Endovascular Interventional Procedure is a Significant Risk Factor of Postsurgical Gout: A Retrospective Cohort Study.

INTRODUCTION: Surgery is a risk factor for flares in people with gout. However, gout flares after endovascular interventional procedures are not well understood. The aim of this study was to evaluate the clinical features and risk factors for gout flare that develop during the postsurgical period including endovascular procedures. METHODS: We enrolled 222 patients with gout who developed postsurgical gout and 196 controls who had histories of gout but did not develop gout flares after surgery within 20 days. Clinical characteristics of patients who developed a postsurgical gout flare were compared with the controls. RESULTS: The rate of endovascular interventional procedures was higher (38.74% vs. 13.48%, P < 0.001) in the flare group than in the no-flare group and lower in orthopedic surgery (13.96% vs. 41.84%, P < 0.001). The Cox model showed that endovascular interventional procedures (HR, hazard ratio 1.752; 95% CI, confidence interval 1.126-2.724, P = 0.013) and presurgical uric acid levels of ≥ 7 mg/dl (HR 1.489; 95% CI 1.081-2.051, P = 0.015) were significantly associated with increased risks of postsurgical gout flare, and taking colchicine before surgery were significantly associated with decreased risk of postsurgical gout flare (HR 0.264; 95% CI 0.090-0.774, P = 0.015). There was no significant difference in the types of endovascular interventional procedures between the flare group and the no-flare group. CONCLUSIONS: Patients with a history of gout should be more alert to recurrence gout flares after endovascular interventional procedures. Adequate presurgical control of serum uric acid levels and/or prophylactic treatment with colchicine will help prevent gout flares during the postsurgical period.

SHMT as a Potential Therapeutic Target for Renal Cell Carcinoma.

BACKGROUND: Serine hydroxymethyltransferase (SHMT) is a serine-glycine-one-carbon metabolic enzyme in which SHMT1 and SHMT2 encode the cytoplasmic and mitochondrial isoenzymes, respectively. SHMT1 and SHMT2 are key players in cancer metabolic reprogramming, and thus are attractive targets for cancer therapy. However, the role of SHMT in patients with renal cell carcinoma (RCC) has not been fully elucidated. We aimed to systematically analyze the expression, gene regulatory network, prognostic value, and target prediction of SHMT1 and SHMT2 in patients with kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), and kidney renal papillary cell carcinoma (KIRP); elucidate the association between SHMT expression and RCC; and identify potential new targets for clinical RCC treatment. METHODS: Several online databases were used for the analysis, including cBioPortal, TRRUST, GeneMANIA, GEPIA, Metascape, UALCAN, LinkedOmics, and TIMER. RESULTS: SHMT1 and SHMT2 transcript levels were significantly down- and upregulated, respectively, in patients with KICH, KIRC, and KIRP, based on sample type, individual cancer stage, sex, and patient age. Compared to men, women with KIRC and KIRP showed significantly up- and downregulated SHMT1 transcript levels, respectively. However, SHMT2 transcript levels were significantly upregulated in the patients mentioned above. KIRC and KIRP patients with high SHMT1 expression had longer survival periods than those with low SHMT1 expression. In patients with KIRC, the findings were similar to those mentioned above. However, in KICH patients, the findings were the opposite regarding SHMT2 expression. SHMT1 versus SHMT2 were altered by 9% versus 3% (n = 66 KICH patients), 4% versus 4% (n = 446 KIRC patients), and 6% versus 7% (n = 280 KIRP patients). SHMT1 versus SHMT2 promoter methylation levels were significantly up- and downregulated in patients with KIRP versus KIRC and KIRP, respectively. SHMT1, SHMT2, and their neighboring genes (NG) formed a complex network of interactions. The molecular functions of SHMT1 and its NG in patients with KICH, KIRC, and KIRP, included clathrin adaptor, metalloendopeptidase, and GTPase regulator activities; lipid binding, active transmembrane transporter activity, and lipid transporter activity; and type I interferon receptor binding, integrin binding, and protein heterodimerization, respectively. Their respective Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were involved in lysosome activity, human immunodeficiency virus 1 infection, and endocytosis; coronavirus disease 2019 and neurodegeneration pathways (multiple diseases); and RIG-I-like receptor signaling pathway, cell cycle, and actin cytoskeleton regulation. The molecular functions of SHMT2 and its NG in patients with KICH, KIRC, and KIRP included cell adhesion molecule binding and phospholipid binding; protein domain-specific binding, enzyme inhibitor activity, and endopeptidase activity; and hormone activity, integrin binding, and protein kinase regulator activity, respectively. For patients with KIRC versus KIRP, the KEGG pathways were involved in cAMP and calcium signaling pathways versus microRNAs (MiRNAs) in cancer cells and neuroactive ligand-receptor interactions, respectively. We identified the key transcription factors of SHMT1 and its NG. CONCLUSIONS: SHMT1 and SHMT2 expression levels were different in patients with RCC. SHMT1 and SHMT2 may be potential therapeutic and prognostic biomarkers in these patients. Transcription factor (MYC, STAT1, PPARG, AR, SREBF2, and SP3) and miRNA (miR-17-5P, miR-422, miR-492, miR-137, miR-30A-3P, and miR-493) regulations may be important strategies for RCC treatment.

