scholarly journals ACE2 Expression in Lungs of Severe COVID-19 Infection: A Study on Minimally Invasive Post- mortem Tissue Samples

2021 ◽  
Author(s):  
Atish Gheware ◽  
Animesh Ray ◽  
Deeksha Rana ◽  
Prashant Bajpai ◽  
Aruna Nambirajan ◽  
...  
Keyword(s):  
Protein Expression ◽  
Virus Disease ◽  
Diffuse Alveolar Damage ◽  
Severe Infection ◽  
Host Protein ◽  
Post Mortem ◽  
Tissue Samples ◽  
Expression Levels ◽  
Increased Risk ◽  
Lung Biopsies

Abstract Angiotensin-converting enzyme 2 (ACE2) is a key host protein by which severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) enters and multiplies within cells. The level of ACE2 expression in the lung is hypothesised to correlate with an increased risk of severe infection and complications in COVID-19 (COrona VIrus Disease 2019). To test this hypothesis, we compared the protein expression status of ACE2 by immunohistochemistry (IHC) in post-mortem lung samples of patients who died of severe COVID-19 and lung samples obtained from non-COVID-9 patients for other indications. IHC for CD61 and CD163 were performed for assessment of platelet-rich microthrombi and macrophages, respectively. IHC for SARS-CoV-2 viral antigen was also performed. Quantification of immunostaining, random sampling, and correlation analysis was used to substantiate the morphologic findings. Our results show that among a total of 44 COVID-19 post-mortem lung tissues and 15 lung biopsies in non-COVID-19 patients included, ACE2 protein expression was significantly higher in COVID-19 patients than in controls, regardless of sample size. Histomorphology in COVID-19 lungs showed diffuse alveolar damage (DAD), acute bronchopneumonia, and acute lung injury with SARS-CoV-2 viral protein detected in a subset of cases. ACE2 expression levels positively correlated with increased expression levels of CD61 and CD163. In conclusion, our results show significantly higher ACE2 protein expression in severe COVID-19 disease, correlating with increased macrophage infiltration and microthrombi, suggesting a pathobiological role in disease severity.

scholarly journals Determination of CYP450 Expression Levels in the Human Small Intestine by Mass Spectrometry-Based Targeted Proteomics

2021 ◽  
Vol 22 (23) ◽  
pp. 12791
Author(s):  
Alexia Grangeon ◽  
Valérie Clermont ◽  
Azemi Barama ◽  
Fleur Gaudette ◽  
Jacques Turgeon ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Small Intestine ◽  
Protein Expression ◽  
Mrna Levels ◽  
Targeted Proteomics ◽  
Tissue Samples ◽  
Human Organ ◽  
Expression Levels ◽  
Protein Levels ◽  
Human Small Intestine

The human small intestine can be involved in the first-pass metabolism of drugs. Under this condition, members of the CYP450 superfamily are expected to contribute to drug presystemic biotransformation. The aim of this study was to quantify protein expression levels of 16 major CYP450 isoforms in tissue obtained from nine human organ donors in seven subsections of the small intestine, i.e., duodenum (one section, N = 7 tissue samples), jejunum (three subsections (proximal, mid and distal), N = 9 tissue samples) and ileum (three subsections, (proximal, mid and distal), N = 9 tissue samples), using liquid chromatography tandem mass spectrometry (LC-MS/MS) based targeted proteomics. CYP450 absolute protein expression levels were compared to mRNA levels and enzyme activities by using established probe drugs. Proteins corresponding to seven of sixteen potential CYP450 isoforms were detected and quantified in various sections of the small intestine: CYP2C9, CYP2C19, CYP2D6, CYP2J2, CYP3A4, CYP3A5 and CYP4F2. Wide inter-subject variability was observed, especially for CYP2D6. CYP2C9 (p = 0.004) and CYP2C19 (p = 0.005) expression levels decreased along the small intestine. From the duodenum to the ileum, CYP2J2 (p = 0.001) increased, and a trend was observed for CYP3A5 (p = 0.13). CYP3A4 expression was higher in the jejunum than in the ileum (p = 0.03), while CYP4F2 expression was lower in the duodenum compared to the jejunum and the ileum (p = 0.005). CYP450 protein levels were better correlated with specific isoform activities than with mRNA levels. This study provides new data on absolute CYP450 quantification in human small intestine that could improve physiologically based pharmacokinetic models. These data could better inform drug absorption profiles while considering the regional expression of CYP450 isoforms.

scholarly journals Activation of JAK2/STAT5 Pathway Reduces Expression Level of DNMT3a in MPN Cell Line

