Tumor immune escape plays an essential role in both cancer progression and immunotherapy responses. For prostate cancer (PC), however, the molecular mechanisms that drive its different immune phenotypes have yet to be fully elucidated. Patient gene expression data were analyzed from The Cancer Genome Atlas-prostate adenocarcinoma (TCGA-PRAD) and the International Cancer Genome Consortium (ICGC) databases. We used a Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) analysis and an unsupervised clustering analysis to identify patient subgroups with distinct immune phenotypes. These distinct phenotypes were then explored for associations for differentially expressed genes (DEGs) and both epigenetic and genetic landscapes. Finally, we used a protein-protein interaction analysis to identify key hub genes. We identified two patient subgroups with independent immune phenotypes associated with the expression of Programmed death-ligand 1 (PD-L1). Patient samples in Cluster 1 (C1) had higher scores for immune-cell subsets compared to Cluster 2 (C2), and C2 samples had higher specific somatic mutations, MHC mutations, and genomic copy number variations compared to C1. We also found additional cluster phenotype differences for DNA methylation, microRNA (miRNA) expression, and long noncoding RNA (lncRNA) expression. Furthermore, we established a 4-gene model to distinguish between clusters by integrating analyses for DEGs, lncRNAs, miRNAs, and methylation. Notably, we found that glial fibrillary acidic protein (GFAP) might serve as a key hub gene within the genetic and epigenetic regulatory networks. These results improve our understanding of the molecular mechanisms underlying tumor immune phenotypes that are associated with tumor immune escape. In addition, GFAP may be a potential biomarker for both PC diagnosis and prognosis.

The present study examined nociceptive behaviors and the expression of phosphorylated cAMP response element-binding protein (pCREB) in the dorsal horn of the lumbar spinal cord and the dorsal root ganglion (DRG) evoked by bee venom (BV). The effect of intraplantar preapplication of the somatostatin analog octreotide on nociceptive behaviors and pCREB expression was also examined. Subcutaneous injection of BV into the rat unilateral hindpaw pad induced significant spontaneous nociceptive behaviors, primary mechanical allodynia, primary thermal hyperalgesia, and mirror-thermal hyperalgesia, as well as an increase in pCREB expression in the lumbar spinal dorsal horn and DRG. Octreotide pretreatment significantly attenuated the BV-induced lifting/licking response and mechanical allodynia. Local injection of octreotide also significantly reduced pCREB expression in the lumbar spinal dorsal horn and DRG. Furthermore, pretreatment with cyclosomatostatin, a somatostatin receptor antagonist, reversed the octreotide-induced inhibition of the lifting/licking response, mechanical allodynia, and the expression of pCREB. These results suggest that BV can induce nociceptive responses and somatostatin receptors are involved in mediating the antinociception, which provides new evidence for peripheral analgesic action of somatostatin in an inflammatory pain state.

P21 activated kinase 4 (PAK4), a key regulator of cytoskeletal rearrangement and endothelial microparticles (EMPs), is released after lipopolysaccharide (LPS) stimulation. In addition, it participates in LPS-induced lung injury. In this study, forty-eight Sprague Dawley (SD) rats were divided into two groups, including PAK4 inhibitor (P) and PAK4 inhibitor + simvastatin (P + S) treatment groups. All rats were given PAK4 inhibitor (15 mg/kg/d) orally. Immediately after PAK4 inhibitor administration, simvastatin was injected intraperitoneally to P + S group animals at 20 mg/kg/day. Then, treatment effects on the intestinal mucosal barrier and lung injury caused by PAK4 inhibitor and simvastatin were assessed. The results showed that gut Zonula Occludens- (ZO-) 1, PAK4, mitogen-activated protein kinase 4 (MPAK4), and CD11c protein levels were reduced, while plasma endotoxin levels were increased after administration of PAK4 inhibitor. Furthermore, compared with normal rats, wet-to-dry (W/D) values of lung tissues and circulating EMP levels were increased in the treatment group, while PAK4 and CD11c protein amounts were reduced. Therefore, in this lung injury process induced by PAK4 inhibitor, the protective effects of simvastatin were reflected by intestinal mucosal barrier protection, inflammatory response regulation via CD11c+ cells, and cytoskeleton stabilization. In summary, PAK4 is a key regulator in the pathophysiological process of acute lung injury (ALI) and can be a useful target for ALI treatment.

