Burden and distribution of monosodium urate deposition in patients with hyperuricemia and gout: a cross-sectional Chinese population-based dual-energy CT study.

Background: To investigate the distribution and burden of monosodium urate (MSU) deposition in hyperuricemia and gout patients with dual-energy computed tomography (DECT). Methods: A total of 1,936 consecutive patients from January 1, 2009, to September 15, 2017, underwent DECT examinations in Jinling Hospital. Of these, 1,294 patients were excluded due to other clinical diagnoses (n=1,041), inappropriate locations (n=82), poor-quality images (n=105), training cases (n=30) and duplicated data (n=36). Finally, 642 patients were included in this study. We retrospectively analyzed 1,127 DECT examinations in 642 consecutive patients (hyperuricemia group, n=121; gout group, n=521) and recorded the volume and number of MSU deposits. For each anatomical location, we recorded MSU deposition in the soft tissue and joint cavity. MSU deposition was analyzed and compared between groups. For normally distributed data, independent sample t-tests were used for comparison between the two groups. The independent samples nonparametric test was used to analyze nonnormally distributed data. Results: (I) The burden of MSU deposition in the gout group {volume [0.14 (0.04-1.36)] and numbers [10.00 (5.00-19.00)]} was significantly higher than that {volume [0.08 (0.02-0.47), P=0.003] and numbers [9.50 (2.00-16.00), P=0.01]} in the hyperuricemia group. (II) The burden of MSU deposition in the knees {volume [0.24 (0.01-1.79), P=0.002] and quantity [6.00 (2.00-12.00), P=0.04]} and feet {volume [0.10 (0.04-0.66)] and number [9.00 (5.00-15.00)]} was significantly higher in the gout group than those {knees: the volume [0.03 (0.00-0.27), P=0.002] and the quantity [4.00 (0.00-9.00), P=0.04]; feet: the volume [0.07 (0.02-0.19), P=0.003)] and number [8.00 (2.25-12.00), P=0.04]} in the hyperuricemia group, respectively. (III) In the hyperuricemia group, the volume of MSU deposition was significantly higher in the soft tissues of the knee (0.022±0.042) and ankle (0.062±0.305) than in those (knee: 0.001±0.005, P=0.02; ankle: 0.027±0.234, P=0.02) in the joint cavity. Conclusions: Although subclinical urate deposition can occur in patients with asymptomatic hyperuricemia, the burden of urate deposition is greater in patients with symptomatic gout, and the distribution is more pronounced in the foot/knee. Thus, more effective patient management and monitoring can be achieved by measuring the burden of MSU deposits in the patient's feet/knees. These data suggest that a threshold for urate crystal volume at typical sites may be required before symptomatic disease develops.

One-year outcomes of CCTA alone versus machine learning-based FFRCT for coronary artery disease: a single-center, prospective study.

OBJECTIVES: To explore downstream management and outcomes of machine learning (ML)-based CT derived fractional flow reserve (FFRCT) strategy compared with an anatomical coronary computed tomography angiography (CCTA) alone assessment in participants with intermediate coronary artery stenosis. METHODS: In this prospective study conducted from April 2018 to March 2019, participants were assigned to either the CCTA or FFRCT group. The primary endpoint was the rate of invasive coronary angiography (ICA) that demonstrated non-obstructive disease at 90 days. Secondary endpoints included coronary revascularization and major adverse cardiovascular events (MACE) at 1-year follow-up. RESULTS: In total, 567 participants were allocated to the CCTA group and 566 to the FFRCT group. At 90 days, the rate of ICA without obstructive disease was higher in the CCTA group (33.3%, 39/117) than that (19.8%, 19/96) in the FFRCT group (risk difference [RD] = 13.5%, 95% confidence interval [CI]: 8.4%, 18.6%; p = 0.03). The ICA referral rate was higher in the CCTA group (27.5%, 156/567) than in the FFRCT group (20.3%, 115/566) (RD = 7.2%, 95% CI: 2.3%, 12.1%; p = 0.003). The revascularization-to-ICA ratio was lower in the CCTA group than that in the FFRCT group (RD = 19.8%, 95% CI: 14.1%, 25.5%, p = 0.002). MACE was more common in the CCTA group than that in the FFRCT group at 1 year (HR: 1.73; 95% CI: 1.01, 2.95; p = 0.04). CONCLUSION: In patients with intermediate stenosis, the FFRCT strategy appears to be associated with a lower rate of referral for ICA, ICA without obstructive disease, and 1-year MACE when compared to the anatomical CCTA alone strategy. KEY POINTS: • In stable patients with intermediate stenosis, ML-based FFRCT strategy was associated with a lower referral ICA rate, a lower normalcy rate of ICA, and higher revascularization-to-ICA ratio than the CCTA strategy. • Compared with the CCTA strategy, ML-based FFRCTshows superior outcome prediction value which appears to be associated with a lower rate of 1-year MACE. • ML-based FFRCT strategy as a non-invasive "one-stop-shop" modality may be the potential to change diagnostic workflows in patients with suspected coronary artery disease.

