scholarly journals Transcriptome-wide Profiling of Cerebral Cavernous Malformations Patients Reveal Important Long noncoding RNA molecular signatures

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Santhilal Subhash ◽  
Norman Kalmbach ◽  
Florian Wegner ◽  
Susanne Petri ◽  
Torsten Glomb ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Vascular Malformations ◽  
Cerebrovascular Disorders ◽  
Gene Set Enrichment Analysis ◽  
Differentially Expressed ◽  
Low Flow ◽  
Pcr Analysis ◽  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations ◽  
Non Coding Rnas

AbstractCerebral cavernous malformations (CCMs) are low-flow vascular malformations in the brain associated with recurrent hemorrhage and seizures. The current treatment of CCMs relies solely on surgical intervention. Henceforth, alternative non-invasive therapies are urgently needed to help prevent subsequent hemorrhagic episodes. Long non-coding RNAs (lncRNAs) belong to the class of non-coding RNAs and are known to regulate gene transcription and involved in chromatin remodeling via various mechanism. Despite accumulating evidence demonstrating the role of lncRNAs in cerebrovascular disorders, their identification in CCMs pathology remains unknown. The objective of the current study was to identify lncRNAs associated with CCMs pathogenesis using patient cohorts having 10 CCM patients and 4 controls from brain. Executing next generation sequencing, we performed whole transcriptome sequencing (RNA-seq) analysis and identified 1,967 lncRNAs and 4,928 protein coding genes (PCGs) to be differentially expressed in CCMs patients. Among these, we selected top 6 differentially expressed lncRNAs each having significant correlative expression with more than 100 differentially expressed PCGs. The differential expression status of the top lncRNAs, SMIM25 and LBX2-AS1 in CCMs was further confirmed by qRT-PCR analysis. Additionally, gene set enrichment analysis of correlated PCGs revealed critical pathways related to vascular signaling and important biological processes relevant to CCMs pathophysiology. Here, by transcriptome-wide approach we demonstrate that lncRNAs are prevalent in CCMs disease and are likely to play critical roles in regulating important signaling pathways involved in the disease progression. We believe, that detailed future investigations on this set of identified lncRNAs can provide useful insights into the biology and, ultimately, contribute in preventing this debilitating disease.

scholarly journals Exosomal microRNAs are novel circulating biomarkers in cigarette, waterpipe smokers, E-cigarette users and dual smokers

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Kameshwar P. Singh ◽  
Krishna P. Maremanda ◽  
Dongmei Li ◽  
Irfan Rahman
Keyword(s):  
Differential Expression ◽  
Tobacco Smoking ◽  
Dna Analysis ◽  
Electronic Cigarettes ◽  
Differential Expression Analysis ◽  
High Sensitivity ◽  
Gene Set Enrichment Analysis ◽  
Differentially Expressed ◽  
Cigarette Smokers ◽  
Non Coding Rnas

