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.     

Glioblastoma multiforme presenting as postpartum depression: a case report

Background

Alterations of mental status are characteristic of psychiatric disorders but may also result from a multitude of organic causes. Generally, physical examination and blood analysis are a part of basic psychiatric differential diagnostics, whereas more sophisticated procedures (for example, brain imaging) are applied only in cases with pathologic diagnostic findings. Our report challenges this approach by describing a case of glioblastoma multiforme presenting as postpartum depression without abnormalities in basic differential diagnostics.

Case presentation

A 28-year-old white woman who had been in outpatient treatment for postpartum depression was taken to the psychiatric emergency room. The psychopathological assessment, however, showed mild disorientation and severe deficits of long-term memory. Moreover, she complained of stabbing, bilateral headaches, but results of her physical examination and blood analysis were unremarkable. Magnetic resonance imaging of the brain was performed, which showed a contrast-enhanced mass lesion in the left frontal lobe. The patient underwent urgent tumor resection, and histologic results revealed an IDH-mutant glioblastoma multiforme. The patient was discharged with a substantially improved psychopathology and without neurological deficits.

Conclusions

This report adds to the evidence that postpartum depression may have organic causes in some cases, a fact that needs to be considered in the clinical setting. Atypical neurocognitive findings in a psychiatric interview may alone justify brain imaging, despite normal physical examination and blood analysis results.

     

AGAP2-AS1 serves as an oncogenic lncRNA and prognostic biomarker in glioblastoma multiforme

Long noncoding RNA (lncRNA) AGAP2 antisense RNA 1 (AGAP2-AS1) has been suggested to function as an oncogenic lncRNA in lung cancer, breast cancer, and anaplastic glioma. However, the expression pattern and molecular mechanism of AGAP2-AS1 in glioblastoma multiforme (GBM) remains unknown. The purpose of this study is to present more evidence about the clinical and biological function of AGAP2-AS1 in GBM. In our results, we found AGAP2-AS1 expression was increased in GBM compared with adjacent normal brain tissues or low-grade glioma tissues, and there was no significantly different between low-grade glioma tissues and normal tissues. Kaplan-Meier survival analysis indicated patients with GBM having high-expression of AGAP2-AS1 had shorter overall survival time than those with low expression of AGAP2-AS1. The loss-of-function studies showed that downregulation of AGAP2-AS1 depressed cell proliferation, migration, and invasion, and promoted cell apoptosis in GBM. In summary, AGAP2-AS1 is a prognostic biomarker for patients with GBM, and functions as an oncogenic lncRNA to modulate GBM cell proliferation, apoptosis, migration, and invasion, which suggests that AGAP2-AS1 is potential therapeutic target for GBM.     

Identification of a 4-miRNA signature as a potential prognostic biomarker for pancreatic adenocarcinoma

An microRNA (miRNA) signature to predict the clinical outcome of pancreatic adenocarcinoma (PAAD) is still lacking. In the current study, we aimed at identifying and evaluating a prognostic miRNA signature for patients with PAAD. The miRNA expression profile and the clinical information regarding patients with PAAD were recruited from The Cancer Genome Atlas database. Differentially expressed miRNAs were identified between normal and tumor samples. By means of survival analysis, a 4-miRNA signature for predicting patients' with PAAD overall survival (OS) was constructed. Receiver operating characteristic (ROC) analysis was applied to determine the efficiency of survival prediction. Furthermore, the biological function of the predicted miRNAs was evaluated using a bioinformatics approach. Four (hsa-mir-126, hsa-mir-3613, hsa-mir-424, and hsa-mir-4772) out of 17 differentially expressed miRNAs were associated to the OS of patients with PAAD. Moreover, the area under the curve (AUC) of the constructed 4-miRNA signature associated to patients' with PAAD 2-year survival was 0.789. The multivariate Cox's proportional hazards regression model suggested that this 4-miRNA signature was an independent prognostic factor of other clinical parameters in patients with PAAD. Further pathway enrichment analyses revealed that the miRNAs in the 4-miRNA signature might regulate genes that affect focal adhesion, Wnt signaling pathway, and PI3K-Akt signaling pathway. Thus, these findings indicated that the 4-miRNA signature might be an effective independent prognostic biomarker in the prediction of PAAD patients' survival.     

