Apolipoprotein A-1 protected hepatic ischaemia-reperfusion injury through suppressing macrophage pyroptosis via TLR4-NF-κB pathway.

BACKGROUND AND AIMS: Apolipoprotein A-1 (ApoA-1), the major apolipoprotein of high-density lipoprotein, plays anti-atherogenic role in cardiovascular diseases and exerts anti-inflammation effect in various inflammatory and infectious diseases. However, the role and mechanism of ApoA-1 in hepatic ischaemia-reperfusion (I/R) injury is unknown. METHODS: In this study, we measured ApoA-1 expression in human liver grafts after transplantation. Mice partial hepatic I/R injury model was made in ApoA-1 knockout mice, ApoA-1 mimetic peptide D-4F treatment mice and corresponding control mice to examine the effect of ApoA-1 on liver damage, inflammation response and cell death. Primary hepatocytes and macrophages were isolated for in vitro study. RESULTS: The results showed that ApoA-1 expression was down-regulated in human liver grafts after transplantation and mice livers subjected to hepatic I/R injury. ApoA-1 deficiency aggravated liver damage and inflammation response induced by hepatic I/R injury. Interestingly, we found that ApoA-1 deficiency increased pyroptosis instead of apoptosis during acute phase of hepatic I/R injury, which mainly occurred in macrophages rather than hepatocytes. The inhibition of pyroptosis compensated for the adverse impact of ApoA-1 deficiency. Furthermore, the up-regulated pyroptosis process was testified to be mediated by ApoA-1 through TLR4-NF-κB pathway and TLR4 inhibition significantly improved hepatic I/R injury. In addition, we confirmed that D-4F ameliorated hepatic I/R injury. CONCLUSIONS: Our study has identified the protective role of ApoA-1 in hepatic I/R injury through inhibiting pyroptosis in macrophages via TLR4-NF-κB pathway. The effect of ApoA-1 may provide a novel therapeutic approach for hepatic I/R injury.

Surgical Strategies for the Treatment of Bismuth Type I and II Hilar Cholangiocarcinoma: Bile Duct Resection with or Without Hepatectomy?

BACKGROUND: The role of hepatic resection in the treatment of type I and II hilar cholangiocarcinoma (HCCA) remains controversial. In the present study, we aimed to identify whether hepatic resection was necessary for type I and II HCCA. METHODS: A total of 23 patients classified as type I and II HCCA undergoing surgical resection were included in this study. The patients were divided into two groups: bile duct resection (BDR) group (n = 15) and hepatic resection (HR) group (n = 8). Systematic review and meta-analysis were performed to compare the R0 resection and long-term survival between BDR and HR for Bismuth type I and II HCCA. A total of 7 studies with 260 cases were included in this meta-analysis. RESULTS: In our cohort, the R0 resection rate was 73.3% in BDR group and 87.5% in HR group. The HR group had a higher number of postoperative complications than the BDR group (P = 0.002). There was no difference in long-term survival (P = 0.544) and recurrence (P = 0.846) between BDR and HR in Bismuth type I and II HCCA. The meta-analysis showed that HR was associated with better R0 resection rate (RR 4.45, 95% CI 2.34-8.48) and overall survival (HR 2.15, 95% CI 1.34-3.44) compared with BDR group. There was no publication bias and undue influence of any single study. CONCLUSIONS: The meta-analysis showed that HR was associated with better R0 resection rate and overall survival compared with BDR for type I and II HCCA patients. More aggressive surgical strategies should be increasingly considered for the treatment of type I and II HCCA patients.

NLRP3 inflammasome induced liver graft injury through activation of telomere-independent RAP1/KC axis.

