Construction of a Tumor Immune Microenvironment-Related Prognostic Model in BRAF-Mutated Papillary Thyroid Cancer.

BRAF mutation is a representative oncogenic mutation, with a frequency of 60% in papillary thyroid carcinoma (PTC), but the reasons for the poor prognosis and more aggressive course of BRAF-mutated PTC are controversial. Tumor immune microenvironment (TIME) is an essential factor permitting the development and progression of malignancy, but whether TIME participates in the prognosis of BRAF-mutated PTC has not yet been reported. The primary goal of the present study was to provide a comprehensive TIME-related prognostic model to increase the predictive accuracy of progression-free survival (PFS) in patients with BRAF-mutated PTC. In this study, we analyzed the mRNA-seq data and corresponding clinical data of PTC patients obtained from the TCGA database. By calculating the TIME scores (immune score, stromal score and ESTIMATE score), the BRAF mutation group (n=237) was dichotomized into the high- and low-score groups. By functional analysis of differentially expressed genes (DEGs) in different high/low score groups, we identified 2 key TIME-related genes, HTR3A and NIPAL4, which affected PFS in BRAF-mutated PTC. A risk scoring system was developed by multivariate Cox analysis based on the abovementioned 2 TIME-related genes. Then, the BRAF-mutated cohort was divided into the high- and low-risk groups using the median risk score as a cutoff. A high risk score correlated positively with a higher HTR3A/NIPAL4 expression level but negatively with PFS in BRAF-mutated PTC. Ultimately, a nomogram was constructed by combining risk score with clinical parameter (Tumor stage), and the areas under the ROC curve (AUCs) of the nomogram for predicting 1-, 3- and 5-year PFS were then calculated and found to be 0.694, 0.707 and 0.738, respectively, indicating the improved accuracy and clinical utility of the nomogram versus the risk score model in the BRAF-mutated PTC cohort. Moreover, we determined the associations between prognostic genes or risk score and immune cell infiltration by two-way ANOVA. In the high-risk score, high HTR3A expression, and high NIPAL4 expression groups, higher infiltration of immune cells was found. Collectively, these findings confirm that the nomogram is effective in predicting the outcome of BRAF-mutated PTC and will add a spatial dimension to the developing risk stratification system.

Microarray Data of Lacrimal Gland Implicates Dysregulated Protein Processing in Endoplasmic Reticulum in Graves' Ophthalmopathy.

Graves' ophthalmopathy (GO) has become one of the most common orbital diseases. Although some evidences announced the potential mechanism of pathological changes in extraocular muscle and orbital adipose tissue, little is known about that in lacrimal enlargement of GO patients. Thus, gene expression profiles of lacrimal gland derived from GO patients and normal controls were investigated using the microarray datasets of GSE105149 and GSE58331. The raw data and annotation files of GSE105149 and GSE58331 were downloaded from Gene Expression Omnibus (GEO) database. Bioinformatics including differentially expressed genes (DEGs), Gene Ontology, Kyoto Encyclopedia of Gene and Genome (KEGG) pathway, protein-protein interaction (PPI) network construction, hub gene identification, and gene set variation analysis (GSVA) were successively performed. A total of 173 overlapping DEGs in GSE105149 and GSE58331 were screened out, including 20 up-regulated and 153 down-regulated genes. Gene Ontology, KEGG and GSVA analyses of these DEGs showed that the most significant mechanism was closely associated with endoplasmic reticulum (ER). Moreover, we identified 40 module genes and 13 hub genes which were also enriched in the ER-associated terms and pathways. Among the hub genes, five genes including HSP90AA1, HSP90B1, DNAJC10, HSPA5, and CANX may be involved in the dysfunction of protein processing in ER. Taken together, our observations revealed a dysregulated gene network which is essential for protein processing in ER in GO patients. These findings provided a potential mechanism in the progression of lacrimal enlargement in GO patients, as a new insight into GO pathogenesis.

Distribution of virulence-associated genes and antimicrobial susceptibility in clinical Acinetobacter baumannii isolates.

Acinetobacter baumannii is undoubtedly one of the most clinically significant pathogens. The multidrug resistance and virulence potential of A. baumannii are responsible for hospital-acquired nosocomial infections. Unlike numerous investigations on the drug-resistant epidemiology of A. baumanni, virulence molecular epidemiology is less studied. Here, we collected 88 A. baumannii clinical isolates, tested their antimicrobial susceptibility to 10 commonly used antibiotics and analyzed the distribution of 9 selected virulence-associated genes, aims to investigate the primary characteristics of the virulence-associated genes that exist in clinically multidrug resistant (MDR) and non-MDR isolates of A. baumannii. The MIC results showed the resistance rates of ciprofloxacin (68.2%, 60/88), gentamicin (67.0%, 59/88), amikacin (58.0%, 51/88), tobramycin (58.0%, 51/88), doxycycline (67.0%, 59/88), meropenem (54.5%, 48/88) and imipenem (65.9%, 58/88) were all above 50%, except for levofloxacin (34.1%, 30/88), minocycline (1.1%, 1/88) and polymyxin B (0%, 0/88). The Pulsed field gel electrophoresis (PFGE) analysis revealed that the resistance rate of MDR A. baumannii isolates in the Epidemic group was predominant (79.5%, 44/58), but in the Sporadic group was only 6.7% (2/30). Further investigation on the distribution of virulence genes showed the virulence genes bap (95.5%), surA1 (92.0%), BasD (92.0%), paaE (88.6%), pld (87.5%), BauA (62.5%), omp33-36 (59.1%) and pglC (53.4%) were accounted for high proportion, except for traT (0%). Overall, our results revealed that MDR isolates predominated in the Epidemic A. baumannii isolates, and contained a very high proportion of virulence genes, which may lead to high risk, high pathogenicity and high treatment challenge.