scholarly journals Peripherally-driven myeloid NFkB and IFN/ISG responses predict malignancy risk, survival, and immunotherapy regime in ovarian cancer

2021 ◽  
Vol 9 (11) ◽  
pp. e003609
Author(s):  
Jenny Sprooten ◽  
Ann Vankerckhoven ◽  
Isaure Vanmeerbeek ◽  
Daniel M Borras ◽  
Yani Berckmans ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
In Silico ◽  
Data Driven ◽  
Serum Profiling ◽  
Malignancy Risk ◽  
Patients With Cancer ◽  
Cell Counts ◽  
Serum Screening

BackgroundTumors can influence peripheral immune macroenvironment, thereby creating opportunities for non-invasive serum/plasma immunobiomarkers for immunostratification and immunotherapy designing. However, current approaches for immunobiomarkers’ detection are largely quantitative, which is unreliable for assessing functional peripheral immunodynamics of patients with cancer. Hence, we aimed to design a functional biomarker modality for capturing peripheral immune signaling in patients with cancer for reliable immunostratification.MethodsWe used a data-driven in silico framework, integrating existing tumor/blood bulk-RNAseq or single-cell (sc)RNAseq datasets of patients with cancer, to inform the design of an innovative serum-screening modality, that is, serum-functional immunodynamic status (sFIS) assay. Next, we pursued proof-of-concept analyses via multiparametric serum profiling of patients with ovarian cancer (OV) with sFIS assay combined with Luminex (cytokines/soluble immune checkpoints), CA125-antigen detection, and whole-blood immune cell counts. Here, sFIS assay’s ability to determine survival benefit or malignancy risk was validated in a discovery (n=32) and/or validation (n=699) patient cohorts. Lastly, we used an orthotopic murine metastatic OV model, with anti-OV therapy selection via in silico drug–target screening and murine serum screening via sFIS assay, to assess suitable in vivo immunotherapy options.ResultsIn silico data-driven framework predicted that peripheral immunodynamics of patients with cancer might be best captured via analyzing myeloid nuclear factor kappa-light-chain enhancer of activated B cells (NFκB) signaling and interferon-stimulated genes' (ISG) responses. This helped in conceptualization of an ‘in sitro’ (in vitro+in situ) sFIS assay, where human myeloid cells were exposed to patients’ serum in vitro, to assess serum-induced (si)-NFκB or interferon (IFN)/ISG responses (as active signaling reporter activity) within them, thereby ‘mimicking’ patients’ in situ immunodynamic status. Multiparametric serum profiling of patients with OV established that sFIS assay can: decode peripheral immunology (by indicating higher enrichment of si-NFκB over si-IFN/ISG responses), estimate survival trends (si-NFκB or si-IFN/ISG responses associating with negative or positive prognosis, respectively), and coestimate malignancy risk (relative to benign/borderline ovarian lesions). Biologically, we documented dominance of pro-tumorigenic, myeloid si-NFκB responseHIGHsi-IFN/ISG responseLOW inflammation in periphery of patients with OV. Finally, in an orthotopic murine metastatic OV model, sFIS assay predicted the higher capacity of chemo-immunotherapy (paclitaxel–carboplatin plus anti-TNF antibody combination) in achieving a pro-immunogenic peripheral milieu (si-IFN/ISG responseHIGHsi-NFκB responseLOW), which aligned with high antitumor efficacy.ConclusionsWe established sFIS assay as a novel biomarker resource for serum screening in patients with OV to evaluate peripheral immunodynamics, patient survival trends and malignancy risk, and to design preclinical chemo-immunotherapy strategies.

scholarly journals Peptide-Based Formulation from Lactic Acid Bacteria Impairs the Pathogen Growth in Ananas Comosus (Pineapple)

Coatings ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 457 ◽  
Author(s):  
Gabriela N. Tenea ◽  
Daniela Olmedo ◽  
Clara Ortega
Keyword(s):  
Significant Proportion ◽  
High Capacity ◽  
Total Cell ◽  
Ananas Comosus ◽  
Street Vending ◽  
E Coli ◽  
Cell Counts ◽  
Total Cell Density

