Crizotinib-induced antitumour activity in human alveolar rhabdomyosarcoma cells is not solely dependent on ALK and MET inhibition

BACKGROUND: Rhabdomyosarcoma (RMS) is the most commonly diagnosed malignant soft tissue tumour in children and adolescents. Aberrant expression of Anaplastic Lymphoma Kinase (ALK) and MET gene has been implicated in the malignant progression of RMS, especially in the alveolar subtype. This observation suggests that crizotinib (PF-02341066), a kinase inhibitor against ALK and MET, may have a therapeutic role in RMS, although its antitumour activity in this malignancy has not yet been studied. METHODS: RH4 and RH30 alveolar RMS (ARMS) cell lines were treated with crizotinib and then assessed by using proliferation, viability, migration and colony formation assays. Multiple approaches, including flow cytometry, immunofluorescence, western blotting and siRNA-based knock-down, were used in order to investigate possible molecular mechanisms linked to crizotinib activity. RESULTS: In vitro treatment with crizotinib inhibited ALK and MET proteins, as well as Insulin-like Growth Factor 1 Receptor (IGF1R), with a concomitant robust dephosphorylation of AKT and ERK, two downstream kinases involved in RMS cell proliferation and survival. Exposure to crizotinib impaired cell growth, and accumulation at G2/M phase was attributed to an altered expression and activation of checkpoint regulators, such as Cyclin B1 and Cdc2. Crizotinib was able to induce apoptosis and autophagy in a dose-dependent manner, as shown by caspase-3 activation/PARP proteolytic cleavage down-regulation and by LC3 activation/p62 down-regulation, respectively. The accumulation of reactive oxygen species (ROS) seemed to contribute to crizotinib effects in RH4 and RH30 cells. Moreover, crizotinib-treated RH4 and RH30 cells exhibited a decreased migratory/invasive capacity and clonogenic potential. CONCLUSIONS: These results provide a further insight into the molecular mechanisms affected by crizotinib in ARMS cells inferring that it could be a useful therapeutic tool in ARMS cancer treatment

(18)F-DOPA Positron Emission Tomography in Medulloblastoma: 2 Case Reports

Medulloblastoma (MDB) is an aggressive embryonal brain tumor, with underlying altered genetics and biological pathways that account for very heterogeneous natural histories and clinical behaviors. Positron emission tomography (PET) using radiolabeled amino acids provides important metabolic information for the diagnosis of cerebral glioma but only a few data are available on amino acid PET in MDB. In particular, no cases of MDB imaging with 6-[(18)F]-fluoro-L-3,4-dihydroxyphenylalanine (F-DOPA) have previously been described

TREATMENT OF PAEDIATRIC GLIOMA TUMORS: RESULTS OF A SINGLE INSTITUTION EXPERIENCE

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Reply to “post-surgical mutism and catatonia”

Catatonia is a complex syndrome characterized by a wide spectrum of speech, motor and behavior disturbances; according to the fifth Diagnostic and Statistical Manual of Mental Disorder (DSM-V), a diagnosis of catatonia can be made if at least 3 out of the following 12 conditions are observed: mutism, stupor, cataplexy, waxy flexibility, agitation, negativism, posturing, mannerisms, stereotypes, grimacing, echolalia or echopraxia [2]. However, several other neurological and neuropsychiatric signs and symptoms can be encountered in a catatonic patient [3], thus generating clinical overlap with a number of conditions such as extrapyramidal side effects, neuroleptic malignant syndrome, non-convulsive status epilepticus, locked-in syndrome, vegetative state, stiff person syndrome and akinetic mutism [4]

Additional file 1: of Crizotinib-induced antitumour activity in human alveolar rhabdomyosarcoma cells is not solely dependent on ALK and MET inhibition

ALK and MET knock-down by RNA interference. A: RH4 and RH30 cells were transfected with either scramble control siRNA (NC siRNA) or ALK siRNA. Cells were harvested 48 h after transfection and ALK, AKT (phosphorylated and total protein) and ERK (phosphorylated and total protein) levels were analysed by Western blotting. B: RH4 and RH30 cells were transfected with either scramble negative control siRNA (NC siRNA) or MET siRNA. Cells were harvested 48 h after transfection and MET, AKT (phosphorylated and total protein) and ERK (phosphorylated and total protein) levels were analysed by Western blotting. Tubulin was used as loading control in all experiments. (TIFF 258 kb