Acute-phase inflammation plays a critical role in liver graft injury. Inflammasomes, multi-molecular complexes in the cytoplasm, are responsible for initiating inflammation. Here, we aimed to explore the role of inflammasomes in liver graft injury and further to investigate the regulatory mechanism. In a clinical liver transplant cohort, we found that intragraft expression of nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasomes was significantly up-regulated post-transplantation. Importantly, overexpression of NLRP3 was strongly associated with poor liver function characterized by high levels of ALT, AST, and urea, as well as neutrophil infiltration after transplantation. The significant correlation between NLRP3 and IL-1ß mRNA levels led us to focus on one of the associated upstream regulators, telomere-independent repressor activator protein 1 (RAP1), which was further proved to be co-localized with NLRP3 in neutrophils. In the liver of a mouse model (hepatic ischaemia/reperfusion and hepatectomy model) and isolated neutrophils from RAP1-/- mice, the expression levels of NLRP3 and keratinocyte chemoattractant (KC) were significantly down-regulated in contrast to those in wild types. The levels of ALT and AST, as well as the neutrophil infiltration, were also decreased by RAP1 deficiency. In our clinical validation, intragraft KC expression was associated with NLRP3 and co-localized with RAP1 in neutrophils. Furthermore, NLRP3 inflammasomes were up-regulated by recombinant KC in the isolated neutrophils and liver of the mouse model. Our data demonstrated that NLRP3 inflammasomes, activated by the RAP1/KC axis, played a critical role in initiating inflammation during the early stage of liver graft injury. Targeting RAP1/KC/NLRP3 inflammasomes may offer a new therapeutic strategy against liver graft injury. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

CXCL10/CXCR3 signaling mobilized-regulatory T cells promote liver tumor recurrence after transplantation.

BACKGROUND & AIMS: Liver graft injury and tumor recurrence are the major challenges of liver transplantation for the patients with hepatocellular carcinoma (HCC). Here, we aimed to explore the role and mechanism of liver graft injury mobilizing regulatory T cells (Tregs), which lead to late phase tumor recurrence after liver transplantation. METHODS: The correlation among tumor recurrence, liver graft injury and Tregs mobilization were studied in 257 liver transplant recipients with HCC and orthotopic rat liver transplantation models. The direct roles of CXCL10/CXCR3 signaling on Tregs mobilization and tumor recurrence were investigated in CXCL10-/- and CXCR3-/- mice models with hepatic IR injury. RESULTS: Clinically, patients received the graft with graft weight ratio (GWR) <60% had higher HCC recurrence after liver transplantation than the recipients with GWR ⩾60% graft. More circulating Tregs and higher intragraft TLR4/CXCL10/CXCR3 levels were detected in recipients with GWR <60% graft. These results were further validated in rat transplantation model. Foxp3+ cells and expressions of TLR4, CXCL10, TGFß, CTLA-4 and CD274 were increased in rat liver tumor tissues from small-for-size graft group. In mouse model, the mobilization and recruitment of Tregs were decreased in TLR4-/-, CXCL10-/- and CXCR3-/- mice compared to wild-type mice. Moreover, less CXCR3+ Tregs were recruited into liver in CXCL10-/- mice after hepatic IR injury. The knockout of CXCL10 and depletion of Tregs inhibited tumor recurrence after hepatic IR injury. CONCLUSION: CXCL10/CXCR3 signaling upregulated at liver graft injury directly induced the mobilization and intragraft recruitment of Tregs, which further promoted HCC recurrence after transplantation. LAY SUMMARY: There were positive correlation among tumor recurrence, circulating Tregs and liver graft injury after human transplantation for HCC patients. The knockout of CXCL10 decreased hepatic recruitment of CXCR3+ Tregs and late phase tumor recurrence after hepatic IR injury.

Alternatively activated (M2) macrophages promote tumour growth and invasiveness in hepatocellular carcinoma.

