Palaeohistology and palaeopathology of an Aeolosaurini (Sauropoda: Titanosauria) from Morro do Cambambe (Upper Cretaceous, Brazil)

Altres ajuts: CAISEP (Comisión de Ayudas a la Investigación de la Sociedad Española de Paleontología) project #2018-07153A recent publication of fossil bones of titanosaurs assigned to Aeolosaurini from the Morro do Cambambe site (Mato Grosso state, Brazil, Upper Cretaceous) reported anomalous growth in some of them. Here, we present osteohistological sections of elements to understand not only the microstructure and growth of such bones, but also the nature of those anomalies. The primary bone of all specimens consisted of a variation of the fibrolamellar complex, with the inner cortex being rich in woven bone with dispersed longitudinal canals, while the outer cortex was parallel-fibred with rows of longitudinal canals, interlayered by Lines of Arrested Growth (LAGs). We identified a maximum of two LAGs in the cervical rib and haemal arch, and four in the dorsal rib. The haemal arch shows an External Fundamental System (EFS) in most sections. The advanced remodelling and variation of the fibrolamellar bone in the cortex suggests that all the specimens represent individuals that reached sexual maturity. However, the haemal arch was distinct due to the wide distribution of EFS. The dorsal rib exhibited periosteal and endosteal outgrowth. Such microstructure was assigned to a reactive bone due to an intra-thoracic infection (a pneumonia, probably related to a tuberculosis), which is the first report in a non-avian dinosaur. The microstructure resembles the medullary bone recovered in dinosaurs, which suggests that further studies of medullary bone in thoracic bones should also regard the pathological cases.En una reciente publicación de los huesos fósiles de titanosaurios asignados al clado Aeolosaurini provenientes del yacimiento de Morro do Cambambe (estado de Mato Grosso, Brasil, Cretácico Superior), se reconocieron anormalidades en el crecimiento de algunos de ellos. En el presente trabajo presentamos cortes osteohistológicos de elementos para entender no sólo la microestructura y crecimiento de los mismos, sino también la naturaleza de aquellas anomalías. Entre ellos, seleccionamos una costilla cervical y una costilla dorsal media posterior, así como un arco hemal. El hueso primario de todos los especímenes comprendía una variación del complejo fibrolamelar, siendo la corteza interna rica en tejido reticular óseo con canales longitudinales dispersos, mientras que la corteza externa tenía fibras paralelas con hileras de canales longitudinales, intercaladas por líneas de crecimiento detenido. Identificamos un máximo de dos líneas de crecimiento detenido tanto en la costilla cervical como en el arco hemal, y cuatro en la costilla dorsal. El arco hemal muestra un Sistema Externo Fundamental en la mayoría de las secciones. La remodelación avanzada y la variación del hueso fibrolamelar en la corteza, se sugiere que todas los especímenes alcanzaron la madurez sexual. Sin embargo, el arco hemal fue distinto debido a la amplia distribución de Sistema Externo Fundamental. Con base en la microestructura, identificamos un semaforonte subadulto, y probablemente a un adulto. La costilla dorsal mostró una excrecencia perióstica y endosteal. Dicha microestructura se ha identificado con un hueso reactivo a una infección intratorácica (una neumonía, probablemente relacionada con una tuberculosis), que es el primer informe de un dinosaurio no aviano. La microestructura se asemeja al hueso medular recuperado en los dinosaurios, lo que sugiere que los estudios posteriores del hueso medular en los huesos torácicos también deberían considerar los casos patológicos

CXCL12-mediated murine neural progenitor cell movement Requires PI3Kß activation

The migratory route of neural progenitor/precursor cells (NPC) has a central role in central nervous system development. Although the role of the chemokine CXCL12 in NPC migration has been described, the intracellular signaling cascade involved remains largely unclear. Here we studied the molecular mechanisms that promote murine NPC migration in response to CXCL12, in vitro and ex vivo. Migration was highly dependent on signaling by the CXCL12 receptor, CXCR4. Although the JAK/STAT pathway was activated following CXCL12 stimulation of NPC, JAK activity was not necessary for NPC migration in vitro. Whereas CXCL12 activated the PI3K catalytic subunits p110α and p110β in NPC, only p110β participated in CXCL12-mediated NPC migration. Ex vivo experiments using organotypic slice cultures showed that p110β blockade impaired NPC exit from the medial ganglionic eminence. In vivo experiments using in utero electroporation nonetheless showed that p110β is dispensable for radial migration of pyramidal neurons. We conclude that PI3K p110β is activated in NPC in response to CXCL12, and its activity is necessary for immature interneuron migration to the cerebral cortex.BLH received an FPI predoctoral fellowship (BES-2006-12965) from the Spanish Ministry of Science and Innovation. This work was supported in part by grants from the Spanish Ministry of Science and Innovation (SAF 2011-27370), the RETICS Program (RD08/0075/0010, RD12/0009/0009; RIER), the Madrid regional government (S2010/BMD-2350; RAPHYME), and the European Union (FP7-integrated project Masterswitch 223404).Peer reviewe

Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling

Genomic sequencing has driven precision-based oncology therapy; however, the genetic drivers of many malignancies remain unknown or non-targetable, so alternative approaches to the identification of therapeutic leads are necessary. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Intracranial ependymomas are segregated on the basis of anatomical location (supratentorial region or posterior fossa) and further divided into distinct molecular subgroups that reflect differences in the age of onset, gender predominance and response to therapy1,2,3. The most common and aggressive subgroup, posterior fossa ependymoma group A (PF-EPN-A), occurs in young children and appears to lack recurrent somatic mutations2. Conversely, posterior fossa ependymoma group B (PF-EPN-B) tumours display frequent large-scale copy number gains and losses but have favourable clinical outcomes1,3. More than 70% of supratentorial ependymomas are defined by highly recurrent gene fusions in the NF-κB subunit gene RELA (ST-EPN-RELA), and a smaller number involve fusion of the gene encoding the transcriptional activator YAP1 (ST-EPN-YAP1)1,3,4. Subependymomas, a distinct histologic variant, can also be found within the supratetorial and posterior fossa compartments, and account for the majority of tumours in the molecular subgroups ST-EPN-SE and PF-EPN-SE. Here we describe mapping of active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts, with the goal of identifying essential super-enhancer-associated genes on which tumour cells depend. Enhancer regions revealed putative oncogenes, molecular targets and pathways; inhibition of these targets with small molecule inhibitors or short hairpin RNA diminished the proliferation of patient-derived neurospheres and increased survival in mouse models of ependymomas. Through profiling of transcriptional enhancers, our study provides a framework for target and drug discovery in other cancers that lack known genetic drivers and are therefore difficult to treat.This work was supported by an Alex's Lemonade Stand Young Investigator Award (S.C.M.), The CIHR Banting Fellowship (S.C.M.), The Cancer Prevention Research Institute of Texas (S.C.M., RR170023), Sibylle Assmus Award for Neurooncology (K.W.P.), the DKFZ-MOST (Ministry of Science, Technology & Space, Israel) program in cancer research (H.W.), James S. McDonnell Foundation (J.N.R.) and NIH grants: CA154130 (J.N.R.), R01 CA169117 (J.N.R.), R01 CA171652 (J.N.R.), R01 NS087913 (J.N.R.) and R01 NS089272 (J.N.R.). R.C.G. is supported by NIH grants T32GM00725 and F30CA217065. M.D.T. is supported by The Garron Family Chair in Childhood Cancer Research, and grants from the Pediatric Brain Tumour Foundation, Grand Challenge Award from CureSearch for Children’s Cancer, the National Institutes of Health (R01CA148699, R01CA159859), The Terry Fox Research Institute and Brainchild. M.D.T. is also supported by a Stand Up To Cancer St. Baldrick’s Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113)

The transcriptional landscape of Shh medulloblastoma

© The Author(s) 2021. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.info:eu-repo/semantics/publishedVersio

Technical Advance: Surface plasmon resonance-based analysis of CXCL12 binding using immobilized lentiviral particles

Use of SPR-based biosensors is an established method for measuring molecular interactions. Their application to the study of GPCRs is nonetheless limited to detergent-solubilized receptors that can then be reconstituted into a lipid environment. Using the chemokine receptor CXCR4 and its specific ligand CXCL12, we outline here a highly reproducible biosensor method based on receptor presentation on the surface of lentiviral particles; the approach is simple and does not require the use of antibodies to achieve correct receptor orientation on the sensorchip surface. We measured the kinetic parameters of CXCR4/CXCL12 binding in a single step and in real time and evaluated the effect of GAG presentation of chemokines on this interaction. The data indicate that at low concentrations, soluble heparin modulates CXCR4/CXCL12 interaction and at high concentrations, abrogates binding. These observations suggest that in addition to their known role in modulating local chemokine availability, GAG affect the receptor/ligand interaction, although their influence on affinity parameters is very limited. The method will also be useful for quantifying these biomarkers in biological fluids and for the development of high-throughput screening for their antagonists.B.V. is supported by a fellowship from the Spanish Ministry of Health FISS. This work was supported in part by grants from the Spanish Ministry of Science and Innovation (SAF 2008- 03388; SAF 2008-00908), the FISS (RD08/0075/0010), and the European Union (Innochem LSHB-CT-2005-518167 and FP7 Integrated Project Masterswitch 223404).Peer Reviewe

Divergent clonal selection dominates medulloblastoma at recurrence

The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples

Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma

Recurrent medulloblastoma and ependymoma are universally lethal, with no approved targeted therapies and few candidates presently under clinical evaluation. Nearly all recurrent medulloblastomas and posterior fossa group A (PFA) ependymomas are located adjacent to and bathed by the cerebrospinal fluid, presenting an opportunity for locoregional therapy, bypassing the blood-brain barrier. We identify three cell-surface targets, EPHA2, HER2 and interleukin 13 receptor α2, expressed on medulloblastomas and ependymomas, but not expressed in the normal developing brain. We validate intrathecal delivery of EPHA2, HER2 and interleukin 13 receptor α2 chimeric antigen receptor T cells as an effective treatment for primary, metastatic and recurrent group 3 medulloblastoma and PFA ependymoma xenografts in mouse models. Finally, we demonstrate that administration of these chimeric antigen receptor T cells into the cerebrospinal fluid, alone or in combination with azacytidine, is a highly effective therapy for multiple metastatic mouse models of group 3 medulloblastoma and PFA ependymoma, thereby providing a rationale for clinical trials of these approaches in humans