Biomarker Of Unfavorable Prognosis Research Articles

Baseline splenic volume as a biomarker for clinical outcome and circulating lymphocyte count in gastric cancer.

The spleen is the largest peripheral lymphoid organ in the body. Studies have implicated the spleen in the development of cancer. However, it is unknown whether splenic volume (SV) is associated with the clinical outcome of gastric cancer. Data of gastric cancer patients treated with surgical resection were retrospectively analyzed. Patients were divided into three groups: underweight, normal-weight and overweight. Overall survival was compared in patients with high and low splenic volume. The correlation between splenic volume and peripheral immune cells were analyzed. Of 541 patients, 71.2% were male and the median age was 60. Underweight, normal-weight and overweight patients accounted for 5.4%, 62.3% and 32.3%, respectively. High splenic volume was associated with unfavorable prognosis across the three groups. In addition, the increase of splenic volume during neoadjuvant chemotherapy was not associated with prognosis. The baseline splenic volume was negatively correlated with lymphocytes (r=-0.21, p<0.001) and positively correlated with NLR (neutrophil-to-lymphocyte ratio) (r=0.24, p<0.001). In a group of patients (n=56), splenic volume was found to have negative correlation with CD4+T cells (r=-0.27, p=0.041) and NK cells (r=-0.30, p=0.025). The presence of high splenic volume is a biomarker of unfavorable prognosis and reduced circulating lymphocytes in gastric cancer.

Increased Expression of NXPH4 Correlates with Immune Cell Infiltration and Unfavorable Prognosis in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the leading malignant carcinomas. Despite the advancement in the treatment for HCC, such as precise hepatectomy, radiotherapy, transarterial therapies, chemotherapy, targeted treatments, and immunotherapy, the 5-year overall survival rate of HCC is extremely low. Hence, novel biomarkers are urgently needed for advancing the therapy and prognosis of HCC. Neurexophilin 4 (NXPH4) is a neuropeptide-like glycoprotein. The study is designed to investigate the function of NXPH4 in HCC through a comprehensive bioinformatics analysis. NXPH4 expression status and prognostic values were analyzed via multiple datasets, such as TCGA, GEO, and ICGC. The association between NXPH4 and immune cell infiltration was estimated by TIMER, TISIDB, and CIBERSORT. In vitro, we explored the biological function of NXPH4 in JHH7 and SNU182 cells through knocking down the expression of NXPH4 via siRNA. In general, NXPH4 was predominantly upregulated in HCC tumors, and increased NXPH4 expression predicted unfavorable prognosis. The gene enrichment analysis displayed that NXPH4 was related with metabolic pathways. NXPH4 expression was correlated with immune cell infiltration. NXPH4 knockdown significantly suppressed proliferation, migration, and invasion of JHH7 and SNU182 cells. This study suggested that the upregulation of NXPH4 is associated with adverse prognosis and immune cell infiltration in HCC. NXPH4 could be a novel biomarker of unfavorable prognosis and an underlying target for immunotherapy in HCC.

Identification and Validation of a Prognostic Signature Based on Methylation Profiles and Methylation-Driven Gene DAB2 as a Prognostic Biomarker in Differentiated Thyroid Carcinoma.

Recurrence is the major death cause of differentiated thyroid carcinoma (DTC), and a better understanding of recurrence risk at early stage may lead to make the optimal medical decision to improve patients' prognosis. The 2015 American Thyroid Association (ATA) risk stratification system primary based on clinic-pathologic features is the most commonly used to describe the initial risk of persistent/recurrent disease. Besides, multiple prognostics models based on multigenes expression profiles have been developed to predict the recurrence risk of DTC patients. Recent evidences indicated that aberrant DNA methylation is involved in the initiation and progression of DTC and can be useful biomarkers for clinical diagnosis and prognosis prediction of DTC. Therefore, there is a need for integrating gene methylation feature to assess the recurrence risk of DTC. Gene methylation profile from The Cancer Genome Atlas (TCGA) was used to construct a recurrence risk model of DTC by successively performed univariate Cox regression, LASSO regression, and multivariate Cox regression. Two Gene Expression Omnibus (GEO) methylation cohorts of DTC were utilized to validate the predictive value of the methylation profiles model as external cohort by receiver operating characteristic (ROC) curve and survival analysis. Besides, CCK-8, colony-formation assay, transwell, and scratch-wound assay were used to investigate the biological significance of critical gene in the model. In our study, we constructed and validated a prognostic signature based on methylation profiles of SPTA1, APCS, and DAB2 and constructed a nomogram based on the methylation-related model, age, and AJCC_T stage that could provide evidence for the long-term treatment and management of DTC patients. Besides, in vitro experiments showed that DAB2 inhibited proliferation, colony-formation, and migration of BCPAP cells and the gene set enrichment analysis and immune infiltration analysis showed that DAB2 may promote antitumor immunity in DTC. In conclusion, promoter hypermethylation and loss expression of DAB2 in DTC may be a biomarker of unfavorable prognosis and poor response to immune therapy.

