PARP inhibitors affect growth, survival and radiation susceptibility of human alveolar and embryonal rhabdomyosarcoma cell lines

PARP inhibitors (PARPi) are used in a wide range of human solid tumours but a limited evidence is reported in rhabdomyosarcoma (RMS), the most frequent childhood soft-tissue sarcoma. The cellular and molecular effects of Olaparib, a specific PARP1/2 inhibitor, and AZD2461, a newly synthesized PARP1/2/3 inhibitor, were assessed in alveolar and embryonal RMS cells both as single-agent and in combination with ionizing radiation (IR)

Feasibility and effectiveness of a telehealth service delivery model for treating childhood posttraumatic stress: A community-based, open pilot trial of trauma-focused cognitive-behavioral therapy

© 2020 American Psychological Association. Telepsychotherapy (also referred to as telehealth or telemental health), the use of videoconferencing to deliver psychotherapy services, offers an innovative way to address significant gaps in access to care and is being used to deliver a variety of treatments for youth. Although recent research has supported the effectiveness of telehealth delivery of a variety of interventions for children, the literature has focused very little on childhood posttraumatic stress disorder. This pilot study examined the feasibility and potential effectiveness of trauma-focused cognitive- behavioral therapy (TF-CBT) delivered via telepsychotherapy in community-based locations of either schools or patient homes. Telepsychotherapy treatment was delivered to 70 traumaexposed youth in 7 underserved communities. Of these, 88.6% completed a full course of TF-CBT and 96.8% of these treatment completers no longer met diagnostic criteria for a trauma-related disorder at posttreatment. Results demonstrated clinically meaningful symptom change posttreatment, with large effect sizes evident for both youthand caregiver-reported reduction in posttraumatic stress disorder symptoms. The results observed in this pilot evaluation are promising and provide preliminary evidence of the feasibility and effectiveness of this novel treatment format. The COVID-19 global pandemic has resulted in an unprecedented need to rethink how mental health services are delivered, which is particularly applicable to high base rate conditions related to posttraumatic stress. Given the existing network of nationally certified TF-CBT therapists, and many international TF-CBT therapists, these findings suggest the potential for providing effective and accessible telepsychotherapy intervention during this public health crisis (as well as those that will occur in the future)

Childhood traumatic grief: Concepts and controversies

Childhood traumatic grief refers to a condition in which characteristi

Antitumour activity of trabectedin in myelodysplastic/myeloproliferative neoplasms

Background: Juvenile myelomonocytic leukaemia (JMML) and chronic myelomonocytic leukaemia (CMML) are myelodysplastic myeloproliferative (MDS/MPN) neoplasms with unfavourable prognosis and without effective chemotherapy treatment. Trabectedin is a DNA minor groove binder acting as a modulator of transcription and interfering with DNA repair mechanisms; it causes selective depletion of cells of the myelomonocytic lineage. We hypothesised that trabectedin might have an antitumour effect on MDS/MPN. Methods: Malignant CD14+ monocytes and CD34+ haematopoietic progenitor cells were isolated from peripheral blood/bone marrow mononuclear cells. The inhibition of CFU-GM colonies and the apoptotic effect on CD14+ and CD34+ induced by trabectedin were evaluated. Trabectedin's effects were also investigated in vitro on THP-1, and in vitro and in vivo on MV-4-11 cell lines. Results: On CMML/JMML cells, obtained from 20 patients with CMML and 13 patients with JMML, trabectedin - at concentration pharmacologically reasonable, 1-5 nM - strongly induced apoptosis and inhibition of growth of haematopoietic progenitors (CFU-GM). In these leukaemic cells, trabectedin downregulated the expression of genes belonging to the Rho GTPases pathway (RAS superfamily) having a critical role in cell growth and cytoskeletal dynamics. Its selective activity on myelomonocytic malignant cells was confirmed also on in vitro THP-1 cell line and on in vitro and in vivo MV-4-11 cell line models. Conclusions: Trabectedin could be good candidate for clinical studies in JMML/CMML patients

Frailty and post-operative delirium influence on functional status in patients with hip fracture: the GIOG 2.0 study

Background: This study analyzes the effect of frailty and Post-Operative Delirium (POD) on the functional status at hospital discharge and at 4-month follow-up in patients with hip fracture (HF). Methods: Multicenter prospective observational study of older patients with HF admitted to 12 Italian Orthogeriatric centers (July 2019-August 2022). POD was assessed using the 4AT. A 26-item Frailty Index (FI) was created using data collected on admission. The outcome measures were Cumulated Ambulation Score (CAS) ≤ 2 at discharge and a telephone-administered CAS ≤ 2 after 4 months. Poisson regression models were used to assess the effect of frailty and POD on outcomes. Results: 984 patients (median age 84 years, IQR = 79–89) were recruited: 480 (48.7%) were frail at admission, 311 (31.6%) developed POD, and 158 (15.6%) had both frailty and POD. In a robust Poisson regression, frailty alone (Relative Risk, RR = 1.56, 95% Confidence Intervals, CI 1.19–2.04, p = 0.001) and its combination with POD (RR = 2.57, 95% CI 2.02–3.26, p < 0.001) were associated with poor functional status at discharge. At 4-month follow-up, the combination of frailty with POD (RR 3.65, 95% CI 1.85–7.2, p < 0.001) increased the risk of poor outcome more than frailty alone (RR 2.38, 95% CI 1.21–4.66, p < 0.001). Conclusions: POD development exacerbates the negative effect that frailty exerts on functional outcomes in HF patients

Association of lifelong occupation and educational level with subclinical atherosclerosis in different European regions. Results from the IMPROVE study

