Identification of BGN positive fibroblasts as a driving factor for colorectal cancer and development of its related prognostic model combined with machine learning.

BACKGROUND: Numerous studies have indicated that cancer-associated fibroblasts (CAFs) play a crucial role in the progression of colorectal cancer (CRC). However, there are still many unknowns regarding the exact role of CAF subtypes in CRC. METHODS: The data for this study were obtained from bulk, single-cell, and spatial transcriptomic sequencing data. Bioinformatics analysis, in vitro experiments, and machine learning methods were employed to investigate the functional characteristics of CAF subtypes and construct prognostic models. RESULTS: Our study demonstrates that Biglycan (BGN) positive cancer-associated fibroblasts (BGN + Fib) serve as a driver in colorectal cancer (CRC). The proportion of BGN + Fib increases gradually with the progression of CRC, and high infiltration of BGN + Fib is associated with poor prognosis in terms of overall survival (OS) and recurrence-free survival (RFS) in CRC. Downregulation of BGN expression in cancer-associated fibroblasts (CAFs) significantly reduces migration and proliferation of CRC cells. Among 101 combinations of 10 machine learning algorithms, the StepCox[both] + plsRcox combination was utilized to develop a BGN + Fib derived risk signature (BGNFRS). BGNFRS was identified as an independent adverse prognostic factor for CRC OS and RFS, outperforming 92 previously published risk signatures. A Nomogram model constructed based on BGNFRS and clinical-pathological features proved to be a valuable tool for predicting CRC prognosis. CONCLUSION: In summary, our study identified BGN + Fib as drivers of CRC, and the derived BGNFRS was effective in predicting the OS and RFS of CRC patients.

Effect of MR-guided perfusion imaging mismatch profiles within 6 h on endovascular thrombectomy outcomes.

BACKGROUND: The treatment of acute ischemic stroke (AIS) aims to achieve early vascular recanalization and reperfusion of the penumbra. However, the effect of early penumbral imaging within 6 h on clinical outcomes remains unclear. The objective of this study was to determine the effect of magnetic resonance-guided (MR-guided) perfusion imaging within 6 h after symptom onset on endovascular thrombectomy outcomes in AIS patients. METHODS: We prospectively collected the clinical information of consecutive AIS patients undergoing endovascular thrombectomy based on MR-guided perfusion imaging within 6 h after symptom onset from AISRNA and EVTRNA studies. The primary outcome was defined as the poor outcome (mRS > 2 within 90 days). The perfusion-weighted imaging/diffusion-weighted imaging (PWI/DWI) mismatch was assessed by an automated software. RESULTS: We enrolled 84 patients (25 in the mismatch ≤ 1.8 group and 59 in the mismatch > 1.8 group). Significant difference was found between the mismatch > 1.8 group and the mismatch ≤ 1.8 group for the incidence of disabling stroke (mRS > 2) within 90 days (40.7% vs. 68.0%, OR: 3.099, 95% CI: 1.154-8.323, P = 0.025). Intracranial hemorrhage occurred in 8 patients (13.6%) in the mismatch > 1.8 group and 10 patients in the mismatch ≤ 1.8 group (40.0%) (P = 0.010). The risk of severe cerebral edema was 2/59 (3.4%) vs. 7/25 (28.0%) (P = 0.004). These findings remained stable after adjustment. CONCLUSIONS: MR-guided perfusion imaging mismatch profiles within 6 h after symptom onset may be feasible to predictclinical outcomes and reduce clinically ineffective reperfusion after endovascular thrombectomy.

Circular RNA circ0104103 inhibits colorectal cancer progression through interactions with HuR and miR-373-5p.