Systematic analysis of the BET family in adrenocortical carcinoma: The expression, prognosis, gene regulation network, and regulation targets.

Background: Bromodomain and extracellular terminal (BET) family (including BRD2, BRD3, and BRD4) is considered to be a major driver of cancer cell growth and a new target for cancer therapy. Currently, more than 30 targeted inhibitors have shown significant inhibitory effects against various tumors in preclinical and clinical trials. However, the expression levels, gene regulatory networks, prognostic value, and target prediction of BRD2, BRD3, and BRD4 in adrenocortical carcinoma (ACC) have not been fully elucidated. Therefore, this study aimed to systematically analyze the expression, gene regulatory network, prognostic value, and target prediction of BRD2, BRD3, and BRD4 in patients with ACC, and elucidated the association between BET family expression and ACC. We also provided useful information on BRD2, BRD3, and BRD4 and potential new targets for the clinical treatment of ACC. Methods: We systematically analyzed the expression, prognosis, gene regulatory network, and regulatory targets of BRD2, BRD3, and BRD4 in ACC using multiple online databases, including cBioPortal, TRRUST, GeneMANIA, GEPIA, Metascape, UALCAN, LinkedOmics, and TIMER. Results: The expression levels of BRD3 and BRD4 were significantly upregulated in ACC patients at different cancer stages. Moreover, the expression of BRD4 was significantly correlated with the pathological stage of ACC. ACC patients with low BRD2, BRD3, and BRD4 expressions had longer survival than patients with high BRD2, BRD3, and BRD4 expressions. The expression of BRD2, BRD3, and BRD4 was altered by 5%, 5%, and 12% in 75 ACC patients, respectively. The frequency of gene alterations in the 50 most frequently altered BRD2, BRD3, and BRD4 neighboring genes in these ACC patients were ≥25.00%, ≥25.00%, and ≥44.44%, respectively. BRD2, BRD3, and BRD4 and their neighboring genes form a complex network of interactions mainly through co-expression, physical interactions, and shared protein domains. Molecular functions related to BRD2, BRD3, and BRD4 and their neighboring genes mainly include protein-macromolecule adaptor activity, cell adhesion molecule binding, and aromatase activity. Chemokine signaling pathway, thiamine metabolism, and olfactory transduction were found to be enriched as per the KEGG pathway analysis. SP1, NPM1, STAT3, and TP53 are key transcription factors for BRD2, BRD4, and their neighboring genes. MiR-142-3P, miR-484, and miR-519C were the main miRNA targets of BRD2, BRD3, BRD4, and their neighboring genes. We analyzed the mRNA sequencing data from 79 patients with ACC and found that ZSCAN12, DHX16, PRPF4B, EHMT1, CDK5RAP2, POMT1, WIZ, ZNF543, and AKAP8 were the top nine genes whose expression were positively associated with BRD2, BRD3, and BRD4 expression. The expression level of BRD2, BRD3, and BRD4 positively correlated with B cell and dendritic cell infiltration levels. BRD4-targeted drug PFI-1 and (BRD2, BRD3, and BRD4)-targeted drug I-BET-151 may have good inhibitory effects on the SW13 cell line. Conclusions: The findings of this study provide a partial basis for the role of BRD2, BRD3, and BRD4 in the occurrence and development of ACC. In addition, this study also provides new potential therapeutic targets for ACC, which can serve as a reference for future basic and clinical research.

Systematic Analysis of CXC Chemokine-Vascular Endothelial Growth Factor A Network in Colonic Adenocarcinoma from the Perspective of Angiogenesis.