Abstract Background Electronic cigarettes (e-cigs) vaping, cigarette smoke, and waterpipe tobacco smoking are associated with various cardiopulmonary diseases. microRNAs are present in higher concentration in exosomes that play an important role in various physiological and pathological functions. We hypothesized that the non-coding RNAs transcript may serve as susceptibility to disease biomarkers by smoking and vaping. Methods Plasma exosomes/EVs from cigarette smokers, waterpipe smokers and dual smokers (cigarette and waterpipe) were characterized for their size, morphology and TEM, Nanosight and immunoblot analysis. Exosomal RNA was used for small RNA library preparation and the library was quantified using the High Sensitivity DNA Analysis on the Agilent 2100 Bioanalyzer system and sequenced using the Illumina NextSeq 500 and were converted to fastq format for mapping genes. Results Enrichment of various non-coding RNAs that include microRNAs, tRNAs, piRNAs, snoRNAs, snRNAs, Mt-tRNAs, and other biotypes are shown in exosomes. A comprehensive differential expression analysis of miRNAs, tRNAs and piRNAs showed significant changes across different pairwise comparisons. The seven microRNAs that were common and differentially expressed of when all the smoking and vaping groups were compared with non-smokers (NS) are hsa-let-7a-5p, hsa-miR-21-5p, hsa-miR-29b-3p, hsa-let-7f-5p, hsa-miR-143-3p, hsa-miR-30a-5p and hsa-let-7i-5p. The e-cig vs. NS group has differentially expressed 5 microRNAs (hsa-miR-224-5p, hsa-miR-193b-3p, hsa-miR-30e-5p, hsa-miR-423-3p, hsa-miR-365a-3p, and hsa-miR-365b-3p), which are not expressed in other three groups. Gene set enrichment analysis of microRNAs showed significant changes in the top six enriched functions that consisted of biological pathway, biological process, molecular function, cellular component, site of expression and transcription factor in all the groups. Further, the pairwise comparison of tRNAs and piRNA in all these groups revealed significant changes in their expressions. Conclusions Plasma exosomes of cigarette smokers, waterpipe smokers, e-cig users and dual smokers have common differential expression of microRNAs which may serve to distinguish smoking and vaping subjects from NS. Among them has-let-7a-5p has high sensitivity and specificity to distinguish NS with the rest of the users, using ROC curve analysis. These findings will pave the way for the utilizing the potential of exosomes/miRNAs as a novel theranostic agents in lung injury and disease caused by tobacco smoking and vaping.

scholarly journals Genomewide analysis of circular RNA in pituitaries of normal and heat-stressed sows

BMC Genomics ◽  
2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Haojie Zhang ◽  
Baoyu Hu ◽  
Jiali Xiong ◽  
Ting Chen ◽  
Qianyun Xi ◽  
...  
Keyword(s):  
Heat Stress ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Noncoding Rna ◽  
Target Genes ◽  
Hormone Secretion ◽  
Circular Rna ◽  
Differentially Expressed ◽  
Pcr Analysis ◽  
Pituitary Hormone

Abstract Background As a newly characterized type of noncoding RNA, circular RNA (circRNA) has been shown to have functions in diverse biological processes of animals. It has been reported that several noncoding RNAs may regulate animals’ response to heat stress which can be easily induced by hyperthermia in summer. However, the expression and functions of circRNAs in the pituitary of sows and whether they participate in heat stress adaption are still unclear. Results In this study, we found that high temperature over the thermoneutral zone of sows during the summer increased the serum heat shock protein 70 (HSP70) level, decreased the superoxide dismutase (SOD) vitality and prolactin (PRL) concentration, and induced heat stress in sows. Then, we explored circRNA in the pituitary of heat-stressed and normal sows using RNA sequencing and bioinformatics analysis. In total, 12,035 circRNAs were detected, with 59 circRNAs differentially expressed, including 42 up-regulated and 17 down-regulated circRNAs in pituitaries of the heat-stressed sows. Six randomly selected circRNAs were identified through reverse transcription PCR followed by DNA sequencing and other 7 randomly selected differentially expressed circRNAs were verified by quantitative real-time PCR analysis. The predicted target genes regulated by circRNAs through sponging microRNAs (miRNAs) were enriched in metabolic pathway. Furthermore, the predicted circRNA–miRNA–mRNA interactions showed that some circRNAs might sponge miRNAs to regulate pituitary-specific genes and heat shock protein family members, indicating circRNA’s roles in pituitary hormone secretion and heat stress response. Conclusions Our results provided a meaningful reference to understand the functions of circRNA in the porcine pituitary and the mechanisms by which circRNA may participate in animals’ response to heat stress.

Are cavernous sinus hemangiomas and cavernous malformations different entities?

