SMARCB1 expression is a novel diagnostic and prognostic biomarker for osteosarcoma

Background: Although weak SWI/SNF related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1) expression is a known diagnostic and prognostic biomarker in several malignancies, its expression and clinical significance in osteosarcoma remain unknown. The aim of the present study was to investigate SMARCB1 expression in osteosarcoma and its clinical significance with respect to chemosensitivity and prognosis.Methods: We obtained 114 specimens from 70 osteosarcoma patients to construct a tissue microarray (TMA) and assess SMARCB1 protein expression via immunohistochemistry (IHC). The mRNA expression of SMARCB1 was in-silico analyzed using open-access RNA sequencing (RNA-Seq) and clinicopathological data provided by the Therapeutically Applicable Research to Generate Effective Treatments on Osteosarcoma (TARGET-OS) project. The correlations between SMARCB1 expression and clinical features were statistically analyzed.Results: Weak SMARCB1 expression occurred in 70% of the osteosarcoma patient specimens in the TMA, and significantly correlated with poor neoadjuvant response as well as shorter overall and progression-free survival (PFS). In addition, mRNA in-silico analysis confirmed that SMARCB1 expression correlates with chemotherapeutic response and prognosis in osteosarcoma patients.Conclusion: To our knowledge, the present study is the first to analyze SMARCB1 expression in osteosarcoma. SMARCB1 may serve as a novel diagnostic and prognostic biomarker in osteosarcoma.     

Circulating exosomal CPNE3 as a diagnostic and prognostic biomarker for colorectal cancer

Exosomal proteins are emerging as relevant diagnostic and prognostic biomarkers for cancer. This study was aimed at illustrating the clinical significance of exosomal Copine III (CPNE3) purified from the plasma of colorectal cancer (CRC) patients. The CPNE3 expression levels in CRC tissues were analyzed by real-time PCR, western blot, and immunohistochemistry. Plasma exosomes were isolated to examine the CPNE3 level using ELISA. Pearson’s correlation analysis was performed to investigate the CPNE3 levels between CRC tissues and matched plasma samples. Receiver operating characteristic curve analysis was developed to measure the diagnostic performance of exosomal CPNE3. The Kaplan–Meier method and Cox's proportional hazards model were utilized to determine statistical differences in survival times. CPNE3 showed increased expressions in the CRC tissues. A moderately significant correlation was found between CPNE3 expression in CRC tissues by immunohistochemistry and matched serum exosomal CPNE3 expression by ELISA (r = 0.645,(r = 0.645, p < 0.001). < 0.001). Exosomal CPNE3 yielded a sensitivity of 67.5% and a specificity of 84.4% in CRC at the cutoff value of 0.143 pg per 1ug1 ug exosome. Combined data from carcinoembryonic antigen and exosomal CPNE3 achieved 84.8% sensitivity and 81.2% specificity as a diagnostic tool. CRC patients with lower exosomal CPNE3 levels had substantially better disease-free survival (hazard ratio [HR], 2.9; 95% confidence interval [CI]: 1.3–6.4; p = 0.009) = 0.009) and overall survival (HR, 3.4; 95% CI: 1.2–9.9; p = 0.026) = 0.026) compared with those with higher exosomal CPNE3 levels. Exosomal CPNE3 show potential implications in CRC diagnosis and prognosis.     

Integrated bioinformatic analysis reveals YWHAB as a novel diagnostic biomarker for idiopathic pulmonary arterial hypertension

