Can uric acid affect the immune microenvironment in bladder cancer? A single-center multi-omics study.

Metabolic abnormalities are one of the important factors in bladder cancer (BCa) progression and microenvironmental disturbance. As an important product of purine metabolism, uric acid's (UA) role in BCa metabolism and immunotherapy remains unclear. In this study, we conducted a retrospective analysis of a cohort comprising 39 BCa patients treated with PD-1 and 169 patients who underwent radical cystectomy at Shanghai Tenth People's Hospital. Kaplan-Meier curves and Cox regression analysis showed that the prognosis of patients with high UA is worse (p = 0.007), and high UA is an independent risk factor for cancer specific survival in patients with BCa (p = 0.025). We established a hyperuricemia mouse model with BCa subcutaneous xenografts in vivo. The results revealed that the subcutaneous tumors of hyperuricemia mice had a greater weight and volume in comparison with the control group. Through flow cytometric analysis, the proportion of CD8+ and CD4+ T cells in these subcutaneous tumors was seen to decline significantly. We also evaluated the relationship of UA and BCa by muti-omic analysis. UA related genes were significantly increased in the CD8+ T cell of non-responders to immunotherapy by single-cell sequencing. An 11-gene UA related signature was constructed and the risk score negatively correlated with various immune cells and immune checkpoints. Finally, a nomogram was established using a UA related signature to forecast the survival rate of patients with BCa. Collectively, this study demonstrated that UA was an independent prognostic biomarker for BCa and was associated with worse immunotherapy response.

Corrigendum: MicroRNA-153 decreases tryptophan catabolism and inhibits angiogenesis in bladder cancer by targeting indoleamine 2,3-dioxygenase 1.

[This corrects the article DOI: 10.3389/fonc.2019.00619.].

Untargeted and targeted metabolomics reveal bile acid profile changes in rats with ethylene glycol-induced calcium oxalate nephrolithiasis.

Calcium oxalate (CaOx) nephrolithiasis is a prevalent disorder linked to metabolism. Examining metabolic alterations could potentially give an initial understanding of the origins of CaOx nephrolithiasis. This study aims to determine gut metabolic biomarkers differentiating CaOx nephrolithiasis utilizing untargeted and targeted metabolomics. CaOx nephrolithiasis model rats were built by 1% ethylene glycol administration. Histologic staining and renal function measurement revealed the presence of crystals in the lumen of the renal tubules, the renal injury and interstitial fibrosis in CaOx rats, demonstrating that the models of CaOx were established successfully. Hematoxylin & eosin (H&E) staining showed that CaOx group had inflammation and damage in the ileal tissue. Immunofluorescence and PCR results displayed that the tight junction proteins, ZO-1 and Occludin levels were decreased in the ileal tissues of the CaOx group. The untargeted metabolomic analysis revealed that 269 gut metabolites were differentially expressed between the CaOx group and the control group. Meanwhile, bile secretion, the main metabolic pathway in CaOx nephrolithiasis, was identified. Following, five significant bile acid metabolites were selected utilizing the targeted bile acid metabolomics, including Hyodeoxycholic acid (HDCA), Glycohyodeoxycholic acid (GHDCA), Nor-Deoxycholic Acid, omega-muricholic acid, and Taurolithocholic acid. Among these metabolites, HDCA and GHDCA presented the highest predictive accuracy with AUC = 1 to distinguish the CaOx group from the control group. As a result of network pharmacology, target genes of HDCA and GHDCA in CaOx nephrolithiasis were enriched in oxidative stress and apoptosis pathways. Conclusively, our study provides insight into bile acids metabolic changes related to CaOx nephrolithiasis. Although alterations in biochemical pathways indicate a complex pathology in CaOx rats, bile acid changes may serve as biomarkers of CaOx nephrolithiasis.

Identification of a novel host protein interacting with the structural protein VP2 of deformed wing virus by yeast two-hybrid screening.

Deformed wing virus (DWV) interacting with Varroa destructor is a possible cause of honeybee colony mortality. VP2 is the structural protein of DWV but its function remains unknown. To clarify the function of VP2 and screen for novel binding proteins that interact with VP2, we carried out a membrane protein yeast two-hybrid screening using VP2 as bait. Subsequently, the interaction between VP2 and the host interacting protein [heat shock protein 10 (Hsp10)] was further verified using glutathione S-transferase pull-down assay in vitro and co-immunoprecipitation assay in cells. Furthermore, fluorescence confocal microscopy revealed that VP2 and Hsp10 were mainly co-localized in the cytoplasm. Using real-time polymerase chain reaction, we found that Hsp10 expression in DWV-infected worker honey bees were downregulated compared with that in healthy honey bees. Additionally, we showed that overexpression of VP2 protein could reduce the expression of Hsp10. These results suggest that Hsp10 plays a vital role in host immunity and antiviral effects.

