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Abstract: The mammalian GATA family of transcription factors comprises of 6 members that are involved in diverse roles. The expression profile of GATA6 has been poorly defined in the central nervous system (CNS). In this report, we identify GATA6 expression in the normal mouse and human CNS, using Northern blot analyses, immunohistochemistry (IHC), and immunofluorescence (IF). GATA6 is expressed as a 2.2 kb transcript in the adult mouse brain and several regions of the adult human brain. Furthermore, cellular characterization demonstrates GATA6 nuclear expression in neurons, astrocytes, choroids plexus epithelium, and endothelial cells. [Copyright &y& Elsevier]

Abstract: Low grade gliomas are a heterogeneous group of tumours representing the most common form of neoplasms in the central nervous system among children. Although gross total resection remains the principal treatment, it is often impractical especially for the resection of tumours within eloquent regions of the brain. Instead Radiotherapy is utilised in such cases, but because of its associated toxicities, it is refrained from use among younger children. These limitations coupled with hypersensitivity and toxicities associated with some commonly used chemotherapeutic agents, have ignited the need to search for safer and more effective treatments for paediatric low grade gliomas. In this study, we investigated the EM011 drug on the growth of two pilocytic and one diffuse paediatric astrocytoma cell lines, using an assortment of cancer assays. We discovered that treatments of low grade gliomas with EM011 abrogated cell viability by inducing a decrease in cell proliferation and an arrest in the S and G2M cell cycle phases, followed by a converse increase in apoptosis in a dose and time dependent manner. The cell migratory and invasion indices, as well as anchorage independent growth in soft agarose, were significantly attenuated. These findings were mechanistically associated with a transient release of AIF, a disruption of microtubule architecture, and a decline in the expression of key genes which drive cancer progression including EGFR, mTORC1, JUN and multiple MMPs. In fact, the activity of MMP2 was also perturbed by EM011. These findings, in conjunction with the insignificant adverse side effects established from other studies, make EM011 an appealing chemotherapeutic agent for the treatment of paediatric low grade gliomas. [Copyright &y& Elsevier]

Abstract: Medulloblastomas are highly aggressive tumors of the cerebellum with an embryonal origin. Despite current treatment modalities which include a combination of surgery, chemotherapy and/or radiation, challenges still exist to effectively treat some patients, especially those within the younger age group. In an effort to find improved therapies, ongoing research led by world-wide teams have explored non-conventional therapeutic strategies, as well as examined the efficacy of several drugs in clinical trials among patients with Medulloblastomas. We outline in this article, recent advances on the efficacy and toxicity of numerous therapeutic agents including those that are DNA damaging agents, microtubules binding compounds, and those that are inhibitors of Topoisomerase and of the Notch and Hedgehog signaling pathway, which were assessed in recent Phase I and II clinical trials. Among these clinical trials, it is unfortunate that the outcomes were dismal with the majority of the patients with Medulloblastomas still succumbing to relapse after conventional therapies. Furthermore, it is yet to be established clearly the clinical efficacy of non-conventional therapies such as immunotherapy and gene therapy. Moreover, there is growing interest in proton therapy as a potential replacement for photon therapy, while high dose chemotherapy and autologous stem cell rescue may improve therapeutic efficacies. However, further research is needed to resolve the inherent toxicity from these novel therapeutic methods. In conclusion, novel therapies based on a better understanding of the biology of Medulloblastomas are pivotal in improving non-conventional therapies in the treatment of this deadly disease. [Copyright &y& Elsevier]

Abstract: Agnathia-otocephaly, a rare, sporadic and lethal malformation, is characterized by microstomia (small mouth), aglossia (absence of the tongue), agnathia (absence of the lower jaw) and abnormally positioned ears. It is a principal anomaly derived from the first pharyngeal arch as a consequence of failed mesenchymal migration of the maxillary prominence and atrophy in the development of the mandibular prominences. Unfortunately, these patients have poor prognoses and may succumb to death shortly after birth due to respiratory problems if appropriate airway management is not implemented. Difficulties persist in the prenatal diagnosis of agnathia-otocephalic patients. However, two- and three-dimensional ultrasonography, computed tomography and magnetic resonance imaging technologies now offer significant improvements in refining the resolution of distinctive facial anomalies. This complex disorder can be attributed to both genetic and teratogenic causes, in addition to other unidentifiable factors. Furthermore, studies in model organisms, in particular mice, have unraveled potential genetic pathways that may contribute to the etiology. This article highlights current perspectives on agnathia-otocephaly with a focus on the etiological causes and issues concerning prenatal diagnosis, differential diagnosis, prognosis and genetic counseling. Finally, studies using animal models especially genetically engineered mice are described to comprehend the molecular genetic interactions that may occur during the genesis of this intriguing craniofacial birth defect. [ABSTRACT FROM AUTHOR]

Abstract: Pediatric low grade gliomas are the most common central nervous system tumors and are still incurable among a subset of patients despite current treatment modalities. Steroid biosynthesis occurs in a wide variety of organs including the brain, to mediate an assortment of functions, including a proposed role in the growth of gliomas. Hence, targeting steroid biosynthesis and/or their signaling pathways, is anticipated as an effective approach for treating gliomas. In this study, we investigated whether our chemical library of steroid inhibitors can modulate the growth of pediatric low grade glioma cell lines (Res186, Res259, R286), and subsequently identified a potent inhibitor of 17β-hydroxysteroid dehydrogenase type 3, referred to as DK16, which functions by attenuating cell viability, proliferation, migration/invasion and anchorage independent growth and conversely induces apoptosis and cell cycle arrest in a dose and duration dependent manner. Further investigations into the mechanisms of how DK16 functions showed that this drug increased the BAX/BCL2 expression ratio, induced phosphatidylserine externalization, and mitochondrial membrane depolarizations culminating to the release and nuclear translocation of AIF. In addition, treatments of low grade glioma cell lines with DK16 increased the expression of pro-apoptotic mediators including CDK2 and CTSL1, and with the converse diminished expression of pro-survival and migratory/invasion genes like PRKCA, TERT, MAPK8, MMP1 and MMP2. Our findings collectively demonstrate the potent anti-neoplastic properties of DK16, a steroid biosynthesis inhibitor, on the growth of pediatric low grade gliomas. [Copyright &y& Elsevier]