Emerging evidence has suggested that circular RNAs (circRNAs) have vital functions during the initiation and progression of various diseases. However, circRNA potential mechanisms in colorectal cancer (CRC) are largely unknown. Here, we sought to investigate the role and underlying regulatory mechanism of circ0104103 in CRC. circ0104103 was validated by quantitative RT-PCR (qRT-PCR) and Sanger sequencing. Gain- and loss-of-function assays in cell lines and mouse xenograft models were utilized to investigate the effects of circ0104103 in CRC. RNA pull-down assays, RNA immunoprecipitation assays, bioinformatics analyses, RNA FISH, and luciferase reporter assays were used to elucidate the potential mechanism of circ0104103 in CRC. We identified circ0104103, which is strongly downregulated in CRC tissues and cell lines. Functional studies revealed that circ0104103 inhibited CRC cell growth, migration, and invasion both in vitro and in vivo. Mechanistically, circ0104103 binds to HuR, a functional RNA-binding protein commonly expressed in CRC. HuR binds to the 3'UTR of LACTB mRNA to facilitate stabilization and increase its expression. Moreover, circ0104103 was verified as a competing endogenous RNA (ceRNA) via negative regulation of miR-373-5p to increase LACTB expression, resulting in inhibiting the occurrence and progression of CRC. Taken together, our study revealed that circ0104103 acts as a tumor suppressor and may be a novel biomarker and therapeutic target in CRC.

Integrated analysis of single cell and bulk RNA sequencing identifies CTHRC1+ INHBA+ CAF as drivers of colorectal cancer progression.

Cancer-associated fibroblasts (CAFs) are a key component of the tumor microenvironment and a critical factor in the progression of colorectal cancer (CRC). The aim of this study was to screen for CAFs specific genes that could serve as promising therapeutic targets for CRC patients. Our findings showed a significant increase in the proportion of fibroblasts in CRC tissues, and a high proportion of fibroblasts was associated with immune escape and poor prognosis in CRC. Collagen triple helix repeat containing 1 (CTHRC1) and inhibin subunit beta A (INHBA) were identified as key genes in the progression of CRC, primarily expressed in CAFs and significantly upregulated in CRC tissues. We defined CTHRC1 and INHBA as cancer-associated fibroblast-related genes (CAFRGs), which were associated with poor prognosis in CRC and macrophage polarization. CAFRGs promoted immune escape and metastasis in CRC and were good predictors of immune therapy response. Drug sensitivity analysis showed that the high expression group of CAFRGs was sensitive to 15 chemotherapy drugs, while the low expression group was sensitive to only 3. Clustering of fibroblasts in the tumor revealed that CTHRC1+ INHBA+ CAF was a poor prognostic factor in CRC and was associated with extracellular matrix remodeling and immune regulation. In conclusion, our study provides new theoretical basis for effective treatment strategies and therapeutic targets for CRC.

The relationship between filial piety and caregiver burden among adult children: A systematic review and meta-analysis.

INTRODUCTION: Filial piety is an important cultural value in aging societies. However, mixed findings were identified regarding its influence on caregiver burden. The purpose of this meta-analysis was to clarify the relationships between filial concepts and caregiver burden. METHOD: Twelve databases on filial piety, filial obligation, and caregiver burden among adult children prior to January, 2020 were systematically cross-culturally reviewed. RESULTS: Twelve studies were finalized for analysis. Fixed effect models indicated that stronger filial piety was significantly correlated (r = -.23) or associated with (ß = -.27) less caregiver burden. However, no significant relationship between filial obligation and caregiver burden was revealed by random effect models. CONCLUSION: Stronger filial piety may lessen caregiver burden. Therefore, filial piety should be assessed and supported in adult child caregivers, particularly in Eastern cultures. However, the concept of filial piety and its tools should be updated transculturally. PROSPERO Registration Number: CRD42020161969.

MiR-142-3p functions as a tumor suppressor by targeting RAC1/PAK1 pathway in breast cancer.

MicroRNA-142-3p (miR-142-3p) was previously investigated in various cancers, whereas, it's role in breast cancer (BC) remains far from understood. In this study, we found that miR-142-3p was markedly decreased both in cell lines and BC tumor tissues. Elevated miR-142-3p expression suppressed growth and metastasis of BC cell lines via gain-of-function assay in vitro and in vivo. Mechanistically, miR-142-3p could regulate the ras-related C3 botulinum toxin substrate 1 (RAC1) expression in protein level, which simultaneously suppressed the epithelial-to-mesenchymal transition related protein levels and the activity of PAK1 phosphorylation, respectively. In addition, rescue experiments revealed RAC1 overexpression could reverse tumor-suppressive role of miR-142-3p. Our results showed miR-142-3p could function as a tumor suppressor via targeting RAC1/PAK1 pathway in BC, suggesting a potent therapeutic target for BC treatment.

