Persistent inflammation alters the function of the endogenous brain stem cell compartment

Endogenous neural stem/precursor cells (NPCs) are considered a functional reservoir for promoting tissue homeostasis and repair after injury, therefore regenerative strategies that mobilize these cells have recently been proposed. Despite evidence of increased neurogenesis upon acute inflammatory insults (e.g. ischaemic stroke), the plasticity of the endogenous brain stem cell compartment in chronic CNS inflammatory disorders remains poorly characterized. Here we show that persistent brain inflammation, induced by immune cells targeting myelin, extensively alters the proliferative and migratory properties of subventricular zone (SVZ)-resident NPCs in vivo leading to significant accumulation…

464P Exome sequencing of ctDNA portrays the mutational landscape of patients with relapsing colon cancer and indicates new actionable targets

In the literature: August 2021

Intrinsically determined cell death of developing cortical interneurons.

The cell death of inhibitory neurons, which originate far from the cortical areas to which they migrate during embryonic development, is determined autonomously rather than by competition for trophic signals from other cell types. It has long been known that apoptosis, a form of programmed cell death, eliminates young cells from developing tissues. In the field of neurobiology, it is widely believed that developmental neuronal-cell death results from cellular competition for environmentally derived survival signals that selects for an optimally sized and properly wired population of neurons. This study of developmental cell death in the mouse cortex in vivo, in vitro and after transplantati…

Congenital undifferentiated sarcoma associated to BCOR-CCNB3 gene fusion

Small round cell sarcomas are aggressive bone and soft tissue tumors that predominantly affect children and young adults. A new group of sarcomas with a recurrent BCOR-CCNB3 gene fusion has been recently identified in previously unclassifiable small round cell sarcomas. BCOR-CCNB3 sarcomas share clinical and pathologic similarities with Ewing sarcoma, but show a stronger male predilection and less aggressiveness, as well as distinct gene expression profiling and pangenomic SNP array analyses. We report the unusual case of a congenital BCOR-CCNB3 retroperitoneal sarcoma in a female born at 34th gestational week, which was diagnosed in necropsy after 21hours of life. Immunohistochemical analy…

Transplanted neural stem/precursor cells instruct phagocytes and reduce secondary tissue damage in the injured spinal cord

Transplanted neural stem/precursor cells possess peculiar therapeutic plasticity and can simultaneously instruct several therapeutic mechanisms in addition to cell replacement. Here, we interrogated the therapeutic plasticity of neural stem/precursor cells after their focal implantation in the severely contused spinal cord. We injected syngeneic neural stem/precursor cells at the proximal and distal ends of the contused mouse spinal cord and analysed locomotor functions and relevant secondary pathological events in the mice, cell fate of transplanted neural stem/precursor cells, and gene expression and inflammatory cell infiltration at the injured site. We used two different doses of neural…

Digital Pathology Enables Automated and Quantitative Assessment of Inflammatory Activity in Patients with Chronic Liver Disease

Traditional histological evaluation for grading liver disease severity is based on subjective and semi-quantitative scores. We examined the relationship between digital pathology analysis and corresponding scoring systems for the assessment of hepatic necroinflammatory activity. A prospective, multicenter study including 156 patients with chronic liver disease (74% nonalcoholic fatty liver disease-NAFLD, 26% chronic hepatitis-CH etiologies) was performed. Inflammation was graded according to the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network system and METAVIR score. Whole-slide digital image analysis based on quantitative (I-score: inflammation ratio) and morphometric (C-sco…

Annulate Lamellae in a Desmoplastic Small Round Cell Tumor

Circulating Tumor DNA Detection by Digital-Droplet PCR in Pancreatic Ductal Adenocarcinoma: A Systematic Review

Simple Summary Pancreatic cancer is a digestive tumor that is most difficult to treat and carries one of the worst prognoses. The anatomical location of the pancreas makes it very difficult to obtain enough tumor material to establish a molecular diagnosis, so knowing the biology of this tumor and implementing new targeted-therapies is still a pending issue. The use of liquid biopsy, a blood sample test to detect circulating-tumor DNA fragments (ctDNA), is key to overcoming this difficulty and improving the evolution of this tumor. Liquid biopsies are equally representative of the tissue from which they come and allow relevant molecular and diagnostic information to be obtained in a faster …

GFP immunogold staining, from light to electron microscopy, in mammalian cells.