Idiopathic pulmonary arterial hypertension (IPAH) is a severe cardiovascular disease that is a serious threat to human life. However, the specific diagnostic biomarkers have not been fully clarified and candidate regulatory targets for IPAH have not been identified. The aim of this study was to explore the potential diagnostic biomarkers and possible regulatory targets of IPAH. We performed a weighted gene coexpression network analysis and calculated module-trait correlations based on a public microarray data set (GSE703) and six modules were found to be related to IPAH. Two modules which have the strongest correlation with IPAH were further analyzed and the top 10 hub genes in the two modules were identified. Furthermore, we validated the data by quantitative real-time polymerase chain reaction (qRT-PCR) in an independent sample set originated from our study center. Overall, the qRT-PCR results were consistent with most of the results of the microarray analysis. Intriguingly, the highest change was found for YWHAB, a gene encodes a protein belonging to the 14-3-3 family of proteins, members of which mediate signal transduction by binding to phosphoserine-containing proteins. Thus, YWHAB was subsequently selected for validation. In congruent with the gene expression analysis, plasma 14-3-3β concentrations were significantly increased in patients with IPAH compared with healthy controls, and 14-3-3β expression was also positively correlated with mean pulmonary artery pressure ( R ² = 0.8783; p < 0.001). Taken together, using weighted gene coexpression analysis, YWHAB was identified and validated in association with IPAH progression, which might serve as a biomarker and/or therapeutic target for IPAH.     

Secernin-1 as a novel prognostic biomarker candidate of synovial sarcoma revealed by proteomics

We aimed to develop prognostic biomarkers for synovial sarcoma employing a proteomic approach. We examined the proteomic profile of synovial sarcoma using two-dimensional difference gel electrophoresis (2D-DIGE). We identified 20 protein spots whose intensity was statistically different (p<0.01) between a group of eight patients who were alive and continuously disease-free for over five years and a group of five patients who died of the disease within two years post diagnosis. Mass spectrometric protein identification demonstrated that these 20 spots corresponded to 17 distinct gene products. Three of the 20 spots corresponded to secernin-1 and had higher intensity in the good prognosis group. The prognostic performance of secernin-1 was further examined immunohistochemically in 45 synovial sarcoma cases. The 5-year survival rate was 77.6% and 21.8% for patients with secernin-1 positive and negative primary tumors respectively (p=0.0015). The metastasis-free survival was significantly higher in the patient group with high secernin-1 expression compared to that with low expression (p=0.0012). Uni- and multivariate analyses revealed that secernin-1 expression was a powerful prognostic factor compared to other clinico-pathological parameters examined. These results indicate that secernin-1 may be used as a biomarker to predict the overall and metastasis-free survival in synovial sarcoma patients.     

Soluble TREM-1 as a diagnostic and prognostic biomarker in patients with septic shock: an observational clinical study

Objectives: The impact of TREM-1-mediated inflammation was investigated in different inflammatory settings.

Methods: Secondary analyses of an observational clinical pilot study, including 60 patients with septic shock, 30 postoperative controls and 30 healthy volunteers.

Results: Plasma levels of sTREM-1 were found to identify patients with septic shock more effectively than procalcitonin and C-reactive protein. Moreover, sTREM-1 was identified to be an early predictor for survival in patients with septic shock.

Conclusion: Due to its diagnostic as well as prognostic value in sepsis syndrome, implementation of sTREM-1 measurements in routine diagnostics should be taken into account.     

MicroRNA-21 as a diagnostic and prognostic biomarker of lung cancer: a systematic review and meta-analysis

Background: The relationship between microRNA-21 (miRNA-21) and pathogenesis of lung cancer is a considerable focus of research interest. However, to our knowledge, no in-depth meta-analyses based on existing evidence to ascertain the value of miRNA-21 in diagnosis and clinical prognosis of lung cancer have been documented.Methods: We comprehensively searched all the literature pertaining to ‘miRNA-21’ and ‘lung cancer’ from four databases from the period of inception of each database until May 2020. Using specific inclusion and exclusion criteria, the literature for inclusion was identified and the necessary data extracted.Results: In total, 46 articles were included in the meta-analysis, among which 31 focused on diagnostic value and 15 on prognostic value. Combined sensitivity (SEN) of miRNA-21 in diagnosis of lung cancer was 0.77 (95% confidence interval (CI): 0.72–0.81), specificity (SPE) was 0.86 (95% CI: 0.80–0.90), diagnostic odds ratio (DOR) was (95% CI: 12–33), and area under the SROC curve (AUC) was 0.87 (95% CI: 0.84–0.90). No significant correlations were observed between abnormal expression of miRNA-21 and gender, smoking habits, pathological type and clinical stage of lung cancer (P>0.05). In terms of overall survival (OS), univariate analysis (hazards ratio (HR) = 1.49, 95% CI: 1.22–1.82) revealed high expression of miRNA-21 as an influencing factor for lung cancer. MiRNA-21 was confirmed as an independent risk factor for poor prognosis in multivariate analysis (HR = 1.65, 95% CI: 1.24–2.19).Conclusion: MiRNA-21 has potential clinical value in the diagnosis and prognosis of lung cancer and may serve as an effective diagnostic marker and therapeutic target in the future.     

