scholarly journals Assessment of Computational Histopathology in Thoracic Aortic Aneurysm

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Michael DeBrota ◽  
Muhammad Idrees ◽  
Benjamin Landis
Keyword(s):  
Aortic Aneurysm ◽  
Thoracic Aortic Aneurysm ◽  
Elastic Fiber ◽  
Aortic Tissue ◽  
Strongly Correlated ◽  
Medial Degeneration ◽  
Aortic Replacement ◽  
Formalin Fixed Paraffin ◽  
Formalin Fixed Paraffin Embedded ◽  
Cellular Area

Background and Hypothesis: Thoracic aortic aneurysm (TAA) histopathology includes elastic fiber (EF) abnormalities, mucoid extracellular matrix (MECM) accumulation, and smooth muscle derangement in the aortic medial layer. While semi-quantitative grading of these characteristics is a standard practice, computational characterization of medial layer components may facilitate novel quantitative analyses at higher throughput. We hypothesized that computational results would correlate with results of semi-quantitative grading of aortic histopathology. Experimental Design: Formalin-fixed, paraffin-embedded human aortic tissue sections were stained with Movat’s pentachrome to characterize aortic microstructure. Sections were also immunostained for nitrotyrosine residues to assess oxidative stress. Samples were initially graded semi-quantitatively by two independent blinded readers. Next, computational histopathology software was used a) to quantify the proportions of EF, MECM, and cellular area in the medial layer of pentachrome-stained sections and b) to quantify the distribution and intensity of positive nitrotyrosine staining in immunostained sections. Association between semi-quantitative grading and computed values was tested with ANOVA. Results: The cohort included 74 participants who underwent prophylactic aortic replacement for TAA and 23 healthy controls. The mean age was 54±17 years. On average, EFs accounted for 49% (range 6-90%) of medial tissue area, whereas MECM accounted for 25% (1-73%). The overall semi-quantitative grade of medial degeneration severity was associated with decrease in EF fraction (p=0.02). The grade of EF thinning also strongly correlated with decrease in EF fraction (p=1x10-6). Meanwhile, grade for accumulation of MECM was associated with increase in MECM (p=0.004). Increased semi-quantitative grading for nitrotyrosine levels was associated with increased nuclear signal optical density (p=9x10-10) and greater percentage of cells labeled as strongly positive (p=8x10-10). Conclusion and Potential Impact: We observed significant correlations between computed quantitative values and semi-quantitative grading. This suggests that computational histopathology is a valid method for investigation of human TAA tissues.

Abstract 15129: Outcomes Related to Age of Elective Surgery and Age of Dissection Within Genetically Triggered Aneurysm Conditions: The Gentac Experience

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Kathryn W Holmes ◽  
Scott A Lemaire ◽  
Richard B Devereux ◽  
William J Ravekes ◽  
Shaine A Morris ◽  
...  
Keyword(s):  
Aortic Aneurysm ◽  
Thoracic Aortic Aneurysm ◽  
Elective Surgery ◽  
Aortic Surgery ◽  
Reference Population ◽  
Ehlers Danlos Syndrome ◽  
Aortic Replacement ◽  
Fourth Decade ◽  
Ascending Aortic Replacement ◽  
Aortic Dissections