Background: Tumor angiogenesis plays a vital role in tumorigenesis, proliferation, and metastasis. Recently, vascular endothelial growth factor A (VEGFA) and CXC chemokines have been shown to play vital roles in angiogenesis. Exploring the expression level, gene regulatory network, prognostic value, and target prediction of the CXC chemokine-VEGFA network in colon adenocarcinoma (COAD) is crucial from the perspective of tumor angiogenesis. Methods: In this study, we analyzed gene expression and regulation, prognostic value, target prediction, and immune infiltrates related to the CXC chemokine-VEGFA network in patients with COAD using multiple databases (cBioPortal, UALCAN, Human Protein Atlas, GeneMANIA, GEPIA, TIMER (version 2.0), TRRUST (version 2), LinkedOmics, and Metascape). Results: Our results showed that CXCL1/2/3/5/6/8/11/16/17 and VEGFA were markedly overexpressed, while CXCL12/13/14 were underexpressed in patients with COAD. Moreover, genetic alterations in the CXC chemokine-VEGFA network found at varying rates in patients with COAD were as follows: CXCL1/2/17 (2.1%), CXCL3/16 (2.6%), CXCL5/14 (2.4%), CXCL6 (3%), CXCL8 (0.8%), CXCL11/13 (1.9%), CXCL12 (0.6%), and VEGFA (1.3%). Promoter methylation of CXCL1/2/3/11/13/17 was considerably lower in patients with COAD, whereas methylation of CXCL5/6/12/14 and VEGFA was considerably higher. Furthermore, CXCL9/10/11 and VEGFA expression was notably correlated with the pathological stages of COAD. In addition, patients with COAD with high CXCL8/11/14 or low VEGFA expression levels survived longer than patients with dissimilar expression levels. CXC chemokines and VEGFA form a complex regulatory network through coexpression, colocalization, and genetic interactions. Moreover, many transcription factor targets of the CXC chemokine-VEGFA network in patients with COAD were identified: RELA, NFKB1, ZFP36, XBP1, HDAC2, SP1, ATF4, EP300, BRCA1, ESR1, HIF1A, EGR1, STAT3, and JUN. We further identified the top three miRNAs involved in regulating each CXC chemokine within the network: miR-518C, miR-369-3P, and miR-448 regulated CXCL1; miR-518C, miR-218, and miR-493 regulated CXCL2; miR-448, miR-369-3P, and miR-221 regulated CXCL3; miR-423 regulated CXCL13; miR-378, miR-381, and miR-210 regulated CXCL14; miR-369-3P, miR-382, and miR-208 regulated CXCL17; miR-486 and miR-199A regulated VEGFA. Furthermore, the CXC chemokine-VEGFA network in patients with COAD was notably associated with immune infiltration. Conclusions: This study revealed that the CXC chemokine-VEGFA network might act as a prognostic biomarker for patients with COAD. Moreover, our study provides new therapeutic targets for COAD, serving as a reference for further research in the future.

Febuxostat Therapy for Patients with Gout and Stage 2-4 CKD: a Retrospective Study.

INTRODUCTION: The aim of this study is to explore the efficacy and renal safety of febuxostat in gout and stage 2-4 chronic kidney disease (CKD) and factors that correlated with target serum urate (SU). METHODS: A single-center retrospective study including male patients with gout and CKD was conducted. SU, the rate of SU < 360 µmol/L (RAT), and renal safety were analyzed in subjects who received febuxostat over 44 weeks. Factors that correlated with target SU were also explored. RESULTS: Between January 2017 and March 2021, 102 patients (stage 2 CKD: n = 27; stage 3 CKD: n = 70; stage 4 CKD: n = 5) were enrolled. The SU level reduced significantly over 44 weeks (600.76 ± 95.42 versus 405.52 ± 111.93 µmol/L; P < 0.05), and RAT increased to 39.20%. The overall estimated glomerular filtration rate (eGFR) level improved over 44 weeks (52.05 ± 11.68 versus 55.46 ± 14.49 mL/min/1.73 cm2, P < 0.05). An obvious improvement of eGFR was observed in stage 3 CKD, in patients with ≤ 1 risk factor (hypertension, diabetic mellitus, hyperlipidemia, or usage of non-steroidal anti-inflammatory drugs), and in patients with terminal SU < 360 µmol/L (P < 0.05). Logistic regression analysis indicated that baseline SU level and body weight were correlated with RAT. Further analysis revealed that patients with SU < 600 µmol/L and body weight ≤ 70 kg reached higher RAT (56.7%). CONCLUSIONS: Febuxostat demonstrated efficacy and renal safety in patients with gout and CKD in clinical practice. Achieving the target SU could obviously improve renal function. Baseline SU level and body weight could affect the achievement of target SU.

A dual-functional fluorescent biosensor based on enzyme-involved catalytic hairpin assembly for the detection of APE1 and miRNA-21.

