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1.
J Am Heart Assoc ; 9(2): e015400, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31959033

RESUMO

Background Although changes in left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume, and global circumferential strain occur during cancer treatment, the relationship of these changes to the 2-year post-cancer-treatment measures of left ventricular ejection fraction (LVEF) are unknown. Methods and Results In a prospective, continuously recruited cohort of 95 patients scheduled to receive potentially cardiotoxic chemotherapy for breast cancer, lymphoma, or soft tissue sarcoma, measures of left ventricular end-diastolic volume, LVESV, global circumferential strain, and LVEF were acquired via cardiac magnetic resonance imaging before and then 3 and 24 months after initiating treatment by individuals blinded to all patient identifiers. Participants had an average age of 54±15 years; 68% were women, and 82% were of white race. LVEF declined from 62±7% to 58±9% over the 24 months (P<0.0001), with 42% of participants experiencing a >5% decline in LVEF at 24 months. Predictors of a 24-month >5% decline in LVEF included the following factors from baseline to 3 months into treatment: (1) >3-mL increases in LVESV (P=0.033), (2) >3-mL increases in LVESV or 10-mL declines in left ventricular end-diastolic volume with little change in LVESV (P=0.001), or (3) ≥10% deteriorations in global circumferential strain with little change in LVESV (P=0.036). Conclusion During receipt of potentially cardiotoxic chemotherapy, increases in LVESV, the absence of its deterioration during decreases of left ventricular end-diastolic volume, or the deterioration of global circumferential strain without a marked decrease in LVESV help identify those who will develop more permanent 2-year declines in LVEF.

2.
Pediatr Diabetes ; 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31943641

RESUMO

BACKGROUND: There is significant global variation in the prevalence of diabetic ketoacidosis (DKA) at diagnosis among youth with type 1 diabetes (T1D). However, data for youth with type 2 diabetes (T2D) are limited, even in developed countries. We compared the prevalence of DKA at diagnosis among individuals with T1D and T2D from the SEARCH for Diabetes in Youth (SEARCH) and the Registry of Youth Onset Diabetes in India (YDR) registries. METHODS: We harmonized the SEARCH and YDR registries to the structure and terminology in the Observational Medical Outcome Partnership Common Data Model. Data used were from youth with T1D and T2D diagnosed before 20 years and newly diagnosed between 2006 and 2012 in YDR and 2009 and 2012 in SEARCH. RESULTS: There were 5366 US youth (4078 with T1D, 1288 with T2D) and 2335 Indian youth (2108 with T1D, 227 with T2D). More than one third of T1D youth enrolled in SEARCH had DKA at diagnosis which was significantly higher than in YDR (35.3% vs 28.7%, P < .0001). The burden of DKA in youth with T1D was significantly higher among younger age groups; this relationship was similar across registries (P = .4). The prevalence of DKA among T2D in SEARCH and YDR were 5.5% and 6.6% respectively (P = .4). CONCLUSIONS: There is significant burden of DKA at diagnosis with T1D among youth from United States and India, especially among the younger age groups. The reasons for this high prevalence are largely unknown but are critical to developing interventions to prevent DKA at diagnosis.

3.
Clin Infect Dis ; 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31899478

RESUMO

BACKGROUND: Cardiovascular disease (CVD) and associated comorbidities increase the risk of cognitive impairment in persons living with HIV (PLWH). Given the potential composite effect of multiple cardiovascular risk factors on cognition, we examined the ability of the Atherosclerotic Cardiovascular Disease (ASCVD) risk score and the Framingham Heart Study Global CVD risk score (FRS) to predict future cognitive function in older PLWH. METHODS: We constructed linear regression models evaluating the association between baseline 10-year CV risk scores and cognitive function (measured by NPZ-4 score) at a Year 4 follow up visit. RESULTS: Among 988 participants (mean age 52 years, 20% women), mean 10-year ASCVD risk score at entry into the cohort was 6.8% (SD 7.1%) and FRS was 13.1% (SD 10.7%). In models adjusted only for cognitive function at entry, the ASCVD risk score significantly predicted Year 4 NPZ-4 in the entire cohort and after stratification by sex (for every 1% higher ASCVD risk, Year 4 NPZ-4 was lower by 0.84 SD +/- 0.28 overall, p=0.003; lower by 2.17 SD +/- 0.67 in women, p=0.001; lower by 0.78 SD +/- 0.32 in men, p=0.016). A similar relationship was observed between FRS and Year 4 NPZ-4. In multivariable models, higher 10-year ASCVD risk and FRS predicted lower NPZ-4 in women. CONCLUSION: Baseline 10-year ASCVD risk and FRS predicted future cognitive function in older PLWH with well-controlled infection. CV risk scores may help to identify individuals, especially women, living with HIV who are at risk for worse cognition over time.

