1,720,984 research outputs found
Evaluation of the Prognostic Power of Complement System in Malignant Pleural Mesothelioma
No full textMalignant pleural mesothelioma (MPM), a rare tumour arising from the mesothelial cells of the pleura, is characterized by poor prognosis and limited therapeutic options. Over recent years, accumulating evidence has shed light on the controversial role of the complement system (C) in different tumour types and contexts, suggesting novel perspectives for therapeutic targeting in selected subgroups of patients.
Here, we aimed to determine the prognostic power of C components in MPM by an innovative tool, the newly-defined “Complement Score”, as an evolution of the classical “Immunoscore”. This system may permit to stratify MPM patients by combining bioinformatics, immunohistochemical and survival analysis. Upon bioinformatics analysis, the protein expression of potentially prognostic C components (C1s, C1INH, C1q, CFB, and CFI) was evaluated both on tissue microarrays (n = 88) and whole tissue sections (n = 17) of MPM patients. Univariate analyses were performed to correlate the expression of each C component with MPM histotype, TILs (CD4+, CD8+), Ki-67, PD-L1, and overall survival. Interestingly, survival analysis showed that C1qHIGH (χ2=6.01; p=0.01) and C1INHHIGH (χ2=5.13; p=0.02) patients displayed significantly increased survival.
The evidence of a favorable prognostic value of C1q in MPM was apparently inconsistent with our previous findings reporting a tumor-promoting role of C1q. Thus, we attempted to dissect the potential implication of C1q, in concert with HA, in the response to chemotherapeutic treatments. We demonstrated that HA-bound C1q could increase MPM cell mortality after cisplatin treatment, due to increased tumour cell proliferation and downregulation of several drug efflux transporters, including MDR1. Moreover, we detected a strong correlation between patients’ response to chemotherapy and the percentage of in vitro cell mortality after cisplatin treatment in MPM primary cells seeded on HA+C1q matrix (R=0.81, p=0.002). The effect of HA-bound C1q was investigated also in high-grade serous ovarian cancer to determine whether it could be tumor-type specific.
Our results confirmed the controversial effect of C1q within the tumour microenvironment. Moreover, we demonstrated that HA-C1q matrix is the optimal culture condition to mimic MPM microenvironment and to predict patients’ response to chemotherapy. The prediction of patient response may allow to move a step towards personalized medicine in several solid tumours.Malignant pleural mesothelioma (MPM), a rare tumour arising from the mesothelial cells of the pleura, is characterized by poor prognosis and limited therapeutic options. Over recent years, accumulating evidence has shed light on the controversial role of the complement system (C) in different tumour types and contexts, suggesting novel perspectives for therapeutic targeting in selected subgroups of patients.
Here, we aimed to determine the prognostic power of C components in MPM by an innovative tool, the newly-defined “Complement Score”, as an evolution of the classical “Immunoscore”. This system may permit to stratify MPM patients by combining bioinformatics, immunohistochemical and survival analysis. Upon bioinformatics analysis, the protein expression of potentially prognostic C components (C1s, C1INH, C1q, CFB, and CFI) was evaluated both on tissue microarrays (n = 88) and whole tissue sections (n = 17) of MPM patients. Univariate analyses were performed to correlate the expression of each C component with MPM histotype, TILs (CD4+, CD8+), Ki-67, PD-L1, and overall survival. Interestingly, survival analysis showed that C1qHIGH (χ2=6.01; p=0.01) and C1INHHIGH (χ2=5.13; p=0.02) patients displayed significantly increased survival.
The evidence of a favorable prognostic value of C1q in MPM was apparently inconsistent with our previous findings reporting a tumor-promoting role of C1q. Thus, we attempted to dissect the potential implication of C1q, in concert with HA, in the response to chemotherapeutic treatments. We demonstrated that HA-bound C1q could increase MPM cell mortality after cisplatin treatment, due to increased tumour cell proliferation and downregulation of several drug efflux transporters, including MDR1. Moreover, we detected a strong correlation between patients’ response to chemotherapy and the percentage of in vitro cell mortality after cisplatin treatment in MPM primary cells seeded on HA+C1q matrix (R=0.81, p=0.002). The effect of HA-bound C1q was investigated also in high-grade serous ovarian cancer to determine whether it could be tumor-type specific.
