Automatic instantiation of abstract tests on specific configurations for large critical control systems

Computer-based control systems have grown in size, complexity, distribution and criticality. In this paper a methodology is presented to perform an abstract testing of such large control systems in an efficient way: an abstract test is specified directly from system functional requirements and has to be instantiated in more test runs to cover a specific configuration, comprising any number of control entities (sensors, actuators and logic processes). Such a process is usually performed by hand for each installation of the control system, requiring a considerable time effort and being an error prone verification activity. To automate a safe passage from abstract tests, related to the so called generic software application, to any specific installation, an algorithm is provided, starting from a reference architecture and a state-based behavioural model of the control software. The presented approach has been applied to a railway interlocking system, demonstrating its feasibility and effectiveness in several years of testing experience

PI3K Functions in Cancer Progression, Anticancer Immunity and Immune Evasion by Tumors

The immunological surveillance of tumors relies on a specific recognition of cancer cells and their associate antigens by leucocytes of innate and adaptive immune responses. However, a dysregulated cytokine release can lead to, or be associated with, a failure in cell-cell recognition, thus, allowing cancer cells to evade the killing system. The phosphatidylinositol 3-kinase (PI3K) pathway regulates multiple cellular processes which underlie immune responses against pathogens or malignant cells. Conversely, there is accumulating evidence that the PI3K pathway is involved in the development of several malignant traits of cancer cells as well as their escape from immunity. Herein, we review the counteracting roles of PI3K not only in antitumor immune response but also in the mechanisms that cancer cells use to avoid leukocyte attack. In addition, we discuss, from antitumor immunological point of view, the potential benefits and disadvantages arising from use of anticancer pharmacological agents targeting the PI3K pathway

Tissue expression of Squamous Cellular Carcinoma Antigen (SCCA) is inversely correlated to tumor size in HCC

<p>Abstract</p> <p>Background</p> <p>This study aimed to investigate squamous cellular carcinoma antigen (SCCA) in serum and in tumoral and paired peritumoral tissues. We studied 27 patients with liver cirrhosis (LC) and 55 with HCC: 20 with a single nodule < 3 cm (s-HCC) and 35 with a single nodule > 3 cm or multifocal (l-HCC).</p> <p>Methods</p> <p>Serum SCCA was measured by the ELISA kit, and in frozen tissues by immunohistochemistry, quantified with appropriate imaging analysis software and expressed in square microns. Continuous variables are reported as means and 95% confidence intervals. Comparisons between independent groups were performed with a generalized linear model and Tukey grouping. Pearson's correlation coefficients were determined to evaluate relations between markers. Qualitative variables were summarized as count and percentage. Statistical significance was set at p-value < 0.05.</p> <p>Results</p> <p>Serum SCCA values in LC patients were 0.41 (0.31–0.55) ng/ml and statistically different from both HCC groups: 1.6 (1.0–2.6) ng/ml in s-HCC, 2.2 (1.28–2.74) ng/ml in l-HCC. SCCA in hepatic tissue was 263.8 (176.6–394.01) μm²in LC patients, statistically different from values in s-HCC: 1163.2 (863.6–1566.8) μm²and l-HCC: 625.8 (534.5–732.6). All pairwise comparisons between groups yielded statistically significant differences. Tumoral SCCA resulted linearly related with nodule size, showing a statistically significant inverse relation between the two variables (b = -0.099, p = 0.024).</p> <p>Conclusion</p> <p>There was no statistically significant correlation between tissue and serum levels of SCCA. The significantly stronger expression of SCCA in smaller compared to larger HCC could be important for early HCC detection. However, the increased expression in peritumoral tissue could affect the significance of serological detection.</p

1H-NMR metabolomics reveals a multitarget action of Crithmum maritimum ethyl acetate extract in inhibiting hepatocellular carcinoma cell growth

