The Barretos Cancer Hospital Animal Facility (BCHAF) is a unique facility in Brazil exclusively d... more The Barretos Cancer Hospital Animal Facility (BCHAF) is a unique facility in Brazil exclusively dedicated to working with animal models for cancer research. In this article, we briefly present our modern facility and the main experiments performed, focusing on mutant strains of mice (PTCH-knockout and ApcMin mice), xenograft models, and patient-derived xenografts (PDXs). Our results show the progress and challenges in establishing these models and the need for having an appropriate representation of our cancer population to better understand tumor biology and to identify cancer biomarkers, which could be putatively targeted, allowing for personalized therapy.
The molecular evolution of medulloblastoma is more complex than previously imagined, as emerging ... more The molecular evolution of medulloblastoma is more complex than previously imagined, as emerging evidence suggests that multiple interactions between the tumor cells and components of the tumor microenvironment (TME) are important for tumor promotion and progression. The identification of several molecular networks within the TME, which interact with tumoral cells, has provided new clues to understand the tumorigenic roles of many TME components as well as potential therapeutic targets. In this review, we discuss the most recent studies regarding the roles of astrocytes in supporting sonic hedgehog (SHH) subgroup medulloblastoma (MB) and provide an overview of MB progression through SHH expression and signal transduction mechanisms into the complex tumor microenvironment. In addition, we highlight the associations between tumor and stromal cells as possible prognostic markers that could be targeted with new therapeutic strategies.
The interaction between distinctive nitric oxide synthase (NOS) isoforms and the dopamine system ... more The interaction between distinctive nitric oxide synthase (NOS) isoforms and the dopamine system provides new avenues to the development of pharmacological tools for the pathophysiological conditions of the dopaminergic system. Our aim was to investigate the influences of dopamine-induced effects in inducible NOS knockout (iNOS KO) mice. In order to characterize iNOS KO mice phenotype, the animals were submitted to the basal analyses of motor, sensorimotor and sensorial abilities. Pharmacological challenging of the dopaminergic system included the investigation of amphetamine-induced prepulse inhibition (PPI) disruption, haloperidol-induced catalepsy, reserpine-induced oral involuntary movements and hyperlocomotion induced by amphetamine in reserpine treated mice. The iNOS KO mice showed significant reduction of spontaneous motor activity, but there was no significant difference in sensorimotor or sensorial responses of iNOS KO mice compared to wild type (WT). Regarding the dopamine...
Mature messenger RNAs (mRNAs) consist of coding sequence (CDS) and 5' and 3' UTRs, typica... more Mature messenger RNAs (mRNAs) consist of coding sequence (CDS) and 5' and 3' UTRs, typically expected to show similar abundance within a given neuron. Examining mRNA from defined neurons, we unexpectedly show extremely common unbalanced expression of cognate 3' UTR and CDS sequences; many genes show high 3' UTR relative to CDS, others show high CDS to 3' UTR. In situ hybridization (19 of 19 genes) shows a broad range of 3' UTR-to-CDS expression ratios across neurons and tissues. Ratios may be spatially graded or change with developmental age but are consistent across animals. Further, for two genes examined, a 3' UTR-to-CDS ratio above a particular threshold in any given neuron correlated with reduced or undetectable protein expression. Our findings raise questions about the role of isolated 3' UTR sequences in regulation of protein expression and highlight the importance of separately examining 3' UTR and CDS sequences in gene expression analyses.
Neste trabalho estudamos os efeitos eletromotores e motores somáticos decorrentes da desinibição ... more Neste trabalho estudamos os efeitos eletromotores e motores somáticos decorrentes da desinibição GABAérgica do toro semicircular dorsal (TSd) em um peixe elétrico de campo fraco, Gymnotus carapo bem como as possíveis vias envolvidas na expressão destes efeitos, valendo-nos de abordagem funcional e de técnica de rastreamento neuronal bidirecional, usando como traçador a amina de dextrana biotinilada (BDA). A microinjeção do antagonista GABA A bicuculina em camadas profundas do TSd induziu paradas na descarga do órgão elétrico (DOE) cuja intensidade é dose-dependente. Nenhum efeito foi observado pela microinjeção nos mesmos sítios, do agonista muscimol ou de salina. Em outros gimnotiformes já estudados, paradas da DOE resultam da atuação de glutamato em receptores NMDA das células relé do núcleo marcapasso (Pn) rombencefálico. O mecanismo parece ser semelhante em Gymnotus carapo pois observamos paradas da DOE por microinjeção de NMDA na região ventral do Pn onde estão as células relé....
There are two main subgroups of midbrain dopaminergic (DA) neurons: the more medially located ven... more There are two main subgroups of midbrain dopaminergic (DA) neurons: the more medially located ventral tegmental area (VTA) DA neurons, which have axons that innervate the ventral-lateral (VL) striatum, and the more laterally located substantia nigra (SN) DA neurons, which preferentially degenerate in Parkinson's disease (PD) and have axons that project to the dorsal-medial (DM) striatum. DA axonal projections in the striatum are not discretely localized and they arborize widely, however they do not stray from one zone to the other so that VTA axons remain in the VL zone and SN axons in the DM zone. Here we provide evidence that Netrin-1 acts in a novel fashion to topographically pattern midbrain DA axons into these two striatal zones by means of a gradient of Netrin-1 in the striatum and by differential attraction of the axons to Netrin-1. Midbrain DA neurons are attracted to the striatum in culture and this attraction is blocked by an anti-DCC (Netrin receptor) antibody. Mechan...
