Small cell-derived extracellular vesicles (EVs) can affect endothelial function. We previously found that patients with sickle cell disease (SCD) have greater numbers of circulating EVs than subjects ...without the disease, and the EVs differentially disrupt endothelial integrity in vitro. Because endothelial disruption is a critical component of acute chest syndrome (ACS), we hypothesized that EVs isolated during ACS would induce greater endothelial damage than those isolated at baseline.
Nine pediatric subjects had plasma isolated at baseline and during ACS from which EVs were isolated. Cultured microvascular endothelial cells were treated with EVs and then studied by immunofluorescence microscopy to localize VE-cadherin and F-actin.
The EVs had a diameter of 95 nm. They contained CD63 and flotillin-1, which were increased in SCD patients (5-13-fold compared to control) and further increased between baseline and ACS (24-57%). The EVs contained hemoglobin, glycophorin A, and ferritin. Treatment with baseline EVs caused modest separation of endothelial cells, while ACS EVs caused substantial disruptions of the endothelial cell monolayers. EVs from subjects with ACS also caused a 50% decrease in protein levels of VE-cadherin.
These results suggest that circulating EVs can modulate endothelial integrity contributing to the development of ACS in SCD patients by altering cadherin-containing intercellular junctions.
Sickle cell disease patients have circulating extracellular vesicles (EVs) that modulate endothelial integrity by altering cadherin-containing intercellular junctions. Disruption is more severe by EVs obtained during acute chest syndrome (ACS). These results expand our knowledge of the pathophysiology of acute chest syndrome and the vasculopathies of sickle cell disease.
Sickle cell disease refers to a group of inherited blood disorders in which hemoglobin polymerization leads to hemolysis and vaso-occlusion. This causes a myriad of complications during a patient's ...life span, ranging from anemia, infections, and acute and chronic pain to stroke and multiorgan dysfunction. Although there have been dramatic improvements in childhood survival thanks to improved supportive care with penicillin prophylaxis, immunizations, and improved transfusion practices, there was a dearth of disease-modifying therapies, with hydroxyurea being the only medication for >20 years. Here, we discuss the newer therapies for sickle cell disease that have emerged in recent years.
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New, more effective strategies are needed to treat highly aggressive neuroblastoma. Our laboratory has previously shown that full-length Secreted Protein Acidic and Rich in Cysteine (SPARC) and a ...SPARC peptide corresponding to the follistatin domain of the protein (FS-E) potently block angiogenesis and inhibit the growth of neuroblastoma tumors in preclinical models. Peptide FS-E is structurally complex and difficult to produce, limiting its potential as a therapeutic in the clinic.
In this study, we synthesized two smaller and structurally more simple SPARC peptides, FSEN and FSEC, that respectively correspond to the N-and C-terminal loops of peptide FS-E. We show that both peptides FSEN and FSEC have anti-angiogenic activity in vitro and in vivo, although FSEC is more potent. Peptide FSEC also significantly inhibited the growth of neuroblastoma xenografts. Histologic examination demonstrated characteristic features of tumor angiogenesis with structurally abnormal, tortuous blood vessels in control neuroblastoma xenografts. In contrast, the blood vessels observed in tumors, treated with SPARC peptides, were thin walled and structurally more normal. Using a novel method to quantitatively assess blood vessel abnormality we demonstrated that both SPARC peptides induced changes in blood vessel architecture that are consistent with blood vessel normalization.
