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Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6347
Author(s):  
Vinay Kumar ◽  
Michael McClelland ◽  
James Nguyen ◽  
Gabriela De Robles ◽  
Michael Ittmann ◽  
...  

Endogenous retroviruses (ERVs) are abundant, repetitive elements dispersed across the human genome and are implicated in various diseases. We investigated two potential roles for ERVs in prostate cancer (PCa). First, the PCa of Black Americans (BA) is diagnosed at an earlier median age and at a more advanced stage than the PCa of White Americans (WA). We used publicly available RNA-seq data from tumor-enriched samples of 27 BA and 65 WA PCa patients in order to identify 12 differentially expressed ERVs (padj < 0.1) and used a tissue microarray of the PCa cores from an independent set of BA and WA patients to validate the differential protein expression of one of these ERVs, ERV3-1 (p = 2.829 × 10−7). Second, we used 57 PCa tumors from patients of all ancestries from one hospital as a training set to identify the ERVs associated with time to biochemical relapse. A 29-ERV prognostic panel was then tested and validated on 35 separate PCa tumors from patients obtained in two different hospitals with a dramatic increase in prognostic power relative to clinical parameters alone (p = 7.4 × 10−11). In summary, ERV RNA expression differences in the prostate tumors of patients of different ancestries may be associated with dissimilarities in the mechanism of cancer progression. In addition, the correlation of expression of certain ERVs in prostate tumors with the risk of biochemical relapse indicates a possible role for ERV expression in cancer progression.


2021 ◽  
pp. 2101674
Author(s):  
Anne-Sophie Lamort ◽  
Jan Christian Kaiser ◽  
Mario A.A. Pepe ◽  
Ioannis Lilis ◽  
Giannoula Ntaliarda ◽  
...  

BackgroundSurvival after curative resection of early-stage lung adenocarcinoma (LUAD) varies and prognostic biomarkers are urgently needed.MethodsLarge-format tissue samples from a prospective cohort of 200 patients with resected LUAD were immunophenotyped for cancer hallmarks TP53, NF1, CD45, PD-1, PCNA, TUNEL, and FVIII, and were followed for median (95%CI)=2.34 (1.71–3.49) years.ResultsUnsupervised hierarchical clustering revealed two patient subgroups with similar clinicopathologic features and genotype, but with markedly different survival: “proliferative” patients (60%) with elevated TP53, NF1, CD45, and PCNA expression had 50% 5-year overall survival while “apoptotic” patients (40%) with high TUNEL had 70% 5-year survival [HR95%CI=2.23 (1.33–3.80); p=0.0069]. Cox regression and machine learning algorithms including random forests built clinically useful models: a score to predict overall survival and a formula and nomogram to predict tumour phenotype. The distinct LUAD phenotypes were validated in TCGA and KMplotter data and showed prognostic power supplementary to IASLC TNM stage and WHO histologic classification.ConclusionsTwo molecular subtypes of LUAD exist and their identification provides important prognostic information.


Author(s):  
Rafael Rubio Díaz ◽  
Elena de Rafael González ◽  
Esther Martín Torres ◽  
Elena Valera Núñez ◽  
Aurora María López Martos ◽  
...  

Objectives. To analyse and compare 30-day mortality prognostic power of several biomarkers (C-reactive protein, procalcitonin, lactate and suPAR) in patients seen in emergency departments (ED) due to infections. Secondly, if these could improve the accuracy of systemic inflammatory response syndrome (SIRS) and quick Sepsis-related Organ Failure Assessment (qSOFA). Methods. A prospective, observational and analytical study was carried out on patients who were treated in an ED of one of the eight participating hospitals. An assessment was made of 32 independent variables that could influence mortality at 30 days. They covered epidemiological, comorbidity, functional, clinical and analytical factors. Results. The study included 347 consecutive patients, 54 (15.6%) of whom died within 30 days of visiting the ED. SUPAR has got the best biomarker area under the curve (AUC)-ROC to predict mortality at 30 days of 0.836 (95% CI: 0.765-0.907; P <.001) with a cut-off > 10 ng/mL who had a sensitivity of 70% and a specificity of 86%. The score qSOFA ≥ 2 had AUC-ROC of 0.707 (95% CI: 0.621-0.793; P < .001) with sensitivity of 53% and a specificity of 89%. The mixed model (suPAR > 10 ng/mL plus qSOFA ≥ 2) has improved the AUC-ROC to 0.853 [95% CI: 0.790-0.916; P < .001] with the best prognostic performance: sensitivity of 39% and a specificity of 97% with a negative predictive value of 90%. Conclusions. suPAR showed better performance for 30-day mortality prognostic power from several biomarkers in the patients seen in ED due to infections. Score qSOFA has better performance that SRIS and the mixed model (qSOFA ≥ 2 plus suPAR > 10 ng/mL) increased the ability of qSOFA.