MicroRNA-153 Decreases Tryptophan Catabolism and Inhibits Angiogenesis in Bladder Cancer by Targeting Indoleamine 2,3-Dioxygenase 1.

Background: Metastasis is the primary cause of cancer deaths, warranting further investigation. This study assessed microRNA-153 (miR-153) expression in bladder cancer tissues and investigated the underlying molecular mechanism of miR-153-mediated regulation of bladder cancer cells. Methods: Paired tissue specimens from 45 bladder cancer patients were collected for qRT-PCR. The Cancer Genome Atlas (TCGA) dataset was used to identify associations of miR-153 with bladder cancer prognosis. Bladder cancer tissues and immortalized cell lines were used for the following experiments: miR-153 mimics and indoleamine 2,3-dioxygenase 1 (IDO1) siRNA transfection; Western blot, cell viability, colony formation, and Transwell analyses; nude mouse xenograft; and chicken embryo chorioallantoic membrane angiogenesis (CAM) assays. Human umbilical vein endothelial cells (HUVECs) were co-cultured with bladder cancer cells for the tube formation assay. The luciferase reporter assay was used to confirm miR-153-targeting genes. Results: miR-153 expression was downregulated in bladder cancer tissues and cell lines, and reduced miR-153 expression was associated with advanced tumor stage and poor overall survival of patients. Moreover, miR-153 expression inhibited bladder cancer cell growth by promoting tumor cell apoptosis, migration, invasion, and endothelial mesenchymal transition (EMT) in vitro and tumor xenograft growth in vivo, while miR-153 expression suppressed HUVEC and CAM angiogenesis. At the gene level, miR-153 targeted IDO1 expression and inhibited bladder cancer cell tryptophan metabolism through inhibiting IL6/STAT3/VEGF signaling. Conclusions: Collectively, our data demonstrate that miR-153 exerts anti-tumor activity in bladder cancer by targeting IDO1 expression. Future studies will investigate miR-153 as a novel therapeutic target for bladder cancer patients.

Expression and clinical value of CD105 in renal cell carcinoma based on data mining in The Cancer Genome Atlas.

The objective of the present study was to assess the expression of CD105 and its association with overall survival in three subtypes of renal cell carcinoma (RCC), namely clear cell (cc)RCC, papillary (p)RCC and chromophobe (ch)RCC. Data regarding the transcriptome and copy number of genes in RCC tumor samples and survival were obtained from The Cancer Genome Atlas. Bioinformatics analysis revealed that CD105 is overexpressed in ccRCC tumor tissue vs. normal renal tissue, and a higher CD105 copy number in ccRCC tissues was significantly associated with longer patient survival. The effect of the mRNA expression of CD105 in all three types of RCC and the copy number in pRCC and chRCC on patient survival was insignificant, but certain trends were observed. In addition, CD105 mRNA expression was associated with the metastasis and tumor stage, as well as pathological stage in ccRCC and pRCC. Pathway enrichment analysis revealed that CD105 may, through translation initiation of associated genes, promote RCC progression. The results of the present study suggest that in RCC tumors, the association of CD105 with different stages is complex. To evaluate the role of CD105 in RCC, its function should be assessed in addition to its expression. The exact influence of CD105 mRNA expression and copy number in RCC tumors on patient survival and the underlying mechanisms require further elucidation.

The Hemoglobin, Albumin, Lymphocyte, and Platelet (HALP) Score is a Novel Significant Prognostic Factor for Patients with Metastatic Prostate Cancer Undergoing Cytoreductive Radical Prostatectomy.