Advances in CRISPR/Cas-based Gene Therapy in Human Genetic Diseases.

CRISPR/Cas genome editing is a simple, cost effective, and highly specific technique for introducing genetic variations. In mammalian cells, CRISPR/Cas can facilitate non-homologous end joining, homology- directed repair, and single-base exchanges. Cas9/Cas12a nuclease, dCas9 transcriptional regulators, base editors, PRIME editors and RNA editing tools are widely used in basic research. Currently, a variety of CRISPR/Cas-based therapeutics are being investigated in clinical trials. Among many new findings that have advanced the field, we highlight a few recent advances that are relevant to CRISPR/Cas-based gene therapies for monogenic human genetic diseases.

Clinical Significance of Routine Blood Test-Associated Inflammatory Index in Breast Cancer Patients.

BACKGROUND It is now widely acknowledged that chronic inflammation is closely associated with the process of cancer development. As a simple noninvasive blood-based test, hematological parameters in the routine blood test have been considered as inflammation markers. We aimed to evaluate platelet count (PC), red blood cell distribution width (RDW), white blood cell count (WBC), mean platelet volume (MPV), number of neutrophils/lymphocytes ratio (NLR), and platelet count/lymphocytes ratio (PLR) as surrogate inflammatory markers in breast cancer (BC) patients, and we compared these to those in healthy individuals. MATERIAL AND METHODS A retrospective study was conducted in Zhongnan Hospital of Wuhan University from July 2014 to April 2015, including 110 cases of pathologically diagnosed BC patients and 78 cases of healthy females. Retrospective analysis of selected hematological parameters was performed between the 2 groups, as well as assessment of the correlation between these indexes and clinicopathological characteristics of the 110 breast cancer patients. RESULTS The mean values of RDW, MPV, NLR, and PLR were significantly higher in BC patients compared to the control group. The level of MPV exhibited positive correlations with lymph node metastasis and the Ki67 proliferation index in preoperative BC patients (P<0.05). Logistic regression analysis further showed that MPV was independently associated with the risk of BC lymph node metastasis (P<0.05). CONCLUSIONS Hematological parameters of RDW, MPV, NLR, and PLR can be used as an adjuvant tool for the diagnosis of BC. More importantly, the value of MPV can reflect the Ki67 proliferation index before surgery and identify patients with positive lymph node metastasis.

Association between Polymorphisms in MicroRNAs and Risk of Urological Cancer: A Meta-Analysis Based on 17,019 Subjects.

