Evidence for PDGFRA, PDGFRB and KIT deregulation in an NSCLC patient.
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Benzamides↗
Biomedical subjects
F Miselli
Publications and source records attributed to F Miselli.
Functional analyses and molecular modeling of two c-Kit mutations responsible for imatinib secondary resistance in GIST patients.
Imatinib-acquired resistance related to the presence of secondary point mutations has become a frequent event in gastrointestinal stromal tumors. Here, transient transfection experiments with plasmids carrying two different KIT-acquired point mutations were performed along with immunoprecipitation of total protein extracts, derived from imatinib-treated and untreated cells. The molecular mechanics/Poisson Boltzmann surface area computational techniques were applied to study the interactions of the wild-type and mutated receptors with imatinib at the molecular level. Biochemical analyses showed KIT phosphorylation in cells transfected with vectors carrying the specific mutant genes. Imatinib treatment demonstrated that T670I was insensitive to the drug at all the applied concentrations, whereas V654A was inhibited by 6 microM of imatinib. The modeling of the mutated receptors revealed that both substitutions affect imatinib-binding site, but to a different extent: T670I substantially modifies the binding pocket, whereas V654A induces only relatively confined structural changes. We demonstrated that T670I and V654A cause indeed imatinib-acquired resistance and that the former is more resistant to imatinib than the latter. The application of molecular simulations allowed us to quantify the interactions between the mutated receptors and imatinib, and to propose a molecular rationale for this type of drug resistance.
Antineoplastic Agents↗
PDGFRalpha, PDGFRbeta and KIT expression/activation in conventional chondrosarcoma.
Chondrosarcomas represent 20% of all primary bone sarcomas, and many studies have attempted to unravel molecular targets for future development of new therapies. The aim of this study was to investigate the expression/activation of PDGFRalpha, PDGFRbeta and KIT receptor tyrosine kinases (RTKs) as potential therapeutic targets in conventional central primary chondrosarcomas (CCS). The expression of PDGFRalpha, PDGFRbeta and KIT RTKs was detected in 16 CCSs using immunohistochemistry (IHC), and their level of expression and activation status were analysed by immunoprecipitation and western blot experiments. PDGFRalpha, PDGFRbeta and KIT cDNAs were screened to verify the presence of activating mutations and the presence of the cognate ligands was analysed by means of RT-PCR. RTK gene amplification was further studied by means of fluorescence in situ hybridization (FISH) analysis. The immunophenotyping and biochemical analyses showed that the CCSs co-expressed PDGFRalpha and PDGFRbeta, with the latter showing definitively greater protein expression and phosphorylation levels. PDGFRbeta was expressed but not activated in control healthy joint cartilage, in line with no PDGFB detection. Conversely, the KIT gene product did not seem to play a relevant role. These findings, in the absence of activating mutations or an abnormal genomic profile and the presence of PDGFA and PDGFB expression, are consistent with an autocrine/paracrine loop activation of the corresponding receptors. The CCS gene profile described here offers a rationale for the use of RTK inhibitors alone or in combination with chemotherapy, and supports further investigation of RTKs and their downstream signals.
Bone Neoplasms↗
[Association between relational and organizational factors and occurrence of musculoskeletal disease in health personnel].
INTRODUCTION AND OBJECTIVES: Even if work musculo-skeletal disorders represent a serious and commonly observed health problem among health care workers, few data are available about physical therapists. This study aims to compare the musculoskeletal disorders prevalence over two different health care populations and MATERIALS AND METHODS: Two populations have been studied: (i) 100 nurses working in the teaching hospital Azienda Policlinico di Modena and (ii) 100 physical therapists working in different hospitals in Modena and Reggio Emilia. The ergonomic risk assessment has been made according to the Ergo Web questionnaire. A self-reported questionnaire [partly built according to Outil de Repérage et d'Evaluation des Gestes (OREGE) method] has been used to collect data about physiological factors, musculo-skeletal symptoms of the upper limb and spine, stress indexes and psychosocial indexes. RESULTS: The two populations are comparable as far as the data of physiological and working anamnesis. The physical therapists have an higher prevalence of neck pain (p<0.01), whereas the nurses have an higher prevalence of low back pain (p<0.01). Furthermore, the physical therapists have an higher index of pain (involving prevalence, number of occurrences and intensity of the disorder) of right upper limb too. The nurses have higher working strain (p=0.00), attention need at work (p=0.00), poor autonomy (p<0.01) indexes than physical therapists. The indexes' analysis shows that musculo-skeletal disorders are associated to stress and psychosocial factors in both populations.
Adult↗