Diagnosis of Metastatic Lymph Nodes in Patients With Hepatocellular Carcinoma Using Dual-Energy Computed Tomography.

OBJECTIVE: Our study aimed to investigate the role of quantitative parameters derived from dual-energy computed tomography (DECT) in discriminating metastatic from nonmetastatic lymph nodes in hepatocellular carcinoma (HCC). METHODS: Forty-two patients (34 males; mean age, 53.7 years) with HCC underwent unenhanced computed tomography scans and triple-phase DECT scans of the upper abdomen. A total of 72 suspected lymph nodes were resected, including 43 nonmetastatic and 29 metastatic lymph nodes. The maximum short-axis diameter of the lymph nodes, iodine concentration, normalized iodine concentration (NIC), and slope of the spectral curve were analyzed for the HCC primary lesions and the suspected lymph nodes. Lymph node metastasis was confirmed by pathologic examination. RESULTS: A maximum short-axis diameter of >10 mm had a sensitivity and a specificity of 75.9% (22/29) and 53.5% (23/43) in diagnosing metastatic lymph nodes. The iodine concentration, NIC, and slope of the spectral curve of the nonmetastatic lymph nodes were significantly higher than those of the primary HCC lesions and the metastatic lymph nodes (all P < 0.05). Among all the analyzed spectral parameters, the NIC in the arterial phase had the highest sensitivity and specificity of 88.4% and 86.2% in diagnosing metastatic lymph nodes. CONCLUSIONS: The arterial phase NIC of DECT has superior diagnostic performance than the traditional lymph node size in diagnosing metastatic lymph nodes in HCC.

Novel Phenylethanoid Glycosides Improve Hippocampal Synaptic Plasticity via the Cyclic Adenosine Monophosphate-CREB-Brain-Derived Neurotrophic Growth Factor Pathway in APP/PS1 Transgenic Mice.

INTRODUCTION: Alzheimer's disease (AD) is a major public health concern worldwide, but there are still no drugs available that treat it effectively. Previous studies have shown that phenylethanoid glycosides have pharmacological effects, which include anti-AD properties, but the underlying mechanisms by which they ameliorate AD symptoms remain unknown. METHODS: In this study, we used an APP/PS1 AD mouse model to explore the function and mechanisms underlying savatiside A (SA) and torenoside B (TB) in the treatment of AD. SA or TB (100 mg·kg-1·d-1) was orally administered to 7-month-old APP/PS1 mice for 4 weeks. Cognitive and memory functions were measured using behavioral experiments (including the Morris water maze test and the Y-maze spontaneous alternation test). Molecular biology experiments (including Western blotting, immunofluorescence, and enzyme-linked immunosorbent assays) were used to detect any corresponding changes in signaling pathways. RESULTS: The results showed that SA or TB treatment could significantly reduce cognitive impairment in APP/PS1 mice. We also showed that chronic treatment with SA/TB could prevent spine loss, synaptophysin immunoreactivity, and neuronal loss in mice, thereby improving synaptic plasticity and moderating learning and memory deficits. SA/TB administration also promoted the expression of synaptic proteins in APP/PS1 mouse brains and upregulated phosphorylation of proteins in the cyclic adenosine monophosphate (cAMP)/CREB/brain-derived neurotrophic growth factor (BDNF) pathway that are responsible for synaptic plasticity. Additionally, chronic SA/TB treatment increased the levels of BDNF and nerve growth factor (NGF) in the brains of APP/PS1 mice. Both astrocyte and microglia volumes, as well as the generation of amyloid ß, were also decreased in SA/TB-treated APP/PS1 mice compared to control APP/PS1 mice. CONCLUSION: In summary, SA/TB treatment was associated with activation of the cAMP/CREB/BDNF pathway and increased BDNF and NGF expression, indicating that SA/TB improves cognitive functioning via nerve regeneration. SA/TB is a promising candidate drug for the treatment of AD.