4.
Pediatr Diabetes ; 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31953884

RESUMO

BACKGROUND: Over the last decades, diabetes in youth has increased in both India and the United States, along with the burden of long-term complications and healthcare costs. However, there are limited standardized population-based data in contemporary youth cohorts for comparison of clinical and demographic characteristics of diabetes for both type 1 (T1D) and type 2 (T2D). METHODS: In partnership, we harmonized demographic and clinical data from the SEARCH for Diabetes in Youth (SEARCH) registry in the United States and the Registry of People with Diabetes with Youth Age at Onset (YDR) in India to the structure and terminology of the Observational Medical Outcomes Partnership Common Data Model. Data were from youth with T1D and T2D, aged <20 years and newly diagnosed between 2006 and 2010. We compared key characteristics across registries using χ2 tests and t-tests. RESULTS: In total, there were 9650 youth with T1D and 2406 youth with T2D from 2006 to 2012. SEARCH youth were diagnosed at younger ages than YDR youth for T1D and T2D (10.0 vs 10.5 years, P < .001 and 14.7 vs 16.1 years, P < .001, respectively). For T2D, SEARCH had a higher proportion of females and significantly lower proportion of youth of high socioeconomic status compared to YDR. For T1D and T2D, SEARCH youth had higher BMI, lower blood pressure, and lower A1c compared to YDR youth. CONCLUSIONS: These data offer insights into the demographic and clinical characteristics of diabetes in youth across the two countries. Further research is needed to better understand why these differences exist.

6.
Plast Reconstr Surg Glob Open ; 7(6): e2259, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31624675

RESUMO

Background: Closed incision negative pressure therapy (ciNPT) is an emerging approach to managing closed incisions of patients at risk of postoperative complications. There are primarily 2 different commercially available ciNPT systems. Both systems consist of a single-use, battery-powered device and foam- or gauze-based peel-and-place dressing designed for closed incisions. These systems vary in design, and there are no data comparing outcomes between the 2 systems. Methods: We performed 2 separate meta-analyses to compare surgical site infection (SSI) rates postuse of (1) ciNPT with foam dressing (FOAM) versus conventional dressings and (2) ciNPT with multilayer absorbent dressing (MLA) versus conventional dressings. Results: Seven articles and 2 abstracts met inclusion criteria in the FOAM group (n = 489) versus the control group (n = 489) in meta-analysis 1; 7 articles and 1 abstract met inclusion criteria in the MLA group (n = 532) versus the control group (n = 540) in meta-analysis 2. Meta-analysis 1 showed that patients in the control group were 3.17 times more likely to develop an SSI compared with patients in the FOAM group [weighted mean odds ratios of FOAM group versus control group was 3.17 (P < 0.0001) with the 95% confidence intervals of 2.17-4.65]. Meta-analysis 2 showed no significant difference in SSI rates between patients in the MLA group and patients in the control group [weighted mean odds ratios of MLA group versus control group was 1.70 (P = 0.08) with the 95% confidence intervals of 0.94-3.08]. Conclusions: Comparing outcomes of two different ciNPT systems with a common comparator (conventional dressings) may provide an interim basis for comparing ciNPT systems until further comparative evidence is available. More comparative research is required to determine outcomes in clinical practice.

