A novel biodegradable polymer-coated sirolimus-eluting stent: 1-year results of the HELIOS registry.

BACKGROUND: The HELIOS stent is a sirolimus-eluting stent with a biodegradable polymer and titanium oxide film as the tie-layer. The study aimed to evaluate the safety and efficacy of HELIOS stent in a real-world setting. METHODS: The HELIOS registry is a prospective, multicenter, cohort study conducted at 38 centers across China between November 2018 and December 2019. A total of 3060 consecutive patients were enrolled after application of minimal inclusion and exclusion criteria. The primary endpoint was target lesion failure (TLF), defined as a composite of cardiac death, non-fatal target vessel myocardial infarction (MI), and clinically indicated target lesion revascularization (TLR) at 1-year follow-up. Kaplan-Meier methods were used to estimate the cumulative incidence of clinical events and construct survival curves. RESULTS: A total of 2998 (98.0%) patients completed the 1-year follow-up. The 1-year incidence of TLF was 3.10% (94/2998, 95% closed interval: 2.54-3.78%). The rates of cardiac death, non-fatal target vessel MI and clinically indicated TLR were 2.33% (70/2998), 0.20% (6/2998), and 0.70% (21/2998), respectively. The rate of stent thrombosis was 0.33% (10/2998). Age ≥60 years, diabetes mellitus, family history of coronary artery disease, acute myocardial infarction at admission, and device success were independent predictors of TLF at 1 year. CONCLUSION: The 1-year incidence rates of TLF and stent thrombosis were 3.10% and 0.33%, respectively, in patients treated with HELIOS stents. Our results provide clinical evidence for interventional cardiologists and policymakers to evaluate HELIOS stent. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03916432.

HS6ST1 overexpressed in cancer-associated fibroblast and inhibited cholangiocarcinoma progression.

BACKGROUD: Fibroblasts turn into cancer associated fibroblasts (CAFs) in the tumor microenvironment, which play an important role in tumor progression. However, the mechanism is unclear. AIMS: To investigate the role of CAFs with HS6ST1-overexpression in cell migration and invasion effects. METHODS: Human primary CAFs were isolated and identified from intrahepatic cholangiocarcinoma. mRNA profiles differences between CAFs and NFs were examined by using transcriptome sequencing. Using Transwell® migration assays, ICCA cells (RBE and HUCCT1) with NF-CM, CAF-CM, CAFsNC-CM, and CAFsHS6ST1-CM were analyzed. Immunohistochemical staining were used to analyze the expression of HS6ST1 in CAF in 152 patients with ICCA. Overall survival (OS) was compared based on CAF HS6ST1 expression were analysed. The relationship between clinicopathological parameters and survival was also examined. RESULTS: Successfully isolated CAFs is positive staining with αSMA, FSP-1, FAP, and PDGFR-ß. Transcriptome sequencing showed that differently expressed genes were enriched in the function of the extracellular matrix and chemokine signaling pathway. HS6ST1 is differentially expressed between CAFs and NFs, and associated with the migration and invasion of ICCA cells. Moreover, HS6ST1 positive expression of CAFs predicted unfavorable prognosis in patients with intrahepatic cholangiocarcinoma and showed correlation with the presence of lymph node metastasis. CONCLUSION: HS6ST1 is new possibilities for targeting the CAFs to reduce cholangiocarcinoma growth and metastasis.

