scholarly journals O-L04 Peri-operative thrombophilia in patients undergoing liver resection for colorectal metastases

2021 ◽  
Vol 108 (Supplement_9) ◽  
Author(s):  
Caoimhe Walsh ◽  
Fenella Welsh ◽  
Wasula Rathnaweera ◽  
Kandiah Chandrakumaran ◽  
Ashok Roy ◽  
...  
Keyword(s):  
Liver Resection ◽  
Perceived Risk ◽  
Mononuclear Cells ◽  
Quantitative Polymerase Chain Reaction ◽  
Major Haemorrhage ◽  
Colorectal Metastases ◽  
Peripheral Blood Mononuclear ◽  
Homogeneous Population ◽  
Messenger Ribonucleic Acid ◽  
The Impact

Abstract Background The risk of major haemorrhage during liver surgery has decreased considerably in the modern era. However, there remains reluctance amongst liver surgeons to give routine peri-operative chemical thromboprophylaxis, either because of the perceived risk of bleeding, or transient post-operative abnormalities in conventional coagulation studies. The aim of this study was to ask whether a defined, homogeneous population of patients undergoing liver resection for colorectal metastases (CRM) were at risk from venous thromboembolism (VTE) prior to surgery, and what the impact of liver resection was on that risk. Methods A single-centre prospective observational cohort study comparing pre-, peri- and post-operative haemostasis variables in patients undergoing liver resection for CRM. Patients with cirrhosis, history of VTE or anticoagulated were excluded, as were patients undergoing small wedge, or laparoscopic liver resections. Blood samples for coagulation assays were collected pre-operatively, peri-operatively (after transection) and first post-operative day (13–20 hours post-operatively). Pre- and post-operative Tissue Factor messenger ribonucleic acid (TFmRNA) activation was measured from peripheral blood mononuclear cells (PBMCs) using semi-quantitative polymerase chain reaction (PCR). Patients received peri-operative mechanical thromboprophylaxis until mobile, plus chemical thromboprophylaxis on the first post-operative day, after venesection. Results Of 336 hepatectomies performed October 2017-December 2019, 60 resections in 57 patients were recruited. This included 46.7% major resections, with median (interquartile range [IQR]) blood loss 150.0mls (76.3-263.7), no blood transfusions, post-operative VTE events or deaths. Patients were prothrombotic pre-operatively (high factor VIIIC and thrombin generation velocity index), an effect exacerbated post-hepatectomy. Major hepatectomies had a significantly greater drop in Protein C, rise in Factor VIIIC and von Willebrand Factor, versus minor resections (p = 0.001,0.005,0.001 respectively). Patients with transection times greater than median (40minutes), had significantly increased median (IQR) PMBC-TFmRNA expression [1.65 (0.93-2.70)2ddCt], versus quicker transections [0.99 (0.69-1.28)2ddCt, p = 0.020]. Conclusions These data show the risk of major haemorrhage in elective liver resection in a high volume unit is low and administration of chemical thromboprophylaxis within 13-20 hours of surgery is safe and effective. The study demonstrates that patients with CRM are prothrombotic pre-operatively. Furthermore, this thrombophilia is exacerbated by liver resection, and most marked in patients with longer, more complex operations. These data suggest that chemical thromboprophylaxis should be considered earlier in the patient pathway, and has resulted in a change in practice for the authors.

scholarly journals Regulation of CTLA-4 and PD-L1 Expression in Relapsing-Remitting Multiple Sclerosis Patients after Treatment with Fingolimod, IFNβ-1α, Glatiramer Acetate, and Dimethyl Fumarate Drugs

2021 ◽  
Vol 11 (8) ◽  
pp. 721
Author(s):  
Afshin Derakhshani ◽  
Zahra Asadzadeh ◽  
Hossein Safarpour ◽  
Patrizia Leone ◽  
Mahdi Abdoli Shadbad ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Mononuclear Cells ◽  
Demyelinating Disease ◽  
Immune Checkpoints ◽  
Peripheral Blood Mononuclear ◽  
Relapsing Remitting ◽  
Remitting Multiple Sclerosis ◽  
Multiple Sclerosis Patients ◽  
Relapsing Remitting Multiple Sclerosis ◽  
The Impact

