oxide signaling in endothelial and vascular smooth muscle cells, focusing on new mechanistic insights, physiological and pathophysiological implications, and advances in therapeutic strategies for hypertension and other diseases.
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Pressão Sanguínea/fisiologia , Óxido Nítrico/fisiologia , Resistência Vascular/fisiologia , Comunicação Celular , Proteínas Quinases Dependentes de GMP Cíclico/fisiologia , Células Endoteliais/fisiologia , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/fisiologia , Oxirredução , Transdução de Sinais/fisiologiaRESUMO
INTRODUCTION: Active surveillance outcomes in minority patients are poorly characterized, as most surveillance series are comprised primarily of Caucasian men. We aimed to characterize outcomes of African American and Hispanic men undergoing surveillance and to identify factors associated with transition to definitive treatment. MATERIAL AND METHODS: We performed a retrospective analysis of men undergoing active surveillance at our institution. Reasons for transition to definitive treatment were determined. Cessation of active surveillance was recommended for Gleason upgrading on surveillance biopsy. We characterized treatment-free survival for men on surveillance and compared this by race/ethnicity (as self reported by patients). Demographic and clinical variables associated with active surveillance cessation were identified using Cox proportional hazards regression. RESULTS: A total of 141 men were on active surveillance: 84 non-Hispanic Black/African American (59.6%), 32 Hispanic (22.7%), and 25 non-Hispanic White/Caucasian (17.7%). Two-year treatment-free survival for Caucasian, Black and Hispanic patients was 81.2%, 54.4%, and 75.0%, respectively. Pairwise Cox proportional hazards analysis showed significantly decreased treatment-free survival in Black compared to Caucasian men (HR 2.42, 95% CI 1.03-5.68). In African American men, cessation of active surveillance occurred most commonly due to grade reclassification at the time of confirmatory biopsy. CONCLUSIONS: Among our active surveillance cohort composed primarily of racial and ethnic minorities, we identified relatively high rates of progression to definitive treatment. African American race was associated with surveillance cessation on univariate analysis. These findings stress the importance of confirmatory biopsy and strict compliance with surveillance protocols in AA men to ensure timely detection of disease reclassification.
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Neoplasias da Próstata/epidemiologia , Negro ou Afro-Americano , Idoso , Estudos de Coortes , Hispânico ou Latino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
BACKGROUND: Previous studies have reported healthcare disparities in the Texas-Mexico border population. Our aim was to evaluate treatment utilization and oncologic outcomes of colon cancer patients in this vulnerable population. METHODS: Patients with localized and regional colon cancer (CC) were identified in the Texas Cancer Registry (1995-2016). Clinicopathological data, hospital factors, receipt of optimal treatment, and overall survival (OS) were compared between Texas-Mexico Border (TMB) and the Non-Texas-Mexico Border (NTMB) cohorts. Multivariable analysis was performed to identify risk factors associated with decreased survival. RESULTS: We identified 43,557 patients with localized/regional CC (9% TMB and 91% NTMB). TMB patients were more likely to be Hispanic (73% versus 13%), less likely to have private insurance (13% versus 21%), were more often treated at safety net hospitals (82% versus 22%) and less likely at ACS-CoC accredited hospitals (32% versus 57%). TMB patients were more likely to receive suboptimal treatment (21% versus 16%) and had a lower median OS for localized (8.58 versus 9.58 y) and regional colon cancer (5.75 versus 6.18 y, all P < 0.001). In multivariable analysis, TMB status was not associated with worse OS. Factors associated with worse survival included receipt of suboptimal treatment, Medicare/insured status, and treatment in safety net and non-accredited ACS-CoC hospitals (all P < 0.001) CONCLUSIONS: While TMB CC patients had worse OS, TMB status itself was not found to be a risk factor for decreased survival. This survival disparity is likely associated with higher rate of suboptimal treatment, Medicare/Uninsured status, and decreased access to ACS-CoC accredited hospitals.
