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The effectiveness of anthracycline chemotherapeutics (e.g., doxorubicin) is limited by anthracycline-induced cardiotoxicity (ACT). A nonsynonymous variant (S427L) in the retinoic acid receptor-γ ( RARG ) gene has been associated with ACT. This variant causes reduced RARG activity, which is hypothesized to lead to increased susceptibility to ACT through reduced activation of the retinoic acid pathway. This study explored the effects of activating the retinoic acid pathway using a RAR-agonist, all-trans retinoic acid (ATRA), in human cardiomyocytes and mice treated with doxorubicin. In human cardiomyocytes, ATRA induced the gene expression of RAR s ( RARG , RARB ) and repressed the expression of topoisomerase II enzyme genes ( TOP2A , TOP2B ), which encode for the molecular targets of anthracyclines and repressed downstream ACT response genes. Importantly, ATRA enhanced cell survival of human cardiomyocytes exposed to doxorubicin. The protective effect of ATRA was also observed in a mouse model (B6C3F1/J) of ACT, in which ATRA treatment improved heart function compared to doxorubicin-only treated mice. Histological analyses of the heart also indicated that ATRA treatment reduced the pathology associated with ACT. These findings provide additional evidence for the retinoic acid pathway’s role in ACT and suggest that the RAR activator ATRA can modulate this pathway to reduce ACT.

Cisplatin is a highly-effective and widely-used chemotherapeutic agent that causes ototoxicity in many patients. Pharmacogenomic studies of key genes controlling drug biotransformation identified variants in thiopurine methyltransferase (TPMT) as predictors of cisplatin-induced ototoxicity, although the mechanistic basis of this interaction has not been reported. Expression constructs of TPMT*3A, *3B and *3C variants were generated and monitored in cultured cells. Cellular TPMT*3A levels were detected at >20-fold lower amounts than the wild type confirming the unstable nature of this variant. The expression of wild type TPMT (TPMT*1) in two murine ear cell lines, HEI-OC1 and UB/OC-1, significantly mitigated their susceptibility to cisplatin toxicity. Cisplatin treatment induced Tlr4 gene expression in HEI-OC1 cells and this response was blunted by the expression of wild type TPMT but not TPMT*3A. In line with the significant mitigation of TPMT*1-expressing cells to cisplatin cytotoxicity, these findings demonstrate a drug-gene interaction between increased TPMT activity and decreased susceptibility to cisplatin-induced toxicity of inner ear cells.

Background/Objectives: Empowerment has been associated with several positive outcomes in healthcare; however, there is limited insight on empowerment levels within the adolescent population of those with a chronic condition/disability. The aim of this scoping review was to identify gaps in the existing literature on empowerment levels within this population. Methods: Five databases (MEDLINE [Ovid], EMBASE [Ovid], PsycINFO [Ebsco], CINHAL [Ebsco] and Web of Science [UBC]) and grey literature were searched. Results: A total of 67 studies were included and used for data extraction including descriptive numerical analysis followed by a narrative review. Extracted data were divided into demographic characteristics (e.g., ethnicity/ancestry), type of disability/condition (e.g., type 1 diabetes), interventions used to increase empowerment or empowerment-adjacent elements, quantitative and qualitative tools used to measure empowerment (e.g., questionnaires and/or interviews), domains/outcomes associated with empowerment (e.g., self-control), and review articles. Several interventions were shown to have positive effects on empowerment levels in adolescents with a chronic condition/disability. Conclusions: Gaps were identified in the consideration of ethnicity/ancestry and socioeconomic status, demonstrating a need for future research in this space to focus on the intersection of disability, ethnicity/ancestry, and socio-economic status and the implementation of interventions promoting empowerment.

Few multicenter pediatric studies have comprehensively described the epidemiologic characteristics of cisplatin-associated acute kidney injury using standardized definitions. To examine the rate of and risk factors associated with acute kidney injury among children receiving cisplatin infusions. This prospective cohort study examined children (aged <18 years) recruited from May 23, 2013, to March 31, 2017, at 12 Canadian pediatric academic health centers who were receiving 1 or more cisplatin infusion. Children whose estimated or measured glomerular filtration rate (GFR) was less than 30 mL/min/1.73 m2 or who had received a kidney transplant were excluded. Data analysis was performed from January 3, 2018, to September 20, 2019. Cisplatin infusions. The primary outcome was acute kidney injury during cisplatin infusion, defined using a Kidney Disease: Improving Global Outcomes serum creatinine criteria-based definition (stage 1 or higher). The secondary outcome was acute kidney injury defined by electrolyte criteria from the National Cancer Institute Common Terminology Criteria for Adverse Events (grade 1 or higher). Assessments occurred at early (first or second cycle) and late (last or second to last cycle) cisplatin infusions. A total of 159 children (mean [SD] age at early cisplatin infusion, 7.2 [5.3] years; 80 [50%] male) participated. The most common diagnoses were central nervous system tumors (58 [36%]), neuroblastoma (43 [27%]), and osteosarcoma (33 [21%]). Acute kidney injury (by serum creatinine level increase) occurred in 48 of 159 patients (30%) at early cisplatin infusions and 23 of 143 patients (16%) at late cisplatin infusions. Acute kidney injury (by electrolyte abnormalities) occurred in 106 of 159 patients (67%) at early cisplatin infusion and 100 of 143 patients (70%) at late cisplatin infusions. Neuroblastoma diagnosis and higher precisplatin GFR were independently associated with acute kidney injury (serum creatinine level increase) at early cisplatin infusions (adjusted odds ratio [aOR] for neuroblastoma vs other, 3.25; 95% CI, 1.18-8.95; aOR for GFR, 1.01; 95% CI, 1.00-1.03) and late cisplatin infusions (aOR for neuroblastoma vs other, 6.85; 95% CI, 1.23-38.0; aOR for GFR, 1.01; 95% CI, 1.00-1.03). Higher cisplatin infusion dose was also independently associated with acute kidney injury (serum creatinine level increase) at later cisplatin infusions (aOR, 1.05; 95% CI, 1.01-1.10). The findings suggest that acute kidney injury is common among children receiving cisplatin infusions and that rate and risk factors differ at earlier vs later infusions. These results may help with risk stratification with a goal of risk reduction.

