Loss of miR-107, miR-181c and miR-29a-3p promote activation of Notch2 signaling in pediatric high-grade gliomas (pHGGs)

The mechanisms by which microRNAs control pediatric high-grade gliomas (pHGGs) have yet to be fully elucidated. Our studies of patient-derived pHGG tissues and of the pHGG cell line KNS42 revealed down-regulation in these tumors of three microRNAs, specifically miR-107, miR-181c, and miR-29a-3p. This down-regulation increases the proliferation of KNS42 cells by de-repressing expression of the Notch2 receptor (Notch2), a validated target of miR-107 and miR-181c and a putative target of miR-29a-3p. Inhibition (either pharmacologic or genetic) of Notch2 or re-expression of the implicated microRNAs (all three combined but also individually) significantly reduced KNS42 cell proliferation. These findings suggest that Notch2 pathway activation plays a critical role in pHGGs growth and reveal a direct epigenetic mechanism that controls Notch2 expression, which could potentially be targeted by novel forms of therapy for these childhood tumors characterized by high-morbidity and high-mortality

SCREENING TEST FOR CONGENITAL HYPOTHYROIDISM: THYROID STIMULATING HORMONE (TSH) AND THYROXINE (T4) IN THE ADAPTED FOR GESTATIONAL AGE NEWBORN (AGA) AND IN THE SMALL FOR GESTATIONAL AGE NEWBORN (SGA) AT TERM AND PRETERM

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Untargeted NMR Metabolomics Reveals Alternative Biomarkers and Pathways in Alkaptonuria

Alkaptonuria (AKU) is an ultra-rare metabolic disease caused by the accumulation of homogentisic acid (HGA), an intermediate product of phenylalanine and tyrosine degradation. AKU patients carry variants within the gene coding for homogentisate-1,2-dioxygenase (HGD), which are responsible for reducing the enzyme catalytic activity and the consequent accumulation of HGA and formation of a dark pigment called the ochronotic pigment. In individuals with alkaptonuria, ochronotic pigmentation of connective tissues occurs, leading to inflammation, degeneration, and eventually osteoarthritis. The molecular mechanisms underlying the multisystemic development of the disease severity are still not fully understood and are mostly limited to the metabolic pathway segment involving HGA. In this view, untargeted metabolomics of biofluids in metabolic diseases allows the direct investigation of molecular species involved in pathways alterations and their interplay. Here, we present the untargeted metabolomics study of AKU through the nuclear magnetic resonance of urine from a cohort of Italian patients; the study aims to unravel molecular species and mechanisms underlying the AKU metabolic disorder. Dysregulation of metabolic pathways other than the HGD route and new potential biomarkers beyond homogentisate are suggested, contributing to a more comprehensive molecular signature definition for AKU and the development of future adjuvant treatment

The Pharmacogenetics of Cannabis in the Treatment of Chronic Pain

Background: The increase in the medical use of cannabis has revealed a number of beneficial effects, a variety of adverse side effects and great inter-individual variability. Association studies connecting consumption, addiction and side effects related to recreational cannabis use have led to the identification of several polymorphic genes that may play a role in the pharmacodynamics and pharmacokinetics of cannabis. Method: In total, 600 patients treated with cannabis were genotyped for several candidate polymorphic genes (single-nucleotide polymorphism; SNP), encoding receptors CNR1 and TRPV1; for the ABCB1 transporter; for biotransformation, bioactivation and biosynthesis; and CYP3A4, COMT and UGT2B7 conjugation. Results: Three polymorphic genes (ABCB1, TRPV1 and UGT2B7) were identified as being significantly associated with decline in pain after treatment with cannabis. Patients simultaneously carrying the most favourable allele combinations showed a greater reduction (polygenic effect) in pain compared to those with a less favourable combination. Considering genotype combinations, we could group patients into good responders, intermediate responders and poor or non-responders. Results suggest that genetic makeup is, at the moment, a significant predictive factor of the variability in response to cannabis. Conclusions: This study proves, for the first time, that certain polymorphic candidate genes may be associated with cannabis effects, both in terms of pain management and side effects, including therapy dropout. Significance: Our attention to pharmacogenetics began in 2008, with the publication of a first study on the association between genetic polymorphisms and morphine action in pain relief. The study we are presenting is the first observational study conducted on a large number of patients involving several polymorphic candidate genes. The data obtained suggest that genetic makeup can be a predictive factor in the response to cannabis therapy and that more extensive and planned studies are needed for the opening of new scenarios for the personalization of cannabis therapy

SCREENING TEST FOR CONGENITAL HYPOTHYROIDISM: THYROID STIMULATING HORMONE (TSH) AND THYROXINE (T4) IN THE ADAPTED FOR GESTATIONAL AGE NEWBORN (AGA) AND IN THE SMALL FOR GESTATIONAL AGE NEWBORN (SGA) AT TERM AND PRETERM

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Desenvolvimento da Morfologia Derivacional nos Primeiros Anos do Ensino Fundamental *

Consciência morfológica é a habilidade de refl etir sobre os morfemas. Essa habilidade está relacionada à aquisição da leitura eda escrita. A maioria dos estudos nessa área foca no desenvolvimento da morfologia fl exional. Menos se sabe sobre a morfologiaderivacional. Este estudo verifi cou o desenvolvimento da morfologia derivacional. Trinta e sete crianças de primeiro e terceiro anoresponderam a uma tarefa de decisão lexical que exigia que a criança julgasse um par de palavras com base na morfologia da línguaportuguesa. Os resultados mostraram que as crianças de primeiro ano fi zeram julgamentos ao nível de chance. As crianças de terceiroano tiveram desempenho acima do nível de chance. No entanto, não houve diferença estatisticamente signifi cativa entre as sériesescolares. Esses resultados contradizem os usualmente encontrados na literatura. O tipo de tarefa e a natureza do sistema escolar sãoapontados como possíveis explicações para as diferenças nos resultados