Differential enrichment of H3K9me3 in intrahepatic cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a malignant tumor, which poses a serious threat to human health. Histone 3 lysine 9 trimethylation (H3K9me3) is a post-translational modification involved in regulating a broad range of biological processes and has been considered as potential therapeutic target in types of cancer. However, there is limited research on investigating profiles of histone modification H3K9me3 in ICC patients. METHODS: In this study, we applied the ChIP-seq technique to investigate the effect of H3K9me3 on ICC. Anti-H3K9me3 antibody was used for ChIP-seq in ICC (RBE cell lines) and HIBEpic (normal cell lines). MACS2 (peak-calling tools) was then used to identify the peaks recorded in RBE and HIBEpic cell lines. Gene expression, mutation and clinical data were downloaded from TCGA and cBioPortal databases. RESULTS: H3K9me3 exhibited abnormal methylation and influenced the process of abnormal gene expression in patients suffering from ICC. The Wnt/ß-Catenin signaling pathway (also known as simply the WNT signaling pathway) was enriched in H3K9me3-regulated genes. CONCLUSIONS: We are the first to report that H3K9me3 may play an important role in the progression of ICC. It promotes the understanding of epigenetic molecular mechanisms for ICC.

Local application of triamcinolone acetonide-conjugated chitosan membrane to prevent benign biliary stricture.

Benign biliary stricture (BBS) is the proliferation of fibrous tissue of the biliary tract caused by the biliary operation, bile duct stones, cholangitis, trauma, and other etiologies due to scar contracture. Recent therapeutic strategies to suppress stenosis are insufficient. Here, we developed a sustained-release membrane (SM) of triamcinolone acetonide (TA) with N-succinyl hydroxypropyl chitosan (TASM) for inhibiting fibroblast proliferation in vitro and bile duct hyperplasia in the rabbit model for benign biliary stricture formation. The TASM were successfully placed in 45 of 50 rabbits. Evaluation of subcutaneous stimulation and acute liver injury confirms the safety of TASM in vivo. Compared to the control group, the TASM can significantly inhibit the proliferation of scar muscle fibroblasts in vitro. ELISA and immunofluorescence showed TASM could increase bFGF level and inhibit expression of TGFß1 and αSMA. Cholangiographic and histologic examinations demonstrated significantly decreased tissue hyperplasia in the TASM groups compared with the model group. The immunohistochemical staining showed that TASM could reduce the level of cytokine-induced scars and inhibit the proliferation of myofibroblasts. Taken together, the chitosan membrane chemically conjugated with TA can effectively inhibit the benign biliary stricture. Further clinical usage of this membrane may effectively reduce the occurrence of benign biliary stricture.

Comparison of intravascular ultrasound-guided with angiography-guided double kissing crush stenting for patients with complex coronary bifurcation lesions: Rationale and design of a prospective, randomized, and multicenter DKCRUSH VIII trial.

BACKGROUND: Double kissing (DK) crush approach for patients with coronary bifurcation lesions, particularly localized at distal left main or lesions with increased complexity, is associated with significant reduction in clinical events when compared with provisional stenting. Recently, randomized clinical trial has demonstrated the net clinical benefits by intravascular ultrasound (IVUS)-guided implantation of drug-eluting stent in all-comers. However, the improvement in clinical outcome after DK crush treatment guided by IVUS over angiography guidance for patients with complex bifurcation lesions have never been studied in a randomized fashion. TRIAL DESIGN: DKCRUSH VIII study is a prospective, multicenter, randomized controlled trial designed to assess superiority of IVUS-guided vs angiography-guided DK crush stenting in patients with complex bifurcation lesions according to DEFINITION criteria. A total of 556 patients with complex bifurcation lesions will be randomly (1:1 of ratio) assigned to IVUS-guided or angiography-guided DK crush stenting group. The primary end point is the rate of 12-month target vessel failure, including cardiac death, target vessel myocardial infarction, or clinically driven target vessel revascularization. The secondary end points consist of the individual component of primary end point, all-cause death, myocardial infarction, and in-stent restenosis. The safety end point is the incidence of definite or probable stent thrombosis. An angiographic follow-up will be performed for all patients at 13 months and clinical follow-up will be continued annually until 3 years after the index procedure. CONCLUSIONS: DKCRUSH VIII trial is the first study designed to evaluate the differences in efficacy and safety between IVUS-guided and angiography-guided DK crush stenting in patients with complex true bifurcation lesions. This study will also provide IVUS-derived criteria to define optimal DK crush stenting for bifurcation lesions at higher complexity.