New Autoantibody Specificities in Systemic Sclerosis and Very Early Systemic Sclerosis.

Chemokine (C-X-C motif) ligand 4 (CXCL4) is a biomarker of unfavorable prognosis in Systemic Sclerosis (SSc), a potentially severe autoimmune condition, characterized by vasculitis, fibrosis and interferon (IFN)-I-signature. We recently reported that autoantibodies to CXCL4 circulate in SSc patients and correlate with IFN-α. Here, we used shorter versions of CXCL4 and CXCL4-L1, the CXCL4 non-allelic variant, to search for autoantibodies exclusively reacting to one or the other CXCL4 form. Moreover, to address whether anti-CXCL4/CXCL4-L1 antibodies were present before SSc onset and predicted SSc-progression, we longitudinally studied two VEDOSS (Very Early Diagnosis of Systemic Sclerosis) patient cohorts, separating SSc-progressors from SSc-non-progressors. We found that anti-CXCL4-specific autoantibodies were present in both SSc and VEDOSS patients (both SSc-progressors and SSc-non-progressors). Anti-CXCL4-L1-specific autoantibodies were especially detected in long-standing SSc (lsSSc). Anti-CXCL4/CXCL4-L1 antibodies correlated with IFN-α and with specific SSc-skin features but only in lsSSc and not in early SSc (eaSSc) or VEDOSS. Thus, a broader antibody response, with reactivity spreading to CXCL4-L1, is characteristic of lsSSc. The early anti-CXCL4 autoantibody response seems qualitatively different from, and likely less pathogenic than, that observed in advanced SSc. Lastly, we confirm that anti-CXCL4 autoantibodies are SSc-biomarkers and uncover that also CXCL4-L1 becomes an autoantigen in lsSSc.

Novel alternative splice variants of the human protein arginine methyltransferase 1 (PRMT1) gene, discovered using next-generation sequencing

Next-generation sequencing (NGS) technology is highly expected to help researchers disclose the complexity of alternative splicing and understand its association with carcinogenesis. Alternative splicing alterations are firmly associated with multiple malignancies, in terms of functional roles in malignant transformation, motility, and/or metastasis of cancer cells. One perfect example illustrating the connection between alternative splicing and cancer is the human protein arginine methyltransferase 1 (PRMT1) gene, previously cloned from members of our research group and involved in a variety of processes including transcription, DNA repair, and signal transduction. Two splice variants of PRMT1 (variants v.1 and v.2) are downregulated in breast cancer. In addition, PRMT1 v.2 promotes the survival and invasiveness of breast cancer cells, while it could serve as a biomarker of unfavorable prognosis in colon cancer patients. The aim of this study was the molecular cloning of novel alternative splice variants of PRMT1 with the use of 3′ RACE coupled with NGS technology. Extensive bioinformatics and computational analysis revealed a significant number of 19 novel alternative splicing events between annotated exons of PRMT1 as well as one novel exon, resulting in the discovery of multiple PRMT1 transcripts. In order to validate the full sequence of the novel transcripts, RT-PCR was carried out with the use of variant-specific primers. As a result, 58 novel PRMT1 transcripts were identified, 34 of which are mRNAs encoding new protein isoforms, whereas the rest 24 transcripts are candidates for nonsense-mediated mRNA decay (NMD).

The prognostic significance of protein arginine methyltransferase 6 expression in colon cancer.