METTL14-mediated N6-methyladenosine modification of SOX4 mRNA inhibits tumor metastasis in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the leading causes of tumor-related death worldwide, and its main cause of death is distant metastasis. Methyltransferase-like 14(METTL14), a major RNA N6-adenosine methyltransferase, is involved in tumor progression via regulating RNA function. The goal of the study is to uncover the biological function and molecular mechanism of METTL14 in CRC. METHODS: Quantitative real-time PCR (qRT-PCR), western blot and immunohistochemical (IHC) assays were employed to detect METTL14 and SOX4 in CRC cell lines and tissues. The biological functions of METTL14 were demonstrated using in vitro and in vivo experiments. Chromatin immunoprecipitation (ChIP), Transcrptomic RNA sequencing (RNA-Seq), m6A-RNA immunoprecipitation sequencing (MeRIP-Seq), RNA immunoprecipitation and luciferase reporter assays were used to explore the mechanism of METTL14 action. RESULTS: METTL14 expression was significantly downregulated in CRC and decreased METTL14 was associated with poor overall survival (OS). Both the univariate and multivariate Cox regression analysis indicated that METTL14 was an independent prognostic factor in CRC. Moreover, lysine-specific histone demethylase 5C(KDM5C)-mediated demethylation of histone H3 lysine 4 tri-methylation(H3K4me3) in the promoter of METTL14 inhibited METTL14 transcription. Functionally, we verified that METTL14 inhibited CRC cells migration, invasion and metastasis through in vitro and in vivo assays, respectively. Furthermore, we identified SRY-related high-mobility-group box 4(SOX4) as a target of METTL14-mediated m6A modification. Knockdown of METTL14 markedly abolished SOX4 mRNA m6A modification and elevated SOX4 mRNA expression. We also revealed that METTL14-mediated SOX4 mRNA degradation relied on the YTHDF2-dependent pathway. Lastly, we demonstrated that METTL14 might inhibit CRC malignant process partly through SOX4-mediated EMT process and PI3K/Akt signals. CONCLUSIONS: Decreased METTL14 facilitates tumor metastasis in CRC, suggesting that METTL14 might be a potential prognostic biomarker and effective therapeutic target for CRC.

LRIG3 represses cell motility by inhibiting slug via inactivating ERK signaling in human colorectal cancer.

Metastasis is responsible for 90% of colorectal cancer (CRC)-related deaths. In the present study, we identified a novel key regulator of CRC metastasis, leucine-rich repeats and immunoglobulin-like domains protein 3 (LRIG3), which was significantly decreased in CRC tissues and cell lines. Downregulation of LRIG3 was attributed to copy number loss and promoter hypermethylation. Low LRIG3 expression was positively correlated with metastatic clinical features and shorter survival time. Functional experiments showed that knockout of LRIG3 markedly enhanced CRC cell migration and invasion ability, whereas reintroduction of LRIG3 exerted the opposite effects. Regarding the mechanism, LRIG3 could facilitate the binding of DUSP6 to ERK1/2, resulting in the dephosphorylation of ERK1/2 and subsequently downregulation of slug, an epithelial-to-mesenchymal transition trigger, thereby constraining CRC cell motility. Importantly, LRIG3 expression was strongly negatively correlated with slug or p-ERK1/2 expression in CRC tissues. Collectively, our data suggest that LRIG3 is a novel suppressor of CRC metastasis, reactivation of LRIG3 may be a promising therapeutic approach for metastatic CRC patients.

LncRNA SATB2-AS1 inhibits tumor metastasis and affects the tumor immune cell microenvironment in colorectal cancer by regulating SATB2.