7.
Ann Epidemiol ; 37: 37-42, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31383511

RESUMO

PURPOSE: Most surveillance efforts in childhood diabetes have focused on incidence, whereas prevalence is rarely reported. This study aimed to assess whether a mathematical illness-death model accurately estimated future prevalence from baseline prevalence and incidence rates in children. METHODS: SEARCH for Diabetes in Youth is an ongoing population-based surveillance study of prevalence and incidence of diabetes and its complications among youth in the United States. We used age-, sex-, and race/ethnicity-specific SEARCH estimates of the prevalence of type I and type II diabetes in 2001 and incidence from 2002 to 2008. These data were used in a partial differential equation to estimate prevalence in 2009 with 95% bootstrap confidence intervals. Model-based prevalence was compared with the observed prevalence in 2009. RESULTS: Most confidence intervals for the difference between estimated and observed prevalence included zero, indicating no evidence for a difference between the two methods. The width of confidence intervals indicated high precision for the estimated prevalence when considering all races/ethnicities. In strata with few cases, precision was reduced. CONCLUSIONS: Future prevalence of type I and type II diabetes in youth may be accurately estimated from baseline prevalence and incidence. Diabetes surveillance could benefit from potential cost savings of this method.

8.
J Am Heart Assoc ; 8(11): e012366, 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31433717

RESUMO

Background Early rapid declines of kidney function may occur in patients with atherosclerotic renal artery stenosis with institution of medical therapy. The causes and consequences are not well understood. Methods and Results Patients enrolled in the medical therapy-only arm of the CORAL (Cardiovascular Outcomes With Renal Artery Lesions) study were assessed for a rapid decline (RD) in estimated glomerular filtration rate (eGFR), defined as a ≥30% decrease from baseline to either 3 months, 6 months, or both. In the medical therapy-only cohort, eGFR was available in 359 subjects at all time points, the subjects were followed for a median of 4.72 years, and 66 of 359 (18%) subjects experienced an early RD. Baseline log cystatin C (odds ratio, 1.78 [1.11-2.85]; P=0.02), age (odds ratio, 1.04 [1.00-1.07]; P<0.05), and Chronic Kidney Disease Epidemiology Collaboration creatinine eGFR (odds ratio, 1.86 [1.15-3.0]; P=0.01) were associated with an early RD. Despite continued medical therapy only, the RD group had an improvement in eGFR at 1 year (6.9%; P=0.04). The RD and nondecline groups were not significantly different for clinical events and all-cause mortality (P=0.78 and P=0.76, respectively). Similarly, renal replacement therapy occurred in 1 of 66 (1.5%) of the RD patients and in 6 of 294 (2%) of the nondecline patients. The regression to the mean of improvement in eGFR at 1 year in the RD group was estimated at 5.8±7.1%. Conclusions Early rapid declines in kidney function may occur in patients with renal artery stenosis when medical therapy is initiated, and their clinical outcomes are comparable to those without such a decline, when medical therapy only is continued.

9.
Environ Int ; 132: 105064, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31419765

RESUMO

BACKGROUND: Evidence remains equivocal regarding the association of inflammation, a precursor to cardiovascular disease, and acute exposures to ambient air pollution from traffic-related particulate matter. Though youth with type 1 diabetes are at higher risk for cardiovascular disease, the relationship of inflammation and ambient air pollution exposures in this population has received little attention. OBJECTIVES: Using five geographically diverse US sites from the racially- and ethnically-diverse SEARCH for Diabetes in Youth Cohort, we examined the relationship of acute exposures to PM2.5 mass, Atmospheric Dispersion Modeling System (ADMS)-Roads traffic-related PM concentrations near roadways, and elemental carbon (EC) with biomarkers of inflammation including interleukin-6 (IL-6), c-reactive protein (hs-CRP) and fibrinogen. METHODS: Baseline questionnaires and blood were obtained at a study visit. Using a spatio-temporal modeling approach, pollutant exposures for 7 days prior to blood draw were assigned to residential addresses. Linear mixed models for each outcome and exposure were adjusted for demographic and lifestyle factors identified a priori. RESULTS: Among the 2566 participants with complete data, fully-adjusted models showed positive associations of EC average week exposures with IL-6 and hs-CRP, and PM2.5 mass exposures on lag day 3 with IL-6 levels. Comparing the 25th and 75th percentiles of average week EC exposures resulted in 8.3% higher IL-6 (95%CI: 2.7%,14.3%) and 9.8% higher hs-CRP (95%CI: 2.4%,17.7%). We observed some evidence of effect modification for the relationships of PM2.5 mass exposures with hs-CRP by gender and with IL-6 by race/ethnicity. CONCLUSIONS: Indicators of inflammation were associated with estimated traffic-related air pollutant exposures in this study population of youth with type 1 diabetes. Thus youth with type 1 diabetes may be at increased risk of air pollution-related inflammation. These findings and the racial/ethnic and gender differences observed deserve further exploration.