Hepatocellular carcinoma (HCC) is nowadays the sixth cause of tumour-related deceases worldwide, estimated to become the third in Western countries by 2030. New drugs for HCC treatment still have many adverse effects. Several lines of evidence indicate that plant metabolites offer concrete opportunities for developing new therapeutic strategies for many diseases, including cancer. We previously reported that ethyl acetate extract of a spontaneous edible plant harvested in Apulia, Crithmum maritimum, significantly inhibited cell growth in HCC cells. By 1H-NMR spectroscopy, here we show that Crithmum maritimum ethyl acetate extract counteracts the Warburg effect, by reducing intracellular lactate, inhibits protein anabolism, by decreasing amino acid level, and affects membrane biosynthesis by lowering choline and phosphocholine. Also, we observed an effect on lipid homeostasis, with a reduction in triglycerides, cholesterol, monounsaturated fatty acids (MUFA), and diunsaturated fatty acids (DUFA), and an increase in polyunsaturated fatty acids (PUFA). Taken together, these data demonstrate that Crithmum maritimum-induced cytostasis is exerted through a multi-effect action, targeting key metabolic processes in HCC cells. Overall, our findings highlight the role of Crithmum maritimum as a promising tool for the prevention and the improvement of the therapeutic options for HCC and other types of tumours

Differential inhibition of the TGF-b signaling pathway in HCC cells using the small molecule inhibitor LY2157299 and the D10 monoclonal antibody against TGF-β receptor Type II

We investigated blocking the TGF-b signaling pathway in HCC using two small molecule inhibitors (LY2157299, LY2109761) and a neutralizing humanized antibody (D10) against TGF-bRII. LY2157299 and LY2109761 inhibited HCC cell migration on Laminin-5, Fibronectin, Vitronectin, Fibrinogen and Collagen-I and de novo phosphorylation of pSMAD2. LY2157299 inhibited HCC migration and cell growth independently of the expression levels of TGF-bRII. In contrast to LY2157299, D10 showed a reduction in pSMAD2 only after a short exposure. This study supports the use of LY2157299 in clinical trials, and presents new insights into TGF-b receptor cycling in cancer cells

Dietary Zinc Supplementation to Prevent Chronic Copper Poisoning in Sheep

The aim of this study was to evaluate whether zinc (Zn) supplementation protects against hepatic copper (Cu) accumulation in copper-loaded sheep. Forty cross-bred lambs were assigned to five experimental groups. These included the control group (C) and four treatment groups that received Cu and/or Zn supplementation (dry matter (DM) basis) over 14 weeks, as follows: Cu (450 mg Cu/kg); Zn-35 (450 mg Cu + 35 mg Zn/kg); Zn-150 (450 mg Cu + 150 mg Zn/kg); and Zn-300 (450 mg Cu + 300 mg Zn/kg). Blood, liver, and bile samples were obtained for mineral determination by inductively coupled plasma optical emission spectrometry (ICP–OES). The hepatic metallothionein (MT) concentrations were also determined. At the end of the experiment, hepatic Cu concentrations were higher in all Cu-supplemented groups than in C. Hepatic Cu accumulation was lower in the groups receiving the Zn supplementation than in the Cu group, although the difference was only statistically significant (66%) in the Zn-300 group. The MT concentrations tended to be higher (almost two-fold) in the Zn groups (but were not dose related) than in the C and Cu groups, and they were related to hepatic Zn concentrations. Zn supplementation at 300 mg/kg DM is useful for preventing excessive hepatic Cu accumulation in sheep exposed to high dietary concentrations of CuThis research was funded by the São Paulo Research Foundation (FAPESP). A research productivity fellowship was granted by the National Council for Scientific and Technological Development (CNPq) to AHHMS

KIT/PDGFRA Variant Allele Frequency as Prognostic Factor in Gastrointestinal Stromal Tumors (GISTs): Results From a Multi-Institutional Cohort Study

