Background Chemotherapeutic agents have many side effects; among them is cardiotoxicity. Ejection fraction fails to detect the subtle alterations of left ventricular (LV) function; that is why there is a need for a more sensitive tool. The aim is to detect subclinical LV systolic dysfunction after chemotherapeutic treatment, using NT-BNP plasma level as well as speckle tracking echo-global longitudinal strain (STE-GLS). Seventy-four asymptomatic, non-metastasizing breast cancer female patients without risk factors were included. They were assessed before and 6 weeks after taking their first chemotherapeutic session. Assessment included clinical characteristics, conventional two-dimensional (2D) and three-dimensional (3D) echocardiography, and 2D STE-GLS. Blood samples for NT-BNP plasma level were collected on both visits and were later analyzed using a Sandwich ELISA technique. Results The median NT-proBNP almost doubled after 6 weeks of chemotherapy (73.50 vs 34.4 pg/L, p value <0.001). Only two patients showed significant reduction of LVEF >10% to less <55%. One patient died before her scheduled follow-up visit, and the cause of death is unknown. Fifty patients showed elevated follow-up levels of the NT-BNP. As compared to the baseline visit, 12 patients had a high relative reduction of the LV-GLS (>15%) and all of them had a relatively higher NT-proBNP. A 2.2 relative elevation of the NT-proBNP was able to define a relative reduction of LV-GLS >15% by a 100% sensitivity and 81.8% specificity. Conclusion The relative reduction of LV-GLS and the relative elevation of NT-proBNP were successful in defining subclinical, subtle chemotherapy-induced cardiotoxicity after 6 weeks of the first chemotherapeutic agent administration.
BackgroundRheumatoid arthritis (RA) is associated with elevated plasma level of inflammatory markers. Chronic inflammation is known to predispose to endothelial dysfunction and increased arterial stiffness, which is an important marker of subclinical atherosclerosis and increased cardiovascular risk.ObjectiveThe aim is to test for the relationship between disease activity and arterial stiffness in RA patients.MethodsThe study included 90 RA patients, at different grades of disease activity and 45 healthy subjects, as a control group. Patients were subjected to full history taking and clinical examination, laboratory investigations including serum lipid profile and high sensitivity CRP (hs-CRP) measurements and plain x-rays of hands and feet. Modified Larsen method was used as radiographic scoring method. Disease activity score (DAS 28) was used for assessment of disease activity. Transthoracic echocardiography was performed to detect aortic stiffness parameters. Duplex ultrasound imaging of both common carotid arteries was performed to measure carotid stiffness parameters.ResultsThe mean age of RA patients was 39.86 ± 9.39 years and most of them (83.3%) were females. RA patients had higher carotid stiffness index compared to control group patients (8.57 ± 4.83 vs 4.08 ± 1.13, p < .001). Very poor correlation was found between DAS-28 and aortic (r = 0.1, p = .28) as well as carotid (r = 0.05, p = .7) stiffness indices. No statistically significant correlation was found between hs-CRP and aortic stiffness index (r = 0.64, p = .55). Disease duration was significantly correlated to intima-media thickness (p < .01) as well as with other carotid stiffness parameters. Age also show a statistically significant positive correlation with carotid stiffness parameters.ConclusionRA is associated with increased arterial stiffness, a well-recognized marker of cardiovascular risk. This is attributed to the inflammatory nature of the disease. It seems that the most important factors determining stiffness are patients' age and duration of illness.
Purpose Protein misfolding and aggregation result in proteotoxic stress and underlie the pathogenesis of many diseases. To overcome proteotoxicity, cells compartmentalize misfolded and aggregated proteins in different inclusion bodies. The aggresome is a paranuclear inclusion body that functions as a storage compartment for misfolded proteins. Choroid plexus tumors (CPTs) are rare neoplasms comprised of three pathological subgroups. The underlying mechanisms of their pathogenesis remain unclear. This study aims to elucidate the prognostic role and the biological effects of aggresomes in pediatric CPTs. Methods We examined the presence of aggresomes in 42 patient-derived tumor tissues by immunohistochemistry and we identified their impact on patients’ outcomes. We then investigated the proteogenomics signature associated with aggresomes using whole-genome DNA methylation and proteomic analysis to define their role in the pathogenesis of pediatric CPTs. Results Aggresomes were detected in 64.2% of samples and were distributed among different pathological and molecular subgroups. The presence of aggresomes with different percentages was correlated with patients’ outcomes. The ≥ 25% cutoff had the most significant impact on overall and event-free survival (p-value < 0.001) compared to the pathological and the molecular stratifications. Conclusions These results support the role of aggresome as a novel prognostic molecular marker for pediatric CPTs that was comparable to the molecular classification in segregating samples into two distinct subgroups, and to the pathological stratification in the prediction of patients’ outcomes. Moreover, the proteogenomic signature of CPTs displayed altered protein homeostasis, manifested by enrichment in processes related to protein quality control.