10.
Am Heart J ; 216: 30-41, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31386936

RESUMO

In patients with atherosclerotic cardiovascular disease (ASCVD), guidelines recommend statins as first-line lipid-lowering therapy (LLT) with addition of nonstatin agents in those with persistently elevated low-density lipoprotein cholesterol levels. METHODS: To estimate the cardiovascular (CV) risk reduction implications of treatment intensification, we used a previously reported simulation model with enhancements. An ASCVD cohort was developed from a US claims database. A Cox model was used to estimate baseline risk of CV events: myocardial infarction, ischemic stroke, unstable angina hospitalization, elective coronary revascularization, or cardiovascular death. Patients were sampled with replacement (bootstrapping) and entered the simulation model, which applied stepwise LLT intensification logic, with a goal of achieving low-density lipoprotein cholesterol less than 70 mg/dL at each step. CV risk reduction assumptions were based on published data. Two treatment intensification scenarios were investigated: ideal and real-world (which accounted for statin intolerance, nonadherence, and payer restrictions). RESULTS: In a cohort of 1,000 patients with ASCVD, approximately 813 (809-818) would require treatment intensification with LLT under an ideal treatment intensification scenario. Before treatment intensification, 183 (179-187) events would be expected to occur over 5 years. With treatment intensification, 40 (34-45) of these events could be avoided. In a real-world scenario, about 818 (813-823) patients require treatment intensification with LLT, resulting in 29 (24-34) events avoided over 5 years. CONCLUSIONS: Intensification of LLT in an ASCVD population translates into a substantial number of CV events avoided. This simulation-based model could assist in assessing the potential benefits of various types of population-level LLT interventions.

12.
EBioMedicine ; 44: 209-224, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31160272

RESUMO

BACKGROUND: Administration of amplitude modulated 27·12 MHz radiofrequency electromagnetic fields (AM RF EMF) by means of a spoon-shaped applicator placed on the patient's tongue is a newly approved treatment for advanced hepatocellular carcinoma (HCC). The mechanism of action of tumour-specific AM RF EMF is largely unknown. METHODS: Whole body and organ-specific human dosimetry analyses were performed. Mice carrying human HCC xenografts were exposed to AM RF EMF using a small animal AM RF EMF exposure system replicating human dosimetry and exposure time. We performed histological analysis of tumours following exposure to AM RF EMF. Using an agnostic genomic approach, we characterized the mechanism of action of AM RF EMF. FINDINGS: Intrabuccal administration results in systemic delivery of athermal AM RF EMF from head to toe at levels lower than those generated by cell phones held close to the body. Tumour shrinkage results from differentiation of HCC cells into quiescent cells with spindle morphology. AM RF EMF targeted antiproliferative effects and cancer stem cell inhibiting effects are mediated by Ca2+ influx through Cav3·2 T-type voltage-gated calcium channels (CACNA1H) resulting in increased intracellular calcium concentration within HCC cells only. INTERPRETATION: Intrabuccally-administered AM RF EMF is a systemic therapy that selectively block the growth of HCC cells. AM RF EMF pronounced inhibitory effects on cancer stem cells may explain the exceptionally long responses observed in several patients with advanced HCC. FUND: Research reported in this publication was supported by the National Cancer Institute's Cancer Centre Support Grant award number P30CA012197 issued to the Wake Forest Baptist Comprehensive Cancer Centre (BP) and by funds from the Charles L. Spurr Professorship Fund (BP). DWG is supported by R01 AA016852 and P50 AA026117.


