Dual IGF1R/IR inhibitors in combination with GD2-CAR T-cells display a potent anti-tumor activity in diffuse midline glioma H3K27M-mutant

BackgroundDiffuse midline gliomas (DMG) H3K27M-mutant, including diffuse intrinsic pontine glioma (DIPG), are pediatric brain tumors associated with grim prognosis. Although GD2-CAR T-cells demonstrated significant anti-tumor activity against DMG H3K27M-mutant in vivo, a multimodal approach may be needed to more effectively treat patients. We investigated GD2 expression in DMG/DIPG and other pediatric high-grade gliomas (pHGG) and sought to identify chemical compounds that would enhance GD2-CAR T-cell anti-tumor efficacy.MethodsImmunohistochemistry in tumor tissue samples and immunofluorescence in primary patient-derived cell lines were performed to study GD2 expression. We developed a high-throughput cell-based assay to screen 42 kinase inhibitors in combination with GD2-CAR T-cells. Cell viability, western blots, flow-cytometry, real time PCR experiments, DIPG 3D culture models, and orthotopic xenograft model were applied to investigate the effect of selected compounds on DIPG cell death and CAR T-cell function.ResultsGD2 was heterogeneously, but widely, expressed in the tissue tested, while its expression was homogeneous and restricted to DMG/DIPG H3K27M-mutant cell lines. We identified dual IGF1R/IR antagonists, BMS-754807 and linsitinib, able to inhibit tumor cell viability at concentrations that do not affect CAR T-cells. Linsitinib, but not BMS-754807, decreases activation/exhaustion of GD2-CAR T-cells and increases their central memory profile. The enhanced anti-tumor activity of linsitinib/GD2-CAR T-cell combination was confirmed in DIPG models in vitro, ex vivo, and in vivo.ConclusionOur study supports the development of IGF1R/IR inhibitors to be used in combination with GD2-CAR T-cells for treating patients affected by DMG/DIPG and, potentially, by pHGG.     

Very Low Alcohol Consumption Is Associated with Lower Prevalence of Cirrhosis and Hepatocellular Carcinoma in Patients with Non-Alcoholic Fatty Liver Disease

The role of moderate alcohol consumption in the evolution of NAFLD is still debated. The aim of this study is to evaluate the impact of current and lifelong alcohol consumption in patients with NAFLD. From 2015 to 2020, we enrolled 276 consecutive patients fulfilling criteria of NAFLD (alcohol consumption up to 140 g/week for women and 210 g/week for men). According to their current alcohol intake per week, patients were divided in: abstainers, very low consumers (C1: <70 g/week) and moderate consumers (C2). We created a new tool, called LACU (Lifetime Alcohol Consuming Unit) to estimate the alcohol exposure across lifetime: 1 LACU was defined as 7 alcohol units per week for 1 drinking year. Patients were divided into lifelong abstainers and consumers and the latter furtherly divided into quartiles: Q1-Q4. Stratification according to alcohol intake, both current and cumulative as estimated by LACU, showed that very low consumers (C1 and Q1-Q3) displayed lower frequency of cirrhosis and hepatocellular carcinoma compared to abstainers and moderate consumers (C2 and Q4). We can speculate that up to one glass of wine daily in the context of a Mediterranean diet may be a long-term useful approach in selected NAFLD patients.     

Apathy and impulsiveness in Parkinson disease: Two faces of the same coin?

Apathy and impulsiveness are 2 common non-motor symptoms in Parkinson disease that could occur in different periods or simultaneously. Apathy and impulsiveness could be interpreted as opposite extremes of a spectrum of motivated behavior dependent on dopaminergic dysfunction, in which, impulsivity, is a result of a hyperdopaminergic state, whereas apathy is viewed as a hypodopaminergic. The study aimed to investigate the presence of impulsiveness and other neuropsychiatric symptoms in Parkinson disease patients with apathy symptoms.Eighty-one patients with Parkinson disease were enrolled in this retrospective study. All subjects were evaluated by the Italian version of the Dimensional Apathy Scale and the Barratt Impulsiveness Scale-version 11, to assess, respectively, apathy and impulsiveness; they were divided into 2 groups (apathy and no apathy). All patients were administered also with questionnaires assessing depressive and anxious symptoms.Statistical analyses showed relevant results. In no-apathy group, education was a significant predictor on impulsiveness (attentional and motor) and apathy (executive and emotional); depression was a significant predictor on planning impulsivity and apathy.This study aimed to consider the importance of apathy and impulsivity in Parkinson disease. Although these are considered as opposite extremes of a spectrum of motivated behavior dependent on dopaminergic dysfunction, these can also occur separately. Moreover, several variables could represent important predictors of apathy and impulsiveness, such as depression. Future investigations should deepen the role of other demographics and psychological variables.     

The Using of Concrete Wash Water from Ready Mixed Concrete Plants in Cement Systems

Concrete plants accumulate large amounts of concrete wash water. This water, which pH is highly alkaline, has a negative impact on the environment. Its reuse in fresh concrete slightly reduces its mechanical properties. The combination of concrete wash water and zeolitic by-product led to an increase of 4.6% in the compressive strength at 7 days hydration and up to 30% at 28 days hydration. The same combination led to the denser microstructure compared to the samples made with concrete wash water. This could be explained by the pozzolanic reaction of the zeolitic by-product. The complex chemical reactions of cement, zeolitic by-product, and fines presented in the concrete wash water occurred. Therefore, it was suggested the reusing method of concrete wash water together with zeolitic by-product in the fresh concrete mixtures by substituting some amount of tap water with concrete wash water. In this way, the consumption of tap water is possible to reduce in cement systems.     