2006 ◽  
Vol 21 (1) ◽  
pp. 1-5 ◽  
Author(s):  
L. Fernando Gonzalez ◽  
Gregory P. Lekovic ◽  
Jennifer Eschbacher ◽  
Stephen Coons ◽  
Randall W. Porter ◽  
...  
Keyword(s):  
Cavernous Sinus ◽  
Cavernous Malformation ◽  
Vascular Malformations ◽  
Response To Treatment ◽  
Vascular Tumors ◽  
Cerebral Cavernous Malformations ◽  
Imaging Studies ◽  
Cavernous Malformations ◽  
Cavernous Hemangiomas

✓Cavernous hemangiomas that occur within the cavernous sinus (CS) are different from cerebral cavernous malformations (CMs) clinically, on imaging studies, and in their response to treatment. Moreover, CMs are true vascular malformations, whereas hemangiomas are benign vascular tumors. Because of these differences, the authors suggest that these two entities be analyzed and grouped separately. Unfortunately, despite these differences, much confusion exists in the literature as to the nature, behavior, and classification of these two distinct lesions. This confusion is exacerbated by subtle histological differences and the inconsistent use of nomenclature. The authors use the term “cavernous malformation” to refer to intraaxial lesions only; they prefer to use the term “cavernous sinus hemangioma” to refer to extraaxial, intradural hemangiomas of the CS.

scholarly journals Developmental timing of CCM2 loss influences cerebral cavernous malformations in mice

2011 ◽  
Vol 208 (9) ◽  
pp. 1835-1847 ◽  
Author(s):  
Gwénola Boulday ◽  
Noemi Rudini ◽  
Luigi Maddaluno ◽  
Anne Blécon ◽  
Minh Arnould ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Vascular Malformations ◽  
Vascular Lesions ◽  
Developmental Timing ◽  
Cerebral Cavernous Malformations ◽  
Loss Of Function ◽  
Cavernous Malformations ◽  
The Central Nervous System ◽  
Dominant Condition

Cerebral cavernous malformations (CCM) are vascular malformations of the central nervous system (CNS) that lead to cerebral hemorrhages. Familial CCM occurs as an autosomal dominant condition caused by loss-of-function mutations in one of the three CCM genes. Constitutive or tissue-specific ablation of any of the Ccm genes in mice previously established the crucial role of Ccm gene expression in endothelial cells for proper angiogenesis. However, embryonic lethality precluded the development of relevant CCM mouse models. Here, we show that endothelial-specific Ccm2 deletion at postnatal day 1 (P1) in mice results in vascular lesions mimicking human CCM lesions. Consistent with CCM1/3 involvement in the same human disease, deletion of Ccm1/3 at P1 in mice results in similar CCM lesions. The lesions are located in the cerebellum and the retina, two organs undergoing intense postnatal angiogenesis. Despite a pan-endothelial Ccm2 deletion, CCM lesions are restricted to the venous bed. Notably, the consequences of Ccm2 loss depend on the developmental timing of Ccm2 ablation. This work provides a highly penetrant and relevant CCM mouse model.

scholarly journals A Novel CCM2 Missense Variant Caused Cerebral Cavernous Malformations in a Chinese Family

2021 ◽  
Vol 14 ◽  
Author(s):  
Guoqing Han ◽  
Li Ma ◽  
Huanhuan Qiao ◽  
Lin Han ◽  
Qiaoli Wu ◽  
...  
Keyword(s):  
Vascular Malformations ◽  
Case Reports ◽  
Chinese Family ◽  
Incomplete Penetrance ◽  
Cerebral Cavernous Malformations ◽  
Missense Mutations ◽  
Inherited Disease ◽  
Cavernous Malformations ◽  
Direct Dna Sequencing ◽  
Number Of Patients

Cerebral cavernous malformations (CCMs) are common vascular malformations in the central nervous system. Familial CCMs (FCCMs) are autosomal dominant inherited disease with incomplete penetrance and variable symptoms. Mutations in the KRIT1, CCM2, and PDCD10 genes cause the development of FCCM. Approximately 476 mutations of three CCM-related genes have been reported, most of which were case reports, and lack of data in stable inheritance. In addition, only a small number of causative missense mutations had been identified in patients. Here, we reported that 8/20 members of a Chinese family were diagnosed with CCMs. By direct DNA sequencing, we found a novel variant c.331G > C (p.A111P) in exon 4 of the CCM2 gene, which was a heterozygous exonic variant, in 7/20 family members. We consider this variant to be causative of disease due to a weaken the protein–protein interaction between KRIT1 and CCM2. In addition, we also found the exon 13 deletion in KRIT1 coexisting with the CCM2 mutation in patient IV-2, and this was inherited from her father (patient III-1H). This study of a Chinese family with a large number of patients with CCMs and stable inheritance of a CCM2 mutation contributes to better understanding the spectrum of gene mutations in CCMs.