Assuntos
Canais de Cálcio Tipo T/metabolismo , Cálcio/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/terapia , Terapia de Campo Magnético , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Carcinoma Hepatocelular/patologia , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Hepáticas/patologia , Terapia de Campo Magnético/métodos , Camundongos , Células-Tronco Neoplásicas/metabolismo , Especificidade de Órgãos , RNA Interferente Pequeno/genética , Radiometria , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Stat Med ; 38(20): 3817-3831, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31211443

RESUMO

When comparing performances of two risk prediction models, several metrics exist to quantify prognostic improvement, including the change in the area under the Receiver Operating Characteristic curve, the Integrated Discrimination Improvement, the Net Reclassification Index at event rate, the change in Standardized Net Benefit, the change in Brier score, and the change in scaled Brier score. We explore the behavior and interrelationships between these metrics under multivariate normality in nested and nonnested model comparisons. We demonstrate that, within the framework of linear discriminant analysis, all six statistics are functions of squared Mahalanobis distance, a robust metric that properly measures discrimination by quantifying the separation between the risk scores of events and nonevents. These relationships are important for overall interpretability and clinical usefulness. Through simulation, we demonstrate that the performance of the theoretical estimators under normality is comparable or superior to empirical estimation methods typically used by investigators. In particular, the theoretical estimators for the Net Reclassification Index and the change in Standardized Net Benefit exhibit less variability in their estimates as compared to their empirically estimated counterparts. Finally, we explore how these metrics behave with potentially nonnormal data by applying these methods in a practical example based on the sex-specific cardiovascular disease risk models from the Framingham Heart Study. Our findings aim to give greater insight into the behavior of these measures and the connections existing among them and to provide additional estimation methods with less variability for the Net Reclassification Index and the change in Standardized Net Benefit.

14.
J Am Coll Cardiol ; 73(17): 2135-2145, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31047001

RESUMO

BACKGROUND: Concentrations of circulating apolipoproteins are strongly linked to risk for coronary artery disease (CAD). The relative importance of the additional knowledge of apolipoprotein concentrations within specific lipoprotein species for CAD risk prediction is limited. OBJECTIVES: This study sought to evaluate the performance of a high-density lipoprotein (HDL) apolipoproteomic score, based on targeted mass spectrometry of HDL-associated apolipoproteins, for the detection of angiographic CAD and outcomes. METHODS: HDL-associated apolipoprotein (apo) A-1, apoC-1, apoC-2, apoC-3, and apoC-4 were measured in 943 participants without prevalent myocardial infarction (MI) referred for coronary angiography in the CASABLANCA (Catheter Sampled Blood Archive in Cardiovascular Diseases) study. A composite HDL apolipoproteomic score (pCAD) was associated with likelihood of obstructive CAD (≥70% lesion in ≥1 vessel) and with incident cardiovascular outcomes over 4-year follow-up. RESULTS: There were 587 (62.2%) patients with coronary stenosis. The pCAD score was associated with the presence of obstructive CAD (odds ratio: 1.39; 95% confidence interval [CI]: 1.14 to 1.69; p < 0.001), independently of conventional cardiovascular risk factors including circulating plasma apoA-1 and apoB. The C-index for pCAD was 0.63 (95% CI: 0.59 to 0.67) for the presence of obstructive CAD. Although pCAD was not associated with cardiovascular mortality among all individuals (hazard ratio: 1.24; 95% CI: 0.93 to 1.66; p = 0.15), there was evidence of association for individuals with obstructive CAD (hazard ratio: 1.48; 95% CI: 1.07 to 2.05; p = 0.019). CONCLUSIONS: An HDL apolipoproteomic score is associated with the presence of CAD, independent of circulating apoA-1 and apoB concentrations and other conventional cardiovascular risk factors. Among individuals with CAD, this score may be independently associated cardiovascular death. (The CASABLANCA Study: Catheter Sampled Blood Archive in Cardiovascular Diseases [CASABLANCA]; NCT00842868).