Association of ESR1 and ESR2 Polymorphisms with Osteoporosis: A Meta-Analysis from 36 Studies.

BACKGROUND: Recently, the roles of ESR1 and ESR2 polymorphisms in osteoporosis have been extensively reported, with conflicting findings. Therefore, we performed this present study to evaluate the potential associations between ESR1 and ESR2 polymorphisms and osteoporosis risk. METHODOLOGY: All included literatures published up to April 2021 were identified by searching Pubmed, Embase, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure (CNKI) and Wanfang databases. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated the associations using a fixed or random effects model. RESULTS: 36 observational studies involving five gene polymorphisms (ESR1 PvuII, ESR1 XbaI, ESR1 G2014A, ESR2 AluI and ESR2 RsaI) covering 12507 cases and 18487 controls were included. The results of our meta-analysis demonstrated the variant A allele of ESR2 RsaI polymorphism might play a remarkable protective role in developing osteoporosis under all genetic models. However, no associations were observed between ESR1 PvuII, ESR1 XbaI, ESR1 G2014A and ESR2 AluI polymorphisms with the risk of osteoporosis under all genetic models. CONCLUSIONS: Our meta-analysis suggests that genetic polymorphism in ESR2 RsaI may lead to decreased risk for osteoporosis. Further larger studies are needed to confirm this conclusion.

Development of a Multivariable Prediction Model for Citrate Accumulation in Liver Transplant Patients Undergoing Continuous Renal Replacement Therapy with Regional Citrate Anticoagulation.

INTRODUCTION: Patients with impaired citrate metabolism may experience citrate accumulation (CA), which causes life-threatening metabolic acidosis and hypocalcemia. CA poses a challenge for clinicians when deciding on the use of regional citrate anticoagulation (RCA) for patients with liver dysfunction. This study aimed to develop a prediction model integrating multiple clinical variables to assess the risk of CA in liver transplant patients. METHODS: This single-center prospective cohort study included postoperative liver transplant patients who underwent continuous renal replacement therapy (CRRT) with RCA. The study end point was CA. A prediction model was developed using a generalized linear mixed-effect model based on the Akaike information criterion. The predictive values were assessed using the receiver operating characteristic curve and bootstrap resampling (times = 500) to estimate the area under the curve (AUC) and the corresponding 95% confidence interval (CI). A nomogram was used to visualize the model. RESULTS: This study included 32 patients who underwent 133 CRRT sessions with RCA. CA occurred in 46 CRRT sessions. The model included lactate, norepinephrine >0.1 µg/kg/min, alanine aminotransferase, total bilirubin, and standard bicarbonate, which were tested before starting each CRRT session and body mass index, diabetes mellitus, and chronic kidney disease as predictors. The AUC of the model was 0.867 (95% CI 0.786-0.921), which was significantly higher than that of the single predictor (p < 0.05). A nomogram visualized the prediction model. CONCLUSIONS: The prediction model integrating multiple clinical variables showed a good predictive value for CA. A nomogram visualized the model for easy application in clinical practice.

A simple and fast LC-MS/MS method for the simultaneous determination of tenofovir alafenamide and tenofovir in human plasma.

A simple and fast liquid chromatography-tandem mass spectrometry method was established and validated for the simultaneous determination of tenofovir alafenamide (TAF) and tenofovir (TNF) in human plasma. A simple protein precipitation procedure was employed to extract analytes from plasma. Chromatographic separation was performed on an Eclipse Plus C18 column utilizing a fast gradient elution starting with 2% of 2 mM ammonium acetate-formic acid (100/0.1, v/v) followed by increasing the percentage of acetonitrile. Detection was performed on a tandem mass spectrometer equipped with an electrospray ionization source operated in the positive ionization mode, using the transitions m/z 477.2 → m/z 346.1 for TAF and m/z 288.1 → m/z 176.1 for TNF. TAF-d5 and TNF-d7 were used as the internal standard of TAF and TNF, respectively. The method was validated in the concentration ranges 1.25-500 ng/mlfor TAF and 0.300-15.0 ng/ml for TNF with acceptable accuracy and precision.

