Imatinib inhibits proliferation of Ewing tumor cells mediated by the stem cell factor/KIT receptor pathway, and sensitizes cells to vincristine and doxorubicin-induced apoptosis.

PURPOSE AND EXPERIMENTAL DESIGN: The stem cell factor/KIT receptor loop may represent a novel target for molecular-based therapies of Ewing tumor. We analyzed the in vitro impact of KIT blockade by imatinib in Ewing tumor cell lines. RESULTS: KIT expression was detected in 4 of 4 Ewing tumor cell lines and in 49 of 110 patient samples (44.5%) by immunohistochemistry and/or Western blot analysis. KIT expression was stronger in Ewing tumors showing EWS-FLI1 nontype 1 fusions. Despite absence of c-kit mutations, constitutive and ligand-inducible phosphorylation of KIT was found in all tumor cell lines, indicating an active receptor. Treatment with KIT tyrosine kinase inhibitor imatinib (0.5-20 micro M) induced down-regulation of KIT phosphorylation and dose response inhibition of cell proliferation (IC(50), 12-15 micro M). However, imatinib administered alone at doses close to IC(50) for growth inhibition (10 micro M) did not induce a significant increase in apoptosis. We then analyzed if blockade of KIT loop through imatinib (10 micro M) was able to increase the antitumor in vitro effect of doxorubicin (DXR) and vincristine (VCR), drugs usually used in Ewing tumor treatment. Addition of imatinib decreased in 15-20 and 15-36% of the proliferative rate of Ewing tumor cells exposed to DXR and VCR, respectively, and increased in 15 and 30% of the apoptotic rate of Ewing tumor cells exposed to the same drugs. CONCLUSIONS: Inhibition of Ewing tumor cell proliferation by imatinib is mediated through blockade of KIT receptor signaling. Inhibition of KIT increases sensitivity of these cells to DXR and VCR. This study supports a potential role for imatinib in the treatment of Ewing tumor.     

Role of Bowel Ultrasound in the Diagnosis and Follow-up of Patients with Crohn's Disease

Crohn's disease (CD) is an inflammatory chronic bowel disorder; it can involve the whole gastrointestinal tract, but its localization in the ileum or colon is most common. The reference standard for the diagnosis of CD is ileocolonoscopy with histologic assessment. The reference standard for the detection of any complications is surgery. However, imaging techniques have an important role both in the detection/localization of CD and in the follow-up of CD patients. In the last few years, the technical development of ultrasound equipment, the advent of new technologies such as elastography and mostly the increased expertise of sonographers have boosted the role of bowel ultrasound in assessment of the gastrointestinal tract. In fact, bowel ultrasound is particularly attractive thanks to its widespread availability, non-invasiveness, low cost and good reproducibility, as it can be easily repeated during follow-up. The aim of this article is to provide an extensive overview of the actual role of bowel ultrasound in the detection and follow-up of patients with CD.     

Small Bowel Ultrasound beyond Inflammatory Bowel Disease: An Updated Review of the Recent Literature

The use of bowel ultrasonography (US) for the evaluation of gut diseases has increased in recent years and has been proven to provide a widely available, non-invasive and inexpensive method for the initial work-up and follow-up of different intestinal diseases, limited mostly by technical challenges posed by the patient's anatomy. The present review aims to provide an extensive overview of the main pathologic features at US examination of intestinal diseases other than inflammatory bowel disease, both acute (e.g., acute appendicitis, colonic diverticulitis, infectious diseases and ischemic conditions) and chronic (e.g., celiac disease, cystic fibrosis and other enterocolites). The identification of typical US features may help in the diagnostic process and guide the treatment approach. Therefore, the application of knowledge of the US appearance of gastrointestinal diseases is of relevance in enabling greater diagnostic performance and better patient management.     

Beer Affects Oxidative Stress due to Ethanol in Rats

The relationship between chronic moderate beerconsumption and oxidative stress was studied in rats.Animals were fed three different isocaloric diets forsix weeks: a beercontaining diet (30% w/w), an ethanol-supplemented diet (1.1 g/100 g, thesame as in the beer diet) and an alcohol-free basaldiet. At the end of the feeding period, rats wereanalyzed for plasma and liver oxidative status. Somelivers were isolated and exposed toischemiareperfusion to assess the additional oxidativestress determined by reperfusion. No significantdifferences in plasma antioxidant status were foundamong the three dietary groups. Lipoproteins from the beer group,however, showed a greater propensity to resist lipidperoxidation. Ischemia caused a decrease in liver energyand antioxidant status in all groups. Nevertheless, ATP was lower in the livers of rats exposed tothe ethanol diet. During reperfusion, lipoperoxidationincreased significantly in all groups. However, liversobtained from ethanoltreated rats showed the higher formation of lipoperoxides. Inconclusion, a moderate consumption of beer in awell-balanced diet did not appear to cause oxidativestress in rats; moreover, probably through its minorcomponents, beer could attenuate the oxidative action ofethanol by itself.     