BACKGROUND: Emerging studies suggest that long non-coding RNAs (lncRNAs) play crucial roles in colorectal cancer (CRC). Here, we report a lncRNA, SATB2-AS1, which is specifically expressed in colorectal tissue and is significantly reduced in CRC. We systematically elucidated its functions and possible molecular mechanisms in CRC. METHODS: LncRNA expression in CRC was analyzed by RNA-sequencing and RNA microarrays. The expression level of SATB2-AS1 in tissues was determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and in situ hybridization (ISH). The functional role of SATB2-AS1 in CRC was investigated by a series of in vivo and in vitro assays. RNA pull-down, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), chromatin isolation by RNA purification (ChIRP), Bisulfite Sequencing PCR (BSP) and bioinformatics analysis were utilized to explore the potential mechanisms of SATB2-AS1. RESULTS: SATB2-AS1 is specifically expressed in colorectal tissues and downregulated in CRC. Survival analysis indicates that decreased SATB2-AS1 expression is associated with poor survival. Functional experiments and bioinformatics analysis revealed that SATB2-AS1 inhibits CRC cell metastasis and regulates TH1-type chemokines expression and immune cell density in CRC. Mechanistically, SATB2-AS1 directly binds to WDR5 and GADD45A, cis-activating SATB2 (Special AT-rich binding protein 2) transcription via mediating histone H3 lysine 4 tri-methylation (H3K4me3) deposition and DNA demethylation of the promoter region of SATB2. CONCLUSIONS: This study reveals the functions of SATB2-AS1 in CRC tumorigenesis and progression, suggesting new biomarkers and therapeutic targets in CRC.

Polymorphisms of IL-23R predict survival of gastric cancer patients in a Chinese population.

IL-17/IL-23 pathway has been hypothesized to play a role in occurrence and progression of gastric cancer. To investigate the susceptibility and prognostic value of polymorphisms in genes in the IL-17/IL-23 pathway to gastric cancer, we performed a case-control study combined a retrospective study in a Chinese population. The Sequenom's MassARRAY® genotyping platform was used to genotype the polymorphisms, and infection of Helicobacter pylori (H. pylori) was determined by using a commercial H. pylori immunogold testing kit. The results showed that IL-17A rs3748067 T allele carriers have a higher gastric cancer risk than non-carriers in the subgroup of individuals with age >64 years old (CT/TT vs. CC: adjusted OR = 1.55, 95% CI = 1.04-2.29). The result of prognosis shown that IL-23R rs1884444 GG and rs6682925 CC genotype were associated with unfavorable survival (rs1884444 GG vs. GT/TT: adjusted HR = 1.40, 95%CI:1.02-1.93; rs6682925 CC vs. CT/TT: HR = 1.43, 95%CI:1.06-1.92), respectively. The stratified analysis revealed that the significant association of rs1884444 was maintained in the subgroup of older than 64 years old, and that rs6682925 was associated with unfavorable survival in the subgroup of female and patients received chemotherapy. In short, we concluded two polymorphisms (rs1884444 and rs6682925) in IL-23R were associated with prognosis of gastric cancer patients.

The long noncoding RNA SNHG1 regulates colorectal cancer cell growth through interactions with EZH2 and miR-154-5p.

BACKGROUND: Mounting evidence demonstrates that long noncoding RNAs (lncRNAs) have critical roles during the initiation and progression of cancers. In this study, we report that the small nucleolar RNA host gene 1 (SNHG1) is involved in colorectal cancer progression. METHODS: We analyzed RNA sequencing data to explore abnormally expressed lncRNAs in colorectal cancer. The effects of SNHG1 on colorectal cancer were investigated through in vitro and in vivo assays (i.e., CCK-8 assay, colony formation assay, flow cytometry assay, EdU assay, xenograft model, immunohistochemistry, and western blot). The mechanism of SNHG1 action was explored through bioinformatics, RNA fluorescence in situ hybridization, luciferase reporter assay, RNA pull-down assay, chromatin immunoprecipitation assay and RNA immunoprecipitation assay. RESULTS: Our analysis revealed that SNHG1 was upregulated in human colorectal cancer tissues, and high SNHG1 expression was associated with reduced patient survival. We also found that high SNHG1 expression was partly induced by SP1. Moreover, SNHG1 knockdown significantly repressed colorectal cancer cells growth both in vitro and in vivo. Mechanistic investigations demonstrated that SNHG1 could directly interact with Polycomb Repressive Complex 2 (PRC2) and modulate the histone methylation of promoter of Kruppel like factor 2 (KLF2) and Cyclin dependent kinase inhibitor 2B (CDKN2B) in the nucleus. In the cytoplasm, SNHG1 acted as a sponge for miR-154-5p, reducing its ability to repress Cyclin D2 (CCND2) expression. CONCLUSIONS: Taken together, the results of our studies illuminate how SNHG1 formed a regulatory network to confer an oncogenic function in colorectal cancer and suggest that SNHG1 may serve as a potential target for colorectal cancer diagnosis and treatment.

