scholarly journals Circulating Markers of Neutrophil Extracellular Traps Are of Prognostic Value in Patients With COVID-19

2020 ◽  
Author(s):  
Henry Ng ◽  
Sebastian Havervall ◽  
Axel Rosell ◽  
Katherina Aguilera ◽  
Kristel Parv ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Disease Progression ◽  
Clinical Decision Making ◽  
White Blood Cells ◽  
Plasma Samples ◽  
Healthy Individuals ◽  
Markers Of Inflammation ◽  
Circulating Markers

Objective: The full spectrum of coronavirus disease 2019 (COVID-19) infection ranges from asymptomatic to acute respiratory distress syndrome, characterized by hyperinflammation and thrombotic microangiopathy. The pathogenic mechanisms are poorly understood, but emerging evidence suggest that excessive neutrophil extracellular trap (NET) formation plays a key role in COVID-19 disease progression. Here, we evaluate if circulating markers of NETs are associated with COVID-19 disease severity and clinical outcome, as well as to markers of inflammation and in vivo coagulation and fibrinolysis. Approach and Results: One hundred six patients with COVID-19 with moderate to severe disease were enrolled shortly after hospital admission and followed for 4 months. Acute and convalescent plasma samples as well as plasma samples from 30 healthy individuals were assessed for markers of NET formation: citrullinated histone H3, cell-free DNA, NE (neutrophil elastase). We found that plasma levels of NET markers were all elevated in patients with COVID-19 relative to healthy controls, were associated with respiratory support requirement and short-term mortality, and declined to those found in healthy individuals 4 months post-infection. Levels of the NET markers also correlated with white blood cells, neutrophils, inflammatory cytokines, and C-reactive protein, as well as to markers of in vivo coagulation, fibrinolysis, and endothelial damage. Conclusions: Our findings suggest a role of NETs in COVID-19 disease progression, implicating their contribution to an immunothrombotic state. Further, we observed an association between circulating markers of NET formation and clinical outcome, demonstrating a potential role of NET markers in clinical decision-making, as well as for NETs as targets for novel therapeutic interventions in COVID-19. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04402944, NCT04541979, NCT04445285, NCT04432987, NCT04402970.

scholarly journals Genetic Suppressor Element 1 (GSE1) Promotes the Oncogenic and Recurrent Phenotypes of Castration-Resistant Prostate Cancer by Targeting Tumor-Associated Calcium Signal Transducer 2 (TACSTD2)

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3959
Author(s):  
Oluwaseun Adebayo Bamodu ◽  
Yuan-Hung Wang ◽  
Chen-Hsun Ho ◽  
Su-Wei Hu ◽  
Chia-Da Lin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Disease Progression ◽  
Therapy Resistance ◽  
Calcium Signal ◽  
Signal Transducer ◽  
Castration Resistance ◽  
Castration Resistant

Background: prostate cancer (PCa) is a principal cause of cancer-related morbidity and mortality. Castration resistance and metastasis are clinical challenges and continue to impede therapeutic success, despite diagnostic and therapeutic advances. There are reports of the oncogenic activity of genetic suppressor element (GSE)1 in breast and gastric cancers; however, its role in therapy resistance, metastasis, and susceptibility to disease recurrence in PCa patients remains unclear. Objective: this study investigated the role of aberrantly expressed GSE1 in the metastasis, therapy resistance, relapse, and poor prognosis of advanced PCa. Methods: we used a large cohort of multi-omics data and in vitro, ex vivo, and in vivo assays to investigate the potential effect of altered GSE1 expression on advanced/castration-resistant PCa (CRPC) treatment responses, disease progression, and prognosis. Results: using a multi-cohort approach, we showed that GSE1 is upregulated in PCa, while tumor-associated calcium signal transducer 2 (TACSTD2) is downregulated. Moreover, the direct, but inverse, correlation interaction between GSE1 and TACSTD2 drives metastatic disease, castration resistance, and disease progression and modulates the clinical and immune statuses of patients with PCa. Patients with GSE1highTACSTD2low expression are more prone to recurrence and disease-specific death than their GSE1lowTACSTD2high counterparts. Interestingly, we found that the GSE1–TACSTD2 expression profile is associated with the therapy responses and clinical outcomes in patients with PCa, especially those with metastatic/recurrent disease. Furthermore, we demonstrate that the shRNA-mediated targeting of GSE1 (shGSE1) significantly inhibits cell proliferation and attenuates cell migration and tumorsphere formation in metastatic PC3 and DU145 cell lines, with an associated suppression of VIM, SNAI2, and BCL2 and the concomitant upregulation of TACSTD2 and BAX. Moreover, shGSE1 enhances sensitivity to the antiandrogens abiraterone and enzalutamide in vitro and in vivo. Conclusion: these data provide preclinical evidence of the oncogenic role of dysregulated GSE1–TACSTD2 signaling and show that the molecular or pharmacological targeting of GSE1 is a workable therapeutic strategy for inhibiting androgen-driven oncogenic signals, re-sensitizing CRPC to treatment, and repressing the metastatic/recurrent phenotypes of patients with PCa.