Both apurinic/apyrimidinic endonuclease 1 (APE1) and microRNA-21 (miRNA-21) have been reported to be related to tumors, enabling them to be the biomarkers of several cancers. This has led to the development of various biosensors to detect APE1 or miRNA-21. However, biosensors that focus on single target detection are subject to low accuracy. In this work, a fluorescent biosensor based on enzyme-involved catalytic hairpin assembly (CHA) for the detection of APE1 and miRNA-21 was developed, aimed at improving the accuracy of early-phase diagnosis of cancers. Two hairpin structured DNA probes (H1 and H2) were utilized to concatenate the enzyme-assisted circuit and CHA circuit in the system. The stem of H1 with a blunt end was modified with an AP site, while H2 was modified with 6-FAM at the 5' terminal and Dabcyl at the 3' terminal. In the presence of APE1, H1 was cleaved from the AP site to expose the toehold sequence. Then, miRNA-21 bound with the toehold sequence to initiate the CHA reaction between H1 and H2. The assembled product of CHA triggered the 6-FAM of H2 at a distance from Dabcyl, which recovered the fluorescence signal. It is worth noting that only under the co-stimulation of APE1 and miRNA-21 can the fluorescence signal be detected, indicating that the biosensor could work as an AND logic gate. The proposed dual-functional biosensor achieved a limit of detection (LOD) of 0.016 U mL-1 for APE1 and 0.25 nM for miRNA-21 and APE1, respectively, and also exhibits good selectivity and stability for the two biomarkers. Thus, the biosensor has great potential to be applied as a new platform for cancer diagnosis.

A rare case of IgG4-related disease masquerading as periurethral malignancy and review of the literature.

Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory disease that typically manifests as mass lesions affecting almost any organ including the pancreas, lacrimal and salivary glands, liver, lung and kidney. However, IgG4-RD with urethra involvement is scarce. We describe a rare case of IgG4-RD involving the urethra mimicking urethral carcinoma and review the published literature. A 64-years-old female presented with progressive dysuria for more than 2 months. Pelvic gadolinium-enhanced magnetic resonance imaging revealed a huge mass encasing the urethra which showed obvious enhancement in the arterial phase. And contrast-enhanced ultrasound showed that the entire mass was heterogeneously enhanced and displayed a fast-forward and fast-out pattern, which was highly suggestive of malignant tumor. The diagnosis of IgG4-RD was finally established by ultrasound-guided transvaginal mass needle biopsy. The patient was treated with methylprednisolone and cyclophosphamide and dysuria disappeared in the first week of therapy. She has been followed up in our clinic for 1 year without recurrence. The diagnosis of IgG4-RD should be considered in the differential diagnosis of a periurethral mass. Ultrasound-guided transvaginal mass needle biopsy is a safe and well-established tissue sampling method and should be performed in order to avoid unnecessary surgery.

PYCR in Kidney Renal Papillary Cell Carcinoma: Expression, Prognosis, Gene Regulation Network, and Regulation Targets.

BACKGROUND: Pyrroline-5-carboxylate reductase (PYCR) includes three human genes encoding three isozymes, PYCR1, PYCR2, and PYCR3 (or PYCRL), which facilitate the final step in the conversion of glutamine to proline. These genes play important roles in regulating the cell cycle and redox homeostasis as well as promoting growth signaling pathways. Proline is abnormally upregulated in a variety of cancers, and as the last key enzyme in proline production, PYCR plays an integral role in promoting tumorigenesis and cancer progression. However, its role in patients with kidney renal papillary cell carcinoma (KIRP) has not been fully elucidated. In this study, we aimed to systematically analyze the expression, gene regulatory network, prognostic value, and target prediction of PYCR in patients with KIRP, elucidate the association between PYCR expression and KIRP, and identify potential new targets for the clinical treatment of KIRP. METHODS: We systematically analyzed the expression, prognosis, gene regulatory network, and regulatory targets of PYCR1, PYCR2, and PYCRL in KIRP using multiple online databases including cBioPortal, STRING, MethSurv, GeneMANIA, Gene Expression Profiling Interactive Analysis (GEPIA), Metascape, UALCAN, LinkedOmics, and TIMER. RESULTS: The expression levels of PYCR1, PYCR2, and PYCRL were considerably upregulated in patients with KIRP based on sample type, sex, age, and individual cancer stage. PYCR1 and PYCR2 transcript levels were markedly upregulated in females than in males, and patients aged 21-40 years had higher PYCR1 and PYCR2 transcript levels than those in other age groups. Interestingly, PYCR2 transcript levels gradually decreased with age. In addition, the expressions of PYCR1 and PYCR2 were notably correlated with the pathological stage of KIRP. Patients with KIRP with low PYCR1 and PYCR2 expression had longer survival than those with high PYCR1 and PYCR2 expression. PYCR1, PYCR2, and PYCRL were altered by 4%, 7%, and 6%, respectively, in 280 patients with KIRP. The methylation levels of cytosine-phosphate-guanine (CpG) sites in PYCR were markedly correlated with the prognosis of patients with KIRP. PYCR1, PYCR2, PYCRL, and their neighboring genes form a complex network of interactions. The molecular functions of the genes, as demonstrated by their corresponding Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, included calcium channel activity, phospholipid binding, RNA polymerase II-specificity, and kinase and GTPase-regulatory activities. PYCR1, PYCR2, and PYCRL targeted miR-21, miR-221, and miR-222, resulting in a better prognosis of KIRP. We analyzed mRNA sequencing data from 290 patients with KIRP and found that ADA, NPM3, and TKT were positively associated with PYCR1 expression; PFDN2, JTB, and HAX1 were positively correlated with PYCR2 expression; SHARPIN, YDJC, and NUBP2 were positively correlated with PYCRL expression; PYCR1 was positively correlated with B cell and CD8+ T-cell infiltration levels; macrophage infiltration was negatively correlated with PYCR2 expression; and PYCRL expression was negatively correlated with B-cell, CD8+ T cell, and dendritic cell infiltration levels. CONCLUSIONS: PYCR1, PYCR2, and PYCRL may be potential therapeutic and prognostic biomarkers for patients with KIRP. The regulation of microRNAs (miRNAs), including miR-21, miR-221, and miR-222, may prove an important strategy for KIRP treatment.

