Sox9 directs divergent epigenomic states in brain tumor subtypes.

Epigenetic dysregulation is a universal feature of cancer that results in altered patterns of gene expression that drive malignancy. Brain tumors exhibit subtype-specific epigenetic alterations; however, the molecular mechanisms responsible for these diverse epigenetic states remain unclear. Here, we show that the developmental transcription factor Sox9 differentially regulates epigenomic states in high-grade glioma (HGG) and ependymoma (EPN). Using our autochthonous mouse models, we found that Sox9 suppresses HGG growth and expands associated H3K27ac states, while promoting ZFTA-RELA (ZRFUS) EPN growth and diminishing H3K27ac states. These contrasting roles for Sox9 correspond with protein interactions with histone deacetylating complexes in HGG and an association with the ZRFUS oncofusion in EPN. Mechanistic studies revealed extensive Sox9 and ZRFUS promoter co-occupancy, indicating functional synergy in promoting EPN tumorigenesis. Together, our studies demonstrate how epigenomic states are differentially regulated in distinct subtypes of brain tumors, while revealing divergent roles for Sox9 in HGG and EPN tumorigenesis.

Subventricular zone cytogenesis provides trophic support for neural repair in a mouse model of stroke.

Stroke enhances proliferation of neural precursor cells within the subventricular zone (SVZ) and induces ectopic migration of newborn cells towards the site of injury. Here, we characterize the identity of cells arising from the SVZ after stroke and uncover a mechanism through which they facilitate neural repair and functional recovery. With genetic lineage tracing, we show that SVZ-derived cells that migrate towards cortical photothrombotic stroke in mice are predominantly undifferentiated precursors. We find that ablation of neural precursor cells or conditional knockout of VEGF impairs neuronal and vascular reparative responses and worsens recovery. Replacement of VEGF is sufficient to induce neural repair and recovery. We also provide evidence that CXCL12 from peri-infarct vasculature signals to CXCR4-expressing cells arising from the SVZ to direct their ectopic migration. These results support a model in which vasculature surrounding the site of injury attracts cells from the SVZ, and these cells subsequently provide trophic support that drives neural repair and recovery.

Activity-dependent induction of astrocytic Slc22a3 regulates sensory processing through histone serotonylation.

Neuronal activity drives global alterations in gene expression within neurons, yet how it directs transcriptional and epigenomic changes in neighboring astrocytes in functioning circuits is unknown. Here we show that neuronal activity induces widespread transcriptional upregulation and downregulation in astrocytes, highlighted by the identification of a neuromodulator transporter Slc22a3 as an activity-inducible astrocyte gene regulating sensory processing in the olfactory bulb. Loss of astrocytic Slc22a3 reduces serotonin levels in astrocytes, leading to alterations in histone serotonylation. Inhibition of histone serotonylation in astrocytes reduces expression of GABA biosynthetic genes and GABA release, culminating in olfactory deficits. Our study reveals that neuronal activity orchestrates transcriptional and epigenomic responses in astrocytes, while illustrating new mechanisms for how astrocytes process neuromodulatory input to gate neurotransmitter release for sensory processing.

Induction of astrocytic Slc22a3 regulates sensory processing through histone serotonylation.

Neuronal activity drives alterations in gene expression within neurons, yet how it directs transcriptional and epigenomic changes in neighboring astrocytes in functioning circuits is unknown. We found that neuronal activity induces widespread transcriptional up-regulation and down-regulation in astrocytes, highlighted by the identification of Slc22a3 as an activity-inducible astrocyte gene that encodes neuromodulator transporter Slc22a3 and regulates sensory processing in the mouse olfactory bulb. Loss of astrocytic Slc22a3 reduced serotonin levels in astrocytes, leading to alterations in histone serotonylation. Inhibition of histone serotonylation in astrocytes reduced the expression of γ-aminobutyric acid (GABA) biosynthetic genes and GABA release, culminating in olfactory deficits. Our study reveals that neuronal activity orchestrates transcriptional and epigenomic responses in astrocytes while illustrating new mechanisms for how astrocytes process neuromodulatory input to gate neurotransmitter release for sensory processing.