2021 ◽  
Vol 8 ◽  
Author(s):  
Na Wei ◽  
Ronghuai Zhang ◽  
Zhanfang Zhu ◽  
Rui Li ◽  
Qi Yu ◽  
...  

Background and Aims: Diagonal earlobe crease (ELC) has been considered a potential cutaneous marker of atherosclerosis. However, the potential mechanism by which ELC and atherosclerosis are linked has not been adequately defined. Roles of adropin and irisin, novel biomarkers of endothelial function, in ELC have not been well-studied. This study aimed to test whether individuals with ELC are deficient in adropin and irisin, a characteristic that would likely promote endothelial dysfunction and provide a plausible common pathological basis for atherosclerosis and ELC.Methods: Patients diagnosed with coronary artery disease (CAD) with (n = 45) and without (n = 45) ELC were consecutively enrolled in the study. The ages of the patients enrolled ranged from 40–70 years. Other patients (n = 45) without ELC or CAD were recruited as the control group. All patients underwent coronary angiography. Serum adropin and irisin concentrations were assessed via enzyme-linked immunosorbent assay.Results: Circulating levels of irisin in the ELC group were significantly lower than those in the non-ELC group, and were highest in the control group. Serum adropin levels of the ELC group were significantly lower than those of the non-ELC group (P &lt; 0.001). Interestingly, although the serum adropin level of the control group was greater than that of the non-ELC group, the difference failed to achieve statistical significance. In subgroup analysis of CAD and ELC, both serum adropin and irisin levels of the CAD and ELC groups were lower than those of the control group (P &lt; 0.001). Receiver-operating characteristic curve analysis revealed that adropin and irisin have similar prognostic power for CAD and ELC.Conclusions: Low adropin and irisin were significantly associated with CAD and ELC. The deficiencies in adropin and irisin may be a common cause of both atherosclerosis and ELC, which explains why patients with ELC are prone to CAD.


2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Ayman M. Ibrahim ◽  
Alan Bilsland ◽  
Steffen Rickelt ◽  
Joanna S. Morris ◽  
Torsten Stein

Abstract Background During pregnancy, the mouse mammary ductal epithelium branches and grows into the surrounding stroma, requiring extensive extracellular matrix (ECM) and tissue remodelling. It therefore shows parallels to cancer invasion. We hypothesised that similar molecular mechanisms may be utilised in both processes, and that assessment of the stromal changes during pregnancy-associated branching may depict the stromal involvement during human breast cancer progression. Methods Immunohistochemistry (IHC) was employed to assess the alterations within the mouse mammary gland extracellular matrix during early pregnancy when lateral branching of the primary ductal epithelium is initiated. Primary mouse mammary fibroblasts from three-day pregnant and age-matched non-pregnant control mice, respectively, were 3D co-cultured with mammary epithelial cells to assess differences in their abilities to induce branching morphogenesis in vitro. Transcriptome analysis was performed to identify the underlying molecular changes. A signature of the human orthologues of the differentially expressed matrisome RNAs was analysed by Kaplan–Meier and multi-variate analysis in two large breast cancer RNA datasets (Gene expression-based Outcome for Breast cancer Online (GOBO) und Kaplan–Meier Plotter), respectively, to test for similarities in expression between early-pregnancy mouse mammary gland development and breast cancer progression. Results The ECM surrounding the primary ductal network showed significant differences in collagen and basement membrane protein distribution early during pregnancy. Pregnancy-associated fibroblasts (PAFs) significantly enhanced branching initiation compared to age-matched control fibroblast. A combined signature of 64 differentially expressed RNAs, encoding matrisome proteins, was a strong prognostic indicator of distant metastasis-free survival (DMFS) independent of other clinical parameters. The prognostic power could be significantly strengthened by using only a subset of 18 RNAs (LogRank P ≤ 1.00e−13; Hazard ratio (HR) = 2.42 (1.8–3.26); p = 5.61e−09). The prognostic power was confirmed in a second breast cancer dataset, as well as in datasets from ovarian and lung cancer patients. Conclusions Our results describe for the first time the early stromal changes that accompany pregnancy-associated branching morphogenesis in mice, specify the early pregnancy-associated molecular alterations in mouse mammary fibroblasts, and identify a matrisome signature as a strong prognostic indicator of human breast cancer progression, with particular strength in oestrogen receptor (ER)-negative breast cancers.


