e-Health solution for home patient telemonitoring in early post-acute TIA/Minor stroke during COVID-19 pandemic

Background: When it comes to critical early post-acute TIA/stroke phase, there is a lack of a comprehensive multi-parametric telemonitoring system. The COVID-19 emergency, its related global mobility restrictions and fear of hospitalization further highlighted the need of a comprehensive solution. Objective: We aimed to design and test a pragmatic e-Health system based on multiparametric telemonitoring to support of TIA/stroke patients in sub-acute phase during the COVID-19 pandemic. Methods: We proposed a telemonitoring system and protocol for TIA/minor stroke patients during COVID-19 pandemic for patients at risk of stroke recurrence. This system involves the use of portable devices for BP/HR/SpO2/temperature sensing, panic-button, gateway, and a dedicated ICT platform. The protocol is a 14-day multiparametric telemonitoring, therapy, and emergency intervention based on vital sign alteration notifications. We conducted a proof-of-concept validation test on 8 TIA/minor stroke patients in the early post-acute phase (< 14 days from ischemic event). Results: The proposed solution allowed to promptly and remotely identify vital sign alterations at home during the early post-acute phase, allowing therapy and behavioral intervention adjustments. Also, we observed a significant improvement of quality of life, as well as a significant reduction of anxiety and depression status. TUQ showed ease of use, good interface quality and high user satisfaction of the proposed solution. The 3-month follow-up showed total adherence of prescribed therapy and no stroke/TIA recurrence or other emergency department admissions. Conclusion: The proposed e-Health solution and telemonitoring protocol may be highly useful for early post-acute remote patient management, thus supporting constant monitoring and patient adherence to the treatment pathway, especially during the COVID-19 emergency

Wake-up Stroke Outcome Prediction by Interpretable Decision Tree Model

Outcome prediction in wake-up ischemic stroke (WUS) is important for guiding treatment strategies, in order to improve recovery and minimize disability. We aimed at producing an interpretable model to predict a good outcome (NIHSS 7-day<5) in thrombolysis treated WUS patients by using Classification and Regression Tree (CART) method. The study encompassed 104 WUS patients and we used a dataset consisting of demographic, clinical and neuroimaging features. The model was produced by CART with Gini split criterion and evaluated by using 5-fold cross-validation. The produced decision tree model was based on NIHSS at admission, ischemic core volume and age features. The predictive accuracy of model was 86.5% and the AUC-ROC was 0.88. In conclusion, in this preliminary study we identified interpretable model based on clinical and neuroimaging features to predict clinical outcome in thrombolysis treated wake-up stroke patients

Drug design and synthesis of first in class PDZ1 targeting NHERF1 inhibitors as anticancer agents

Targeted approaches aiming at modulating NHERF1 activity, rather than its overall expression, would be preferred to preserve the normal functions of this versatile protein. We focused our attention on the NHERF1/PDZ1 domain that governs its membrane recruitment/displacement through a transient phosphorylation switch. We herein report the design and synthesis of novel NHERF1 PDZ1 domain inhibitors. These compounds have potential therapeutic value when used in combination with antagonists of β-catenin to augment apoptotic death of colorectal cancer cells refractory to currently available Wnt/β-catenin-targeted agents

Decipher the glioblastoma microenvironment: The first milestone for new groundbreaking therapeutic strategies

Glioblastoma (GBM) is the most common primary malignant brain tumour in adults. Despite the combination of novel therapeutical approaches, it remains a deadly malignancy with an abysmal prognosis. GBM is a polymorphic tumour from both molecular and histological points of view. It consists of different malignant cells and various stromal cells, contributing to tumour initiation, progression, and treatment response. GBM’s microenvironment is multifaceted and is made up of soluble factors, extracellular matrix components, tissue-resident cell types (e.g., neurons, astrocytes, endothelial cells, pericytes, and fibroblasts) together with resident (e.g., microglia) or recruited (e.g., bone marrow-derived macrophages) immune cells. These latter constitute the so-called immune microenvironment, accounting for a substantial GBM’s tumour volume. Despite the abundance of immune cells, an intense state of tumour immunosuppression is promoted and developed; this represents the significant challenge for cancer cells’ immune-mediated destruction. Though literature data suggest that distinct GBM’s subtypes harbour differences in their microenvironment, its role in treatment response remains obscure. However, an in-depth investigation of GBM’s microenvironment may lead to novel therapeutic opportunities to improve patients’ outcomes. This review will elucidate the GBM’s microenvironment composition, highlighting the current state of the art in immunotherapy approaches. We will focus on novel strategies of active and passive immunotherapies, including vaccination, gene therapy, checkpoint blockade, and adoptive T-cell therapies

Metronomic ceramide analogs inhibit angiogenesis in pancreatic cancer through up-regulation of caveolin-1 and thrombospondin-1 and down-regulation of cyclin D1

