Features and prognostic impact of distant metastases in 45 dogs with de novo stage IV cutaneous mast cell tumours: A prospective study

BACKGROUND: Distant metastases in dogs with cutaneous mast cell tumors (cMCT) are rare and incurable. The aims of this prospective study were to clarify the clinico-pathological features of stage IV cMCTs and to identify possible prognostic factors for progression-free interval (PFI) and survival time (ST). MATERIAL AND METHODS: Dogs were eligible for recruitment if they had a previously untreated, histologically confirmed cMCT and if they underwent complete staging demonstrating stage IV disease. Dogs were uniformly followed-up, whereas treatment was not standardized and included no therapy, surgery, radiation therapy, chemotherapy, tyrosine-kinase inhibitors or a combination of these. RESULTS: 45 dogs with stage IV cMCT were enrolled. All dogs had distant metastatic disease, and 41 (91.1%) dogs had also metastasis in the regional lymph node. Histopathological grade and mutational status greatly varied among dogs. Median ST was 110 days. Notably, PFI and ST were independent of well-known prognostic factors, including anatomic site, histological grade, and mutational status. Conversely, tumor diameter >3\u2009cm, more than 2 metastatic sites, bone marrow infiltration, and lack of tumor control at the primary site were confirmed to be negative prognostic factors by multivariate analysis. CONCLUSION: Currently, there is no satisfactory treatment for stage IV cMCT. Asymptomatic dogs with tumor diameter <3\u2009cm and a low tumor burden, without bone marrow infiltration may be candidates for multimodal treatment. Stage IV dogs without lymph node metastasis may enjoy a surprisingly prolonged survival. The achievement of local tumor control seems to predict a better outcome in dogs with stage IV cMCT

WARM UP LUBE SYSTEM (WULS) RELATION BETWEEN A NEW APPROACH TO LUBRICATION DURING START-UP PHASES AND THE THERMAL SHOCK ON THE DIE SURFACE AND SCRAP REDUCTION

The continuous research for efficiency, associated with higher and higher quality standards in the different industrial production processes, has led, in the last few years, to further and more exhaustive analysis of the various machine cycle phases in the light alloy diecasting sector. The result of these studies was the development of new interdisciplinary technologies, which have firstly highlighted, and then solved “chronic” inefficiencies during the start-up phases. Today, the WULS system is able to optimize the Warm Up phase, being based on the die surface temperature value (thanks to the C.T.C. - acquisition module) and retroacting on the lubrication equipment. In this paper the authors present the WULS technology and highlight the existing relation between the Warm Up phase and the thermal shock generated on the die surface, emphasizing its high level of influence. It has been well shown by means of several tests in an Italian foundry that WULS technology, together with a specific warm-up phase lubricant, ensure: - decreasing thermal shock (approx. 66% of reduction in temperature drop) - reduction of scrap pieces during production starting (approx. - 50%)

Does Bentonite Cause Cytotoxic and Whole-Transcriptomic Adverse Effects in Enterocytes When Used to Reduce Aflatoxin B1 Exposure?

Aflatoxin B1 (AFB1) is a major food safety concern, threatening the health of humans and animals. Bentonite (BEN) is an aluminosilicate clay used as a feed additive to reduce AFB1 presence in contaminated feedstuff. So far, few studies have characterized BEN toxicity and efficacy in vitro. In this study, cytotoxicity (WST-1 test), the effects on cell permeability (trans-epithelial electrical resistance and lucifer yellow dye incorporation), and transcriptional changes (RNA-seq) caused by BEN, AFB1 and their combination (AFB1 + BEN) were investigated in Caco-2 cells. Up to 0.1 mg/mL, BEN did not affect cell viability and permeability, but it reduced AFB1 cytotoxicity; however, at higher concentrations, BEN was cytotoxic. As to RNA-seq, 0.1 mg/mL BEN did not show effects on cell transcriptome, confirming that the interaction between BEN and AFB1 occurs in the medium. Data from AFB1 and AFB1 + BEN suggested AFB1 provoked most of the transcriptional changes, whereas BEN was preventive. The most interesting AFB1-targeted pathways for which BEN was effective were cell integrity, xenobiotic metabolism and transporters, basal metabolism, inflammation and immune response, p53 biological network, apoptosis and carcinogenesis. To our knowledge, this is the first study assessing the in vitro toxicity and whole-transcriptomic effects of BEN, alone or in the presence of AFB1