Long pentraxin‐3 as an epithelial–stromal fibroblast growth factor‐targeting inhibitor in prostate cancer

Fibroblast growth factors (FGFs) exert autocrine/paracrine functions in prostate cancer by stimulating angiogenesis and tumour growth. Here dihydrotestosterone (DHT) up‐regulates FGF2 and FGF8b production in murine TRAMP‐C2 prostate cancer cells, activating a FGF‐dependent autocrine loop of stimulation. The soluble pattern recognition receptor long pentraxin‐3 (PTX3) acts as a natural FGF antagonist that binds FGF2 and FGF8b via its N‐terminal domain. We demonstrate that recombinant PTX3 protein and the PTX3‐derived pentapeptide Ac‐ARPCA‐NH₂ abolish the mitogenic response of murine TRAMP‐C2 cells and human LNCaP prostate cancer cells to DHT and FGFs. Also, PTX3 hampers the angiogenic activity of DHT‐activated TRAMP‐C2 cells on the chick embryo chorioallantoic membrane (CAM). Accordingly, human PTX3 overexpression inhibits the mitogenic activity exerted by DHT or FGFs on hPTX3_TRAMP‐C2 cell transfectants and their angiogenic activity. Also, hPTX3_TRAMP‐C2 cells show a dramatic decrease of their angiogenic and tumourigenic potential when grafted in syngeneic or immunodeficient athymic male mice. A similar inhibitory effect is observed when TRAMP‐C2 cells overexpress only the FGF‐binding N‐terminal PTX3 domain. In keeping with the anti‐tumour activity of PTX3 in experimental prostate cancer, immunohistochemical analysis of prostate needle biopsies from primary prostate adenocarcinoma patients shows that parenchymal PTX3 expression, abundant in basal cells of normal glands, is lost in high‐grade prostatic intraepithelial neoplasia and in invasive tumour areas. These results identify PTX3 as a potent FGF antagonist endowed with anti‐angiogenic and anti‐neoplastic activity in prostate cancer. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Unique deficit in embodied simulation in autism: An fMRI study comparing autism and developmental coordination disorder

A deficit in pre‐cognitively mirroring other people''s actions and experiences may be related to the social impairments observed in autism spectrum disorder (ASD). However, it is unclear whether such embodied simulation deficits are unique to ASD or instead are related to motor impairment, which is commonly comorbid with ASD. Here we aim to disentangle how, neurologically, motor impairments contribute to simulation deficits and identify unique neural signatures of ASD. We compare children with ASD (N = 30) to children with Developmental Coordination Disorder (DCD; N = 23) as well as a typically developing group (N = 33) during fMRI tasks in which children observe, imitate, and mentalize about other people''s actions. Results indicate a unique neural signature in ASD: during action observation, only the ASD group shows hypoactivity in a region important for simulation (inferior frontal gyrus, pars opercularis, IFGop). However, during a motor production task (imitation), the IFGop is hypoactive for both ASD and DCD groups. For all tasks, we find correlations across groups with motor ability, even after controlling for age, IQ, and social impairment. Conversely, across groups, mentalizing ability is correlated with activity in the dorsomedial prefrontal cortex when controlling for motor ability. These findings help identify the unique neurobiological basis of ASD for aspects of social processing. Furthermore, as no previous fMRI studies correlated brain activity with motor impairment in ASD, these findings help explain prior conflicting reports in these simulation networks.     

Delirium in COVID-19 patients: a multicentric observational study in Italy

Neurological Sciences - Although recent data show that SARS-CoV-2 infection seems to affect the central nervous system (CNS), little is known about the neuropsychiatric effects resulting from this...     

A coordinated approach for the assessment of molecular subgroups in pediatric ependymomas using low-cost methods

Journal of Molecular Medicine - Although ependymoma (EPN) molecular subgroups have been well established by integrated high-throughput platforms, low- and middle-income countries still need...     

Expanded spectrum of Pelizaeus–Merzbacher-like disease: literature revision and description of a novel GJC2 mutation in an unusually severe form

Homozygous or compound heterozygous mutations in the GJC2 gene, encoding the gap junction protein connexin47 (Cx47), cause the autosomal recessive hypomyelinating Pelizaeus–Merzbacher-like disease (PMLD1, MIM# 608804). Although clinical and neuroradiological findings resemble those of the classic Pelizaeus–Merzbacher disease, PMLD patients usually show a greater level of cognitive and motor functions. Unpredictably a homozygous missense GJC2 mutation (p.Glu260Lys) was found in a patient presenting with a very severe clinical picture characterised by congenital nystagmus and severe neurological impairment. Also magnetic resonance imaging was unusually severe, showing an abnormal supra- and infratentorial white matter involvement extending to the spinal cord. The novel p.Glu260Lys (c.778G>A) mutation, occurring in a highly conserved motif (SRPTEK) of the Cx47 extracellular loop-2 domain, was predicted, by modelling analysis, to break a ‘salt bridge network'', crucial for a proper connexin–connexin interaction to form a connexon, thus hampering the correct formation of the connexon pore. The same structural analysis, extended to the previously reported missense mutations, predicted that most changes were expected to have less severe impact on protein functions, correlating with the mild PMLD1 form of the patients. Our study expands the spectrum of PMLD1 and provides evidence that the extremely severe clinical and neuroradiological PMLD1 form of our patient likely correlates with the predicted impairment of gap junction channel assembly resulting from the detrimental effect of the new p.Glu260Lys mutant allele on Cx47 protein.