scholarly journals AB0827 SERUM NESPHATIN-1 IN PATHOGENESIS RHEUMATOID ARTHRITIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1437.2-1438
Author(s):  
T. Kvlividze ◽  
V. Polyakov ◽  
В. Zavodovsky ◽  
Y. Polyakova ◽  
L. Seewordova ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Blood Serum ◽  
Inflammatory Cytokines ◽  
Inflammatory Markers ◽  
Healthy People ◽  
Healthy Individuals ◽  
Markers Of Inflammation ◽  
High Level ◽  
Pro Inflammatory Cytokines

Background:Interest in highly specialized tissue cytokines contributed to the discovery of new biologically active molecules. Nesfatin-1 (NF) - discovered in 2006 as an anorexigenic factor. NF-1 is believed to be involved in the regulation of energy homeostasis by regulating appetite and water intake. The role of NF-1 in the pathogenesis of inflammatory diseases is poorly understood. Recently, studies have found a relationship between an increased level of NF-1 and inflammatory markers in various pathologies.Objectives:Study of the level of nesfatin-1 in the blood serum of healthy people, determination of the correlation between the level of NF-1 with the severity of clinical symptoms and classic markers of inflammation in patients with RA.Methods:120 persons were examined: 90 patients with RA and 30 healthy people. All patients underwent a complete clinical and laboratory examination. Plasma NF-1 levels were determined using commercial test systems (RaiBiotech, cat # EIA-NESF) according to the manufacturer’s instructions. Patients with various forms of RA were comparable in age to the group of healthy individuals. Statistical processing of clinical examination data was carried out using the “STATISTICA 10.0 for Windows” software package. Quantitative data were processed statistically using the parametric Student’s t-test, qualitative data using the non-parametric chi-square test. The significance of differences between groups was determined using analysis of variance. The results were considered statistically significant at p <0.05.Results:The average level of NF-1 in blood serum in healthy individuals was 31.79 ± 3.21 ng / ml (M ± σ). The level of normal NF-1 values in healthy individuals, defined as M ± 2σ, ranged from 25.3 to 37.83 ng / ml. There was no significant difference in the levels of circulating NF-1 and BMI in healthy individuals and patients with RA (p> 0.05). The inverse relationship of a lower level of NF-1 with an increase in BMI was not significant.Group 1 (66 patients with RA) with increased serum NF-1 levels (> 37.83 ng / ml), and group 2 (44 patients) with normal values (<37.83 ng / ml). A high level of NF-1 was characteristic for patients with high activity according to DAS28, RF seropositive, ACCP-positive, with extra-articular manifestations, who had been ill for 10 years or more. A reliable relationship between the level of NF-1 in the blood serum and laboratory parameters of RA activity - ESR, CRP, was shown, and secondary synovitis was more common. Our data show a direct correlation between the NF-1 level of the pro-inflammatory markers of RA.Conclusion:The positive correlation between the level of NF-1 and classical markers of inflammation, such as CRP and ESR, confirms the involvement of NF-1 in the pathophysiology of inflammation in RA. This is also evidenced by the correlation of a high level of NF-1 in the blood serum with a more severe clinical picture of RA. It is known that NF-1 can promote the release of pro-inflammatory cytokines such as interleukin-8 (IL-8), interleukin-6 (IL-6), and macrophage inflammatory protein-1a (MIP-1a) in the chondrocytes of RA patients.It is necessary to further study the role of NF-1 in the pathogenesis of systemic inflammatory reactions and the possibility of targeting pro-inflammatory cytokines, the possibility of regulating the level of NF-1 by drugs.References:[1]Kvlividze T.Z., Zavodovsky B.V., Akhverdyan Yu.R. Kvlividze T.Z., Zavodovsky B.V., Akhverdyan Yu.R., Polyakova Yu.V., Sivordova L.E., Yakovlev A.T., Zborovskaya I.A. Serum nesfatin -1 as a marker of systemic inflammation in rheumatoid arthritis. Klinicheskaya Laboratornaya Diagnostika (Russian Clinical Laboratory Diagnostics). 2019; 64 (1): 53-56 (in Russ.).Disclosure of Interests:None declared