In vivo functional characterization of EGFR variants identifies novel drivers of glioblastoma.

BACKGROUND: Glioblastoma is the most common and aggressive primary brain tumor. Large-scale sequencing initiatives have cataloged its mutational landscape in hopes of elucidating mechanisms driving this deadly disease. However, a major bottleneck in harnessing this data for new therapies is deciphering "driver" and "passenger" events amongst the vast volume of information. METHODS: We utilized an autochthonous, in vivo screening approach to identify driver, EGFR variants. RNA-Seq identified unique molecular signatures of mouse gliomas across these variants, which only differ by a single amino acid change. In particular, we identified alterations to lipid metabolism, which we further validated through an unbiased lipidomics screen. RESULTS: Our screen identified A289I as the most potent EGFR variant, which has previously not been characterized. One of the mechanisms through which A289I promotes gliomagenesis is to alter cellular triacylglycerides through MTTP. Knockout of Mttp in mouse gliomas, reduces gliomagenesis in multiple models. CONCLUSIONS: EGFR variants that differ by a single amino acid residue differentially promote gliomagenesis. Among the identified mechanism that drives glioma growth include lipid metabolism through MTTP. Understanding triacylglyceride accumulation may present a prospective therapeutic pathway for this deadly disease.

Glioma epileptiform activity and progression are driven by IGSF3-mediated potassium dysregulation.

Seizures are a frequent pathophysiological feature of malignant glioma. Recent studies implicate peritumoral synaptic dysregulation as a driver of brain hyperactivity and tumor progression; however, the molecular mechanisms that govern these phenomena remain elusive. Using scRNA-seq and intraoperative patient ECoG recordings, we show that tumors from seizure patients are enriched for gene signatures regulating synapse formation. Employing a human-to-mouse in vivo functionalization pipeline to screen these genes, we identify IGSF3 as a mediator of glioma progression and dysregulated neural circuitry that manifests as spreading depolarization (SD). Mechanistically, we discover that IGSF3 interacts with Kir4.1 to suppress potassium buffering and found that seizure patients exhibit reduced expression of potassium handlers in proliferating tumor cells. In vivo imaging reveals that dysregulated synaptic activity emanates from the tumor-neuron interface, which we confirm in patients. Our studies reveal that tumor progression and seizures are enabled by ion dyshomeostasis and identify SD as a driver of disease.

Antimicrobial effect of Casiopeinas® copper- and ruthenium-based compounds on Aggregatibacter actinomycetemcomitans and in vitro cell viability onto osteoblasts cells.

OBJECTIVES: The present study aims to evaluate the antimicrobial property of Casiopeinas® copper- and ruthenium-based compounds against Aggregatibacter actinomycetemcomitans serotype b (ATCC® 43,718™), as well as the cytotoxicity on an osteoblasts cell line of both compounds. MATERIAL AND METHODS: The antibacterial effect of the copper-based compounds (CasII-gly, CasIII-ia) and the ruthenium-based compound (RuN-6) at four different concentrations was evaluated as the inhibition ratio of the bacterial growth after 48 h under anaerobic conditions, and the cell viability was measured through resazurin assay. RESULTS: The copper- and ruthenium-based compounds used for this assay were (CasII-gly, CasIII-ia, and RuN-6), showing inhibitory activity between 39 and 62% compared to the antibiotic employed as control 66%. Cell viability was established between 61 and 96%. CONCLUSIONS: Casiopeinas® and ruthenium showed dose and time dependent, inhibitory activity on A. actinomycetemcomitans, and low toxicity on cells (osteoblast) underexposure. The compound CasII-gly showed the best antimicrobial effect, and it could be considered a possible antimicrobial agent in periodontal therapy.

Trans-Endodontic Zirconium Oxide Implants: A Clinical Alternative / Implantes trans-endodónticos de óxido de zirconia: Una alternativa clínica

Abstract 24. Dental trauma, mainly from the anterior area of the mouth in the incisor teeth at the level of the radicular third, has the extraction of the dental organ as an elective treatment, depending on the severity of the lesion and the site where it presented. This paper reports two cases: one in a young 13-year-old male patient with dental trauma in central incisors, and another in an 18-year-old female patient with radicular reabsorption in central incisors. Both were treated using trans-endodontic implants on teeth 2.1 and 1.1-2.2 each case, respectively. The treatment approach proposed for each case provided good functional and esthetic outcomes. Clinical and radiographic results after 1 year were successful.