Prolonging Bacterial Viability in Biological Concrete: Coated Expanded Clay Particles

One of the biggest challenges in the development of a biological self-healing concrete is to ensure the long-term viability of bacteria that are embedded in the concrete. In the present study, a coated expanded clay (EC) is investigated for its potential use as a bacterial carrier in biological concrete. Eight different materials for coatings were selected considering cost, workability and accessibility in the construction industry. Long-term (56 days) viability analysis was conducted with a final evaluation of each coating performance. Our results indicate that healing efficiency in biological concrete specimens is strongly related to viable bacteria present in the healing agent. More viable bacteria-containing specimens exhibited a higher crack closure ratio. Our data suggest that the additional coating of EC particles improves long-term bacterial viability and, consequently, provides efficient crack healing in biological concrete.     

Real-life appraisal on blood pressure targets achievement in adult outpatients at high cardiovascular risk

Background and aimAlthough hypertension guidelines highlight the benefits of achieving the recommended blood pressure (BP) targets, hypertension control rate is still insufficient, mostly in high or very high cardiovascular (CV) risk patients. Thus, we aimed to estimate BP control in a cohort of patients at high CV risk in both primary and secondary prevention.Methods and resultsA single-center, cross-sectional study was conducted by extracting data from a medical database of adult outpatients aged 40–75 years, who were referred to our Hypertension Unit, Rome (IT), for hypertension assessment. Office BP treatment targets were defined according to 2018 ESC/ESH guidelines as: a)<130/80 mmHg in individuals aged 40–65 years; b)<140/80 mmHg in subjects aged >65 years. Primary prevention patients with SCORE <5% were considered to be at low-intermediate risk, whilst individuals with SCORE ≥5% or patients with comorbidities were defined to be at very high risk. Among 6354 patients (47.2% female, age 58.4 ± 9.6 years), 4164 (65.5%) were in primary prevention with low-intermediate CV risk, 1831 (28.8%) in primary prevention with high-very high CV risk and 359 (5.6%) in secondary prevention. In treated hypertensive outpatients, uncontrolled hypertension rate was significantly higher in high risk primary prevention than in low risk primary prevention and secondary prevention patients (18.4% vs 24.4% vs. 12.5%, respectively; P < 0.001). In high risk primary prevention diabetic patients only 10% achieved the recommended BP targets.ConclusionsOur data confirmed unsatisfactory BP control among high-risk patients, both in primary and secondary prevention, and suggest the need for a more stringent BP control policies in these patients.     

Satisfaction,quality of life and therapy adherence assessment in real life patients transitioning from vitamin K antagonists to direct oral anticoagulants

Journal of Thrombosis and Thrombolysis - Anticoagulant therapy has undergone a significant change since direct oral anticoagulants (DOACs) introduction. Their obvious advantages including the fixed...     

Construction, training and clinical validation of an interpretation system for genotypic HIV-1 drug resistance based on fuzzy rules revised by virological outcomes

OBJECTIVES: To evaluate whether fuzzy operators can be usefully applied to the interpretation of genotypic HIV-1 drug resistance by experts, and to improve the prediction of salvage therapy outcome by adapting interpretation rules of genotypic resistance on the basis of their association with virological response data. METHODS: We used a clinical dataset of 231 patients failing highly active antiretroviral therapy (HAART) and starting salvage therapy with baseline resistance genotyping and virological outcomes after 3 and 6 months. A set of rules predicting genotypic resistance was initially derived from an expert (ADL). Rules were implemented using a fuzzy logic approach and the virological outcomes dataset used for the training phase. The resulting algorithm was validated using a separate set of 184 selected patients by correlating the resulting predicted activity with observed virological response at 3 months. For comparison, the expert systems from the drug resistance group of the Agence Nationale de Recherches sur le SIDA (ANRS-AC11) and the algorithm from the Stanford's HIV drug resistance database (Stanford HIVdb) were evaluated on the same set. RESULTS: The starting algorithm had a correlation with virological outcomes of R2=0.06 (P=0.0001). After the training phase the correlation with virological outcomes increased to R2=0.19 (P<0.000001). In the validation set of patients, the activity of the salvage regimen predicted by the fuzzy algorithm was the only variable independently predictive of the 3-month viral load change even after adjusting by the activity predicted by the two expert systems and baseline viral load (for each 10% salvage regimen's activity increase, mean HIV RNA change from baseline: -0.27 log10 copies/ml; 95% CI -0.39, -0.15). CONCLUSION: Using fuzzy operators in a virological outcomes training database to implement a rules-based algorithm for genotypic resistance interpretation, significant improvements of outcomes prediction were obtained. The resulting algorithm showed an independent predictive capability of virological outcomes over that of two rules-based interpretation algorithms made by experts. Although the system was trained and validated on a limited number of cases, the approach deserves further evaluation.