Circulating MicroRNAs as Biomarkers in Hepatocellular Carcinoma Screening: A Validation Set From China

Hepatocellular carcinoma (HCC) is a global public health concern. Current diagnostic methods show poor performance in early-stage HCC detection. Accumulating evidences revealed the great potential of microRNAs (miRNAs) as noninvasive biomarkers in HCC detection. In this study, we examined the diagnostic performance of serum miR-10b, miR-106b, and miR-181a for HCC screening in China. Furthermore, a systematic review of previous related studies was conducted to confirm our results.One hundred eight participants including 27 HCC patients, 31 chronic liver disease (CLD) patients, and 50 healthy people were recruited in this study. Blood specimen was drawn from each participant to extract serum miRNAs. Statistical analyses were performed to assess the 3 miRNAs levels in HCC, CLD patients, and normal controls. A meta-analysis was conducted to further assess the diagnostic value of miRNAs in HCC detection based on previous studies.All these miRNAs (miR-10b, miR-181a, miR-106b) could well discriminate HCC patients from normal controls, with area under the receiver-operating characteristic curve (AUC) values of 0.85 (95% confidence interval [CI]: 0.76–0.94), 0.82 (95% CI: 0.72–0.91), and 0.89 (95% CI: 0.81–0.97), respectively. In addition, these miRNAs could distinguish HCC cases from CLD controls with a medium accuracy. However, the ability of these miRNAs in differentiating CLD patients from normal controls was not satisfactory. Panel of these miRNAs displayed a better performance compared with single miRNA assay, with AUC values of 0.94 (95% CI: 0.89–0.99) in discriminating HCC patients from normal controls and 0.91 (95% CI: 0.80–0.97) in discriminating HCC patients from CLD controls. Results of meta-analysis of previous studies combined with the current study suggested that circulating miRNAs could well differentiate HCC from normal controls, with AUC values of 0.86 (95% CI: 0.82–0.89) for single miRNA assay and 0.94 (95% CI: 0.91–0.96) for miRNA panel assay.Serum miR-10b, miR-106b, and miR-181a have great potential to serve as accurate and noninvasive biomarkers for HCC preliminary screening. Meta-analysis of previous studies combined with current study further confirmed that circulating miRNAs could play an important role in HCC detection. Further large-scale studies are needed to confirm the clinical significance of circulating miRNAs in HCC screening.     

循环microRNA早期诊断肝细胞癌研究现状及方法学探讨

肝细胞癌（HCC）是发病率和死亡率很高的恶性肿瘤,对高危人群的筛查和监测十分重要。定期检查肝脏超声和血清AFP是目前主要的筛查手段,但灵敏度和准确性仍不尽如人意。microRNA与HCC的发生、转移、复发等病理过程密切相关,相关研究也方兴未艾。循环microRNA是HCC血清学标志物中的重要成员,在HCC诊断和筛查方面具有广阔的应用前景。选择合适的microRNA和确定高效的诊断方法是相关研究的重点,更多高质量的研究还在持续进行中。     

Alpha-fetoprotein,protein induced by vitamin K absence or antagonist-II,lens culinaris agglutinin-reactive fraction of alpha-fetoprotein alone and in combination for early detection of hepatocellular carcinoma from nonalcoholic fatty liver disease: A multicenter analysis

