scholarly journals Proteomic and Transcriptomic Analysis Identify Spliceosome as a Significant Component of the Molecular Machinery in the Pituitary Tumors Derived from POU1F1- and NR5A1-Cell Lineages

Genes ◽  
2020 ◽  
Vol 11 (12) ◽  
pp. 1422
Author(s):  
Keiko Taniguchi-Ponciano ◽  
Eduardo Peña-Martínez ◽  
Gloria Silva-Román ◽  
Sandra Vela-Patiño ◽  
Ana Laura Guzman-Ortiz ◽  
...  
Keyword(s):  
Profile Analysis ◽  
Mrna Level ◽  
Pituitary Tumors ◽  
Transcriptomic Analysis ◽  
Mrna Isoforms ◽  
Tumor Subtypes ◽  
Exon Level ◽  
Molecular Machinery ◽  
The Central Nervous System ◽  
Level Analysis

Background: Pituitary adenomas (PA) are the second most common tumor in the central nervous system and have low counts of mutated genes. Splicing occurs in 95% of the coding RNA. There is scarce information about the spliceosome and mRNA-isoforms in PA, and therefore we carried out proteomic and transcriptomic analysis to identify spliceosome components and mRNA isoforms in PA. Methods: Proteomic profile analysis was carried out by nano-HPLC and mass spectrometry with a quadrupole time-of-flight mass spectrometer. The mRNA isoforms and transcriptomic profiles were carried out by microarray technology. With proteins and mRNA information we carried out Gene Ontology and exon level analysis to identify splicing-related events. Results: Approximately 2000 proteins were identified in pituitary tumors. Spliceosome proteins such as SRSF1, U2AF1 and RBM42 among others were found in PA. These results were validated at mRNA level, which showed up-regulation of spliceosome genes in PA. Spliceosome-related genes segregate and categorize PA tumor subtypes. The PA showed alterations in CDK18 and THY1 mRNA isoforms which could be tumor specific. Conclusions: Spliceosome components are significant constituents of the PA molecular machinery and could be used as molecular markers and therapeutic targets. Splicing-related genes and mRNA-isoforms profiles characterize tumor subtypes.

scholarly journals Constitutive expression of Mpl ligand transcripts during thrombocytopenia or thrombocytosis

Blood ◽  
1996 ◽  
Vol 88 (7) ◽  
pp. 2578-2584 ◽  
Author(s):  
K Cohen-Solal ◽  
JL Villeval ◽  
M Titeux ◽  
S Lok ◽  
W Vainchenker ◽  
...  
Keyword(s):  
Splice Variants ◽  
Mrna Level ◽  
Constitutive Expression ◽  
Experimental Models ◽  
Northern Analysis ◽  
Transcriptional Level ◽  
Severe Thrombocytopenia ◽  
Wild Type ◽  
Mrna Isoforms ◽  
Liver And Kidney

Mpl ligand (thrombopoietin [TPO]) is the physiological regulator of platelet production. In mice, mRNA encoding the Mpl ligand (Mpl-L) is predominantly found by Northern blot analysis in the liver and kidney. To investigate the mode of regulation of the Mpl-L gene, we have developed several experimental models of severe thrombocytopenia differing in their kinetics and an opposite model of chronic thrombocytosis. Northern analysis performed at various times after induction of a thrombocytopenic state demonstrates that, whatever the number of circulating platelets, no change in Mpl-L mRNA level occurs in liver and kidney. By ribonuclease protection assays, we analyzed the ratios between mRNAs coding for the wild-type Mpl-L form and various splice variants encoding inactive or nonsecreted Mpl-L proteins. No modification in levels of these various isoforms was detected confirming the data of a previous report. Because the highest level of Mpl-L bioactivity in sera was observed only in mice with drastically reduced numbers of both platelets and megakaryocytes, these results further suggest that not only platelets, but also megakaryocytes, must be involved in the regulation of the level of circulating Mpl-L. In addition, we show that no downregulation of wild-type Mpl-L mRNA and no change in the ratio of Mpl-L mRNA isoforms were detected in mice in which a chronic thrombocytosis was induced. Together, these different models extend and further confirm that the regulation of Mpl-L does not occur at a transcriptional level or by a modulation in the ratios of Mpl-L mRNA isoforms.

scholarly journals Pharmacologic Depletion of Microglia Increases Viral Load in the Brain and Enhances Mortality in Murine Models of Flavivirus-Induced Encephalitis

2018 ◽  
Vol 92 (16) ◽  
Author(s):  
Scott Seitz ◽  
Penny Clarke ◽  
Kenneth L. Tyler
Keyword(s):  
Immune Cells ◽  
Mrna Level ◽  
Cns Injury ◽  
Cytokines And Chemokines ◽  
Life Threatening ◽  
The Central Nervous System ◽  
The Brain ◽  
Stimulating Factor ◽  
Life Threatening Event