Objective: The hemoglobin, albumin, lymphocyte, and platelet (HALP) score has been shown to be an important prognostic marker in some tumor types. The aim of this study was to evaluate the prognostic impact of the preoperative HALP score, with the intent to develop a new prognostic index for patients with metastatic prostate cancer (mPCA) after cytoreductive radical prostatectomy (cRP). Methods: We retrospectively analyzed the data from 82 patients with mPCA after cRP in our institution. Of these patients, 70 patients were diagnosed with oligometastatic prostate cancer (oPCA). The main outcome measure was prostate-specific antigen (PSA) progression-free survival (PFS), which was assessed using Kaplan-Meier curves with log-rank statistics. In addition, univariate and multivariate Cox regression analyses were performed to determine the prognostic factors associated with PSA-PFS. The prediction accuracy was evaluated by assessing the area under the receiver operating characteristic (AUC) curve. Results: The median follow-up time for all patients was 17.47 months (range: 11.73-24.38 months). Based on the Kaplan-Meier curve analysis, it was noticed that a low preoperative HALP value (<32.4) was significantly associated with a decreased PSA-PFS in both the mPCA and oPCA subgroups (P < 0.001, P = 0.002, respectively). In addition, multivariate analysis predicted that a low HALP score was a common independent prognostic factor of an overall shorter PSA-PFS (HR: 0.352; range: 0.154-0.804; P = 0.013). However, among the different subgroups, a low HALP score (HR: 0.275; range: 0.116-0.653; P = 0.003) was confirmed to be an independent predictor of a shorter PSA-PFS in patients from the oPCA subgroup. Furthermore, the effective combination of the pathologic Gleason score (PGS) and the HALP score (HALPG) as a new index was found to be an independent risk factor. Also, the AUC of the HALPG score for PSA-PFS was observed to be higher than other conventional clinical indices. Conclusion: Overall, our results confirmed the HALP score as an independent prognostic factor for PSA-PFS in patients with mPCA or oPCA after cRP. Moreover, the new index, HALPG, also appeared to be an independent prognostic factor and was better than the HALP score. Importantly, it is evident that this new prognostic index has the ability to accurately identify patients at low, intermediate, and high risk of recurrence, thus easily allowing informed treatment decisions to be made.

Alleviation of mycotoxin biodegradation agent on zearalenone and deoxynivalenol toxicosis in immature gilts.

BACKGROUND: The current study was carried out to evaluate the effects of mycotoxin biodegradation agent (MBA, composed of Bacillus subtilis ANSB01G and Devosia sp. ANSB714) on relieving zearalenone (ZEA) and deoxynivalenol (DON) toxicosis in immature gilts. METHODS: A total of forty pre-pubertal female gilts (61.42 ± 1.18 kg) were randomly allocated to four diet treatments: CO (positive control); MO (negative control, ZEA 596.86 µg/kg feed and DON 796 µg/kg feed); COA (CO + 2 g MBA/kg feed); MOA (MO + 2 g MBA/kg feed). Each treatment contained 10 replicates with 1 gilt per replicate. Gilts were housed in an environmentally controlled room with the partially slatted floor. RESULTS: During the entire experimental period of 28 d, average daily gain (ADG) and average daily feed intake (ADFI) of gilts in MO group was significantly reduced compared with those in CO group. The vulva size of gilts was significantly higher in MO group than CO group. In addition, significant increases in the plasma levels of IgA, IgG, IL-8, IL-10 and PRL were determined in MO group compared with that in CO group. ZEA and DON in the diet up-regulated apoptotic caspase-3 in ovaries and uteri, along with down-regulated the anti-apoptotic protein Bcl-2 in ovaries. The supplementation of MBA into diets co-contaminated with ZEA and DON significantly increased ADG, decreased the vulva sizes, reduced the levels of IgG, IL-8 and PRL in plasma, and regulated apoptosis in ovaries and uteri of gilts. CONCLUSIONS: The present results indicated that feeding diet contaminated with ZEA and DON simultaneously (596.86 µg/kg + 796 µg/kg) had detrimental effects on growth performance, plasma immune function and reproductive status of gilts. And MBA could reduce the negative impacts of these two toxins, believed as a promising feed additive for mitigating toxicosis of ZEA and DON at low levels in gilts.

A Polyaromatic Nano-nest for Hosting Fullerenes C60 and C70.

A "Janus" type of hexa- cata-hexabenzocoronene with three triptyceno subunits fused symmetrically on the periphery of coronene has been synthesized using a covalent self-assembly strategy. The triptyceno subunits form a nanosized nest on one side of the aromatic plane with space-matching fullerenes such as C60 and C70 to afford shape-complementary supramolecular complexes. The formation of the complexes in solution was confirmed by 1H NMR and fluorescence titration. Four complexes with C60 or C70 were obtained and studied by single-crystal X-ray diffraction analysis. In the crystal structure, the host shows a proper tunability to adjust its conformation in accordance with the shape of the guest. The different stoichiometric ratios and various stacking patterns of the complexes suggest the diversity of this nonplanar polyaromatic host in complexation with fullerenes.

Dynamic contrast-enhanced MRI versus 18F-FDG PET/CT: Which is better in differentiation between malignant and benign solitary pulmonary nodules?