BackgroundCurrent surveillance strategies for hepatocellular carcinoma (HCC) among patients with nonalcoholic fatty liver disease (NAFLD) are insufficient. This study aimed to investigate the diagnostic performance of alpha-fetoprotein (AFP), protein induced by vitamin K absence or antagonist-II (PIVKA-II), lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), and their combinations in HCC underlying NAFLD patients.MethodsSerologic AFP, AFP-L3, and PIVKA-II levels in NAFLD patients with and without HCC were measured. By receiver operating characteristic (ROC) analyses, the area under the curve (AUC), sensitivity, and specificity were obtained to evaluate the diagnostic accuracy of each biomarker and their combinations.ResultsThis study was conducted on 139 patients with NAFLD-HCC and 345 NAFLD controls. The elevation of these three biomarkers was observed in patients with NAFLD-HCC compared to those in NAFLD controls (all P < 0.001). When they were analyzed individually, PIVKA-II showed the best performance in diagnosing any-stage HCC with an AUC of 0.869, followed by AFP (0.763; vs. PIVKA-II, P < 0.001) and AFP-L3 (0.689; vs. PIVKA-II, P < 0.001). When they were analyzed in combination, AFP + PIVKA-II yielded the highest AUC (0.906), followed by AFP + PIVKA-II + AFP-L3 (0.904; vs. AFP + PIVKA-II, P = 0.086), PIVKA-II + AFP-L3 (0.881; vs. AFP + PIVKA-II, P < 0.001), and AFP + AFP-L3 (0.759; vs. AFP + PIVKA-II, P < 0.001). Similar findings were obtained in the subgroup with early-stage NAFLD-HCC, as well as the non-cirrhotic subgroup.ConclusionsThese data validated the better diagnostic ability of PIVKA-II than AFP or AFP-L3 alone for diagnosing any-stage HCC among patients with NAFLD, and the combination of AFP + PIVKA-II significantly improved the diagnostic accuracy of NAFLD-HCC.     

MicroRNA-29a and MicroRNA-124 as novel biomarkers for hepatocellular carcinoma

BackgroundNumerous microRNAs (miRNAs) have been observed to be abnormally expressed in cancer. Therefore, miRNA signatures could be potential noninvasive diagnostic and prognostic biomarkers for hepatocellular carcinoma (HCC).AimsTo correlate miRNA-29a and miRNA-124 expression levels with the clinical features and survival rates of HCC patients.MethodsSerum miRNA expression in 150 samples (50 patients with HCC, 50 patients with liver cirrhosis, and 50 healthy controls) were quantified using real-time qRT-PCR.ResultsThe expression levels of serum miRNA-29a were higher and the levels of miRNA-124 were lower in patients with HCC than in patients with liver cirrhosis and controls. ROC curve analysis showed promising accuracy for both miRNAs in distinguishing patients with HCC from those with liver cirrhosis. Levels of miRNA-29a were related to tumor number, size, stage, and outcome, whereas levels of miRNA-124 were related to vascular invasion. The overall survival rate of patients with low miRNA-29a expression was significantly higher than that of patients with high expression. Additionally, the multivariate analysis identified miRNA-29a as an independent prognostic variable.ConclusionsThe investigated miRNAs showed acceptable accuracy in the diagnosis of HCC; therefore, both could be utilized as diagnostic biomarkers. Additionally, miRNA-29a could be used as a prognostic biomarker.     

Clinical significance of cylindromatosis expression in primary hepatocellular carcinoma

Background and study aimThere is currently a lack of sensitive biomarkers for the diagnosis of hepatocellular carcinoma (HCC). Low expression of cylindromatosis (CYLD), a tumor suppressor gene that encodes a deubiquitinase, is associated with the development of HCC. The present study, therefore, aimed to determine the clinical utility of measuring CYLD expression in the early diagnosis of HCC.Patients and methodsThe present study comprised 257 patients from the Affiliated Hospital of Qingdao University including 90 patients with HCC, 41 patients with liver cirrhosis (LC), 46 patients with hepatitis B (HB), and 80 healthy controls. qPCR was used to measure the amounts of CYLD mRNA in stored blood samples. The sensitivity and specificity of CYLD mRNA in diagnosing HCC was analyzed using receiver operator characteristic (ROC) curves. We also obtained HCC data from the Oncomine database to further verify our results.ResultsThe relative levels of CYLD mRNA in peripheral blood from patients with HCC (median, 0.060; interquartile range [IQR], 0.019–0.260) was significantly lower than in blood from patients with LC (median, 3.732; IQR, 0.648–14.573), HB (median, 0.419; IQR, 0.255–1.809) and healthy controls (median, 1.262; IQR, 0.279–3.537; P < 0.05). CYLD mRNA levels in peripheral blood were significantly higher in patients with LC compared to healthy controls and patients with HB. Oncomine data demonstrated that CYLD mRNA expression levels in HCC tissues were significantly lower than in normal liver tissues. ROC analysis demonstrated that the combined use of peripheral blood levels of CYLD and AFP had the greatest diagnostic accuracy for HCC (area under the curve (AUC), 0.897; 95 % confidence interval [CI], 0.853–0.942). CYLD had utility as a supplementary marker to AFP for diagnosing HCC.ConclusionCirculating levels of CYLD mRNA are significantly decreased in patients with HCC, indicating CYLD may have utility as a biomarker of HCC. Combined measurement of CYLD mRNA and AFP protein had the greatest diagnostic accuracy.     