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5394-5394
Author(s):  
Jie Zhou ◽  
Aibin Liang ◽  
Shaoguang Li ◽  
Wenjun Zhang ◽  
Jianfei FU
Keyword(s):  
Protein Expression ◽  
Cell Line ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Expression Level ◽  
Hematopoietic Stem ◽  
Expression Levels ◽  
Increased Risk

Introduction: Myeloproliferative neoplasms (MPN) are clonal hematopoietic stem cell (HSC) disorders characterized by overproduction of mature blood cells and increased risk of transformation to acute myeloid leukemia (AML), and JAK2V167F is the most frequent MPN driving mutation detected in >95% of PV and 50-60% ET and PMF. DNMT3A is a de novo DNA methyltransferase that catalyzes the addition of methyl groups into active chromatin in CpG-rich regions leading to gene inactivation. Dnmt3a-/- HSC have enhanced self-renewal and a block in differentiation in vivo. Previous study showed that JAK2V617F and Dnmt3a loss cooperate to induce myelofibrosis through activated enhancer-driven inflammation, while whether JAK2V617F regulates DNMT3a still remains unclear. AZ960 is a potent and selective ATP competitive inhibitor of the JAK2 kinase, and previous studies reported that AZ960 possessed the activity selectively against JAK2. LY2784544 has been identified as a selective inhibitor of JAK2V617F and has undergone clinical trials for the treatment of several myeloproliferative disorders. Methods: Empty vector (control) and mutant JAK2V617F were transduced into BaF3 cells using a lentivirus system. JAK2V617F-expressing BaF3 cells grow IL-3 independent and were selected by fluorescence-activated cell sorting (FACS) for GFP expression. The protein expression levels of p-STAT5 and DNMT3a were detected by western blotting. JAK2V617F-expressing and control BaF3 cells were incubated with gradient concentration of LY2784544 or AZ960 to inhibit JAK2/STAT5 pathway. Results: The expression levels of p-STAT5 were obviously up-regulated in the JAK2V617F-expressing BaF3 cells, and DNMT3a was down-regulated. After 1-hour incubation in the serial diluted LY2784544, p-STAT5 were reduced in JAK2V617F-expressing BaF3 cells, with expression of DNMT3a elevated. To further confirm the correlation between JAK2/STAT5 pathway and expression of DNMT3a, another JAK2 inhibitor AZ960 was tested similar to LY2784544. With p-STAT5 expression suppressed, protein level of DNMT3a showed significantly promotion. Conclusion: We observed that JAK2V167F mutation suppresses protein expression levels of DNMT3a in MPN cell lines. JAK2 inhibition by AZ960 and LY2784544 significantly improved expression levels of DNMT3a. The activation of JAK2/STAT5 pathway reduces expression level of DNMT3a in MPN cell line, and the specific mechanism still needs to be explored. Figure Disclosures No relevant conflicts of interest to declare.

scholarly journals Circadian PERformance in breast cancer: a germline and somatic genetic study of PER3VNTR polymorphisms and gene co-expression

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Jaume Fores-Martos ◽  
Raimundo Cervera-Vidal ◽  
Julia Sierra-Roca ◽  
Carlos Lozano-Asencio ◽  
Vita Fedele ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Variable Number ◽  
Luminal A ◽  
Tissue Samples ◽  
Free Survival ◽  
Expression Levels ◽  
Cancer Subtypes ◽  
Increased Risk ◽  
Combined Data

AbstractPolymorphisms in the PER3 gene have been associated with several human disease phenotypes, including sleep disorders and cancer. In particular, the long allele of a variable number of tandem repeat (VNTR) polymorphism has been previously linked to an increased risk of breast cancer. Here we carried out a combined germline and somatic genetic analysis of the role of the PER3VNRT polymorphism in breast cancer. The combined data from 8284 individuals showed a non-significant trend towards increased breast cancer risk in the 5-repeat allele homozygous carriers (OR = 1.17, 95% CI: 0.97–1.42). We observed allelic imbalance at the PER3 locus in matched blood and tumor DNA samples, showing a significant retention of the long variant (risk) allele in tumor samples, and a preferential loss of the short repetition allele (p = 0.0005). Gene co-expression analysis in healthy and tumoral breast tissue samples uncovered significant associations between PER3 expression levels with those from genes which belong to several cancer-associated pathways. Finally, relapse-free survival (RFS) analysis showed that low expression levels of PER3 were linked to a significant lower RSF in luminal A (p = 3 × 10−12) but not in the rest of breast cancer subtypes.

scholarly journals High FREM2 Gene and Protein Expression Are Associated with Favorable Prognosis of IDH-WT Glioblastomas

