87,692 research outputs found
Cardiotoxicity mechanisms of the combination of BRAF-inhibitors and MEK-inhibitors
No full textMany new drugs have appeared in last years in the oncological treatment scenario. Each drug carries an important set of adverse events, not less, cardiovascular adverse events. This aspect is even more important considering the increasing use of combination therapies with two drugs, or three drugs as in some ongoing clinical trials. Besides it represents a growing problem for Cardiologists, that face it in every day clinical practice and that will face it probably more and more in the coming years. This work reviews the mechanism of action of BRAF-inhibitors and MEK-inhibitors used together, the pathophysiological mechanisms that lead to cardiovascular toxicity. Particularly, it focuses on hypertension and ejection fraction reduction development. Then, it follows the examination of published data for each combination therapy. A Literature research was carried out using Pubmed selecting review articles, original studies and clinical trials, but mainly focusing on phase 3 studies. This work aims to summarize the knowledge about BRAF-inhibitor and MEK-inhibitor treatment and its cardiovascular toxicity to make it usable and give the basic tools to Cardiologists and Oncologists for a better management of cancer patient undergoing this treatment. Besides a deeper knowledge of the cardiovascular adverse events linked to this treatment and the magnitude of their expression and frequency can lead to a targeted cardiological treatment
Emily Brontë : the mind of a visionary
No full textBibliography: leaves 216-226.This dissertation is an investigation of the visionary and philosophical aspects of Emily Brontë's works. The first five chapters deal with the visionary process such as visions, spirit guides, dreams, imagination, encounters with the darker side of the self and a union with the divine. There is considerable evidence of these mystical avenues in both her poetry and in Wuthering Heights which have been explored. It is shown how Emily Brontë's mysticism is a direct result of personal experiences which augment her reputation as one of the leading mystics in the world of literature. There are however tensions in her works, such as the cynicism of her own intellect in accepting the visionary experiences as authentic and periods of suffering when her faith is tested. These tensions have been considered within the context of her mystical encounters and philosophy. The remaining four chapters deal with the philosophy of Emily Brontë per se. Her beliefs in respect of heaven and hell, mercy and justice, power and survival, and pantheism are considered in depth. It is argued that she is an unorthodox thinker who does not believe in an eternal hell and that she has drawn inspiration for this idea from Frederick Maurice and Ralph Waldo Emerson. It is also shown how issues of power have been of interest to her from a young age and how this needs to be integrated within her philosophy. To the writer power needs to be tempered by compassion if it is to be of use to society or the individual. Her pantheistic spirit is also investigated and related to the mystical ideas
Responses of Mouse Lymphocytes To Extracellular Adenosine 5'-triphosphate (atp) - Lymphocytes With Cyto-toxic Activity Are Resistant To the Permeabilizing Effects of Atp
No full textThe effects of extracellular ATP on plasma membrane permeability in mouse lymphocytes were studied with plasma membrane depolarization, uptake of ethidium bromide, and release of lactate dehydrogenase as indicators of increased permeability. Extracellular ATP induced sustained depolarization of plasma membrane potential as well as uptake of low m.w. fluorescent markers in mouse lymphocytes derived from thymus and spleen, and in two lymphoma lines YAC-1 and MBL-2. The fully ionized form ATP4- rather than MgATP2- mediated the increased permeability of the plasma membrane. Although prolonged exposure to exogenous ATP ultimately lysed the lymphocytes, two CTL populations (CHM-14 clone and CTLL-2 line) and IL-2-treated spleen lymphocytes with unrestricted killing activity were highly resistant to the permeabilizing action of extracellular ATP at all concentrations tested. In addition, CTL derived from primary immune peritoneal exudate and enriched by in vitro culture for 5 days in the presence of specific stimulator cells were also resistant to this permeabilizing effect. These findings show that exogenous ATP has a lytic effect on mouse lymphocytes but not on CTL, and suggest a role for ATP in cell-mediated cytotoxicity