Clinical significance of cylindromatosis expression in primary hepatocellular carcinoma

Background and study aimThere is currently a lack of sensitive biomarkers for the diagnosis of hepatocellular carcinoma (HCC). Low expression of cylindromatosis (CYLD), a tumor suppressor gene that encodes a deubiquitinase, is associated with the development of HCC. The present study, therefore, aimed to determine the clinical utility of measuring CYLD expression in the early diagnosis of HCC.Patients and methodsThe present study comprised 257 patients from the Affiliated Hospital of Qingdao University including 90 patients with HCC, 41 patients with liver cirrhosis (LC), 46 patients with hepatitis B (HB), and 80 healthy controls. qPCR was used to measure the amounts of CYLD mRNA in stored blood samples. The sensitivity and specificity of CYLD mRNA in diagnosing HCC was analyzed using receiver operator characteristic (ROC) curves. We also obtained HCC data from the Oncomine database to further verify our results.ResultsThe relative levels of CYLD mRNA in peripheral blood from patients with HCC (median, 0.060; interquartile range [IQR], 0.019–0.260) was significantly lower than in blood from patients with LC (median, 3.732; IQR, 0.648–14.573), HB (median, 0.419; IQR, 0.255–1.809) and healthy controls (median, 1.262; IQR, 0.279–3.537; P < 0.05). CYLD mRNA levels in peripheral blood were significantly higher in patients with LC compared to healthy controls and patients with HB. Oncomine data demonstrated that CYLD mRNA expression levels in HCC tissues were significantly lower than in normal liver tissues. ROC analysis demonstrated that the combined use of peripheral blood levels of CYLD and AFP had the greatest diagnostic accuracy for HCC (area under the curve (AUC), 0.897; 95 % confidence interval [CI], 0.853–0.942). CYLD had utility as a supplementary marker to AFP for diagnosing HCC.ConclusionCirculating levels of CYLD mRNA are significantly decreased in patients with HCC, indicating CYLD may have utility as a biomarker of HCC. Combined measurement of CYLD mRNA and AFP protein had the greatest diagnostic accuracy.     

Serum interleukin-18: Does it have a role in the diagnosis of hepatitis C virus related hepatocellular carcinoma?

Background and study aimsEarly diagnosis of hepatocellular carcinoma (HCC) is the only hope for cure. Although the role of alpha foetoprotein (AFP) in the diagnosis of advanced HCC is well recognised, at least one-third of cases will be missed unless another diagnostic tool is used. Increased levels of circulating interleukin-18 (IL-18) have been observed in patients with several cancer types and were described in patients with chronic hepatitis. The aim of this study is to assess the role of serum IL-18 level in the diagnosis of hepatitis C virus (HCV)-related HCC.Patients and methodsA total of 75 subjects categorised into four groups, including 25 patients with HCV-related HCC and AFP above 200 ng/ml, 25 patients with HCV-related HCC and AFP below 200 ng/ml, 15 patients with HCV-related chronic liver disease and 10 healthy controls, were enrolled. HCC was diagnosed according to guidelines of the American Association for the Study of Liver Diseases. AFP and IL-18 were assessed in all subjects.ResultsAFP and IL-18 levels are significantly higher in patients with HCC than in disease control and healthy control subjects. IL-18 level is not correlating with the size or the number of hepatic focal lesions neither with the presence of lymphovascular invasion or abdominal lymphadenopathy. The best cut-off value of IL-18 for the diagnosis of HCC is 500 pg/ml with 84% sensitivity and 86.7% specificity and the area under receiver operating characteristic curve is 0.675.ConclusionSerum IL-18 level is a suitable marker for the diagnosis of HCV-related HCC complementary to AFP, especially in cases with AFP level less than the diagnostic value.     

