Effect of tocilizumab plus corticosteroid on clinical outcome in patients hospitalized with severe fever with thrombocytopenia syndrome: A randomized clinical trial.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging viral hemorrhagic fever with high fatality rates. The blockade of pro-inflammatory cytokines presents a promising therapeutic strategy. METHODS: We conducted a randomized clinical trial at the 154th hospital, Xinyang, Henan Province. Eligible patients with severe SFTS disease were randomly assigned in a 1:2 ratio to receive either a single intravenous infusion of tocilizumab plus usual care; or usual care only. The primary outcome was the clinical status of death/survival at day 14, while secondary outcomes included improvement from baseline in liver and kidney damage and time required for hospital discharge. The efficacy of tocilizumab plus corticosteroid was compared to those receiving corticosteroid alone. The trial is registered with the Chinese Clinical Trial Registry website (ChiCTR2300076317). RESULTS: 63 eligible patients were assigned to the tocilizumab group and 126 to the control group. The addition of tocilizumab to usual care was associated with a reduced death rate (9.5%) compared to those received only usual care (23.0%), with an adjusted hazard ratio (aHR) of 0.37 (95% confidence interval [CI], 0.15 to 0.91, P = 0.029). Combination therapy of tocilizumab and corticosteroids was associated with a significantly reduced fatality (aHR, 0.21; 95% CI, 0.08 to 0.56; P = 0.002) compared to those receiving corticosteroids alone. CONCLUSIONS: A significant benefit of reducing fatality in severe SFTS patients was observed by using tocilizumab. A combined therapy of tocilizumab plus corticosteroids was recommended for the therapy of severe SFTS.

Strong Correlation between the Expression of CHEK1 and Clinicopathological Features of Patients with Multiple Myeloma.

Multiple myeloma (MM) is one of the most common malignancies, and the clinical outcome of patients with MM remains poor. Our objective is to screen biomarkers correlated with clinicopathological features and survival of patients with MM. A gene co-expression network was constructed to screen hub genes related to the three stages in the International Staging System (ISS) of MM. Functional analysis and protein-protein interaction analysis of the hub genes was performed. CHEK1, a gene most related to the ISS stages of MM, was selected for further clinical validation. A total of 780 hub genes correlated with ISS stages of MM were identified. Functional enrichment analysis of hub genes suggested that these genes were mostly enriched in several gene ontology (GO) terms and pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG) that were involved in cell proliferation and immune response. Expression of the gene for the protein checkpoint kinase I (CHEK1) was increased in MM cells from newly diagnosed patients (P = 0.0304) and relapsed patients (P = 0.0002) as compared to normal plasma cells. Meanwhile, CHEK1 was increased more in MM patients with stage II disease (P = 0.0321) and stage III disease (P = 0.0076) than in those with stage I disease. Survival analysis indicated that MM patients in the group characterized by low CHEK1 expression were associated with better clinical outcomes in terms of time to progression, event-free survival, and overall survival. High expression of CHEK1 predicted poor clinical characteristics of MM patient, and our results indicate that it can be considered a biomarker for the diagnosis of MM.

Development and validation of a 4-gene combination for the prognostication in lung adenocarcinoma patients.

Objective: To identify a multi-gene prognostic factor in patients with lung adenocarcinoma (LUAD). Materials and methods Prognosis-related genes were screened in the TCGA-LUAD cohort. Then, patients in this cohort were randomly separated into training set and test set. Least absolute shrinkage and selection operator (LASSO) regression was performed to the penalized the Cox proportional hazards regression (CPH) model on the training set, and a prognostication combination based on the result of LASSO analysis was developed. By performing Kaplan-Meier curve analysis, univariate and multivariable CPH model on the overall survival (OS) as well as recurrence free survival (RFS), the prognostication performance of the multigene combination were evaluated. Moreover, we constructed a nomogram and performed decision curve analysis to evaluate the clinical application of the multigene combination. Results We obtained 99 prognosis-related genes and screened out a 4-gene combination (including CIDEC, ZFP3, DKK1, and USP4) according to the LASSO analysis. The results of survival analyses suggested that patients in the 4-gene combination low-risk group had better OS and RFS than those in the 4-gene combination high-risk group. The 4-gene mentioned was demonstrated to be independent prognostic factor of patients with LUAD in the training set(OS, HR=11.962, P<0.001; RFS, HR=9.281, P<0.001) and test set (OS, HR=5.377, P=0.003; RFS, HR=2.949, P=0.104). More importantly, its prognosis performance was well in the validation set (OS, HR=0.955, P=0.002; RFS, HR=1.042, P<0.001). Conclusions We introduced a 4-gene combination which could predict the survival of LUAD patients and might be an independent prognostic factor in LUAD.