RPB5-Mediating Protein Promotes Cholangiocarcinoma Tumorigenesis and Drug Resistance by Competing With NRF2 for KEAP1 Binding.

BACKGROUND AND AIMS: Cancer cell survival depends on the balance between reactive oxygen species production and scavenging, which is regulated primarily by NRF2 during tumorigenesis. Here, we demonstrate that deletion of RBP5-mediating protein (RMP) in an autonomous mouse model of intrahepatic cholangiocarcinoma (ICC) delays tumor progression. APPROACH AND RESULTS: RMP-overexpressing tumor cells exhibited enhanced tolerance to oxidative stress and apoptosis. Mechanistically, RMP competes with NRF2 for binding to the Kelch domain of KEAP1 (Kelch-like ECH-associated protein 1) through the E**E motif, leading to decreased NRF2 degradation via ubiquitination, thus increasing NRF2 nuclear translocation and downstream transactivation of antioxidant genes. This RMP-KEAP1-NRF2 axis promotes ICC tumorigenesis, metastasis, and drug resistance. Consistent with these findings, the RMP level in human ICC is positively correlated with the protein level of NRF2 and is associated with poor prognosis. CONCLUSION: These findings reveal that RMP is involved in the oxidative stress defense program and could be exploited for targeted cancer therapies.

ID3 Promotes Stem Cell Features and Predicts Chemotherapeutic Response of Intrahepatic Cholangiocarcinoma.

Cancer stem cells contribute to a high rate of recurrence and chemotherapeutic resistance in many types of cancer, including intrahepatic cholangiocarcinoma (ICC). Inhibitor of differentiation 3 (ID3) has been reported to promote cancer stem cells, but its role in ICC is obscure. In this study, we identified that ID3 is highly expressed in human ICC tissues compared with matched normal tissues and correlates with poor prognosis. Functional studies demonstrate that ID3 is required for stemness maintenance in cholangiocarcinoma both in vitro and in vivo. Consistent with the regulation of cancer stem cell features by ID3, transgenic expression of ID3 enhances chemoresistance of cholangiocarcinoma cells. Moreover, we found that ICC patients with low ID3 levels benefited from postoperative transarterial chemoembolization, whereas patients with high ID3 levels did not, indicating the significance of ID3 in individualized ICC therapy. Mechanistically, ID3 could interact with E47 and block E47 recruitment to the promoter of ß-catenin, which leads to activation of Wnt/ß-catenin signaling. Conclusion: Our results show that ID3 could promote the stemness of ICC by increasing the transcriptional activity of ß-catenin and could serve as a biomarker in predicting ICC patients' response to adjuvant chemotherapeutics.

MiR-377-3p suppresses colorectal cancer through negative regulation on Wnt/ß-catenin signaling by targeting XIAP and ZEB2.

Aberrant activation of Wnt/ß-catenin signaling is a common event in the development of colorectal cancer (CRC). It is important to identify new molecules and mechanisms that can negatively regulate Wnt/ß-catenin signaling. MicroRNAs are considered as promising candidates for cancer diagnosis and therapy. In our study, we found that miR-377-3p was significantly decreased in CRC samples compared to the normal mucosa tissues, especially in the patients at stage III/IV. Functional studies showed that overexpression of miR-377-3p suppressed and silence of miR-377-3p enhanced the proliferation, migration and chemoresistance of CRC cells. Molecularly, miR-377-3p inhibited Wnt/ß-catenin signaling by directly targeting ZEB2 and XIAP, which were the positive regulators of Wnt/ß-catenin signaling. Overexpression of ZEB2/XIAP could counteract the tumor suppressing phenotypes induced by miR-377-3p. Therefore, we uncovered the anti-cancer role and the relevant mechanisms of miR-377-3p in CRC, which might provide novel targets for designing new anti-tumor strategies.

