ResearchPad - biomarkers https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Circular RNA hsa_circ_0072309 inhibits non-small cell lung cancer progression by sponging miR-580-3p]]> https://www.researchpad.co/article/elastic_article_9229 Objective: Non-small cell lung cancer (NSCLC) continues to top the list of cancer mortalities worldwide. Early diagnosis and therapeutic interventions targeting NSCLC is becoming the world’s significant challenge. Circular RNAs (circRNAs) are emerging as a group of potential cancer biomarkers.

Materials and methods: Quantitative real-time PCR (qRT-PCR) was employed to examine the expression of circ_0072309 in NSCLC tissues and cell lines. Cell counting kit 8 (CCK-8), wound healing and Transwell assays were used to analyze cell proliferation, migration and invasion in A549 and H1299 cells. The relationship between circ_0072309 and miR-580-3 was analyzed by Luciferase reporter and RNA pull down assays.

Results: We screened circ_0072309 from Gene Expression Omnibus and found that circ_0072309 was lowly expressed in NSCLC tissues and cell lines. The transfection of circ_0072309-overexpressing vector significantly suppressed the cell proliferation, migration and invasion in A549 and H1299 cells. We predicted that miR-580-3p is a target of circ_0072309 by using publicly available bioinformatic algorithms Circinteractome tool and confirmed that circ_0072309 directly bound to miR-580-3p. Furthermore, the addition of miR-580-3p mitigated the blockage of cell proliferation, migration and invasion induced by circ_0072309.

Conclusions: These data showed that circ_0072309 inhibits the progression of NSCLC progression via blocking the expression of miR-580-3p. These findings revealed the anti-tumor role of circ_0072309 during the development of NSCLC and provided a novel diagnostic biomarker and potential therapy for NSCLC.

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<![CDATA[Plasma Galectin-3 predicts deleterious vascular dysfunction affecting post-myocardial infarction patients: An explanatory study]]> https://www.researchpad.co/article/elastic_article_7712 In a previous analysis of a post-myocardial infarction (MI) cohort, abnormally high systemic vascular resistances (SVR) were shown to be frequently revealed by MRI during the healing period, independently of MI severity, giving evidence of vascular dysfunction and limiting further recovery of cardiac function. The present ancillary and exploratory analysis of the same cohort was aimed at characterizing those patients suffering from high SVR remotely from MI with a large a panel of cardiovascular MRI parameters and blood biomarkers.MethodsMRI and blood sampling were performed 2–4 days after a reperfused MI and 6 months thereafter in 121 patients. SVR were monitored with a phase-contrast MRI sequence and patients with abnormally high SVR at 6-months were characterized through MRI parameters and blood biomarkers, including Galectin-3, an indicator of cardiovascular inflammation and fibrosis after MI. SVR were normal at 6-months in 90 patients (SVR-) and abnormally high in 31 among whom 21 already had high SVR at the acute phase (SVR++) while 10 did not (SVR+).ResultsWhen compared with SVR-, both SVR+ and SVR++ exhibited lower recovery in cardiac function from baseline to 6-months, while baseline levels of Galectin-3 were significantly different in both SVR+ (median: 14.4 (interquartile range: 12.3–16.7) ng.mL-1) and SVR++ (13.0 (11.7–19.4) ng.mL-1) compared to SVR- (11.7 (9.8–13.5) ng.mL-1, both p < 0.05). Plasma Galectin-3 was an independent baseline predictor of high SVR at 6-months (p = 0.002), together with the baseline levels of SVR and left ventricular end-diastolic volume, whereas indices of MI severity and left ventricular function were not. In conclusion, plasma Galectin-3 predicts a deleterious vascular dysfunction affecting post-MI patients, an observation that could lead to consider new therapeutic targets if confirmed through dedicated prospective studies. ]]> <![CDATA[Identification of miRNA signatures associated with radiation-induced late lung injury in mice]]> https://www.researchpad.co/article/elastic_article_7641 Acute radiation exposure of the thorax can lead to late serious, and even life-threatening, pulmonary and cardiac damage. Sporadic in nature, late complications tend to be difficult to predict, which prompted this investigation into identifying non-invasive, tissue-specific biomarkers for the early detection of late radiation injury. Levels of circulating microRNA (miRNA) were measured in C3H and C57Bl/6 mice after whole thorax irradiation at doses yielding approximately 70% mortality in 120 or 180 days, respectively (LD70/120 or 180). Within the first two weeks after exposure, weight gain slowed compared to sham treated mice along with a temporary drop in white blood cell counts. 52% of C3H (33 of 64) and 72% of C57Bl/6 (46 of 64) irradiated mice died due to late radiation injury. Lung and heart damage, as assessed by computed tomography (CT) and histology at 150 (C3H mice) and 180 (C57Bl/6 mice) days, correlated well with the appearance of a local, miRNA signature in the lung and heart tissue of irradiated animals, consistent with inherent differences in the C3H and C57Bl/6 strains in their propensity for developing radiation-induced pneumonitis or fibrosis, respectively. Radiation-induced changes in the circulating miRNA profile were most prominent within the first 30 days after exposure and included miRNA known to regulate inflammation and fibrosis. Importantly, early changes in plasma miRNA expression predicted survival with reasonable accuracy (88–92%). The miRNA signature that predicted survival in C3H mice, including miR-34a-5p, -100-5p, and -150-5p, were associated with pro-inflammatory NF-κB-mediated signaling pathways, whereas the signature identified in C57Bl/6 mice (miR-34b-3p, -96-5p, and -802-5p) was associated with TGF-β/SMAD signaling. This study supports the hypothesis that plasma miRNA profiles could be used to identify individuals at high risk of organ-specific late radiation damage, with applications for radiation oncology clinical practice or in the context of a radiological incident.

