Imidazo[2,1-b] [1,3,4]thiadiazoles with antiproliferative activity against primary and gemcitabine-resistant pancreatic cancer cells

A new series of eighteen imidazo [2,1-b] [1,3,4]thiadiazole derivatives was efficiently synthesized and screened for antiproliferative activity against the National Cancer Institute (NCI-60) cell lines panel. Two out of eighteen derivatives, compounds 12a and 12h, showed remarkably cytotoxic activity with the half maximal inhibitory concentration values (IC50) ranging from 0.23 to 11.4 mM, and 0.29e12.2 mM, respectively. However, two additional compounds, 12b and 13g, displayed remarkable in vitro antiproliferative activity against pancreatic ductal adenocarcinoma (PDAC) cell lines, including immortalized (SUIT-2, Capan-1, Panc-1), primary (PDAC-3) and gemcitabine-resistant (Panc-1R), eliciting IC50 values ranging from micromolar to sub-micromolar level, associated with significant reduction of cell-migration and spheroid shrinkage. These remarkable results might be explained by modulation of key regulators of epithelial-to-mesenchymal transition (EMT), including E-cadherin and vimentin, and inhibition of metalloproteinase-2/-9. High-throughput arrays revealed a significant inhibition of the phosphorylation of 45 tyrosine kinases substrates, whose visualization on Cytoscape highlighted PTK2/FAK as an important hub. Inhibition of phosphorylation of PTK2/FAK was validated as one of the possible mechanisms of action, using a specific ELISA. In conclusion, novel imidazothiadiazoles show potent antiproliferative activity, mediated by modulation of EMT and PTK2/FAK

Torcicollo A Tuttalè! (Note) Coccolini, E.a, Bruzzi, P.b, Bergonzini, P.b, Iughetti, L.ab

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Grisel’s Syndrome in Children: Two Case Reports and Systematic Review of the Literature

Background and Objective. Grisel’s syndrome is a rare syndrome characterized by nontraumatic rotatory subluxation of the atlantoaxial joint. It usually affects children and typically presents with torticollis after ear, nose, and throat (ENT) surgery or head and neck infections. In the pediatric literature, there is only a small amount of available data; moreover, no systematic review has been previously done with focus on the pediatric population. We report our experience of two cases, and we provide a systematic review on Grisel’s syndrome in children in order to offer a deeper insight about its clinical presentation, its current diagnosis, and principles of treatment. Case Reports and Review. We describe two boys of 9 and 8 years old, who developed atlantoaxial subluxation after adenoidectomy. Considering the early diagnosis, a conservative treatment was chosen, with no recurrence and no sequelae at follow-up. We identified 114 case reports, of which 90 describe children, for a total of 171 pediatric patients. Of the 154 cases in which cause was reported, 59.7% presented a head and neck infection and 35.7% had previous head and neck surgery. There is no sex prevalence (49.7% males versus 50.2% females). Mean delay in diagnosis is 33 days. Eight % of the patients had neurological impairment of the 165 cases which mentioned treatment, 96% underwent a conservative treatment, of whom the 8.8% recurred with the need of surgery. As a whole, 12% underwent surgery as a first- or second-line treatment. 3 6% of the patients whose follow-up was reported developed a sequela, minor limitation of neck movement being the most frequent. Conclusion. Grisel’s syndrome should be suspected in children with painful unresponsive torticollis following ENT procedures or head and neck inflammation. CT scan with 3D reconstruction is the gold standard for diagnosis, allowing the identification of the subluxation and the classification according to the Fielding–Hawkins grading system. Surgical treatment is indicated in case of high-grade instability or failure of conservative treatment. Review of the literature shows how early diagnosis based on clinical and radiological evaluation is crucial in order to avoid surgical treatment and neurologic sequelae

Infantile neuroaxonal dystrophy and PLA2G6-associated neurodegeneration: An update for the diagnosis

Infantile neuroaxonal dystrophy is a rare neurodegenerative disorder characterized by infantile onset of rapid motor and cognitive regression and hypotonia evolving into spasticity. Recessively inherited mutations of the PLA2G6 gene are causative of infantile neuroaxonal dystrophy and other PLA2G6-associated neurodegeneration, which includes conditions known as atypical neuroaxonal dystrophy, Karak syndrome and early-onset dystonia-parkinsonism with cognitive impairment. Phenotypic spectrum continues to evolve and genotype-phenotype correlations are currently limited. Due to the overlapping phenotypes and heterogeneity of clinical findings characterization of the syndrome is not always achievable. We reviewed the most recent clinical and neuroradiological information in the way to make easier differential diagnosis with other degenerative disorders in the paediatric age. Recognizing subtle signs and symptoms is a fascinating challenge to drive towards better diagnostic and genetic investigations

Further delineation of PIGB-related early infantile epileptic encephalopathy

Pathogenic variants in phosphatidylinositol glycan anchor biosynthesis class B (PIGB) gene have been first described as the cause of early infantile epileptic encephalopathy 80 (EIEE-80) in 2019. This disorder, an inherited glycosylphosphatidylinositol deficiency, is associated with a complex neurologic phenotype, including developmental delay, early-onset epilepsy and peripheral neuropathy. We report on a 5 year-old girl born from consanguineous parents, manifesting severe global developmental delay with absent speech, mixed peripheral polyneuropathy, hypotonia, bilateral equino-varo-supinated-cavus foot, early-onset scoliosis, elevated serum alkaline phosphatase and a single episode of febrile status epilepticus. Hypomyelination was documented on brain MRI. Whole-exome sequencing (WES) disclosed the likely pathogenic biallelic PIGB NM_004855.4: c.463G > C, p.(Asp155His) missense variant. In our patient, while other characteristic clinical, neuroimaging and laboratory findings (as described in the first research paper) were present, seizures were not a major clinical issue, thus contributing to our knowledge on this ultra-rare disorder

Predictive diagnostic value for the clinical features accompanying intellectual disability in children with pathogenic copy number variations: A multivariate analysis

Background: Array comparative genomic hybridization (a-CGH) has become the first-tier investigation in patients with unexplained developmental delay/intellectual disability (DD/ID). Although the costs are progressively decreasing, a-CGH is still an expensive and labour-intensive technique: for this reason a definition of the categories of patients that can benefit the most of the analysis is needed. Aim of the study was to retrospectively analyze the clinical features of children with DD/ID attending the outpatient clinic of the Mother & Child Department of the University Hospital of Modena subjected to a-CGH, to verify by uni- and multivariate analysis the independent predictors of pathogenic CNVs. Methods. 116 patients were included in the study. Data relative to the CNVs and to the patients' clinical features were analyzed for genotype/phenotype correlations. Results and conclusions. 27 patients (23.3%) presented pathogenic CNVs (21 deletions, 3 duplications and 3 cases with both duplications and deletions). Univariate analysis showed a significant association of the pathogenic CNVs with the early onset of symptoms (before 1 yr of age) and the presence of malformations and dysmorphisms. Logistic regression analysis showed a significant independent predictive value for diagnosing a pathogenic CNV for malformations (P = 0.002) and dysmorphisms (P = 0.023), suggesting that those features should address a-CGH analysis as a high-priority test for diagnosis. © 2014 Caramaschi et al.; licensee BioMed Central Ltd