OBJECTIVE: To prospectively compare the discriminative capacity of dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) with that of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in the differentiation of malignant and benign solitary pulmonary nodules (SPNs). METHODS: Forty-nine patients with SPNs were included in this prospective study. Thirty-two of the patients had malignant SPNs, while the other 17 had benign SPNs. All these patients underwent DCE-MRI and 18F-FDG PET/CT examinations. The quantitative MRI pharmacokinetic parameters, including the trans-endothelial transfer constant (Ktrans), redistribution rate constant (Kep), and fractional volume (Ve), were calculated using the Extended-Tofts Linear two-compartment model. The 18F-FDG PET/CT parameter, maximum standardized uptake value (SUVmax), was also measured. Spearman's correlations were calculated between the MRI pharmacokinetic parameters and the SUVmax of each SPN. These parameters were statistically compared between the malignant and benign nodules. Receiver operating characteristic (ROC) analyses were used to compare the diagnostic capability between the DCE-MRI and 18F-FDG PET/CT indexes. RESULTS: Positive correlations were found between Ktrans and SUVmax, and between Kep and SUVmax (P<0.05). There were significant differences between the malignant and benign nodules in terms of the Ktrans, Kep and SUVmax values (P<0.05). The areas under the ROC curve (AUC) of Ktrans, Kep and SUVmax between the malignant and benign nodules were 0.909, 0.838 and 0.759, respectively. The sensitivity and specificity in differentiating malignant from benign SPNs were 90.6% and 82.4% for Ktrans; 87.5% and 76.5% for Kep; and 75.0% and 70.6% for SUVmax, respectively. The sensitivity and specificity of Ktrans and Kep were higher than those of SUVmax, but there was no significant difference between them (P>0.05). CONCLUSIONS: DCE-MRI can be used to differentiate between benign and malignant SPNs and has the advantage of being radiation free.

Facile Synthesis of π-Extended Viologens: Electron-Deficient Polycyclic Aza-aromatics.

A novel family of π-extended viologens has been synthesized by a concise 3-step route from simple and readily available chemicals. The π-enlargement gives the system new photophysical and electrochemical properties such as photoluminescence and changed redox potentials.

High-throughput sequencing technology to reveal the composition and function of cecal microbiota in Dagu chicken.

BACKGROUND: The chicken gut microbiota is an important and complicated ecosystem for the host. They play an important role in converting food into nutrient and energy. The coding capacity of microbiome vastly surpasses that of the host's genome, encoding biochemical pathways that the host has not developed. An optimal gut microbiota can increase agricultural productivity. This study aims to explore the composition and function of cecal microbiota in Dagu chicken under two feeding modes, free-range (outdoor, OD) and cage (indoor, ID) raising. RESULTS: Cecal samples were collected from 24 chickens across 4 groups (12-w OD, 12-w ID, 18-w OD, and 18-w ID). We performed high-throughput sequencing of the 16S rRNA genes V4 hypervariable regions to characterize the cecal microbiota of Dagu chicken and compare the difference of cecal microbiota between free-range and cage raising chickens. It was found that 34 special operational taxonomic units (OTUs) in OD groups and 4 special OTUs in ID groups. 24 phyla were shared by the 24 samples. Bacteroidetes was the most abundant phylum with the largest proportion, followed by Firmicutes and Proteobacteria. The OD groups showed a higher proportion of Bacteroidetes (>50 %) in cecum, but a lower Firmicutes/Bacteroidetes ratio in both 12-w old (0.42, 0.62) and 18-w old groups (0.37, 0.49) compared with the ID groups. Cecal microbiota in the OD groups have higher abundance of functions involved in amino acids and glycan metabolic pathway. CONCLUSION: The composition and function of cecal microbiota in Dagu chicken under two feeding modes, free-range and cage raising are different. The cage raising mode showed a lower proportion of Bacteroidetes in cecum, but a higher Firmicutes/Bacteroidetes ratio compared with free-range mode. Cecal microbiota in free-range mode have higher abundance of functions involved in amino acids and glycan metabolic pathway.

[Optimizing cultural conditions of measles vaccine working seed lot with orthogonal experiments].

OBJECTIVE: To improve the quality of measles vaccine and find out good combination of cultural factors of measles vaccine virus seeds. METHODS: Orthogonal experiments were made to confirm optimized cultural factors. 5 lots of optimized measles vaccine working seed lot were prepared. RESULTS: The titers of the optimized vaccine seed improved significantly (> or = 0.69 +/- 0.35 LgCCID50/1.0 ml, P < 0.05), compared with 5 lots of traditional working seed lot. With these seeds we trial-prepared 5 lots of lyophilized vaccines respectively, the titer and stability met the Chinese Requirements of Biological Products. CONCLUSION: The orthogonal experiment is a kind of good method for optimizing cultural conditions of measles vaccine working seed lot. The yield and quality of measles vaccine can be improved in the optimized working seed lot with high titer and good stability.