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<![CDATA[Characterization of tumor mutation burden, PD-L1 and DNA repair genes to assess relationship to immune checkpoint inhibitors response in metastatic renal cell carcinoma]]> https://www.researchpad.co/article/Nb196bd4e-e98c-4fc9-9715-0b77bd7eabe8 Immune checkpoint inhibitors (ICIs) have expanded treatment options for metastatic renal cell carcinoma (mRCC); however, there are limited predictive biomarkers for response to ICIs in this indication, with programmed death-ligand 1 (PD-L1) status demonstrating little predictive utility in mRCC. While predictive of ICI response in other tumor types, the utility of tumor mutation burden (TMB) in mRCC is unclear. Here, we assess TMB, loss of antigen presentation genes and PD-L1 status correlated with outcomes to ICI treatment in mRCC.MethodsTumor samples from 34 patients with mRCC treated with ICI therapy at Duke Cancer Institute were retrospectively evaluated using Personal Genome Diagnostics elio tissue complete (RUO version), a tumor genomic profiling assay for somatic variants, TMB, microsatellite status and genomic status of antigen presentation genes. Tumor samples were also analyzed with the Dako 28-8 PD-L1 immunohistochemistry assay. Deidentified clinical information was extracted from the medical record, and tumor response was evaluated based on the Response Evaluation Criteria In Solid Tumors (RECIST) V.1.1 criteria.ResultsPatients were stratified by overall response following ICI therapy and designated as progressive disease (PD; n=18) or disease control groups (DC; n=16). TMB scores ranged from 0.36 to 12.24 mutations/Mb (mean 2.83 mutations/Mb) with no significant difference between the PD and DC groups (3.01 vs 2.63 mutations/Mb, respectively; p=0.7682). Interestingly, 33% of PD patients displayed loss of heterozygosity of major histocompatibility complex class I genes (LOH-MHC) vs 6% of DC patients. Nine of 34 samples were PD-L1-positive (4 in the PD group; 5 in the DC group), suggesting no correlation between PD-L1 expression and response to ICI therapy. Notably, the DC group displayed an enrichment of mutations in DNA repair genes (p=0.04), with 68.8% exhibiting at least one mutated homologous recombination repair (HRR)-related gene compared with only 38.9% of the PD group (p=0.03).ConclusionsOverall, neither TMB nor PD-L1 correlated with ICI response and TMB was not significantly associated with PD-L1 expression. The higher incidence of LOH-MHC in PD group suggests that loss of antigen presentation may restrict response to ICIs. Separately, enrichment of HRR gene mutations in the DC group suggests potential utility in predicting ICI response and a potential therapeutic target, warranting future studies. ]]> <![CDATA[Circular RNA expression profile of lung squamous cell carcinoma: identification of potential biomarkers and therapeutic targets]]> https://www.researchpad.co/article/N4d0388e9-7ab4-45f1-93ad-4d6fc64e5203 Emerging evidences indicated that exosomal circular RNAs (circRNAs) could serve as diagnostic biomarkers for cancers. However, the expression profiles and clinical significance of circRNAs in lung squamous cell carcinoma (LUSC) remain largely unknown. Herein, we analyzed circRNAs expression profile in six pairs of plasma exosome samples of LUSC patients using high-throughput sequencing. A total of 252 differentially expressed exosomal circRNAs were identified, including 133 up-regulated circRNAs and 119 down-regulated circRNAs. Subsequently, the circRNAs–miRNAs–mRNAs interaction network was built to investigate potential function of circRNAs. Three up-regulated circRNAs (hsa_circ_0014235, hsa_circ_0025580 and hsa_circ_0026403) were implied to participate in cancer-related pathways. QRT-PCR experiment confirmed the up-regulation of hsa_circ_0014235 and hsa_circ_0025580. Finally, clinical studies indicated that hsa_circ_0014235 and hsa_circ_0025580 could serve as novel diagnostic biomarkers for LUSC. Taken together, our study revealed exosomal circRNAs expression profile in LUSC for the first time and showed the important diagnostic potential for circRNAs in LUSC.