The Barretos Cancer Hospital Animal Facility (BCHAF) is a unique facility in Brazil exclusively d... more The Barretos Cancer Hospital Animal Facility (BCHAF) is a unique facility in Brazil exclusively dedicated to working with animal models for cancer research. In this article, we briefly present our modern facility and the main experiments performed, focusing on mutant strains of mice (PTCH-knockout and ApcMin mice), xenograft models, and patient-derived xenografts (PDXs). Our results show the progress and challenges in establishing these models and the need for having an appropriate representation of our cancer population to better understand tumor biology and to identify cancer biomarkers, which could be putatively targeted, allowing for personalized therapy.
The molecular evolution of medulloblastoma is more complex than previously imagined, as emerging ... more The molecular evolution of medulloblastoma is more complex than previously imagined, as emerging evidence suggests that multiple interactions between the tumor cells and components of the tumor microenvironment (TME) are important for tumor promotion and progression. The identification of several molecular networks within the TME, which interact with tumoral cells, has provided new clues to understand the tumorigenic roles of many TME components as well as potential therapeutic targets. In this review, we discuss the most recent studies regarding the roles of astrocytes in supporting sonic hedgehog (SHH) subgroup medulloblastoma (MB) and provide an overview of MB progression through SHH expression and signal transduction mechanisms into the complex tumor microenvironment. In addition, we highlight the associations between tumor and stromal cells as possible prognostic markers that could be targeted with new therapeutic strategies.
The interaction between distinctive nitric oxide synthase (NOS) isoforms and the dopamine system ... more The interaction between distinctive nitric oxide synthase (NOS) isoforms and the dopamine system provides new avenues to the development of pharmacological tools for the pathophysiological conditions of the dopaminergic system. Our aim was to investigate the influences of dopamine-induced effects in inducible NOS knockout (iNOS KO) mice. In order to characterize iNOS KO mice phenotype, the animals were submitted to the basal analyses of motor, sensorimotor and sensorial abilities. Pharmacological challenging of the dopaminergic system included the investigation of amphetamine-induced prepulse inhibition (PPI) disruption, haloperidol-induced catalepsy, reserpine-induced oral involuntary movements and hyperlocomotion induced by amphetamine in reserpine treated mice. The iNOS KO mice showed significant reduction of spontaneous motor activity, but there was no significant difference in sensorimotor or sensorial responses of iNOS KO mice compared to wild type (WT). Regarding the dopamine...
Mature messenger RNAs (mRNAs) consist of coding sequence (CDS) and 5' and 3' UTRs, typica... more Mature messenger RNAs (mRNAs) consist of coding sequence (CDS) and 5' and 3' UTRs, typically expected to show similar abundance within a given neuron. Examining mRNA from defined neurons, we unexpectedly show extremely common unbalanced expression of cognate 3' UTR and CDS sequences; many genes show high 3' UTR relative to CDS, others show high CDS to 3' UTR. In situ hybridization (19 of 19 genes) shows a broad range of 3' UTR-to-CDS expression ratios across neurons and tissues. Ratios may be spatially graded or change with developmental age but are consistent across animals. Further, for two genes examined, a 3' UTR-to-CDS ratio above a particular threshold in any given neuron correlated with reduced or undetectable protein expression. Our findings raise questions about the role of isolated 3' UTR sequences in regulation of protein expression and highlight the importance of separately examining 3' UTR and CDS sequences in gene expression analyses.
Neste trabalho estudamos os efeitos eletromotores e motores somáticos decorrentes da desinibição ... more Neste trabalho estudamos os efeitos eletromotores e motores somáticos decorrentes da desinibição GABAérgica do toro semicircular dorsal (TSd) em um peixe elétrico de campo fraco, Gymnotus carapo bem como as possíveis vias envolvidas na expressão destes efeitos, valendo-nos de abordagem funcional e de técnica de rastreamento neuronal bidirecional, usando como traçador a amina de dextrana biotinilada (BDA). A microinjeção do antagonista GABA A bicuculina em camadas profundas do TSd induziu paradas na descarga do órgão elétrico (DOE) cuja intensidade é dose-dependente. Nenhum efeito foi observado pela microinjeção nos mesmos sítios, do agonista muscimol ou de salina. Em outros gimnotiformes já estudados, paradas da DOE resultam da atuação de glutamato em receptores NMDA das células relé do núcleo marcapasso (Pn) rombencefálico. O mecanismo parece ser semelhante em Gymnotus carapo pois observamos paradas da DOE por microinjeção de NMDA na região ventral do Pn onde estão as células relé....
There are two main subgroups of midbrain dopaminergic (DA) neurons: the more medially located ven... more There are two main subgroups of midbrain dopaminergic (DA) neurons: the more medially located ventral tegmental area (VTA) DA neurons, which have axons that innervate the ventral-lateral (VL) striatum, and the more laterally located substantia nigra (SN) DA neurons, which preferentially degenerate in Parkinson's disease (PD) and have axons that project to the dorsal-medial (DM) striatum. DA axonal projections in the striatum are not discretely localized and they arborize widely, however they do not stray from one zone to the other so that VTA axons remain in the VL zone and SN axons in the DM zone. Here we provide evidence that Netrin-1 acts in a novel fashion to topographically pattern midbrain DA axons into these two striatal zones by means of a gradient of Netrin-1 in the striatum and by differential attraction of the axons to Netrin-1. Midbrain DA neurons are attracted to the striatum in culture and this attraction is blocked by an anti-DCC (Netrin receptor) antibody. Mechan...
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