Purpose: The aberrant expression of miR-221 is a hallmark of human cancers, including hepatocellular carcinoma (HCC), and its involvement in drug resistance, together with a proved in vivo efficacy of anti-miR-221 molecules, strengthen its role as an attractive target candidate in the oncologic field. The discovery of biomarkers predicting the response to treatments represents a clinical challenge in the personalized treatment era. This study aimed to investigate the possible role of miR-221 as a circulating biomarker in HCC patients undergoing sorafenib treatment as well as to evaluate its contribution to sorafenib resistance in advanced HCC. Experimental Design: A chemically induced HCC rat model and a xenograft mouse model, together with HCC-derived cell lines were employed to analyze miR-221 modulation by Sorafenib treatment. Data from the functional analysis were validated in tissue samples from surgically resected HCCs. The variation of circulating miR-221 levels in relation to Sorafenib treatment were assayed in the animal models and in two independent cohorts of patients with advanced HCC. Results: MiR-221 over-expression was associated with Sorafenib resistance in two HCC animal models and caspase-3 was identified as its target gene, driving miR-221 anti-apoptotic activity following Sorafenib administration. Lower pre-treatment miR-221 serum levels were found in patients subsequently experiencing response to Sorafenib and an increase of circulating miR-221 at the two months assessment was observed in responder patients. Conclusions: MiR-221 might represent a candidate biomarker of likelihood of response to Sorafenib in HCC patients to be tested in future studies. Caspase-3 modulation by miR-221 participates to Sorafenib resistance. Clin Cancer Res; 23(14); 3953–65. ©2017 AACR.

Background The prognostic relevance of left atrial (LA) morphological and functional variables, including those derived from speckle tracking echocardiography (STE), has been little investigated in veterinary medicine. Objectives To assess the prognostic value of several echocardiographic variables, with a focus on LA morphological and functional variables in dogs with myxomatous mitral valve disease (MMVD). Animals One‐hundred and fifteen dogs of different breeds with MMVD. Methods Prospective cohort study. Conventional morphologic and echo‐Doppler variables, LA areas and volumes, and STE‐based LA strain analysis were performed in all dogs. A survival analysis was performed to test for the best echocardiographic predictors of cardiac‐related death. Results Most of the tested variables, including all LA STE‐derived variables were univariate predictors of cardiac death in Cox proportional hazard analysis. Because of strong correlation between many variables, only left atrium to aorta ratio (LA/Ao > 1.7), mitral valve E wave velocity (MV E vel > 1.3 m/s), LA maximal volume (LAVmax > 3.53 mL/kg), peak atrial longitudinal strain (PALS < 30%), and contraction strain index (CSI per 1% increase) were entered in the univariate analysis, and all were predictors of cardiac death. However, only the MV E vel (hazard ratio [HR], 4.45; confidence interval [CI], 1.76‐11.24; P < .001) and LAVmax (HR, 2.32; CI, 1.10‐4.89; P = .024) remained statistically significant in the multivariable analysis. Conclusions and Clinical Importance The assessment of LA dimension and function provides useful prognostic information in dogs with MMVD. Considering all the LA variables, LAVmax appears the strongest predictor of cardiac death, being superior to LA/Ao and STE‐derived variables.

