230 research outputs found
Role of HGF-MET signaling in primary and acquired resistance to targeted therapies in cancer
No full textThe Hepatocyte growth factor (HGF)-mesenchymal-epithelial transition (MET) pathway is deregulated in several cancers and is associated with aggressive phenotype and worse prognosis. MET, a tyrosine kinase receptor activated by HGF, plays a physiological role in embryogenesis, promoting cell growth, survival and motility. HGF-MET aberrant activation in tumorigenesis acts through various mechanisms: paracrine/autocrine HGF production, MET overexpression, MET germ-line and sporadic mutations and cross-talk with other growth factor receptors. In addition, MET activation could represent a mechanism of escape from other targeted therapies, through receptor amplification or over-stimulation by the ligand, as demonstrated in non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) models with acquired resistance to epidermal growth factor receptor (EGFR) inhibitors and also in models of melanoma resistant to the BRAF inhibitor vemurafenib. As a consequence, a lot of molecules targeting MET signaling are under clinical investigation as single agent or in combination with other targeted drugs. Patient selection, based on MET expression on tumor samples (eventually, by re-biopsy of new metastatic sites), and pharmacokinetic/pharmacodynamic markers are needed. Authors review the latest data on the role of MET and the molecular mechanism underlying primary or acquired resistance to biological agents, focusing on NSCLC, CRC and melanoma
Pulmonary Large-Cell Neuroendocrine Carcinoma: From Epidemiology to Therapy
No full textLung neuroendocrine tumors are a heterogeneous subtype of pulmonary cancers representing approximately 20% of all lung cancers, including small-cell lung cancer (SCLC) and large-cell neuroendocrine carcinoma (LCNEC). The frequency appears to be approximately 3% for LCNEC. Diagnosis of LCNEC requires attention to neuroendocrine features by light microscopy and confirmation by immunohistochemical staining for neuroendocrine markers. Both SCLC and pulmonary LCNEC are high-grade and poor-prognosis tumors, with higher incidence in males and smokers and peripheral localization. LCNEC is very rare, and the precise diagnosis on small specimens is very difficult, so we have still too few data to define a standard of treatment for pulmonary LCNECs. Data of literature, most based on retrospective analysis, indicated a poor 5-year overall survival, with a high incidence of recurrence after surgery, even in stage I disease. Primary surgery should be the first option in all operable patients because there is no validate therapeutic approach for LCNEC due to lack of clinical trials in this setting. Neoadjuvant platinum-based regimens remain only an option for potentially resectable tumors. In advanced stages, SCLC-like chemotherapy seems the best option of treatment, with a good response rate but a poor overall survival (from 8 to 16 months in different case series). New agents are under clinical investigation to improve LCNEC patients' outcome. We reviewed all data on treatment options feasible for pulmonary LCNEC, both for localized and extensive disease
51PD Effect of MEK inhibition on PDL1 and and on cytokinesproduction profilein NSCLC cell lines and in human lymphocites
No full textImplication of the Hedgehog pathway in hepatocellular carcinoma.
No full textThe prognosis for patients who are diagnosed with advanced stage hepatocellular carcinoma (HCC) is poor because there are few treatment options. Recent research has focused on the identification of novel molecular entities that can be targeted to inhibit oncogenic signals that are involved in the carcinogenesis, proliferation and progression of HCC. Among all of the pathways that are involved in the development of HCC, Hedgehog (HH) signalling has demonstrated a substantial role in hepatocarcinogenesis and HCC progression. HH plays a physiological role in embryogenesis, through the induction of the differentiation of hepatocytes from endodermal progenitors. The re-activation of the HH pathway in chronic damaged liver is a mechanism of fibrotic degeneration and is implicated in various stages of HCC development. HH activation sustains the sub-population of immature liver epithelial cells that are involved in the pathogenesis of cirrhosis and HCC, and HH itself is a mediator of the alcohol-derived malignant transformation of liver cells. High levels of expression of HH protein markers in liver tumour tissues are correlated with aggressive histological and biological features and a poor clinical outcome. In vitro and in vivo inhibition models of the HH pathway confirm that HH is essential in maintaining tumour growth, metastasis and a mesenchymal phenotype
Experimental characterization and numerical analysis of the 4H-SiC p-i-n diodes static and transient behaviour
No full textSteady-state and turn-off switching characteristics of aluminium-implanted 4H-SiC p-i-n diodes designed for high current density operation, are investigated experimentally and by mean of numerical simulations in the 298-523 K temperature range. The diodes present circular structure with a diameter of 350 μm and employ an anode region with an aluminium depth profile peaking at 6?1019 cm−3 at the surface. The profile edge and the junction depth are located at 0.2 and 1.35 μm, respectively. At room temperature the measured forward current density is close to 370 A/cm2 at 5 V with an ideality factor always less than 2 before high current injection or device series resistance became dominant. The transient analysis reveals a strong potential of this diodes for use in high speed, high power applications, especially at high temperature, with a very low turn-off recovery time (<80 ns) in the whole range of test conditions. The simulated results match the experimental data, showing that the switching performance is mainly due to the poor minority charge carrier lifetime estimated to be 15 ns for these implanted devices
Urtica dioica L. inhibits proliferation and enhances cisplatin cytotoxicity in NSCLC cells via Endoplasmic Reticulum-stress mediated apoptosis
No full textNon-small cell lung cancer (NSCLC) is the most common type of lung cancer and the ineffectiveness of the current therapies seriously limits the survival rate of NSCLC patients. In the search for new antitumor agents, nature has played a pivotal role providing a variety of molecules, which are likely to exert selective anti-tumour properties. Herein, we investigated the antiproliferative potential of Urtica dioica L. extract (UD) against NSCLC cell models with low sensitivity to cisplatin, a cytotoxic agent largely employed to cure NSCLCs. UD inhibited cell proliferation in the selected cells, while no toxic effects were observed in normal lung cells. Furthermore, the co-treatment of UD and cisplatin notably sensitised NSCLC cells to cisplatin. Mechanistically, we discovered that UD-promoted endoplasmic reticulum (ER) stress via activation of the growth arrest and DNA damage-inducible gene 153 (GADD153) triggering apoptosis. We also performed an extensive NMR analysis of UD, identifying rutin and oxylipins as the main secondary metabolites present in the mixture. Additionally, we discovered that an oxylipins' enriched fraction contributes to the antiproliferative activity of the plant extract. In the future, this study may provide new chemical scaffolds for the design of anti-cancer agents that target NSCLCs with low sensitivity to cisplatinum
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