Clinical significance and diagnostic value of serum dickkopf-1 in patients with hepatocellular carcinoma

Background: Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide. It has been widely established that the early detection of HCC enables more treatment options and translates to improved survival.

Aim: To assess the diagnostic accuracy of DKK1 as a serum protein marker for HCC by examining its diagnostic sensitivity and specificity in HCC.

Methods: We analyzed data for 50 patients with hepatitis C virus (HCV) related HCC as the studied group. Twenty patients with chronic hepatitis C and 20 patients with HCV-related liver cirrhosis will serve as control group. DKK1 was measured in serum by ELISA. We used receiver operating characteristics (ROC) to calculate its diagnostic accuracy.

Results: We assessed serum DKK1 in 90 participants: 50 with HCC (studied group), 20 with chronic HCV infection, and 20 with liver cirrhosis (as control group). Serum concentration of DKK1 was significantly higher in HCC group and values did not differ significantly between the two control groups. We performed multivariate regression analysis using AFP level, number of focal lesions, focal lesion size and Portal vein thrombosis as an independent variable. ROC curves showed the optimum diagnostic cut off was 1.5?ng/mL (sensitivity 67.5%, specificity 89.3%).

Conclusion: Serum DKK1 could potentially be used for early diagnosis of HCC and complement measurement of AFP in the diagnosis of HCC.     

Identification of Circulating MicroRNAs as Novel Potential Biomarkers for Gastric Cancer Detection: A Systematic Review and Meta-Analysis

Background

Recent studies show that microRNAs (miRNAs) in serum or plasma can be stably detected and used as potential biomarkers in cancer diagnosis.

Objectives

To systematically evaluate circulating miRNAs from numerous gastric cancer (GC) expression profiling studies and to determine miRNA biomarkers for GC detection.

Methods

A systematic review and meta-analysis of published studies comparing the circulating miRNA expressions between GC patients and healthy controls were carried out. An miRNA ranking system that considered the number of comparisons in agreement, total number of samples, and average fold change was used. Then the receiver-operating characteristic curve (ROC) results of the top miRNAs were combined to further evaluate their diagnostic value by using Meta-disc 1.4.

Results

A total of 35 miRNAs were reported in the 22 included studies, with 7 miRNAs reported in at least 2 studies. MiR-21 is the most consistently reported miRNA with upregulation. In further analysis, the sensitivity, specificity, and area under the curve of summary ROC for miR-21 in GC diagnosis are 0.78 (95 % CI 0.71–0.85), 0.89 (95 % CI 0.82–0.94), and 0.91, respectively.

Conclusion

Circulating miR-21 can serve as a potential biomarker for detection of GC.     

Soluble cluster of differentiation 26/soluble dipeptidyl peptidase-4 and glypican-3 are promising serum biomarkers for the early detection of Hepatitis C virus related hepatocellular carcinoma in Egyptians