scholarly journals Bacteriocin-like activity of oral Fusobacterium nucleatum isolated from human and non-human primates

1999 ◽  
Vol 30 (4) ◽  
pp. 324-346 ◽  
Author(s):  
Elerson Gaetti-Jardim Júnior ◽  
Mario Julio Avila-Campos
Keyword(s):  
Oral Cavity ◽  
Microbial Ecology ◽  
Dental Plaque ◽  
Fusobacterium Nucleatum ◽  
Antagonistic Activity ◽  
Healthy Individuals ◽  
Bacterial Microbiota ◽  
Reference Strains

Fusobacterium nucleatum is indigenous of the human oral cavity and has been involved in different infectious processes. The production of bacteriocin-like substances may be important in regulation of bacterial microbiota in oral cavity. The ability to produce bacteriocin-like substances by 80 oral F. nucleatum isolates obtained from periodontal patients, healthy individuals and Cebus apella monkeys, was examinated. 17.5% of all tested isolates showed auto-antagonism and 78.8% iso- or hetero-antagonism. No isolate from monkey was capable to produce auto-inhibition. In this study, the antagonistic substances production was variable in all tested isolates. Most of the F. nucleatum showed antagonistic activity against tested reference strains. These data suggest a possible participation of these substances on the oral microbial ecology in humans and animals. However, the role of bacteriocins in regulating dental plaque microbiota in vivo is discussed.

scholarly journals Large-Scale Evidence for an Association Between Peripheral Inflammation and White Matter Free Water in Schizophrenia and Healthy Individuals

2020 ◽  
Author(s):  
Maria A Di Biase ◽  
Andrew Zalesky ◽  
Suheyla Cetin-Karayumak ◽  
Yogesh Rathi ◽  
Jinglei Lv ◽  
...  
Keyword(s):  
White Matter ◽  
Large Scale ◽  
Interleukin 2 ◽  
Free Water ◽  
Markers Of Inflammation ◽  
Brain White Matter ◽  
Inflammatory Processes ◽  
Weighted Magnetic Resonance Imaging

Abstract Introduction Clarifying the role of neuroinflammation in schizophrenia is subject to its detection in the living brain. Free-water (FW) imaging is an in vivo diffusion-weighted magnetic resonance imaging (dMRI) technique that measures water molecules freely diffusing in the brain and is hypothesized to detect inflammatory processes. Here, we aimed to establish a link between peripheral markers of inflammation and FW in brain white matter. Methods All data were obtained from the Australian Schizophrenia Research Bank (ASRB) across 5 Australian states and territories. We first tested for the presence of peripheral cytokine deregulation in schizophrenia, using a large sample (N = 1143) comprising the ASRB. We next determined the extent to which individual variation in 8 circulating pro-/anti-inflammatory cytokines related to FW in brain white matter, imaged in a subset (n = 308) of patients and controls. Results Patients with schizophrenia showed reduced interleukin-2 (IL-2) (t = −3.56, P = .0004) and IL-12(p70) (t = −2.84, P = .005) and increased IL-6 (t = 3.56, P = .0004), IL-8 (t = 3.8, P = .0002), and TNFα (t = 4.30, P &lt; .0001). Higher proinflammatory signaling of IL-6 (t = 3.4, P = .0007) and TNFα (t = 2.7, P = .0007) was associated with higher FW levels in white matter. The reciprocal increases in serum cytokines and FW were spatially widespread in patients encompassing most major fibers; conversely, in controls, the relationship was confined to the anterior corpus callosum and thalamic radiations. No relationships were observed with alternative dMRI measures, including the fractional anisotropy and tissue-related FA. Conclusions We report widespread deregulation of cytokines in schizophrenia and identify inflammation as a putative mechanism underlying increases in brain FW levels.