The pro-metastasis effect of circANKS1B in breast cancer.

BACKGROUND: Recent studies indicate that circular RNA (circRNA) plays a pivotal role in cancer progression. Here, we sought to investigate its role in breast cancer. METHODS: CircANKS1B (a circRNA originated from exons 5 to 8 of the ANKS1B gene, hsa_circ_0007294) was identified by RNA-sequencing and validated by qRT-PCR and Sanger sequencing. Clinical breast cancer samples were used to evaluate the expression of circANKS1B and its associations with clinicopathological features and prognosis. Gain- and loss-of-function experiments in cell lines and mouse xenograft models were performed to support clinical findings and elucidate the function and underlying mechanisms of circANKS1B in breast cancer. RESULTS: CircANKS1B was significantly up-regulated in triple-negative breast cancer (TNBC) compared with non-TNBC tissues and cell lines. Increased circANKS1B expression was closely associated with lymph node metastasis and advanced clinical stage and served as an independent risk factor for overall survival of breast cancer patients. Functional studies revealed that circANKS1B promoted breast cancer invasion and metastasis both in vitro and in vivo by inducing epithelial-to-mesenchymal transition (EMT), while had no effect on breast cancer growth. Mechanistically, circANKS1B abundantly sponged miR-148a-3p and miR-152-3p to increase the expression of transcription factor USF1, which could transcriptionally up-regulate TGF-ß1 expression, resulting in activating TGF-ß1/Smad signaling to promote EMT. Moreover, we found that circANKS1B biogenesis in breast cancer was promoted by splicing factor ESRP1, whose expression was also regulated by USF1. CONCLUSIONS: Our data uncover an essential role of the novel circular RNA circANKS1B in the metastasis of breast cancer, which demonstrate that therapeutic targeting of circANKS1B may better prevent breast cancer metastasis.

Polymorphisms of TGFBR1, TLR4 are associated with prognosis of gastric cancer in a Chinese population.

BACKGROUND: Helicobacter pylori (H. pylori)-induced gastric cancer is an intricate progression of immune response against H. pylori infection. IL-16, TGF-ß1 and TLR4 pathways were the mediators involved in the immune response. We hypothesized that genetic variations in genes of these pathways have potential susceptibility to gastric cancer risk, and predict clinical outcomes of patients. METHODS: To investigate the susceptibility and prognostic value of genetic variations of IL-16, TGFBR1 and TLR4 pathways to gastric cancer, we performed a case-control study combined a retrospective study in a Chinese population. Genotyping for all polymorphisms was based on the Sequenom's MassARRAY platform, and H. pylori infection was determined by using an immunogold testing kit. RESULTS: We found rs10512263 CC genotype was found to be a decreased risk of gastric cancer (CC vs. TT: adjusted OR = 0.54, 95% CI 0.31-0.97); however, rs334348 GG genotype was associated with increased risk of gastric cancer (GG vs. AA: adjusted OR = 1.51, 95% CI 1.05-2.18). We found that carriers harboring rs1927911 A allele (GA/AA) or rs10512263 C allele (CT/CC) have unfavorable survival time than none carriers (rs1927911: GA/AA vs. GG: adjusted HR = 1.27, 95% CI 1.00-1.63; rs10512263: CT/CC vs. TT: adjusted HR = 1.29, 95% CI 1.02-1.63) and that individuals harboring both two minor alleles (rs1927911 GA/AA and rs10512263 CT/CC) suffered a significant unfavorable survival (adjusted HR = 1.64, 95% CI 1.17-2.31). CONCLUSION: In short, we concluded that two polymorphisms (rs334348, rs10512263) in TGFBR1 were associated with risk of gastric cancer, and that TLR4 rs1927911 and TGFBR1 rs10512263 were associated with clinical outcomes of gastric cancer patients.