Proteomics identified nuclear N-myc downstream-regulated gene 1 as a prognostic tissue biomarker candidate in renal cell carcinoma

The aim of this study was to identify proteins with aberrant expression in clear cell renal cell carcinoma (ccRCC), and elucidate their clinical utilities. The protein expression profiles of primary ccRCC tumor tissues and neighboring non-tumor tissues were obtained from 9 patients by two-dimensional difference gel electrophoresis and mass spectrometry. Comparative analysis of 3771 protein spots led to the identification of 73 proteins that were expressed at aberrant levels in tumor tissues compared with non-tumor tissues. Among these 73 proteins, we further focused on N-myc downstream-regulated gene 1 protein (NDRG1). NDRG1 expression is regulated by members of myc family as well as by p53, HIF1A, and SGK1. The biological and clinical significance of NDRG1 is controversial for various malignancies and no detailed studies on NDRG1 have been reported in ccRCC until our study. For the 82 newly enrolled ccRCC patients, immunohistochemical analysis revealed a significant association between nuclear NDRG1 and favorable prognosis (p < 0.05). Multivariate analysis demonstrated the role of NDRG1 as an independent factor of progression-free survival (p = 0.01). Subsequent in vitro gene suppression assay demonstrated that NDRG1 silencing significantly enhanced cell proliferation and invasion of RCC cells. The cytotoxic effects of NDRG1 up-regulation induced by an iron chelator were also confirmed. These findings suggest that nuclear NDRG1 has tumor suppressive effects, and the NDRG1 expression may have clinical values in ccRCC. Nuclear NDRG1 may provide additional insights on molecular backgrounds of ccRCC progression, and contribute to the development of novel therapeutic strategy.     

Metallothionein as a prognostic biomarker in breast cancer

Breast cancer is the most common cancer in women, with a general upward trend in incidence. Basic and clinical breast cancer research has continued at a rapid pace, in the endeavor to understand the biology of the disease so as to improve management of patients. Besides traditional pathological indicators, expression of molecular markers in breast cancer has also been comprehensively investigated. This paper will focus on the prognostic utility of metallothioneins (MTs), a family of low molecular weight metal binding proteins encoded by at least 10 functional MT genes that are associated with cell proliferation in breast cancer. Evidence that MT is a potential prognostic biomarker for breast cancer is supported by many reports in the literature. Expression of the MT protein has been detected by immunohistochemistry in a significant portion of invasive ductal breast cancers. MT expression has also been well studied in association with traditional clinico-pathological parameters of breast cancers. Generally, higher MT expression in breast cancers is predictive of worse patient outcomes. The relationship of MT isoforms to histological grade, estrogen receptor (ER) status, and prognosis will also be discussed.     

Identification of a novel tumour microenvironment-based prognostic biomarker in skin cutaneous melanoma