Background and study aimsMany patients are diagnosed with hepatocellular carcinoma (HCC) in the late stage when it is already untreatable. Therefore, there is an increased need for sensitive biomarkers to detect HCC at an earlier stage in high risk patients with hepatitis C virus (HCV)-induced cirrhosis. This study aimed to evaluate the diagnostic performance of soluble cluster of differentiation 26/dipeptidyl peptidase 4 (sCD26/sDPP4) and glypican-3 (GPC3) as serum biomarkers for the early detection of HCV related HCC and compare it with that of the conventional tumor marker serum alpha fetoprotein (AFP).Patients and methodsThe study included 80 participants, 30 patients diagnosed with HCV infection without HCC (HCV group), 30 patients diagnosed with HCV- related HCC (HCV group), and 20 healthy volunteers (control group). The serum levels of GPC3 and sCD26 were measured using specific enzyme linked immunosorbant assay (ELISA) kits, whereas AFP levels were determined using chemiluminescence.ResultsThe serum levels of both sCD26 and GPC3 were found to be significantly higher in patients with early-stage HCC than in the HCV group, (1450 and 1.16 ng/mL, respectively). sCD26 at a cutoff value of > 1000 ng/ml, showed a high sensitivity (83.3%) and 63.3% specificity with an area under curve (AUC) of 0.811 and a 95% confidence interval (CI) of (0.682–0.94). While, the combination of GPC3 and sCD26 exhibited the best diagnostic performance for early-stage-HCC because it increased the sensitivity and specificity (85% and 93.3% respectively), with an AUC of 0.986 and a 95% CI of (0.899–1.00) compared to sCD26 alone.ConclusionWe conclude that serum sCD26 could be a sensitive biomarker for the early detection of HCC among HCV patients. Moreover, the combination of sCD26 and GPC3 increases both the sensitivity and specificity for the early detection of HCV related HCC compared with AFP and could help in the monitoring of HCC in high risk patients with HCV induced cirrhosis.     

A panel of circulating miRNAs as diagnostic biomarkers for screening multiple myeloma: a systematic review and meta‐analysis

Circulating microRNAs (miRNAs) have been proved to be effective diagnostic markers for multiple myeloma (MM). The meta‐analysis was aimed to evaluate the diagnostic value of related miRNAs. Multiple databases (PubMed, Web of Science, EMBASE, Cochrane Library, CBM, and CNKI) were systematically searched for available studies up to March 2016. All data were analyzed with the help of software revman 5.3 and metadisc 1.4. The eligible articles’ quality was estimated by QUADAS‐2, and pooled parameters were acquired with the bivariate random‐effects meta‐analysis model. Subgroup analysis and meta‐regression were conducted to explore the heterogeneity of studies included. After steps of screening, seven qualified literatures were selected. They consisted of 22 studies that included 486 newly diagnosed MM patients and 292 healthy controls. Summary receiver operating characteristic (SROC) analyses of all miRNAs showed an area under the curve (AUC) of 0.86 (95%CI, 0.82–0.91). Together with the AUC, the positive likelihood ratio‐PLR 4.45 (95%CI, 3.28–6.04), negative likelihood ratio‐NLR 0.29 (95%CI, 0.24–0.35), and diagnostic odds ratio‐DOR 17.59 (95%CI, 11.26–27.4) confirmed that circulating miRNAs possessed relatively high diagnostic value in discriminating MM patients from healthy controls. For miRNAs combined together, miRNA‐1308/miRNA‐720 had the highest sensitivity 0.96 (95%CI, 0.79–1.00) and specificity 0.92 (95%CI 0.64–1.0). The subgroup and meta‐regression analyses also showed that miRNAs profiling was the sole source of heterogeneity, and the diagnostic accuracy of combined miRNAs was 6.02 times higher than single one. Combined circulating miRNAs in serum or plasma may be highly effective biomarker for diagnosis of MM.     

Performance of protein induced by vitamin K absence or antagonist-II assessed by chemiluminescence enzyme immunoassay for hepatocellular carcinoma detection: a meta-analysis

Objectives: In the setting of surveillance for hepatocellular carcinoma (HCC) detection, the use of serum biomarkers in addition to ultrasonography (US) is still a matter of debate. Hence, we performed a meta-analysis to evaluate the diagnostic accuracy of protein induced by vitamin K absence or antagonist-II (PIVKA-II) and alpha-fetoprotein (AFP) alone or in combination for HCC detection in patients at risk of tumor development.

Materials and methods: We performed a systematic search in PubMed and Scopus database for original articles published in English from 2011 to 2017, investigating the accuracy of PIVKA-II alone or in combination with AFP (reported as area under the curve [AUC]) for HCC detection among patients at risk of tumor development. Furthermore, we focused on studies in which serum PIVKA-II was assessed by highly sensitive chemiluminescence immunoassay (CLEIA).