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<![CDATA[非小细胞肺癌患者肿瘤组织和外周血血浆中ENO1蛋白水平分析]]> https://www.researchpad.co/article/5c052c80d5eed0c4848a8336 肺癌严重威胁人类生存健康,有效的肿瘤标志物可以辅助诊断、判断预后和指导治疗。本研究旨在检测非小细胞肺癌患者肿瘤组织和血浆中烯醇化酶1(alpha-enolase, ENO1)蛋白水平,初步探讨ENO1作为肺癌相关蛋白标志物的可能性。方法采用Western blot方法检测16例肺鳞癌患者的肿瘤组织及其配对正常肺组织中ENO1蛋白水平。采用双抗体夹心酶联免疫吸附分析(enzyme-linked immunosorbent assay, ELISA)测定42例健康体检者、34例肺部良性疾病患者和84例非小细胞肺癌患者三组人群血浆中ENO1蛋白水平。结果在87.5%(14/16)的肺鳞癌患者肿瘤组织中ENO1蛋白表达量高于其配对正常肺组织;非小细胞肺癌患者血浆中ENO1蛋白水平高于健康体检者(P=0.031)和肺部良性疾病者(P=0.019),且ENO1蛋白在肺腺癌患者血浆中的水平高于肺鳞癌患者(P=0.023)。结论非小细胞肺癌肿瘤组织和血浆中ENO1蛋白水平升高,提示ENO1可作为潜在的非小细胞肺癌相关血浆蛋白标志物。 ]]> <![CDATA[肿瘤分子标志的发现和验证:问题和策略探讨]]> https://www.researchpad.co/article/5c052c7ed5eed0c4848a8308 <![CDATA[肿瘤标志物CYFRA21-1在非小细胞肺癌诊断中的价值]]> https://www.researchpad.co/article/Nb17c6ac7-bfbb-414b-91e2-4edb3471231d 细胞角蛋白19片段(cytokeratin 19 fragment, CYFRA21-1)是血液中的一种可溶性蛋白质,它可能是一种潜在的循环肿瘤标志物。本研究旨在探讨CYFRA21-1在非小细胞肺癌(non-small cell lung cancer, NSCLC)诊断中的应用价值。方法采用酶联免疫吸附法分别检测107例NSCLC患者和51例肺部良性疾病患者外周血中CYFRA21-1含量,应用受试者工作曲线(receiver operaing characteristic curves, ROC)对检测结果进行临床评价。结果NSCLC组织与肺良性疾病组外周血CYFRA21-1水平差别有统计学意义(χ2=47.343, P < 0.001);以3.3 μg/L为诊断临界点,CYFRA21-1诊断NSCLC的敏感性和特异性分别为74.77%和76.47%,ROC曲线下面积为0.813 9;NSCLC各病理类型之间CYFRA21-1水平差别无有统计学意义(χ2=0.450, P=0.799);外周血CYFRA21-1在广泛期(Ⅲb、Ⅳ)病例中明显高于局限期(Ⅰ、Ⅱ、Ⅲb)病例(χ2=7.057, P=0.008)。结论CYFRA21-1作为肺癌肿瘤标志物具有相对较高的敏感性和特异性;血浆中CYFRA21-1水平升高提示肺癌患者可能已经发展为广泛期。 ]]> <![CDATA[非小细胞肺癌患者肿瘤组织与外周血中EGFR表达相关性研究]]> https://www.researchpad.co/article/N544c705f-487f-4756-afe7-12f689fde39c 表皮生长因子受体(epidermal growth factor receptor, EGFR)在肿瘤细胞的增殖中起重要作用,肿瘤组织中EGFR表达水平可为肺癌的诊断、预后判断提供依据。本研究通过检测EGFR在非小细胞肺癌患者肿瘤组织和外周血中的表达,探讨利用外周血中EGFR表达水平来预测肿瘤组织中的表达并作为肿瘤标记物的可行性。方法应用real-time RT-PCR技术检测46例非小细胞肺癌组织和10例肺良性病变组织中EGFR mRNA的表达;应用ELISA法检测46例非小细胞肺癌患者外周血中EGFR蛋白的表达,并以10例肺良性疾病患者的外周血作对照。结果直线相关分析表明EGFR在外周血中的蛋白表达水平与肿瘤组织中的mRNA表达水平具有相关性(R2=0.83, P=0.016)。结论血清中EGFR蛋白水平的测定有可能替代肿瘤组织中mRNA的检测,为无法取得肿瘤组织或取到肿瘤组织困难的患者提供一种更快捷、简便的替代检测方法,尽早为临床选择治疗方法及预后判断提供依据。 ]]> <![CDATA[肺癌血清肿瘤标志物<i>meta</i>分析]]> https://www.researchpad.co/article/Nb9e1ab96-0dd2-4238-8ed2-0f09323f0320 血清肿瘤标志物的检测对肺癌的早期诊断有着重要的意义。本研究旨在通过回顾性统计分析,总结肺癌血清肿瘤标志物检测的临床意义及特点。方法应用meta分析方法对有关肺癌血清肿瘤标志物的文献进行综合定量评价。入选712篇文献,病例组、对照组病例均 > 20例,共统计肿瘤血清52 832例,对照血清32 037例。结果13项肿瘤标志物对肺癌具有诊断意义,CEA、CA125、CYFRA21-1、TPA、SCCAg、DKK1、NSE和ProGRP的敏感度分别为47.50%、50.11%、57.00%、50.93%、49.00%、69.50%、39.73%和51.48%,特异度分别为92.34%、80.19%、90.16%、88.41%、91.07%、92.20%、89.11%和94.89%。多指标联合分析显示,NSE+ProGRP对小细胞肺癌的诊断敏感度和特异度分别为88.90%和72.82%。SCCAg+CYFRA21-1联合肿瘤生长因子TSGF对鳞癌诊断的敏感度和特异度分别为95.30%和74.20%;CA153+Ferrtin+CEA对肺癌诊断的敏感度和特异度分别为91.90%和44.00%。结论肿瘤血清标志物对早期肺癌的诊断有临床意义,单项指标检测敏感度及特异度较低,多指标联合检测能提高诊断的敏感度和特异度。 ]]> <![CDATA[Zebrafish as an integrative vertebrate model to identify miRNA mechanisms regulating toxicity]]> https://www.researchpad.co/article/Nf1715fec-8a11-4238-b36f-9aac20643261 Zebrafish (Danio rerio) are an integrative vertebrate model ideal for toxicity studies. The zebrafish genome is sequenced with detailed characterization of all life stages. With their genetic similarity to humans, zebrafish models are established to study biological processes including development and disease mechanisms for translation to human health. The zebrafish genome, similar to other eukaryotic organisms, contains microRNAs (miRNAs) which function along with other epigenetic mechanisms to regulate gene expression. Studies have now established that exposure to toxins and xenobiotics can change miRNA expression profiles resulting in various physiological and behavioral alterations. In this review, we cover the intersection of miRNA alterations from toxin or xenobiotic exposure with a focus on studies using the zebrafish model system to identify miRNA mechanisms regulating toxicity. Studies to date have addressed exposures to toxins, particulate matter and nanoparticles, various environmental contaminants including pesticides, ethanol, and pharmaceuticals. Current limitations of the completed studies and future directions for this research area are discussed.