Development of a 21-miRNA Signature Associated With the Prognosis of Patients With Bladder Cancer.

Objective: To develop a prognostic signature for patients with bladder cancer (BC). Methods: We identified differentially expressed miRNAs between normal bladder tissue and bladder cancer in the TCGA-BCLA dataset and evaluated prognostic values of these miRNAs. Then, a 21-miRNA signature was constructed based on the results of Cox proportional hazards regression model. Furthermore, functional enrichment analyses were conducted to explore the potential effects of the target genes of these 21 miRNAs. Results: Seventy six differentially expressed miRNAs were identified, among which 21 miRNAs including hsa-let-7c, mir-143, mir-944, mir-192, mir-590, mir-490, mir-141, mir-93, mir-1-2, mir-200c, mir-133a-1, mir-1-1, mir-133b, mir-20a, mir-185, mir-19a, mir-19b-2, mir-19b-1, mir-17, mir-15a, and mir-133a-2 were demonstrated to be significantly correlated with the overall survival (OS) of bladder cancer patients using Kaplan-Meier survival analysis and Log-rank test. The results of Chi-square test and multivariable logistic regression analysis showed that the 21-miRNA signature was significantly associated with the diagnosis type and T stage of bladder cancer. Univariate and multivariable survival analyses indicated that the 21-miRNA signature was an independent factor in predicting the overall survival of patients with bladder cancer. The results of functional enrichment analysis suggested that the target genes of these 21 miRNAs were mostly enriched in critical cancer-related biological processes and pathways, and the PPI network suggested that 60 targeted genes interacted with a minimum of 30 genes were at the hub of the whole network. In addition, we performed a multivariate nomogram and decision curve analysis (DCA) to evaluate the clinical application of 21-microRNA signature. Conclusion: We introduced a 21-miRNA signature which was associated the prognosis of patients of bladder cancer, and inspirational ideas for the future basic and clinical exploration.

DHCR24 predicts poor clinicopathological features of patients with bladder cancer: A STROBE-compliant study.

To investigate the prognostic value of DHCR24 for patients with bladder cancer (BC). We used public bladder cancer microarray studies to evaluate the expression of DHCR24 between normal bladder tissues and BC cells, to investigate the relationship between the expression of DHCR24 and the clinical features of BC patients. Survival analysis was performed to investigate the correlation between DHCR24 expression and the survivals of BC patients. Gene set enrichment analysis was conducted to identify relevant mechanisms. The results showed that DHCR24 was up-regulated in BC cells compared with that in normal bladder tissues (P = .0389). Results of chi-square test suggested that BC patients in DHCR24 low expression group were proved to have better clinical characteristics (including tumor grade, disease progression, T staging, and N staging) as compared with those in DHCR24 low expression group (P < .0001, P = .002, P = .005, and P = .002, respectively). BC patients in DHCR24 low expression group were associated with better cancer-specific survival and overall survival (P < .0001 and P = .0008, respectively). DHCR24 might promote the proliferation of BC cells through several oncogenesis-associated biological processes (estrogen response, heme metabolism, P53 pathway, cholesterol homeostasis, mTORC1 signaling, peroxisome, xenobiotic metabolism, glycolysis, and protein secretion). Thus, DHCR24 might be a therapeutic target for patients with BC.