Diagnostic Accuracy of SWAN in the Diagnosis of Low-Flow Brain Vascular Malformations in Childhood

2021 ◽  
Author(s):  
Nazlı Gülsüm Akyel ◽  
Ayşe Gül Alımlı ◽  
Mesut Sivri ◽  
Havva Akmaz Ünlü ◽  
Mehmet Tiftik
Keyword(s):  
Diagnostic Accuracy ◽  
Vascular Malformations ◽  
False Negative ◽  
Vascular Anomaly ◽  
Low Flow ◽  
Developmental Venous Anomaly ◽  
Cavernous Malformations ◽  
Capillary Telangiectasia ◽  
Cerebral Vascular Malformations ◽  
Cerebral Vascular

Abstract Purpose The main objective of this study is to demonstrate the diagnostic accuracy of susceptibility-weighted angiography (SWAN) in the diagnosis of slow-flow cerebral vascular malformations, especially developmental venous anomaly (DVA). We also aimed to determine the prevalence of DVAs identified by SWAN at 1.5 T. Methods We retrospectively evaluated 1,760 axial SWAN images for the diagnosis of low-flow vascular anomaly. Among them were 305 patients who underwent contrast-enhanced examination due to different indications. Postcontrast images were analyzed by different radiologists who were blinded to patients. The presence of DVA and other features such as location, length, depth, and direction of drainage vein was evaluated. Results Twenty-six patients with DVA had both SWAN and postcontrast images. There were four false-negative patients with SWAN. The sensitivity of the SWAN sequence was 84.6%. In addition, totally 77 DVA (4.36%), 2 capillary telangiectasia (0.11%), and 2 cavernous malformations (0.11%) were detected in 1,760 patients. Conclusion SWAN is an effective method for the diagnosis of developmental venous anomalies and other low-flow cerebral vascular malformations. Especially in the pediatric age, susceptibility-weighted imaging sequences are useful to limit contrast use.

scholarly journals Identification of Blut, a Novel Long-Noncoding RNA Differentially Expressed in Burkitt Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3875-3875
Author(s):  
Jessica I Hoell ◽  
Kunal Das Mahapatra ◽  
Kebria Hezaveh ◽  
Andreas Kloetgen ◽  
Stephan Bernhart ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Nuclear Localization ◽  
Burkitt Lymphoma ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Differentially Expressed ◽  
Comprehensive Cancer Center ◽  
Non Coding Rnas ◽  
Coding Potential