BACKGROUND & AIMS: The roles of alternatively activated (M2) macrophages on pro-tumour phenotypes have been well documented in many cancers except hepatocellular carcinoma (HCC). Considering their close relationship with chronic tissue injuries as well as enhanced tumour invasiveness and growth, we aimed to investigate the direct effects of M2 macrophages on HCC. METHODS: M2 macrophages in 95 HCC clinical specimens were quantified using immunohistochemistry and quantitative PCR. The pro-tumour functions and the underlying molecular mechanisms of M2 macrophages in HCC were investigated in vivo and in an in vitro co-culture system. RESULTS: In the clinical study, high M2-specific CD163 (hazard ratio=2.693; p=0.043) and scavenger receptor A (hazard ratio=3.563; p=0.044) levels indicated poor prognosis and correlated with increased tumour nodules and venous infiltration in HCC patients. In an orthotopic model, the liver tumour volume was increased 3.26-fold (1.27 cm3±0.36) after M2 macrophage injection compared with the control (0.39 cm3±0.05) (p=0.032). An increased rate of lung metastasis was also found in the treatment group. In vitro, co-cultivation with M2 macrophages elevated the number of HCC cells (MHCC97L) and migration events by 1.3-fold and 3.2-fold, respectively (p<0.05). Strongly induced by MHCC97L, M2 macrophage-derived CCL22 was proven to enhance tumour migration capacities and correlate with venous infiltration in HCC patients. Increased epithelial-mesenchymal transition (EMT) via Snail activation in MHCC97L was found to be promoted by M2 macrophages and CCL22. CONCLUSIONS: M2 macrophages contribute to poor prognosis in HCC and promote tumour invasiveness through CCL22-induced EMT.

Post-transplant endothelial progenitor cell mobilization via CXCL10/CXCR3 signaling promotes liver tumor growth.

BACKGROUND & AIMS: Patients with hepatocellular carcinoma (HCC) receiving living donor liver transplantation appear to possess significantly higher tumor recurrence than the recipients receiving deceased donor liver transplantation. The underlying mechanism for HCC recurrence after transplantation remains unclear. Here, we aim to investigate the impact of small-for-size liver graft injury on HCC recurrence after transplantation. METHODS: The correlation between tumor recurrence, liver graft injury, CXCL10 expression and endothelial progenitor cell (EPC) mobilization was studied in 115 liver transplant recipients and rat orthotopic liver transplantation (OLT) models. The direct role of CXCL10/CXCR3 signaling on EPC mobilization was investigated in CXCL10(-/-) mice and CXCR3(-/-) mice. The role of EPCs on tumor growth and angiogenesis was further investigated in an orthotopic liver tumor model. RESULTS: Clinically, patients with small-for-size liver grafts (<60% of standard liver weight, SLW) had significantly higher HCC recurrence (p=0.04), accompanied by more circulating EPCs and higher early-phase intragraft and plasma CXCL10 levels, than the recipients with large grafts (≥60% of SLW), which were further validated in rat OLT models. Circulatory EPC mobilization was reduced after liver injury both in CXCL10(-/-) mice and CXCR3(-/-) mice in comparison to wild-type controls. CXCL10 recruited EPCs in dose-dependent and CXCR3-dependent manners in vitro. Early-phase EPC/CXCL10 injection enhanced orthotopic liver tumor growth, angiogenesis and metastasis in nude mice. CONCLUSIONS: Post-transplant enhanced CXCL10/CXCR3 signaling in small-for-size liver grafts directly induced EPC mobilization, differentiation and neovessel formation, which further promotes tumor growth. Targeting CXCL10/CXCR3 signaling may attenuate early-phase liver graft injury and prevent late-phase tumor recurrence/metastasis after transplantation.

The roles of lipocalin-2 in small-for-size fatty liver graft injury.