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1060 ◽  
Author(s):  
Ivana Jovčevska ◽  
Alja Zottel ◽  
Neja Šamec ◽  
Jernej Mlakar ◽  
Maxim Sorokin ◽  
...  
Keyword(s):  
Protein Expression ◽  
The Cancer Genome Atlas ◽  
World Health ◽  
Low Grade ◽  
Lower Grade ◽  
Tissue Samples ◽  
Expression Levels ◽  
Favorable Prognosis ◽  
Gene And Protein Expression ◽  
Reference Samples

World Health Organization grade IV diffuse gliomas, known as glioblastomas, are the most common malignant brain tumors, and they show poor prognosis. Multimodal treatment of surgery followed by radiation and chemotherapy is not sufficient to increase patient survival, which is 12 to 18 months after diagnosis. Despite extensive research, patient life expectancy has not significantly improved over the last decade. Previously, we identified FREM2 and SPRY1 as genes with differential expression in glioblastoma cell lines compared to nonmalignant astrocytes. In addition, the FREM2 and SPRY1 proteins show specific localization on the surface of glioblastoma cells. In this study, we explored the roles of the FREM2 and SPRY1 genes and their proteins in glioblastoma pathology using human tissue samples. We used proteomic, transcriptomic, and bioinformatics approaches to detect changes at different molecular levels. We demonstrate increased FREM2 protein expression levels in glioblastomas compared to reference samples. At the transcriptomic level, both FREM2 and SPRY1 show increased expression in tissue samples of different glioma grades compared to nonmalignant brain tissue. To broaden our experimental findings, we analyzed The Cancer Genome Atlas glioblastoma patient datasets. We discovered higher FREM2 and SPRY1 gene expression levels in glioblastomas compared to lower grade gliomas and reference samples. In addition, we observed that low FREM2 expression was associated with progression of IDH-mutant low-grade glioma patients. Multivariate analysis showed positive association between FREM2 and favorable prognosis of IDH-wild type glioblastoma. We conclude that FREM2 has an important role in malignant progression of glioblastoma, and we suggest deeper analysis to determine its involvement in glioblastoma pathology.

scholarly journals Postmortem Biopsies of the Lung, Heart, Liver, and Spleen of COVID-19 Patients

2021 ◽  
Author(s):  
Isil Yurdaisik ◽  
Ahu Senem Demiroz ◽  
Aysim Buge Oz ◽  
Mustafa Akker ◽  
Ayse Gul Agirman ◽  
...  
Keyword(s):  
Histopathological Examination ◽  
Diffuse Alveolar Damage ◽  
Case Series ◽  
Neutrophil Infiltration ◽  
Underlying Disease ◽  
Heart Tissue ◽  
Ct Images ◽  
Tissue Samples ◽  
Tissue Acquisition ◽  
Lung Biopsies

Objective: We aimed to evaluate histopathologic alterations in the lung, heart, liver, and spleen of coronavirus disease 2019 (COVID-19) decedents through postmortem core needle biopsies. Materials and Methods: Patients who died of reverse transcription-polymerase chain reaction-proven COVID-19 were included in this postmortem case series. Postmortem percutaneous ultrasound-guided biopsies using 14- and 16-gauge needles were performed in the lungs, heart, liver, and spleen. Biopsy samples were stained with hematoxylin-eosin and examined under a light microscope. Clinicodemographic characteristics, chest computed tomography (CT) images, and COVID-19-related treatments of the patients were also collected. Results: Seven patients were included in this study. Liver and heart tissue samples were available from all patients, and lung and spleen tissues were available from five and three patients, respectively. Chest CT images predominantly revealed bibasilar ground-glass opacities. Lung biopsies showed diffuse alveolar damage in all biopsy specimens. Heart findings were nonspecific and largely compatible with the underlying disease. Patchy necrosis, steatosis, and mononuclear cellular infiltration were the main findings in the liver biopsies. Splenic histopathological examination showed that splenic necrosis and neutrophil infiltration were the common findings in all patients. Conclusion: Tissue acquisition was complete for the heart and liver and acceptable for lungs. The amount of tissue was sufficient for a proper histopathologic examination. The histopathological findings were generally in accordance with previous autopsy studies. The lung radiological findings were also correlated with the histopathologic findings. We consider that a postmortem biopsy is a feasible alternative for histopathological examinations in COVID-19 decedents.

scholarly journals PDE4 and Epac1 Synergistically Promote Rectal Carcinoma via the cAMP Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-5 ◽  
Author(s):  
Xiangyu Kong ◽  
Ganghao Ai ◽  
Dai Wang ◽  
Renzhen Chen ◽  
Dongbei Guo ◽  
...  
Keyword(s):  
Protein Expression ◽  
Rectal Carcinoma ◽  
Connexin 43 ◽  
Synergistic Effects ◽  
Tissue Samples ◽  
Expression Levels ◽  
Cyclin E1 ◽  
Positive Rate ◽  
Tissue Specimens ◽  
Degree Of Differentiation