Prognostic significance of the neutrophil-to-lymphocyte ratio with distal cholangiocarcinoma patients.

BACKGROUND: The present study aimed to investigate the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) in distal cholangiocarcinoma (DCC) following radical surgery. METHODS: The clinicopathological data of 59 patients with DCC were retrospectively reviewed. Patients were treated by radical surgery and diagnosed by postoperative pathology at the Second Affiliated Hospital of Kunming Medical University (Yunnan, China), between July 2015 and December 2017. The optimal cut-off value for the NLR was determined by generating receiver operating characteristic (ROC) curves. Kaplan-Meier survival analysis and Cox proportional hazards models were used to determine the risk factors and independent risk factors influencing the prognosis of patients with DCC. RESULTS: According to the ROC curve, the optimal cut-off value for the NLR was 2.933. The results of Kaplan-Meier survival analysis and the Cox proportional hazards model showed that carbohydrate antigen 125, NLR, perineural, vascular and fat invasion, regional lymph node metastasis, and the American Joint Committee on Cancer stage were risk factors for DCC; the only independent risk factor to affect the prognosis of DCC patients was the NLR. CONCLUSIONS: The preoperative NLR plays an important guiding role in evaluating the prognosis of patients with DCC, and an increase in the NLR is associated with poor patient prognosis.

A meta-analysis of adoptive immunotherapy in postoperative hepatocellular carcinoma.

BACKGROUND: Adoptive immunotherapy (AIT) has been adopted as an adjuvant treatment for hepatocellular carcinoma (HCC) patients after curative therapy. However, the outcomes of AIT remain controversial. PURPOSE: The purpose of this study is to analyze the safety and efficacy of AIT with the recurrence rate and mortality. MATERIALS AND METHODS: We identified eight randomized controlled trials (RCTs) that adopted AIT to HCC after curative treatments. A meta-analysis was carried out to assess the recurrence rate and mortality. RESULTS: Eight RCTs with 964 patients were included in the study. The overall analysis showed that AIT treatment can not only decrease the 1-year (risk ratio [RR] =0.59, 95% confidence interval [95% CI] = 0.48-0.72, P < 0.00001), 2-year (RR = 0.69, 95% CI = 0.60-0.79, P < 0.00001), and 3-year (RR = 0.82, 95% CI = 0.74-091, P = 0.0001) recurrence, but also decrease the 1-year (RR = 0.43, 95% CI = 0.30-0.62, P = 0.00001), 2-year (RR = 0.56, 95% CI = 0.46-0.74, P < 0.00001), and 3-year (RR = 0.85, 95% CI = 0.73-0.99, P = 0.03) mortality. The results also indicate that the group of lymphokine-activated killer (LAK) cells showed lower pooled RR values compared to the group of cytokine-induced killer cells among every subgroups. However, the AIT treatment failed to affect the 5-year recurrence rate and mortality (P > 0.05). CONCLUSIONS: This review provides available evidences that AIT, especially the treatment of LAK, can be used to decrease the early recurrence and mortality of postoperative HCC but may not the long term.

Role of the overexpression of TRAF4 in predicting the prognosis of intrahepatic cholangiocarcinoma.

