Background/Aims: Early detection and effective prognosis prediction in patients with hepatocellular carcinoma (HCC) provide an avenue for survival improvement, yet more effective approaches are greatly needed. We sought to develop the detection and prognosis models with ultra-sensitivity and low cost based on fragmentomic features of circulating cell free mtDNA (ccf-mtDNA). Methods: Capture-based mtDNA sequencing was carried out in plasma cell-free DNA samples from 1168 participants, including 571 patients with HCC, 301 patients with chronic hepatitis B or liver cirrhosis (CHB/LC) and 296 healthy controls (HC). Results: The systematic analysis revealed significantly aberrant fragmentomic features of ccf-mtDNA in HCC group when compared with CHB/LC and HC groups. Moreover, we constructed a random forest algorithm-based HCC detection model by utilizing ccf-mtDNA fragmentomic features. Both internal and two external validation cohorts demonstrated the excellent capacity of our model in distinguishing early HCC patients from HC and highrisk population with CHB/LC, with AUC exceeding 0.983 and 0.981, sensitivity over 89.6% and 89.61%, and specificity over 98.20% and 95.00%, respectively, greatly surpassing the performance of alpha-fetoprotein (AFP) and mtDNA copy number. We also developed an HCC prognosis prediction model by LASSO-Cox regression to select 20 fragmentomic features, which exhibited exceptional ability in predicting 1-year, 2-year and 3-year survival (AUC=0.8333, 0.8145 and 0.7958 for validation cohort, respectively). Conclusions We have developed and validated a high-performing and low-cost approach in a large clinical cohort based on aberrant ccf-mtDNA fragmentomic features with promising clinical translational application for the early detection and prognosis prediction of HCC patients.

Background/Aims: Early detection and effective prognosis prediction in patients with hepatocellular carcinoma (HCC) provide an avenue for survival improvement, yet more effective approaches are greatly needed. We sought to develop the detection and prognosis models with ultra-sensitivity and low cost based on fragmentomic features of circulating cell free mtDNA (ccf-mtDNA). Methods: Capture-based mtDNA sequencing was carried out in plasma cell-free DNA samples from 1168 participants, including 571 patients with HCC, 301 patients with chronic hepatitis B or liver cirrhosis (CHB/LC) and 296 healthy controls (HC). Results: The systematic analysis revealed significantly aberrant fragmentomic features of ccf-mtDNA in HCC group when compared with CHB/LC and HC groups. Moreover, we constructed a random forest algorithm-based HCC detection model by utilizing ccf-mtDNA fragmentomic features. Both internal and two external validation cohorts demonstrated the excellent capacity of our model in distinguishing early HCC patients from HC and highrisk population with CHB/LC, with AUC exceeding 0.983 and 0.981, sensitivity over 89.6% and 89.61%, and specificity over 98.20% and 95.00%, respectively, greatly surpassing the performance of alpha-fetoprotein (AFP) and mtDNA copy number. We also developed an HCC prognosis prediction model by LASSO-Cox regression to select 20 fragmentomic features, which exhibited exceptional ability in predicting 1-year, 2-year and 3-year survival (AUC=0.8333, 0.8145 and 0.7958 for validation cohort, respectively). Conclusions We have developed and validated a high-performing and low-cost approach in a large clinical cohort based on aberrant ccf-mtDNA fragmentomic features with promising clinical translational application for the early detection and prognosis prediction of HCC patients.