Dextran-g-PEI nanoparticles as a carrier for co-delivery of adriamycin and plasmid into osteosarcoma cells

Combination of chemotherapy and gene therapy of cancer has synergistic effects on overcoming drug resistance. Macromolecular materials such as dextran and PEI have been a potential module for chemotherapeutics and gene delivery. Herein, we hypothesize the combinational strategy of chemotherapy and gene therapy in a single dextran-PEI nanoplatform. The physicochemical properties, cytotoxicity, transfection efficiency were investigated in vitro. Ultra-violet spectrum and ¹H NMR revealed adriamycin and PEI were grafted to dextran chain. Agarose gel electrophoresis demonstrated that the migration of plasmid was completely retarded when the N/P ratio of complex was 4. The sizes of DEX-ADM-PEI/DNA nanoparticles decreased and the zeta potentials enhanced with the increasing N/P ratio. Transmission electron microscope indicated a round morphology of the nanoparticles. DEX-ADM-PEI conjugation has higher cytotoxicity, compared to free adriamycin, in MG-63 and Saos-2 osteosarcoma cells but DEX-PEI maintained over 65% cell viability at the concentration of 8 mg/mL. The transfection efficiency of DEX-ADM-PEI/pEGFP-N1 at N/P ratio of 4:1 both in MG-63 and Saos-2 cell were slightly low than that of PEI 25k. But our nanoplatform efficiently delivered both plasmid pEGFP-N1 and adriamycin into osteosarcoma cells. This study demonstrated that DEX-ADM-PEI efficiently and selectively delivered both plasmid pEGFP-N1 and adriamycin to osteosarcoma cells with low cytotoxicity.     

Identification of isocitrate dehydrogenase 1 as a potential diagnostic and prognostic biomarker for non-small cell lung cancer by proteomic analysis

Lung cancer is the leading cause of cancer-related death in the world. To explore tumor biomarkers for clinical application, two-dimensional fluorescence difference gel electrophoresis and subsequent MALDI-TOF/TOF mass spectrometry were performed to identify proteins differentially expressed in 12 pairs of lung squamous cell tumors and their corresponding normal tissues. A total of 28 nonredundant proteins were identified with significant alteration in lung tumors. The up-regulation of isocitrate dehydrogenase 1 (IDH1), superoxide dismutase 2, 14-3-3ε, and receptor of activated protein kinase C1 and the down-regulation of peroxiredoxin 2 in tumors were validated by RT-PCR and Western blot analysis in independent 15 pairs of samples. Increased IDH1 expression was further verified by the immunohistochemical study in extended 73 squamous cell carcinoma and 64 adenocarcinoma clinical samples. A correlation between IDH1 expression and poor overall survival of non-small cell lung cancer (NSCLC) patients was observed. Furthermore, ELISA analysis showed that the plasma level of IDH1 was significantly elevated in NSCLC patients compared with benign lung disease patients and healthy individuals. In addition, knockdown of IDH1 by RNA interference suppressed the proliferation of NSCLC cell line and decreased the growth of xenograft tumors in vivo. These observations suggested that IDH1, as a protein promoting tumor growth, could be used as a plasma biomarker for diagnosis and a histochemical biomarker for prognosis prediction of NSCLC.     