La relazione tra abilità linguistiche verbali e di scrittura in bambini sordi e udenti di età scolare
No full textGENETIC, VIROLOGICAL AND CLINICAL FACTORS ASSOCIATED WITH HEPATOCELLULAR CARCINOMA DEVELOPEMENT IN PATIENTS WITH CHRONIC HBV AND HCV INFECTION
No full textExtracellular ATP causes lysis of mouse thymocytes and activates a plasma membrane ion channel
No full textExtracellular ATP (ATPo) caused a concentration-dependent lysis of mouse thymocytes. Lysis, as judged by release of the cytosolic enzyme lactate dehydrogenase, was preceded by depolarization of the plasma membrane and by Ca2+ influx. Both Na+ uptake (which sustained plasma membrane depolarization) and Ca2+ influx showed (1) the same dependence on the ATPo concentration; (2) the same nucleotide specificity; and (3) the same Hill coefficient. However, whereas the rise in the cytosolic free Ca2+ concentration ([Ca2+]i) was fully inhibited by the known Ca2+ blocker verapamil, plasma membrane depolarization was enhanced under these conditions. Plasma membrane depolarization was greater and was shifted to lower ATPo concentrations in the absence of extracellular Ca2+ (Ca2+o), whereas the rise in [Ca2+]i was greater in Na(+)-free media. Plasma membrane depolarization also occurred in Na(+)-free choline- or methylglucamine-containing media, and was potentiated by chelation of free divalent ions with EDTA, supporting previous reports pointing to ATP4-as the active species. Among a number of purine and pyrimidine nucleotides, only adenosine 5'-[gamma-thio]triphosphate and ADP were partially effective. Furthermore, ethidium bromide (Mr 380), Lucifer Yellow (Mr 463) and Eosin Yellowish (Mr 692) did not permeate through the ATPo-activated channel. These findings suggest that lytic effects of ATPo in mouse thymocytes depend on the activation of a membrane channel with low selectivity for cations and an Mr cut-off of 200
HepatomiRNoma: The proposal of a new network of targets for diagnosis, prognosis and therapy in hepatocellular carcinoma
No full textThe diagnosis and treatment of hepatocellular carcinoma (HCC) underwent a huge advancement in the last years. Recently, microRNAs (miRNAs) have been also studied to provide a new tool for early diagnosis of high risk patients, for prognostic classification to identify those patients who benefit cancer treatment and for predictive definition to select the right targeted drug.In this review we revised all the available data obtained to explore the role of miRNAs in HCC. This analysis led to identification of miRNAs which could gain a diagnostic, prognostic or predictive role.The results of studies on miRNAs involved in HCC are initial and far from providing scientific evidences to translate into clinical practice. We propose a classification of these miRNAs, that we could name HepatomiRNoma as a whole. Anyway prospective studies have to be designed to clarify the real clinical impact of this new tool
What links BRAF to the heart function? New insights from the cardiotoxicity of BRAF inhibitors in cancer treatment
No full textThe RAS-related signalling cascade has a fundamental role in cell. It activates differentiation and survival. It is particularly important one of its molecules, B-RAF. B-RAF has been a central point for research, especially in melanoma. Indeed, it lacked effective therapeutic weapons since the early years of its study. Molecules targeting B-RAF have been developed. Nowadays, two classes of molecules are approved by FDA. Multi-target molecules, such as Sorafenib and Regorafenib, and selective molecules, such as Vemurafenib and Dabrafenib. Many other molecules are still under investigation. Most of them are studied in phase 1 trials. Clinical studies correlate B-RAF inhibitors and QT prolongation. Though this cardiovascular side effect is not common using these drugs, it must be noticed early and recognize its signals. Indeed, Oncologists and Cardiologists should work in cooperation to prevent lethal events, such as fatal arrhythmias or sudden cardiac death. These events could originate from an uncontrolled QT prolongation
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