GFP has emerged as an important reporter for monitoring gene expression, protein localization, cell transformation and cell lineage. The development of GFP as a marker in many different biological systems has emphasized the need to image GFP at high resolution. GFP immunogold labeling with colloidal gold particles becomes essential for electron microscopy (EM) ultrastructural detection. Because of the small size, colloidal gold particles require silver enhancement, a procedure to increase the size of the particle as well as gold toning to stabilize the silver layer. GFP preembedding immunogold staining enables high quality cellular-ultrastructural EM analysis mainly for two reasons, on one …

Ultrastructural Pathology of Anaplastic and Grade II Ependymomas reveals Distinctive Ciliary Structures - Electron Microscopy Redux

Ependymoma tumors likely derive from the ependymal cells lining the CNS ventricular system. In grade II ependymomas, tumor cells resemble typical ependymocytes, while anaplastic ependymomas are poorly differentiated. We studied three grade II and one anaplastic ependymoma, focusing on the ciliary structures. To unambiguously characterize the ultrastructure and number of cilia, we performed electron microscopy serial section analysis of individual cells. Differentiated ependymomas contained large basal bodies and up to three cilia, and lacked centrioles. Anaplastic ependymoma cells showed instead two perpendicularly oriented centrioles and lacked cilia or basal bodies. These findings could c…

Sarcoma fibromixoide de bajo grado, un diagnóstico diferencial esencial en los tumores mixoides de apariencia benigna

Resumen El sarcoma fibromixoide de bajo grado es una neoplasia poco frecuente que afecta preferentemente a adultos jovenes. Se trata de un tumor fibroblastico de apariencia enganosamente benigna que puede presentar recurrencias locales y metastasis a distancia tardias. Presentamos el caso de una nina de 11 anos que presentaba una lesion en el muslo, de la que se realizo exeresis completa. El estudio histologico mostro una neoplasia bien delimitada de estroma mixoide, con celularidad fusiforme sin atipia ni mitosis. La expresion inmunohistoquimica de MUC4, junto con el estudio de biologia molecular que detecto la expresion del gen de fusion FUS-CREB3L2, confirmaron el diagnostico de sarcoma …

Imbalance of immunological synapse-kinapse states reflects tumor escape to immunity in glioblastoma

Since the proper activation of T cells requires the physical interaction with target cells through the formation of immunological synapses (IS), an alteration at this level could be a reason why tumors escape the immune response. As part of their life cycle, it is thought that T cells alternate between a static phase, the IS, and a dynamic phase, the immunological kinapse (IK), depending on high or low antigen sensing. Our investigation performed in tissue samples of human glioma shows that T cells are able to establish synapsing interactions not only with glioma tumorigenic cells, but also with stromal myeloid cells. Particularly, the IS displaying a T cell receptor-rich (TCR-rich) central…

Anatomía Patológica para el estudiante de Medicina: videotutoriales con integración de Patología digital como una valiosa herramienta para hacer la asignatura más práctica y atractiva

Resumen Introduccion y objetivo La asignatura de Anatomia Patologica es fundamental en la formacion del estudiante de Medicina. Sin embargo, para muchos estudiantes la asignatura presenta un excesivo contenido teorico, poco trasladable a la practica clinica. Presentamos los resultados de un proyecto de innovacion docente dirigido a facilitar la transmision del conocimiento a distancia y hacer de la Anatomia Patologica una asignatura mas practica y atractiva para el estudiante de Medicina. Materiales y metodos Elaboramos material didactico integrando imagenes de enfermedad digital con videotutoriales para la exposicion de casos clinicos donde los alumnos debian llegar al diagnostico final. C…

Extracellular Vesicles from Neural Stem Cells Transfer IFN-γ via Ifngr1 to Activate Stat1 Signaling in Target Cells

The idea that stem cell therapies work only via cell replacement is challenged by the observation of consistent intercellular molecule exchange between the graft and the host. Here we defined a mechanism of cellular signaling by which neural stem/precursor cells (NPCs) communicate with the microenvironment via extracellular vesicles (EVs), and we elucidated its molecular signature and function. We observed cytokine-regulated pathways that sort proteins and mRNAs into EVs. We described induction of interferon gamma (IFN-γ) pathway in NPCs exposed to proinflammatory cytokines that is mirrored in EVs. We showed that IFN-γ bound to EVs through Ifngr1 activates Stat1 in target cells. Finally, we…

Neoadjuvant treatment for locally advanced unresectable and borderline resectable pancreatic cancer: oncological outcomes at a single academic centre.

INTRODUCTION: Pancreatic cancer (PC), even in the absence of metastatic disease, has a dismal prognosis. One-third of them are borderline resectable (BRPC) or locally advanced unresectable PC (LAUPC) at diagnosis. There are limited prospective data supporting the best approach on these tumours. Neoadjuvant chemotherapy (ChT) is being increasingly used in this setting. METHODS: This is a retrospective series of consecutive patients staged as BRPC or LAUPC after discussion in the multidisciplinary board (MDB) at an academic centre. All received neoadjuvant ChT, followed by chemoradiation (ChRT) in some cases, and those achieving enough downstaging had a curative-intent surgery. Descriptive da…

Immune regulatory neural stem/precursor cells protect from central nervous system autoimmunity by restraining dendritic cell function.