Introduction: The GenTAC Registry ( G enetically Triggered T horacic A ortic Aneurysms and Cardiovascular C onditions) followed patients with aortopathies over 8 years among 8 centers with the goal of evaluating cardiovascular outcomes. Methods: Enrollment initiated in 2007, and data were collected until 2015. We included diagnoses with >100 participants: Bicuspid aortic valve with aneurysm (BAV, n=879), Marfan syndrome (MFS, n=861), Familial thoracic aortic aneurysm or dissection (FTAAD, n=378), Other thoracic aortic aneurysm at < 50 years of age (Other<50, n=524), Turner syndrome (TS, n=298), Vascular Ehlers Danlos syndrome (VEDS, n=149), and Loeys-Dietz syndrome (LDS, n=121). We identified patients who underwent elective ascending aortic replacement, total unique dissections, and time to first dissection. With MFS as a reference population and adjusted for sex, endpoints were analyzed by a Firth penalized Cox-PH regression model to account for diagnosis groups with low event numbers. Results: LDS participants at a mean age of (24.5 ± 15.0y) were youngest at elective aortic surgery followed by MFS (32.3 ±12.3y), TS (37.6 ±13.6y), VEDS (35.0 ±SD 7.4y), Other<50 (40.3 ±SD 10.3y), FTAAD (42.9 ±14.2y), and BAV(49.4 ± 13.8 y). Dissections were reported in all diagnosis groups with a total of 472 unique dissections in 3210 patients (14%). Mean age at first dissection was in the third decade for LDS, TS, MFS, VEDS and in the fourth decade for BAV, FTAD, and Other<50. Adjusted hazard ratio for time to first dissection was higher in LDS, 1.77 (95%CI 1.14- 2.77), compared to MFS and other diagnosis groups (Figure 1). Conclusions: Reported aortic dissections were prominent in the GenTAC cohort. Despite elective surgery at a younger age, LDS patients had a higher hazard risk of dissection compared to other diagnosis groups.

Vascular Disease

2016 ◽  
pp. 129-142
Author(s):  
Robert D. McBane
Keyword(s):  
Risk Factors ◽  
Aortic Aneurysm ◽  
Vascular Disease ◽  
Thoracic Aorta ◽  
Thoracic Aortic Aneurysm ◽  
Ascending Aorta ◽  
Tobacco Exposure ◽  
Degree Relative ◽  
Men And Women ◽  
Medial Degeneration

Aneurysms of the ascending aorta are typically due to medial degeneration, whereas aneurysms of the descending thoracic aorta are primarily due to atherosclerosis. Men and women are equally affected, and the prevalence of thoracic aortic aneurysm (TAA) increases with advancing age. Overall, the incidence is approximately 1 per 10,000 individuals, and 20% of patients with TAA have at least 1 affected first-degree relative. Typical risk factors include tobacco exposure, hypertension, infection, and trauma.

scholarly journals Long Noncoding RNAs CARMN, LUCAT1, SMILR, and MALAT1 in Thoracic Aortic Aneurysm: Validation of Biomarkers in Clinical Samples

2020 ◽  
Vol 2020 ◽  
pp. 1-6 ◽  
Author(s):  
Vaiva Patamsytė ◽  
Giedrius Žukovas ◽  
Dovydas Gečys ◽  
Diana Žaliaduonytė ◽  
Povilas Jakuška ◽  
...  
Keyword(s):  
Aortic Aneurysm ◽  
Blood Plasma ◽  
Thoracic Aortic Aneurysm ◽  
Noncoding Rnas ◽  
Long Noncoding Rnas ◽  
Clinical Samples ◽  
Aortic Tissue ◽  
Relative Expression ◽  
Clinical Patient ◽  
Diagnostic Potential

Background and Objectives. Thoracic aortic aneurysm (TAA) is a silent disease characterised by aortic wall expansion and vascular smooth muscle cell (VSMC) dedifferentiation from contractile to synthetic phenotype. Long noncoding RNAs (lncRNAs) involved in VSMC phenotypic regulation could be considered as potential diagnostic indicators and therapeutic targets of TAA. In vitro studies show that lncRNAs CARMN, LUCAT1, MALAT1, and SMILR are associated with the VSMC phenotypic state. Our aim was to test if these lncRNAs are dysregulated during TAA formation in clinical patient samples. Materials and Methods. Relative expression of lncRNAs CARMN, LUCAT1, SMILR, and MALAT1 was tested in clinical aortic tissue and blood plasma samples from TAA and non-TAA patients using the qRT-PCR method. The Mann–Whitney U test was used to compare ΔCt values between the study groups. ROC curve analysis was performed to evaluate the diagnostic value of plasma lncRNAs. Results. We found significantly reduced CARMN (p=0.033) and LUCAT1 (p=0.009) expression in aortic tissue samples from TAA patients. Relative expression of MALAT1 (p=0.117) and SMILR (p=0.610) did not differ in aortic tissue between the TAA and non-TAA groups. Expression of both LUCAT1 and SMILR was significantly decreased in TAA patients’ blood plasma compared to controls (p=0.018 and p=0.032, respectively). However, only LUCAT1 showed the ability to discriminate aneurysmal disease in patients’ blood plasma (AUC=0.654, 95%CI=0.534‐0.775, p=0.018). Conclusions. We have shown that the expression of lncRNAs CARMN and LUCAT1 is reduced in dilated aortic tissue and that the LUCAT1 and SMILR expression is lower in the blood plasma of TAA patients. Decreased LUCAT1 expression in TAA patients’ blood plasma may have diagnostic potential in discriminating patients with TAA.