Embryonal tumor with multilayered rosettes (ETMR) is an aggressive and rare pediatric embryonal brain tumor. Amplification of C19MC microRNA cluster and expression of LIN28 are distinctive features of ETMR. Despite the increasing efforts to decipher ETMR, the biology remains poorly understood. To date, the role of aberrant alternative splicing in ETMR has not been thoroughly investigated. In the current study, a comprehensive analysis was performed on published unprocessed RNA-seq reads of tissue-matched ETMR and fetal controls datasets. Gene expression was quantified in samples using Kallisto/sleuth pipeline. For the alternative splicing analysis, STAR, SplAdder and rMATS were used. Functional enrichment analysis was subsequently performed using Metascape. The expression analysis identified a total of 3622 differentially expressed genes (DEGs) between ETMR and fetal controls while 1627 genes showed differential alternative splicing patterns. Interestingly, genes with significant alternative splicing events in ETMR were identified to be involved in signaling pathways such as ErbB, mTOR and MAPK pathways as well as ubiquitin-mediated proteolysis, cell cycle and autophagy. Moreover, up-regulated DEGs with alternative splicing events were involved in important biological processes including nuclear transport, regulation of cell cycle and regulation of Wnt signaling pathway. These findings highlight the role of aberrant alternative splicing in shaping the ETMR tumor landscape, and the identified pathways constitute potential therapeutic targets.
Introduction Lymphoblastic lymphoma (LBL) and acute lymphoblastic leukemia (ALL) are neoplasms of immature B or T-cell precursors. They are considered as a unique biological entity in the 2008 World Health Organization Classification of Hematologic Neoplasm. Both entities are arbitrarily separated by a cut-off point of 20-25% of blast cells in the bone marrow. Treatment of LBL has evolved over time from conventional high-grade NHL schedules to ALL-derived protocols. The aim of this work is to report the clinical characteristics, overall survival (OS), event free survival (EFS), and common chemotherapy toxicities of lymphoblastic lymphoma (LBL) patients during a 5.5year period. Patients and methods A Retrospective review of patient's charts diagnosed and treated as LBL during the period between July 2007 and end of December 2012 was done. Patients were treated according to St. Jude Children Research Hospital ALL Total Therapy XV protocol, standard risk arm. Results This study included 77 patients. T-cell LBL patients were 67, while 10 were of B-cell origin. The median age at diagnosis was 9years (95% CI: 7-10). The majority were males 54/77. Stage III patients were 51, stage IV 13, stage II 11 and stage I 2 patients. Two patients were excluded from analysis as they died before receiving chemotherapy. Complete remission post induction chemotherapy was seen in 22 patients considered early responders, and partial remission in 55 considered late responders. With a median follow up duration of 47months (95% CI: 38-56), the 4year overall survival and event free survival were 86.45% (95% CI: 73.78-94.09) and 82.18% (95% CI: 69.25-90.61) respectively. Twelve patients died during the study period; 2 early deaths before starting chemotherapy from disease progression, 2 in CR due to chemotherapy related toxicity and 8 from disease progression. All the relapsed patients were T-cell, had advanced disease at presentation (6 with stage III; 2 with stage IV). Two patients (2.6%) had isolated local, BM, and CNS relapse each, while 1 (1.3%) had both local and CNS relapse. Disease recurrence was local in 3 patients (3.9%), and systemic in 5 (6.4%), while it was early in 6 (7.8%), and late in 2 (2.6%) patients. Median time to disease progression was 20months (range 5-39months). All relapsed patients did not survive salvage chemotherapy. The most common chemotherapy toxicities were cerebral venous thrombosis (20%), followed by bone infarcts (10.6%), and avascular necrosis (AVN) of head of femur (9.3%). One patient developed secondary acute myeloid leukemia after 3years of FU with unfavorable cytogenetic abnormalities. Conclusion Results of treatment of LBL on the St Jude's total therapy XV study are comparable to most of the similar reported studies. Outcome of relapsing patients is extremely poor, hence there is a need to identify biologic or clinical prognostic factors including minimal residual tumor to better evaluate chemotherapy response. Steroid induced AVN, and cerebral vascular thrombosis were the main chemotherapeutic advers...
Embryonal tumor with multilayered rosettes (ETMR) is an aggressive and rare variant of embryonal brain tumors. Amplification of C19MC microRNA cluster and expression LIN28 are distinctive features of ETMR. Despite the increasing efforts to decipher ETMR, the biology remains poorly understood. To date, the role of aberrant alternative splicing in ETMR is not thoroughly investigated. In the current study a comprehensive analysis was performed on published unprocessed RNA-seq reads of tissue- matched ETMR (SRP032476), and fetal controls from the Human Developmental Biology Resource (HDBR) (E-MTAB-4840) datasets. Gene expression was quantified in samples using kallisto/sleuth pipeline. For the alternative splicing analysis, reads were mapped to the genome (hg38) using STAR. Identification and quantification of alternative splicing events (skipped exon, alternative 5′ and 3′splice sites, mutually exclusive exons, multi Exons Skip and retained intron) were carried out using SplAdder. Functional enrichment analysis for the differentially expressed and the differentially spliced genes was subsequently performed using Metascape. All statistical values reported were corrected for multiple hypothesis testing by Benjamini-Hochberg false discovery rate (q-values).The expression analysis revealed a total of 2205 differentially expressed genes (DEGs) between ETMR and fetal controls while 2446 showed differential alternative splicing patterns. DEGs with significant alternative splicing events were identified to be involved in ubiquitin mediated proteolysis, endocytosis, RNA transport, regulation of actin cytoskeleton pathways as well as histone modification. Interestingly, DEGs with intron retention events were involved in various signaling pathways including TGF-beta signaling pathway, MAPK signaling pathway and ErbB signaling pathway. These findings highlight the role of defective alternative splicing in shaping ETMR tumor landscape, and the identified pathways constitute potential therapeutic targets. Citation Format: Dina Hesham AbouRaya, Shahenda El-Naggar. Functional consequences of aberrant alternative splicing in embryonal tumor with multilayered rosettes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-220.
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