Abstract The class of the so-called long non-coding RNAs (lncRNAs) is defined by their lacking coding potential and their length of more than 200 nucleotides. LncRNAs are readily detected in transcriptome analysis but have so far not been characterized or catalogued exhaustively. Although lncRNAs make up a major portion of the mammalian non-coding transcriptome, it is challenging to predict their functions due to their diversity in terms of size, sequence and biogenesis. However, several lncRNAs have already been shown to be involved in crucial cellular processes such as imprinting, regulation of cell proliferation and cellular differentiation. Their mode of action generally involves epigenetic modifications as well as transcriptional and post-transcriptional regulation. Within the ICGC (International Cancer Genome Consortium)-MMML-Seq (Molecular Mechanisms in Malignant Lymphoma by Sequencing) Consortium, which aims at fully characterizing a total of 250 germinal center derived B-cell lymphomas, including Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), we conducted a search for yet unidentified genes. We here report the identification of a novel transcript, which we have named BLUT (Burkitt Lymphoma Unknown Transcript). BLUT is highly expressed in BL, with only very low expression levels in FL and no detectable expression in DLBCL. It is around 1050 nucleotides long with splice evidence for three exons, whereby exons 1 and 3 are shared between all isoforms. BLUT represents a putative lncRNA since it lacks conserved protein domains and has a splice site conservation pattern typical of non-coding transcripts. Furthermore, it is predicted as non-coding by the software Coding Potential Calculator and there was not a single peptide match between a published peptide database (Human Proteome Map) and any potential BLUT peptide (all isoforms). Moreover, BLUT shares a high sequence identity with two (so far) uncharacterized non-coding RNAs (Pan Troglodyte, Chlorocebus sabeus). We tested a cell line panel (consisting of 16 different cell lines including non-lymphoma cell lines) for BLUT expression but could only detect it in the two BL cell lines Namalwa and Raji. Cellular fractionation experiments showed that BLUT is predominantly localized in the nucleus in both Namalwa and Raji. Overexpression of BLUT in SU-DHL-4 resulted in the identification of 222 differentially regulated genes (FDR < 0.05) with a logFC of ± 0.25, among which 49 genes had a logFC of ± 0.50. Several lymphoma relevant genes were part of this list including BIN1, CCL22, CCR7, EBI3, ID2, JAG1, NQO1, and RGS1. Given its nuclear localization, we currently perform chromatin isolation by RNA purification experiments to identify the genomic regions which BLUT binds to. In combination with our overexpression data this will allow further insights into the functions of BLUT. In summary, we have identified a novel long-noncoding RNA termed BLUT, which is differentially expressed between lymphoma subtypes with a high expression in Burkitt lymphoma. Overexpression of BLUT resulted in the deregulation of several genes with known roles in lymphomagenesis. Given its predominantly nuclear localization, we are currently investigating its functions on chromatin regulation. (Supported by BMBF through 01KU1002A-J and by the Duesseldorf School of Oncology (funded by the Comprehensive Cancer Center Duesseldorf/Deutsche Krebshilfe and the Medical Faculty HHU Düsseldorf)) Disclosures Truemper: Amgen, roche, Mundipharma: Research Funding; Sandoz, Celgene, AMGEN, Nordic Nanovector: Other: Advisory board.

scholarly journals Genetic Genealogy Uncovers a Founder Deletion Mutation in the Cerebral Cavernous Malformations 2 Gene

2021 ◽  
Author(s):  
Carol J Gallione ◽  
Matthew R Detter ◽  
Henrietta M Christmas ◽  
Cornelia Lee ◽  
Douglas A Marchuk
Keyword(s):  
Vascular Malformations ◽  
Cerebral Cavernous Malformations ◽  
Autosomal Dominant Trait ◽  
Cavernous Malformations ◽  
North American Continent ◽  
The North ◽  
Genealogical Data ◽  
The Brain ◽  
Recombination Junction ◽  
Pair Level

Abstract Cerebral cavernous malformations (CCM) are vascular malformations consisting of collections of enlarged capillaries occurring in the brain or spinal cord. These vascular malformations can occur sporadically or susceptibility to develop these can be inherited as an autosomal dominant trait due to mutation in one of three genes. Over a decade ago, we described a 77.6 Kb germline deletion spanning exons 2-10 in the CCM2 gene found in multiple affected individuals from seemingly unrelated families. Segregation analysis using linked, microsatellite markers indicated that this deletion may have arisen at least twice independently. In the ensuing decades, many more CCM patients have been identified with this deletion. In this present study we examined 27 reportedly unrelated affected individuals with this deletion. To investigate the origin of the deletion at base pair level resolution, we sequenced approximately 10 Kb upstream and downstream from the recombination junction on the deleted allele. All patients showed the identical SNP haplotype across this combined 20 Kb interval. In parallel, genealogical records have traced 11 of these individuals to five separate pedigrees dating as far back as the 1600-1700’s. These haplotype and genealogical data suggest that these families and the remaining “unrelated” samples converge on a common ancestor due to a founder mutation occurring centuries ago on the North American continent. We also note that another gene, NACAD, is included in this deletion. Although patient self-reporting does not indicate an apparent phenotypic consequence for heterozygous deletion of NACAD, further investigation is warranted for these patients.