Accumulating evidence has demonstrated that some single nucleotide polymorphisms (SNPs) existing in miRNAs correlate with the susceptibility to urological cancers. However, a clear consensus still not reached due to the limited statistical power in individual study. Thus, we concluded a meta-analysis to systematically evaluate the association between microRNA SNPs and urological cancer risk. Eligible studies were collected from PubMed, Embase, Web of Science, and CNKI databases. Pooled odds ratio (OR) and corresponding 95% confidence interval (95% CI) were calculated to assess the strength of the relationships between three SNPs (miR-196a2, C>T rs11614913; miR-146a, G>C rs2910164; and miR-499, A>G rs3746444) and the risk of urological cancers. In addition, the stability of our analysis was evaluated by publication bias, sensitivity and heterogeneity analysis. Overall, a total of 17,019 subjects from 14 studies were included in this meta-analysis. We found that CT (miR-196a2, C>T rs11614913) was a risk factor for renal cell carcinoma (CT vs. CC: OR = 1.72, 95%CI = 1.05-2.80, P = 0.03, I2 = 66%), especially in Asian population (CT vs. CC: OR = 1.17, 95%CI = 1.04-1.32, P < 0.01, I2 = 0%). miR-146a G>C rs2910164 was a protective factor of urological cancers (C vs. G: OR = 0.87, 95%CI = 0.81-0.93, P < 0.01, I2 = 0%), especially for bladder cancer. miR-499 A>G rs3746444 was correlated with an increased risk of urological cancers, specifically in Asian population. In conclusion, our meta-analysis suggests that polymorphisms in microRNAs, miR-196a2, C>T rs11614913, miR-146a G>C rs2910164 and miR-499 A>G rs3746444, may be associated with the development of urological cancers and the risks mainly exist in Asian populations.

miR-22 targets YWHAZ to inhibit metastasis of hepatocellular carcinoma and its down-regulation predicts a poor survival.

Many miRNAs are associated with the carcinogenesis of hepatocellular carcinoma (HCC) and some exhibit potential prognostic value. In this study, to further confirm the prognostic value of miRNAs in HCC, we employed miRNA-sequencing data of tumor tissues of 372 HCC patients released by The Cancer Genome Atlas (TCGA) and identified 3 miRNAs including miR-22, miR-9-1 and miR-9-2 could be used as independent predictors for HCC prognostic evaluation. As a tumor-suppressive miRNA, miR-22 was down-regulated in HCC tissues. This down-regulation correlated with tumor vascular invasion, Edmondson-Steiner grade, TNM stage, and AFP level. Moreover, biofunctional investigations revealed that miR-22 significantly attenuated cellular proliferation, migration and invasion of HCC cells. Additionally, through gene expression profiles and bioinformatics analysis, YWHAZ was identified to be a direct target of miR-22 and its overexpression partially counteracted the inhibitory effects of miR-22 on HCC cells. Finally, molecular studies further confirmed that miR-22 promoted the accumulation of FOXO3a in nucleus and subsequently reversed invasive phenotype of HCC cells by repressing YWHAZ-mediated AKT phosphorylation. Taken together, these data demonstrate that miR-22 exhibits tumor-suppressive effects in HCC cells by regulating YWHAZ/AKT/FOXO3a signaling and might be used as an independent prognostic indicator for HCC patients.

Meta-analysis of the prognostic value of abnormally expressed lncRNAs in hepatocellular carcinoma.

Many long noncoding RNAs (lncRNAs) have been reported to be abnormally expressed in hepatocellular carcinoma (HCC), and may have the potential to serve as prognostic markers. In this study, a meta-analysis was conducted to systematically evaluate the prognostic value of various lncRNAs in HCC. Eligible literatures were systematically collected from PubMed, Embase, Web of Science, and Cochrane Library (up to December 30, 2015). The main outcomes including overall survival, relapse-free survival, and disease-free survival were analyzed. Pooled hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated using random- or fixed-effects models. A total of 2,991 patients with HCC in People's Republic of China from 27 studies were included in the analysis. The level of lncRNAs showed a significant association with clinical outcomes. Abnormally elevated lncRNA transcription level predicted poor overall survival (HR: 1.68, 95% CI: 1.20-2.34, P=0.002; I (2)=75.5%, P=0.000) and relapse-free survival (HR: 2.08, 95% CI: 1.65-2.61, P<0.001; I (2)=24.0%, P=0.215), while no association was observed with disease-free survival of HCC patients (HR: 1.39, 95% CI: 0.51-3.78, P=0.524; I (2)=81.3%, P=0.005). Subgroup analysis further showed that lncRNA transcription level was significantly associated with tumor size (relative risk [RR]: 1.19, 95% CI: 1.01-1.39, P=0.035), microvascular invasion (RR: 1.44, 95% CI: 1.10-1.89, P=0.009), and portal vein tumor thrombus (RR: 1.50, 95% CI: 1.03-2.20, P=0.036). Publication bias and sensitivity analysis further confirmed the stability of our results. Our present meta-analysis indicates that abnormal lncRNA transcription level may serve as a promising indicator for prognostic evaluation of patients with HCC in People's Republic of China.