Our results demonstrate that SPARC peptide FSEC has potent anti-angiogenic and anti-tumorigenic effects in neuroblastoma. Its simple structure and ease of production indicate that it may have clinical utility in the treatment of high-risk neuroblastoma and other types of pediatric and adult cancers, which depend on angiogenesis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Introduction:
Sickle Cell Disease (SCD) is a chronic, congenital hemoglobinopathy characterized by progressive multiorgan dysfunction (Vichinsky, ASH proceedings). The brain is one of the major ...organs affected by SCD. While it is known that neurocognitive defects can be seen even in the absence of overt stroke and silent cerebral infarcts, there are no specific guidelines for performing neurocognitive assessments on patients with SCD. We report our findings in 20 patients that received neurocognitive testing at our institution within the last 3 years
Methods:
Eligible participants were identified through the Chicago Sickle Cell Disease Research Group (CSCDRG) Registry in conjunction with the SCD medical team and pediatric psychologist. Enrolled subjects took part in child/caregiver interviews, caregiver questionnaires, and review of relevant medical and school records. Participants and caregivers completed a baseline neuropsychological evaluation, which included the Wechsler Intelligence Scale for Children (WISC). Questionnaires were also sent to participants' teachers. Medical chart review was used to collect information about genotype and relevant imaging.
Results:
Neurocognitive testing was performed on 20 pediatric patients ranging in age from 6 to 14 years of age. The majority of patients had sickle cell genotype Hgb SS (n=16, 80%). Five patients (25%) had an abnormal MRI prior to testing. Brain abnormalities included CVA (n=2), Moya Moya (n=2), and T2 signal intensity (n=4). Cohort average full scale IQ was 75. Average full-scale IQ scores did not differ between patients who had a known brain abnormality (75) and patients who did not have a known brain abnormality (76) prior to testing. Most of the patients (n=15, 75%) were in the grade appropriate for age but only about half of the patients had an Individualized Education Plan (IEP) at the school. Interestingly, we also found that prior to neurocognitive testing, only one patient had a known Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5) diagnosis. Following testing, we identified ten additional patients who met criteria for at least one DSM-5 diagnosis. DSM-5 diagnoses in pediatric patients fell under primarily three categories including Neurodevelopmental Disorders (i.e., Attention-Deficit Hyperactivity Disorder, Specific Learning Disability in Mathematics), Trauma and Stressor Related Disorders (i.e., Adjustment Disorder with depressed mood), and Disruptive, Impulse Control and Conduct Disorders (i.e., Oppositional Defiant Disorder).
Conclusion:
We have described the differences in a pediatric sickle cell patient population who underwent neurocognitive testing. Our cohort of children with sickle cell disease exhibit significant neurocognitive deficits even in the absence of overt imaging findings or clinical stroke. Our findings also suggest that patients with SCD are at a higher risk of clinically significant mental health disorders which, if left undiagnosed, have the potential to hinder scholastic and occupational achievement. Individualized educational plans and specific interventions and addressing learning disabilities will help improve academic performance. Furthermore, neurocognitive testing should be a part of routine evaluation in patients with sickle cell disease.
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No relevant conflicts of interest to declare.
Purpose: Tumor vasculature is disorganized and glomeruloid microvascular proliferation (MVP) has been identified as a poor prognosticator
in some adult cancers. To determine the clinical significance ...of MVP, including glomeruloid MVP in neuroblastoma, we initially
examined vessel architecture in tumor sections from 51 children diagnosed at Children's Memorial Hospital (CMH) and subsequently
evaluated 154 neuroblastoma tumors on a tissue microarray constructed at Children's Hospital of Philadelphia (CHOP).
Experimental Design: H&E sections were examined for the presence of structurally abnormal vessels and further characterized by immunostaining
for CD31 and von Willebrand factor to highlight endothelial cells and α-smooth muscle actin for pericytes. Tumors with thickened
walls containing a complete layer of hypertrophic endothelial cells plus additional layers of vascular mural cells were classified
as MVP positive. Associations between MVP and established clinicopathologic features and outcome were assessed.
Results: In both series, MVP was significantly associated with Schwannian stroma-poor histology (CMH, P = 0.008; CHOP, P < 0.001) and decreased survival probability (CMH, P = 0.017; CHOP, P = 0.014). In the CHOP series, MVP was associated with high-risk group classification ( P < 0.001), although this association was not seen in the smaller CMH cohort.
Conclusions: The association between MVP and poor outcome provides further support for the concept that angiogenesis plays an important
role in determining the biological behavior of neuroblastoma tumors. Our results also indicate that angiogenesis is regulated
differently in Schwannian stroma-rich versus stroma-poor neuroblastoma tumors. Further studies investigating the activity
of angiogenic inhibitors in children with clinically aggressive stroma-poor neuroblastoma are warranted.