Longitudinal transcriptomic and genetic landscape of radiotherapy response in canine melanoma

Canine malignant melanoma (MM) is a highly aggressive tumour with a low survival rate and represents an ideal spontaneous model for the human counterpart. Considerable progress has been recently obtained, but the therapeutic success for canine melanoma is still challenging. Little is known about the mechanisms beyond pathogenesis and melanoma development, and the molecular response to radiotherapy has never been explored before. A faster and deeper understanding of cancer mutational processes and developing mechanisms are now possible through next generation sequencing technologies. In this study, we matched whole exome and transcriptome sequencing in four dogs affected by MM at diagnosis and at disease progression to identify possible genetic mechanisms associated with therapy failure. According to previous studies, a genetic similarity between canine MM and its human counterpart was observed. Several somatic mutations were functionally related to MAPK, PI3K/AKT and p53 signalling pathways, but located in genes other than BRAF, RAS and KIT. At disease progression, several mutations were related to therapy effects. Natural killer cell-mediated cytotoxicity and several immune-system-related pathways resulted activated opening a new scenario on the microenvironment in this tumour. In conclusion, this study suggests a potential role of the immune system associated to radiotherapy in canine melanoma, but a larger sample size associated with functional studies are needed

Relationship between low Ankle-Brachial Index and rapid renal function decline in patients with atrial fibrillation: A prospective multicentre cohort study

OBJECTIVE: To investigate the relationship between Ankle-Brachial Index (ABI) and renal function progression in patients with atrial fibrillation (AF). DESIGN: Observational prospective multicentre cohort study. SETTING:Atherothrombosis Center of I Clinica Medica of 'Sapienza' University of Rome; Department of Medical and Surgical Sciences of University Magna Græcia of Catanzaro; Atrial Fibrillation Registry for Ankle-Brachial Index Prevalence Assessment-Collaborative Italian Study. PARTICIPANTS: 897 AF patients on treatment with vitamin K antagonists. MAIN OUTCOME MEASURES: The relationship between basal ABI and renal function progression, assessed by the estimated Glomerular Filtration Rate (eGFR) calculated with the CKD-EPI formula at baseline and after 2 years of follow-up. The rapid decline in eGFR, defined as a decline in eGFR >5 mL/min/1.73 m(2)/year, and incident eGFR<60 mL/min/1.73 m(2) were primary and secondary end points, respectively. RESULTS: Mean age was 71.8±9.0 years and 41.8% were women. Low ABI (ie, ≤0.90) was present in 194 (21.6%) patients. Baseline median eGFR was 72.7 mL/min/1.73 m(2), and 28.7% patients had an eGFR60 mL/min/1.73 m(2), 153 (23.9%) had a reduction of the eGFR <60 mL/min/1.73 m(2). ABI ≤0.90 was also an independent predictor for incident eGFR<60 mL/min/1.73 m(2) (HR 1.851, 95% CI 1.205 to 2.845, p=0.005). CONCLUSIONS: In patients with AF, an ABI ≤0.90 is independently associated with a rapid decline in renal function and incident eGFR<60 mL/min/1.73 m(2). ABI measurement may help identify patients with AF at risk of renal function deterioration