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<![CDATA[Proenkephalin A Adds No Incremental Prognostic Value After Acute Ischemic Stroke]]> https://www.researchpad.co/article/Nb42a9d58-70ec-4363-8ab0-eda7cb7c696a

Objective:

The aim of this study was to confirm previous observations that proenkephalin A (PENK-A) may serve as prognostic marker in the setting of acute ischemic stroke in a large stroke cohort.

Methods:

The plasma concentration of PENK-A was measured within 72 hours of symptom onset in 320 consecutively enrolled patients with stroke. The primary outcome measures were unfavorable functional outcome (modified Rankin Scale score 0-2 vs 3-6) and mortality within 90 days. Logistic and cox proportional regression analyses were fitted to estimate odds ratios (ORs), hazard ratios (HRs) and 95% confidence intervals (CIs), respectively, for the association between PENK-A and the primary outcome measures.

Results:

After adjusting for demographic and vascular risk factors, PENK-A was neither independently associated with functional outcome (OR: 1.29, 95% CI: 0.16-10.35) nor mortality (HR: 1.02, 95% CI: 0.14-7.33).

Conclusion:

Among patients with acute stroke, PENK-A does not serve as an independent prognostic marker in this external validation cohort.

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<![CDATA[Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios Predict All-Cause Mortality in Acute Pulmonary Embolism]]> https://www.researchpad.co/article/N7351fb3a-ec25-48dc-bcb8-e0d04a90c0cb

The aim of this study was to investigate the utility of the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) to predict all-cause mortality in patients presenting with acute pulmonary embolism (PE). Three hundred consecutive patients with acute PE between March 2016 and December 2018 were retrospectively analyzed. We identified 191 patients who met the study inclusion criteria. Twenty-eight patients died during the study period. There was a significant difference in PLR, but not NLR, between patients with low risk, submassive, and massive risk PE (P = .02 and P = .58, respectively, by the Kruskal-Wallis test). Elevated NLR and PLR were associated with all-cause mortality (P < .01 and P < .01, respectively). Neutrophil-to-lymphocyte ratio of 5.46 was associated with all-cause mortality with sensitivity of 75.0% and specificity of 66.9% (area under the curve [AUC]: 0.692 [95% confidence interval, CI]: 0.568-0.816); P < .01). Platelet-to-lymphocyte ratio of 256.6 was associated with all-cause mortality with sensitivity of 53.6% and specificity of 82.2% (AUC: 0.693 [95% CI: 0.580-0.805]; P < .01). Neutrophil-to-lymphocyte ratio and PLR are simple biomarkers that are readily available from routine laboratory values and may be useful components of PE risk prediction models.

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<![CDATA[Early differential diagnosis model for acute radiation pneumonitis based on multiple parameters]]> https://www.researchpad.co/article/N2270efba-2cb3-4c3f-a022-8776357447a4

Abstract

Objective: The present study aimed to construct a diagnosis model for the early differentiation of acute radiation pneumonitis (ARP) and infectious pneumonitis based on multiple parameters.