Protein arginine methylation is involved in cellular differentiation and proliferation. Recently, aberrant expression of protein arginine methyltransferases, which are responsible for the methylation reaction, has been reported in various types of cancer. However, there is no clear evidence regarding the prognostic value of abnormal PRMT6 expression in colorectal cancer or the effect of PRMT6 regulation on CRC cells. We investigated the expression patterns of PRMT6 in patients with stage II and III CRC. We detected nuclear expression of PRMT6 in 23.7% of carcinoma samples by immunohistochemistry. Among the clinicopathological parameters, the ratio of poorly differentiated cancer cells was approximately two-fold higher in patients with PRMT6-positive disease than in those with PRMT6-negative disease (p = 0.002). Patients with PRMT6-positive CRC had a shorter disease-free survival than those with PRMT6-negative CRC in both univariate and multivariate analyses (p = 0.018 and p = 0.035, respectively). siRNA-mediated inhibition of PRMT6 expression in CRC cells induced p21WAF1/CIP1 overexpression and suppressed cell growth and colony-forming ability. Concomitantly, apoptosis was induced in PRMT6-suppressed CRC cells. These data suggest that PRMT6 can serve as a biomarker for unfavorable prognosis and as a therapeutic target in CRC.

ICT1 predicts a poor survival and correlated with cell proliferation in diffuse large B-cell lymphoma

Immature colon carcinoma transcript-1 (ICT1) is a crucial member of the large mitoribosomal subunit in mitochondrial ribosome, which has been shown to be closely related to tumorigenesis. Its expression and function in human diffuse large B-cell lymphoma (DLBCL), however, remained elusive. In this study, analysis of public available Oncomine database suggested that the expression levels of ICT1 mRNA was significantly upregulated in DLBCL tissues. Consistently, we described ICT1 was remarkably upregulated in fresh DLBCL samples compared with the corresponding normal tissues using quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and Western blotting. Moreover, ICT1 overexpression was associated with the poor overall survival (OS) of DLBCL patients. Finally, we used DLBCL cell lines to further probe the potential mechanisms, and found shRNA-mediated knockdown of ICT1 significantly suppressed DLBCL cell proliferation, induced cell cycle arrest at G0/G1 phase and apoptosis in vitro. Further verification showed that inhibition of ICT1 gene expression caused the upregulation of the p21, Bad and caspase-3, and downregulation of PCNA, Survivin, CDK4, CDK6 and Cyclin D1. Taken together, this study suggested that ICT1 may play an oncogenic role in human DLBCL by promoting cell proliferation and it might be a biomarker of unfavorable prognosis in DLBCL patients.

The overexpression of KIFC1 was associated with the proliferation and prognosis of non-small cell lung cancer.

The kinesin family member C1 (KIFC1, also known as HSET) is a kinesin superfamily protein (KIFs). Although KIFC1 acts as a crucial role in the development of several human cancers, the KIFC1 expression profile and functional remain unclear in non-small cell lung cancer (NSCLC). We collected the fresh NSCLC samples and paired normal lung tissue in patients with lung cancer operation, and detected KIFC1 expression using quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and Western blotting. To expand on previous smaller-scale studies, NSCLC tissue microarrays (TMA) were analyzed by IHC. Finally, cell lines were employed to further probe the potential mechanisms. In this study, we described that KIFC1 was significantly upregulated in NSCLC tissues compared with the corresponding normal tissues. Moreover, KIFC1 overexpression was associated with the poor overall survival (OS) of NSCLC patients, and siRNA-mediated knockdown of KIFC1 significantly suppressed tumor cell proliferation in vitro. Further verification showed that inhibition of KIFC1 gene expression caused the upregulation of the cyclin-dependent kinases inhibitor p21 and downregulation of the cell cycle driver protein cdc2, which arrested cells in the G2-M phase. we report that increased KIFC1 expression may promote cell proliferation and identified it as a biomarker of unfavorable prognosis in NSCLC patients.