Background: The patient selection for optimal adjuvant therapy in gastrointestinal stromal tumors (GISTs) is provided by nomogram based on tumor size, mitotic index, tumor location, and tumor rupture. Although mutational status is not currently used to risk assessment, tumor genotype showed a prognostic influence on natural history and tumor relapse. Innovative measures, such as KIT/PDGFRA-mutant-specific variant allele frequency (VAF) levels detection from next-generation sequencing (NGS), may act as a surrogate of tumor burden and correlate with prognosis and overall survival of patients with GIST, helping the choice for adjuvant treatment. Patients and methods: This was a multicenter, hospital-based, retrospective/prospective cohort study to investigate the prognostic role of KIT or PDGFRA-VAF of GIST in patients with radically resected localized disease. In the current manuscript, we present the results from the retrospective phase of the study. Results: Two-hundred (200) patients with GIST between 2015 and 2022 afferent to 6 Italian Oncologic Centers in the EURACAN Network were included in the study. The receiver operating characteristic (ROC) curves analysis was used to classify "low" vs. "high" VAF values, further normalized on neoplastic cellularity (nVAF). When RFS between the low and high nVAF groups were compared, patients with GIST with KIT/PDGFRA nVAF &gt; 50% showed less favorable RFS than patients in the group of nVAF ≤ 50% (2-year RFS, 72.6% vs. 93%, respectively; P = .003). The multivariable Cox regression model confirmed these results. In the homogeneous sub-population of intermediate-risk, patients with KIT-mutated GIST, the presence of nVAF &gt;50% was statistically associated with higher disease recurrence. Conclusion: In our study, we demonstrated that higher nVAF levels were independent predictors of GIST prognosis and survival in localized GIST patients with tumors harboring KIT or PDGFRA mutations. In the cohort of intermediate-risk patients, nVAF could be helpful to improve prognostication and the use of adjuvant imatinib

Avaliação do potencial da polpa cítrica em provocar acidose láctica ruminal aguda em bovinos

With the aim to evaluate the risk of citrus pulp to induce acute rumen lactic acidosis (ARLA), 15 rumen cannulated cattle didn't adapted to concentrates were randomly allocated in 3 groups: G1- CONTROL - group fed only the basal diet; G2 - SUCROSE animals with ARLA induced by rumen administration of sucrose; G3 CITRUS PULP animals received citrus pulp into rumen (1.65% of BW). Blood and rumen samples were drawn throughout the next 24 h to determine pH, lactic acid concentration and the packet cell volume, blood base excess. Clinical signs were also recorded and food intake followed by the next 7 days. Sucrose caused a systemic and ruminal acidosis and characteristic ARLA signs such as, apathy, dehydration, diarrhea and tachycardia, while citrus pulp gave rise to mild and brief rumen acidosis, reaching the lowest pH (5.35) at the 6th h, without any changing in the blood pH and any typical clinical sign, but temporary reduction in the rumination and excretion of semi liquid feces. Appetite was fully recovered after two and seven days in the pulp and sucrose group, respectively. These results showed that citrus pulp may be used as a feedstuff for cattle with low risk to cause ARLA.Com o objetivo de avaliar o potencial da polpa cítrica (PC) em provocar acidose láctica ruminal aguda (ALRA), 15 bovinos com peso médio de 160 kg providos de cânula ruminal não-adaptados à dieta contendo concentrado foram alocados aleatoriamente em três grupos: CONTROLE animais receberam apenas a dieta basal; SACAROSE animais receberam sacarose diretamente no rumem a fim de provocar ALRA; POLPA - grupo que recebeu subitamente alta quantidade de PC no rúmen (equivalente a 1,65% do peso corporal). Em vários tempos no decorrer de 24 horas, após administração dos substratos, foram determinados o volume globular, pH, excesso de bases (BE) e lactato total no sangue e pH e concentração de ácido láctico total no conteúdo ruminal. Exame clínico foi realizado no decorrer do 1º dia e o consumo de alimento acompanhado nos próximos sete dias. A administração de sacarose provocou um característico quadro de ALRA com o desenvolvimento de acidose ruminal e sistêmica, apatia, desidratação, diarréia e taquicardia. Por outro lado, a polpa cítrica produziu discreta e temporária acidose ruminal, atingindo na 6ª hora o pH ruminal mais baixo (5,35), sem provocar acidose sistêmica e quadro clínico mais evidente de ALRA, com exceção de uma diminuição temporária na ruminação e eliminação de fezes semilíquidas. A regularização do apetite ocorreu após dois dias no grupo com PC e sete dias no grupo com sacarose. Tais resultados indicam que a polpa cítrica pode ser utilizada na alimentação de bovinos com baixo risco de provocar ALRA