A novel siRNA-gemcitabine construct as a potential therapeutic for treatment of pancreatic cancer.

The non-nucleoside analog gemcitabine has been the standard of care for treating pancreatic cancer. The drug shows good potency in pancreatic cancer cells in vitro but, due to poor bioavailability, requires administration in large doses by infusion and this systemic exposure results in significant toxicity for the patient. Genes have been identified that, when silenced by siRNA, synergize with gemcitabine treatment and offer a means of reducing the gemcitabine dosage required for efficacy. However, benefiting from the synergism between the two agents requires that the gemcitabine and siRNA penetrate the same cells. To ensure co-delivery, we incorporated gemcitabine covalently within siRNAs against targets synergistic with gemcitabine (CHK1 or RAD17). We demonstrated that specific bases within an siRNA can be replaced with gemcitabine to increase efficacy. The result is a single drug molecule that simultaneously co-delivers gemcitabine and a synergistic siRNA. The siRNA-gemcitabine constructs demonstrate a 5-30-fold improvement in potency compared with gemcitabine alone. Co-delivering a CHK1 siRNA-gemcitabine construct together with a WEE1 siRNA resulted in a 10-fold improvement in IC50 compared with gemcitabine alone. These constructs demonstrate efficacy across a wide array of pancreatic tumor cells and may represent a novel therapeutic approach for treating pancreatic cancer.

Delivery of RIPK4 small interfering RNA for bladder cancer therapy using natural halloysite nanotubes.

RNA interference (RNAi) technology can specifically silence the expression of a target gene and has emerged as a promising therapeutic method to treat cancer. In the present study, we showed that natural halloysite nanotube (HNT)-assisted delivery of an active small interfering RNA (siRNA) targeting receptor-interacting protein kinase 4 ( RIPK4 ) efficiently silenced its expression to treat bladder cancer. The HNTs/siRNA complex increased the serum stability of the siRNA, increased its circulation lifetime in blood, and promoted the cellular uptake and tumor accumulation of the siRNA. The siRNA markedly down-regulated RIPK4 expression in bladder cancer cells and bladder tumors, thus inhibiting tumorigenesis and progression in three bladder tumor models (a subcutaneous model, an in situ bladder tumor model, and a lung metastasis model), with no adverse effects. Thus, we revealed a simple but effective method to inhibit bladder cancer using RIPK4 silencing, indicating a promising therapeutic method for bladder cancer.

Vasoactive intestinal peptide-induced tolerogenic dendritic cells attenuated arthritis in experimental collagen-induced arthritic mice.

AIM: Cumulative evidence has revealed that tolerogenic dendritic cells (tolDC) could relieve inflammation reactions in various autoimmune diseases. This study investigated the potential therapeutic application of vasoactive intestinal peptide (VIP)-induced tolDC (VIP-DC) on arthritis using collagen-induced arthritis (CIA) mice. METHODS: Bone marrow cells were differentiated into dendritic cells (DC) using granulocyte macrophage colony-stimulating factor and interleukin (IL)-4. tolDC were induced by either VIP or Bay 11-7082 in vitro. Immunophenotypes and cytokine production of VIP-DC and Bay-DC were detected by fluorescence-activated cell sorting and enzyme-linked immunosorbent assay, respectively. Bay-DC, VIP-DC and untreated DC were ip administrated to CIA mice on day 40 when arthritis was onset. The treatment effects on arthritic and pathological changes, including synovial hyperplasia, pannus formation, inflammation and bone erosion, were assessed. RESULTS: VIP-DC (40 ng/mL) and Bay-DC (0.5 µg/mL) had a lower level of major histocompatibility complex II, CD40 and CD86 expression, reduced γ-interferon and increased IL-4 production (P < 0.05 or 0.01), compared with untreated DC. The administration of VIP-DC and Bay-DC decreased the arthritis score clinically at the end of the therapy. Pathological assessments showed that bone erosion and inflammation were alleviated in the VIP-DC group compared with those in the untreated DC group (P < 0.05 and P < 0.01, respectively). CONCLUSION: VIP-DC showed reduced immunogenicity and enhanced anti-inflammatory cytokine production. Both VIP-DC and Bay-DC could ameliorate arthritis in CIA mice clinically. VIP-DC were not inferior to Bay 11-7082-induced tolDC but may exert a better preventive effect on bone destruction.

