Ceruloplasmin overexpression is associated with oncogenic pathways and poorer survival rates in clear-cell renal cell carcinoma.

Clear-cell renal cell carcinoma (ccRCC) is the most prevalent renal malignancy. The pathogenesis of the disease is currently poorly understood, and the prognosis is poor. Therefore, in this study, we focused on exploring and identifying genes and signal transduction pathways that are closely related to ccRCC. Differentially expressed genes (DEGs) were analyzed using the renal cell oncogene expression profiles GSE100666 and GSE68417. DAVID evaluation of gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses was used. We constructed a protein-protein interaction (PPI) network of DEGS using Cytoscape software and analyzed the submodules with the CytoHubba plugin. Finally, we performed western blot, immunohistochemistry, and PCR validation by collecting tissues, and also utilized cells for in vitro functional analysis of ceruloplasmin (CP). In total, 202 DEGs (52 upregulated and 150 downregulated genes) were identified. Upregulated DEGs are significantly rich in angiogenesis, cell adhesion, and response to hypoxia, whereas downregulated DEGs are involved in intracellular pH regulation, excretion, coagulation, and chloride transmembrane transport. We selected the interactions of the top 20 hub genes provided by the PPI network, all of which are involved in important physiological pathways in vivo, such as complement and coagulation cascades. Tissue protein assays demonstrated that renal cancer highly expressed CP, while in vitro experiments showed that CP could promote the invasion of renal cancer cells. Our study suggests that ALB, C3, LOX, HRG, CXCR4, GPC3, SLC12A3, CP, and CASR may be involved in the development of ccRCC, and is expected to provide theoretical support for future studies on the diagnosis and targeted therapy of ccRCC.

Access to 2-arylquinazolines via catabolism/reconstruction of amino acids with the insertion of dimethyl sulfoxide.

Quinazoline skeletons are synthesized by amino acid catabolism/reconstruction combined with the insertion/cyclization of dimethyl sulfoxide for the first time. The amino acid acts as a carbon and nitrogen source through HI-mediated catabolism and is then reconstructed using aromatic amines and dimethyl sulfoxide (DMSO) as a one-carbon synthon. This protocol is of great significance for the further study of the conversion of amino acids.

Dual inhibition of DNA-PKcs and mTOR by CC-115 potently inhibits human renal cell carcinoma cell growth.

CC-115 is a dual inhibitor of DNA-PKcs and mTOR, both are valuable therapeutic targets for renal cell carcinoma (RCC). Our results showed that CC-115 inhibited survival and proliferation of established RCC cell lines (786-O and A489) and primary human RCC cells. The dual inhibitor induced selective apoptosis activation in RCC cells, as compared to no cytotoxicity nor apoptotic effects toward normal renal epithelial cells. CC-115 inhibited DNA-PKcs and mTORC1/2 activation in RCC cells. It was however ineffective in DNA-PKcs-mTOR double knockout (DKO) 786-O cells. CC-115 induced feedback autophagy activation in RCC cells. Autophagy inhibitors or Beclin-1/Light chain 3 (LC3) silencing potentiated CC-115-induced anti-RCC cell activity. Conversely, ectopic overexpression of Beclin-1 inhibited CC-115-induced cytotoxicity. At last CC-115 oral administration inhibited 786-O subcutaneous xenograft growth in nude mice. Taken together, dual inhibition of DNA-PKcs and mTOR by CC-115 potently inhibited RCC cell growth.

The Effect Of Food On The Pharmacokinetic Properties And Bioequivalence Of Two Formulations Of Levocetirizine Dihydrochloride In Healthy Chinese Volunteers.

PURPOSE: The aim of this study is to assess the bioequivalence of a new generic formulation and the branded formulation of levocetirizine dihydrochloride in healthy Chinese volunteers under fasting and fed conditions, and food-intake effect on the pharmacokinetic properties is also evaluated. PATIENTS AND METHODS: Volunteers were randomly allocated into two groups to receive a single oral dose of generic formulation and branded formulation under fasting or fed conditions, respectively. Blood samples were collected at designated time points. Plasma concentrations of levocetirizine were determined by UFLC-MS/MS. Safety evaluations were carried out through the study. The main pharmacokinetic parameters of the two formulations of levocetirizine were calculated using non-compartmental analysis incorporated in WinNonlin® 7.0 software. RESULTS: Forty-nine volunteers were enrolled; 46 completed the studies. Under fasting and fed conditions, the 90% confidence intervals for the geometric mean of generic/branded ratios were in the range of 94.75-107.24% and 99.98-114.69% for the maximum observed concentration, and 97.13-102.50% and 98.36-103.98% for the area under the concentration-time curve. As a result of food intake before administration, the reduced rate and extent of absorption of levocetirizine were observed. Both formulations were generally well tolerated, with no serious adverse reactions reported. CONCLUSION: The two formulations demonstrated essentially identical pharmacokinetic profiles and were all well within the FDA/CFDA bioequivalence standards. Meanwhile, food intake can delay the absorption rate and reduced the bioavailability of levocetirizine in healthy Chinese volunteers.

p38gamma overexpression promotes renal cell carcinoma cell growth, proliferation and migration.