scholarly journals Prokaryotic and Eukaryotic Fecal Microbiota in Irritable Bowel Syndrome Patients and Healthy Individuals Colonized With Blastocystis

2021 ◽  
Vol 12 ◽  
Author(s):  
Céline Nourrisson ◽  
Julien Scanzi ◽  
Julie Brunet ◽  
Frédéric Delbac ◽  
Michel Dapoigny ◽  
...  
Keyword(s):  
Irritable Bowel Syndrome ◽  
High Throughput Sequencing ◽  
Fecal Microbiota ◽  
Healthy Individuals ◽  
High Prevalence ◽  
Potential Link ◽  
Irritable Bowel

Blastocystis is the most frequently isolated protozoan from human stool. Its role in human health is still debated, and a high prevalence was reported in irritable bowel syndrome (IBS) subjects, suggesting a potential link with microbiota. In the present study, we aimed to investigate prokaryotic and eukaryotic microbiota in both IBS-C (constipated) and healthy individuals. We recruited 35 IBS-C patients and 23 healthy subjects, from which 12 and 11 carried Blastocystis, respectively. We performed 16S and 18S rRNA high-throughput sequencing on feces. Whereas we did not observe differences between infected and non-infected controls, several phyla were significantly modified in IBS-C patients according to the presence of Blastocystis. Tenericutes phylum and Ruminococcaceae family were especially increased in Blastocystis carriers. Furthermore, colonization with Blastocystis was associated with discrete changes in the microbial eukaryome, particularly among the Fungi taxa. Depending on the group of patients considered, the mycobiota changes do not go in the same direction and seem more deleterious in the IBS-C group. These results encourage further in vivo and in vitro investigations concerning the role of Blastocystis in the gut environment.

scholarly journals Impact of short-term storage of plasma samples on quantitation of ultra-low levels of interleukin-6

2021 ◽  
Vol 49 (11) ◽  
pp. 030006052110568
Author(s):  
Masaki Yamaguchi ◽  
Tomonobu Koizumi ◽  
Mitsutoshi Sugano
Keyword(s):  
Interleukin 6 ◽  
Blood Cells ◽  
Ethylenediaminetetraacetic Acid ◽  
White Blood Cells ◽  
Blood Collection ◽  
Plasma Samples ◽  
Healthy Individuals ◽  
Short Term ◽  
Short Term Storage ◽  
Term Storage

Objective To quantitate plasma interleukin-6 (IL-6) levels in healthy individuals and to clarify how these levels are affected by blood sample handling procedures during short-term storage. Methods Ethylenediaminetetraacetic acid (EDTA)-treated plasma samples were simultaneously collected from 14 healthy individuals and stored on ice prior to analysis of the IL-6 levels. White blood cells (WBCs), red blood cells, and platelets were counted immediately after blood collection. IL-6 levels were analyzed every 30 minutes using a commercial electrochemiluminescence immunoassay. Results Correlation coefficients between plasma IL-6 levels and WBC counts ranged between 0.605 and 0.554, higher than those for other cell types. The lowest IL-6 value in healthy individuals was estimated at 0.04 pg/mL and the mean values remained under 2 pg/mL over time. Conclusion Analysis of IL-6 levels in EDTA-treated plasma samples centrifuged within 1 hour and stored on ice can be performed within 90 minutes of short-term storage if the analytical method has a sensitivity in the range of 10 fg/mL.