Background. Criteria for antiretroviral treatment (ART) were adjusted to enable early HIV treatment for people living HIV/AIDS (PLHIV) in China in recent years. This study aims to determine how pretreatment waiting time after HIV confirmation affects subsequent adherence and outcomes over the course of treatment. Methods. A retrospective observational cohort study was conducted using treatment data from PLHIV in Yuxi, China, between January 2004 and December 2015. Results. Of 1,663 participants, 348 were delayed testers and mostly initiated treatment within 28 days. In comparison, 1,315 were nondelayed testers and the median pretreatment waiting time was 599 days, but it significantly declined over the study period. Pretreatment CD4 T-cell count drop (every 100 cells/mm3) contributed slowly in CD4 recovery after treatment initiation (8% less, P < 0.01) and increased the risk of poor treatment adherence by 15% (ARR = 1.15, 1.08-1.25). Every 100 days of extensive pretreatment waiting time increased rates of loss to follow-up by 20% (ARR = 1.20, 1.07-1.29) and mortality rate by 11% (ARR = 1.11, 1.06-1.21), based on multivariable Cox regression. Conclusion. Long pretreatment waiting time in PLHIV can lead to higher risk of poor treatment adherence and HIV-related mortality. Current treatment guidelines should be updated to provide ART promptly.

DNA-binding proteins (DBPs) play vital roles in all aspects of genetic activities. However, the identification of DBPs by using wet-lab experimental approaches is often time-consuming and laborious. In this study, we develop a novel computational method, called PredDBP-Stack, to predict DBPs solely based on protein sequences. First, amino acid composition (AAC) and transition probability composition (TPC) extracted from the hidden markov model (HMM) profile are adopted to represent a protein. Next, we establish a stacked ensemble model to identify DBPs, which involves two stages of learning. In the first stage, the four base classifiers are trained with the features of HMM-based compositions. In the second stage, the prediction probabilities of these base classifiers are used as inputs to the meta-classifier to perform the final prediction of DBPs. Based on the PDB1075 benchmark dataset, we conduct a jackknife cross validation with the proposed PredDBP-Stack predictor and obtain a balanced sensitivity and specificity of 92.47% and 92.36%, respectively. This outcome outperforms most of the existing classifiers. Furthermore, our method also achieves superior performance and model robustness on the PDB186 independent dataset. This demonstrates that the PredDBP-Stack is an effective classifier for accurately identifying DBPs based on protein sequence information alone.

Previous studies have demonstrated that stroke characteristics and social and psychological factors jointly contribute to the development of poststroke depression (PSD). The purpose of this study was to identify altered functional connectivity (FC) of the affective network (AN) in patients with PSD and to explore the correlation between FC and the severity of PSD.

Recently, many studies showed that long noncoding RNAs (lncRNAs) are involved in tumor progression. It is reported that lncRNA-LET is downregulated and has antitumor effect on several types of cancer. This study focuses on the role of lncRNA-LET on lung adenocarcinoma (LAC) progression. RT-PCR results indicated that frequent downregulation of lncRNA-LET in LAC tissues was related to clinicopathologic factors. lncRNA-LET knockdown significantly promoted LAC cell proliferation, invasion, and migration while lncRNA-LET overexpression obviously inhibited LAC cell proliferation, invasion, and migration, indicating a tumor inhibition of lncRNA-LET in LAC progression. Besides, lncRNA-LET inhibited EMT and negatively regulated Wnt/β-catenin pathway in part. Our study suggests that lncRNA-LET exhibits an important tumor-suppressive effect on LAC progression by inhibiting EMT and Wnt/β-catenin pathway, which provides potential therapeutic targets for LAC.

Alpha-L-fucosidase (AFU) has been reported to be a predictor of survival in patients with several cancers, but it is unclear whether AFU is associated with prognosis in patients with intrahepatic cholangiocarcinoma (iCCA). In this study, we used receiver operating characteristic (ROC) analysis to generate the cutoff point of AFU for overall survival (OS). The prognostic influence of the AFU level in serum on OS was studied using Kaplan-Meier curves. Moreover, invasion assays and Western blotting were performed to explore the effects of AFU on iCCA invasion in vitro. We found that higher AFU levels (≥20.85 U/L) were significantly associated with favorable median OS (44.3 months versus 20.1 months; P = 0.022) in iCCA patients. Cox regression models' analyses showed that the AFU level was an independent predictor for OS (P = 0.006). Moreover, our results revealed that the AFU could impair the invasion capability of the iCCA cells, HuH28, and also downregulated the expression of matrix metalloproteinase 2 and matrix metalloproteinase 9. In conclusion, our results indicate that AFU is a significantly favorable prognostic factor in iCCA patients.