Aims. The aims of this study were to evaluate the antitumor and antiangiogenic activity of metronomic ceramide analogs and to investigate their relevant molecular mechanisms. Methods. Human endothelial cells (HMVEC-d, HUVEC) and pancreatic cancer cells (Capan-1, MIAPaCa-2) were treated with the ceramide analogs (C2, AL6, C6 and C8), at low concentrations for 144h to evaluate any antiproliferative and pro-apoptotic effects, inhibition of migration, and to measure the expression of caveolin-1 (CAV-1) and thrombospondin-1 (TSP-1) mRNAs by real time RT-PCR. Assessment of ERK1/2 and Akt phosphorylation, and of CAV-1 and cyclin-D1 protein expression was performed by ELISA. Maximum tolerated dose (MTD) gemcitabine was compared against metronomic doses of the ceramide analogs by evaluating the inhibition of MIAPaCA-2 subcutaneous tumor growth in nude mice. Results. Metronomic ceramide analogs preferentially inhibited cell proliferation and enhanced apoptosis in endothelial cells. Low concentrations of AL6 and C2 caused a significant inhibition of HUVEC cell migration. ERK1/2 and Akt phosphorylation were significantly decreased after metronomic ceramide analog treatment. Such treatment caused the over-expression of CAV-1 and TSP-1 mRNA and protein in endothelial cells, whereas cyclin-D1 protein levels were reduced significantly. The antiangiogenic and antitumor impact in vivo of metronomic C2 and AL6 regimens was similar to that caused by MTD gemcitabine. C6 and C8 did not show any significant in vivo antitumor effects. Conclusions. Metronomic C2 and AL6 analogs have antitumor and antiangiogenic activity, determining the upregulation of CAV-1 and TSP-1 and the suppression of cyclin-D1

Antiangiogenic and anticolorectal cancer effects of metronomic irinotecan chemotherapy alone and in combination with semaxinib

Metronomic chemotherapy refers to the administration of chemotherapy at low, nontoxic doses on a frequent schedule with no prolonged breaks. The aim of the study is to rationally develop a CPT-11 metronomic regimen in preclinical settings of colon cancer. In vitro cell proliferation, apoptosis and thrombospondin-1/vascular endothelial growth factor (TSP-1/VEGF) expression analyses were performed on endothelial (HUVEC, HMVEC-d) and colorectal cancer (HT-29, SW620) cells exposed for 144 h to metronomic concentrations of SN-38, the active metabolite of CPT-11. HT-29 human colorectal cancer xenograft model was used, and tumour growth, microvessel density and VEGF/TSP-1 quantification was performed in tumours. In vitro and in vivo combination studies with the tyrosine inhibitor semaxinib were also performed. SN-38 preferentially inhibited endothelial cell proliferation alone and interacted synergistically with semaxinib; it induced apoptosis and increased the expression and secretion of TSP-1. Metronomic CPT-11 alone and combined with semaxinib significantly inhibits tumour growth in the absence of toxicity, which was accompanied by decreases in microvessel density and increases in TSP-1 gene expression in tumour tissues. In vitro results show the antiangiogenic properties of low-concentration SN-38, suggesting a key role of TSP-1 in this effect. In vivo, the CPT-11 metronomic schedule is effective against tumour and microvessel growth without toxic effect on mice

PO-0632: Dose-volume related dysphagia in head and neck cancer Intensity Modulated Radiation Treatment

n/

Circulating endothelial progenitor cells are actively involved in the reparative mechanisms of stable ischemic myocardium

Background: Myocardial fibrosis (MF) is an adverse correlate of severe aortic valve stenosis (SAVS). microRNA expression modulates different pathophysiological pathways in cardiovascular disease. In particular miRNA­21, has been associated to MF due to pressure overload. Non­invasive estimation of MF, using speckle­tracking echocardiography (2D­STE), could be useful in determining early myocardial damage. Purpose: To analyze the correlation between 2D­STE parameters, MF, plasmatic and tissue miRNA­21 in SAVS. Methods: We evaluated 36 consecutive patients (75.2±8 y.o., 63% F) with SAVS and preserved ejection fraction (EF), undergoing to surgical aortic valve replacement (AVR; Euroscore II 2.28±1.13%; Logistic Euroscore: 6±4.1%). Clinical, ECG, biohumoral evaluation (including plasma miRNA­21) and a complete echocardiography, including 2D­STE, was performed before AVR. 28 patients eventually underwent AVR and, in 23 of them, a basal interventricular septum biopsy was performed. MF and tissue miRNA­21 expression (micro­dissection) were evaluated in each sample. Results: All patients with SAVS (AVAi 0.33±0.1 cm2/m2; V max 4.4±0.4 m/sec; Mean Grad. 50±9 mmHg) showed concentric hypertrophy (LVMi 147±20.7 g/m2, RWT 0.51±0.07), diastolic dysfunction and increased Valvulo­Arterial Impedance (ZVA: 5.9±2.3 mmHg/ml/m2). Despite a preserved EF (66±11%), an altered global and septal deformation (Global longitudinal strain, GLS −13±6.1; Global longitudinal strain rate, GLSr −0.8±0.2 1/sec; Global early diastolic Sr, GLSrE 1±0.35 1/sec; Septal longitudinal strain, SLS −8.6±2.8%; SL­Sr −0,6±0.1 1/sec; SL­SrE 0.6±0.29 1/sec) were observed. We found a significant association between MF and 2D­STE parameters, stroke volume and end­diastolic pressure (all p&lt;0.05). Tissue miRNA­21 was mainly expressed in fibrous tissue than in myocardium (p&lt;0.0001). Myocardial miRNA­21 was associated with AVAi (r=0.46; p=0.043) and cardiac index (r=0.5; p=0.02) while fibrous tissue miRNA­21 was associated to GLS (r=0.8; p=0.0003), GLSrE (r=−0.72; p=0.005), SLS (r=0.6; p=0.01), SL­Sr (r=0.54; p=0.03), SL­SrE (r=0.5; p=0.04) and PAPs (r=0.66; p=0.004). Plasma miRNA­21 was associated to MF (r=0.5; p=0.02) and septal longitudinal strain (r=0.38; p=0.037). Conclusions: In SAVS with preserved EF, MF is associated to impaired myocardial deformation. miRNA­21 has a potential pathophysiological role in fibrogenesis. Non­invasive evaluation of plasmatic miRNA­21 and 2D­STE could be useful in risk stratification, to optimize the timing of surgery in SAVS patients