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Neoplasias do Colo , Medicare , Idoso , Neoplasias do Colo/terapia , Disparidades em Assistência à Saúde , Humanos , México , Texas/epidemiologia , Estados UnidosRESUMO
BACKGROUND: Many patients with heart failure with preserved ejection fraction have metabolic syndrome and develop exercise-induced pulmonary hypertension (EIPH). Increases in pulmonary vascular resistance in patients with heart failure with preserved ejection fraction portend a poor prognosis; this phenotype is referred to as combined precapillary and postcapillary pulmonary hypertension (CpcPH). Therapeutic trials for EIPH and CpcPH have been disappointing, suggesting the need for strategies that target upstream mechanisms of disease. This work reports novel rat EIPH models and mechanisms of pulmonary vascular dysfunction centered around the transcriptional repression of the soluble guanylate cyclase (sGC) enzyme in pulmonary artery (PA) smooth muscle cells. METHODS: We used obese ZSF-1 leptin-receptor knockout rats (heart failure with preserved ejection fraction model), obese ZSF-1 rats treated with SU5416 to stimulate resting pulmonary hypertension (obese+sugen, CpcPH model), and lean ZSF-1 rats (controls). Right and left ventricular hemodynamics were evaluated using implanted catheters during treadmill exercise. PA function was evaluated with magnetic resonance imaging and myography. Overexpression of nuclear factor Y α subunit (NFYA), a transcriptional enhancer of sGC ß1 subunit (sGCß1), was performed by PA delivery of adeno-associated virus 6. Treatment groups received the SGLT2 inhibitor empagliflozin in drinking water. PA smooth muscle cells from rats and humans were cultured with palmitic acid, glucose, and insulin to induce metabolic stress. RESULTS: Obese rats showed normal resting right ventricular systolic pressures, which significantly increased during exercise, modeling EIPH. Obese+sugen rats showed anatomic PA remodeling and developed elevated right ventricular systolic pressure at rest, which was exacerbated with exercise, modeling CpcPH. Myography and magnetic resonance imaging during dobutamine challenge revealed PA functional impairment of both obese groups. PAs of obese rats produced reactive oxygen species and decreased sGCß1 expression. Mechanistically, cultured PA smooth muscle cells from obese rats and humans with diabetes or treated with palmitic acid, glucose, and insulin showed increased mitochondrial reactive oxygen species, which enhanced miR-193b-dependent RNA degradation of nuclear factor Y α subunit (NFYA), resulting in decreased sGCß1-cGMP signaling. Forced NYFA expression by adeno-associated virus 6 delivery increased sGCß1 levels and improved exercise pulmonary hypertension in obese+sugen rats. Treatment of obese+sugen rats with empagliflozin improved metabolic syndrome, reduced mitochondrial reactive oxygen species and miR-193b levels, restored NFYA/sGC activity, and prevented EIPH. CONCLUSIONS: In heart failure with preserved ejection fraction and CpcPH models, metabolic syndrome contributes to pulmonary vascular dysfunction and EIPH through enhanced reactive oxygen species and miR-193b expression, which downregulates NFYA-dependent sGCß1 expression. Adeno-associated virus-mediated NFYA overexpression and SGLT2 inhibition restore NFYA-sGCß1-cGMP signaling and ameliorate EIPH.
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Fator de Ligação a CCAAT/metabolismo , Insuficiência Cardíaca/etiologia , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/etiologia , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , MicroRNAs/genética , Espécies Reativas de Oxigênio/metabolismo , Guanilil Ciclase Solúvel/genética , Animais , Animais Geneticamente Modificados , Biomarcadores , Modelos Animais de Doenças , Suscetibilidade a Doenças , Exercício Físico , Regulação da Expressão Gênica , Insuficiência Cardíaca/diagnóstico , Humanos , Síndrome Metabólica/complicações , Mitocôndrias Cardíacas , Miócitos de Músculo Liso/metabolismo , Fenótipo , Ratos , Transdução de Sinais , Estresse Fisiológico , Volume Sistólico , Disfunção Ventricular DireitaRESUMO
BACKGROUND: Migration of Venezuelan citizens to other South American countries has increased in recent years. While the prevalence, morbidity, and mortality of infectious diseases in Venezuelan migrants across South America appears to be well described, the non-communicable disease (NCD) and maternal and child health needs in this population is less clear. A scoping review of existing peer-reviewed primary research and grey literature describing the epidemiology of NCDs and maternal and child health needs in Venezuelan migrants in major South American host countries was performed in order to highlight important gaps in knowledge. METHODS: A scoping review was performed of peer-reviewed research and grey literature for NCD and maternal and child health needs among Venezuelan migrants living in the following host South American countries with greater than 100,000 migrants: Argentina, Brazil, Chile, Colombia, Ecuador, and Peru. A total of 47 electronic databases were searched for primary research published between 2017 and 2020 in either English or Spanish. RESULTS: Out of 1,098 initial articles retrieved, 17 records met inclusion criteria, with the majority identified from the grey literature. Most studies were published in 2019 and most were either primary reports published by non-governmental organizations within the grey literature search or cross-sectional qualitative studies. Studies came from Argentina, Chile, Colombia, and Peru, with three records offering a regional perspective. Most studies provided broad data on NCDs and maternal and child health needs but lacked granular statistics. Our analysis found the rate of chronic disease among Venezuelan migrants to range from 9-14% within countries who reported this data. Significant rates of psychiatric conditions such as depression and post-traumatic stress disorder were reported. Other conditions described were ophthalmologic diseases, diabetes, chronic pain, asthma, cough, dyslipidemia, hypertension, arthritis, malnutrition, and obstetric complications, although exact statistics were limited. Obstacles to care included lack of healthcare access and affordability. CONCLUSIONS: Existing reports discuss important needs related to NCDs and maternal and child health in Venezuelan migrants in South American countries, but there are significant gaps in knowledge. Further research must describe in greater detail the prevalence, morbidity, and mortality of NCDs and maternal and child health needs in Venezuelan migrants in this region in order to assist local governments and international humanitarian organizations with providing strategic and unified responses.