Surgical flaps are frequently affected by ischemia/reperfusion (I/R) injury. Calcium-sensing receptor (CaSR) and stromal cell-derived factor-1α (SDF-1α) are closely associated with myocardial I/R injury. This study was performed to evaluate the feasibility of applying SDF-1α to counteract CaSR activation-mediated I/R injury in ischemic free flaps. Free flaps that underwent ischemia for 3 h were equally randomized into five groups: CaCl2, NPS2143 + CaCl2, SDF-1α + CaCl2, AMD3100 + SDF-1α + CaCl2, and normal saline. The free flaps were harvested to evaluate flap necrosis and neovascularization after 2 h or 7 d of reperfusion. p-CaSR/CaSR was extensively expressed in vascular endothelial cells of free flaps after I/R injury, and activation of the SDF-1α/CXCR4 axis and NPS2143 could reduce the expression of cleaved caspase-3, caspase-9, FAS, Cyt-c, and Bax and increase Bcl-2 expression; the opposite was true after CaSR activation. Interestingly, initiation of the SDF-1α/CXCR4 axis might abrogate CaSR activation-induced I/R injury through enhancement of microvessel density. In conclusion, CaSR might become a novel therapeutic target of free flaps affected by I/R injury. Activation of the SDF-1α/CXCR4 axis and NPS2143 could counteract CaSR activation-mediated I/R injury and promote free flap survival through inhibition of caspase-3/caspase-9-related cell apoptosis and enhancement of neovascularization.

Paraquat is a widely used nonselective and fast-acting contact herbicide worldwide. This study identified the early predictor of mortality in patients with acute paraquat poisoning.

The study aimed to investigate the safety and efficacy of the Solitaire™ AB Stent System (ev3 Inc., Plymouth, MN, USA) for the treatment of acute lower extremity ischemia (ALLI) compared with conventional catheter-directed thrombolytic therapy.

In cartilage tissue engineering, the target cells' functional performance depends on the biomaterials. However, it is difficult to develop an appropriate scaffold to differentiate mouse adipose-derived stem cells (mADSCs) into chondrocyte despite an increasing number of studies on biological scaffold materials. The purpose of this study was to create a novel scaffold for mADSC culture and chondrogenic differentiation with a new series of microgels based on polyethyleneimine (PEI), polyethylene glycol (PEG), and poly (L-lactic acid) (PLLA) and able to resist swelling with changes in temperature, pH, and polymer concentration. The biocompatibility and ability of the nonswelling microgels were then examined and served as scaffolds for cell culture and for cartilage differentiation. The results show that the new microgels are a novel biomaterial that both retains its nonswelling properties under various conditions and facilitates important scaffold functions such as cell adhesion, proliferation, and cartilage induction.

Thirty-three consecutive patients with 34 TVIAs were prospectively recruited and treated with endovascular techniques. The volume of TVIAs and the required length of coils were calculated by the AngioSuite software before embolization. The treatment efficacy of TVIAs was assessed using the Raymond scale (Rs) and the modified Rankin scale (mRs).

The plant-specific sucrose nonfermenting 1-related protein kinase 2 (SnRK2) family is considered an important regulator of plant responses to abiotic stresses such as drought, cold, salinity, and nutrition deficiency. However, little information is available on how SnRK2s regulate sulfur deprivation responses in Arabidopsis. Large-scale production of SnRK2 kinases in vitro can help to elucidate the biochemical properties and physiological functions of this protein family. However, heterogenous expression of SnRK2s usually leads to inactive proteins. In this study, we expressed a recombinant Arabidopsis SnRK2.1 in a modified E. coli cell-free system, which combined two kinds of extracts allowing for a convenient and affordable protein preparation. The recombinant SnRK2.1 was produced in large-scale and the autophosphorylation activity of purified SnRK2.1 was characterized, allowing for further biochemical and substrate binding analysis in sulfur signaling. The application of this improved E. coli cell-free system provides us a promising and convenient platform to enhance expression of the target proteins economically.