Skin cutaneous melanoma (SKCM) is one of the most destructive skin malignancies and has attracted worldwide attention. However, there is a lack of prognostic biomarkers, especially tumour microenvironment (TME)-based prognostic biomarkers. Therefore, there is an urgent need to investigate the TME in SKCM, as well as to identify efficient biomarkers for the diagnosis and treatment of SKCM patients. A comprehensive analysis was performed using SKCM samples from The Cancer Genome Atlas and normal samples from Genotype-Tissue Expression. TME scores were calculated using the ESTIMATE algorithm, and differential TME scores and differentially expressed prognostic genes were successively identified. We further identified more reliable prognostic genes via least absolute shrinkage and selection operator regression analysis and constructed a prognostic prediction model to predict overall survival. Receiver operating characteristic analysis was used to evaluate the diagnostic efficacy, and Cox regression analysis was applied to explore the relationship with clinicopathological characteristics. Finally, we identified a novel prognostic biomarker and conducted a functional enrichment analysis. After considering ESTIMATEScore and tumour purity as differential TME scores, we identified 34 differentially expressed prognostic genes. Using least absolute shrinkage and selection operator regression, we identified seven potential prognostic biomarkers (SLC13A5, RBM24, IGHV3OR16-15, PRSS35, SLC7A10, IGHV1-69D and IGHV2-26). Combined with receiver operating characteristic and regression analyses, we determined PRSS35 as a novel TME-based prognostic biomarker in SKCM, and functional analysis enriched immune-related cells, functions and signalling pathways. Our study indicated that PRSS35 could act as a potential prognostic biomarker in SKCM by investigating the TME, so as to provide new ideas and insights for the clinical diagnosis and treatment of SKCM.     

Identification of a three-miRNA signature as a novel potential prognostic biomarker in patients with clear cell renal cell carcinoma

Current studies suggest that some microRNAs (miRNAs) are associated with prognosis in clear cell renal cell carcinoma (ccRCC). In this paper, we aimed to identify a miRNAs signature to improve prognostic prediction for ccRCC patients. Using ccRCC RNA-Seq data of The Cancer Genome Atlas (TCGA) database, we identified 177 differentially expressed miRNAs between ccRCC and paracancerous tissue. Then all the ccRCC tumor samples were divided into training set and validation set randomly. Three-miRNA signature including miR130b, miR-18a, and miR-223 were constructed by the least absolute shrinkage and selection operator (LASSO) Cox regression model in training set. According to optimal cut-off value of three-miRNA signature risk score, all the patients could be classified into high-risk group and low-risk group significantly. Survival of patients was significantly different between two groups (hazard ratio, 5.58, 95% confidence interval, 3.17-9.80; P < 0.0001), and three-miRNA signature performed favorably prognostic and predictive accuracy. The results were further validated in the validation set and total set. Multivariate Cox regression analyses and subgroup analyses showed that three-miRNA signature was an independent prognostic factor. Two nomograms that integrated three-miRNA signature and three clinicopathological risk factors were constructed to predict overall survival and disease-free survival after surgery for ccRCC patients. Functional enrichment analysis showed the possible roles of three-miRNA signature in some cancer-associated biological processes and pathways. In conclusion, we developed a novel three-miRNA signature that performed reliable prognostic for patient survival with ccRCC, it might facilitate ccRCC patients counseling and individualize management.     

Identification of phospholipid scramblase 1 as a biomarker and determination of its prognostic value for colorectal cancer

The purpose of this study was to examine the expression of phospholipid scramblase 1 (PLSCR1) in tumor tissues and plasma specimens of patients with colorectal cancer (CRC), as well as analyze its association with clinical parameters. The expression levels of PLSCR1 protein in 104 matched CRC and adjacent normal tissue sections and 50 pairs of CRC tissue blocks were determined by use of immunohistochemical and Western blot analyses, respectively. To evaluate the diagnostic potential of PLSCR1, the plasma levels of PLSCR1 were investigated in 111 additional subjects (59 CRC patients and 52 healthy controls) by Western blot. PLSCR1 was overexpressed in malignant adenocarcinoma tissues compared with normal colorectal mucosa (P < 0.001). In addition, the plasma level of PLSCR1 was not only significantly elevated in CRC patients compared with healthy individuals (P < 0.001), but it was also substantially increased in early stage CRC (P < 0.001). Importantly, the overall sensitivity and specificity of PLSCR1 for CRC detection were 80% and 59.6%, respectively. The area under the ROC curve of PLSCR1 for CRC diagnosis is 0.75, which increases to 0.8 if combined with the measurement of carcinoembryonic antigen. Univariate analysis with the Cox regression model revealed that elevated PLSCR1 expression indicated a poor prognosis for CRC. This study showed that PLSCR1 protein levels were significantly elevated in both the cancer tissue and plasma of CRC patients. Moreover, the plasma levels of PLSCR1 were significantly elevated in patients with early stage CRC compared with healthy individuals, suggesting that PLSCR1 might be used as a noninvasive serological diagnostic and prognostic biomarker for CRC.     