Vincristine-induced peripheral neuropathy is a common and highly debilitating toxicity from vincristine treatment that affects quality of life and often requires dose reduction, potentially affecting survival. Although previous studies demonstrated genetic factors are associated with vincristine neuropathy risk, the clinical relevance of most identified variants is limited by small sample sizes and unclear clinical phenotypes. A genome-wide association study was conducted in 1100 cases and controls matched by vincristine dose and genetic ancestry, uncovering a statistically significant (p < 5.0 × 10−8) variant in MCM3AP gene that substantially increases the risk of neuropathy and 12 variants protective against neuropathy within/near SPDYA, METTL8, PDE4D, FBN2, ZFAND3, NFIB, PAPPA, LRRTM3, NRG3, VTI1A, ARHGAP5, and ACTN1. A follow-up pathway analysis reveals the involvement of four key pathways, including nerve structure and development, myelination, neuronal transmission, and cytoskeleton/microfibril function pathways. These findings present potential actionable genomic markers of vincristine neuropathy and offer opportunities for tailored interventions to improve vincristine safety in children with cancer. This study is registered with ClinicalTrials.gov under the title National Active Surveillance Network and Pharmacogenomics of Adverse Drug Reactions in Children (ID NCT00414115, registered on December 21, 2006).

Colin Ross and colleagues report the association of variants in TPMT and COMT to cisplatin-induced hearing loss in children. Cisplatin is a widely used and effective chemotherapeutic agent, although its use is restricted by the high incidence of irreversible ototoxicity associated with it 1 . In children, cisplatin ototoxicity is a serious and pervasive problem, affecting more than 60% of those receiving cisplatin 2 , 3 , 4 , 5 and compromising language and cognitive development. Candidate gene studies have previously reported associations of cisplatin ototoxicity with genetic variants in the genes encoding glutathione S-transferases and megalin 6 , 7 , 8 . We report association analyses for 220 drug-metabolism genes in genetic susceptibility to cisplatin-induced hearing loss in children. We genotyped 1,949 SNPs in these candidate genes in an initial cohort of 54 children treated in pediatric oncology units, with replication in a second cohort of 112 children recruited through a national surveillance network for adverse drug reactions in Canada. We identified genetic variants in TPMT (rs12201199, P value = 0.00022, OR = 17.0, 95% CI 2.3–125.9) and COMT (rs9332377, P value = 0.00018, OR = 5.5, 95% CI 1.9–15.9) associated with cisplatin-induced hearing loss in children.

PEHO syndrome (OMIM no. 260565) is characterized by myoclonic jerking and infantile spasms, profound psychomotor retardation with the absence of motor milestones and speech, absence or early loss of visual fixation with atrophy of optic discs by 2 years of age and progressive brain atrophy on neuroimaging. We describe the results of a genomic study of a girl with PEHO syndrome and review the literature on cases with a disease-causing variant in the same gene. Exome sequencing of the index and unaffected parents followed by Sanger confirmation identified nine candidate genes harboring nonsynonymous rare variants identified by trio whole-exome sequencing. The de novo variant, a missense variant (c.296C>T, p.(T99M)), affecting the motor domain of KIF1A was considered the pathogenic mutation. The literature review revealed 24 cases with disease-causing variants in the motor domain of KIF1A, of which three met all the criteria for PEHO syndrome and an additional patient with incomplete clinical data met four of the five criteria. If the criteria were modified to include cases with any convulsive disorder and less profound intellectual disability, a total of six patients met all five of the criteria, three patients met four of the criteria and six met three of the criteria. Our results indicate that the molecular basis for PEHO syndrome, in at least a subset of patients, is a dominant KIF1A variant affecting the motor domain of the protein. Variable expressivity is seen with recurrent variants causing the full phenotype of PEHO syndrome in some patients and in other patients, a partial or milder PEHO phenotype.