15.
Eur Radiol ; 29(11): 6140-6148, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31049733

RESUMO

OBJECTIVES: To investigate the association between directly measured density and morphology of coronary artery calcium (CAC) with cardiovascular disease (CVD) events, using computed tomography (CT). METHODS: Framingham Heart Study (FHS) participants with CAC in noncontrast cardiac CT (2002-2005) were included and followed until 2016. Participants with known CVD or uninterpretable CT scans were excluded. We assessed and correlated (Spearman) CAC density, CAC volume, and the number of calcified segments. Moreover, we counted morphology features including shape (cylindrical, spherical, semi-tubular, and spotty), location (bifurcation, facing pericardium, or facing myocardium), and boundary regularity. In multivariate Cox regression analyses, we associated all CAC characteristics with CVD events (CVD-death, myocardial infarction, stroke). RESULTS: Among 1330 included participants (57.8 ± 11.7 years; 63% male), 73 (5.5%) experienced CVD events in a median follow-up of 9.1 (7.8-10.1) years. CAC density correlated strongly with CAC volume (Spearman's ρ = 0.75; p < 0.001) and lower number of calcified segments (ρ = - 0.86; p < 0.001; controlled for CAC volume). In the survival analysis, CAC density was associated with CVD events independent of Framingham risk score (HR (per SD) = 2.09; 95%CI, 1.30-3.34; p = 0.002) but not after adjustment for CAC volume (p = 0.648). The extent of spherically shaped and pericardially sided calcifications was associated with fewer CVD events accounting for the number of calcified segments (HR (per count) = 0.55; 95%CI, 0.31-0.98; p = 0.042 and HR = 0.66; 95%CI, 0.45-0.98; p = 0.039, respectively). CONCLUSIONS: Directly measured CAC density does not predict CVD events due to the strong correlation with CAC volume. The spherical shape and pericardial-sided location of CAC are associated with fewer CVD events and may represent morphological features related to stable coronary plaques. KEY POINTS: • Coronary calcium density may not be independently associated with cardiovascular events. • Coronary calcium density correlates strongly with calcium volume. • Spherical shape and pericardial-sided location of CAC are associated with fewer CVD events.


Assuntos
Cálcio/metabolismo , Angiografia Coronária/métodos , Doença da Artéria Coronariana/diagnóstico , Vasos Coronários/diagnóstico por imagem , Tomografia Computadorizada Multidetectores/métodos , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prevalência , Estudos Prospectivos , Curva ROC , Fatores de Risco , Estados Unidos/epidemiologia
16.
EBioMedicine ; 44: 194-208, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31129098

RESUMO

BACKGROUND: Brain metastases are a major cause of death in patients with metastatic breast cancer. While surgical resection and radiation therapy are effective treatment modalities, the majority of patients will succumb from disease progression. We have developed a novel therapy for brain metastases that delivers athermal radiofrequency electromagnetic fields that are amplitude-modulated at breast cancer specific frequencies (BCF). METHODS: 27.12 MHz amplitude-modulated BCF were administered to a patient with a breast cancer brain metastasis by placing a spoon-shaped antenna on the anterior part of the tongue for three one-hour treatments every day. In preclinical models, a BCF dose, equivalent to that delivered to the patient's brain, was administered to animals implanted with either brain metastasis patient derived xenografts (PDXs) or brain-tropic cell lines. We also examined the efficacy of combining radiation therapy with BCF treatment. Additionally, the mechanistic underpinnings associated with cancer inhibition was identified using an agnostic approach. FINDINGS: Animal studies demonstrated a significant decrease in growth and metastases of brain-tropic cell lines. Moreover, BCF treatment of PDXs established from patients with brain metastases showed strong suppression of their growth ability. Importantly, BCF treatment led to significant and durable regression of brain metastasis of a patient with triple negative breast cancer. The tumour inhibitory effect was mediated by Ca2+ influx in cancer cells through CACNA1H T-type voltage-gated calcium channels, which, acting as the cellular antenna for BCF, activated CAMKII/p38 MAPK signalling and inhibited cancer stem cells through suppression of ß-catenin/HMGA2 signalling. Furthermore, BCF treatment downregulated exosomal miR-1246 level, which in turn decreased angiogenesis in brain environment. Therefore, targeted growth inhibition of breast cancer metastases was achieved through CACNA1H. INTERPRETATION: We demonstrate that BCF, as a single agent or in combination with radiation, is a novel treatment approach to the treatment of brain metastases. This paradigm shifting modality warrants further clinical trials for this unmet medical need.