Background/Aims: Early detection and effective prognosis prediction in patients with hepatocellular carcinoma (HCC) provide an avenue for survival improvement, yet more effective approaches are greatly needed. We sought to develop the detection and prognosis models with ultra-sensitivity and low cost based on fragmentomic features of circulating cell free mtDNA (ccf-mtDNA). Methods: Capture-based mtDNA sequencing was carried out in plasma cell-free DNA samples from 1168 participants, including 571 patients with HCC, 301 patients with chronic hepatitis B or liver cirrhosis (CHB/LC) and 296 healthy controls (HC). Results: The systematic analysis revealed significantly aberrant fragmentomic features of ccf-mtDNA in HCC group when compared with CHB/LC and HC groups. Moreover, we constructed a random forest algorithm-based HCC detection model by utilizing ccf-mtDNA fragmentomic features. Both internal and two external validation cohorts demonstrated the excellent capacity of our model in distinguishing early HCC patients from HC and highrisk population with CHB/LC, with AUC exceeding 0.983 and 0.981, sensitivity over 89.6% and 89.61%, and specificity over 98.20% and 95.00%, respectively, greatly surpassing the performance of alpha-fetoprotein (AFP) and mtDNA copy number. We also developed an HCC prognosis prediction model by LASSO-Cox regression to select 20 fragmentomic features, which exhibited exceptional ability in predicting 1-year, 2-year and 3-year survival (AUC=0.8333, 0.8145 and 0.7958 for validation cohort, respectively). Conclusions We have developed and validated a high-performing and low-cost approach in a large clinical cohort based on aberrant ccf-mtDNA fragmentomic features with promising clinical translational application for the early detection and prognosis prediction of HCC patients.

Tumor biomarkers have multiple characteristics, including noninvasive, repeatable analysis and real-time monitoring, and they have important application value in early diagnosis and prognosis monitoring of hepatocellular carcinoma (HCC). In recent years, the researches on tumor markers of HCC have developed rapidly. There are not only traditional serological tumor markers, such as alpha fetoprotein, des-gamma carboxy prothrombin, Golgi protein 73, glypican-3, etc., but also new emerging "liquid biopsy" tumor markers, such as circulating tumor cells, circulating tumor DNA etc. Further study on the correlation between tumor biomarkers and HCC can provide reference for the treatment and prognosis evaluation of HCC.

Endovascular technology has become the first choice for the treatment of lower extremities arteriosclerotic obliterans. Bioresorbable vascular scaffolds have attracted more and more attention as a choice of endovascular technology. In the last decade, poly(L-lactic acid) bioresorbable scaffolds with or without drug coating have shown acceptable medium and long-term safety and efficacy in lower extremities arteriosclerotic obliterans, but the lesions of the subjects were relatively simple. Magnesium alloy bioresorbable scaffolds are safe but less effective in the treatment of lower extremities arteriosclerotic obliterans. Both iron and zinc alloy bioresorbable scaffolds have shown considerable results in animal experiments. In particular, the success of implantation of drug-coated iron alloy bioresorbable scaffolds in below-the-knee artery indicated that the iron alloy bioresorbable scaffolds have officially entered the clinical trial stage. Through the comprehensive summation of the previous clinical and experimental data of bioresorbable vascular scaffolds and the pathological characteristics of lower extremities arteriosclerotic obliterans, it is shown that the drug-coated poly(L-lactic acid) bioresorbable scaffolds and iron alloy bioresorbable scaffolds will have greater development potential in the treatment of lower extremities arteriosclerotic obliterans.

Endovascular technology has become the first choice for the treatment of lower extremities arteriosclerotic obliterans. Bioresorbable vascular scaffolds have attracted more and more attention as a choice of endovascular technology. In the last decade, poly(L-lactic acid) bioresorbable scaffolds with or without drug coating have shown acceptable medium and long-term safety and efficacy in lower extremities arteriosclerotic obliterans, but the lesions of the subjects were relatively simple. Magnesium alloy bioresorbable scaffolds are safe but less effective in the treatment of lower extremities arteriosclerotic obliterans. Both iron and zinc alloy bioresorbable scaffolds have shown considerable results in animal experiments. In particular, the success of implantation of drug-coated iron alloy bioresorbable scaffolds in below-the-knee artery indicated that the iron alloy bioresorbable scaffolds have officially entered the clinical trial stage. Through the comprehensive summation of the previous clinical and experimental data of bioresorbable vascular scaffolds and the pathological characteristics of lower extremities arteriosclerotic obliterans, it is shown that the drug-coated poly(L-lactic acid) bioresorbable scaffolds and iron alloy bioresorbable scaffolds will have greater development potential in the treatment of lower extremities arteriosclerotic obliterans.

