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 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. 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. 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. 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. .

BackgroundThe assessment of left atrial (LA) function by 2‐dimensional speckle tracking echocardiography (STE) holds important clinical implications in human medicine. Few similar data are available in dogs.ObjectivesTo assess LA function by STE in dogs with and without myxomatous mitral valve disease (MMVD), analyzing LA areas, systolic function, and strain.AnimalsOne hundred and fifty dogs were divided according to the American College of Veterinary Internal Medicine classification of heart failure: 23 dogs in class A, 52 in class B1, 36 in class B2, and 39 in class C + D.MethodsProspective observational study. Conventional morphologic and Doppler variables, LA areas, and STE‐based LA strain analysis were performed in all dogs and results were compared among groups. Correlation analysis was carried out between LA STE variables and other echocardiographic variables.ResultsVariability study showed good reproducibility for all the tested variables (coefficient of variation <16%). Left atrial areas, fractional area change, peak atrial longitudinal strain (PALS), peak atrial contraction strain, and contraction strain index (CSI) differed significantly between groups B2 and C + D and all the other groups (overall P < .001), whereas only PALS differed between groups B1 and A (P = .01). Left atrial areas increased with progression of the disease, whereas LA functional parameters decreased. Only CSI increased nonsignificantly from group A to group B1 and then progressively decreased. Thirty‐one significant correlations (P < .001, r > .3) were found between conventional left heart echocardiographic variables and LA areas and strain variables.Conclusions and Clinical ImportanceLeft atrial STE analysis provides useful information on atrial function in the dog, highlighting a progressive decline in atrial function with worsening of MMVD.

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BackgroundThe 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.ObjectivesTo 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).AnimalsOne‐hundred and fifteen dogs of different breeds with MMVD.MethodsProspective 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.ResultsMost 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 ImportanceThe 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.

BackgroundRed blood cell distribution width (RDW) is a quantitative measurement of anisocytosis. RDW has prognostic value in humans with different cardiovascular and systemic disorders, but few studies have investigated this biomarker in dogs.ObjectivesTo compare the RDW in dogs with precapillary and postcapillary pulmonary hypertension (PH) and a control population of dogs and to correlate RDW with demographic, echocardiographic, and laboratory variables.AnimalsOne hundred and twenty‐seven client‐owned dogs including 19 healthy dogs, 82 dogs with myxomatous mitral valve disease (50 dogs without PH and 32 dogs with postcapillary PH), and 26 dogs with precapillary PH.MethodsProspective study. Dogs were allocated to groups according to clinical and echocardiographic evaluation. RDW and selected laboratory and echocardiographic variables were compared among dog groups. Associations between RDW and demographic, laboratory, and echocardiographic variables were analyzed using correlation and multiple regression analysis.ResultsMedian RDW in dogs with precapillary PH (13.8%, interquartile range 13.2–14.9%) and postcapillary PH (13.7, 13.2–14.7%) was significantly increased compared to healthy dogs (13.3, 12.3–13.7%; P < .05 for both comparisons), but only dogs with severe PH had significantly increased RDW compared to dogs without PH (P < .05). Peak tricuspid regurgitation pressure gradient was significantly associated with increased RDW (rho = 0.263, P = .007). Serum urea concentration, hematocrit, age, and white blood cell number were significantly associated with RDW in the multivariate analysis.Conclusions and Clinical ImportanceUnderlying pathophysiologic processes associated with PH instead of severity of PH are likely responsible for increased RDW in dogs with PH.