scholarly journals Molecular profiles and mutation burden analysis in Chinese patients with gastric carcinoma

2018 ◽  
Author(s):  
Chao Chen ◽  
Chunmei Shi ◽  
Xiaochun Huang ◽  
Jianwei Zheng ◽  
Zhongyi Zhu ◽  
...  
Keyword(s):  
Gastric Carcinoma ◽  
Chinese Patients ◽  
Strongly Correlated ◽  
Tissue Samples ◽  
Whole Exome ◽  
Formalin Fixed Paraffin ◽  
Mutation Burden ◽  
Formalin Fixed Paraffin Embedded ◽  
Molecular Profiles ◽  
Genomic Regions

AbstractThe goal of this work was to investigate the molecular profiles and mutation burden in Chinese patients with gastric carcinoma (GC). In total, we performed whole exome sequencing (WES) on 74 GC patients with tumor and adjacent normal formalin-fixed, paraffin-embedded (FFPE) tissue samples. The mutation spectrum of these samples showed a high concordance with TCGA and other studies on GC. We found the alterations of 17 DNA repair genes (including BRCA2, POLE and MSH3, etc.) were strongly correlated with the tumor mutation burden (TMB) and tumor neoantigen burden (TNB) of GC patients. Patients with mutations of these genes tend to have high TMB (median of TMB = 12.77, p=2.3e-6) and TNB (median of TNB = 5.97, p= 2.8e-3). In addition, younger GC patients (age < 60) have lower TMB (p = 0.0021) and TNB (p = 0.034) than older patients (age >= 60). Furthermore, we found a list of 18 genes and two genomic regions (1p36.21 and Xq26.3) were associated with peritoneal metastasis (PM) of GC, and patients with amplification of 1p36.21 and Xq26.3 have a worse prognosis (p=0.002, 0.01, respectively). Our analysis provides GC patients with potential markers for single and combination therapies.

M30 Expression Demonstrates Apoptotic Cells, Correlates With In Situ End-Labeling, and Is Associated With Ki-67 Expression in Large Intestinal Neoplasms

2000 ◽  
Vol 124 (12) ◽  
pp. 1768-1772 ◽  
Author(s):  
Norman John Carr
Keyword(s):  
Regression Line ◽  
Strong Positive Correlation ◽  
Strongly Correlated ◽  
Ki 67 ◽  
Formalin Fixed Paraffin ◽  
Formalin Fixed Paraffin Embedded ◽  
Secondary Objective ◽  
Formalin Fixed ◽  
Number Of Cells