Minimal hepatic encephalopathy (MHE) refers to a state of neuropsychological or neurophysiological abnormality and normal cognitive function in patients with liver cirrhosis, which is commonly seen in patients with liver cirrhosis. Early diagnosis and treatment of MHE can improve the quality of life of patients and reduce accidental deaths. At present, Psychometric Hepatic Encephalopathy Score is mainly used for the diagnosis of MHE, but its operation is complicated and time-consuming and is affected by age and educational level, with unsatisfactory reliability in clinical diagnosis. Serum biomarkers are objective reference indicators with simple and convenient measurement and can easily be promoted in clinical practice. Potential serum biomarkers such as S100β, 3-nitrotyrosine, and arterial blood ammonia have their own advantages and disadvantages in specificity, sensitivity, and diagnostic value. This article reviews the above-mentioned serum biomarkers.

Objective:To investigate the application value of new urinary biomarkers insulin-like growth factor binding protein 7 (IGFBP7) and tissue matrix metalloproteinase inhibitor-2 (TIMP-2) in acute kidney injury with decompensated hepatitis B virus-related liver cirrhosis.Methods:45 newly hospitalized cases with decompensated hepatitis B virus-related liver cirrhosis were selected. Among them, 19 cases were combined with AKI on admission (cirrhosis-AKI group), 26 cases without AKI (cirrhosis-non-AKI group), and 12 healthy cases (normal control group). First-morning urine samples were collected and IGFBP7 and TIMP-2 were detected by enzyme-linked immunosorbent assay (ELISA). Urinary IGFBP7 and serum creatinine (SCr) were dynamically monitored after hospitalization in cirrhosis-non-AKI group. Normally distributed measurement data were compared by t-test, and non-normally distributed measurement data were compared by rank sum test. The receiver operating characteristic (ROC) curve and area under the curve (AUC) were used to evaluate the diagnostic accuracy of the indicators.Results:Urinary IGFBP7, IGFBP7 with TIMP-2 (IGFBP7×TIMP-2) in cirrhosis-AKI group ( n = 19) were equally higher than that of the cirrhosis-non-AKI group ( P < 0.05). Urinary IGFBP7, TIMP-2 and IGFBP7×TIMP-2 in cirrhosis-AKI group or cirrhosis-non-AKI group were significantly higher than those of the normal control group ( P < 0.01). The AUC of urinary IGFBP7 and urinary IGFBP7×TIMP-2 for diagnosis of AKI were 0.703 (95% CI 0.547-0.860) and 0.700 (95% CI 0.541-0.859), respectively. In the liver cirrhosis-non-AKI group ( n = 26), 5 cases of AKI were newly diagnosed according to the changes in SCr during hospitalization (progressive group). Urinary IGFBP7 was significantly increased 2 days before the diagnosis of AKI. The concentration of urinary IGFBP7 at admission in the progressive group ( n = 5) was higher than that of the non-progressive group ( n = 21) ( P < 0.05). Conclusion:Urinary IGFBP7 and TIMP-2 concentrations were significantly increased in patients with decompensated hepatitis B virus-related liver cirrhosis. When AKI occurred, urinary IGFBP7 and IGFBP7×TIMP-2 was further increased. Urinary IGFBP7 is valuable for early AKI diagnosis, and may play a role in predicting AKI occurrence.

Objective: To establish a quantitative assay of serum Golgi protein 73 (GP73) using xMAP technology and evaluate its performance. Methods: Monoclonal antibodies against GP73 were prepared and purified, and antibody pair screening was performed by double-antibody sandwich enzyme-linked immunosorbent assay. The screened antibodies were used to construct a Luminex liquid chip detection system, and the analysis performance of the detection system was evaluated. The serum levels of GP73 were detected in 90 clinical samples from healthy controls and patients with chronic hepatitis B infection (CHB) and hepatocellular carcinoma (HCC). Results: Five anti-GP73 monoclonal antibodies were prepared and purified, and 5 antibody pairs were successfully screened. The Luminex liquid chip detection system of GP73 was successfully constructed using 8F10D1 and 10B9F11 antibody pairs. The analytical performance evaluation showed that the sensitivity of this system was 0.25 ng/ml and the dynamic range was 0.25-100 ng/ml. No cross reactivity was observed. The intra- and inter-assay variation for GP73 was <8% and <11%, respectively. The recovery was 83%-92%. The linear regression equation was y=1.141x+ 6.436 (r²=0.998 4, P<0.001). The GP73 concentrations in the serum samples of healthy control, CHB group, and HCC group were 42.8 (38.68, 55.90) ng/ml, 61.49 (43.59, 81) ng/ml, and 122.78 (49.36 liter, 264.55) ng/ml, respectively. The levels of GP73 in HCC group were significantly higher than those in CHB group and healthy controls (P<0.05). Moreover, the levels of GP73 in CHB group were significantly higher than those in healthy controls (P<0.05). Conclusions A liquid chip detection system of GP73 was successfully constructed. It provides a powerful tool for the clinical application of GP73 in the future.

