role of evaluating tumor infiltrating lymphocytes programmed death ligand 1 and mismatch repair proteins expression in malignant mesothelioma

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Involvement of epigenetic modification of TERT promoter in response to all-trans retinoic acid in ovarian cancer cell lines.

All-trans retinoic acid (ATRA) is currently being used to treat hematological malignancies, given the ability to inhibit cell proliferation. This effect seems to be related to epigenetic changes of the TERT (Telomerase Reverse Transcriptase) promoter. When hypomethylated, ATRA-inducible TERT repressors can bind the promoter, repressing transcription of TERT, the rate-limiting component of telomerase. Ovarian carcinomas are heterogeneous tumors characterized by several aberrantly methylated genes among which is TERT. We recently found a hypomethylation of TERT promoter in about one third of serous carcinoma, the most lethal histotype. Our aim was to investigate the potential role of ATRA as an anticancer drug in a sub-group of ovarian carcinoma where the TERT promoter was hypomethylated. The potential antiproliferative and cytotoxic effect of ATRA was investigated in seven serous ovarian carcinoma and one teratocarcinoma cell lines and the results were compared to the methylation status of their TERT promoter. The serous ovarian carcinoma cell line OVCAR3, harboring a hypomethylated TERT promoter, was the best and fastest responder. PA1 and SKOV3, two cell lines with an intermediate methylated promoter, revealed a weaker and delayed response. On the contrary, the other 5 cell lines with a highly methylated promoter did not respond to ATRA, indicative of ATRA-resistant cells. Our results demonstrate an inverse correlation between the methylation level of TERT promoter and ATRA efficacy in ovarian carcinoma cell lines. Although these results are preliminary, ATRA treatment could become a new powerful, personalized therapy in serous ovarian carcinoma patients, but only in those with tumors harboring a hypomethylated TERT promoter

Analysis and characterization of diffusive flows and movement of the human acinar region: An experimentally validated CFD model

This paper presents a study of the gas exchanges at the alveolar level to define the respiratory capacity of a subject. A numerical multidimensional approach is proposed for the prediction of the diffusive flows of gases (oxygen and carbon dioxide) in the alveoli accounting for the gas exchange phenomena including the surface variation due to the alveoli motion. The overset mesh technique is used to reproduce a realistic surface variation during inspiration and expiration and simulate the expansion and retraction of the alveolar sac. A gas-exchange model is implemented to predict the gas distribution in the alveolar sac wall by assigning a gas flow function through the membrane. The numerical analysis enables to evaluate the flow field within the single alveoli in terms of total and partial pressure of the considered alveolar gases, as well as the species distribution due to the diffusive flows. The predictive capabilities of the numerical model are addressed by comparing the calculations with the values obtained by means the mobile metabolic system K5 from COSMED. An experimental campaign on a set of healthy subjects is used to evaluate the diffusive flows through the membrane and a good agreement between the numerical results and the experimental measurements is found. These evaluations are suitable for the characterization of the breathing capacity in physiological or pathological conditions; therefore, the proposed model can be used as a valid support for bioengineering studies in terms of respiratory gas exchange prediction

An engineering approach to model blood cells electrical characteristics: From biological to digital-twin

Some of the most effective methods to separate circulating tumor cells (CTCs) from normal blood cells can be implemented using ultra-filtration, and/or electro-magnetic fields. As well known, each biological cell presents, on both sides of its membrane, different concentrations of ionic species that produce an electric charge concentration with respect to the lipid double layer (impermeable to ions). In this way, the bio-cell can be seen as an electric capacitor, which has the lipid double layer acting as an insulator inserted between two conductive plates, concentrated on the lipid double layer inner and outer surfaces. In this paper, firstly, the electrical capacitor equivalent system is used to treat different types of bio-cells normally flowing in blood vessels (red blood cells, lymphocytes and various types of CTCs-like), and to transform their biological characteristics into digital twin information useful for engineering applications. After, the preliminary 3D geometric analysis of the bio-cells shapes allowed to associate each bio-cell to a different capacitor model, and to predict the electric-equivalent dimensions characterizing its electric behavior. Finally, the equivalent capacitor model is used to study the influence of bio-cells characteristics variation on human blood cells, with particular attention devoted to liver and lung CTCs-like ones

An innovative approach to CTCs' liquid surgery

Circulating Tumor Cells (CTCs) can be defined as cancerous cells, which detach from a tumor and flow through the vascular or lymphatic systems. The blood flow can carry the tumor cells in another region of human body where they can become the starting point for the growth of additional metastases. Because of this behavior, in the CTCs study it is paramount to acquire new data and knowledge to understand the mechanisms that lead to the separation of the cell from the tumor as well as the major characteristics of these cells. The aim of this work is the development of an innovative therapeutic and diagnostic approach able to lead to a new medical device for removing CTCs from the peripheral blood of a patient. The main target of the approach is to detect the CTCs and separate them during a conventional extracorporeal circulation procedure, similar to that used for renal failure. In this work, the CTCs physical properties are investigated in order to explore the possible characteristics that can be exploited in an ad-hoc developed medical device to remove them from the blood flow. The CTCs physical properties are analyzed numerically, and their behavior is studied by means of CFD simulations. The preliminary numerical tests have been carried out on simple geometries in order to assess the influence of magnetic and electric fields on tumor cells' trajectory. These results are the baseline information to develop more complicated geometries and prototypes for real operations

Influences of nitrogen base excess on ARGET ATRP of styrene with ascorbic acid acetonide and traces of oxygen and water

Ascorbic acid is a promising regenerating agent for Activators ReGenerated by Electron Transfer Atom Transfer Radical Polymerization (ARGET ATRP) thanks to its sustainability and environmental friendlyness. The ascorbate anion has even more potential because it has a higher kinetic rate constant of reduction toward the copper catalyst than its protonated counterpart. Although ascorbic acid can be easily neutralized with inorganic bases, the resulting heterogeneous system in the polymerization of hydrophobic monomers (such as styrene) is not well-suited for industrial applications. To overcome this problem, in this study we investigate the use of ascorbic acid acetonide, a more lipophilic derivative, together with soluble nitrogen bases of different basicity. The results show how the pK(a) of the protonated form of the nitrogen base affects the process, especially in the presence of traces of water and/or oxygen. Additionally, we report that milder bases yield better results in terms of dispersity and chain-end fidelity, while high pK(a) bases lead to a complete loss of control