Recent studies have proposed that p38gamma (p38γ) might be critically involved in tumorigenesis and cancer progression. Its expression and potential functions in human renal cell carcinoma (RCC) are studied here. We show that p38γ mRNA and protein levels are upregulated in human RCC tissues, as compared to its levels in the surrounding normal renal tissues. p38γ upregulation was also detected in established (786-O line) and primary human RCC cells. Functional studies in 786-O cells and primary human RCC cells demonstrated that p38γ silencing (by targeted shRNAs) or CRISPR/Cas9-mediated p38γ knockout (KO) potently inhibited cell growth, viability, proliferation and migration. Furthermore, p38γ shRNA or KO in RCC cells decreased retinoblastoma (Rb) phosphorylation and downregulated cyclin E1/A expression. Additionally, significant apoptosis activation was detected in p38γ-silenced and p38γ-KO RCC cells. Contrarily, ectopic overexpression of p38γ facilitated cell growth, viability, proliferation and migration in RCC cells. Taken together, we show that p38γ overexpression promotes RCC cell growth, proliferation and migration. p38γ could be a novel therapeutic target for human RCC.

[Establishment of a scoring system for predicting the positive rate of prostatic biopsy for prostate cancer].

OBJECTIVE: To identify the predictors of the positive results of transrectal ultrasound (TRUS)-guided biopsy for prostate cancer. METHODS: We performed univariate and multivariate logistic regression analyses on the relevant data on 385 male patients that underwent TRUS-guided biopsy for prostate cancer, including such potential predictors as age, body mass index (BMI), symptoms, results of digital rectal examination (DRE), tPSA, fPSA, free/total PSA ratio (f/tPSA), prostate volume (PV), and PSA density (PSAD) for identification of the risk factors related to the positive rate of biopsy. Then we constructed a scoring system as a tool for predicting prostate cancer in repeat biopsies and determined the sensitivity of the system by calculating the false positive rate using the receiver operating characteristic curve. RESULTS: Among the 385 patients, 139 (36.1%) were diagnosed with prostate cancer. On multivariate analysis, age (P < 0.01), DRE (P < 0.01), tPSA (P < 0.01), fPSA (P < 0.01), f/tPSA (P < 0.01), PV (P < 0.01), and PSAD (P < 0.01) were all significant predictors of prostate cancer. Multivariate logistic regression analysis showed age, tPSA, f/tPSA, PV, and PSAD to be independent predictors, with ORs and 95% CIs of 1.07 (1.05-1.16), 1.05 (1.02-1.15), 0.97 (0.86-0.99), 0.98 (0.87-0.96), and 1.79 (1.48-2.06), respectively. Moreover, patients with the risk score of 3-5 had a significantly higher rate of prostate cancer than those with 0-2 (64% vs 11%, P < 0.001). CONCLUSION: The scoring system on the key predictors of prostate cancer can help urologists to identify the men in need of prostatic biopsy.

Pseudomonas aeruginosa injection enhanced antitumor cytotoxicity of cytokine-induced killer cells derived from cord blood.

Cord blood (CB) is becoming an extensive source of cytokine-induced killer cells. It had been used in several clinical settings and proven to be efficacious and safe. Therefore, we investigated the possibility of combining CIK cells derived from cord blood (CB-CIK) and Pseudomonas aeruginosa injection (PA-MSHA) in order to enhance the cytotoxicity of CB-CIK cells against tumors. Compared with the CB-CIK cells, the PA-MSHA-treated CB-CIK cells demonstrated with increased proliferation rates, higher expression of activated cell surface marker CD28 and lower expression of inhibited cell surface markers PD-1 and CTLA-4. Furthermore, PA-MSHA-treated CB-CIK cells exhibited more effectively for secreting pro-inflammatory cytokine such as IFN-γ and expressing high levels of TLR2, TLR4 and TLR6. The expression of CD107a was higher in the CD3(+)CD56(+) subset of PA-MSHA-treated CB-CIK cells. Our results indicate that the PA-MSHA-treated CB-CIK cells exhibited a more potent in cytotoxic activity against tumor cells. Thus, PA-MSHA enhanced the antitumor ability of CB-CIK cells.