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) that is characterized by inflammation which typically results in significant impairment in most patients. Immune checkpoints act as co-stimulatory and co-inhibitory molecules and play a fundamental role in keeping the equilibrium of the immune system. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) and Programmed death-ligand 1 (PD-L1), as inhibitory immune checkpoints, participate in terminating the development of numerous autoimmune diseases, including MS. We assessed the CTLA-4 and PD-L1 gene expression in the different cell types of peripheral blood mononuclear cells of MS patients using single-cell RNA-seq data. Additionally, this study outlines how CTLA-4 and PD-L1 expression was altered in the PBMC samples of relapsing-remitting multiple sclerosis (RRMS) patients compared to the healthy group. Finally, it investigates the impact of various MS-related treatments in the CTLA-4 and PD-L1 expression to restrain autoreactive T cells and stop the development of MS autoimmunity.

scholarly journals Peripheral Blood Gene Expression and IgG Glycosylation Profiles as Markers of Tocilizumab Treatment in Rheumatoid Arthritis

2012 ◽  
Vol 39 (5) ◽  
pp. 916-928 ◽  
Author(s):  
BERTALAN MESKO ◽  
SZILARD POLISKA ◽  
SZILVIA SZAMOSI ◽  
ZOLTAN SZEKANECZ ◽  
JANOS PODANI ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Peripheral Blood ◽  
Multiple Testing ◽  
Mononuclear Cells ◽  
Expression Profiles ◽  
Quantitative Polymerase Chain Reaction ◽  
Response To Treatment ◽  
Peripheral Blood Mononuclear ◽  
Gene Sets

Objective.Tocilizumab, a humanized anti-interleukin-6 receptor monoclonal antibody, has recently been approved as a biological therapy for rheumatoid arthritis (RA) and other diseases. It is not known if there are characteristic changes in gene expression and immunoglobulin G glycosylation during therapy or in response to treatment.Methods.Global gene expression profiles from peripheral blood mononuclear cells of 13 patients with RA and active disease at Week 0 (baseline) and Week 4 following treatment were obtained together with clinical measures, serum cytokine levels using ELISA, and the degree of galactosylation of the IgG N-glycan chains. Gene sets separating responders and nonresponders were tested using canonical variates analysis. This approach also revealed important gene groups and pathways that differentiate responders from nonresponders.Results.Fifty-nine genes showed significant differences between baseline and Week 4 and thus correlated with treatment. Significantly, 4 genes determined responders after correction for multiple testing. Ten of the 12 genes with the most significant changes were validated using real-time quantitative polymerase chain reaction. An increase in the terminal galactose content of N-linked glycans of IgG was observed in responders versus nonresponders, as well as in treated samples versus samples obtained at baseline.Conclusion.As a preliminary report, gene expression changes as a result of tocilizumab therapy in RA were examined, and gene sets discriminating between responders and nonresponders were found and validated. A significant increase in the degree of galactosylation of IgG N-glycans in patients with RA treated with tocilizumab was documented.

Carfilzomib can induce tumor cell death through selective inhibition of the chymotrypsin-like activity of the proteasome

Blood ◽  
2009 ◽  
Vol 114 (16) ◽  
pp. 3439-3447 ◽  
Author(s):  
Francesco Parlati ◽  
Susan J. Lee ◽  
Monette Aujay ◽  
Erika Suzuki ◽  
Konstantin Levitsky ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Mononuclear Cells ◽  
Proteasome Inhibitors ◽  
Selective Inhibition ◽  
Tumor Cell Death ◽  
Clinical Safety ◽  
Peripheral Blood Mononuclear ◽  
Non Hodgkin Lymphoma ◽  
Proteasome Subunits ◽  
The Impact

Abstract Carfilzomib is a proteasome inhibitor in clinical development that primarily targets the chymotrypsin-like (CT-L) subunits in both the constitutive proteasome (c20S) and the immunoproteasome (i20S). To investigate the impact of inhibiting the CT-L activity with carfilzomib, we set out to quantitate the levels of CT-L subunits β5 from the c20S and LMP7 from the i20S in normal and malignant hematopoietic cells. We found that the i20S is a major form of the proteasome expressed in cells of hematopoietic origin, including multiple myeloma (MM) CD138+ tumor cells. Although specific inhibition of either LMP7 or β5 alone was insufficient to produce an antitumor response, inhibition of all proteasome subunits was cytotoxic to both hematologic tumor cells and peripheral blood mononuclear cells. However, selective inhibition of both β5 and LMP7 was sufficient to induce an antitumor effect in MM, non-Hodgkin lymphoma, and leukemia cells while minimizing the toxicity toward nontransformed cells. In MM tumor cells, CT-L inhibition alone was sufficient to induce proapoptotic sequelae, including proteasome substrate accumulation, Noxa and caspase 3/7 induction, and phospho-eIF2α suppression. These data support a hypothesis that hematologic tumor cells are uniquely sensitive to CT-L inhibition and provide a mechanistic understanding of the clinical safety profile and antitumor activity of proteasome inhibitors.