Genomic profiles of BRAF inhibitor resistance mechanisms in metastatic colorectal cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15527-e15527
Author(s):  
Ting Xu ◽  
Xicheng Wang ◽  
Qi Changsong ◽  
Zhenghang Wang ◽  
Jian Li ◽  
...  
Keyword(s):  
Disease Progression ◽  
Signaling Pathway ◽  
Clinical Decision Making ◽  
Braf Inhibitor ◽  
Resistance Mechanisms ◽  
Genetic Alterations ◽  
Braf V600e ◽  
Plasma Samples ◽  
Braf Inhibitors ◽  
Braf Mutations

e15527 Background: BRAF mutations are present in 5-10% of metastatic colorectal cancers (mCRCs). Patients with mCRC whose tumors harbor BRAF V600 mutation generally respond poorly to standard chemotherapy. Treatment with BRAF inhibitors has been shown to improve outcomes, whereas the resistance develops through undefined mechanisms. Therefore, it is imperative to accurately comprehend the genomic profiling of resistance mechanisms to BRAF inhibitors in mCRC for exploring its clinical treatment strategies. Methods: We analyzed next-generation sequencing results in 520 cancer-associated genes for 22 patients who had BRAF V600E mutant mCRC in order to characterize genomic predictors of treatment outcome and track the acquired resistance (AR) mechanisms during the vemurafenib/dabrafenib/encorafenib treatment in combination with cetuximab +/- trametinib. The median age of the patients was 61 years old, 54.5% were male, 54.5% had right-sided mCRC, and 81.8% received one or more prior chemotherapy lines. Tissue and/or plasma samples were collected at baseline (prior to anti-BRAF treatment) and upon disease progression (PD). Objective tumor responses were radiologically assessed every 6 weeks according to RECIST v1. 1. Results: By Feb 2021, treatment had been discontinued in 15 (63.2%) of the patients due to disease progression, while the other 7 cases were still under treatment. The median PFS (mPFS) for all patients was 4.5 months. The overall response rate was 32%, and the disease control rate was 86%. In addition to BRAF V600E, the most common concomitant mutations were identified in TP53 (20/22), RNF43 (8/22), LRP18 (7/22), APC (7/22) and PIK3CA (5/22). Patients with baseline alterations in RNF43 (n = 8; p = 0.0466), or RECQL4 (n = 4; p = 0.0406) had significantly longer PFS than their respective wild type counterparts. In contrast, baseline alterations in PPP2R2A (n = 3; p = 0.0131), RUNX1T1 (n = 3; p = 0.0147), and receptor tyrosine kinase (RTK) signaling pathway genes (n = 6; p = 0.0057) were each significantly associated with shorter PFS. Among the 15 patients whose disease progressed, 9 were identified with newly developed AR mutations in PD tumor or plasma samples. MET amplification was the most common AR mechanism (n = 4) followed by BRAF amplification, KRAS, NRAS mutations (n = 3 each), and MAP2K1, PIK3R1 mutations (n = 1 each). Q61 substitution was the most dominant form for both KRAS and NRAS AR mutations (83%, 5/6). In terms of signaling pathway, MAPK (67%, 6/9) and RTK (44%, 4/9) pathway alterations were most frequently observed. Conclusions: Our study illustrated the landscape of genetic alterations in patients with BRAF V600E mutant mCRC upon BRAF inhibitor treatment, which could be critical to predict responses to BRAF inhibitors and guide personalized clinical decision-making after disease progression.

scholarly journals Role of Anthrax Toxins in Dissemination, Disease Progression, and Induction of Protective Adaptive Immunity in the Mouse Aerosol Challenge Model

2008 ◽  
Vol 77 (1) ◽  
pp. 255-265 ◽  
Author(s):  
Crystal L. Loving ◽  
Taruna Khurana ◽  
Manuel Osorio ◽  
Gloria M. Lee ◽  
Vanessa K. Kelly ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Disease Progression ◽  
Anthrax Lethal Toxin ◽  
Lethal Challenge ◽  
In Vivo Experiments ◽  
Secondary Challenge ◽  
Anthrax Toxins ◽  
Disseminated Disease

