The role of pulmonary vascular endothelium in chronic obstructive pulmonary disease (COPD): Does endothelium play a role in the onset and progression of COPD?

Chronic obstructive pulmonary disease (COPD) is an inflammatory lung pathology characterized by persistent airflow limitation and is the third leading cause of death globally. COPD pathophysiology includes both environmental and host risk factors and the presence of comorbidities contributes to its harmful outcome. Cardiovascular disease (CVD) is closely related to COPD and their coexistence is associated with worse outcomes than either condition alone. COPD impairs the cardiovascular system favoring mostly endothelial dysfunction that is a significant COPD prognostic factor at different stages of the disease. The mechanisms promoting endothelial dysfunction in the systemic and/or pulmonary circulation of COPD patients are different and include systemic inflammation, alteration of adhesion and pro-inflammatory molecules, oxidative stress, cellular senescence, and apoptosis. Nevertheless, the role of endothelium in the onset and progression of COPD and CVD is not yet fully understood. Hence, the purpose of this narrative review is to analyze the literature and provide evidence supporting the importance of endothelial dysfunction in COPD

Integrated MRI–Immune–Genomic Features Enclose a Risk Stratification Model in Patients Affected by Glioblastoma

Simple Summary: Despite crucial scientific advances, Glioblastoma (GB) remains a fatal disease with limited therapeutic options and a lack of suitable biomarkers. The unveiled competence of the brain immune system together with the breakthrough advent of immunotherapy has shifted the present translational research on GB towards an immune-focused perspective. Several clinical trials targeting the immunosuppressive GB background are ongoing. So far, results are inconclusive, underpinning our partial understanding of the complex cancer-immune interplay in brain tumors. High throughput Magnetic Resonance (MR) imaging has shown the potential to decipher GB heterogeneity, including pathologic and genomic clues. However, whether distinct GB immune contextures can be deciphered at an imaging scale is still elusive, leaving unattained the non-invasive achievement of prognostic and predictive biomarkers. Along these lines, we integrated genetic, immunopathologic and imaging features in a series of GB patients. Our results suggest that multiparametric approaches might offer new efficient risk stratification models, opening the possibility to intercept the critical events implicated in the dismal prognosis of GB. Abstract: Background: The aim of the present study was to dissect the clinical outcome of GB patients through the integration of molecular, immunophenotypic and MR imaging features. Methods: We enrolled 57 histologically proven and molecularly tested GB patients (5.3% IDH-1 mutant). Two- Dimensional Free ROI on the Biggest Enhancing Tumoral Diameter (TDFRBETD) acquired by MRI sequences were used to perform a manual evaluation of multiple quantitative variables, among which we selected: SD Fluid Attenuated Inversion Recovery (FLAIR), SD and mean Apparent Diffusion Coefficient (ADC). Characterization of the Tumor Immune Microenvironment (TIME) involved the immunohistochemical analysis of PD-L1, and number and distribution of CD3+, CD4+, CD8+ Tumor Infiltrating Lymphocytes (TILs) and CD163+ Tumor Associated Macrophages (TAMs), focusing on immune-vascular localization. Genetic, MR imaging and TIME descriptors were correlated with overall survival (OS). Results: MGMT methylation was associated with a significantly prolonged OS (median OS = 20 months), while no impact of p53 and EGFR status was apparent. GB cases with high mean ADC at MRI, indicative of low cellularity and soft consistency, exhibited increased OS (median OS = 24 months). PD-L1 and the overall number of TILs and CD163+TAMs had a marginal impact on patient outcome. Conversely, the density of vascular-associated (V) CD4+ lymphocytes emerged as the most significant prognostic factor (median OS = 23 months in V-CD4high vs. 13 months in V-CD4low, p = 0.015). High V-CD4+TILs also characterized TIME of MGMTmeth GB, while p53mut appeared to condition a desert immune background. When individual genetic (MGMTunmeth), MR imaging (mean ADClow) and TIME (V-CD4+TILslow) negative predictors were combined, median OS was 21 months (95% CI, 0–47.37) in patients displaying 0–1 risk factor and 13 months (95% CI 7.22–19.22) in the presence of 2–3 risk factors (p = 0.010, HR = 3.39, 95% CI 1.26–9.09). Conclusion: Interlacing MRI–immune–genetic features may provide highly significant risk-stratification models in GB patients