Methods: The present study included data of 152 patients admitted to the Department of Radiochemotherapy, Tangshan People’s Hospital, who developed ARP (91 patients) or infectious pneumonia (IP; 61 patients) after radiotherapy. The radiophysical parameters, imaging characteristics, serological indicators, and other data were collected as independent variables, and ARP was considered as a dependent variable. Logistics univariate analysis and Spearman correlation analysis were used for selecting independent variables. Logistics multivariate analysis was used to fit the variables into the regression model to predict ARP.

Results: The univariate analysis showed that the positional relation between lesions and V20 area (PRLV), procalcitonin (PCT), C-reactive protein (CRP), mean lung dose (MLD), and lung volume receiving ≥20 Gy (V20) correlated with ARP while the planning target volume (PTV) dose marginally correlated with ARP. The multivariate analysis showed that the PRLV, PCT, white blood cell (WBC), and MLD were independent diagnostic factors. The nomogram was drawn on the basis of the logistics regression model. The area under the curve (AUC) of the model was 0.849, which was significantly better than that of a single indicator and the sensitivity and specificity of the model were high (82.4 and 82.0%, respectively). These results predicted by the model were highly consistent with the actual diagnostic results. The decision curve analysis (DCA) demonstrated a satisfactory positive net benefit of the model.

Conclusion: The diagnosis model constructed in the present study is of certain value for the differential diagnosis of ARP and IP.

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<![CDATA[Serum levels of bone sialoprotein correlate with portal pressure in patients with liver cirrhosis]]> https://www.researchpad.co/article/Nd170950f-0b0f-46af-a42d-6b06a3bc49ed

Liver cirrhosis represents the common end-stage of chronic liver diseases regardless of its etiology. Patients with compensated disease are mostly asymptomatic, however, progression to a decompensated disease stage is common. The available stratification strategies are often unsuitable to identify patients with a higher risk for disease progression and a limited prognosis. SIBLINGs, soluble glycophosphoproteins, are secreted into the blood by immune-cells. While osteopontin, the most prominent member of the SIBLINGs family, has been repeatedly associated with liver cirrhosis, data on the diagnostic and/or prognostic value of bone sialoprotein (BSP) are scarce and partly inconclusive. In this study, we analyzed the diagnostic and prognostic potential of circulating BSP in comparison to other standard laboratory markers in a large cohort of patients with liver cirrhosis receiving transjugular intrahepatic portosystemic shunt (TIPS). Serum levels of BSP were similar in patients with different disease stages and were not indicative for prognosis. Interestingly, BSP serum levels did correlate inversely with portal pressure, as well as its surrogates such as platelet count, the portal vein cross-sectional area and correlated positively with the portal venous velocity. In summary, our data highlight that BSP might represent a previously unrecognized marker for portal hypertension in patients with liver cirrhosis.

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<![CDATA[Circulating lncRNA DANCR as a potential auxillary biomarker for the diagnosis and prognostic prediction of colorectal cancer]]> https://www.researchpad.co/article/Na74d7a58-1127-4384-9b07-24c0fc3ade70

Abstract

Studies have shown that long non-coding RNAs (lncRNAs) play vital roles in the development of cancer, including colorectal cancer (CRC). Our purpose is to validate the diagnostic value of serum differentiation antagonizing non-protein coding RNA (DANCR) in CRC by focusing on its expression and clinical application. lncRNA expression profiles of CRC patients were obtained and analyzed by repurposing the publically available microarray data. Tissue or serum specimens were obtained from 40 patients with primary CRC, 10 patients with recurrent CRC, 40 patients with colorectal polyps, and 40 healthy controls. It was found that DANCR level in the CRC tissue and serum was significantly increased, and serum DANCR expression was decreased in post-operative patients as compared with that in pre-treatment patients and recurrent patients. In addition, serum DANCR expression was significantly correlated with different TNM stages. Correlation analysis of DANCR and other diagnostic indicators showed that the serum DANCR expression level was significantly correlated with CA199 but not with CEA in CRC patients. As for diagnostic efficiency by ROC analysis, the area under the curve (AUC) of serum DANCR was higher than that of CEA and CA199 in CRC group vs. colorectal polyp group. Simultaneous detection of DANCR, CEA and CA199 yielded the highest sensitivity and AUC as compared with either of them alone. Taken together, serum DANCR was up-regulated in CRC patients and high expression of DANCR may prove to be a potential biomarker for the diagnosis of CRC.