Worldwide, street vending commerce has grown exponentially, representing in some countries, including Ecuador, a significant proportion of food consumed by the urban population. Pineapple is one of the common fruits sold as ready-to-eat slices by ambulant vendors in the street or on public transport at risk of contamination by various microorganisms. Previously, we selected Lactobacillus plantarum UTNCys5-4 and Lactococcus lactis subsp. lactis Gt28 strains producing peptides with high capacity to inhibit pathogen growth in vitro. In this study, the effect of different edited formulations containing a mixture of Cys5-4/Gt28 peptides was evaluated in vitro and ex vitro against a pathogenic cocktail containing E. coli (2), Salmonella (2) and Shigella (1). The growth of bacterial cocktail co-inoculated with cell-free supernatant containing peptides (formulation T1) and precipitated peptides (formulation T6), in a ratio of Cys5-4/Gt28:1:1 (v/v), results in a decrease of total cell viability with 1.85 and 1.2 log CFU/mL orders of magnitude at 6 h of incubation. About the same decrease (1.9 log CFU/g) was observed when pineapple slices artificially inoculated with the pathogenic cocktail were coated with T1 formulation, indicating the capacity to diminish simultaneous pathogens in situ, thus demonstrating its great biological control and protection. However, the E. coli cell counts reduced by 2.08 log CFU/g while Salmonella and Shigella cell counts reduced by 1.43 and 1.91 log CFU/g, respectively, at 5 days of refrigeration. In the untreated pineapple slices, the total cell density was maintained during storage, suggesting the adaptation of the pathogens to the fruit matrix. The peptide-based formulation exerted a bacteriolytic mode of action inducing pathogenic cell death. The results indicate that coating pineapple slices with peptide-based formulation is a promising approach to protect them from further contamination by microbial spoilage as well as an alternative to increase the food safety.

scholarly journals New Actors Driving the Epithelial–Mesenchymal Transition in Cancer: The Role of Leptin

Biomolecules ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1676
Author(s):  
Monserrat Olea-Flores ◽  
Juan C. Juárez-Cruz ◽  
Miriam D. Zuñiga-Eulogio ◽  
Erika Acosta ◽  
Eduardo García-Rodríguez ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Progression ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Epithelial Cancers ◽  
Patients With Cancer

Leptin is a hormone secreted mainly by adipocytes; physiologically, it participates in the control of appetite and energy expenditure. However, it has also been linked to tumor progression in different epithelial cancers. In this review, we describe the effect of leptin on epithelial–mesenchymal transition (EMT) markers in different study models, including in vitro, in vivo, and patient studies and in various types of cancer, including breast, prostate, lung, and ovarian cancer. The different studies report that leptin promotes the expression of mesenchymal markers and a decrease in epithelial markers, in addition to promoting EMT-related processes such as cell migration and invasion and poor prognosis in patients with cancer. Finally, we report that leptin has the greatest biological relevance in EMT and tumor progression in breast, lung, prostate, esophageal, and ovarian cancer. This relationship could be due to the key role played by the enriched tumor microenvironment in adipose tissue. Together, these findings demonstrate that leptin is a key biomolecule that drives EMT and metastasis in cancer.

scholarly journals Two microRNAs, miR-330 and miR-125b-5p, mark the juxtaglomerular cell and balance its smooth muscle phenotype

2012 ◽  
Vol 302 (1) ◽  
pp. F29-F37 ◽  
Author(s):  
Silvia Medrano ◽  
Maria C. Monteagudo ◽  
Maria Luisa S. Sequeira-Lopez ◽  
Ellen S. Pentz ◽  
R. Ariel Gomez
Keyword(s):  
Smooth Muscle ◽  
In Situ Hybridization ◽  
In Silico ◽  
Smooth Muscle Actin ◽  
In Silico Analysis ◽  
Screening Strategy ◽  
The Other ◽  
Kidney Cortex

We have shown that microRNAs (miRNAs) are necessary for renin cell specification and kidney vascular development. Here, we used a screening strategy involving microarray and in silico analyses, along with in situ hybridization and in vitro functional assays to identify miRNAs important for renin cell identity. Microarray studies using vascular smooth muscle cells (SMCs) of the renin lineage and kidney cortex under normal conditions and after reacquisition of the renin phenotype revealed that of 599 miRNAs, 192 were expressed in SMCs and 234 in kidney cortex. In silico analysis showed that the highly conserved miR-330 and miR-125b-5p have potential binding sites in smoothelin ( Smtn), calbindin 1, smooth muscle myosin heavy chain, α-smooth muscle actin, and renin genes important for the myoepithelioid phenotype of the renin cell. RT-PCR studies confirmed miR-330 and miR-125b-5p expression in kidney and SMCs. In situ hybridization revealed that under normal conditions, miR-125b-5p was expressed in arteriolar SMCs and in juxtaglomerular (JG) cells. Under conditions that induce reacquisition of the renin phenotype, miR-125b-5p was downregulated in arteriolar SMCs but remained expressed in JG cells. miR-330, normally absent, was expressed exclusively in JG cells of treated mice. In vitro functional studies showed that overexpression of miR-330 inhibited Smtn expression in SMCs. On the other hand, miR-125b-5p increased Smtn expression, whereas its inhibition reduced Smtn expression. Our results demonstrate that miR-330 and miR-125b-5p are markers of JG cells and have opposite effects on renin lineage cells: one inhibiting and the other favoring their smooth muscle phenotype.

scholarly journals Developing Innolysins Against Campylobacter jejuni Using a Novel Prophage Receptor-Binding Protein

2021 ◽  
Vol 12 ◽  
Author(s):  
Athina Zampara ◽  
Martine C. Holst Sørensen ◽  
Yilmaz Emre Gencay ◽  
Dennis Grimon ◽  
Sebastian Hougaard Kristiansen ◽  
...  
Keyword(s):  
Campylobacter Jejuni ◽  
Receptor Binding ◽  
Capsular Polysaccharide ◽  
Binding Protein ◽  
Log Reduction ◽  
Cell Counts ◽  
Phage Receptor ◽  
Receptor Binding Protein