ABSTRACT Flaviviruses account for most arthropod-borne cases of human encephalitis in the world. However, the exact mechanisms of injury to the central nervous system (CNS) during flavivirus infections remain poorly understood. Microglia are the resident immune cells of the CNS and are important for multiple functions, including control of viral pathogenesis. Utilizing a pharmacologic method of microglia depletion (PLX5622 [Plexxikon Inc.], an inhibitor of colony-stimulating factor 1 receptor), we sought to determine the role of microglia in flaviviral pathogenesis. Depletion of microglia resulted in increased mortality and viral titer in the brain following infection with either West Nile virus (WNV) or Japanese encephalitis virus (JEV). Interestingly, microglial depletion did not prevent virus-induced increases in the expression of relevant cytokines and chemokines at the mRNA level. In fact, the expression of several proinflammatory genes was increased in virus-infected, microglia-depleted mice compared to virus-infected, untreated controls. In contrast, and as expected, expression of the macrophage marker triggering receptor expressed on myeloid cells 2 (TREM2) was decreased in virus-infected, PLX5622-treated mice compared to virus-infected controls. IMPORTANCE As CNS invasion by flaviviruses is a rare but life-threatening event, it is critical to understand how brain-resident immune cells elicit protection or injury during disease progression. Microglia have been shown to be important in viral clearance but may also contribute to CNS injury as part of the neuroinflammatory process. By utilizing a microglial depletion model, we can begin to parse out the exact roles of microglia during flaviviral pathogenesis with hopes of understanding specific mechanisms as potential targets for therapeutics.

scholarly journals GENE-24. DNA METHYLATION SIGNATURES DETECTED IN A SERUM-BASED LIQUID BIOPSY DISTINGUISH FUNCTIONAL AND INVASIVENESS FEATURES IN PITUITARY ADENOMAS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi102-vi102
Author(s):  
Michael Wells ◽  
Thais Sarraf Sabedot ◽  
Karam Asmaro ◽  
Maritza Mosella ◽  
Tathiane Malta ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Liquid Biopsy ◽  
Pituitary Tumors ◽  
Blood Draw ◽  
Tumor Subtypes ◽  
Molecular Features ◽  
Control Serum ◽  
Resected Tumor ◽  
Invasive Status ◽  
Tissue Specimens

Abstract Pituitary tumors are the second most common CNS neoplasia (~15%). Despite mostly benign and slow-growing, they may be nonfunctioning and invade surrounding structures resulting in significant comorbidities. Currently, classification of PT according to their risk for aggressiveness is mainly based on invasiveness detected by imaging methods and histopathological features which requires surgically resected tumor. Being able to detect molecular markers associated with tumor subtypes and behavior pre-surgically using minimally invasive approaches (blood draw) is desirable in these tumors and may help to address current diagnostic and therapeutic challenges. In tissue specimens, distinct DNA methylation patterns distinguish PT according to their functional status but their role in invasiveness is still unclear. We hypothesized that profiling cell-free DNA (cfDNA) released by PT into the bloodstream allow the identification of epigenetic markers associated with relevant clinicopathological features. Genome-wide methylome profile of paired serum cfDNA (EPIC array) and tissue from 13 patients with pituitary macroadenomas (9 males; median age: 62; 9 Nonfunctioning/4 functioning, 6 invasive/7 noninvasive) and 3 controls serum (patients with epilepsy). Unsupervised analysis of the serum methylome from patients harboring PT was distinct from controls and other diseases (hypopituitarism, glioma and colorectal cancer) and supervised analysis (Wilcoxon Rank-sum Test) identified significant differentially methylated probes (DMP) that segregated PT from control serum specimens. Nonfunctioning and invasive-specific DMPs identified in the serum also defined functional, and less prominently invasive status, in the tissue of an independent cohort of PT. This is the first study to show the feasibility to profile the serum methylome from patients with PT using cfDNA. In addition, we identified unique methylation signatures that distinguished PT according to functional and invasiveness subtypes. These results underpin the potential role of methylation profile and liquid biopsy as a noninvasive approach to assess clinically relevant molecular features in the serum of patients harboring PT.

Cerebellar metastasis from a prolactinoma during treatment with bromocriptine

1981 ◽  
Vol 55 (4) ◽  
pp. 615-619 ◽  
Author(s):  
Neil A. Martin ◽  
Martha Hales ◽  
Charles B. Wilson
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Pituitary Adenoma ◽  
Pituitary Tumors ◽  
Metastatic Tumor ◽  
Metastatic Spread ◽  
Content Type ◽  
The Central Nervous System ◽  
Cerebellar Metastasis ◽  
Fine Print

✓ A 31-year-old woman developed a cerebellar metastasis from an invasive prolactin-secreting pituitary adenoma while undergoing treatment with bromocriptine. The metastatic tumor was totally excised. Metastatic spread of pituitary tumors within the central nervous system is reviewed briefly.