ABSTRACT Anthrax toxins significantly contribute to anthrax disease pathogenesis, and mechanisms by which the toxins affect host cellular responses have been identified with purified toxins. However, the contribution of anthrax toxin proteins to dissemination, disease progression, and subsequent immunity after aerosol infection with spores has not been clearly elucidated. To better understand the role of anthrax toxins in pathogenesis in vivo and to investigate the contribution of antibody to toxin proteins in protection, we completed a series of in vivo experiments using a murine aerosol challenge model and a collection of in-frame deletion mutants lacking toxin components. Our data show that after aerosol exposure to Bacillus anthracis spores, anthrax lethal toxin was required for outgrowth of bacilli in the draining lymph nodes and subsequent progression of infection beyond the lymph nodes to establish disseminated disease. After pulmonary exposure to anthrax spores, toxin expression was required for the development of protective immunity to a subsequent lethal challenge. However, immunoglobulin (immunoglobulin G) titers to toxin proteins, prior to secondary challenge, did not correlate with the protection observed upon secondary challenge with wild-type spores. A correlation was observed between survival after secondary challenge and rapid anamnestic responses directed against toxin proteins. Taken together, these studies indicate that anthrax toxins are required for dissemination of bacteria beyond the draining lymphoid tissue, leading to full virulence in the mouse aerosol challenge model, and that primary and anamnestic immune responses to toxin proteins provide protection against subsequent lethal challenge. These results provide support for the utility of the mouse aerosol challenge model for the study of inhalational anthrax.

scholarly journals AML Associated Mesenchymal Stroma Cells Support Growth of AML Cells As a Result of Activated Notch Signaling and This Can be Targeted By Dexamethasone

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 1-1
Author(s):  
Helal Mohammed Mohammed Ahmed Ahmed ◽  
Yahya Saleh Al-Matary ◽  
Subbaiah Chary Nimmagadda ◽  
Maren Fiori ◽  
Pradeep Kumar Patnana ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Clinical Outcome ◽  
Notch Signaling ◽  
Research Funding ◽  
Gene Set Enrichment Analysis ◽  
Leukemic Cells ◽  
Anti Inflammatory