Sickle cell disease (SCD) is a chronic, debilitating condition that negatively impacts patient quality of life (QOL). In addition to causing frequent crises that lead patients to seek medical ...attention, it can also exacerbate socioeconomic inequities patients with SCD often already face. A specific subset of patients, adolescents and young adults (AYA), defined by the NCI as individuals ages 15-39, are particularly at risk, which can lead to worse outcomes and increased healthcare utilization (HCU). However, analyses on social determinants of health, QOL, HCU, and clinical disease outcomes (CDO) in SCD are limited, particularly among the AYA population. Our group seeks to investigate the impact of social determinants of health on patients with SCD. We have previously reported on food insecurity (FI), QOL, and HCU in children with SCD. This project aims to specifically study the interplay of these metrics further, while also incorporating CDO. Furthermore, we seek to understand these relationships in AYA patients and how they may be uniquely related in this population. We hypothesize that FI is associated with decreased QOL, increased HCU, and worse CDO. We also hypothesize that the magnitude of this association is greater in AYA patients.
We designed an observational study where patients with SCD ages 0- 24 years were recruited during routine SCD visits from June 2015- June 2019. We designed a baseline survey to measure FI and QOL using validated instruments, including the USDA Food Security Short Form and the PedsQL TM Sickle Cell Disease module. All patients were also consented to participate in our clinical registry, allowing for abstraction of HCU and CDO. Surveys were scored and transformed via established methods: USDA FS (range 0-6; >1 indicating some level of FI), and PedsQL TM (range 0-100; ≤60 indicating low QOL). Chart review captured number of ER visits, admissions, annual rate of vaso-occlusive crises (VOC) and acute chest syndrome (ACS). Other CDOs were also captured and these included presence of neurocognitive/psychiatric conditions (i.e., silent stroke, DSM diagnosis), ischemic events like avascular necrosis, and surgeries like cholecystectomies. Linear regressions, Chi squared analyses, Wilcoxon rank-sum tests, and Fisher's exact tests were performed to check for differences within and amongst these variables based on AYA status.
Of surveyed patients (n=115), 56% were female, 39% were AYA, and 75% had SS disease. Some level of food insecurity (FS score > 1) was present in 34% of our population (compared to 10.5% of households nationally per the USDA) with no difference observed between AYA and non-AYA patients (Coleman 7). Average QOL score was 74, but this differed significantly between AYA and non-AYA patients. Specifically, total QOL scores for AYA patient were 10 points lower (p=0.003) and AYA patients were three times as likely to have QOL scores < 60 (p=0.005). Additionally, as previously reported, all patients in the cohort with FI had lower QOL (p=0.008). FI was also tested against HCU. While no difference was observed in number of ER visits, median admissions were twice as high for those with FI (p=0.07). This relationship was not affected by AYA status, but AYA patients did have 1.5 times as many ER visits and admissions combined (p=0.03). Food insecurity was associated with certain CDO measures such as VOC rates, which were four times higher in FI patients (p=0.03), and ACS rates (p=0.03). VOC/ACS rates did not differ between AYA and non-AYA patients and AYA status did not affect the relationship between FI and these CDO. However, AYA patients did demonstrate higher rates of neurocognitive/psychiatric conditions (p=0.009), cholecystectomies (p=0.03), and avascular necrosis (p=0.003).
This study indicates that FI among our SCD patients was highly prevalent, associated with worse QOL, and increased HCU. We also show that FI is associated with worse CDO, which is an impetus for future intervention. Although AYA status did not significantly affect the magnitude of these relationships, it was associated with worsened QOL, increased HCU, and worse CDO. We plan to further study these trends with additional variables associated with sickle cell CDO, the role of preventative care in these populations, and how other social determinants of health impact the care and outcomes of our patients.
Coleman, et al. Household Food Security in the United States in 2019, USDA, Economic Research Service.
No relevant conflicts of interest to declare.
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