OBJECTIVE: To investigate the roles and underlying mechanism of an inflammatory mediator-lipocalin-2 (Lcn2) in small-for-size fatty graft liver injury. BACKGROUND: Understanding of the distinct mechanism regulating small-for-size fatty liver graft injury will be crucial to prevent marginal graft failure during living donor liver transplantation (LDLT). METHODS: The roles of Lcn2 in small fatty graft injury were investigated in orthotopic liver transplantation model rats, human LDLT samples, an in vitro simulated ischemia-reperfusion (IR) model, and a hepatic ischemic reperfusion plus major hepatectomy (IR + H) model in mice. RESULTS: Our result showed that Lcn2 was significantly upregulated together with elevation of chemokine (C-X-C motif) ligand 10 (CXCL10) and activation/infiltration of intragraft macrophages after liver transplantation using small-for-size fatty liver graft compared with that of using small-for-size normal liver graft. Intragraft and plasma levels of Lcn2 were intensified in patients who underwent transplantation with small-for-size fatty graft after LDLT. Lcn2 and CXCL10 were expressed higher in fatty hepatocytes after the simulated IR injury compared with normal hepatocytes. Overexpression of Lcn2 significantly deteriorated IR + H-induced hepatic injury in correlation with upregulation of CXCL10 and augmentation of infiltrated macrophages. On the contrary, hepatic injury of small fatty liver remnant after IR + H operation was attenuated in the Lcn-2 mice because of suppression of CXCL10 expression and diminishment of macrophage infiltration. CONCLUSIONS: Lcn2 is an important regulator in small-for-size fatty liver graft injury and targeting Lcn2 may be feasible for preventing marginal graft failure in LDLT.

The inhibition of aldose reductase attenuates hepatic ischemia-reperfusion injury through reducing inflammatory response.

OBJECTIVE: We aim to investigate the role of aldose reductase (AR) in hepatic ischemia-reperfusion injury (IRI) of normal and fatty livers and to explore the underlying mechanisms. BACKGROUND: Hepatic IRI is a typical inflammatory response during liver surgery. It contributes to liver graft failure or nonfunction after transplantation. Increasing evidence implicates that AR plays a key role in a number of inflammatory diseases. However, the role of AR in hepatic IRI is still unknown. METHODS: Intragraft AR expression profile and the association with liver graft injury were investigated in both human and rat liver transplantation using normal or fatty graft. The direct role of AR in hepatic IRI was studied in the AR knockout mice IRI model with or without fatty liver. They were further validated by the simulated IRI in vitro model using fatty LO2 cells with or without AR inhibitor zopolrestat and primary peritoneal macrophages isolated from AR knockout and wild-type mice. Gene expression of inflammatory cytokines/chemokines, the infiltration of macrophages/neutrophils, and NF-κB pathway activation were compared among different groups. RESULTS: AR was overexpressed in liver graft after human and rat liver transplantation and correlated with consequent liver injuries. The knockout of AR significantly attenuated hepatic sinusoidal damage and apoptosis in both normal and fatty livers after IRI. The expression of proinflammatory cytokines/chemokines and neutrophil chemoattractants, infiltration of macrophage and neutrophil, and activation of inflammation-associated NF-κB and JNK pathway were downregulated in AR knockout mice. Furthermore, the inhibition of AR effectively suppressed macrophage migration and decreased lipopolysaccharide (LPS)-induced production of proinflammatory cytokines/chemokines in isolated macrophages. CONCLUSIONS: The deficiency of AR attenuated hepatic IRI in both normal and fatty livers by reducing liver inflammatory responses.

A novel oxygen carrier "YQ23" suppresses the liver tumor metastasis by decreasing circulating endothelial progenitor cells and regulatory T cells.