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<![CDATA[Low efficacy of vaccination against serogroup B meningococci in patients with atypical hemolytic uremic syndrome]]> https://www.researchpad.co/article/N063b6d00-2073-4190-8d9a-fb913cdb54b6

Abstract

Background: The C5 complement inhibitor eculizumab is first-line treatment in atypical hemolytic uremic syndrome (aHUS) going along with a highly increased risk of meningococcal infections. Serogroup B meningococci (MenB) are the most frequently encountered cause for meningococcal infections in Europe. Efficacy of the protein-based MenB-vaccine Bexsero in aHUS has not been determined and testing is only possible in patients off-treatment with eculizumab as a human complement source is required.

Methods: Patients with aHUS were vaccinated with two doses of the protein-based MenB-vaccine Bexsero. Serum bactericidal antibody (SBA) titers against factor H binding protein (fHbp) of MenB were determined in 14 patients with aHUS off-treatment with eculizumab.

Results: Only 50% of patients showed protective human serum bactericidal antibody (hSBA) titers (≥1:4) against MenB following two vaccinations. Bactericidal antibody titers were relatively low (≤1:8) in three of seven patients with protective titers. While 71% of patients were on immunosuppressive treatment for either thrombotic microangiopathy or renal transplantation at either first or second vaccination, all four patients not receiving any immunosuppressive treatment showed protective bactericidal antibody response. Time between second vaccination and titer measurement was not significantly different between patients with protective titers compared with those with non-protective titers, while time between first and second vaccination was significantly longer in patients with protective titers going along with a tendency for reduction in immunosuppressive treatment.

Conclusions: Efficacy of vaccination against MenB is insufficient in patients with aHUS. Response to vaccination seems to be hampered by immunosuppression. Therefore, implementation of adequate antibiotic prophylaxis seems pivotal.

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<![CDATA[Down-regulation of protease-activated receptor 2 ameliorated osteoarthritis in rats through regulation of MAPK/NF-κB signaling pathway in vivo and in vitro]]> https://www.researchpad.co/article/N23ff7292-a7a0-4903-9f18-e29c0a2bb86e

Abstract

Recently, protease-activated receptor 2 (PAR2) has been proved to be involved in the inflammatory response including osteoarthritis (OA). In the present study, we found that PAR2 antagonist could remarkably improve the pathological condition of OA rats in vivo. In addition, we also found that PAR2 antagonist could suppress the production of inflammatory factors (TNF-α and Cox-2), decrease the levels of MMP-1 and MMP-13, and restrain the levels of P62 proteins and aggravate the expression of LC3-II both in vivo and in vitro. Besides, in vitro, PAR2 antagonist could increase the proliferation and colony formation of chondrocytes induced with IL-1β. Moreover, PAR2 antagonist could decrease the expression of expressions of p-p38, p-IκBα and p-NF-κB in vitro. However, PAR2 agonist exhibited the opposite effects. Furthermore, SB203580, a p38 MAPK inhibitor, could remarkably promote the proliferation of chondrocytes induced with IL-1β, could alleviate the production of TNF-α and Cox-2, could down-regulate the protein expressions of MMP-1 and MMP-13, and could decrease the expression of P62 and increase the expressions of LC3-II of chondrocytes induced with IL-1β. Importantly, SB203580 could reverse the effects of PAR2 agonist on the functions of chondrocytes induced with IL-1β. Taken together, the present data suggest that down-regulation of PAR2 can ameliorate OA through inducing autophagy via regulation of MAPK/NF-κB signaling pathway in vivo and in vitro, and PAR2 can be considered as a potential candidate to treat OA.