AGR2 is controlled by DNMT3a-centered signaling module and mediates tumor resistance to 5-Aza in colorectal cancer.

Human anterior gradient-2 (AGR2), a member of protein disulfide isomerase (PDI) family, is upregulated in various human cancers and reportedly has oncogenic activities. However, the functional roles of AGR2 and its regulation in colorectal cancer (CRC) remain unclear. Here, we showed that AGR2 promoted CRC tumorigenesis and progression in vitro and in vivo and acted as an independent prognostic factor of poor outcome. AGR2 was negatively regulated by DNA methyltransferase 3a (DNMT3a) through directly methylating AGR2 promoter and by a DNMT3a-SPRY2-miR-194 axis. Moreover, AGR2 mediated the resistance to 5-Aza-2'-deoxycytidine (5-Aza) treatment. Knockdown of AGR2 improved the therapeutic effect of 5-Aza in human CRC xenograft tumor model. Thus, our work supports AGR2's oncogenic role in CRC, reveals DNMT3a-mediated epigenetic modulation on AGR2 promoter, and uncovers a new DNMT3a signaling module controlling expression of AGR2. Upregulated AGR2 offset 5-Aza mediated epigenetic therapy. This work might provide potential targets for clinical anti-cancer therapy.

Arginine methylation of the C-terminus RGG motif promotes TOP3B topoisomerase activity and stress granule localization.

DNA topoisomerase 3B (TOP3B) is unique among all mammalian topoisomerases for its dual activities that resolve both DNA and RNA topological entanglements to facilitate transcription and translation. However, the mechanism by which TOP3B activity is regulated is still elusive. Here, we have identified arginine methylation as an important post-translational modification (PTM) for TOP3B activity. Protein arginine methyltransferase (PRMT) 1, PRMT3 and PRMT6 all methylate TOP3B in vitro at its C-terminal arginine (R) and glycine (G)-rich motif. Site-directed mutagenesis analysis identified R833 and R835 as the major methylation sites. Using a methylation-specific antibody, we confirmed that TOP3B is methylated in cells and that mutation of R833 and R835 to lysine (K) significantly reduces TOP3B methylation. The methylation-deficient TOP3B (R833/835K) is less active in resolving negatively supercoiled DNA, which consequently lead to accumulation of co-transcriptionally formed R-loops in vitro and in cells. Additionally, the methylation-deficient TOP3B (R833/835K) shows reduced stress granule localization, indicating that methylation is critical for TOP3B function in translation regulation. Mechanistically, we found that R833/835 methylation is partially involved in the interaction of TOP3B with its auxiliary factor, the Tudor domain-containing protein 3 (TDRD3). Together, our findings provide the first evidence for the regulation of TOP3B activity by PTM.

Production, Characterization and Immunomodulatory Activity of an Extracellular Polysaccharide from Rhodotorula mucilaginosa YL-1 Isolated from Sea Salt Field.

A novel exopolysaccharide from marine-derived red yeast Rhodotorula mucilaginosa strain YL-1 was produced and characterized. The highest yield of polysaccharide reached 15.1 g/L after medium and culture parameter optimization. This exopolysaccharide, composed of four neural monosaccharides including glucose, mannose, galactose and fucose, had an average molecular weight of 1200 KDa. It had good immunomodulatory activity on RAW256.7 cell lines. ELISA (enzyme linked immunosorbent assay) and Q-PCR (quantitative real-time PCR) results showed that the cell was stimulated to express more IL-6, IL-18, IL-1ß and TNFα cytokines than the control group. This is the first report of an exopolysaccharide with immunomodulatory activity from marine-derived Rhodotorula mucilaginosa.

Identification and validation of a potent multi-mRNA signature for the prediction of early relapse in hepatocellular carcinoma.