Phenotyping juvenile myoclonic epilepsy. Praxis induction as a biomarker of unfavorable prognosis

PurposeJuvenile myoclonic epilepsy (JME) is a heterogeneous syndrome with seizures presenting typical fluctuation in diurnal cycle and relation with awakening. Few publications have approached clinical expressions of praxis induction (PI) in the nosology of JME as well as its impact on outcome. The aim of this study is to characterize PI as the only reflex trait in JME and its relation with prognosis. MethodJME with PI reported on a questionnaire and confirmed by video-EEG testing (Group 1, 20 patients) were compared with JME without any reflex epileptic trait (Group 2, 25 patients) and followed for a mean of 7.82 years (SD=3.98). Circadian distribution and frequency of seizures were assessed in a diary. Patients also had psychiatric evaluation. ResultsPrevalence of PI was 20/133 (15%) JME patients, and was predominant in males (1.5 male: 1 female; OR 13; p=0.042). Among Group 1 patients, only 2/20 presented seizures exclusively in the morning (p=0.013), and none, exclusively on awakening (p<0.001). PI patients had worse prognosis regarding control of myocloni (p=0.02) and absences (p=0.01); only 7/20 (35.0%) could be treated with VPA in monotherapy (p=0.01). At the last follow-up, 2/20 (10.0%) of Group 1 and 10 (40.0%) of Group 2 patients were free of all three seizure types (p=0.02). Even though relative risk of stress as a precipitant of seizures increased 3.82 times in Group 1, psychiatric comorbidities were not different between groups. ConclusionPI reflex trait in JME is related to seizures without preferential circadian occurrence and reduced response to antiepileptic drugs.

Proteomic Approach to Gastrointestinal Stromal Tumor Identified Prognostic Biomarkers

Biomarker development is a major research theme in cancer proteomics. Cancer is a genetically and clinically diverse disease, and biomarkers for risk stratification therapy are urgently required. A considerable number of biomarker candidates have been discovered by proteomics, and over the last decade proteomics modalities have been developed to identify promising candidates. Validation studies involving hundreds of samples in independent cohorts is the next challenge to prove the clinical utility of any discovered biomarker candidates. Here, we review our efforts directed toward tissue biomarker development using a proteomics approach. With the aim of developing a prognostic biomarker for gastrointestinal stromal tumor (GIST), we examined the protein expression profiles of primary tumors from 17 GIST patients with different risks of recurrence and prognosis after surgery. Through a comparative study using two-dimensional difference gel electrophoresis and mass spectrometry, we found that overexpression of pfetin was specific to GIST patients with a low risk of metastasis and a favorable prognosis after surgery. Using immunohistochemistry, we examined pfetin expression in 422 additional cases of GIST at four hospitals, and confirmed that GIST patients with pfetin-positive primary tumors had a significantly favorable prognosis in all four cohorts. Moreover, the other research group independently validated the prognostic significance of pfetin in 62 cases of GIST at two hospitals. Pfetin was found to be an independent prognostic factor with significant prognostic utility in all risk classification groups, which are based on tumor size and mitosis status. In addition to pfetin, we also identified DDX39 as a biomarker of unfavorable prognosis using a proteomics approach, and KCTD10 as a marker of favorable prognosis using a knowledge-based approach. Our experience demonstrates the utility of proteomics for biomarker discovery, and the possible clinical application of pfetin for risk stratification therapy in GIST.

Nuclear expression of YB‐1 in diffuse large B‐cell lymphoma: correlation with disease activity and patient outcome

The aim of this study is to investigate the correlations among Y-box binding protein-1 (YB-1) and P-glycoprotein(P-gp) and their prognostic significance in diffuse large B-cell lymphoma (DLBCL). The expression of YB-1 and P-gp was examined immunohistochemically on 68 patients with DLBCL who were treated from 2003 to 2005. Samples were paraffin-embedded newly diagnosed DLBCL tissues taken from the surgical specimens before adjuvant chemotherapy. We determined the prognostic significance of YB-1 and its relationship with P-gp in patients with DLBCL. Of the 68 tumors examined, 42 (61.8%) were positive for YB-1 expression in the nucleus. The nuclear expression of YB-1 was significantly associated with clinical stages, bone marrow involvement, extra nodal involvement, and poor response to chemotherapy. No associations were observed between P-gp and clinical features, in context of the poor response to chemotherapy. Nuclear expression of YB-1 was correlated significantly with increased expression of P-gp patients with a nuclear YB-1 tumor had a poorer prognosis than did those with a cytoplasmic YB-1 tumor in all of the DLBCL patients (P = 0.035). Thus, correlation of YB-1 and P-gp emerged as a possible biomarker for unfavorable prognosis in DLBCL. It may provide useful information for clinicians to determine the appropriate therapy for each type of DLBCL.