Objective. To assess the expression levels of exchange protein 1 directly activated by cAMP (Epac1) and phosphodiesterase 4 (PDE4) in rectal carcinoma, and their associations with clinicopathological indexes. In addition, the associations of PDE4 and Epac1 with A-kinase anchor protein 95, connexin 43, cyclin D1, and cyclin E1 were evaluated. Methods. The PV-9000 two-step immunohistochemistry method was used to determine protein expression in 44 rectal carcinoma tissue samples and 16 paracarcinoma tissue specimens. Results. The positive rate of PDE4 protein expression in rectal carcinoma tissues was higher than that of paracarcinoma tissues (59.09% vs. 12.5%, P<0.05). Similar findings were obtained for Epac1 (55% vs. 6.25%, P<0.05). No significant associations of PDE4 and Epac1 with degree of differentiation, histological type, and lymph node metastasis were found in rectal carcinoma (P>0.05). Correlations between PDE4 and Epac1, PDE4 and Cx43, PDE4 and cyclin E1, and Epac1 and Cx43 were observed (all P<0.05). There was no correlation between the other protein pairs examined (P>0.05). Conclusion. PDE4 and Epac1 expression levels are increased in rectal carcinoma tissues, suggesting that the two proteins may be involved in the development of this malignancy. Meanwhile, correlations between PDE4 and Epac1, PDE4 and Cx43, PDE4 and cyclin E1, and Epac1 and Cx43 suggested synergistic effects of these proteins in promoting rectal carcinoma.

scholarly journals Coronavirus Disease 2019 (COVID‐19) Pandemic Implications in Pediatric and Adult Congenital Heart Disease

2020 ◽  
Vol 9 (12) ◽  
Author(s):  
Tarek Alsaied ◽  
Jamil A. Aboulhosn ◽  
Timothy B. Cotts ◽  
Curt J. Daniels ◽  
Susan P. Etheridge ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Congenital Heart ◽  
Virus Disease ◽  
Health Care Systems ◽  
Adult Congenital Heart Disease ◽  
Adult Population ◽  
Severe Infection ◽  
Corona Virus ◽  
Increased Risk

Abstract The corona virus disease ‐2019 (COVID‐19) is a recently described infectious disease caused by the severe acute respiratory syndrome corona virus 2 with significant cardiovascular implications. Given the increased risk for severe COVID‐19 observed in adults with underlying cardiac involvement, there is concern that patients with pediatric and congenital heart disease (CHD) may likewise be at increased risk for severe infection. The cardiac manifestations of COVID‐19 include myocarditis, arrhythmia and myocardial infarction. Importantly, the pandemic has stretched health care systems and many care team members are at risk for contracting and possibly transmitting the disease which may further impact the care of patients with cardiovascular disease. In this review, we describe the effects of COVID‐19 in the pediatric and young adult population and review the cardiovascular involvement in COVID‐19 focusing on implications for patients with congenital heart disease in particular.

scholarly journals Expression and clinical significance of miR-3615 in hepatocellular carcinoma

2021 ◽  
Vol 49 (1) ◽  
pp. 030006052098154
Author(s):  
Xin Yuan ◽  
Yize Zhang ◽  
Zujiang Yu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Survival Curve ◽  
Clinicopathological Characteristics ◽  
The Cancer Genome Atlas ◽  
Prognostic Information ◽  
Ki 67 ◽  
Tissue Samples ◽  
Expression Levels ◽  
Kaplan Meier ◽  
Serum Alpha Fetoprotein

Objective To investigate the association between microRNA-3615 (miR-3615) expression and the prognosis and clinicopathological features in patients with hepatocellular carcinoma (HCC). Methods We obtained clinicopathological and genomic data and prognostic information on HCC patients from The Cancer Genome Atlas (TCGA) database. We then analyzed differences in miR-3615 expression levels between HCC and adjacent tissues using SPSS software, and examined the relationships between miR-3615 expression levels and clinicopathological characteristics. We also explored the influence of miR-3615 expression levels on the prognosis of HCC patients using Kaplan–Meier survival curve analysis. Results Based on data for 345 HCC and 50 adjacent normal tissue samples, expression levels of miR-3615 were significantly higher in HCC tissues compared with adjacent tissues. MiR-3615 expression levels in HCC patients were negatively correlated with overall survival time and positively correlated with high TNM stage, serum Ki-67 expression level, and serum alpha-fetoprotein level. There were no significant correlations between miR-3615 expression and age, sex, and pathological grade. Conclusion MiR-3615 may be a promising new biomarker and prognostic factor for HCC.

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