Objective—To evaluate the diagnostic accuracy of radiographically derived measurements of vertebral heart score (VHS) and sphericity index (SI) in the detection of pericardial effusion (PE) in dogs. Design—Retrospective case-control study. Animals—51 dogs with PE associated with various cardiac disorders, 50 dogs with left- or right-sided cardiac disorders without PE, 50 dogs with bilateral cardiac disorders without PE, and 50 healthy dogs. Procedures—Measurements of VHS on lateral (lateral VHS) and ventrodorsal (ventrodorsal VHS) radiographs, SI on lateral (lateral SI) and ventrodorsal (ventrodorsal SI) radiographs, and global SI (mean of lateral SI and ventrodorsal SI) were obtained. Receiver operating characteristic curves were calculated to evaluate the diagnostic accuracy of the radiographic indexes at differentiating dogs with PE from those with other cardiac disorders without PE. Results—Measurements of lateral and ventrodorsal VHS were significantly higher in dogs with PE, compared with values for all dogs without PE. Measurements of lateral, ventrodorsal, and global SI were significantly lower in dogs with PE, compared with values for all dogs without PE. Cutoff values of > 11.9, > 12.3, and ≤ 1.17 for lateral VHS, ventrodorsal VHS, and global SI, respectively, were the most accurate radiographic indexes for identifying dogs with PE. Conclusions and Clinical Relevance—Cardiac silhouettes of dogs with PE were larger and more rounded, compared with those of dogs with other cardiac disorders without PE. Objective radiographic indexes of cardiac size and roundness were only moderately accurate at distinguishing dogs with PE from dogs with other cardiac disorders without PE.

To identify the predictive value on time to onset of heart failure (HF) or cardiac death of clinical, radiographic, and echocardiographic variables, as well as cardiac biomarkers N-terminal pro brain natriuretic peptide (NT-proBNP) and cardiac troponin I in dogs with preclinical myxomatous mitral valve disease (MMVD). One hundred sixty-eight dogs with preclinical MMVD and left atrium to aortic root ratio ≥1.6 (LA:Ao) and normalized left ventricular end-diastolic diameter ≥1.7 were included. Prospective, randomized, multicenter, single-blinded, placebo-controlled study. Clinical, radiographic, echocardiographic variables and plasma cardiac biomarkers concentrations were compared at different time points. Using receiving operating curves analysis, best cutoff for selected variables was identified and the risk to develop the study endpoint at six-month intervals was calculated. Left atrial to aortic root ratio >2.1 (hazard ratio [HR] 3.2, 95% confidence interval [95% CI] 1.9-5.6), normalized left ventricular end-diastolic diameter > 1.9 (HR: 6.3; 95% CI: 3.3-11.8), early transmitral peak velocity (E peak) > 1 m/sec (HR: 3.9; 95% CI: 2.3-6.7), and NT-proBNP > 1500 ρmol/L (HR: 5.7; 95% CI: 3.3-9.5) were associated with increased risk of HF or cardiac death. The best fit model to predict the risk to reach the endpoint was represented by the plasma NT-proBNP concentrations adjusted for LA:Ao and E peak. Logistic and survival models including echocardiographic variables and NT-proBNP can be used to identify dogs with preclinical MMVD at higher risk to develop HF or cardiac death.

A retrospective search was conducted to evaluate the diagnostic accuracy of the vertebral heart score (VHS) and other related radiographic indices in the detection of cardiac enlargement associated with different cardiac disorders in the cat. One hundred and five cats with a complete echocardiographic examination and radiographic examination of the thorax with at least two orthogonal views were enrolled. Eighty-three cats had different cardiac disorders, 72 with left-sided cardiac disorders (LSCD) and 11 with right-sided cardiac disorders; 22 cats were free of cardiovascular abnormalities. Measurements of VHS and cardiac long and short axes on lateral (L) and dorsoventral or ventrodorsal radiographs were obtained. Receiver operating characteristic curves were calculated to evaluate the diagnostic accuracy of each radiographic index in differentiating between cats with cardiac disorders or cats with LSCD and cats without cardiac abnormalities and, among cats with LSCD, between those with no or mild left atrial enlargement (LAE) or those with moderate-to-severe LAE and healthy cats. The L-VHS at the cut-off of 7.9 had high diagnostic accuracy in distinguishing cats with LSCD and moderate-to-severe LAE from healthy cats, but all the other radiographic indices were moderately accurate in distinguishing between cats with overall cardiac disorders or LSCD, either with no or mild LAE and moderate-to-severe LAE, and healthy cats. The considered radiographic indices were also moderately accurate in predicting different degrees of LAE in cats with LSCD. Radiographic indices are reasonably specific, but less sensitive predictors of cardiac enlargement in cats with heart disorders.