BACKGROUND: Surgical therapies are the first-line treatments for hepatocellular carcinoma (HCC) patients. However, the high incidence of tumor metastasis after liver surgery remains a severe problem. We aim to investigate the roles and the underlying mechanism of YQ23, stabilized non-polymeric diaspirin cross-linked tetrameric hemoglobin, in liver tumor metastasis after major hepatectomy and partial hepatic ischemia reperfusion (I/R) injury. METHODS: An orthotopic liver tumor model in Buffalo rat was established using the hepatocellular carcinoma cell line McA-RH7777. Major hepatectomy for tumor-bearing lobe and partial hepatic I/R injury were performed at two weeks after orthotopic liver tumor implantation. YQ23 (0.2 g/kg) was administered at 1 hour before ischemia and immediately after reperfusion. Blood samples were collected at day 0, 1, 7, 14, 21 and 28 for detection of circulating endothelial progenitor cells (EPCs) and regulatory T cells (Tregs). RESULTS: Our results showed that YQ23 treatment effectively inhibited intrahepatic and lung metastases together with less tumor angiogenesis at 4 weeks after major hepatectomy and partial hepatic I/R injury. The levels of circulating EPCs and Tregs were significantly decreased in YQ23 treatment group. Furthermore, YQ23 treatment also increased liver tissue oxygenation during hepatic I/R injury. Up-regulation of HO1 and down-regulation of CXCR3, TNF-α and IL6 were detected after YQ23 treatment. CONCLUSIONS: YQ23 treatment suppressed liver tumor metastasis after major hepatectomy and partial hepatic I/R injury in a rat liver tumor model through increasing liver oxygen and reducing the populations of circulating EPCs and Tregs.

Apolipoprotein A-1 Accelerated Liver Regeneration Through Regulating Autophagy Via AMPK-ULK1 Pathway.

BACKGROUND & AIMS: Apolipoprotein A-1 (ApoA-1), the main apolipoprotein of high-density lipoprotein, has been well studied in the area of lipid metabolism and cardiovascular diseases. In this project, we clarify the function and mechanism of ApoA-1 in liver regeneration. METHODS: Seventy percent of partial hepatectomy was applied in male ApoA-1 knockout mice and wild-type mice to investigate the effects of ApoA-1 on liver regeneration. D-4F (ApoA-1 mimetic peptide), autophagy activator, and AMPK activator were used to explore the mechanism of ApoA-1 on liver regeneration. RESULTS: We demonstrated that ApoA-1 levels were highly expressed during the early stage of liver regeneration. ApoA-1 deficiency greatly impaired liver regeneration after hepatectomy. Meanwhile, we found that ApoA-1 deficiency inhibited autophagy during liver regeneration. The activation of autophagy protected against ApoA-1 deficiency in inhibiting liver regeneration. Furthermore, ApoA-1 deficiency impaired autophagy through AMPK-ULK1 pathway, and AMPK activation significantly improved liver regeneration. The administration of D-4F could accelerated liver regeneration after hepatectomy. CONCLUSIONS: These findings suggested that ApoA-1 played an essential role in liver regeneration through promoting autophagy in hepatocytes via AMPK-ULK1 pathway. Our findings enrich the understanding of the underlying mechanism of liver regeneration and provide a potential therapeutic strategy for liver injury.

[Optimal protocol of MR contrast imaging in diabetic foot].

OBJECTIVE: To identify the optimal protocol of MR contrast imaging in diabetic foot. METHODS: 20 patients with diabetic feet were enrolled and examined with 3D FLASH-MRA, 3D VIBE-WE, 2D SE-FS, 2D TSE-FS and 2D FLASH-FS at a 1.5T MR scanner for vascular changes in feet. Their effectiveness in displaying blood vessels, venous aliasing and articular cartilage, as well as the signal-to-noise ratio (SNR) and contrast ratio (CR) of plantar skins calcaneus, flexor digitorum brevis, dorsal artery, and talocalcaneal joint cartilage in diabetic feet were compared. RESULTS: (1) 3D FLASH-MRA was better in displaying blood vessels and venous aliasing than the others (P < 0.05); (2) 3D VIBE-WE was better in displaying articular cartilage than 2D SE-FS, 2D TSE-FS and 2D FLASH-FS (P < 0.05); (3) 3D VIBE-WE had higher SNR and CR of plantar skins, dorsal artery, talocalcaneal joint cartilage, calcaneus, and flexor digitorum brevis than the others (P < 0.05). CONCLUSION: 3D VIBE-WE is the preferred sequence for T1 weighted imaging with contrast in diabetic feet. It can also serve as the supplemental sequence of 3D FLASH-MRA in MR angiography.