CXCR4 as a prognostic biomarker in gastrointestinal cancer: a meta-analysis

Background: CXCR4 is a member of the C-X-C chemokine receptor family, which is associated with multiple types of cancer. Although it has been widely reported, the prognostic value of CXCR4 expression in gastrointestinal (GI) cancer remains controversial.

Methods: A meta-analysis was conducted to investigate the relationship between CXCR4 and prognosis of patients with GI cancer. Subgroup analysis was also performed according to tumour subtypes and heterogeneity test.

Results: A total of 24 studies including 3637 cases suggested that overexpression of CXCR4 is significantly associated with overall survival (OS) for patients with GI cancer (HR = 1.71, 95% CI = 1.45–2.03, p?=?0.000). Subgroup analysis also indicated that high CXCR4 expression in oesophagus, gastric and colorectal cancer all predicted a worse prognosis (HR = 1.52, 95% CI = 1.26–1.84, p?=?0.001 for oesophagus cancer; HR = 1.59, 95% CI = 1.10–2.30, p?=?0.015 for gastric cancer; HR = 2.21, 95% CI = 1.56–3.14, p?=?0.000 for colorectal cancer).

Conclusions: CXCR4 may serve as a prognostic indicator in GI cancer patients.     

In silico studies on marine actinomycetes as potential inhibitors for Glioblastoma multiforme

Glioblastoma multiforme (GBM) is considered to be the most common and often deadly disorder which affects the brain. It is caused by the over expression of proteins such as ephrin type-A receptor 2 (EphA2), epidermal growth factor receptor (EGFR) and EGFRvIII. These 3 proteins are considered to be the potential therapeutic targets for GBM. Among these, EphA2 is reported to be over-expressed in ˜90% of GBM. Herein we selected 35 compounds from marine actinomycetes, 5 in vitro and in vivo studied drug candidates and 4 commercially available drugs for GBM which were identified from literature and analysed by using comparative docking studies. Based on the glide scores and other in silico parameters available in Schrödinger, two selected marine actinomycetes compounds which include Tetracenomycin D and Chartreusin exhibited better binding energy among all the compounds studied in comparative docking. In this study we have demonstrated the inhibition of the 3 selected targets by the two bioactive compounds from marine actinomycetes through in-silico docking studies. Furthermore molecular dynamics simulation were also been performed to check the stability and the amino acids interacted with the 3 molecular targets (EphA2 receptor, EGFR, EGFRvIII) for GBM. Our results suggest that Tetracinomycin D and Chartreusin are the novel and potential inhibitor for the treatment of GBM.     

Identification of complement C3a as a candidate biomarker in human chronic hepatitis C and HCV-related hepatocellular carcinoma using a proteomics approach

Although the significant risk factors for hepatocellular carcinoma (HCC) are well known from epidemiological studies, diagnosis of this disease at an early stage is difficult, and HCC remains one of the leading causes of cancer death worldwide. Thus, to identify any useful HCC-related biomarkers is still a need. We performed SELDI-TOF MS to identify differentially expressed proteins in HCC serum using weak cation exchange protein chips. Protein characterization was performed by 2-DE separation and nano flow LC-MS/MS. A total of 55 sera were collected from HCC patients and compared with those from 48 patients with chronic hepatitis and 9 healthy individuals. A candidate marker of about 8900 Da was detected as differentially expressed in patients with chronic hepatitis C and hepatitis C virus (HCV)-related HCC. We identified this differentially expressed protein as complement C3a. The expression of C3a in HCC sera was further validated by PS20 chip immunoassay and Western blotting. Complement C3a was found to be elevated in patients with chronic hepatitis C and HCV-related HCC. The combination of SELDI-TOF MS and 2-DE provides a solution to identify disease-associated serum biomarkers.     