IL-1ß functionally attenuates ABCG2 and PDZK1 expression in HK-2 cells partially through NF-ĸB activation.

Long-standing untreated hyperuricemia could lead to gout. Several recent studies have demonstrated a significant decrease of serum urate during acute gout attack, which is an aseptic inflammation process focusing on IL-1ß. However, how IL-1ß, by itself, alters the expression and the functional activity of urate transporters in renal tubular epithelial cells is still unclear. Herein, we revealed that IL-1ß could attenuate the mRNA and protein levels of ABCG2, a major urate efflux pump, in HK-2 cells by real-time PCR and Western-blot assays. Moreover, using an ABCG2 specific inhibitor and a new sensitive and specific detection system, it was found that IL-1ß also reduced the ABCG2 transporter activities. Incubation with specific inhibitors of the NF-κB pathway partly dampened the inhibitory effect of IL-1ß on ABCG2, indicating that IL-1ß reduced the ABCG2 expression partially through the NF-ĸB pathway. Furthermore, the decreased expression of PDZK1 induced by IL-1ß, which is dependent on the NF-κB pathway, could account for the imbalance between the functions and expressions of ABCG2 on this status. These findings demonstrated a new role for IL-1ß, whereby it leads to the inhibition of ABCG2 in renal tubular epithelial cells; this new role probably does not encompass its involvement in the process of renal urate excretion mediated by inflammation. Therefore, other regulation mechanisms of urate reabsorption in renal tubular epithelial cells deserve to be examined in further studies.

Extraperiosteal segmental excision for osteofibrous dysplasia of tibia with reconstruction by liquid nitrogen-treated recycled autograft.

BACKGROUND: Osteofibrous dysplasia usually progresses until ten years of age and occasionally regresses spontaneously after puberty. Patients with osteofibrous dysplasia usually require close observation. Surgery is an option considered only for extensive, deforming lesions and those with pathological fractures and rapid progression prior to puberty. If surgery is indicated, the traditional intra-lesional curettage or subperiosteal resection usually leads to high recurrence. Hence, extraperiosteal wide excision and various methods of reconstruction after resection have been advocated for this lesion. We reviewed the clinical results of patients managed with extraperiosteal segmental excision and reconstruction by liquid nitrogen-treated tumor-bearing autograft combined with allograft. METHODS: From January 2010 to December 2014, twelve patients with final diagnosis of tibial osteofibrous dysplasia were studied retrospectively. All these patients were treated with extraperiosteal segmental excision and reconstruction by liquid nitrogen-treated tumor-bearing autograft combined with allograft. RESULTS: The patient group consisted of 5 males and 7 females, with a median age of 13 years (6-24 years). 3 lesions were located in left tibia and 9 in right. The median length of resected segment was 8 cm (5-11 cm). The patients were followed for 36-84 months (median 52 months). Follow-up radiographs showed that the median time for complete union of the grafted bone was 9 months (6-15 months). There was no evidence of recurrence. All patients had full range of motion in the knee and ankle joints after surgery. CONCLUSIONS: Extraperiosteal segmental excision for osteofibrous dysplasia of tibia with reconstruction by liquid nitrogen-treated recycled autograft and allograft is a good surgical option to prevent recurrence and fill bone defects in this rare lesion.

Hybrid Molecular Container Based on Glycoluril and Triptycene: Synthesis, Binding Properties, and Triggered Release.