Early recurrence of hepatocellular carcinoma (HCC) is implicated in poor patient survival and is the major obstacle to improving prognosis. The current staging systems are insufficient for accurate prediction of early recurrence, suggesting that additional indicators for early recurrence are needed. Here, by analyzing the gene expression profiles of 12 Gene Expression Omnibus data sets (n = 1533), we identified 257 differentially expressed genes between HCC and non-tumor tissues. Least absolute shrinkage and selection operator regression model was used to identify a 24-messenger RNA (mRNA)-based signature in discovery cohort GSE14520. With specific risk score formula, patients were divided into high- and low-risk groups. Recurrence-free survival within 2 years (early-RFS) was significantly different between these two groups in discovery cohort [hazard ratio (HR): 7.954, 95% confidence interval (CI): 4.596-13.767, P < 0.001], internal validation cohort (HR: 8.693, 95% CI: 4.029-18.754, P < 0.001) and external validation cohort (HR: 5.982, 95% CI: 3.414-10.480, P < 0.001). Multivariable and subgroup analyses revealed that the 24-mRNA-based classifier was an independent prognostic factor for predicting early relapse of patients with HCC. We further developed a nomogram integrating the 24-mRNA-based signature and clinicopathological risk factors to predict the early-RFS. The 24-mRNA-signature-integrated nomogram showed good discrimination (concordance index: 0.883, 95% CI: 0.836-0.929) and calibration. Decision curve analysis demonstrated that the 24-mRNA-signature-integrated nomogram was clinically useful. In conclusion, our 24-mRNA signature is a powerful tool for early-relapse prediction and will facilitate individual management of HCC patients.

Hepatocellular Carcinoma-Associated Protein TD26 Interacts and Enhances Sterol Regulatory Element-Binding Protein 1 Activity to Promote Tumor Cell Proliferation and Growth.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Increased lipogenesis has been reported to play a critical role in HCC progression. However, the underlying mechanism contributing to lipogenesis increase in HCC remains elusive. Here, we show that HCC-associated protein TD26 (TD26) was highly expressed in HCC tumor tissues compared to matched normal tissues. From the clinicopathologic analyses of two independent HCC cohorts, we demonstrate that TD26 expression was positively correlated with tumor size and was an independent predictor of overall survival (OS) and recurrence-free survival (RFS) in HCC patients. Our metabolomics assays demonstrate that TD26 had no effect on glycometabolism, but significantly increased lipogenesis in HCC cells. In addition, our functional assays indicate that TD26 promoted HCC cell proliferation and tumor growth. We further demonstrate that TD26-mediated increase in lipogenesis and tumor cell proliferation was SREBP1 dependent. Mechanistically, we demonstrate that, through its C-terminus (amino acids [aa] from 121 to 198), TD26 interacted with the truncated nuclear sterol regulatory element-binding protein 1 (SREBP1) form (nSREBP1), but not full-length SREBP1 (flSREBP1), to block adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)-mediated inhibition on SREBP1 activity, resulting in increased lipogenesis, elevated tumor cell proliferation, and enhanced tumor progression. Conclusion: We propose that TD26 is a positive regulator on SREBP1 transactivity, and the interaction between TD26 and SREBP1 can serve as a potential therapeutic target for HCC treatment.

Rictor Deficiency Aggravates Hepatic Ischemia/Reperfusion Injury in Mice by Suppressing Autophagy and Regulating MAPK Signaling.