Our results confirmed the controversial effect of C1q within the tumour microenvironment. Moreover, we demonstrated that HA-C1q matrix is the optimal culture condition to mimic MPM microenvironment and to predict patients’ response to chemotherapy. The prediction of patient response may allow to move a step towards personalized medicine in several solid tumours
Beyond the Norm: The emerging interplay of complement system and extracellular matrix in the tumor microenvironment
Full text linkGround-breaking awareness has been reached about the intricate and dynamic connection between developing tumors and the host immune system. Being a powerful arm of innate immunity and a functional bridge with adaptive immunity, the complement system (C) has also emerged as a pivotal player in the tumor microenvironment (TME). Its “double-edged sword” role in cancer can find an explanation in the controversial relationship between C capability to mediate tumor cell cytolysis or, conversely, to sustain chronic inflammation and tumor progression by enhancing cell invasion, angiogenesis, and metastasis to distant organs. However, comprehensive knowledge about the actual role of C in cancer progression is impaired by several limitations of the currently available studies. In the current review, we aim to bring a fresh eye to the controversial role of C in cancer by analyzing the interplay between C and extracellular matrix (ECM) components as potential orchestrators of the TME. The interaction of C components with specific ECM components can determine C activation or inhibition and promote specific non-canonical functions, which can, in the tumor context, favor or limit progression based on the cancer setting. An in-depth and tumor-specific characterization of TME composition in terms of C components and ECM proteins could be essential to determine their potential interactions and become a key element for improving drug development, prognosis, and therapy response prediction in solid tumors
A non-redundant role of complement protein C1q in normal and adverse pregnancy
Full text linkAvailability of data and materials: Not applicable.Copyright © The Author(s) 2022. Complement component 1q (C1q) is the recognition molecule of the classical pathway of the complement system that can bind to an array of closely spaced antigen-bound immunoglobulin G (IgG) and IgM antibodies. In addition to its involvement in defence against a range of pathogens and clearance of apoptotic and necrotic cells, C1q has also been implicated in immune and non-immune homeostasis. C1q is locally produced by immune cells such as monocytes, macrophages, and dendritic cells. C1q is also synthesized by decidual endothelial cells, thus acting as a link between decidual cells and trophoblasts, as well as contributing to the remodelling of spiral arteries. Furthermore, C1q is produced by the extravillous trophoblasts (EVTs) invading the decidua. As a pro-angiogenic molecule, C1q is also important for normal placentation processes as it favors the active angiogenesis in the developing decidua. These observations have been validated by C1q gene knock-out mice which showed pre-eclampsia (PE)-like symptoms, characterized by hypertension, proteinuria, glomerular endotheliosis, and increased soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio, and increased oxidative stress. The role of C1q in normal and adverse human pregnancy is being studied extensively due to its absence or low level as a likely precipitating factor for the development of PE.Funding: Not applicable
Systematic review of the complement components as potential biomarkers of pre-eclampsia: pitfalls and opportunities
Full text linkUnlabelled: The complement system (C) is a crucial component of the innate immune system. An increasing body of research has progressively shed light on the pivotal role of C in immunological tolerance at the feto-maternal interface. Excessive C activation or impaired C regulation may determine the onset of pregnancy-related pathological conditions, including pre-eclampsia (PE). Thus, several studies have investigated the presence of C components or split products in blood matrixes (i.e., plasma, serum), urine, and amniotic fluid in PE. In the current study, we systematically reviewed the currently available scientific literature reporting measurements of C components as circulating biomarkers in PE, based on a literature search using Pubmed, Scopus, and Embase databases. A total of 41 out of 456 studies were selected after full-text analysis. Fourteen studies (34.1%) were identified as measuring the blood concentrations of the classical pathway, 5 (12.1%) for the lectin pathway, 28 (68.3%) for the alternative pathway, 17 (41.5%) for the terminal pathway components, and 16 (39%) for C regulators. Retrieved results consistently reported C4, C3, and factor H reduction, and increased circulating levels of C4d, Bb, factor D, C3a, C5a, and C5b-9 in PE compared to normal pregnancies, depicting an overall scenario of excessive C activation and aberrant C regulation. With evidence of C activation and dysregulation, C-targeted therapy is an intriguing perspective in PE management. Moreover, we also discussed emerging pitfalls in C analysis, mainly due to a lack of experimental uniformity and biased cohort selection among different studies and laboratories, aiming to raise a more comprehensive awareness for future standardization. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42024503070
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Zinc Oxide Exerts Anti-Inflammatory Properties on Human Placental Cells
Full text linkAn aberrant and persistent inflammatory state at the fetal-maternal interface is considered as a key contributor in compromised pregnancies. Decidual endothelial cells (DECs) play a pivotal role in the control of the local decidual inflammation. The aim of the current study was to determine whether dietary supplement with zinc oxide (ZnO), due to its very low adverse effects, may be useful for modulating the inflammatory response in the first trimester of pregnancy
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Epigenetic regulation of complement C1Q gene expression
Full text linkHuman C1q is a multifaceted complement protein whose functions range from activating the complement classical pathway to immunomodulation and promoting placental development and tumorigenesis. It is encoded by the C1QA, C1QB, and C1QC genes located on chromosome 1. C1q, unlike most complement components, has extrahepatic expression by a range of cells including macrophages, monocytes and immature dendritic cells. Its local synthesis under the conditions of inflammation and for the purpose of removal of altered self requires its strict transcriptional regulation. To delve into C1Q transcriptional regulation and unravel potential epigenetic influences, we conducted an in silico analysis utilizing a range of online tools and datasets. Co-expression analysis revealed tight coordination between C1QA, C1QB, and C1QC genes. Strikingly, distinct epigenetic patterns emerged across various cell types expressing or lacking these genes, with unique histone marks and DNA methylation status characterizing their regulatory landscape. Notably, the investigation extended to tumor contexts, unveiled potential epigenetic roles in malignancies. The cell type and tumor-specific histone modifications and chromatin accessibility patterns underscore the dynamic nature of epigenetic regulation of C1Q, providing crucial insights into the intricate mechanisms governing the expression of these immunologically significant genes. The findings provide a foundation for future investigations into targeted epigenetic modulation, offering insights into potential therapeutic avenues for immune-related disorders and cancer mediated via C1q
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