scholarly journals Decreased levels of miR-28-5p and miR-361-3p and increased levels of insulin-like growth factor 1 mRNA in mononuclear cells from patients with hereditary hemorrhagic telangiectasia

2019 ◽  
Vol 97 (6) ◽  
pp. 562-569 ◽  
Author(s):  
Anthony Cannavicci ◽  
Qiuwang Zhang ◽  
Si-Cheng Dai ◽  
Marie E. Faughnan ◽  
Michael J.B. Kutryk
Keyword(s):  
Growth Factor ◽  
Peripheral Blood ◽  
Hereditary Hemorrhagic Telangiectasia ◽  
Mononuclear Cells ◽  
Quantitative Polymerase Chain Reaction ◽  
Clinical Manifestations ◽  
Mrna Levels ◽  
Insulin Like Growth Factor ◽  
Peripheral Blood Mononuclear ◽  
Micro Rnas

Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular disorder inherited in an autosomal dominant manner. Patients with HHT can develop vascular dysplasias called telangiectasias and arteriovenous malformations (AVMs). Our objective was to profile and characterize micro-RNAs (miRNAs), short noncoding RNAs that regulate gene expression posttranscriptionally, in HHT patient-derived peripheral blood mononuclear cells (PBMCs). PBMCs, comprised mostly of lymphocytes and monocytes, have been reported to be dysfunctional in HHT. A total of 40 clinically confirmed HHT patients and 22 controls were enrolled in this study. PBMCs were isolated from 16 mL of peripheral blood and purified for total RNA. MiRNA expression profiling was conducted with a human miRNA array analysis. Select dysregulated miRNAs and miRNA targets were validated with reverse transcription–quantitative polymerase chain reaction. Of the 377 miRNAs screened, 41 dysregulated miRNAs were identified. Both miR-28-5p and miR-361-3p, known to target insulin-like growth factor 1 (IGF1), a potent angiogenic growth factor, were found to be significantly downregulated in HHT patients. Consequently, IGF1 mRNA levels were found to be significantly elevated. Our research successfully identified miRNA dysregulation and elevated IGF1 mRNA levels in PBMCs from HHT patients. This novel discovery represents a potential pathogenic mechanism that could be targeted to alleviate clinical manifestations of HHT.

scholarly journals 2109

2017 ◽  
Vol 1 (S1) ◽  
pp. 1-1
Author(s):  
Stephanie Davis ◽  
Jeffrey Huang
Keyword(s):  
Mononuclear Cells ◽  
Age Of Onset ◽  
Quantitative Polymerase Chain Reaction ◽  
Study Groups ◽  
Interleukin 4 ◽  
Enzyme Linked Immunosorbent Assay ◽  
Peripheral Blood Mononuclear ◽  
Repair Capacity ◽  
Relapsing Remitting ◽  
Inflammatory Profile

OBJECTIVES/SPECIFIC AIMS: The overall objective of this proposal is to establish and modulate the inflammatory profile of individuals across the spectrum of multiple sclerosis (MS), with a focus on determining the potential of interleukin 4-induced protein 1 (IL4I1) as a possible marker of progression and modulator of inflammation in human blood samples. METHODS/STUDY POPULATION: The proposed experimental approach involves isolating plasma and peripheral blood mononuclear cells (PBMCs) from individuals across the spectrum of MS phenotypes, and analyzing these samples primarily by quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA) methods. Specifically, study groups include: (1) actively relapsing-remitting MS (a-RRMS), (2) non-actively relapsing-remitting MS (n-RRMS), (3) non-active secondary-progressive MS (SPMS), (4) other autoimmune diseases (OAD), (5) healthy controls (HC). RESULTS/ANTICIPATED RESULTS: We expect that IL4I1 treatment increases regulatory cytokine (eg, IL10, TGFb) expression while decreasing Th1 and Th17-derived cytokines (IFNg, IL17), as well as increasing relative composition of regulatory cells (Th2, Treg, M2) as compared with Th1, Th17, M1 (aim 1). Preliminary data on healthy control cells support this prediction. Our central hypothesis is that IL4I1 level indicates the body’s ability to repair itself. As such, we anticipate that all MS groups are deficient in IL4I1, to varying degrees, such that HC>n-RRMS>a-RRMS>SPMS. HC have full repair capacity. RRMS>SPMS as remission indicates existent repair capacity, which is lost in SPMS. n-RRMS>a-RRMS since both, as RRMS, capable of repair response, but a-RRMS triggered this response more recently in response to more recent relapse. In all groups, we expect IL4I-treatment to mitigate inflammation (aim 2). Finally, we expect that H2O2 production by IL4I1 is a key player in IL4I1 function, and that H2O2 will preferentially induce oxidative stress to pro-inflammatory subsets of PBCMs (aim 3). DISCUSSION/SIGNIFICANCE OF IMPACT: MS is a chronic inflammatory neurodegenerative disease of the central nervous system that, with an average age of onset of 34, afflicts over 2.3 million individuals worldwide during many of the most productive years of their lives. The pathogenesis of MS, which involves autoimmune destruction of myelin, is poorly understood. Accurate biomarkers, which could predict disease progression, are yet to be identified and would provide valuable information to patients and their treating clinicians. Likewise, effective treatments are few and in high demand. IL4I1 is a promising candidate for both roles.