Cerebral Cavernous Malformations and Pregnancy

Neurosurgery ◽  
2012 ◽  
Vol 71 (3) ◽  
pp. 626-631 ◽  
Author(s):  
Christopher D. Witiw ◽  
Amal Abou-Hamden ◽  
Abhaya V. Kulkarni ◽  
Joseph A. Silvaggio ◽  
Carol Schneider ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Intracranial Hemorrhage ◽  
Health Care Professionals ◽  
Vascular Malformations ◽  
Post Partum ◽  
Study Group ◽  
Cerebral Cavernous Malformations ◽  
Pregnancy Risk ◽  
Cavernous Malformations ◽  
University Of Toronto

Abstract BACKGROUND: Cerebral cavernous malformations are brain vascular malformations associated with intracranial hemorrhage. It is unclear whether pregnancy is a risk factor for hemorrhage, yet there is speculation that it may be. OBJECTIVE: To compare the risk of clinically significant hemorrhage during pregnancy and nonpregnancy. METHODS: A total of 186 patients from the University of Toronto Vascular Malformations Study Group were enrolled. The obstetrical history of each patient was collected and matched to their neurological history from the records of the study group. All hemorrhagic events occurring during childbearing years were associated with either a defined pregnancy risk period or nonpregnancy period. Patients were also asked to recall advice that they received from health care professionals regarding risk of hemorrhage in pregnancy. RESULTS: Among our patient population there were 349 pregnancies (283 live births) and 49 hemorrhages during childbearing years, 3 of which were during pregnancy but none during delivery or within 6 weeks post partum. The hemorrhage rate for pregnant women was 1.15% (95% confidence interval: 0.23-3.35) per person-year and 1.01% (95% confidence interval: 0.75-1.36) per person-year for nonpregnant women. Relative risk of pregnancy was 1.13 (95% confidence interval: 0.34-3.75) (P = .84). Neurosurgeons and obstetricians were the source of most hemorrhage risk advice. The majority of neurosurgeons suggested that the risk was unchanged, but the obstetricians were divided. Four patients never conceived, and 2 others began contraception because of the advice that they received. CONCLUSION: The risk of intracranial hemorrhage from cerebral cavernous malformations is likely not changed during pregnancy, delivery, or post partum.

Cerebral cavernous malformations: epidemiological, clinical and diagnostic imaging aspects

2018 ◽  
Vol 8 (2) ◽  
pp. 8-17
Author(s):  
I. Czekalska ◽  
Z. Tyrakowska-Dadełło ◽  
P. Werel ◽  
E. Tarasów ◽  
E. Grodzka
Keyword(s):  
Clinical Symptoms ◽  
Vascular Malformations ◽  
Epileptic Seizures ◽  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations ◽  
Large Size ◽  
Wide Range ◽  
Mean Size ◽  
The Central Nervous System

<b>Introduction:</b> Cerebral cavernous malformations (CCMs) are one of the most common vascular malformations of the central nervous system. Symptoms of CCMs are not typical; the disease can be asymptomatic or be manifested by a wide range of neurological symptoms. <b>Purpose:</b> To evaluate chosen epidemiologic and clinical issues as well as advanced imaging diagnostics of CCMs in computed tomography and magnetic resonance imaging. <b>Materials and methods:</b> The study was based on retrospective analysis of CT and MRI examinations from the 5 years period. The analysis covered 61 persons, 29 males, and 32 females. The CCMs were diagnosed based on MRI examination in 43 patients and CT in 13 patients. <b>Results:</b> The rate of CCMs occurrence in own material was 0.2%. Single lesions were present in 90.2%, while multiple in 9.8% of cases. Supratentorial CCMs were observed in 77% of cases whereas subtentorial in 23%. Mean size of CCMs in the supra- and subtentorial area equaled 10.6±6.3 and 15.1±5.8 mm, respectively (p<0.05). Clinical symptoms occurred in 65.8% of patients, most frequently in patients with CCMs above 5 mm or with subtentorial lesions. All CCMs were hyperdense in CT images, with calcifications in 13.1%. In MRI, malformations showed diverse intensity of the central part with peripheral low-intensity rim of hemosiderine deposits in T2-weighted images. <b>Conclusions:</b> The clinical symptoms occur in most cases of CCMs. These patients require periodic follow-up MRI examinations, specifically those with haemorrhagic incidents or epileptic seizures, with large size or subtentorial CCMs.

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