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<![CDATA[Pre-existing inflammatory immune microenvironment predicts the clinical response of vulvar high-grade squamous intraepithelial lesions to therapeutic HPV16 vaccination]]> https://www.researchpad.co/article/Nff1ff5ca-eb0c-4739-8a5a-93458833b194

Background

Vulvar high-grade squamous intraepithelial lesion (vHSIL) is predominantly induced by high-risk human papilloma virus type 16 (HPV16). In two independent trials, therapeutic vaccination against the HPV16 E6 and E7 oncoproteins resulted in objective partial and complete responses (PRs/CRs) in half of the patients with HPV16+ vHSIL at 12-month follow-up. Here, the prevaccination and postvaccination vHSIL immune microenvironment in relation to the vaccine-induced clinical response was investigated.

Methods

Two novel seven-color multiplex immunofluorescence panels to identify T cells (CD3, CD8, Foxp3, Tim3, Tbet, PD-1, DAPI) and myeloid cells (CD14, CD33, CD68, CD163, CD11c, PD-L1, DAPI) were designed and fully optimized for formalin-fixed paraffin-embedded tissue. 29 prevaccination and 24 postvaccination biopsies of patients with vHSIL, and 27 healthy vulva excisions, were stained, scanned with the Vectra multispectral imaging system, and automatically phenotyped and counted using inForm advanced image analysis software.

Results

Healthy vulvar tissue is strongly infiltrated by CD4 and CD8 T cells expressing Tbet and/or PD-1 and CD14+HLA-DR+ inflammatory myeloid cells. The presence of such a coordinated pre-existing proinflammatory microenvironment in HPV16+ vHSIL is associated with CR after vaccination. In partial responders, a disconnection between T cell and CD14+ myeloid cell infiltration was observed, whereas clinical non-responders displayed overall lower immune cell infiltration. Vaccination improved the coordination of local immunity, reflected by increased numbers of CD4+Tbet+ T cells and HLA-DR+CD14+ expressing myeloid cells in patients with a PR or CR, but not in patients with no response. CD8+ T cell infiltration was not increased after vaccination.

Conclusion

A prevaccination inflamed type 1 immune contexture is required for stronger vaccine-induced immune infiltration and is associated with better clinical response. Therapeutic vaccination did not overtly increase immune infiltration of cold lesions.

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<![CDATA[Identification of tumor immune infiltration-associated lncRNAs for improving prognosis and immunotherapy response of patients with non-small cell lung cancer]]> https://www.researchpad.co/article/N0d8f8065-3439-4072-841a-6231a05f0997

Background

Increasing evidence has demonstrated the functional relevance of long non-coding RNAs (lncRNAs) to immunity regulation and the tumor microenvironment in non-small cell lung cancer (NSCLC). However, tumor immune infiltration-associated lncRNAs and their value in improving clinical outcomes and immunotherapy remain largely unexplored.

Methods

We developed a computational approach to identify an lncRNA signature (TILSig) as an indicator of immune cell infiltration in patients with NSCLC through integrative analysis for lncRNA, immune and clinical profiles of 115 immune cell lines, 187 NSCLC cell lines and 1533 patients with NSCLC. Then the influence of the TILSig on the prognosis and immunotherapy in NSCLC was comprehensively investigated.

Results

Computational immune and lncRNA profiling analysis identified an lncRNA signature (TILSig) consisting of seven lncRNAs associated with tumor immune infiltration. The TILSig significantly stratified patients into the immune-cold group and immune-hot group in both training and validation cohorts. These immune-hot patients exhibit significantly improved survival outcome and greater immune cell infiltration compared with immune-cold patients. Multivariate analysis revealed that the TILSig is an independent predictive factor after adjusting for other clinical factors. Further analysis accounting for TILSig and immune checkpoint gene revealed that the TILSig has a discriminatory power in patients with similar expression levels of immune checkpoint genes and significantly prolonged survival was observed for patients with low TILSig and low immune checkpoint gene expression implying a better response to immune checkpoint inhibitor (ICI) immunotherapy.

Conclusions

Our finding demonstrated the importance and value of lncRNAs in evaluating the immune infiltrate of the tumor and highlighted the potential of lncRNA coupled with specific immune checkpoint factors as predictive biomarkers of ICI response to enable a more precise selection of patients.

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