Modification of chemokine receptor expression to enhance levels of trafficking receptors on autologous cytokine-induced killer cells derived from patients with colorectal cancer.

Cytokine-induced killer (CIK) cells have achieved therapeutic benefit in treatment of solid tumors in clinic. However, some patients show no response after CIK treatment. Animal assays have shown that successful infiltration of CIK cells to the tumor sites could affect the outcome. Chemokines play important roles in lymphocyte trafficking. Understanding the molecular mechanism of chemokines in the process of CIK cell homing is important for further modification of CIK therapy. In this study, we investigated the spectrum of chemokine ligands in the colorectal cancer sites and observed that chemokine ligands CCL20 and CXCL10 were overexpressed in the CRC tumor tissues compared with adjacent tissues. Although the corresponding receptors CCR6 and CXCR3 increased on CIK cells compared with PBMCs, their expression on CIK cells derived from CRC patients had lower levels than healthy donors, which might be a limited factor for autologous-CIK cells trafficking to tumor site. Importantly, stimulation with chemokines CCL20 and CXCL10 promotes the expression levels of CCR6 and CXCR3 on CIK cells, thus augmenting the relative migration of CIK cells in vitro. Our results suggest that modification of surface chemokine receptors may enhance the homing ability of CIK cells for better therapeutic achievements.

Expression and prognostic relevance of centromere protein A in primary osteosarcoma.

Centromere protein A (CENP-A) is one of the fundamental components of the human active kinetochore and plays important roles in cell-cycle regulation, cell survival, and genetic stability. The aim of the present study was to explore the expression and prognostic significance of CENP-A in osteosarcoma. The results of real-time quantitative PCR and Western blotting analysis revealed an enhanced expression of CENP-A in osteosarcomas relative to adjacent non-tumorous bone tissues at both mRNA and protein levels. Immunohistochemically, 72 of the 123 osteosarcoma specimens (58.5%) had high expression of CENP-A. CENP-A overexpression was significantly correlated with tumor size (P=0.002), poor response to neoadjuvant chemotherapy (P=0.016), local recurrence/lung metastasis (P=0.001), high Ki-67 index (P=0.004), and P53 positivity (P=0.005). Median overall and recurrence-free survival time was significantly shorter in patients with high-CENP-A osteosarcomas than in those with low-CENP-A osteosarcomas. Multivariate analysis identified CENP-A as an independent poor prognostic factor for osteosarcoma. In conclusion, our results demonstrate that elevated CENP-A expression is significantly associated with osteosarcoma progression and has an independent prognostic value in predicting overall and recurrence-free survival for patients with osteosarcoma.

5,6-Dihydro-1,10-phenanthroline-1,10-diium µ-oxido-bis-[penta-fluoridotantalate(V)].

In the title compound, (C(12)H(12)N(2))[Ta(2)F(10)O], the doubly protonated 5,6-dihydro-1,10-phenantroline-1,10-diium cation is located on a twofold rotation axis, whereas the isolated [Ta(2)OF(10)](2-) dianion has -1 symmetry. In the so far unknown dianion, the symmetry-related Ta(V) atoms are octa-hedrally coordinated by five F atoms and a bridging O atom, the latter being located on an inversion centre. The two pyridine rings in the cation make a dihedral angle of 22.8 (4)°. The cations and dianions are arranged in layers parallel to (100) and are connected through N-H⋯F and C-H⋯F hydrogen-bonding inter-actions into a three-dimensional structure.

[Study on blood biochemical variables of obese children screened by new BMI and weight-for-height criterion].

OBJECTIVE: To evaluate the abnormal state of liver function and plasma lipid levels of obese schoolchildren who were screened by weight-for-height criterion and new body mass index criterion respectively. METHODS: 280 obese children were screened by weight-for-height criterion and 125 obese children were screened by body mass index criterion in a routine school check-up program. All of the latter subjects was included in the former one. One obese child and 1 non-obese child were matched for gender and age. 14 items related to liver functions and plasma lipids were measured. RESULTS: Of the abnormal items,7 items in 125 obese children screened by new BMI criterion and 5 items in 155 "obese children" excluded by BMI criterion, were significantly higher than those children among controlled group. The abnormal rates were 10.4%-22.9% in the former and 3.2%-13.0% in the latter. CONCLUSIONS: The new BMI criterion seemed to be more stringent than weight-for-height. Less than a half of the obese children screened by weight-for-height were taken on obese children by new BMI criterion. The overweight children who were screened by BMI criterion also had abnormal liver functions and plasma lipids.