Anthracyclines are highly effective chemotherapeutic agents; however, their clinical utility is limited by severe anthracycline-induced cardiotoxicity (ACT). Genome-wide association studies (GWAS) have uncovered several genetic variants associated with ACT, but the impact of these findings requires further elucidation. We conducted a transcriptome-wide association study (TWAS) using our previous GWAS summary statistics (n = 280 patients) to identify gene expression-related associations with ACT. We identified a genetic association between decreased expression of GDF5 and ACT (Z-score = −4.30, P = 1.70 × 10−5), which was replicated in an independent cohort (n = 845 patients, P = 3.54 × 10−3). Additionally, cell viability of GDF5-silenced human cardiac myocytes was significantly decreased in response to anthracycline treatment. Subsequent gene set enrichment and pathway analyses of the TWAS data revealed that genes essential for survival, cardioprotection and response to anthracyclines, as well as genes involved in ribosomal, spliceosomal and cardiomyopathy pathways are important for the development of ACT.

BackgroundFew studies describe acute kidney injury (AKI) burden during paediatric cisplatin therapy and post-cisplatin kidney outcomes. We determined risk factors for and rate of (1) AKI during cisplatin therapy, (2) chronic kidney disease (CKD) and hypertension 2–6 months post-cisplatin, and (3) whether AKI is associated with 2–6-month outcomes.MethodsThis prospective cohort study enrolled children (aged < 18 years at cancer diagnosis) treated with cisplatin from twelve Canadian hospitals. AKI during cisplatin therapy (primary exposure) was defined based on Kidney Disease: Improving Global Outcomes (KDIGO) serum creatinine criteria (≥ stage one). Severe electrolyte abnormalities (secondary exposure) included ≥ grade three hypophosphatemia, hypokalemia, or hypomagnesemia (National Cancer Institute Common Terminology Criteria for Adverse Events v4.0). CKD was albuminuria or decreased kidney function for age (KDIGO guidelines). Hypertension was defined based on the 2017 American Academy of Pediatrics guidelines.ResultsOf 159 children (median [interquartile range [IQR]] age: 6 [2–12] years), 73/159 (46%) participants developed AKI and 55/159 (35%) experienced severe electrolyte abnormalities during cisplatin therapy. At median [IQR] 90 [76–110] days post-cisplatin, 53/119 (45%) had CKD and 18/128 (14%) developed hypertension. In multivariable analyses, AKI was not associated with 2–6-month CKD or hypertension. Severe electrolyte abnormalities during cisplatin were associated with having 2–6-month CKD or hypertension (adjusted odds ratio (AdjOR) [95% CI]: 2.65 [1.04–6.74]). Having both AKI and severe electrolyte abnormalities was associated with 2–6-month hypertension (AdjOR [95% CI]: 3.64 [1.05–12.62]).ConclusionsSevere electrolyte abnormalities were associated with kidney outcomes. Cisplatin dose optimization to reduce toxicity and clear post-cisplatin kidney follow-up guidelines are needed.

Background Cisplatin is associated with acute kidney injury (AKI) and electrolyte abnormalities. Urine tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP-7) may be early cisplatin-AKI biomarkers. Methods We conducted a 12-site prospective cohort study with pediatric patients treated with cisplatin (May 2013–December 2017). Blood and urine (measured for TIMP-2, IGFBP-7) were collected pre-cisplatin, 24-h post-cisplatin, and near hospital discharge during the first or second cisplatin cycle (early visit (EV)) and during second-to-last or last cisplatin cycle (late visit (LV)). Primary outcome: serum creatinine (SCr)-defined AKI (≥ stage 1). Results At EV (median (interquartile (IQR)) age: 6 (2–12) years; 78 (50%) female), 46/156 (29%) developed AKI; at LV, 22/127 (17%) experienced AKI. At EV, TIMP-2, IGFBP-7, and TIMP-2*IGFBP-7 pre-cisplatin infusion concentrations were significantly higher in participants with vs. those without AKI. At EV and LV, biomarker concentrations were significantly lower in participants with vs. those without AKI at post-infusion and near-hospital discharge. Biomarker values normalized to urine creatinine were higher in patients with AKI compared to without (LV post-infusion, median (IQR): TIMP-2*IGFBP-7: 0.28 (0.08–0.56) vs . 0.04 (0.02–0.12) (ng/mg creatinine) 2 /1000; P  < .001). At EV, pre-infusion biomarker concentrations had the highest area under the curves (AUC) (range: 0.61–0.62) for AKI diagnosis; at LV, biomarkers measured post-infusion and near discharge yielded the highest AUCs (range: 0.64–0.70). Conclusions TIMP-2*IGFBP-7 were poor to modest at detecting AKI post-cisplatin. Additional studies are needed to determine whether raw biomarker values or biomarker values normalized to urinary creatinine are more strongly associated with patient outcomes. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information