We designed and synthesized a "hybrid" molecular container 1, which is structurally related to both cucurbit[n]uril (CB[n]) and pillar[n]arene type receptors. Receptor 1 was fully characterized by 1 H NMR, 13 C NMR, IR, MS and X-ray single crystal diffraction. The self-association behavior, host-guest recognition properties of 1, and the [salt] dependence of Ka were investigated in detail by 1 H NMR and isothermal titration calorimetry (ITC). Optical transmittance and TEM measurements provide strong evidence that receptor 1 undergoes co-assemble with amphiphilic guest C10 in water to form supramolecular bilayer vesicles (diameter 25.6±2.7 nm, wall thickness ≈3.5 nm) that can encapsulate the hydrophilic anticancer drug doxorubicin (DOX) and the hydrophobic dye Nile red (NR). The release of encapsulated DOX or NR from the vesicles can be triggered by hexamethonium (8 c) or spermine (10) which leads to the disruption of the supramolecular vesicles.

Soluble uric acid increases PDZK1 and ABCG2 expression in human intestinal cell lines via the TLR4-NLRP3 inflammasome and PI3K/Akt signaling pathway.

BACKGROUND: In addition to the kidney, the intestine is one of the most important organs involved in uric acid excretion. However, the mechanism of urate excretion in the intestine remains unclear. Therefore, the relationship between soluble uric acid and the gut excretion in human intestinal cells was explored. The relevant signaling molecules were then also examined. METHODS: HT-29 and Caco-2 cell lines were stimulated with soluble uric acid. Western blotting and qRT-PCR were used to measure protein and mRNA levels. Subcellular fractionation methods and immunofluorescence were used to quantify the proteins in different subcellular compartments. Flow cytometry experiments examined the function of ATP-binding cassette transporter, subfamily G, member 2 (ABCG2). Small interfering RNA transfection was used to assess the interaction between ABCG2 and PDZ domain-containing 1 (PDZK1). RESULTS: Soluble uric acid increased the expression of PDZK1 and ABCG2. The stimulation of soluble uric acid also facilitated the translocation of ABCG2 from the intracellular compartment to the plasma membrane and increased its transport activity. Moreover, the upregulation of PDZK1 and ABCG2 by soluble uric acid was partially decreased by either TLR4-NLRP3 inflammasome inhibitors or PI3K/Akt signaling inhibitors. Furthermore, PDZK1 knockdown significantly inhibited the expression and transport activity of ABCG2 regardless of the activation by soluble uric acid, demonstrating a pivotal role for PDZK1 in the regulation of ABCG2. CONCLUSIONS: These findings suggest that urate upregulates the expression of PDZK1 and ABCG2 for excretion in intestinal cells via activating the TLR4-NLRP3 inflammasome and PI3K/Akt signaling pathway.

Untargeted saliva metabonomics study of breast cancer based on ultra performance liquid chromatography coupled to mass spectrometry with HILIC and RPLC separations.

Breast cancer (BC) is not only the most frequently diagnosed cancer, but also the leading cause of cancer death among women worldwide. This study aimed to screen the potential salivary biomarkers for breast cancer diagnosis, staging, and biomarker discovery. For the first time, a UPLC-MS based method along with multivariate data analysis, was proposed for the global saliva metabonomics analysis and diagnosis of BC, which used both hydrophilic interaction chromatography (HILIC) and reversed-phase liquid chromatography (RPLC) separations and operated in both positive (ESI+) and negative (ESI-) ionization modes. On account of different polarities of endogenous metabolites, this method was established to overcome the boundedness of a single chromatographic approach. As a result, 18 potential metabolites for diagnosing BC were identified. A nonparametric Mann-Whitney U test, heat map, and the receiver operating characteristic (ROC) were exploited to analyze the data with the purpose of evaluating the predictive power of the 18 biomarkers. Significant differences (P<0.05) were disclosed in terms of the levels of the 18 potential biomarkers between BC patients and healthy controls (HC). Among the 18 biomarkers, three up-regulated metabolites, LysoPC (18:1), LysoPC (22:6) and MG (0:0/14:0/0:0) displayed the area under the curve (AUC) values of 0.920, 0.920 and 0.929, respectively, indicating the high accuracy of this method to predict BC. In this study, an integrated metabonomics analysis in human saliva for identifying potential biomarkers to diagnose and stage BC was successfully eastablished, which was non-invasive, reliable, low-cost, and simple. The HILIC was demonstrated to be essential for a comprehensive saliva metabonomics profiling as well as RPLC separation. This saliva metabonomics technique may provide new insight into the discovery and identification of diagnostic biomarkers for BC.

Eosinophilic granulomatosis with polyangiitis complicated by cholecystitis: a case report and review of the literature.