Meta-Analysis Results on the Association Between TP53 Codon 72 Polymorphism With the Susceptibility to Oral Cancer.

Objectives: TP53 is an important tumor suppressor gene to maintain genomic integrity, and its mutations increase the susceptibility to oral carcinoma. Previous published studies have reported the relation of TP53 codon 72 polymorphism with the risk of oral carcinoma, but the results remain controversial and inconclusive. Methods: We therefore utilized meta-analysis based on a comprehensive search in PubMed, EMBASE, and Google of Scholar databases up to August 19, 2017. Results: Total 3,525 cases and 3,712 controls from 21 case-control studies were selected. We found no significant association between TP53 codon 72 polymorphism and oral carcinoma susceptibility in all genetic contrast models, including subgroup analysis based on control source and ethnicity. Furthermore, TP53 codon 72 polymorphism was not significant associated with oral carcinoma susceptibility in tobacco or alcohol use, and HPV infection status. Our results were confirmed by sensitivity analysis and no publication bias was found. Conclusions: Taken together, our data indicate that TP53 codon 72 polymorphism is not associated with the susceptibility to oral carcinoma.

The Clinical Relevance of Fragile Histidine Triad Protein (FHIT) in Patients with Bladder Cancer.

BACKGROUND The present study aimed to investigate the clinical relevance of fragile histidine triad protein (FHIT) in patients with bladder cancer (BC). MATERIAL AND METHODS Three independent BC microarray studies were collected and reanalyzed. The expression of FHIT was evaluated between BC samples and normal bladder tissues. The correlation between the expression of FHIT and clinicopathological features was analyzed using the chi-square test. Log-rank based survival analysis was conducted to detect the survival significance of FHIT in patients with BC. Gene set enrichment analysis (GSEA) was performed to identify the mechanisms. RESULTS FHIT was significantly downregulated in BC cells (p=0.0044). BC patients in the FHIT high expression group had better clinical characteristics (including invasiveness, tumor grade, disease progression, and T staging) than those in the FHIT low expression group (p<0.0001, p<0.0001, p=0.031, p<0.0001, and p=0.056, respectively). Patients in the FHIT high expression group had better cancer-specific survival (p<0.0001) and overall survival (p=0.0008) than those in the FHIT low expression. GSEA results indicated that BC samples in the FHIT low expression group were enriched in interferon alpha response, apoptosis, androgen response, interferon gamma response, heme metabolism, and transforming growth facto r(TGF) beta signaling. CONCLUSIONS FHIT predicts better clinical relevance for patients with BC, which may be a promising therapeutic target.

3D thickness distributions of plano lenses as a means of cavity pressure characterization in microinjection molding.

This work presents a novel nondestructive cavity pressure characterization approach in microinjection molding (µIM) through measuring 3D part thickness distributions. For this purpose, a plano lens was designed and experiments based on Taguchi method were conducted. Both overall and local lens thickness distributions under various process conditions were analyzed in terms of their relevance with the cavity pressure during molding. Unexpectedly, a reliable linear regression model was developed fulfilling nondestructive multi-point or even continuous cavity pressure characterization with the overall lens thickness distribution. Furthermore, the topography of the constructed 3D thickness surface was found to depend on both process condition and measuring position. Finally, the process conditions were optimized for obtaining uniform distributions of both 3D thickness and cavity pressure.

Development and Validation of a 9-Gene Prognostic Signature in Patients With Multiple Myeloma.