Results: A total of 11 studies (873 patients with HCC and 1244 patients with advanced liver disease/cirrhosis) were included in the meta-analysis. The weighted summary AUC (sAUC) of PIVKA-II and AFP for the discrimination between patients with HCC and those without was 0.791 (0.746–0.837) and 0.767 (0.732–0.803), respectively. The combination of PIVKA-II?+?AFP results in a sAUC of 0.859 (0.837–0.882). The performance for HCC detection of PIVKA-II?+?AFP was significantly superior to each biomarker used alone (ΔsAUC?=?0.068, p?=?.032 and ΔsAUC?=?0.092, p?Conclusion: In clinical practice, the use of PIVKA-II?+?AFP in addition to US examination may improve the effectiveness of surveillance among patients at risk for HCC development.     

A combination of α-fetoprotein,midkine, thioredoxin and a metabolite for predicting hepatocellular carcinoma

Introduction and objectivesThe heterogenous nature of hepatocellular carcinoma (HCC) motivated this attempt at developing and validating a model based on combined biomarkers for improving early HCC detection.Patients/materials and methodsThis study examined 196 patients for an estimation study (104 patients with HCC, 52 with liver cirrhosis and 40 with liver fibrosis) and 122 patients for the validation study (80 patients with HCC, 42 with liver cirrhosis). All patients were positive for hepatitis C virus. Four markers were measured: Midkine and thioredoxin using ELISA, 1-methyladenosine and 1-methylguanosine using a gas chromatography–mass spectrometry (GC–MS). The results were compared with alpha-fetoprotein (AFP). The performance of the model was estimated in BCLC, CLIP and Okuda staging systems of HCC.ResultsThe model yielded high performance with an area under ROC (AUC) of 0.94 for predicting HCC in patients with liver cirrhosis, compared with AUC of 0.69 for AFP. This model had AUCs of 0.93, 0.94 and 0.94 in patients who had only one single nodule, absent macrovascular invasion and tumor size <2 cm, respectively, compared with AUCs of 0.71, 0.6 and 0.59 for AFP. The model produced AUCs of 0.91 for BCLC (0-A), 0.92 for CLIP (0–1) and 0.94 for Okuda (stage I) compared with AUCs of 0.56, 0.58 and 0.64 for AFP. No significant difference was found between AUC in the estimation and the validation groups.ConclusionThis model may enhance early-stage HCC detection and help to overcome insufficient sensitivity of AFP.     

Identification of serum microRNAs as diagnostic and prognostic biomarkers for acute pancreatitis

Background/objectivesTo identify serum microRNA (miRNA) as diagnostic and prognostic biomarkers for acute pancreatitis (AP).Materials and methodsSera microRNA expression was profiled from 12 AP patients with varying disease severity and three healthy controls. Differentially expressed miRNAs were validated in a larger cohort of patients and controls. The diagnostic and prognostic potentials of differentially expressed miRNAs were evaluated using receiver operating characteristic (ROC) curve analysis and compared to that of classic prognostic markers for AP.ResultsmiRNA microarray analyses identified 205 differentially expressed miRNAs between sera from AP patients and that from controls. Nine miRNAs were differentially expressed between severe and mild AP patients. Further validation confirmed the down-regulation of miR-92b, miR-10a, and miR-7 in AP patients, and ROC analysis revealed that these miRNAs can differentiate AP from health cases. Furthermore, the serum miR-551b-5p level was significantly higher in patients with disease complications or a low plasma calcium level. ROC analysis showed that the serum miR-551b-5p level can distinguish between severe and mild AP.ConclusionThe expressions of miR-92b, miR-10a, and miR-7 in AP might be used for the early diagnosis of AP and miR-551b-5p may be used for predicting AP severity.     