The objectives are to report an atypical case of eosinophilic granulomatosis with polyangiitis (EGPA) associated with cholecystitis and to review the main clinical features, therapy, and prognosis of it. We present a 49-year-old male with non-classic clinical manifestations of EGPA and EGPA-related cholecystitis. EGPA was diagnosed by histology of the gallbladder after cholecystectomy. In addition, 11 cases of EGPA-associated cholecystitis have been reported and were described in details in this article. Gallbladder involvement is very uncommon in EGPA. All cases reviewed showed multiple organs involved as well as obviously elevated eosinophilic granulocyte proportion with inflammatory index, although antineutrophil cytoplasmic antibody may be negative. All patients in this cohort that showed gallbladder involvement were eventually confirmed with EGPA by histology examination after cholecystectomy. The pathological change could be infiltration of inflammatory mononuclear cells of small- and medium-sized vessels. Of the cases, 91.7% responded well to steroid and immunosuppressant therapy. Gallbladder involvement is a very rare comorbid condition in EGPA. However, it is an important symptom or secondary condition to alert physicians the diagnosis of EGPA. Moreover, timely diagnosis and correct administration in the early stage of this disease could obviously improve the prognosis.

[ANALYSIS OF IMPLANT-RELATED COMPLICATIONS AFTER HINGE KNEE REPLACEMENT FOR TUMORS AROUND THE KNEE].

OBJECTIVE: To investigate the reasons and managements of implant-related complications after hinge knee replacement for tumors around the knee. METHODS: A retrospective analysis was made on the clinical data of 96 patients undergoing hinge knee replacement between January 2000 and December 2012. There were 64 males and 32 females with the mean age of 31.0 years (range, 15-72 years). The most common tumor type was osteosarcoma (72 cases), and the second was giant cell tumor (15 cases). The tumor located at the distal femurs in 52 cases and at the proximal tibias in 44 cases. Fifteen hinge and 81 rotating hinge prostheses were used. The recurrence, metastasis, and survival were recorded. The implant-related complications were observed. RESULTS: The median follow-up time was 43.5 months (range, 10-156 months). Complications were observed in 21 patients (25 implant-related complications); 13 complications located at the femur and 12 complications at the tibia. The complications included aseptic loosening (8 cases), deep infection (7 cases), prosthetic breakage (4 cases), peri-prosthetic fracture (2 cases), and dislocation (4 cases). Most deep infection occurred within 12 months after operation (6/7), and most aseptic loosening after 40 months of operation (6/8). The rate of limb salvage was 90.6% (87/96) and the amputation rate was 9.4% (9/96). The overall survival rate of the prosthesis was 76.7% (5-year) and 47.2% (10-year). The 5-year survival rate was 82.9% for femoral prosthesis and 71.0% for tibial prosthesis, showing no significant difference (P = 0.954). CONCLUSION: Hinge knee prosthesis still has a high rate of complications. Deep infection is main reason to decrease short-term prosthetic survival rate, and aseptic loosening shortens the long-short prosthetic survival time.

Matrine inhibits the activity of translation factor eIF4E through dephosphorylation of 4E-BP1 in gastric MKN45 cells.

Matrine, from Sophora flavescens, could remarkably inhibit tumor growth and induce apoptosis in various cancer cells in vitro. eIF4E and its inhibitor 4E-BP1 play key roles in regulating mRNA translation and cell proliferation. However, it remained elusive whether matrine inhibited cancer cells growth through attenuating the activity of 4E-BP1. In this study, we analyzed the effects of matrine on 4E-BP1 and eIF4E in gastric cancer MKN45 cells. Immunoblots showed that matrine inhibited the activity of eIF4E through dephosphorylation of 4E-BP1 in a dose- and time-dependent manner. We found that matrine inactivated Erk1/2, an upstream regulator of 4E-BP1 and eIF4E, and remarkably reduced the phosphorylation level of 4E-BP1 and eIF4E, whereas 4E-BP1 was little influenced by JNK, p38 or Akt/mTOR. Inactivation of PP2A obviously decreased the phosphorylation of 4E-BP1 in matrine-treated cells. These findings suggested that matrine inhibits the activity of eIF4E by dephosphorylating 4E-BP1, which partly counts for the growth inhibition in gastric MKN45 cells.

Matrine induced gastric cancer MKN45 cells apoptosis via increasing pro-apoptotic molecules of Bcl-2 family.

Matrine, one of the main active components from the dry roots of Sophora flavescence, was known to induce apoptosis in a variety of tumor cells in vitro. However, the molecular mechanism of cell apoptosis induced by Matrine remains elusive. Here, we investigated the apoptosis in Matrine-treated human gastric cancer MKN45 cells. The results showed that Matrine could inhibit cell proliferation and induce apoptosis in a dose-dependent manner. Further immunoblots revealed that in Matrine-treated cells, caspase-3, -7 were activated and the pro-apoptotic molecules Bok, Bak, Bax, Puma, and Bim were also up-regulated. Our results suggested that Matrine induced gastric cancer MKN45 cells apoptosis via increasing pro-apoptotic molecules of Bcl-2 family.