OBJECTIVES:Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) is a newly defined disease in neuropsychiatry and occurs with an autoimmune mechanism after Group A Beta Hemolytic Streptococcus (GABHS) infection. Tumor necrosis factor (TNF), encoded by TNF-α gene has an important role in the apoptotic mechanisms of autoimmune diseases. Recently, TNF-α polymorphisms and autoimmune/psychiatric disorders have been reported to be related. In this regard, we focused on to investigate a possible relation between the TNF-α gene promoter region−308 G/A and − 850 C/T polymorphisms and PANDAS.MATERIALS AND METHODS:In this study, ages of PANDAS patient and control groups were ranging from 4 years to 12-year-old. Patient group includes childhood onset PANDAS patients (n = 42) and control group includes healthy children (n = 58). Diagnoses have been carried out according to Diagnostic and Statistical Manual of Mental Disorder (DSM-IV) criteria with Affective Disorders and Schizophrenia-Present and Lifetime (KSAD-S-PL) and Children Yale-Brown Obsessive Compulsive Scale Moreover, PANDAS criteria established by the American National Psychiatry Institute have been employed for diagnoses. For identifying polymorphisms; Polymerase Chain Reaction, Restriction Fragment Length Polymorphism and Polyacrylamid Gel Electrophoresis were used.RESULTS AND DISCUSSION:For −308 polymorphism, 37 of 42 PANDAS patients’ results and for −850 C/T polymorphism, 38 of 42 PANDAS patients’ results were obtained. According to our statistical analysis there is a positive relationship between PANDAS patients for −308 G/A polymorphism but not for −850 C/T polymorphism. There is no positive relationship between −308 G/A polymorphism and antistrep-tolysin O (ASO) titers and no relationship between −850 C/T polymorphism and ASO titers. We found, however, positive relationship between genders of patients (boys) and the disease. According to our results, we propose that the AA polymorphism of −308 G/A polymorphism can be used as a molecular indicator for PANDAS.
Pentasomy X is an extremely rare sex chromosome abnormality, a condition that only affects females, in which three more X chromosomes are added to the normally present two chromosomes in females. We investigated the novel clinical findings in a 1-year-old female baby with pentasomy X, and determined the parental origins of the X chromosomes. Our case had thenar atrophy, postnatal growth deficiency, developmental delay, mongoloid slant, microcephaly, ear anomalies, micrognathia and congenital heart disease. A conventional cytogenetic technique was applied for the diagnosis of the polysomy X, and quantitative fluorescent polymerase chain reaction (QF-PCR) using 11 inherited short tandem repeat (STR) alleles specific to the chromosome X for the determination of parental origin of X chromosomes. A cytogenetic evaluation revealed that the karyotype of the infant was 49,XXXXX. Comparison of the infant’s features with previously reported cases indicated a clinically recognizable specific pattern of malformations referred to as the pentasomy X syndrome. However, to the best of our know-ledge, this is the first report of thenar atrophy in a patient with 49,XXXXX. The molecular analysis suggested that four X chromosomes of the infant originated from the mother as a result of the non disjunction events in meiosis I and meiosis II. We here state that the clinical manifestations seen in our case were consistent with those described previously in patients with pentasomy X. The degree of early hypotonia constitutes an important early prognostic feature in this syndrome. The pathogenesis of pentasomy X is not clear at present, but it is thought to be caused by successive maternal non disjunctions.
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers. Uncovering mechanisms responsible for the heterogeneous clinical features of this disease is an essential step toward developing improved and more specific therapeutic approaches. Here, we sought to identify transcriptional regulators of aggressive PDAC growth through in vivo CRISPR screening of epigenetic and transcription factors in an orthotopic model. We identified the ISL LIM homeobox 2 (ISL2) gene as a tumor suppressor whose depletion enhances the proliferation of human PDAC cells in vitro and in vivo and cooperates with activated KRAS to initiate PDAC in a murine model. Conversely, the upregulation of ISL2 expression through CRISPR-mediated locus-specific epigenetic editing results in reduced cell proliferation. Importantly, ISL2 is epigenetically silenced through DNA methylation in ~60% of PDAC tumors, which correlates with poor patient outcome.Functional studies showed that ISL2 loss rewires metabolic gene expression, and consequently potentiates oxidative phosphorylation while reducing glycolysis. This metabolic shift creates selective vulnerability to small molecule inhibitors of mitochondrial respiration and fatty acid oxidation. Collectively, these findings reveal ISL2 as a novel tumor suppressor whose inactivation drives metabolic reprogramming in an aggressive PDAC subset and point to potential therapeutic vulnerabilities in these tumors.
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