Assuntos
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/secundário , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Canais de Cálcio Tipo T/metabolismo , Cálcio/metabolismo , Terapia de Campo Magnético , Animais , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/terapia , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Campos Eletromagnéticos , Feminino , Perfilação da Expressão Gênica , Proteína HMGA2 , Humanos , Imuno-Histoquímica , Sistema de Sinalização das MAP Quinases , Terapia de Campo Magnético/métodos , Camundongos , Modelos Biológicos , Células-Tronco Neoplásicas/metabolismo
17.
Int J Nephrol Renovasc Dis ; 12: 49-58, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30962703

RESUMO

Background: Data derived from the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) study were analyzed in an effort to employ machine learning methods to predict the composite endpoint described in the original study. Methods: We identified 573 CORAL subjects with complete baseline data and the presence or absence of a composite endpoint for the study. These data were subjected to several models including a generalized linear (logistic-linear) model, support vector machine, decision tree, feed-forward neural network, and random forest, in an effort to attempt to predict the composite endpoint. The subjects were arbitrarily divided into training and testing subsets according to an 80%:20% distribution with various seeds. Prediction models were optimized within the CARET package of R. Results: The best performance of the different machine learning techniques was that of the random forest method which yielded a receiver operator curve (ROC) area of 68.1%±4.2% (mean ± SD) on the testing subset with ten different seed values used to separate training and testing subsets. The four most important variables in the random forest method were SBP, serum creatinine, glycosylated hemoglobin, and DBP. Each of these variables was also important in at least some of the other methods. The treatment assignment group was not consistently an important determinant in any of the models. Conclusion: Prediction of a composite cardiovascular outcome was difficult in the CORAL population, even when employing machine learning methods. Assignment to either the stenting or best medical therapy group did not serve as an important predictor of composite outcome. Clinical Trial Registration: ClinicalTrials.gov, NCT00081731.

18.
Artigo em Inglês | MEDLINE | ID: mdl-30869772

RESUMO

BACKGROUND: Lack of consensus on how to diagnose sarcopenia has limited the ability to diagnose this condition and hindered drug development. The Sarcopenia Definitions and Outcomes Consortium (SDOC) was formed to develop evidence-based diagnostic cut-points for lean mass and/or muscle strength that identify people at increased risk of mobility disability. We describe here the proceedings of a meeting of SDOC and other experts to discuss strategic considerations in the development of evidence-based sarcopenia definition. METHODS: Presentations and panel discussions reviewed the usefulness of sarcopenia as a biomarker, the analytical approach used by SDOC to establish cut-points, preliminary findings, and provided strategic direction to develop an evidence-based definition of sarcopenia. RESULTS: The SDOC assembled data from 8 Epidemiologic Cohorts consisting of 18,831 participants; clinical populations from 10 randomized trials and observational studies; and 2 nationally representative cohorts. In preliminary assessments, grip strength or grip strength/body mass index (BMI) were identified as discriminators of risk for mobility disability (walking speed<0.8 m/sec), while DXA-derived lean mass measures were not good discriminators of mobility disability. Candidate definitions based on grip strength variables were associated with increased risk of mortality, falls, mobility disability and instrumental activities of daily living (IADL) disability. The prevalence of low grip strength increased with age. The attendees recommended the establishment of an International Expert panel to review a series of position statements on sarcopenia definition that are informed by the findings of the SDOC analyses and synthesis of literature. CONCLUSIONS: International consensus on an evidence-based definition of sarcopenia is needed. Grip strength - absolute or adjusted for BMI - is an important discriminator of mobility disability and other endpoints. Additional research is needed to develop a predictive risk model that takes into account sarcopenia components as well as age, sex, and race, and comorbidities.