BACKGROUND/AIMS: The role of Rictor in hepatic ischemia/reperfusion (I/R) injury remains unknown. Here, we comprehensively examined the role of Rictor in hepatic I/R injury. METHODS: We studied the expression of Rictor during hepatic I/R injury. The regulatory effects of Rictor on inflammatory responses, cytokine and chemokine release, apoptotic and anti-apoptotic responses, and autophagy induction during hepatic I/R injury were identified via the shRNA-mediated knockdown of Rictor. Subsequently, we collected the liver and blood samples of these mice to evaluate liver injury, mRNA and protein levels. Additionally, the signaling pathways induced by Rictor were investigated. Furthermore, the extent of activation of MAPKs in response to Rictor deficiency was investigated in lipopolysaccharide (LPS)-treated RAW264.7 cells. The mRNA expression levels were analyzed by real-time PCR, and the protein expression levels were analyzed using Western blot, immunofluorescence staining and enzyme-linked immunosorbent assay (ELISA). RESULTS: The expression of Rictor was increased during hepatic I/R injury in vivo and hypoxia/reoxygenation (H/R) injury in vitro. Rictor deficiency enhanced the extent of liver injury by increasing macrophage and neutrophil infiltration, promoting cytokine and chemokine release, aggravating hepatocyte apoptosis, suppressing anti-apoptotic responses, and inhibiting autophagy induction during both hepatic I/R and H/R injury. Rictor was associated with the activation of hepatic I/R injury-induced MAPK signaling. In addition, Rictor deficiency affected MAPK activation in LPS-treated RAW264.7 cells. CONCLUSION: Rictor can substantially ameliorate I/R-induced liver injury. Therefore, our findings strongly suggest a therapeutic value of the Rictor/mTORC2 axis in hepatic I/R injury.

Deciphering the Spectrum of Mitochondrial DNA Mutations in Hepatocellular Carcinoma Using High-Throughput Sequencing.

Accumulation of mitochondrial DNA (mtDNA) mutations has been proposed to contribute to the initiation and progression of tumors. By using high-throughput sequencing strategies, we measured 33 specimens including 11 hepatocellular carcinoma (HCC) tissues, 11 corresponding adjacent tissues, and 11 normal liver tissues. We identified 194 single nucleotide variants (SNVs; including insert and deletion) in 33 liver tissues, and 13 somatic novel mutations were detected, including 7 mutations in the coding region. One of the seven somatic mutations (T7609C, 91.09%) is synonymous, which does not change amino acid coding; the other four somatic mutations (T6115C, 65.74%; G8387A, 12.23%; G13121A, 93.08%; and T14180C, 28.22%) could result in amino acid substitutions, potentially leading to mitochondrial dysfunction. Furthermore, two mutations in tRNA might influence amino acid transportation. Consistent with a previous study, we also found that mtDNA copy number was significantly reduced in HCC tissues. Therefore, we established a mitochondrial genome depletion cell line ρ0 and revealed that mtDNA loss reduced proliferation and migration in HCC cells but promoted their resistance to 5-fluorouracil. Our results suggested that somatic mtDNA mutations may cause mitochondrial dysfunction and affect chemoresistance of HCC cells. These new identified somatic mutations may serve as a reference for future studies of cancer mitochondrial genomes.

Derivation and validation of plasma endostatin for predicting renal recovery from acute kidney injury: a prospective validation study.

BACKGROUND: Acute kidney injury (AKI) is associated with high morbidity and mortality in surgical patients. Nonrecovery from AKI may increase mortality and early risk stratification seems key to improving clinical outcomes. The aim of the current study was to explore and validate the value of endostatin for predicting failure to recover from AKI. METHODS: We conducted a prospective cohort study of 198 patients without known chronic kidney disease who underwent noncardiac major surgery and developed new-onset AKI in the first 48 h after admission to the ICU. The biomarkers of plasma endostatin, neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C were detected immediately after AKI diagnosis. The primary endpoint was nonrecovery from AKI (within 7 days). Cutoff values of the biomarkers for predicting nonrecovery were determined in a derivation cohort (105 AKI patients). Predictive accuracy was then analyzed in a validation cohort (93 AKI patients). RESULTS: Seventy-six of 198 (38.4%) patients failed to recover from AKI onset, with 41 in the derivation cohort and 35 in the validation cohort. Compared with NGAL and cystatin C, endostatin showed a better prediction for nonrecovery, with an area under the receiver operating characteristic curve (AUC) of 0.776 (95% confidence interval (CI) 0.654-0.892, p < 0.001) and an optimal cutoff value of 63.7 ng/ml. The predictive ability for nonrecovery was greatly improved by the prediction model combining endostatin with clinical risk factors of Sequential Organ Failure Assessment (SOFA) score and AKI classification, with an AUC of 0.887 (95% CI 0.766-0.958, p < 0.001). The value of the endostatin-clinical risk prediction model was superior to the NGAL-clinical risk and cystatin C-clinical risk prediction models in predicting failure to recover from AKI, which was supported by net reclassification improvement and integrated discrimination improvement. Further, the endostatin-clinical risk prediction model achieved sensitivity and specificity of 94.6% (76.8-99.1) and 72.7% (57.2-85.0), respectively, when validated in the validation cohort. CONCLUSION: Plasma endostatin shows a useful value for predicting failure to recover from AKI. The predictive ability can be greatly improved when endostatin is combined with the SOFA score and AKI classification.