Combination of preoperative NLR, PLR and CEA could increase the diagnostic efficacy for I-III stage CRC.

BACKGROUND: Inflammation plays an important role in the development and progression of CRC. The members of inflammatory biomarkers, preoperative NLR and PLR, have been proved by numerous studies to be promising prognostic biomarkers for CRC. However, the diagnostic value of the two biomarkers in CRC remains unknown, and no study reported the combined diagnostic efficacy of NLR, PLR and CEA. METHODS: Five hundred and fifty-nine patients with I-III stage CRC undergoing surgical resection and 559 gender- and age-matched healthy controls were enrolled in this retrospective study. NLR and PLR were calculated from preoperative peripheral blood cell count detected using white blood cell five classification by Sysmex XT-1800i Automated Hematology System and serum CEA were measured by electrochemiluminescence by ELECSYS 2010. The diagnostic performance of NLR, PLR and CEA for CRC was evaluated by ROC curve. RESULTS: Levels of NLR and PLR in the cases were significantly higher than them in the healthy controls. ROC curves comparison analyses showed that the diagnostic efficacy of NLR (AUC=.755, 95%CI=.728-.780) alone for CRC was significantly higher than PLR (AUC=.723, 95%CI=.696-.749, P=.037) and CEA (AUC=.690, 95%CI=.662-.717, P=.002) alone. In addition, the diagnostic efficacy of the combination of NLR, PLR and CEA(AUC=.831, 95%CI=.807-.852)for CRC was not only significantly higher than NLR alone but also higher than any combinations of the two of these three biomarkers (P<.05). Moreover, the NLR and PLR in the patients with TNM stage I/II was higher than that in the healthy controls, and patients with stage III had a higher NLR and PLR than those with stage I/II, but no significant difference was observed. CONCLUSION: Our study indicated that preoperative NLR could be a CRC diagnostic biomarker, even for early stage CRC, and the combination of NLR, PLR and CEA could significantly improve the diagnostic efficacy.

The Relationship Between Mutuality and Health-Related Quality of Life in Adult Child Caregivers in China.

The strain inherent in caregiving relationships between adult children and aging parents is a prominent issue in contemporary China due to a combination of demographic and socioeconomic changes. The purpose of this study was to explore how mutuality, a positive quality of caregiving relationships, contributes to the physical health and mental health (health-related quality of life [HRQoL]) of adult child caregivers [ACCs] of parent stroke survivors. A cross-sectional correlational study was conducted on a nonproportional quota sample of 126 ACCs, using questionnaires of demographics, the 15-item Mutuality Scale, and the Second Version of the Standard 12-Item Health Survey (SF-12v2). Higher mutuality was found to be correlated with better caregiver physical health and mental health. However, after adjusting for the covariates, mutuality significantly explained 4.6% of the variance of caregiver physical health (ß = .22, ΔR2 = .046, p < .01) but it did not significantly explain the variance of caregiver mental health. Although multiple factors correlate with Chinese family caregivers' HRQoL, this was the first study exploring the impact of caregiver-care receiver dyadic relationships on caregiver HRQoL in mainland China by using a mutuality scale with SF-12v2. Despite the fact that the Chinese tradition of filial piety can facilitate mutuality, socioeconomic changes and legislation that require adult children to care for aging parents appear to create high stress among family caregivers. Higher levels of mutuality contribute to better physical health in Chinese family caregivers. Therefore, culturally appropriate family nursing strategies and social policies in China could enhance caregiver mutuality and potentially promote their HRQoL, in particular physical health.

Circulating miR-148/152 family as potential biomarkers in hepatocellular carcinoma.