The incidence of intrahepatic cholangiocarcinoma (ICC) is progressively increasing worldwide, and its prognosis remains poor. Accumulating evidence has demonstrated that tumor necrosis factor receptor-associated factor 4 (TRAF4), an adaptor protein, is involved in the carcinogenesis and progression of several tumor types. However, the function of TRAF4 in predicting prognosis, and mediating migration and invasion of ICC remains to be elucidated. In the present study, immunohistochemistry, western blotting and reverse transcription-quantitative polymerase chain reaction assays were used to determine that the expression of TRAF4 at the mRNA and protein levels in ICC tissues was significantly higher compared with that in non­tumor tissues. The overexpression of TRAF4 was positively correlated with poor differentiation, regional lymphatic metastasis, and high tumor­node-metastasis staging. Inhibiting the expression of TRAF4 using small interfering RNA decreased the migration and invasion of ICC cells in vitro. In addition, the AKT inhibitor perifosine eliminated the effect of TRAF4 on the invasion and migration of ICC cells in vitro. Clinically, the overexpression of TRAF4 was correlated with shorter overall survival rate and elevated recurrence rate in patients with ICC. Furthermore, patients with ICC with a high expression of TRAF4 and lymphatic metastasis were closely associated with a poorer prognosis compared with the other groups. Multivariate analysis indicated that the overexpression of TRAF4 was an independent prognostic indicator for patients with ICC. It was identified that a high level of TRAF4 facilitated the invasiveness of ICC cells via the activation of AKT signaling. The overexpression of TRAF4 may be a prognostic biomarker and candidate therapeutic target for patients with ICC.

Characterization and prognostic significance of mortalin, Bcl-2 and Bax in intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is an aggressive type of cancer, and its incidence and mortality rates are increasing worldwide. Mortalin is a highly conserved chaperone protein involved in multiple pathological and physiological processes, including anti-apoptosis, carcinogenesis and metastasis. The Bcl-2 family of proteins can be divided into pro-survival and pro-apoptotic members, including B-cell lymphoma 2 (Bcl-2) and Bcl-2-like protein 4 (Bax). The aim of the present study was to investigate the association between mortalin, Bcl-2 and Bax, as well as the prognostic significance of the combined expression of mortalin, Bcl-2 and Bax in ICC. Immunohistochemistry was used to determine the expression of mortalin, Bcl-2 and Bax in 116 ICC samples and to assess the association between expression of 3 markers and clinicopathological features of ICC patients. This revealed that ICC tumor tissues overexpressed mortalin and Bcl-2 and exhibited low expression of Bax in ICC tumor tissues compared with that in corresponding peritumoral samples. According to Pearson's correlation coefficient analysis, high expression of mortalin in ICC was positively correlated with Bcl-2 expression and negatively correlated with Bax expression. Furthermore, multiple linear regression analysis demonstrated that mortalin was positively associated with Bcl-2, but not with Bax, in patients with ICC. Patients with ICC exhibiting high expression of mortalin/Bcl-2 or low expression of Bax were closely associated with a malignant ICC phenotype, a relatively low overall survival rate and a high recurrence rate. Multivariate analysis indicated that mortalin and Bcl-2 were independent prognostic indicators for ICC patients. Meanwhile, the concomitant overexpression of mortalin and Bcl-2 and the low expression of Bax were independent markers for predicting a relatively poor prognosis of ICC. The overexpression of mortalin and Bcl-2 and/or the low expression of Bax are implicated in the anti-apoptotic effect and tumor progression of ICC. Mortalin or Bcl-2, or a combination of mortalin, Bcl-2 and Bax may be used to predict the prognosis of ICC, as well as potential therapeutic targets.

Water regime-nitrogen fertilizer incorporation interaction: Field study on methane and nitrous oxide emissions from a rice agroecosystem in Harbin, China.

Water regime and nitrogen (N) fertilizer are two important factors impacting greenhouse gases (GHG) emission from paddy field, whereas their effects have not been well studied in cold region. In this study, we conducted a two-year field experiment to study the impacts of water regime and N fertilizer on rice yields and GHG emissions in Harbin, China, a cold region located in high latitudes. Our results showed that intermittent irrigation significantly decreased methane (CH4) emission compared with continuous flooding, however, the decrement was far lower than the global average level. The N2O emissions were very small when flooded but peaked at the beginning of the disappearance of floodwater. The N fertilizer treatments increased CH4 emissions at low level (75kgN/ha). But both CH4 and N2O emissions were uninfluenced at the levels of 150kgN/ha and 225kgN/ha. Rice yields increased under intermittent irrigation and were highest at the level of 150kgN/ha. From our results, we recommended that the intermittent irrigation and 150kgN/ha as the ideal water regime-nitrogen fertilizer incorporation for this area to achieve low GHG emissions without impacting rice yields.