Resveratrol has recently been used as a supplemental treatment for several neurological and nonneurological diseases. It is not known whether resveratrol has neuroprotective effect on amyotrophic lateral sclerosis (ALS). To assess the effect of resveratrol on the disease, we tested this agent on an ALS model of SOD1(G93A) transgenic mouse. Rotarod measurement was performed to measure the motor function of the ALS mice. Nissl staining and SMI-32 immunofluorescent staining were used to determine motor neurons survival in the spinal cord of the ALS mice. Hematoxylin-eosin (H&E), succinic dehydrogenase (SDH), and cytochrome oxidase (COX) staining were applied to pathologically analyze the skeletal muscles of the ALS mice. We found that resveratrol treatment significantly delayed the disease onset and prolonged the lifespan of the ALS mice. Furthermore, resveratrol treatment attenuated motor neuron loss, relieved muscle atrophy, and improved mitochondrial function of muscle fibers in the ALS mice. In addition, we demonstrated that resveratrol exerted these neuroprotective effects mainly through increasing the expression of Sirt1, consequently suppressing oxidative stress and downregulating p53 and its related apoptotic pathway. Collectively, our findings suggest that resveratrol might provide a promising therapeutic intervention for ALS.

Previous studies have investigated that the expression levels of MALAT-1 were higher in cancerous tissues than matched histologically normal tissues. And, to some extent, overexpression of MALAT-1 was inclined to lymph node metastasis. This meta-analysis collected all relevant articles and explored the association between MALAT-1 expression levels and lymph node metastasis. We searched PubMed, EmBase, Web of Science, Cochrane Library, and OVID to address the level of MALAT-1 expression in cancer cases and noncancerous controls (accessed February 2015). And 8 studies comprising 696 multiple cancer patients were included to assess this association. The odds ratio (OR) and its corresponding 95% confidence interval (CI) were calculated to assess the strength of the association using Stata 12.0 version software. The results revealed there was a significant difference in the incidence of lymph node metastasis between high MALAT-1 expression group and low MALAT-1 expression group (OR = 1.94, 95% CI 1.15-3.28, P = 0.013 random-effects model). Subgroup analysis indicated that MALAT-1 high expression had an unfavorable impact on lymph node metastasis in Chinese patients (OR = 1.87, 95% CI 1.01-2.46). This study demonstrated that the incidence of lymph node metastasis in patients detected with high MALAT-1 expression was higher than that in patients with low MALAT-1 expression in China.

Qushi Huayu Decoction (QHD), an important clinically proved herbal formula, has been reported to be effective in treating fatty liver induced by high-fat diet in rats. However, the mechanism of action has not been clarified at the metabolic level. In this study, a urinary metabolomic method based on gas chromatography-mass spectrometry (GC-MS) coupled with pattern recognition analysis was performed in three groups (control, model, and QHD group), to explore the effect of QHD on fatty liver and its mechanism of action. There was obvious separation between the model group and control group, and the QHD group showed a tendency of recovering to the control group in metabolic profiles. Twelve candidate biomarkers were identified and used to explore the possible mechanism. Then, a pathway analysis was performed using MetaboAnalyst 3.0 to illustrate the pathways of therapeutic action of QHD. QHD reversed the urinary metabolite abnormalities (tryptophan, uridine, and phenylalanine, etc.). Fatty liver might be prevented by QHD through regulating the dysfunctions of phenylalanine, tyrosine, and tryptophan biosynthesis, phenylalanine metabolism, and tryptophan metabolism. This work demonstrated that metabolomics might be helpful for understanding the mechanism of action of traditional Chinese medicine for future clinical evaluation.