19.
Circ Heart Fail ; 12(3): e005234, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30871347

RESUMO

Background Anthracycline chemotherapeutics, such as doxorubicin, are used widely in the treatment of numerous malignancies. The primary dose-limiting adverse effect of anthracyclines is cardiotoxicity that often presents as heart failure due to dilated cardiomyopathy years after anthracycline exposure. Recent data from animal studies indicate that anthracyclines cause cardiac atrophy. The timing of onset and underlying mechanisms are not well defined, and the relevance of these findings to human disease is unclear. Methods and Results Wild-type mice were sacrificed 1 week after intraperitoneal administration of doxorubicin (1-25 mg/kg), revealing a dose-dependent decrease in cardiac mass ( R2=0.64; P<0.0001) and a significant decrease in cardiomyocyte cross-sectional area (336±29 versus 188±14 µm2; P<0.0001). Myocardial tissue analysis identified a dose-dependent upregulation of the ubiquitin ligase, MuRF1 (muscle ring finger-1; R2=0.91; P=0.003) and a molecular profile of muscle atrophy. To investigate the determinants of doxorubicin-induced cardiac atrophy, we administered doxorubicin 20 mg/kg to mice lacking MuRF1 (MuRF1-/-) and wild-type littermates. MuRF1-/- mice were protected from cardiac atrophy and exhibited no reduction in contractile function. To explore the clinical relevance of these findings, we analyzed cardiac magnetic resonance imaging data from 70 patients in the DETECT-1 cohort and found that anthracycline exposure was associated with decreased cardiac mass evident within 1 month and persisting to 6 months after initiation. Conclusions Doxorubicin causes a subacute decrease in cardiac mass in both mice and humans. In mice, doxorubicin-induced cardiac atrophy is dependent on MuRF1. These findings suggest that therapies directed at preventing or reversing cardiac atrophy might preserve the cardiac function of cancer patients receiving anthracyclines.


Assuntos
Antineoplásicos/efeitos adversos , Doxorrubicina/efeitos adversos , Insuficiência Cardíaca/induzido quimicamente , Coração/efeitos dos fármacos , Proteínas Musculares/genética , Atrofia Muscular/induzido quimicamente , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases/genética , Animais , Antineoplásicos/administração & dosagem , Cardiotoxicidade/diagnóstico por imagem , Cardiotoxicidade/etiologia , Cardiotoxicidade/genética , Cardiotoxicidade/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Ecocardiografia , Expressão Gênica , Coração/diagnóstico por imagem , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Humanos , Injeções Intraperitoneais , Imagem por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Musculares/metabolismo , Atrofia Muscular/diagnóstico por imagem , Atrofia Muscular/genética , Atrofia Muscular/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Regulação para Cima
20.
Am Heart J ; 209: 36-46, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30641399

RESUMO

BACKGROUND: Kidney injury is common in patients with cardiovascular disease. OBJECTIVES: We determined whether blood measurement of kidney injury molecule-1 (KIM-1), would predict kidney outcomes in patients undergoing angiographic procedures for various indications. METHODS: One thousand two hundred eight patients undergoing coronary and/or peripheral angiography were prospectively enrolled; blood was collected for KIM-1 measurement. Peri-procedural acute kidney injury (AKI) was defined as AKI within 48 hours of contrast exposure. Non-procedural AKI was defined as AKI beyond 48 hours. Development of chronic kidney disease (CKD) was defined as progression to an estimated glomerular filtration rate (eGFR) <60 milliliters/minute/1.73 m2 by study conclusion. Univariate and multivariable Cox proportional hazards models were used to identify predictors of non-procedural AKI, while univariate and multivariable logistic regression analysis was used to evaluate peri-procedural AKI and predictors of progression to CKD. RESULTS: During mean follow up of 4 years, peri-procedural AKI occurred in 5.0%, non-procedural AKI in 27.3%, and 12.4% developed new reduction in eGFR <60 mL/min/1.73 m2. Higher KIM-1 concentrations were associated with prevalent comorbidities associated with risk in cardiovascular disease and worse left ventricular function. In adjusted analyses, elevated pre- and post-procedural KIM-1 concentrations predicted not only peri-procedural AKI (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.09-2·18, P = .01 and OR 1.54, 95% CI 1.10-2.15, P = .01, respectively) and non-procedural AKI (hazard ratio [HR] 1·49, 95% CI 1·24-1·78, P < .001 and HR 1.46, 95% CI 1.23-1.74, P < .001, respectively), but also progression to CKD (OR 1.99, 95% CI 1.32-2.99, P = .001 and OR 2·02, 95% CI 1·35-3·03, P = .001, respectively). CONCLUSIONS: In a typical at-risk population undergoing coronary and/or peripheral angiography, blood concentrations of KIM-1 may predict incident peri-procedural and non-procedural AKI, as well as progression to CKD.


Assuntos
Doenças Cardiovasculares/diagnóstico , Cateteres , Angiografia Coronária/efeitos adversos , Receptor Celular 1 do Vírus da Hepatite A/sangue , Insuficiência Renal Crônica/sangue , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Progressão da Doença , Feminino , Taxa de Filtração Glomerular/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/fisiopatologia
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