scholarly journals Integrated microRNA and mRNA Gene Expression in Peripheral Blood Mononuclear Cells in Response to Acute Psychosocial Stress: A Repeated-Measures Within-Subject Pilot Study

2021 ◽  
Author(s):  
Magdalena Maria Jurkiewicz ◽  
Anett Müller-Alcazar ◽  
Dirk Moser ◽  
Indralatha Jayatilaka ◽  
Anatoly Mikhailik ◽  
...  
Keyword(s):  
Gene Expression ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Psychosocial Stress ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Time Points ◽  
Blood Mononuclear Cells ◽  
The Impact ◽  
Acute Psychosocial Stress

Abstract Objective: The impact of psychosocial stress on a variety of negative health outcomes is well documented, with current research efforts directed at possible mechanisms. Here, we focused on a potential mechanism involving differential expression of mRNA and microRNA in response to acute psychosocial stress. We utilized a validated behavioral paradigm, the Trier Social Stress Test (TSST), to induce acute psychosocial stress in a cohort of volunteers. Stress reactivity was assessed repeatedly during the TSST using saliva samples that were analyzed for levels of cortisol. Peripheral blood mononuclear cells were extracted from blood drawn at baseline and at two time points following the stress paradigm. Total RNA was extracted, and mRNA and microRNA microarrays were utilized to assess within-subject changes in gene expression between baseline and the two post-stressor time points. Results: For microarray gene expression analysis, we focused on 12 participants who showed a robust cortisol response to the task, as an indicator of robust HPA-axis activation. We discovered a set of mRNAs and miRNAs that exhibited dynamic expression change in response to the TSST in peripheral blood mononuclear cells, further characterizing the link between psychosocial stress and cellular response mechanisms.

scholarly journals Gene-regulatory network study of rheumatoid arthritis in single-cell chromatin landscapes of peripheral blood mononuclear cells

2021 ◽  
Author(s):  
Cantong Zhang ◽  
Xiaoping Hong ◽  
Haiyan Yu ◽  
Hongwei Wu ◽  
Huixuan Xu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Single Cell ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells ◽  
High Resolution Map ◽  
The Impact ◽  
Accessible Chromatin

Abstract Rheumatoid arthritis is a chronic autoinflammatory disease with an elusive etiology. Assays for transposase-accessible chromatin with single-cell sequencing (scATAC-seq) contribute to the progress in epigenetic studies. However, the impact of epigenetic technology on autoimmune diseases has not been objectively analyzed. Therefore, scATAC-seq was performed to generate a high-resolution map of accessible loci in peripheral blood mononuclear cells (PBMCs) of RA patients at the single-cell level. The purpose of our project was to discover the transcription factors (TFs) that were involved in the pathogenesis of RA at single-cell resolution. In our research, we obtained 22 accessible chromatin patterns. Then, 10 key TFs were involved in the RA pathogenesis by regulating the activity of MAP kinase. Consequently, two genes (PTPRC, SPAG9) regulated by 10 key TFs were found that may be associated with RA disease pathogenesis and these TFs were obviously enriched in RA patients (p<0.05, FC>1.2). With further qPCR validation on PTPRC and SPAG9 in monocytes, we found differential expression of these two genes, which were regulated by eight TFs (ZNF384, HNF1B, DMRTA2, MEF2A, NFE2L1, CREB3L4 (var. 2), FOSL2::JUNB (var. 2), MEF2B). What is more, the eight TFs showed highly accessible binding sites in RA patients. These findings demonstrate the value of using scATAC-seq to reveal transcriptional regulatory variation in RA-derived PBMCs, providing insights on therapy from an epigenetic perspective.

scholarly journals Statin-induced microRNAome alterations modulating inflammation pathways of peripheral blood mononuclear cells in patients with hypercholesterolemia