Leptin promotes proliferation and metastasis of human gallbladder cancer through OB-Rb leptin receptor.

Emerging evidence has shown that leptin, an adipocyte-derived cytokine that is closely associated with obesity, play a significant role in carcinogenesis and tumorigenesis. However, its impact on gallbladder cancer (GBC) remains unclear. In this study, we firstly found that leptin and its functional receptor OB-Rb were significantly co-expressed in human GBC tissues and cell lines, the content of which were higher than those in normal human gallbladder tissues. Treatment with leptin promoted the proliferation, migration and invasion of GBC cells, which were attenuated by OB-Rb shRNA. Blocking in the G2/M period of cell cycle, increasing of MMP3 and MMP9, increasing of VEGF-C/D, activation of SOCS3/JAK2/p-STAT3 pathway was demonstrated after treatment with leptin. All of these positive responses were attenuated by OB-Rb receptor shRNA. Taken together, our findings suggest that leptin promoted the proliferation, migration and invasion of GBC cells by increasing OB-Rb expression through the SOCS3/JAK2/p-STAT3 signal pathway. Targeting the leptin/OB-Rb axis could be an attractive therapeutic strategy for treatment of GBC.

[Changes of rice yield and quality in different accumulated temperature zones in Heilongjiang Province of Northeast China].

Field experiments were installed in different accumulated temperature zones in Heilongjiang Province to study the changes of the grain yield and quality of five major rice varieties with accumulated temperature. The rice yield changed with accumulated temperature in quadratic curve, and the correlation degree differed with the varieties. The panicle number and the grain number per panicle changed significantly in quadratic curve with accumulated temperature, while the 1000-grain mass had less correlation with accumulated temperature. The sterile spikelet rate of grain increased obviously from suitable accumulated temperature zone to low accumulated temperature zone, but had no obvious change from suitable accumulated temperature zone to high accumulated temperature zone. The rates of chalky and head milled rice also changed with accumulated temperature in quadratic curve, i. e., there were both the lowest and the highest values in suitable accumulated temperature zone. The protein and amylose contents of the grain as well as the taste varied little with accumulated temperature. According to the sensitivity to temperature, the test rice varieties were divided into sensitive, medium, and blunt types, with the optimal and allowable cultivation accumulated temperature limits being 300 degrees C and 420 degrees C, 360 degrees C and 440 degrees C, and 380 degrees C and 520 degrees C, respectively. It would be very important to select the rice varieties with higher yield and better quality according to the local conditions, especially the accumulated temperature.

[Relationships between rice empty grain rate and low temperature at booting stage in Heilongjiang Province].

Six major rice varieties (Longdao 3, Kendao 12, Kongyu 131, Longdao 7, Longjing 16, and Songjing 6) in Heilongjiang Province were treated with low temperature 15 degrees C, 17 degrees C, and 19 degrees C for 2, 4, 6 and 8 days at booting stage, and the relationships between their empty grain rate per panicle and low temperature at booting stage were analyzed by using linear interpolation and linear regression methods. In the province, the critical temperature of sterile-type cool injury was 17 degrees C for sensitive varieties, and 16 degrees C for resistant varieties. The most sensitive period of rice to low temperature was 14-18 days before heading. At 15 degrees C for 8 days, the empty grain rate of Songjing 6 and Kendao 12 increased significantly, while that of Kongyu 131 increased less, suggesting that the cold tolerance of Songjing 6 and Kendao 12 was relatively weak, while Kongyu 131 was insensitive to low temperature. There was a significant correlation between the accumulated cool temperature and the empty grain rate of Kendao 12, Longjing 16, and Kongyu 131 (P<0.01). With the increase of accumulated cool temperature, the rice empty grain rate increased significantly, but the increment varied with rice variety.