Cardiac hypertrophy and microvascular deficit in kinin B2 receptor knockout mice

Experimental and clinical evidence suggests kinin involvement in adaptive myocardial growth. Kinins are growth-inhibitory to cardiomyocytes. Knockout of kinin B2 receptor (B2R) signaling causes dilated and failing cardiomyopathy in 129/J mice, and a 9-bp deletion polymorphism of human B2R is associated with reduced receptor expression and exaggerated left ventricular growth response to physical stress. We reasoned that genetic background and aging may significantly influence the impact of B2R mutation on cardiac phenotype. The theory was challenged in C57BL/6 mice, a strain that naturally differs from the 129/J strain, carrying 1 instead of 2 renin genes. C57BL/6 B2R knockouts (B2R-KO) showed higher blood pressure and heart rate levels ( P <0.05) compared with wild-type controls (WT) at all ages examined. At 12 months, left ventricular contractility and diastolic function were mildly altered ( P <0.05) and histological and morphological analyses revealed ventricular hypertrophy and cardiomyocyte enlargement in B2R-KO ( P <0.01). Reparative fibrosis was enhanced by 208% and capillary density reduced by 38% ( P <0.01). Functional and structural alterations induced by B2R deletion in C57BL/6 mice were less severe than those reported previously in the 129/J strain. We conclude that interaction of B2R signaling with other genetic determinants influences aging-related changes in myocardial structure and function. These findings may help us understand the role of kinins in the development of cardiac failure

Development and validation of an high performance liquidchromatography–tandem mass spectrometry method for the determination of imatinib in rat tissues

An high performance liquid chromatography–tandem mass-spectrometry (HPLC–MS/MS) method was developed and validated for the determination in rat heart and liver of the tyrosine kinase inhibitor imatinib (IM), an anticancer drug approved for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. Extraction of the drug from tissues was performed by solvent extraction and the obtained extracts were analyzed by HPLC–MS/MS in selected reaction monitoring mode. The developed method was validated according to the criteria for bioanalytical method, showing good performances in terms of lower limit of quantification (LLOQ = 0.02 μg ml−1), linearity (R2 = 0.998), repeatability (RSD 89%). The developed method was then applied to the analysis of heart and liver of rats treated with different doses of IM, with and without the simultaneous administration of carvedilol, a beta-blocking agent with cardioprotective effect, in order to evaluate tissue levels of the tyrosine kinase inhibitor. The obtained results revealed that the amount of IM in the rat heart was significantly affected by the administered dose, whereas carvedilol had no effect on IM concentrations. Thus, we have developed a method that allows the detection of IM traces in complex tissues such as the heart and liver and that may be proposed for the determination of the drug in other clinically relevant biological samples

Is cytology reliable for epidermal growth factor receptor gene evaluation in non-small cell lung cancer?

BACKGROUND: Epidermal growth factor receptor (EGFR) gene copy number has been proposed as predictor of response to epidermal growth factor receptor tyrosine kinase inhibitors in advanced non-small cell lung cancer (NSCLC).METHODS: Cytologic and matched histologic samples from 33 primary non-small cell lung cancers were analyzed by fluorescence in situ hybridization (FISH) for epidermal growth factor receptor gene.RESULTS: FISH was positive in 52% and negative in 35% of the 31 matched evaluable samples. Four of 31 (13%) cases were discordant (K = 0.736; p &lt; 0.001).CONCLUSION: Our data support the feasibility and reliability of epidermal growth factor receptor gene assessment by FISH on cytology