Objective To investigate the effect of time interval between diagnosis and surgical treatment on the prognosis of breast cancer.Methods A retrospective study that include a total of 252 female patients who underwent breast cancer diagnosis and treatment in the Second Affiliated Hospital of Xi'an Jiaotong University from April 2012 to August 2014 were included in the present study,the average age was (58.2 ± 10.8) years old,range from 31 to 67 years old.General demographic information and data of tumor were collected.Information on postoperative recurrence,metastasis,death,and disease-free survival status of breast cancer patients were followed up 5 years by outpatient follow-up or telephone follow-up.All participants were divided into four groups (＜2 weeks,2-4 weeks,4-8 weeks,≥8 weeks) by the time interval between diagnosis and surgical treatment,including 26,118,78 and 30 cases,respectively.In addition,according to the diameter of breast cancer tumors,all participants were divided into three groups (＜20 mm,20-40 mm,and ≥40 mm),including 99,124,and 29 cases,respectively.According to the results of pathological examination of the lymph nodes obtained during intraoperative dissection,the all participants were divided into three groups (lymph nodes without metastasis,1 to 3 metastasis,and ≥3 metastasis),including 66,124,and 62 cases,respectively.The Cox proportional regression risk models were used to assess the hazard ratio (HR) and its 95％ confidence interval (CI) of time interval between diagnosis and surgical treatment with the prognosis of breast cancer,with adjustment for age,education levels and body mass index.Further,stratified analysis by tumor characteristics,including pathological type,histological grade,tumor diameter,lymph node metastasis,and receptor expression were also conducted to evaluated the above association.Kaplan-Meier survival curve was used to evaluate the effects of time interval between diagnosis and surgical treatment on the prognosis of breast cancer.Results The Kaplan-Meier survival curves for the five-year follow-up of total survival time between 4 different time intervals groups showed significantly different (P ＜0.001),and patients with a pre-treatment interval of ＜2 weeks had the longest survival time,while those with ≥8 weeks had the lowest survival time.With a one-week interval before treatment,the overall risk of death in breast cancer patients increased by 6％ (HR =1.06,95％ CI:1.01-1.1 l),and the risk of breast cancer death increased by 8％ (HR =1.08,95％ CI:1.02-1.14),the risk of distant metastasis of breast cancer cells increased by 10％ (HR =1.10,95％ CI:1.08-1.13).With the increase in breast cancer tumor diameter (＜20 mm,20-40 mm,≥40 mm),the overall risk of death due to prolonged treatment interval increased gradually,with HR (95％CI) were 1.06 (1.03-1.09),1.08 (1.02-1.12) and 1.11 (1.05-1.17),respectively.With the increase of lymph node metastasis in breast cancer (no metastasis,metastasis at 1-3,≥ 3 metastasis),the total mortality risk caused by prolonged treatment time interval also showed an increasing trend,with HR (95％CI) were 1.04 (1.02-1.08),1.06 (1.04-1.08) and 1.08 (0.99-1.11),respectively.The same results were also shown in the effect of tumor diameter or distant lymph node metastasis on the association between treatment time interval and breast cancer survival and distant metastasis of breast cancer cells.Conclusion With the prolongation of the time interval between the diagnosis of the breast cancer and the surgical treatment of breast cancer patients,the risk of postoperative death is significantly increased,and the association is more pronounced in breast cancer patients with larger tumor volume or higher distant lymph node metastasis.