Resumen 28. El traumatismo dental del área anterior de la boca en los dientes incisivos a nivel del tercio radicular, indica la extracción del órgano dental como un tratamiento electivo dependiendo de la gravedad de la lesión y el sitio donde se presentó. Este artículo reporta dos casos: uno en un paciente masculino joven de 13 años con trauma dental en los incisivos centrales y otro en una paciente de 18 años con reabsorción radicular en los incisivos centrales. Ambos fueron tratados con implantes trans-endodónticos en los dientes 2.1 y 1.1-2.2 en cada caso, respectivamente. El enfoque de tratamiento propuesto para cada caso proporcionó buenos resultados funcionales y estéticos. Los resultados clínicos y radiográficos después de 1 año fueron exitosos.

Chemical and Microscopy Characterization of Trans-Endodontic Implants / Caracterización química y microscópica de implantes trans-endodónticos

Abstract Trans-endodontic implants are an artificial extension through root apex anchored in periradicular bone tissue. The aim is to improve the crown-root ratio and to provide stability to dental organ present. Zirconium oxide (ZrO2) is a material of great technological importance, having good natural color, high strength, high toughness, high chemical stability, does not suffer any corrosion, chemical and microbial resistance and excellent esthetic properties. Objective: The aim of this study was to evaluate chemical and microscopy of surface conditions of ZrO2 trans-endodontic implant. Materials and Methods: A blocks of ZrO2 were manufactured for produce trans-endodontic implants and divided in two groups: monoclinic and tetragonal phase. They were evaluated using Scanning Electroning Microscope (SEM), EnergyDispersive X-ray Spectroscopy (EDS), and Atomic Force Microscope (AFM) and Vickers Micro hardness. Results: The Monoclinic phase through AFM analysis showed roughness Ra = 0.320μm, whereas in the Tetragonal phase was 0.126μm, SEM/EDX indicated that the phases are not properly uniform and the addition of the Yttrium to favor the stabilization of the Tetragonal phase. The Vickers hardness analysis showed a value of 1500HV. Conclusion: The characterization of the surface of trans-endodontic zirconium oxide implants provides a guideline to know the surface characteristics of the material, since a greater roughness on the surface of the implant will favor the Osseo-integration capacity.

Resumen Los implantes trans-endodónticos son una extensión artificial a través del ápice radicular anclado en el tejido óseo periradicular. El objetivo es mejorar la relación corona-raíz y proporcionar estabilidad al órgano dental presente. El óxido de zirconio (ZrO2) es un material de gran importancia tecnológica, con buen color natural, alta resistencia, alta tenacidad, alta estabilidad química, no sufre corrosión, resistencia química y microbiana y excelentes propiedades estéticas. Objetivo: El objetivo de este estudio fue evaluar las condiciones superficiales de ZrO2 para su aplicación clínica a los implantes transendodónticos. Materiales y Métodos: se trituraron bloques de ZrO2 en implantes trans-endodónticos y se dividieron en: monoclínico y tetragonal. Luego se evaluaron mediante microscopía electrónica de barrido (SEM), espectroscopia de rayos X de energía dispersiva (EDS) y microscopio de fuerza atómica (AFM) y microdureza vickers. Resultados: La fase monoclínica a través del análisis AFM presenta Ra = 0.320 μm, mientras que en la fase Tetragonal es 0.126 μm, SEM / EDS muestra que las fases no son adecuadamente uniformes y la adición del Ytrio para favorecer la estabilización de la fase tetragonal. El análisis de microdureza mostro un valor de 1500HV. Conclusión: La caracterización de la superficie de los implantes trans-endodónticos de óxido de zirconio, brinda una pauta para conocer las características superficiales del material, ya que al haber una mayor rugosidad en la superficie del implante se verá favorecida la capacidad de oseointegración.