2021 ◽  
Vol 12 ◽  
Author(s):  
Pier Luigi Meroni ◽  
Maria Orietta Borghi

Antiphospholipid antibodies (aPL) are mandatory for the diagnosis but are also a risk factor for the antiphospholipid syndrome (APS) clinical manifestations. Lupus anticoagulant (LA), anticardiolipin (aCL), and anti-beta2 glycoprotein I (β2GPI) assays are the formal laboratory classification/diagnostic criteria. Additional nonclassification assays have been suggested; among them, antiphosphatidylserine-prothrombin (aPS/PT) and antidomain 1 β2GPI antibodies are the most promising ones although not yet formally accepted. aPL represent the example of a laboratory test that moved from dichotomous to quantitative results consistent with the idea that reporting quantitative data offers more diagnostic/prognostic information for both vascular and obstetric manifestations. Although the general rule is that the higher the aPL titer, the higher the test likelihood ratio, there is growing evidence that this is not the case for persistent low titers and obstetric events. LA displays the highest diagnostic/prognostic power, although some isolated LAs are apparently not associated with APS manifestations. Moreover, isotype characterization is also critical since IgG aPL are more diagnostic/prognostic than IgA or IgM. aPL are directed against two main autoantigens: β2GPI and PT. However, anti-β2GPI antibodies are more associated with the APS clinical spectrum. In addition, there is evidence that anti-β2GPI domain 1 antibodies display a stronger diagnostic/prognostic value. This finding supports the view that antigen and even epitope characterization represents a further step for improving the assay value. The strategy to improve aPL laboratory characterization is a lesson that can be translated to other autoantibody assays in order to improve our diagnostic and prognostic power.


2021 ◽  
Vol 1 ◽  
Author(s):  
Hande Beklen ◽  
Sema Arslan ◽  
Gizem Gulfidan ◽  
Beste Turanli ◽  
Pemra Ozbek ◽  
...  

There is a critical requirement for alternative strategies to provide the better treatment in colorectal cancer (CRC). Hence, our goal was to propose novel biomarkers as well as drug candidates for its treatment through differential interactome based drug repositioning. Differentially interacting proteins and their modules were identified, and their prognostic power were estimated through survival analyses. Drug repositioning was carried out for significant target proteins, and candidate drugs were analyzed via in silico molecular docking prior to in vitro cell viability assays in CRC cell lines. Six modules (mAPEX1, mCCT7, mHSD17B10, mMYC, mPSMB5, mRAN) were highlighted considering their prognostic performance. Drug repositioning resulted in eight drugs (abacavir, ribociclib, exemestane, voriconazole, nortriptyline hydrochloride, theophylline, bromocriptine mesylate, and tolcapone). Moreover, significant in vitro inhibition profiles were obtained in abacavir, nortriptyline hydrochloride, exemestane, tolcapone, and theophylline (positive control). Our findings may provide new and complementary strategies for the treatment of CRC.


HPB ◽  
2021 ◽  
Author(s):  
Shruthi H.S. Reddy ◽  
Neil Mehta ◽  
Jennifer L. Dodge ◽  
Abdul R. Hakeem ◽  
Shirin E. Khorsandi ◽  
...  

Author(s):  
Yunqin Chen ◽  
Zhen Wang ◽  
Hong Li ◽  
Yixue Li

BackgroundNasopharyngeal carcinoma (NPC) is an Epstein–Barr virus-associated epithelial malignancy, which is rare in America but endemic in China. The current clinical gold TNM-based standard for prognosis may not be enough. Although some studies have reported that some miRNAs have a prognostic power in NPC, there is a scarcity of independent validation for these miRNAs.MethodsIn this work, we firstly conducted a literature review of all miRNA profiling datasets with survival information, then integrated miRNA expression data across different profiling platforms and built prognostic models using machine learning methods. The Kaplan–Meier method and log-rank tests were applied to estimate correlations of the miRNA signature with survival, and the area under the time-dependent ROC curve (AUC) and concordance index (C-index) were used to assess the predictive power of prognostic models. We also investigated the biological roles of the prognostic miRNAs through identifying their regulated genes and association with immune infiltration.ResultsWe constructed a prognostic model based on 6-miRNA signature (ebv-miR-BART12, ebv-miR-BART15, miR-29c-3p, miR-30e-5p, hsa-miR-375-3p, has-miR-93-5p) using the elastic net penalized Cox regression model. The AUCs of our model predicting 1-, 3-, and 5-year overall survival rates were 0.90, 0.73, and 0.70 for the external validation dataset and showed better prognostic power than models using previously reported miRNA signatures. The 6-miRNA risk score was an independent prognostic predictor for overall survival (OS), disease-free survival (DFS), and metastasis-free survival (MFS). It could stratify patients into low-risk and high-risk groups; patients in the low-risk group treated with concurrent chemotherapy had a better survival. On the basis that the 6-miRNA risk score improved the current clinical gold standard for prognosis, we built a nomogram integrating both clinical characterizations and the risk score to predict 3-, 5-, and 10-year overall survival. Functional analysis suggested that the six miRNAs mainly play roles in virus infection pathways and oncogenic signaling pathways and associated with B-cell expression.ConclusionWe identified a 6-miRNA prognostic signature in nasopharyngeal carcinoma across miRNA profiling platforms and patient geographical difference, which showed good prediction capability in terms of OS, DFS, and MFS. The 6-miRNA risk score might be helpful for clinicians to make treatment strategies and predict patient outcomes.


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