Risk stratification system to predict recurrence of intrahepatic cholangiocarcinoma after hepatic resection.

BACKGROUND: Previous nomograms for intrahepatic cholangiocarcinoma (ICC) were conducted to predict overall survival, which could be influenced by various factors. Herein, we conducted our nomogram to predict recurrence of the tumor only after hepatic resection. METHODS: The nomogram was established with prognostic factors for the relapse-free survival (RFS) analyzed from our single center cohort and was evaluated by comparing with the American Joint Committee on Cancer (AJCC) staging system for the predictive accuracy. RESULTS: Seropositivity of hepatitis B surface antigen (hazard ratio [HR], 0.505; 95% confidence interval [CI], 0.279 to 0.914; P = 0.024), tumor size of larger than 5 cm (HR, 1.947; 95% CI, 1.177 to 3.219; P = 0.009), Child-Pugh score of B (HR, 3.067; 95% CI, 1.293 to 7.275; P = 0.011), and lymph node metastasis (HR, 2.790; 95% CI, 1.628 to 4.781; P < 0.001) were found to be independent prognostic factors that significantly affected RFS. The calibration curve for the prediction revealed excellent agreement between estimation by our stratification system and actual RFS. The concordance C index of the nomogram (0.71; 95% CI, 0.65 to 0.77) revealed to be significantly higher than the AJCC staging system (0.66; 95% CI, 0.60 to 0.72). In the validation cohort, our risk stratification system (C-index 0.65; 95% CI, 0.59 to 0.71) also revealed more precise prediction than the AJCC staging system (C-index, 0.57; 95% CI, 0.50 to 0.64). CONCLUSIONS: Our nomogram could more accurately predict recurrence of ICC after hepatic resection than the AJCC staging system.

Diagnostic value of urinary tissue inhibitor of metalloproteinase-2 and insulin-like growth factor binding protein 7 for acute kidney injury: a meta-analysis.

BACKGROUND: Tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7), inducers of G1 cell cycle arrest, are two recently discovered good biomarkers for early diagnosis of acute kidney injury (AKI). To obtain a more robust performance measurement, the present meta-analysis was performed, pooling existing studies. METHODS: Literature in the MEDLINE (via PubMed), Ovid, Embase, and Cochrane Library databases was systematically searched from inception to 12 October 2016. Studies that met the set inclusion and exclusion criteria were identified by two independent investigators. The diagnostic value of urinary [TIMP-2] × [IGFBP7] for AKI was evaluated by pooled sensitivity, specificity, likelihood ratio (LR), diagnostic odds ratio (DOR), and summary receiver operating characteristic (SROC) curve analyses. The causes of heterogeneity were explored by sensitivity and subgroup analyses. RESULTS: A total of nine published and eligible studies assessing 1886 cases were included in this meta-analysis. Early diagnostic value of urinary [TIMP-2] × [IGFBP7] for AKI was assessed using a random-effects model. Pooled sensitivity and specificity with corresponding 95% CIs were 0.83 (95% CI 0.79-0.87, heterogeneity I 2 = 68.8%) and 0.55 (95% CI 0.52-0.57, I 2 = 92.9%), respectively. Pooled positive LR, negative LR, and DOR were 2.37 (95% CI 1.87-2.99, I 2 = 82.6%), 0.30 (95% CI 0.21-0.41, I 2 = 43.4%), and 9.92 (95% CI 6.09-16.18, I 2 = 38.5%), respectively. The AUC estimated by SROC was 0.846 (SE 0.027) with a Q* value of 0.777 (SE 0.026). Sensitivity analysis indicated that one study significantly affected the stability of pooled results. Subgroup analysis showed that population setting and AKI threshold were the key factors causing heterogeneity in pooled sensitivity and specificity. CONCLUSIONS: On the basis of recent evidence, urinary [TIMP-2] × [IGFBP7] is an effective predictive factor of AKI. TRIAL REGISTRATION: PROSPERO registration number: CRD42016051186 . Registered on 10 November 2016.