Copeptin as a diagnostic biomarker for sepsis-related deaths

Copeptin has been shown to increase in patients with sepsis, severe sepsis and septic shock. In the study herein described, copeptin was measured in a series of sepsis-related fatalities and control cases that underwent medico-legal investigations. No age-dependent differences in copeptin levels in either sepsis or control cases were observed. No correlation between copeptin concentrations and postmortem interval was identified in either group. Copeptin levels were significantly higher in sepsis cases. Moreover, copeptin concentrations in septic cases correlated with procalcitonin, C-reactive protein and interleukin 6 values. These preliminary findings seem to indicate that copeptin can be reliably measured in biological samples collected during postmortem investigations. These results also suggest that hemodynamic instability associated with sepsis and septic shock can be characterized by copeptin measurement also in the forensic casework.     

Pseudogene DUXAP10 can be used as a diagnostic and prognostic biomarker in human cancers

The pseudogene DUXAP10 is overexpressed in numerous types of human cancers. However, the diagnostic and prognostic value of DUXAP10 in cancers has yet to be characterized. PubMed, EMBASE, Web of Science, the Cancer Genome Atlas (TCGA), and Gene Expression Omnibus databases were comprehensively searched in this study. A total of 50 studies comprising 11,292 patients were collected in this integrated analysis. DUXAP10 was confirmed to be significantly overexpressed in various human cancers (p < .05). Summary receiver operating characteristic (SROC) curve analysis was implemented, which indicated that DUXAP10 was a potential diagnostic biomarker for human cancers (area under the curve [AUC] of SROC curve = 0.81 [0.77–0.84]; pooled sensitivity = 0.69 [0.62–0.75]; pooled specificity = 0.81 [0.73–0.87]). In addition, hazard ratios (HRs) with 95% confidence intervals (CIs) were obtained to evaluate the association of DUXAP10 expression with overall survival (OS) time of cancer patients. Outcomes of meta-analysis suggested that upregulation of DUXAP10 was closely associated with poor OS (pooled HR = 1.11 [1.03–1.18]). Our study revealed that the pseudogene DUXAP10 was upregulated in multiple types of cancers and could be a potential biomarker with good diagnostic and prognostic value for human cancers.     

Serum circulating cell free DNA as potential diagnostic and prognostic biomarker in non small cell lung cancer

BackgroundNon-small cell lung cancer (NSCLC) is leading cause of cancer related death and the survival rate for patients with NSCLC remain poor so early diagnosis of NSCLC represents the best opportunity for cure. Cell-free DNA (cf-DNA) is extracellular nucleic acids found in cell-free plasma/serum of humans, given the recent approval of a liquid biopsy in lung cancer, the use of circulating tumor DNA as a novel non-invasive diagnostic and prognostic biomarker is promising.ObjectivesStudying whether the concentrations of circulating Cell Free DNA in serum can be used as a diagnostic and prognostic biomarker for NSCLC patients.MethodThis study was carried out on 140 subjects included 60 patients with non small cell lung cancer,40 patients with Chronic Obstructive Pulmonary Disease (COPD) and 40 healthy controls. Quantitative analysis of serum circulating cf-DNA was done b y AlU-based quantitative real time PCR. Serum level of CEA was measured by ELISA.ResultsNSCLC patients demonstrated significantly higher values of each of ALU 215, ALU 247, and DNA integrity than both COPD patients and controls. On ROC curve analysis, the total accuracy of ALU 247, ALU 115, DNA integrity (92.1%, 83.6%, 56.4%) at cutoff points (325, 565 & 0.48) respectively. On combining both DNA integrity and CEA, improved sensitivity to 93.3% was noted. For NSCLC patients, ALU 115 & ALU 247 increased significantly with more advanced stage and highest level was noticed in metastatic patients. Regarding survival there was better overall survival among patients with low DNA integrity.ConclusionSerum cf-DNA concentrations and integrity index may be valuable tool in early diagnosis of NSCLC and prediction of prognosis of those patients.     