Background and aims We aimed to examine the association between socioeconomic status (SES) and subclinical atherosclerosis, as assessed by carotid intima-media-thickness (C-IMT) and to investigate whether the effect of social inequality on C-IMT is mediated by cardiovascular (CV) risk factors and whether it is dissimilar in men and women, and in different European countries. Methods We assessed the association of lifelong occupation and educational level with C-IMT in the IMPROVE study cohort including 3703 subjects (median age 64.4 years; 48% men) from Southern (Italy), Western (France and the Netherlands) and Northern Europe (Finland and Sweden). Three summary measures of C-IMT (IMTmean, IMTmax, IMTmean-max), obtained from four segments of both carotids, were considered. Results After adjusting for conventional CV risk factors, current employment status and diet, C-IMT was higher in manual workers than in white collars (+7.7%, +5.3%, +4.6% for IMTmax, IMTmean-max and IMTmean, respectively; all p<.0001). Similar results were obtained by stratification for educational level. The effect of occupation on C-IMT was comparable in men and women and in different age groups, and was only partially mediated by differences in CV risk factors. Of note, the association of C-IMT with occupation was significant in Western and Northern Europe but not in Italy, with a significant statistical interaction (p = .0005). Conclusions Low SES was associated with subclinical atherosclerosis in subjects with at least three CV risk factors. Such association was stronger in Northern and Western Europe than in Italy. This difference was not completely explained by inequalities in CV risk factors and behavioural variables

Increased Levels of Circulating Fatty Acids Are Associated with Protective Effects against Future Cardiovascular Events in Nondiabetics

Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide, particularly in individuals with diabetes. The current study objective was to determine the circulating metabolite profiles associated with the risk of future cardiovascular events, with emphasis on diabetes status. Nontargeted metabolomics analysis was performed by LC–HRMS in combination with targeted quantification of eicosanoids and endocannabinoids. Plasma from 375 individuals from the IMPROVE pan-European cohort was included in a case-control study design. Following data processing, the three metabolite data sets were concatenated to produce a single data set of 267 identified metabolites. Factor analysis identified six factors that described 26.6% of the variability in the given set of predictors. An association with cardiovascular events was only observed for one factor following adjustment (p = 0.026). From this factor, we identified a free fatty acid signature (n = 10 lipids, including saturated, monounsaturated, and polyunsaturated fatty acids) that was associated with lower risk of future cardiovascular events in nondiabetics only (OR = 0.65, 0.27–0.80 95% CI, p = 0.030), whereas no association was observed among diabetic individuals. These observations support the hypothesis that increased levels of circulating omega-6 and omega-3 fatty acids are associated with protective effects against future cardiovascular events. However, these effects were only observed in the nondiabetic population, further highlighting the need for patient stratification in clinical investigations

A priori-defined Mediterranean-like dietary pattern predicts cardiovascular events better in north Europe than in Mediterranean countries

The Mediterranean Diet (MD) is a model of healthy eating contributing to a favorable health status, but its clinical usefulness is still debated. The aim of this study was to relate the adherence to MD with the incidence of cardio/cerebro-vascular events (VEs) in north and south European participants of the IMPROVE study

The size of juxtaluminal hypoechoic area in ultrasound images of asymptomatic carotid plaques predicts the occurrence of stroke

Objective: To test the hypothesis that the size of a juxtaluminal black (hypoechoic) area (JBA) in ultrasound images of asymptomatic carotid artery plaques predicts future ipsilateral ischemic stroke. Methods: A JBA was defined as an area of pixels with a grayscale value &lt;25 adjacent to the lumen without a visible echogenic cap after image normalization. The size of a JBA was measured in the carotid plaque images of 1121 patients with asymptomatic carotid stenosis 50% to 99% in relation to the bulb (Asymptomatic Carotid Stenosis and Risk of Stroke study); the patients were followed for up to 8 years. Results: The JBA had a linear association with future stroke rate. The area under the receiver-operating characteristic curve was 0.816. Using Kaplan-Meier curves, the mean annual stroke rate was 0.4% in 706 patients with a JBA &lt;4 mm 2, 1.4% in 171 patients with a JBA 4 to 8 mm2, 3.2% in 46 patients with a JBA 8 to 10 mm2, and 5% in 198 patients with a JBA &gt;10 mm2 (P &lt;.001). In a Cox model with ipsilateral ischemic events (amaurosis fugax, transient ischemic attack [TIA], or stroke) as the dependent variable, the JBA (&lt;4 mm2, 4-8 mm2, &gt;8 mm2) was still significant after adjusting for other plaque features known to be associated with increased risk, including stenosis, grayscale median, presence of discrete white areas without acoustic shadowing indicating neovascularization, plaque area, and history of contralateral TIA or stroke. Plaque area and grayscale median were not significant. Using the significant variables (stenosis, discrete white areas without acoustic shadowing, JBA, and history of contralateral TIA or stroke), this model predicted the annual risk of stroke for each patient (range, 0.1%-10.0%). The average annual stroke risk was &lt;1% in 734 patients, 1% to 1.9% in 94 patients, 2% to 3.9% in 134 patients, 4% to 5.9% in 125 patients, and 6% to 10% in 34 patients. Conclusions: The size of a JBA is linearly related to the risk of stroke and can be used in risk stratification models. These findings need to be confirmed in future prospective studies or in the medical arm of randomized controlled studies in the presence of optimal medical therapy. In the meantime, the JBA may be used to select asymptomatic patients at high stroke risk for carotid endarterectomy and spare patients at low risk from an unnecessary operation