Campylobacter contaminated poultry remains the major cause of foodborne gastroenteritis worldwide, calling for novel antibacterials. We previously developed the concept of Innolysin composed of an endolysin fused to a phage receptor binding protein (RBP) and provided the proof-of-concept that Innolysins exert bactericidal activity against Escherichia coli. Here, we have expanded the Innolysin concept to target Campylobacter jejuni. As no C. jejuni phage RBP had been identified so far, we first showed that the H-fiber originating from a CJIE1-like prophage of C. jejuni CAMSA2147 functions as a novel RBP. By fusing this H-fiber to phage T5 endolysin, we constructed Innolysins targeting C. jejuni (Innolysins Cj). Innolysin Cj1 exerts antibacterial activity against diverse C. jejuni strains after in vitro exposure for 45 min at 20°C, reaching up to 1.30 ± 0.21 log reduction in CAMSA2147 cell counts. Screening of a library of Innolysins Cj composed of distinct endolysins for growth inhibition, allowed us to select Innolysin Cj5 as an additional promising antibacterial candidate. Application of either Innolysin Cj1 or Innolysin Cj5 on chicken skin refrigerated to 5°C and contaminated with C. jejuni CAMSA2147 led to 1.63 ± 0.46 and 1.18 ± 0.10 log reduction of cells, respectively, confirming that Innolysins Cj can kill C. jejuni in situ. The receptor of Innolysins Cj remains to be identified, however, the RBP component (H-fiber) recognizes a novel receptor compared to lytic phages binding to capsular polysaccharide or flagella. Identification of other unexplored Campylobacter phage RBPs may further increase the repertoire of new Innolysins Cj targeting distinct receptors and working as antibacterials against Campylobacter.

scholarly journals Экспериментальные модели сократительной активности миометрия

2020 ◽  
Author(s):  
A.A. Yakovleva ◽  
N.G. Pavlova
Keyword(s):  
In Silico ◽  
Contractile Activity ◽  
Experimental Models ◽  
Pacemaker Activity ◽  
Single View ◽  
Uterine Contractile ◽  
Experimental Approaches

Сократительная деятельность матки до настоящего времени остается актуальным вопросом фундаментальных исследований, поскольку отсутствуют единые представления о биомеханике маточного сокращения, необходимые для профилактики родового и акушерского травматизма. Цель работы - оценка ограничений и возможностей экспериментальных моделей, предназначенных для изучения сократительной активности миометрия. Методика. Основными экспериментальными подходами к изучению сократительной активности матки являлись исследования in vitro, in situ, in vivo, in silico, а также их сочетание. Результаты. В статье рассмотрены исследования, в которых использованы различные сочетания экспериментальных подходов, обсуждаются результаты, полученные при моделировании в экспериментах, обсуждаются результаты изучения синхронизации сокращения отделов матки на различных моделях, а также результаты исследования пейсмейкерной активности миометрия и возможность экстраполяции полученных данных на человека. В связи с активным развитием компьютерных технологий в статье поднимается вопрос об их использовании в моделировании сократительной активности матки человека. Заключение. Делается заключение, что комплексный подход, включающий электромиографические, биохимические и морфологические исследования в хроническом эксперименте, является наиболее адекватным для изучения сократительной активности миометрия и функционального состояния нормально развитых и отставших в развитии плодов, что позволит разработать комплексные методы профилактики родового и акушерского травматизма.Uterine contractile activity remains an important issue of fundamental research as there is no single view of the biomechanics of uterine contraction necessary for the prevention of parturition and obstetric trauma until now. The aim of the review was to assess advantages and limitations of experimental models described in the literature for study uterine contractile activity. At the present time main experimental approaches for study myometrium contractile activity are research in vitro, in situ, in vivo, in silico and the their combinations. The literature presents experimental approaches, different models of uterine contractions synchronization and study of myometrium pacemaker activity. Due to active development of computer technologies there is a need to model human uterine contractile activity with a simplified anatomy. The authors propose that combination of electromyographic, biochemical and morphological methods in chronic experiment is the most correct and appropriate direction for the assessment of the myometrium contractile activity and functional state of normally developed and growth restricted fetuses.

IN SILICO AND IN VITRO SCREENING FOR INHIBITION OF CYTOCHROME P450 CYP3A4 BY COMEDICATIONS COMMONLY USED BY PATIENTS WITH CANCER

2006 ◽  
Vol 34 (4) ◽  
pp. 534-538 ◽  
Author(s):  
Jean-Didier Marechal ◽  
Jinglei Yu ◽  
Simon Brown ◽  
Iouri Kapelioukh ◽  
Elaine M. Rankin ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
In Silico ◽  
In Vitro Screening ◽  
Patients With Cancer
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