2020 ◽  
Vol 40 (9) ◽  
Author(s):  
Hung-Ju Lin ◽  
Sung-Liang Yu ◽  
Ta-Chen Su ◽  
Hsiu-Ching Hsu ◽  
Ming-Fong Chen ◽  
...  
Keyword(s):  
Peripheral Blood Mononuclear Cells ◽  
Immune Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Transforming Growth Factor ◽  
Quantitative Polymerase Chain Reaction ◽  
Density Lipoprotein ◽  
Cardiovascular Risks ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells

Abstract Statins inhibit cholesterol biogenesis and modulate atheroma inflammation to reduce cardiovascular risks. Promoted by immune and non-immune cells, serum C-reactive protein (CRP) might be a biomarker suboptimal to assess inflammation status. Although it has been reported that statins modulated inflammation via microRNAs (miRNAs), evidence remains lacking on comprehensive profiling of statin-induced miRNAome alterations in immune cells. We recruited 19 hypercholesterolemic patients receiving 2 mg/day pitavastatin and 15 ones receiving 10 mg/day atorvastatin treatment for 12 weeks, and performed microarray-based profiling of 1733 human mature miRNAs in peripheral blood mononuclear cells (PBMCs) before and after statin treatment. Differentially expressed miRNAs were determined if their fold changes were &gt;1.50 or &lt;0.67, after validated using quantitative polymerase chain reaction (qPCR). The miRSystem and miTALOS platforms were utilized for pathway analysis. Of the 34 patients aged 63.7 ± 6.2 years, 27 were male and 19 were with coronary artery disease. We discovered that statins induced differential expressions of miR-483-5p, miR-4667-5p, miR-1244, and miR-3609, with qPCR-validated fold changes of 1.74 (95% confidence interval, 1.33–2.15), 1.61 (1.25–1.98), 1.61 (1.01–2.21), and 1.68 (1.19–2.17), respectively. The fold changes of the four miRNAs were not correlated with changes of low-density-lipoprotein cholesterol or CRP, after sex, age, and statin type were adjusted. We also revealed that RhoA and transforming growth factor-β signaling pathways might be regulated by the four miRNAs. Given our findings, miRNAs might be involved in statin-induced inflammation modulation in PBMCs, providing likelihood to assess and reduce inflammation in patients with atherosclerotic cardiovascular diseases.

scholarly journals Fecal microbiota transplantation increases colonic IL-25 and dampens tissue inflammation in patients with recurrent Clostridioides difficile

2021 ◽  
Author(s):  
Ning-Jiun Jan ◽  
Noah Oakland ◽  
Pankaj Kumar ◽  
Girija Ramakrishnan ◽  
Brian W. Behm ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Fecal Microbiota Transplantation ◽  
Alpha Diversity ◽  
The United States ◽  
Fecal Microbiota ◽  
Peripheral Blood Mononuclear ◽  
Clostridioides Difficile ◽  
Rdna Sequencing ◽  
Clostridioides Difficile Infection ◽  
The Impact

Background: Clostridioides difficile infection (CDI) is the most common hospital-acquired infection in the United States. Antibiotic-induced dysbiosis is the primary cause of susceptibility and fecal microbiota transplantation (FMT) has emerged as an effective therapy for recurrence. We previously demonstrated in the mouse model of CDI that antibiotic-induced dysbiosis reduced colonic expression of IL-25, and that FMT protected in part by restoring gut commensal bacteria-mediated IL-25 signaling. Here we conducted a prospective clinical trial to test the impact of FMT on immunity, specifically testing in humans if FMT induced IL-25 expression in the colon. Methods: Subjects received colonic biopsies and blood sampling at the time of FMT and 60-days later. Colon biopsies were assayed for IL-25 by immunoassay, for mRNA by RNAseq, and for bacterial content by 16 S rDNA sequencing. High dimensional flow cytometry was also conducted on peripheral blood mononuclear cells pre- and post-FMT. Results: All 10 subjects who received FMT had no CDI recurrences over a 2 year follow-up post FMT. FMT increased alpha diversity of the colonic microbiota and was associated with several immunologic changes. The cytokine IL-25 was increased in colonic tissue. In addition, increased expression of homeostatic genes and repression of inflammatory genes was observed in colonic mRNA transcripts. Finally, circulating Th17 cells were decreased post-FMT. Conclusion: The increase in the cytokine IL-25 accompanied by decreased inflammation is consistent with FMT acting in part to protect from recurrent CDI via restoration of commensal activation of type 2 immunity.

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