Liquid Biopsy of Hepatocellular Carcinoma: Circulating Tumor-Derived Biomarkers.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide due to latent liver disease, late diagnosis, and nonresponse to systemic treatments. Till now, surgical and/or biopsy specimens are still generally used as a gold standard by the clinicians for clinical decision-making. However, apart from their invasive characteristics, tumor biopsy only mirrors a single spot of the tumor, failing to reflect current cancer dynamics and progression. Therefore, it is imperative to develop new diagnostic strategies with significant effectiveness and reliability to monitor high-risk populations and detect HCC at an early stage. In the past decade, the potent utilities of "liquid biopsy" have attracted intense concern and were developed to evaluate cancer progression in several clinical trials. "Liquid biopsies" represent a series of noninvasive tests that detect cancer byproducts easily accessible in peripheral blood, mainly including circulating tumor cells (CTCs) and cell-free nucleic acids (cfNAs) that are shed into the blood from the tumor sites. In this review, we focus on the recent developments in the field of "liquid biopsy" as well as the diagnostic and prognostic significance of CTCs and cfNAs in HCC patients.

Subtractive Cell-SELEX Selection of DNA Aptamers Binding Specifically and Selectively to Hepatocellular Carcinoma Cells with High Metastatic Potential.

Relapse and metastasis are two key risk factors of hepatocellular carcinoma (HCC) prognosis; thus, it is emergent to develop an early and accurate detection method for prognostic evaluation of HCC after surgery. In this study, we sought to acquire oligonucleotide DNA aptamers that specifically bind to HCC cells with high metastatic potential. Two HCC cell lines derived from the same genetic background but with different metastatic potential were employed: MHCC97L (low metastatic properties) as subtractive targets and HCCLM9 (high metastatic properties) as screening targets. To mimic a fluid combining environment, initial DNA aptamers library was firstly labelled with magnetic nanoparticles using biotin-streptavidin system and then applied for aptamers selection. Through 10-round selection with subtractive Cell-SELEX, six aptamers, LY-1, LY-13, LY-46, LY-32, LY-27/45, and LY-7/43, display high affinity to HCCLM9 cells and do not bind to MHCC97L cells, as well as other tumor cell lines, including breast cancer, lung cancer, colon adenocarcinoma, gastric cancer, and cervical cancer, suggesting high specificity for HCCLM9 cells. Thus, the aptamers generated here will provide solid basis for identifying new diagnostic targets to detect HCC metastasis and also may provide valuable clues for developing new targeted therapeutics.

Identification of an aptamer through whole cell-SELEX for targeting high metastatic liver cancers.

Hepatocellular carcinoma (HCC) is one of the most deadly human cancers due to its ability of invasion and metastasis. Thus, the approaches to identify potential compounds that inhibit invasion and metastasis of HCC are critical for treatment of this disease. In the present study, we used HCCLM9 cells with high metastatic potential and MHCC97L with low metastatic potential as a model system to study the molecular mechanisms of HCC metastasis. By applying cell- Systematic Evolution of Ligands by Exponential enrichment (SELEX) against living cells, we used HCCLM9 as target cells and MHCC97L cells as control to screen a group of HCC metastasis- and cell-specific DNA aptamers. One of selected aptamers, LY-1, could specifically bind to metastatic HCC with a dissociation constant (Kd) in nanomolar range. In vitro studies demonstrated that LY-1 can recognize and bind to membrane protein of metastatic HCC cells. Furthermore, QD605 labeled LY-1 aptamer could recognize HCC cells in both local liver cancer tissues and pulmonary metastatic sites in a xenograft model of HCC with pulmonary metastasis. Further biochemical and immunostaining studies showed that LY-1 could selectively bind to a subpopulation of more metastatic cells in HCCLM9 cells, which express more CK19 and vimentin. Finally, treatment of highly metastatic cells with LY-1 led to reduced migration and invasiveness of HCCLM9 cells in vitro and suppression of xenograft growth in vivo. Taken together, the present study demonstrated the tumor targeting and tumor suppressive effects of LY-1, which could be a promising molecular probe for metastatic HCC and a potential candidate of chemotherapy for metastatic HCC.