Pancreatic cancer (PC) is highly malignant and lacks an effective therapeutic schedule, hence that early diagnosis is of great importance to achieve a good prognosis. Oral bacteria have been proved to be associated with pancreatic cancer, but the specific mechanism has not been comprehensively illustrated. In our study, thirty-seven saliva samples in total were collected with ten from PC patients, seventeen from benign pancreatic disease (BPD) patients, and ten from healthy controls (HC). The oral bacterial community of HC, PC, and BPD groups was profiled by 16S rDNA high-throughput sequencing and bioinformatic methods. As shown by Simpson, Inverse Simpson, Shannon and Heip, oral microbiome diversity of HC, BPD and PC groups is in increasing order with the BPD and PC groups significantly higher than the HC group. Principal coordinate analysis (PCoA) suggested that grouping by PC, BPD and HC was statistically significant. The linear discriminant analysis effect size (LEfSe) identified high concentrations of Fusobacterium periodonticum and low concentrations of Neisseria mucosa as specific risk factors for PC. Furthermore, predicted functions showed changes such as RNA processing and modification as well as the pathway of NOD-like receptor signaling occurred in both PC and HC groups. Conclusively, our findings have confirmed the destruction of oral bacterial community balance among patients with PC and BPD and indicated the potential of Fusobacterium periodonticum and Neisseria mucosa as diagnostic biomarkers of PC.

Idiopathic nephrotic syndrome (INS) is a disease involving injury to podocytes in the glomerular filtration barrier, and its specific causes have not been elucidated. Transfer RNA-derived fragments (tRFs), products of precise tRNA cleavage, have been indicated to play critical roles in various diseases. Currently, there is no relevant research on the role of tRFs in INS. This study intends to explore the changes in and importance of tRFs during podocyte injury in vitro and to further analyze the potential mechanism of INS. Differentially expressed tRFs in the adriamycin-treated group were identified by high-throughput sequencing and further verified by quantitative RT-PCR. In total, 203 tRFs with significant differential expression were identified, namely, 102 upregulated tRFs and 101 downregulated tRFs (q < 0.05, ∣log2FC | ≥2). In particular, AS-tDR-008924, AS-tDR-011690, tDR-003634, AS-tDR-013354, tDR-011031, AS-tDR-001008, and AS-tDR-007319 were predicted to be involved in podocyte injury by targeting the Gpr, Wnt, Rac1, and other genes. Furthermore, gene ontology analysis showed that these differential tRFs were strongly associated with podocyte injury processes such as protein binding, cell adhesion, synapses, the actin cytoskeleton, and insulin-activate receptor activity. KEGG pathway analysis predicted that they participated in the PI3K-Akt signaling pathway, Wnt signaling pathway, and Ras signaling pathway. It was reported that these pathways contribute to podocyte injury. In conclusion, our study revealed that changes in the expression levels of tRFs might be involved in INS. Seven of the differentially expressed tRFs might play important roles in the process of podocyte injury and are worthy of further study.

Studies have shown that human interferon inducible transmembrane protein (hIFITMs) family proteins have broad-spectrum antiviral capabilities. Preliminary studies in our laboratory have tentatively proved that hIFITMs have the effect of inhibiting influenza viruses. In order to further study its mechanism and role in the occurrence and development of influenza A, relevant studies have been carried out. Fluorescence quantitative polymerase chain reaction (PCR) detection technology was used to observe the effect of hIFITM3 on the replication of influenza A virus (IVA) and the interaction with hABHD16A. In HEK293 cells, overexpression of hIFITM3 protein significantly inhibited the replication of IVA at 24 h, 48 h, and 72 h; yeast two-hybrid experiment proved that hIFITM3 interacts with hABHD16A; laser confocal microscopy observations showed that hIFITM3 and hABHD16A colocalized in the cell membrane area; the expression level of inflammation-related factors in cells overexpressing hIFITM3 or hABHD16A was detected by fluorescence quantitative PCR, and the results showed that the mRNA levels of interleukin- (IL-) 1β, IL-6, IL-10, tumor necrosis factor- (TNF-) α, and cyclooxygenase 2 (COX2) were significantly increased. But when hIFITM3/hABHD16A was coexpressed, the mRNA expression levels of these cytokines were significantly reduced except COX2. When influenza virus infected cells coexpressing hIFITM3/hABHD16A, the expression level of inflammatory factors decreased compared with the control group, indicating that hIFITM3 can play an important role in regulating inflammation balance. This study confirmed that hIFITM3 has an effect of inhibiting IVA replication. Furthermore, it was found that hIFITM3 interacts with hABHD16A, following which it can better inhibit the replication of influenza virus and the inflammatory response caused by the disease process.