Abstract Context.—The monoclonal antibody M30 recognizes a neoepitope of cytokeratin 18 produced during apoptosis. It is reactive in formalin-fixed, paraffin-embedded tissue and has great potential in the study of apoptosis in clinical and experimental material. Objectives.—To compare the results of M30 immunoexpression with a more established technique of demonstrating apoptosis in tissue sections, in situ end-labeling. A secondary objective was to compare the results with immunoexpression of the proliferation-associated antigen Ki-67. Design.—Retrospective analysis of adenomas and adenocarcinomas of the large intestine. Interventions.—Immunohistochemistry for M30 and Ki-67, and in situ end-labeling. Formalin-fixed, paraffin-embedded tissue was used. Main Outcome Measures.—The number of cells positive for M30, Ki-67, and in situ end-labeling, expressed as a proportion of the total number of cells counted. Results.—A strong positive correlation was found between in situ end-labeling and expression of M30, although the counts were widely scattered around the regression line. Counts of Ki-67 were strongly correlated with both M30 expression and in situ end-labeling. Immunoexpression of M30 was generally easier to interpret than in situ end-labeling, and the procedures for M30 immunohistochemistry were technically less exacting. Conclusion.—These findings support the application of M30 immunoreactivity in the study of apoptosis.

Abstract 4280: Combination of Doxycycline and Losartan is an Effective Secondary Prevention Treatment for the Thoracic Aortic Aneurysm in Marfan Syndrome

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Hh C Yang ◽  
Cornelis van Breemen ◽  
Ada Chung
Keyword(s):  
Aortic Aneurysm ◽  
Secondary Prevention ◽  
Marfan Syndrome ◽  
Thoracic Aortic Aneurysm ◽  
Combined Treatment ◽  
Elastic Fiber ◽  
Specific Inhibitor ◽  
Untreated Group ◽  
Vasomotor Function ◽  
Aortic Media

Losartan, an antihypertensive drug, has been shown to prevent thoracic aortic aneurysm (TAA) in Marfan syndrome (MFS) through the inhibition of transforming growth factor (TGF)-β. Recently we have suggested doxycycline, a non-specific inhibitor of matrix metalloproteinases (MMPs), suppressed aneurysm and normalized vasomotor function in TA. We hypothesized that a combination of doxycycline and losartan could be effective in the secondary prevention to ameliorate TAA in MFS. A well-defined mouse model of Marfan syndrome (Fbn1 C1039G/+ ) were untreated (n=20), given doxycycline (0.24g/L, n=15), losartan (0.6g/L, n=15), or doxycycline+losartan (0.12g/L+0.3g/L, respectively, n=15) from drinking water at the age of 4 months. The littermate Fbn1 +/+ mice served as control (n=20). Ascending thoracic aortae from each group at 9 months were studied. Mortality (2%) and TAA (increase in diameter by >35%) were observed in the untreated group. Mild aneurysm (diameter of aorta was increased by 15% compared with controls) was evident in either losartan-or doxycycline-groups, but TAA was prevented by the combined treatment. From the aortic media of untreated, losartan- and doxcycline-groups, elastic fiber degeneration shown on Movat’s histology was pronounced, which accompanied with increased aortic stiffness. Combined treatment attenuated elastic fiber degradation and normalized the aortic elasticity to the control levels. The impairment of smooth muscle contraction and endothelial-dependent relaxation in the untreated group were also completely normalized by the combined treatment. Either losartan- or doxcycline-groups improved aortic contractility by 75% compared with the untreated, but was not effective in improving endothelium-dependent relaxation. Combined treatment reduced activities of MMP-2 and -9 in the aortic media by 60 – 80%, and activation of TGF-β by 70%. Delayed treatment reduced effectiveness of both losartan and doxycycline in the prevention of TAA. Combination of doxycycline and losartan is effective in the secondary prevention to preserve elastic fiber integrity and normalize vasomotor function, indicating that both MMP and TGF-β are crucial mediators in TAA formation in MFS.

scholarly journals MiR-574-5p: A Circulating Marker of Thoracic Aortic Aneurysm

2019 ◽  
Vol 20 (16) ◽  
pp. 3924 ◽  
Author(s):  
Boileau ◽  
Cardenas ◽  
Courtois ◽  
Zhang ◽  
Rodosthenous ◽  
...  
Keyword(s):  
Aortic Aneurysm ◽  
Extracellular Vesicles ◽  
Thoracic Aortic Aneurysm ◽  
Characteristic Curve ◽  
Serum Levels ◽  
Aortic Tissue ◽  
Wild Type ◽  
Serum Samples ◽  
Tissue Samples ◽  
Aortic Media