Introduction: Acute myeloid leukemia (AML) is a hematological malignancy characterized by poor prognosis. Interaction with bone marrow mesenchymal stromal cells (BM-MSC) supports leukemic cells to evade chemotherapy-induced apoptosis. Of particular interest, massive parallel transcriptome sequencing of MSCs from mice and patients with preleukemic syndromes identified inflammatory signaling in inducing genotoxic stress, leukemogenesis, and clinical outcome. Recently, Dexamethasone (Dex), an anti-inflammatory drug, demonstrated antileukemic activity and improved clinical outcome in AML patients. These observations intrigued us to further investigate leukemia-BM niche-associated signaling and to identify signaling cascades supporting leukemic cells and BM-MSC interaction. Methods: BM-MSC from AML patients at diagnosis, or in remission were cultured alone or together with human AML cell lines (Kasumi-1 and M-07e) in direct contact or separated by transwells. Following transplantation experiments, BM-MSC were analyzed by microarray analysis. Gene set enrichment analysis (GSEA) was used to identify the hallmark gene sets overrepresented in AML MSC. The functional characterization of BM-MSC and AML cell interaction was investigated using in vitro (cell proliferation and apoptosis) and in vivo (leukemia development, drug response, and survival) analysis. Results: To functionally evaluate the role of BM-MSC, we co-cultured MSCs from AML (AML-MSC) or non-leukemic (non-AML-MSC) patients with Kasumi-1 or M-07e cells. AML-MSCs significantly supported proliferation of AML cells by altering cell cycle distribution from G0/G1 to S phase (30.5 vs 51.3%, p&lt;0.01). Strikingly, the cell cycle profile was unchanged when the cells were separated by a transwell. Consistently, in vivo,MLL-AF9 leukemic cells (Lin-cells transduced with an MLL-AF9 oncogene) and AML-MSCs succumbed to leukemia only when cotransplanted (40 vs 143 days, p&lt;0.05). To gain further insights into leukemic cell-induced changes in MSC, we performed gene expression profiling in MSCs sorted from secondary transplanted leukemic (AML-MSC, n=3) and healthy (HD-MSC, n=3) mice. GSEA analysis identified hallmark-Notch signaling to be significantly overrepresented in AML-MSC as compared to controls (p&lt;0.005, NES: 1.7). Increased Notch-1 and -2 expression could be verified at both the mRNA and protein levels in AML-MSCs. To functionally determine the contribution of Notch activation in MSC, we ectopically expressed the Notch intracellular domain (Notch-ICN) in a murine stromal cell line, MS-5 (Notch-ICN). Underscoring a role for Notch signaling in AML-MSC interaction, Notch-ICN expression significantly supported the proliferation of both MLL-AF9 leukemic cells and MSCs. A role for Notch signaling in the modulation of the inflammatory response has been previously reported. Dex an anti-inflammatory corticosteroid enhanced clinical outcome in AML patients. We, therefore, investigated whether Notch-dependent AML-MSC interaction could be therapeutically targeted using Dex. Interestingly, Dex treatment affected Notch1 expression (52%; p&lt;0.005) and proliferation of leukemia cells (63%; p&lt;0.001). Finally, we evaluated the therapeutic efficacy of Dex by treating mice transplanted with MLL-AF9 leukemic cells. Interestingly, mice treated with Dex exhibited significantly prolonged survival (73 vs 21 days, p&lt;0.01) and had a lower percentage of blasts (50%, p&lt;0.01) and MSC compared to leukemic mice receiving vehicle treatment. Our data thus identified Dex mediated abrogation of AML-MSC interaction is in part mediated by affecting Notch signaling. Conclusion: Our study demonstrated distinct functional differences between AML and non-AML-MSC and direct AML-MSC interaction as an indispensable factor in influencing cell proliferation, leukemogenesis, and survival in mice. We further identified and confirmed the role of Notch signaling in AML-MSC interaction. Therapeutically, Dex abrogated AML-MSC interaction, decreasing AML cell viability, and leukemic mice survival. Further studies are warranted to better understand how aberrant Notch signaling in MSC contributes to AML development and whether the use of Dex alone or in combination with Notch inhibitors could circumvent chemoresistance and relapse in AML patients. Disclosures Lenz: Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy; Agios: Research Funding; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Speakers Bureau; Morphosys: Consultancy, Honoraria, Research Funding; AQUINOX: Research Funding; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Verastem: Research Funding; BMS: Consultancy. Khandanpour:Astra Zeneca: Research Funding; Sanofi: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Celgene: Consultancy.

scholarly journals The Role of Molecular Imaging as a Marker of Remyelination and Repair in Multiple Sclerosis

2021 ◽  
Vol 23 (1) ◽  
pp. 474
Author(s):  
Ido Ben-Shalom ◽  
Arnon Karni ◽  
Hadar Kolb
Keyword(s):  
Multiple Sclerosis ◽  
Molecular Imaging ◽  
Disease Progression ◽  
Acute Inflammation ◽  
Imaging Biomarkers ◽  
Underlying Mechanisms

The appearance of new disease-modifying therapies in multiple sclerosis (MS) has revolutionized our ability to fight inflammatory relapses and has immensely improved patients’ quality of life. Although remarkable, this achievement has not carried over into reducing long-term disability. In MS, clinical disability progression can continue relentlessly irrespective of acute inflammation. This “silent” disease progression is the main contributor to long-term clinical disability in MS and results from chronic inflammation, neurodegeneration, and repair failure. Investigating silent disease progression and its underlying mechanisms is a challenge. Standard MRI excels in depicting acute inflammation but lacks the pathophysiological lens required for a more targeted exploration of molecular-based processes. Novel modalities that utilize nuclear magnetic resonance’s ability to display in vivo information on imaging look to bridge this gap. Displaying the CNS through a molecular prism is becoming an undeniable reality. This review will focus on “molecular imaging biomarkers” of disease progression, modalities that can harmoniously depict anatomy and pathophysiology, making them attractive candidates to become the first valid biomarkers of neuroprotection and remyelination.

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