Background: Multiple myeloma (MM) is one of the most common types of hematological malignance, and the prognosis of MM patients remains poor. Objective: To identify and validate a genetic prognostic signature in patients with MM. Methods: Co-expression network was constructed to identify hub genes related with International Staging System (ISS) stage of MM. Functional analysis of hub genes was conducted. Univariate Cox proportional hazard regression analysis was conducted to identify genes correlated with the overall survival (OS) of MM patients. Least absolute shrinkage and selection operator (LASSO) penalized Cox proportional hazards regression model was used to minimize overfitting and construct a prognostic signature. The prognostic value of the signature was validated in the test set and an independent validation cohort. Results: A total of 758 hub genes correlated with ISS stage of MM patients were identified, and these hub genes were mainly enriched in several GO terms and KEGG pathways involved in cell proliferation and immune response. Nine hub genes (HLA-DPB1, TOP2A, FABP5, CYP1B1, IGHM, FANCI, LYZ, HMGN5, and BEND6) with non-zero coefficients in the LASSO Cox regression model were used to build a 9-gene prognostic signature. Relapsed MM and ISS stage III MM was associated with high risk score calculated based on the signature. Patients in the 9-gene signature low risk group was significantly associated with better clinical outcome than those in the 9-gene signature high risk group in the training set, test, and validation set. Conclusions: We developed a 9-gene prognostic signature that might be an independent prognostic factor in patients with MM.

Association of APOE polymorphism with the change of brain function in the early stage of aneurysmal subarachnoid hemorrhage.

Recent studies have indicated that early brain injury may be responsible for the detrimental effects seen in patients after subarachnoid hemorrhage (SAH). In this study, we investigated the relationship between apolipoprotein E gene (APOE) polymorphism and the change of brain function in the early stage of aneurysmal SAH. A total of 79 patients admitted within 5 days after aneurysmal SAH were recruited in the study. Patient characteristics, such as age, gender, Fisher and Hunt-Hess grade were collected when admitted. Electroencephalogram (EEG) was recorded on admission and at 3-5 days after onset to assess the change of brain function of the patients in acute stage of SAH. The result of the second EEG recording was defined as EEG deterioration if the decrease in alpha wave frequency, increase in slow wave or decline in amplitude were observed when compared with the first EEG recording. The APOE polymorphism was determined in all patients by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Ten of 17 patients with APOEε4 (58.8%) showed the deteriorated EEGs, which was significantly different from those without APOEε4 (18 of 62 patients, 29.0%, p=0.023). However, neither the presence of ε2 nor of ε3 was significantly different from those absent of it (p>0.05). Univariate logistic regression analyses showed that both high Fisher grade (p=0.028, OR=2.917, 95% CI=1.124-7.572) and APOEε4 (p=0.027, OR=3.492, 95% CI=1.150-10.604) were risk factors to EEG aggravation after aneurysmal SAH. The association of APOEε4 for deteriorated EEG was more significant after adjustment for age, gender, Hunt-Hess grade on admission, and Fisher grade (p=0.007, OR=5.741, 95% CI=1.625-20.280). Our findings suggest that APOEε4 allele is a risk factor to brain function aggravation in the early stage of aneurysmal SAH, and it may contribute to early brain injury after SAH.

Value of noninvasive imaging in follow-up of intracranial aneurysm.

Follow-up is necessary for treated and untreated aneurysms. The purpose of this study is to assess the results of treated aneurysms, the development of untreated aneurysms and the incidence of new aneurysms through short-term follow-up with noninvasive imaging, including CTA and MRA. More-than-once follow-up imaging with either CTA or MRA was performed in 73 patients, 65 of them suffering SAH. CTA was performed in 46 patients with clipped aneurysms, 9 patients with coiled aneurysms and 8 cases with untreated aneurysms. MRA was performed in ten patients with coiled aneurysms. CTA follow-up demonstrated that in 48 clipped aneurysms, 47 aneurysms completely disappeared; one aneurysm with neck remnant and one new aneurysm was found. No recurrence was found after microsurgical clipping. CTA follow-up provided limited information for ten coiled aneurysms because of poor quality images due to artifacts from coil. MRA follow-up of 12 coiled aneurysms showed there were no recanalization, recurrence or new aneurysm. In 20 untreated aneurysms, 19 stayed unchanged, and one aneurysm automatically disappeared. The newest generation of CTA and MRA can be used for following-up of intracranial aneurysms, and is more readily accepted by Chinese patients because of convenience, non-invasiveness and low price.