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PURPOSE: Neurotrophic tyrosine receptor kinase (NTRK) fusions have been described as oncogenic drivers in a variety of tumors. However, little is known about the overall frequency of NTRK fusion in unselected pediatric tumors. Here, we assessed the frequency, fusion partners, and clinical course in pediatric patients with NTRK fusion-positive tumors. PATIENTS AND METHODS: We studied 1,347 consecutive pediatric tumors from 1,217 patients who underwent tumor genomic profiling using custom-designed DNA and RNA next-generation sequencing panels. NTRK fusions identified were orthogonally confirmed. RESULTS AND DISCUSSION: NTRK fusions were identified in 29 tumors from 27 patients with a positive yield of 2.22% for all patients and 3.08% for solid tumors. Although NTRK2 fusions were found exclusively in CNS tumors and NTRK1 fusions were highly enriched in papillary thyroid carcinomas, NTRK3 fusions were identified in all tumor categories. The most canonical fusion was ETV6-NTRK3 observed in 10 patients with diverse types of tumors. Several novel NTRK fusions were observed in rare tumor types, including KCTD16-NTRK1 in ganglioglioma and IRF2BP2-NTRK3 in papillary thyroid carcinomas. The detection of an NTRK fusion confirmed the morphologic diagnosis including five cases where the final tumor diagnosis was largely based on the discovery of an NTRK fusion. In one patient, the diagnosis was changed because of the identification of an ETV6-NTRK3 fusion. One patient with infantile fibrosarcoma was treated with larotrectinib and achieved complete pathologic remission. CONCLUSION: NTRK fusions are more frequently seen in pediatric tumors than in adult tumors and involve a broader panel of fusion partners and a wider range of tumors than previously recognized. These results highlight the importance of screening for NTRK fusions as part of the tumor genomic profiling for patients with pediatric cancer.
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INTRODUCTION: Radiation therapy (XRT) has been investigated as a possible treatment for high-risk non-muscle invasive bladder cancer (NMIBC) with the goal of bladder preservation, especially with the ongoing Bacillus Calmette-Guerin (BCG) shortage. Yet, little is known about the clinical efficacy and the quality of evidence supporting XRT for NMIBC. Herein, we performed a systematic review and meta-analysis to evaluate XRT in the treatment of patients with high-risk NMIBC. METHODS: Cochrane Central Register of Controlled Trials, EMBASE, MEDLINE, and Web of Science were searched for high-risk NMIBC (high grade T1, T1/Ta with associated risk features: carcinoma in-situ (CIS), multifocality, > 5cm in diameter, and/or multiple recurrences) treated with primary XRT. Outcomes evaluated were recurrence-free survival (RFS), cancer-specific-survival (CSS), overall survival (OS), and salvage cystectomy and progression to metastatic disease rates. A meta-analysis was performed to assess outcomes for XRT in NMIBC. RESULTS: Overall,13 studies including 746 patients met the search criteria. The 5-year rates of RFS, CSS and OS were 54% (95% CIâ¯=â¯38% - 70%), 86% (95% CIâ¯=â¯80% - 92%), and 72% (95% CIâ¯=â¯64% - 79%). Notably, 13% of patients proceeded to salvage radical cystectomy and 9% developed metastatic disease. All studies were of poor quality, comprising single institution and retrospective studies with only one clinical trial. CONCLUSION: XRT for high-risk NMIBC provides some degree of oncologic control, although distant progression was noted. In the setting of the low-quality evidence, a prospective clinical trial is needed to clearly define the risks and benefits of this approach.