Aberrant expressions of the miR-148/152 family (miR-148a, miR-148b, and miR-152) have been documented in many tumor tissues, including hepatocellular carcinoma (HCC). However, the expression pattern and clinical significance of circulating miR-148/152 family in HCC remain elusive. In this study, we conducted quantitative real-time polymerase chain reaction (qRT-PCR) to examine the levels of serum miR-148a, miR-148b, and miR-152 in 76 HCC cases, as well as 62 controls with benign liver diseases and 55 healthy volunteers. Our results showed that serum levels of three microRNAs (miRNAs) were significantly decreased in HCC cases than those in benign and healthy controls (all P < 0.05). Moreover, they showed strong correlations with each other in HCC group (r = 0.6716, 0.5381, and 0.7712; all P < 0.001). Receiver operating characteristic (ROC) analysis revealed that the combination of circulating miR-148/152 family had an increased area under the curve (AUC) = 0.940 (95 % confidence interval (CI), 0.886-0.973) with the sensitivity of 96.1 % and the specificity of 91.9 %, which were significantly higher than those of serum alpha-fetoprotein (AFP) and three miRNAs alone in differentiating HCC from benign liver diseases. In addition, serum miR-148a and miR-148b were significantly associated with tumor size (P = 0.011 and 0.037) and tumor-node-metastasis (TNM) stage (P < 0.001 and P = 0.034), yet serum miR-152 was only correlated with TNM stage (P = 0.009). Also, dynamic monitoring three miRNAs can help us predict recurrence or metastasis in HCC cases after surgical resection. Besides, Kaplan-Meier analyses demonstrated that the decreased serum miR-148a (P < 0.001) and miR-152 (P = 0.012) was closely correlated with shorten overall survival of HCC patients. Additionally, Cox regression model further indicated that serum miR-148a was strongly associated with the prognosis of HCC patients. Our study suggests that downregulated circulating miR-148/152 family can provide positive diagnostic value for HCC. Moreover, serum miR-148a might be as independent prognostic factor for HCC patients.

Enhanced Platelet Response to Clopidogrel in Abcc3-deficient Mice Due to Its Increased Bioactivation.

Resistance of the patient to clopidogrel (an inactive prodrug) has been recently reported to be associated with increased messenger RNA expression of ABCC3 that encodes MRP3 (multidrug resistance-associated protein 3). However, there is no evidence showing the effects of MRP3 on altered platelet responses to clopidogrel and their underlying mechanisms. To further clarify whether the presence or absence of Mrp3 could affect the formation of and response to clopidogrel active metabolite (CAM) in Abcc3 knockout (KO) versus wild-type (WT) mice, we determined pharmacokinetic profiles of clopidogrel and CAM and measured inhibition of adenosine diphosphate-induced platelet aggregation by clopidogrel after administration of a single oral dose of clopidogrel to KO and WT mice, respectively. Results indicated that Abcc3 KO mice exhibited increased formation of CAM and greater systemic exposure to clopidogrel and enhanced inhibition of adenosine diphosphate-induced platelet aggregation ex vivo by clopidogrel when compared with well-matched WT mice. We conclude that Abcc3 KO mice have enhanced platelet response to clopidogrel due to increased formation of CAM.

Analysis of Diagnostic Value of YKL-40 in Ovarian Cancer.

OBJECTIVE: Early diagnosis of ovarian cancer is crucial in clinical practice but is difficult. Accumulating studies have investigated the utility of YKL-40 in early detection of ovarian cancer. The aim of this study was to evaluate the overall accuracy of YKL-40 in diagnosis of ovarian cancer through a meta-analysis of published studies. METHODS: A comprehensive search of related literature was performed in PubMed, Web of Science, and China National Knowledge Infrastructure databases. Meta-DiSc 1.4 and STATA 11.0 were selected for data analysis, and Quality Assessment of Diagnostic Accuracy Studies tool version 2 was used to assess the quality of included studies. Data from selected studies were pooled to yield summary sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratio, and summary receiver operating characteristic curve. RESULTS: A total of 13 studies dating up to May 2015 with 1623 individuals were enrolled in the present study. The pooled characteristics of these studies were as follows: sensitivity 0.71 (95% confidence interval [CI], 0.68-0.75), specificity 0.90 (95% CI, 0.88-0.92), positive likelihood ratio 7.24 (95% CI, 4.22-12.43), negative likelihood ratio 0.34 (95% CI, 0.27-0.42), and diagnostic odds ratio 24.93 (95% CI, 12.61-49.27), respectively. The area under the curve was 0.8471. CONCLUSIONS: The results indicated that YKL-40 could be regarded as an effective biomarker for diagnosis of ovarian cancer.