Value of circulating cell-free DNA in diagnosis of hepatocelluar carcinoma

AIM:To investigate the value of combined detection of circulating cell-free DNA(cfDNA),a-fetal protein(AFP) and a L-fucosidase(AFU) for diagnosis of hepatocellular carcinoma(HCC).METHODS:Serum samples from 39 HCC patients and 45 normal controls were collected.Branched DNA(bDNA) was used to detect the level of cfDNA,and a receiver operating characteristic curve was employed to evaluate the diagnostic sensitivity,specificity,accuracy,positive predictive value,negative predictive value,positive likelihood ratio,negative likelihood ratio and Youden index,and to assess the diagnostic efficiency and their correlations with the clinicopathological features.AFP and AFU were detected by chemiluminescence and colorimetry,respectively.The significance of combined detection of the three biomarkers was discussed.RESULTS:cfDNA level was increased in 22 of the 39 HCC samples and in 2 of the 45 normal controls.cfDNA level in HCC samples was significantly higher than that in normal controls(P < 0.05).There were significant differences in sex and extra-and intrahepatic metastasis(P < 0.05).There was no significant correlation between cfDNA,AFP and AFU in the detection of HCC.The sensitivity of combined detection of cfDNA with one marker(AFP or AFU) and cfDNA with two markers(AFP and AFU) was 71.8%,87.2% and 89.7% vs 56.4%,53.8% and 66.7% for cfDNA,AFP and AFU used alone,respectively,the difference being statistically significant(P < 0.05).CONCLUSION:Quantitative analysis of cfDNA is sensitive and feasible,and the combined detection of cfDNA with AFP or AFU or both could improve the diagnostic sensitivity for HCC.     

Change in circulating microRNA profile of obese children indicates future risk of adult diabetes

PurposeChildhood obesity increases susceptibility to type 2 diabetes (T2D) in adults. Circulating microRNAs (miRNAs) in serum have been proposed as potential diagnostic biomarkers, and they may contribute to the progression toward T2D. Here, we investigated the possibility of predicting the future risk of adult T2D in obese children by using circulating miRNAs.Basic ProceduresWe performed miRNA high-throughput sequencing to screen relevant circulating miRNAs in obese children. The expression patterns of targeted miRNAs were further explored in obese children and adults with T2D. To investigate the underlying contributions of these miRNAs to the development of T2D, we detected the impacts of the candidate miRNAs on preadipocyte proliferation, insulin secretion by pancreatic β-cell, and glucose uptake by skeletal muscle cells.Main FindingsThree miRNAs (miR-486, miR-146b and miR-15b), whose expression in the circulation was most dramatically augmented in obese children and adult T2D patients, were selected for further investigation. Of these 3 miRNAs, miR-486 was implicated in accelerating preadipocyte proliferation and myotube glucose intolerance, miR-146b and miR-15b were engaged in the suppression of high concentration glucose-induced pancreatic insulin secretion, and they all contributed to the pathological processes of obesity and T2D.Principal ConclusionsOur results provide a better understanding of the role of circulating miRNAs, particularly miR-486, miR-146b and miR-15b, in predicting the future risk of T2D in obese children.     

A modified TNM-based Japan Integrated Score combined with AFP level may serve as a better staging system for early-stage predominant hepatocellular carcinoma patients

BackgroundCombinations of Child-Pugh classification and Liver Cancer Study Group of Japan/Tumor-Node-Metastasis (LCSGJ/TNM) have been reported as Japan Integrated Staging (JIS). We previously modified the 6th AJCC/TNM to serve as a better staging system than the 5th and 6th AJCC/TNM.AimsTo develop a modified TNM-based JIS to predict the survival of hepatocellular carcinoma (HCC) patients more accurately.Methods3764 HCC patients were enrolled from 1986 to 2002 (2882 patients from 1986 to 2000 and 882 patients from 2001 to 2002). We compared the performance of original JIS, modified TNM-based JIS, modified TNM-based JIS combined α-fetoprotein (AFP), BCLC, and CLIP. Lower Akaike information criteria (AIC) values indicated better discriminatory abilities.ResultsAIC value was lowest in CLIP during all periods. However, during 2001–2002, when early-stage HCC patients were predominant, AIC value was lowest when modified TNM-based JIS combined AFP was used.ConclusionThe CLIP system provided the best prognostic stratification in the present cohort of HCC patients who were mainly at late stages. However, early detection of HCCs has become more common in Taiwan in recent years, which has led to the predominance of early-stage HCC patients. Therefore, modified TNM-based JIS combined AFP may now be the most applicable system in recent years.