Background: The systemic injection of neural stem/precursor cells (NPCs) provides remarkable amelioration of the clinicopathological features of experimental autoimmune encephalomyelitis (EAE). This is dependent on the capacity of transplanted NPCs to engage concurrent mechanisms of action within specific microenvironments in vivo. Among a wide range of therapeutic actions alternative to cell replacement, neuroprotective and immune modulatory capacities of transplanted NPCs have been described. However, lacking is a detailed understanding of the mechanisms by which NPCs exert their therapeutic plasticity. This study was designed to identify the first candidate that exemplifies and sustains …

Migration of Neuronal Precursors From the Telencephalic Ventricular Zone Into the Olfactory Bulb in Adult Zebrafish

In the brain of adult mammals, neuronal precursors are generated in the subventricular zone in the lateral wall of the lateral ventricles and migrate into the olfactory bulbs (OBs) through a well-studied route called the rostral migratory stream (RMS). Recent studies have revealed that a comparable neural stem cell niche is widely conserved at the ventricular wall of adult vertebrates. However, little is known about the migration route of neuronal precursors in nonmammalian adult brains. Here, we show that, in the adult zebrafish, a cluster of neuronal precursors generated in the telencephalic ventricular zone migrates into the OB via a route equivalent to the mammalian RMS. Unlike the mamm…

Biciliated ependymal cell proliferation contributes to spinal cord growth

Two neurogenic regions have been described in the adult brain, the lateral ventricle subventricular zone and the dentate gyrus subgranular zone. It has been suggested that neural stem cells also line the central canal of the adult spinal cord. Using transmission and scanning electron microscopy and immunostaining, we describe here the organization and cell types of the central canal epithelium in adult mice. The identity of dividing cells was determined by 3D ultrastructural reconstructions of [3H]thymidine-labeled cells and confocal analysis of bromodeoxyuridine labeling. The most common cell type lining the central canal had two long motile (9+2) cilia and was vimentin+, CD24+, FoxJ1+, So…

Extracellular vesicles from neural stem cells transfer the IFN-gamma/IFNGR1 complex to activate Stat1-dependent signalling in target cells

Peroxisome proliferator-activated receptor γ ligands regulate neural stem cell proliferation and differentiation in vitro and in vivo.

Peroxisome proliferator-activated receptor gamma (PPARγ) belongs to a family of ligand-activated nuclear receptors and its ligands are known to control many physiological and pathological situations. Its role in the central nervous system has been under intense analysis during the last years. Here we show a novel function for PPARγ in controlling stem cell expansion in the adult mammalian brain. Adult rats treated with pioglitazone, a specific ligand of PPARγ, had elevated numbers of proliferating progenitor cells in the subventricular zone and the rostral migratory stream. Electron microscopy analysis also showed important changes in the subventricular zone ultrastructure of pioglitazone-t…

N-Acetylcysteine Amide Exerts Possible Neuroprotective Effects in Newborn Pigs after Perinatal Asphyxia

<b><i>Background:</i></b> Perinatal asphyxia and ensuing reoxygenation change the antioxidant capacity of cells and organs. <b><i>Objectives:</i></b> To analyze the neuroprotective effect of the antioxidant N-acetylcysteine amide (NACA) after perinatal hypoxia-reoxygenation with an emphasis on proinflammatory cytokines and the transcription factor NF-κB in the prefrontal cortex of neonatal pigs. <b><i>Methods:</i></b> Twenty-nine newborn pigs, aged 12-36 h, were subjected to global hypoxia and hypercapnia. One sham-operated group (n = 5) and 2 experimental groups (n = 12) were exposed to 8% oxygen, until the …

Differential diagnosis of myxoid soft tissue tumors. Experience in the Clinical University Hospital of Valencia.

Abstract Soft tissue tumors with myxoid components are often a diagnostic challenge for the pathologist. We retrospectively reviewed 41 cases of soft tissue tumors with myxoid components diagnosed in our center over a five-year period. The most frequent diagnoses were myxofibrosarcoma and myxoid liposarcoma, followed by low-grade fibromyxoid sarcoma, low-grade fibromyxoid tumor and myxoid neurofibroma. Other diagnoses included were extraskeletal myxoid chondrosarcoma, myxoinflammatory fibroblastic sarcoma, low-grade myxoliposarcoma, myofibrosarcoma, fibromatosis, solitary fibrous tumor, non-ossifying variant of ossifying fibromyxoid tumor and ancient neurinoma with myxoid degeneration. Immu…

Utilización de Kahoot! en las clases teóricas de Anatomía Patológica: mejorando la motivación e interacción en la docencia virtual