Thoracic aortic aneurysm (TAA) can lead to fatal complications such as aortic dissection. Since aneurysm dimension poorly predicts dissection risk, microRNAs (miRNAs) may be useful to diagnose or risk stratify TAA patients. We aim to identify miRNAs associated with TAA pathogenesis and that are possibly able to improve TAA diagnosis. MiRNA microarray experiments of aortic media tissue samples from 19 TAA patients and 19 controls allowed identifying 232 differentially expressed miRNAs. Using interaction networks between these miRNAs and 690 genes associated with TAA, we identified miR-574-5p as a potential contributor of TAA pathogenesis. Interestingly, miR-574-5p was significantly down-regulated in the TAA tissue compared to the controls, but was up-regulated in serum samples from a separate group of 28 TAA patients compared to 20 controls (p < 0.001). MiR-574-5p serum levels discriminated TAA patients from controls with an area under the receiver operating characteristic curve of 0.87. In the Fbn1C1041G/+ mouse model, miR-574-5p was down-regulated in aortic tissue compared to wild-type (p < 0.05), and up-regulated in plasma extracellular vesicles from Fbn1C1041G/+ mice compared to wild-type mice (p < 0.05). Furthermore, in vascular smooth muscle cells, angiotensin II appears to induce miR-574-5p secretion in extracellular vesicles. In conclusion, miR-574-5p is associated with TAA pathogenesis and may help in diagnosing this disease.

scholarly journals Cyclophilin A/EMMPRIN Axis Is Involved in Pro-Fibrotic Processes Associated with Thoracic Aortic Aneurysm of Marfan Syndrome Patients

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 154 ◽  
Author(s):  
Gianluca L. Perrucci ◽  
Erica Rurali ◽  
Maria Corlianò ◽  
Maria Balzo ◽  
Michela Piccoli ◽  
...  
Keyword(s):  
Aortic Aneurysm ◽  
Marfan Syndrome ◽  
Thoracic Aortic Aneurysm ◽  
Cyclophilin A ◽  
Aortic Tissue ◽  
Tissue Samples ◽  
Abdominal Aortic ◽  
Tgf Β1 ◽  
In Vitro Treatment

Background: Marfan syndrome (MFS) is a genetic disease, characterized by thoracic aortic aneurysm (TAA), which treatment is to date purely surgical. Understanding of novel molecular targets is mandatory to unveil effective pharmacological approaches. Cyclophilin A (CyPA) and its receptor EMMPRIN are associated with several cardiovascular diseases, including abdominal aortic aneurysm. Here, we envisioned the contribution of CyPA/EMMPRIN axis in MFS-related TAA. Methods: We obtained thoracic aortic samples from healthy controls (HC) and MFS patients’ aortas and then isolated vascular smooth muscle cells (VSMC) from the aortic wall. Results: our findings revealed that MFS aortic tissue samples isolated from the dilated zone of aorta showed higher expression levels of EMMPRIN vs. MFS non-dilated aorta and HC. Interestingly, angiotensin II significantly stimulated CyPA secretion in MFS-derived VSMC (MFS-VSMC). CyPA treatment on MFS-VSMC led to increased levels of EMMPRIN and other MFS-associated pro-fibrotic mediators, such as TGF-β1 and collagen I. These molecules were downregulated by in vitro treatment with CyPA inhibitor MM284. Our results suggest that CyPA/EMMPRIN axis is involved in MFS-related TAA development, since EMMPRIN is upregulated in the dilated zone of MFS patients’ TAA and the inhibition of its ligand, CyPA, downregulated EMMPRIN and MFS-related markers in MFS-VSMC. Conclusions: these insights suggest both a novel detrimental role for CyPA/EMMPRIN axis and its inhibition as a potential therapeutic strategy for MFS-related TAA treatment.

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