Clear Cell Tumors of the Central Nervous System: A Case-Based Review

2012 ◽  
Vol 136 (8) ◽  
pp. 915-926 ◽  
Author(s):  
Sandra Camelo-Piragua
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Clear Cell ◽  
Diagnostic Tools ◽  
Tumor Subtypes ◽  
System A ◽  
The Central Nervous System ◽  
Complex Features ◽  
Case Based ◽  
Radiologic Features

Clear cell tumors of the central nervous system (CNS) encompass a variety of tumor subtypes that are challenging to diagnose given their similar morphologic features. Here, I use a case-based approach to review the clinicopathologic and radiologic features to help guide the general pathologist in the diagnosis of clear cell tumors of the CNS. First, the reader is invited to study 6 images of different CNS tumors with clear cell morphology. Then, each case is expanded in light of clinical and radiologic data and includes a histopathologic description of the tumor. A brief discussion follows with up-to-date diagnostic tools. Finally, I propose an immunohistochemical algorithm to navigate through the complex features that characterize clear cell tumors of the CNS. This review aims to provide a comprehensive approach to diagnosing clear cell neoplasms of the CNS based on improved assessment of the clinicopathologic and radiologic features of each entity.

Multiparameter Flow Cytometric Analysis of Neoplasms of the Central Nervous System: Correlation of Nuclear Antigen p105 and DNA Content with Clinical Behavior

Neurosurgery ◽  
1990 ◽  
Vol 27 (1) ◽  
pp. 83-96 ◽  
Author(s):  
Alan J. Appley ◽  
Patrick L. Fitzgibbons ◽  
Parakrama T. Chandrasoma ◽  
David R. Hinton ◽  
Michael L. J. Apuzzo
Keyword(s):  
Cell Cycle ◽  
Central Nervous System ◽  
Nervous System ◽  
Dna Content ◽  
Proliferative Activity ◽  
Pituitary Tumors ◽  
Nuclear Antigen ◽  
Clinical Behavior ◽  
The Central Nervous System ◽  
Well Differentiated

Abstract Analysis of the DNA content of various solid tumors and hematological malignancies may provide useful prognostic information. To date, however, there has been a striking lack of correlation between DNA content in neoplasms of the central nervous system and clinical behavior. Simultaneous quantitation of DNA content and proliferation-associated nuclear antigen (p105) by flow cytometry was performed on paraffin-embedded tissues representing three major groups of central nervous system neoplasms—1) 21 astrocytic tumors, 2) 13 pituitary tumors, and 3) 19 meningiomas-and the results were correlated with clinical behavior. All 4 well-differentiated gliomas were diploid, while 3 of 9 anaplastic astrocytomas and 1 of 8 glioblastomas had a demonstrable aneuploid peak. Three of 13 pituitary tumors had an identifiable aneuploid peak, while only 2 of 19 meningiomas had an aneuploid DNA content. Cell-cycle analysis of the malignant gliomas revealed a significantly higher proliferative index (PI, %S + G2M) compared with the well-differentiated astrocytomas (P< 0.05). Within the subgroup of diploid anaplastic astrocytomas, however, extended patient survival appeared to be associated with a higher PI. For diploid pituitary adenomas, the PI was consistently lower in the 3 tumors that recurred than it was in the remaining 8 adenomas. Nuclear antigen quantitation of diploid tumors showed a wide range of p105 expression in G0G1cells, suggesting that, within each tumor, the cells are heterogeneous with respect to proliferative activity. Aneuploid nuclei of glial tumors showed enhanced expression of p105 relative to diploid cells of the same specimen. In pituitary tumors, the median G2M/G0G1fluorescence ratio for p105 was significantly higher (P< 0.05) for the 3 diploid recurrent tumors than for those that did not recur. These data support the assumption that the aggressive clinical course of malignant glial neoplasms may be related to an abnormal DNA stemline and/or an alteration in cell proliferative activity. Cell cycle analysis and measurement of p105 by this technique may provide information useful from both a prognostic standpoint and in directing adjuvant therapy.