Prognostic value of cell cycle arrest biomarkers in patients at high risk for acute kidney injury: A systematic review and meta-analysis.

Urinary tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7) are G1 cell cycle arrest biomarkers. This systematic review aimed to evaluate the prognostic value of urinary [TIMP-2]·[IGFBP7] in patients at high risk for AKI. The MEDLINE (via PubMed), Ovid, EMBASE and Cochrane Library databases were systematically searched from inception to December 25, 2016. Original clinical studies which met the eligibility criteria were included in this study. The prognostic accuracy of urinary [TIMP-2]·[IGFBP7] for assessing the need for renal replacement therapy (RRT) and mortality was evaluated by pooled sensitivity, specificity, diagnostic odds ratio, and summary receiver operating characteristic curves. A total of four prospective cohort studies evaluating 277 patients were included. The estimated area under the receiver operating characteristic curve (AUC) of urinary [TIMP-2]·[IGFBP7] for predicting the need for RRT in patients at high risk for AKI was 0.915 (standard error [SE] = 0.040). Pooled sensitivity and specificity with corresponding 95% confidence intervals (CI) were 0.69 (95% CI 0.53-0.82) and 0.81 (95% CI 0.75-0.86), respectively. Urinary [TIMP-2]·[IGFBP7] for mortality prediction in patients at high risk for AKI was assessed by qualitative description. Based on the above data, urinary [TIMP-2]·[IGFBP7] performs well in predicting the need for RRT and mortality in patients at high risk for AKI. However, further meta-analyses are warranted as more data become available.

Expression and Prognostic Role of FHIT, Fibronectin, and PTEN in Hepatocellular Carcinoma.

BACKGROUND: Fragile histidine triad (FHIT), fibronectin (FN), and phosphatase and tensin homology deleted on chromosome ten (PTEN) are widely reported as having abnormal expression in malignant tumors. The role of FHIT, fibronectin, PTEN expression in patients with hepatocellular carcinoma (HCC) has not been characterized. Our study aims to investigate the expression of FHIT, fibronectin, and PTEN in human HCC and their relationship with clinicopathological features and prognosis of HCC. METHODS: Immunohistochemistry was used to detect expression of FHIT, FN, and PTEN in tumor tissues from 138 HCC patients. The correlation between their expression and clinicopathological features and prognosis were analyzed. RESULTS: FHIT, fibronectin, and PTEN proteins have different expressions between HCC and adjacent nontumor tissue (χ2 = 5.968, 7.380, 4.962; p < 0.05), which are expressed differently in the groups of different tumor stage, grade, tumor size, tumor number, lymph node metastasis, HBV infection, and cirrhosis in the background of nontumor sections (p < 0.05). In the FHIT and fibronectin positive expression group, the cumulative survival times were shorter than those in the negative expression groups (χ2 = 4.443, 9.867; p < 0.05), and in the PTEN positive expression group the cumulative survival times were longer than in the negative expression group (χ2 = 4.199; p < 0.05). CONCLUSIONS: FHIT, fibronectin, and PTEN were abnormally expressed in HCC cells, which have stimulative or suppressive effects on HCC carcinogenesis and progression. FHIT and fibronectin can be used as negative makers for prognosis and PTEN as a positive one.