No topoisomerase I alteration in a neuroblastoma model with in vivo acquired resistance to irinotecan

CPT-11 (irinotecan) is a DNA-topoisomerase I inhibitor with preclinical activity against neuroblastoma (NB) xenografts. The aim was to establish in vivo an NB xenograft resistant to CPT-11 in order to study the resistance mechanisms acquired in a therapeutic setting. IGR-NB8 is an immature NB xenograft with MYCN amplification and 1p deletion, which is sensitive to CPT-11. Athymic mice bearing advanced-stage subcutaneous tumours were treated with CPT-11 (27 mg kg−1 day−1 × 5) every 21 days (1 cycle) for a maximum of four cycles. After tumour regrowth, a new in vivo passage was performed and the CPT-11 treatment was repeated. After the third passage, a resistant xenograft was obtained (IGRNB8-R). The tumour growth delay (TGD) was reduced from 115 at passage 1 to 40 at passage 4 and no complete or partial regression was observed. After further exposure to the drug, up to 28 passages, the resistant xenograft was definitively established with a TGD from 17 at passage 28. Resistant tumours reverted to sensitive tumours after 15 passages without treatment. IGR-NB8-R remained sensitive to cyclophosphamide and cisplatin and cross-resistance was observed with the topoisomerase I inhibitor topotecan. No quantitative or qualitative topoisomerase I modifications were observed. The level of expression of multidrug resistance 1 (MDR1), MDR-associated protein 1 (MRP1) and, breast cancer resistance protein, three members of the ATP-binding cassette transporter family was not modified over passages. Our results suggest a novel resistance mechanism, probably not involving the mechanisms usually observed in vitro

Prevalence and diagnostic significance of de-novo 12-lead ECG changes after COVID-19 infection in elite soccer players.

BACKGROUND AND AIM: The efficacy of pre-COVID-19 and post-COVID-19 infection 12-lead ECGs for identifying athletes with myopericarditis has never been reported. We aimed to assess the prevalence and significance of de-novo ECG changes following COVID-19 infection. METHODS: In this multicentre observational study, between March 2020 and May 2022, we evaluated consecutive athletes with COVID-19 infection. Athletes exhibiting de-novo ECG changes underwent cardiovascular magnetic resonance (CMR) scans. One club mandated CMR scans for all players (n=30) following COVID-19 infection, despite the absence of cardiac symptoms or de-novo ECG changes. RESULTS: 511 soccer players (median age 21 years, IQR 18-26 years) were included. 17 (3%) athletes demonstrated de-novo ECG changes, which included reduction in T-wave amplitude in the inferior and lateral leads (n=5), inferior leads (n=4) and lateral leads (n=4); inferior T-wave inversion (n=7); and ST-segment depression (n=2). 15 (88%) athletes with de-novo ECG changes revealed evidence of inflammatory cardiac sequelae. All 30 athletes who underwent a mandatory CMR scan had normal findings. Athletes revealing de-novo ECG changes had a higher prevalence of cardiac symptoms (71% vs 12%, p<0.0001) and longer median symptom duration (5 days, IQR 3-10) compared with athletes without de-novo ECG changes (2 days, IQR 1-3, p<0.001). Among athletes without cardiac symptoms, the additional yield of de-novo ECG changes to detect cardiac inflammation was 20%. CONCLUSIONS: 3% of athletes demonstrated de-novo ECG changes post COVID-19 infection, of which 88% were diagnosed with cardiac inflammation. Most affected athletes exhibited cardiac symptoms; however, de-novo ECG changes contributed to a diagnosis of cardiac inflammation in 20% of athletes without cardiac symptoms

Prevalence and diagnostic significance of de-novo 12-lead ECG changes after COVID-19 infection in elite soccer players.

Background and aim: The efficacy of pre-COVID-19 and post-COVID-19 infection 12-lead ECGs for identifying athletes with myopericarditis has never been reported. We aimed to assess the prevalence and significance of de-novo ECG changes following COVID-19 infection. Methods: In this multicentre observational study, between March 2020 and May 2022, we evaluated consecutive athletes with COVID-19 infection. Athletes exhibiting de-novo ECG changes underwent cardiovascular magnetic resonance (CMR) scans. One club mandated CMR scans for all players (n=30) following COVID-19 infection, despite the absence of cardiac symptoms or de-novo ECG changes. Results: 511 soccer players (median age 21 years, IQR 18-26 years) were included. 17 (3%) athletes demonstrated de-novo ECG changes, which included reduction in T-wave amplitude in the inferior and lateral leads (n=5), inferior leads (n=4) and lateral leads (n=4); inferior T-wave inversion (n=7); and ST-segment depression (n=2). 15 (88%) athletes with de-novo ECG changes revealed evidence of inflammatory cardiac sequelae. All 30 athletes who underwent a mandatory CMR scan had normal findings. Athletes revealing de-novo ECG changes had a higher prevalence of cardiac symptoms (71% vs 12%, p<0.0001) and longer median symptom duration (5 days, IQR 3-10) compared with athletes without de-novo ECG changes (2 days, IQR 1-3, p<0.001). Among athletes without cardiac symptoms, the additional yield of de-novo ECG changes to detect cardiac inflammation was 20%. Conclusions: 3% of athletes demonstrated de-novo ECG changes post COVID-19 infection, of which 88% were diagnosed with cardiac inflammation. Most affected athletes exhibited cardiac symptoms; however, de-novo ECG changes contributed to a diagnosis of cardiac inflammation in 20% of athletes without cardiac symptoms

Supervisory alliance: Key to positive alliances and outcomes in home-based parenting support?

Objectives: This study investigated whether the supervisory alliance between professionals and supervisors contributes to strong client-professional alliances and positive outcomes of home-based parenting support provided by youth care organizations. Methods: Multi-informant self-report supervisory alliance, alliance, and outcome data from 124 parents (M age = 39.83 years, SD = 6.98), professionals (n = 84, M age = 43.66 years, SD = 10.46), and supervisors (n = 26, M age = 47.18 years, SD = 8.28) collected early and late in care were analyzed using structural equation modeling. Results: A stronger professional-reported supervisory alliance was related to a stronger professional-reported alliance early in care (beta = 0.27, p < 0.01), and predicted higher levels of parent-reported satisfaction with care (beta = 0.19, p < .05; beta = 0.25, p < 0.01), and professional-reported satisfaction with care (beta = 0.21, p < 0.01). A stronger supervisory alliance reported by supervisors predicted parent-reported improvement in parent functioning (beta = 0.26, p < 0.05), and higher levels of professional-reported satisfaction with care (beta = 0.19, p < 0.05; beta = .14, p < 0.05). Finally, effects of professional-reported supervisory alliance on professional-reported satisfaction with care were mediated through higher levels of professional-reported alliance (beta = 0.06, p < 0.05; beta = .07, p < 0.05). Conclusions: A strong supervisory alliance may relate to strong alliances and positive outcomes of home-based parenting support. Future research needs to identify factors that contribute to strong supervisory alliances and explain linkages between the supervisory alliance, the alliance, and outcomes