Serum ferritin as a candidate diagnostic biomarker of polycystic ovarian syndrome: a meta-analysis

Objective: In this study, we investigated about the potential of serum ferritin as a complementary diagnostic biomarker of polycystic ovarian syndrome (PCOS) by performing a meta-analysis of existing literature.

Materials and methods: Eleven studies written in English were retrieved up to 30 June 2018. Data were extracted from the selected studies by two of the authors and was subjected to statistical analysis. Levels of serum ferritin were compared between women with PCOS and controls using the standardized mean difference (SMD) and 95% confidence interval (CI). Subgroup analysis was also performed and stratified by ethnicity (Asians versus Caucasians).

Results: Overall post-outlier outcomes indicated that elevated serum ferritin is strongly associated with PCOS (SMD: 0.52; 95% CI: 0.40–0.64; P^A?=?10^?5). Subgroup analysis by ethnicity showed no significant difference between Asian and Caucasian population. Post-outlier receiving operations characteristics curve were plotted and showed that values for serum ferritin showed good potential in discriminating patients with and without PCOS (AUC?=?0.827, p?=?0.006).

Conclusion: Our findings suggest that high serum ferritin level is significantly associated with PCOS and its potential as a biomarker is evident in its high diagnostic accuracy. However, additional studies are needed to confirm our claims.     

Identification SYT13 as a novel biomarker in lung adenocarcinoma

Synaptotagmins are a class of proteins that play an important role in the secretion of neurotransmitters by synaptic vesicles. However, recent studies have shown that members of this family also have a certain function in the development of tumors. In this study, we first identified through The Cancer Genome Atlas data analyzed that a novel synaptotagmin, SYT13, was closely related to the prognosis of lung adenocarcinoma, but was not significantly correlated with the prognosis of lung squamous cell carcinoma. Then we knocked down the expression of SYT13 gene in lung adenocarcinoma cell lines A549 and H1299, and successfully induced decreased proliferation and clonality of lung adenocarcinoma cell lines, and observed cell cycle arrest and apoptosis enhancement in both cell lines. In addition, we detected the migration ability of SYT13 knockdown lung adenocarcinoma cell lines by the cell scratch test and the transwell test. Interestingly, there was a decreased migration ability of SYT13 knockdown in H1299 cells even though there was no significant difference in the migration of A549 cells. These results demonstrate that SYT13 plays an important role in the development of lung adenocarcinoma, which deepens our understanding of the mechanism of lung adenocarcinoma development and provides new possibilities for targeted therapy of lung adenocarcinoma.     

Identification of citrullinated alpha-enolase as a candidate autoantigen in rheumatoid arthritis

Antibodies against citrullinated proteins are highly specific for rheumatoid arthritis (RA), but little is understood about their citrullinated target antigens. We have detected a candidate citrullinated protein by immunoblotting lysates of monocytic and granulocytic HL-60 cells treated with peptidylarginine deiminase. In an initial screen of serum samples from four patients with RA and one control, a protein of molecular mass 47 kDa from monocytic HL-60s reacted with sera from the patients, but not with the serum from the control. Only the citrullinated form of the protein was recognised. The antigen was identified by tandem mass spectrometry as alpha-enolase, and the positions of nine citrulline residues in the sequence were determined. Serum samples from 52 patients with RA and 40 healthy controls were tested for presence of antibodies against citrullinated and non-citrullinated alpha-enolase by immunoblotting of the purified antigens. Twenty-four sera from patients with RA (46%) reacted with citrullinated alpha-enolase, of which seven (13%) also recognised the non-citrullinated protein. Six samples from the controls (15%) reacted with both forms. Alpha-enolase was detected in the RA joint, where it co-localised with citrullinated proteins. The presence of antibody together with expression of antigen within the joint implicates citrullinated alpha-enolase as a candidate autoantigen that could drive the chronic inflammatory response in RA.