The proteasomal and apoptotic phenotype determine bortezomib sensitivity of non-small cell lung cancer cells

Bortezomib is a novel anti-cancer agent which has shown promising activity in non-small lung cancer (NSCLC) patients. However, only a subset of patients respond to this treatment. We show that NSCLC cell lines are differentially sensitive to bortezomib, IC50 values ranging from 5 to 83 nM. The apoptosis-inducing potential of bortezomib in NSCLC cells was found to be dependent not only on the apoptotic phenotype but also on the proteasomal phenotype of individual cell lines. Upon effective proteasome inhibition, H460 cells were more susceptible to apoptosis induction by bortezomib than SW1573 cells, indicating a different apoptotic phenotype. However, exposure to a low dose of bortezomib did only result in SW1573 cells, and not in H460 cells, in inhibition of proteasome activity and subsequent apoptosis. This suggests a different proteasomal phenotype as well. Additionally, overexpression of anti-apoptotic protein Bcl-2 in H460 cells did not affect the proteasomal phenotype of H460 cells but did result in decreased bortezomib-induced apoptosis. In conclusion, successful proteasome-inhibitor based treatment strategies in NSCLC face the challenge of having to overcome apoptosis resistance as well as proteasomal resistance of individual lung cancer cells. Further studies in NSCLC are warranted to elucidate underlying mechanisms

Plantar erythrodysesthesia with bullous otitis externa, toxicities from sorafenib: a case report

Lung cancer is the leading cause of cancer death worldwide and the use of novel agents, such as sorafenib has now demonstrated activity in Non Small Cell Lung Cancer. We present a case of a 77-year-old Caucasian male with advanced adenocarcinoma of the lung, who was being treated on clinical trial with single agent sorafenib. After seven weeks of treatment the patient presented to clinic with difficulty walking. Physical exam revealed acral erythema with bollous formation on bilateral soles of his feet. Otoscopic exam revealed bilateral external canal bullous lesion. The patient was diagnosed with plantar erythrodysesthesia with bullous otitis externa, a new toxicities in patients being treated with sorafenib

Studio di impatto ambientale nell'area portuale antistante lo stabilimento industriale EniChem di Porto Torres

This paper reports environmental study carried out in the seaport wear Petro-chemical Plant of Porto Torres (North-Western Sardinia) eight years after study where four areas at different level of pollution were described. In the meantime specific, ecological plants are realized i.e. liquid effluent collectors, biological water treatment plant and a stelling basin of depurated effluents. The present work shows a general improvement of the harbour area, as water quality and transparency, heavy metals content of sediments and aquatic flora. In this way two different methods are used (synecological and chemical), i.e. mapping of biotic community, density of Posidonia oceanica seagrass, chemical analysis of oysters, posidonia's rhizome and leaf, water and sediments

La Vegetazione marina bentonica nel Mediterraneo: 1.: sopralitorale e mesolitorale: proposte di aggiornamento

In questo primo contributo gli autori presentano un aggiornamento degli aggruppamenti vegetali marini del sopralitorale e del mesolitorale del Mediterraneo. Nel piano sopralitorale è stata riconosciuta la presenza di una sola associazione; nel piano mesolitorale di otto associazioni: tre nel sottopiano superiore e cinque nel sottopiano inferiore. A phytosociological revision of both supralittoral and midlittoral marine algal communities from the Mediterranean Sea, is presented. In all, nine associations can be recognized: one in the supralittoral zone; three in the upper and five in the lower midlittoral zone

Functional analysis of cancer-associated EGFR mutants using a cellular assay with YFP-tagged EGFR intracellular domain

<p>Abstract</p> <p>Background</p> <p>The presence of EGFR kinase domain mutations in a subset of NSCLC patients correlates with the response to treatment with the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. Although most EGFR mutations detected are short deletions in exon 19 or the L858R point mutation in exon 21, more than 75 different EGFR kinase domain residues have been reported to be altered in NSCLC patients. The phenotypical consequences of different EGFR mutations may vary dramatically, but the majority of uncommon EGFR mutations have never been functionally evaluated.</p> <p>Results</p> <p>We demonstrate that the relative kinase activity and erlotinib sensitivity of different EGFR mutants can be readily evaluated using transfection of an YFP-tagged fragment of the EGFR intracellular domain (YFP-EGFR-ICD), followed by immunofluorescence microscopy analysis. Using this assay, we show that the exon 20 insertions Ins770SVD and Ins774HV confer increased kinase activity, but no erlotinib sensitivity. We also show that, in contrast to the common L858R mutation, the uncommon exon 21 point mutations P848L and A859T appear to behave like functionally silent polymorphisms.</p> <p>Conclusion</p> <p>The ability to rapidly obtain functional information on EGFR variants of unknown relevance using the YFP-EGFR-ICD assay might prove important in the future for the management of NSCLC patients bearing uncommon EGFR mutations. In addition, our assay may be used to determine the response of resistant EGFR mutants to novel second-generation TKIs.</p

Tissue micro array analysis of ganglioside N-glycolyl GM3 expression and signal transducer and activator of transcription (STAT)-3 activation in relation to dendritic cell infiltration and microvessel density in non-small cell lung cancer

Background: Tumor immune escape and angiogenesis contribute to tumor progression, and gangliosides and activation of signal transducer and activator of transcription (STAT)-3 are implicated in these processes. As both are considered as novel therapeutic targets, we assessed the possible association of ganglioside GM3 expression and STAT3 activation with suppression of dendritic cell (DC) activation and angiogenesis in non-small cell lung cancer (NSCLC). Methods: Immunohistochemistry was performed on a tissue array to determine N-glycolyl GM3 (GM3) and phosphorylated STAT3 (pSTAT3) expression in 176 primary NSCLC resections. Median values of GM3 and pSTAT3 expression were used as cut off. Microvessel density (MVD) was determined by CD34 staining and morphology. CD1a and CD83 were used to determine infiltrating immature and mature dendritic cells, respectively. Results: 94% and 71% of the NSCLC samples expressed GM3 and nuclear pSTAT3, respectively. Median overall survival was 40.0 months. Both low GM3 expression and high pSTAT3 expression were associated with a worse survival, which reached near significance for GM3 (P = 0.08). Microvessel density (MVD), determined by CD34 staining and morphology, was lower in NSCLC samples with high GM3 expression. CD1a(+) cells (immature DCs) were more frequent in NSCLC tissues as compared to peritumoral lung tissue, while CD83(+) cells (mature DCs) were more frequent in peritumoral lung tissue. CD83(+) DCs were less frequent in NSCLC tissues with high GM3 expression. Conclusion: GM3 and pSTAT3 are widely expressed in NSCLC. Based on CD83 expression, GM3, but not pSTAT3, appeared to be involved in tumor-induced DC suppression. pSTAT3 expression was not associated with MVD, while GM3 might play an anti-angiogenic rol