The survivin molecule as a double-edged sword in cellular physiologic and pathologic conditions and its role as a potential biomarker and therapeutic target in cancer

Survivin is a member of the family of apoptosis inhibitory proteins with increased expression level in most cancerous tissues. Evidence shows that survivin plays regulatory roles in proliferation or survival of normal adult cells, principally vascular endothelial cells, T lymphocytes, primitive hematopoietic cells, and polymorphonuclear neutrophils. Survivin antiapoptotic role is, directly and indirectly, related to caspase proteins and shows its role in cell division through the chromosomal passenger complex. Survivin contains many genetic polymorphisms that the role of some variations has been proven in several cancers. The −31G/C polymorphism is one of the most important survivin mutations which is located in the promoter region on a CDE/CHR motif. This polymorphism can upregulate the survivin messenger RNA. In addition, its allele C can increase the risk of cancers in 1.27-fold than allele G. Considering the fundamental role of survivin in different cancers, this protein could be considered as a new therapeutic target in cancer treatment. For this purpose, various strategies have been designed including the prevention of survivin expression through inhibition of mRNA translation using antagonistic molecules, inhibition of survivin gene function through small inhibitory molecules, gene therapy, and immunotherapy. In this study, we describe the structure, played roles in physiological and pathological states and genetic polymorphisms of survivin. Finally, the role of survivin as a potential target in cancer therapy given challenges ahead has been discussed.     

Targeting HMGB1-mediated autophagy as a novel therapeutic strategy for osteosarcoma

Autophagy is a catabolic process critical to maintaining cellular homeostasis and responding to cytotoxic insult. Autophagy is recognized as “programmed cell survival” in contrast to apoptosis or programmed cell death. Upregulation of autophagy has been observed in many types of cancers and has been demonstrated to both promote and inhibit antitumor drug resistance depending to a large extent on the nature and duration of the treatment-induced metabolic stress as well as the tumor type. Cisplatin, doxorubicin and methotrexate are commonly used anticancer drugs in osteosarcoma, the most common form of childhood and adolescent cancer. Our recent study demonstrated that high mobility group box 1 protein (HMGB1)-mediated autophagy is a significant contributor to drug resistance in osteosarcoma cells. Inhibition of both HMGB1 and autophagy increase the drug sensitivity of osteosarcoma cells in vivo and in vitro. Furthermore, we demonstrated that the ULK1-FIP200 complex is required for the interaction between HMGB1 and BECN1, which then promotes BECN1-PtdIns3KC3 complex formation during autophagy. Thus, these findings provide a novel mechanism of osteosarcoma resistance to therapy facilitated by HMGB1-mediated autophagy and provide a new target for the control of drug-resistant osteosarcoma patients.     

In silico assessment of EpCAM transcriptional expression and determination of the prognostic biomarker for human lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC)

Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein which is involved in cell signaling, proliferation, maturation, and movement, all of which are crucial for the proper development of cells and tissues. Cleavage of the EpCAM protein leads to the up-regulation of c-myc, e-fabp, and cyclins A and E which promote tumorigenesis. EpCAM can act as potential diagnostic and prognostic biomarker for different types of cancers as it is also found to be expressed in epithelia and epithelial-derived neoplasms. Hence, we aimed to analyze the EpCAM gene expression and any associated feedback in the patients of two major types of lung cancer (LC) i.e., lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), based on the publicly available online databases. In this study, server-based gene expression analysis represents the up-regulation of EpCAM in both LUAD and LUSC subtypes as compared to the corresponding normal tissues. Besides, the histological sections revealed the over-expression of EpCAM protein in cancerous tissues by depicting strong staining signals. Furthermore, mutation analysis suggested missense as the predominant type of mutation both in LUAD and LUSC in the EpCAM gene. A significant correlation (P-value < 0.05) between the higher EpCAM expression and lower patient survival was also found in this study. Finally, the co-expressed genes were identified with their ontological features and signaling pathways associated in LC development. The overall study suggests EpCAM to be a significant biomarker for human LC prognosis.