Frequency of left ventricular hypertrophy in non-valvular atrial fibrillation

Left ventricular hypertrophy (LVH) is significantly related to adverse clinical outcomes in patients at high risk of cardiovascular events. In patients with atrial fibrillation (AF), data on LVH, that is, prevalence and determinants, are inconsistent mainly because of different definitions and heterogeneity of study populations. We determined echocardiographic-based LVH prevalence and clinical factors independently associated with its development in a prospective cohort of patients with non-valvular (NV) AF. From the "Atrial Fibrillation Registry for Ankle-brachial Index Prevalence Assessment: Collaborative Italian Study" (ARAPACIS) population, 1,184 patients with NVAF (mean age 72 \ub1 11 years; 56% men) with complete data to define LVH were selected. ARAPACIS is a multicenter, observational, prospective, longitudinal on-going study designed to estimate prevalence of peripheral artery disease in patients with NVAF. We found a high prevalence of LVH (52%) in patients with NVAF. Compared to those without LVH, patients with AF with LVH were older and had a higher prevalence of hypertension, diabetes, and previous myocardial infarction (MI). A higher prevalence of ankle-brachial index 640.90 was seen in patients with LVH (22 vs 17%, p = 0.0392). Patients with LVH were at significantly higher thromboembolic risk, with CHA2DS2-VASc 652 seen in 93% of LVH and in 73% of patients without LVH (p &lt;0.05). Women with LVH had a higher prevalence of concentric hypertrophy than men (46% vs 29%, p = 0.0003). Logistic regression analysis demonstrated that female gender (odds ratio [OR] 2.80, p &lt;0.0001), age (OR 1.03 per year, p &lt;0.001), hypertension (OR 2.30, p &lt;0.001), diabetes (OR 1.62, p = 0.004), and previous MI (OR 1.96, p = 0.001) were independently associated with LVH. In conclusion, patients with NVAF have a high prevalence of LVH, which is related to female gender, older age, hypertension, and previous MI. These patients are at high thromboembolic risk and deserve a holistic approach to cardiovascular prevention

Protective effects of quercetin towards aflatoxin B1-induced hepatotoxicity in cattle: a whole transcriptomic in vitro study

Introduction: Aflatoxin B1 (AFB1) is a natural feed and food contaminant. In the dairy industry, AFB1 and its derivatives are of concern for the related economic losses and their possible presence in milk and dairy food products. Oxidative stress is one of the prominent toxic effects of AFB1, thus, dietary supplementation with natural antioxidants is a valid strategy to mitigate AFB1 toxicity. In this respect, quercetin (QUE) is a promising bioactive compound. Here we assessed the protective role of QUE in bovine foetal hepatocyte-derived cells (BFH12) exposed to AFB1, by measuring the QUE impact on AFB1-induced cytotoxicity and related whole- transcriptional changes. Methods: to increase cells responsiveness to AFB1, monolayers were pre-treated with 1 nM PCB126 for 24h and then exposed to 3.6 μM AFB1, alone or in combination with sub-cytotoxic concentrations of QUE (10, 20, 30 μM). Cytotoxicity was then assessed. For the whole-transcriptome study, we exposed cells to 30 μM QUE, 3.6 μM AFB1, or their combination. Cells pre-treated with PCB126 and exposed to DMSO were used as control (CTRL). Total RNA was isolated, 12 tagged RNA-seq libraries were prepared and sequenced (50 bp single-end). Reads were quality checked, trimmed and mapped to cow reference genome using validated pipelines. EdgeR and clusterProfiler were used to identify differentially expressed genes (DEGs) and perform the functional enrichment analysis, respectively. Results: 30 μM QUE significantly reduced AFB1-induced cytotoxicity by 13.39%. As to RNA-seq, the differential expression analysis comparing QUE vs CTRL and QUE+AFB1 vs AFB1 identified 1028 and 1890 DEGs, respectively. QUE alone affected the expression of genes related to steroids metabolism, inflammation, immunity, and P450-mediated drug metabolism. When comparing QUE+AFB1 vs AFB1, top upregulated genes possess antiapoptotic and antioxidant activity (e.g. SEMA5A, TF), while top downregulated genes play a role in inflammation and cancer progression (e.g. CXCL5, IL6). If comparing these results with the mRNA changes induced in cells exposed to AFB1 alone, all the top-10 genes upregulated by the cotreatment were inhibited by AFB1; on the opposite, all the top-10 downregulated genes were induced by AFB1 alone. Conclusions: we showed the QUE potential to mitigate AFB1-induced toxicity and the underneath molecular mechanisms. If the beneficial effects will be confirmed in vivo, QUE-supplemented diets might be adopted to improve health status of cattle exposed to AFB1-contaminated feed

Experimental Tests of the Q2 Drift Tubes Prototype Chamber for the CMS Muon Barrel

The performances of cells with stainless steel wire and gold-plated tungsten wire are compared in terms of collected charge and time resolution. The multiplication factor has been measured with cosmic rays and a radioactive source