Multiple dural metastases from a pituitary adenoma

1994 ◽  
Vol 81 (4) ◽  
pp. 624-626 ◽  
Author(s):  
William A. S. Taylor ◽  
David Uttley ◽  
P. R. Wilkins
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Pituitary Adenoma ◽  
Pituitary Tumors ◽  
Content Type ◽  
Original Tumor ◽  
The Central Nervous System ◽  
Dural Metastases ◽  
Fine Print

✓ Only 12 cases of pituitary tumors that metastasized within the central nervous system have been reported. A further case is presented in which the histology of the multiple dural metastases remained identical to that of the original tumor, a pituitary adenoma. The authors discuss management of these rare lesions that appear histologically benign.

scholarly journals Inter-Observer Variation in the Grading of Meningiomas using the WHO Classification of CNS Tumors Criteria

2020 ◽  
pp. 1-5
Author(s):  
Hisham Alkhalidi
Keyword(s):  
Who Classification ◽  
Observer Variation ◽  
World Health ◽  
Original Diagnosis ◽  
Brain Invasion ◽  
Tumor Subtypes ◽  
The Central Nervous System ◽  
Health Organization ◽  
Treatment Prognosis

Background: Grading of meningiomas using the World health organization (WHO) Classification of the Central Nervous System criteria currently has an essential role in classification, treatment, prognosis prediction, and research of these tumors. Aims: This is a retrospective study that assessed the interobserver variation between Anatomical Pathologists in grading meningiomas using material obtained from ten resection specimens. The WHO grading system includes different methods, including the mitotic count, the tumor subtypes or the presence of three out of five certain morphological features. This paper focuses on the interobserver variability in the latter method. Methods: Meningiomas that were originally graded based upon mitoses, brain invasion, or morphological subtype were excluded. Ten different Anatomical Pathologists, including two Neuropathologists, who were blinded to the original diagnosis and grade graded the tumors independently.

scholarly journals New Transcriptional Insights into Silent and Active Corticotroph Pituitary Tumors at Single Cell Resolution

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A646-A647
Author(s):  
Dongyun Zhang ◽  
Willy Hugo ◽  
Marvin Bergsneider ◽  
Marilene B Wang ◽  
Won Kim ◽  
...  
Keyword(s):  
Single Cell ◽  
Tumor Cells ◽  
Pituitary Tumors ◽  
Dependent Manner ◽  
Recurrence Rates ◽  
Mesenchymal Transition ◽  
Tumor Subtypes ◽  
Distinct Cell ◽  
Endothelial To Mesenchymal Transition ◽  
A Minor

Abstract Silent pituitary corticotroph tumors derive from the Tpit (aka TBX19) pituitary lineage. Accounting for ~ 30% of corticotroph tumors, they are not infrequently clinically aggressive and invade locally into adjacent sellar structures, making complete surgical resection challenging and contributing to their higher recurrence rates. How silent and active corticotroph tumor subtypes differ is not clear although some studies reported that silent corticotroph tumors exhibit reduced PC1 expression causing impaired POMC processing. We used single cell RNAseq to compare the transcriptome between silent (n = 2) and active (n = 4) corticotroph tumors at the single cell level. We obtained an average of 265 million reads, and 24,682 genes per patient with an average of 1,240 genes expressed and 3,5442 unique molecular identifiers (UMIs) detected per cell. We further defined 5 distinct cell populations from a total of 23,269 cells, namely tumor cells (62%), stromal cells (25%), immune cells (7%), progenitor cells (5%), and a minor population of erythrocytes (1%). Tumor cells clustered in an origin-dependent manner and all expressed POMC and TBX19. However, the gene signatures of silent and active corticotroph tumors differed in 3 major aspects. Firstly, and supporting prior studies, a series of hormone processing peptidase genes, including PC1 (aka PCSK1), PDIA3, SEC11C, SPCS1 and CTSB, were reduced in silent corticotroph tumors (p=5.54e-5) compared to active corticotroph tumors. Secondly, genes involved in organization of secretory vesicles such as SCG5, TIMP1, VGF, SYT17, LGALS3 and CALY were also reduced in silent corticotroph tumors, which could further compound their inability to secrete ACTH. Thirdly, the silent corticotroph tumors exhibited several features of endothelial-to-mesenchymal transition (EMT), including increased expression of the mesenchymal genes CDH2 (aka NCAD), COL1A1, PCDH9, FGF5, ID2 (p=8.4e-3), and loss of EPCAM, which regulate cell migration and movement. Upstream analysis suggested that aberrant STAT3 activation may be related to these changes. Consequently, we noted that the stromal content was higher in silent corticotroph tumors (47.5% vs. 18.13%), concordant with the observed EMT de-differentiation of tumor cells. In summary, our scRNAseq analysis provides an unprecedented precise investigation of the transcriptomic features of thousands of heterogenous corticotroph tumor cells simultaneously. We demonstrate that although silent corticotroph tumor cells still express the pituitary lineage markers PITX1 and TBX19, they exhibit EMT, potentially affording increased migratory capacity at the cost of reduced neuroendocrine function with inability to produce and secrete mature ACTH. Our findings provide novel insights into the pathogenesis of silent versus active corticotroph tumor, but may reveal novel molecular targets for treatment of these challenging tumors.

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