[EN] Faced with the COVID-19 pandemic situation, education has had to adapt to online teaching, trying to preserve the essential student-teacher interaction. In this project we used the interactive tool Kahoot! in the theory lectures of Special Anatomical Pathology of the Degree in Medicine, which were fully taught online. The games consisted of questions about the lesson´s contents, to strengthen learning and self-evaluation. After playing Kahoot!, results were discussed to highlight important concepts and explain doubts. The perception of the students was evaluated through an online survey. The results indicate that using Kahoot! in the theory classes has been very satisfactory and has en…

Sustained activation of mTOR pathway in embryonic neural stem cells leads to development of tuberous sclerosis complex-associated lesions

SummaryTuberous Sclerosis Complex (TSC) is a multisystem genetic disorder characterized by hamartomatous neurological lesions that exhibit abnormal cell proliferation and differentiation. Hyperactivation of mTOR pathway by mutations in either the Tsc1 or Tsc2 gene underlies TSC pathogenesis, but involvement of specific neural cell populations in the formation of TSC-associated neurological lesions remains unclear. We deleted Tsc1 in Emx1-expressing embryonic telencephalic neural stem cells (NSCs) and found that mutant mice faithfully recapitulated TSC neuropathological lesions, such as cortical lamination defects and subependymal nodules (SENs). These alterations were caused by enhanced gen…

The Adult Macaque Spinal Cord Central Canal Zone Contains Proliferative Cells And Closely Resembles The Human

The persistence of proliferative cells, which could correspond to progenitor populations or potential cells of origin for tumors, has been extensively studied in the adult mammalian forebrain, including human and nonhuman primates. Proliferating cells have been found along the entire ventricular system, including around the central canal, of rodents, but little is known about the primate spinal cord. Here we describe the central canal cellular composition of the Old World primate Macaca fascicularis via scanning and transmission electron microscopy and immunohistochemistry and identify central canal proliferating cells with Ki67 and newly generated cells with bromodeoxyuridine incorporation…

Unique Organization of the Nuclear Envelope in the Post-natal Quiescent Neural Stem Cells

Summary Neural stem cells (B1 astrocytes; NSCs) in the adult ventricular-subventricular-zone (V-SVZ) originate in the embryo. Surprisingly, recent work has shown that B1 cells remain largely quiescent. They are reactivated postnatally to function as primary progenitors for neurons destined for the olfactory bulb and some corpus callosum oligodendrocytes. The cellular and molecular properties of quiescent B1 cells remain unknown. Here we found that a subpopulation of B1 cells has a unique nuclear envelope invagination specialization similar to envelope-limited chromatin sheets (ELCS), reported in certain lymphocytes and some cancer cells. Using molecular markers, [3H]thymidine birth-dating, …

Folliculotropic Mycosis Fungoides With Flexural Eruptive Cysts and Comedones in a 14-Year-Old Boy

Cutaneous Lymphadenoma Is a Distinct Trichoblastoma-like Lymphoepithelial Tumor With Diffuse Androgen Receptor Immunoreactivity, Notch1 Ligand in Reed-Sternberg-like Cells, and Common EGFR Somatic Mutations.

The term "cutaneous lymphadenoma" was coined in this journal for an unusual lymphoepithelial cutaneous adnexal neoplasm, possibly with immature pilosebaceous differentiation. Some authors further proposed that cutaneous lymphadenoma was an adamantinoid trichoblastoma. However, although a hair follicle differentiation is widely accepted, the fact that this is a lymphoepithelial tumor is not appropriately explained by the trichoblastoma hypothesis. Our goal was to further clarify the phenotypic and genotypic features of cutaneous lymphadenoma in a series of 11 cases. Histologically, a lobular architecture surrounded by a dense fibrous stroma was present in all cases. The lobules were composed…

1432P Characterizing diversity in the immune profile by a transcriptomic customized gene signature to potentially personalize treatment in advanced gastric cancer patients

Cellular Composition and Organization of the Subventricular Zone and Rostral Migratory Stream in the Adult and Neonatal Common Marmoset Brain

The adult subventricular zone (SVZ) of the lateral ventricle contains neural stem cells. In rodents, these cells generate neuroblasts that migrate as chains toward the olfactory bulb along the rostral migratory stream (RMS). The neural-stem-cell niche at the ventricular wall is conserved in various animal species, including primates. However, it is unclear how the SVZ and RMS organization in nonhuman primates relates to that of rodents and humans. Here we studied the SVZ and RMS of the adult and neonatal common marmoset (Callithrix jacchus), a New World primate used widely in neuroscience, by electron microscopy, and immunohistochemical detection of cell-type-specific markers. The marmoset …

Ichthyosis, atopic dermatitis, and alopecia

488P Patient-derived organoids as a tool for modelling localized colorectal cancer