[Comparative study of ultrasonography and magnetic resonance imaging in midline structures of fetal brain].

OBJECTIVE: To evaluate the accuracy of ultrasonography (US) and magnetic resonance imaging (MRI) in midline structures of fetal brain. METHODS: Thirty-two fetuses underwent US and MRI examinatiom. Imagings acquired from US and MRI were analysed, the results were compared with the final outcomes which were obtained after fetal birth or pathological study after induction of labor. RESULTS: There were 20 cases found abnormal in prenatal CNS ultrasonography (18 cases involving midline structures ). Among these 20 cases, 12 cases were normal in MRI and the fetuses were born in full-term without special problem, 8 cases were abnormal in MRI and fetal autopsy confirmed their abnormalities. Diagnostic accuracy rate of US was 93.8%, sensitivity was 100%, specificity was 87.5%, positive predictive value was 88.9%, negatvie predictive value was 100%. Diagnostic accuracy rate of MRI was 100%, modifying the US results in 4 cases. CONCLUSION: US and MRI examinations are important in fetal central nervous system. US could be the first line examination, and MRI is an important supplement because of the high diagnostic accuracy, especially in the image study of midline structures of fetal brain.

[Comparison of the efficacy of gadobutrol and multihance in contrast-enhanced MRI for diagnosis of brain metastasis in lung cancer].

OBJECTIVE: To investigate the diagnostic efficacy of gadobutrol for assessing brain metastases in lung cancer patients in comparison with multihance. METHODS: 21 patients with lung cancer suspected of brain metastasis were enrolled in this study. All patients underwent twice MRI scans on a 3.0T MRI scanner (Siemens MAGENETOM Trio) with 8-channel head coil, first with 0.5 mol/L multihance and then with 1.0 mol/L gadobutrol as contrast agent. The dosage of contrast agent was set at 0.1 mmol/kg body mass. The interval between the two scans was 24-72 hours. The detection and delineation of lesions were evaluated visually. The signal-to-noise ratios (SNR), contrast-to-noise ratios (CNR) of lesion to normal brain white matter and the percentage of lesion enhancement were calculated and compared between the two scans by 2 experienced neuroradiologists. RESULTS: One patient was excluded because he received radiation therapy between the two scans. 15 patients were found to have brain metastases with a total of 35 lesions. There were no statistical differences between the two scans in SNR, CNR and percentage enhancement for both normal brain and lesions (t = 0.545, P = 0.592; t = 1.143, P = 2.267; t = 0.592, P = 0.557; t = 0.473, P = 0.639). CONCLUSION: Half-dose gadobutrol (1.0 mol/L) can achieve the same enhancement effects compared with full-dose multihance (0.5 mol/L).

[Peripheral MR angiography without contrast agent using fresh blood imaging (FBI) with ECG-trigger: initial experience].

OBJECTIVE: To examine the efficacy of fresh blood imaging (FBI) in detecting vascular diseases in lower extremity. METHODS: Thirty-six patients suspected of having lower extremity vascular diseases were imaged with a 1.5-T MRI system (Toshiba Excelart Vantage). Contrast-enhanced MRA (CEMRA) and FBI technology, with maximum intensity projection (MIP) reconstruction were adopted to visualize lower extremity vascular. Signal to noise ratios (SNR) were measured on the FBI and CEMRA images. Two experienced radiologists assessed the imaging quality of peripheral artery MRA on MIP reconstructed images. RESULTS: All patients successfully underwent both FBI and CEMRA. All arterial segments were obtained in the 36 patients. The SNR values on FBI and CEMRA were 108.39 +/- 9.76 and 87.46 +/- 14.77 (t = - 6.782, P = 0.001), respectively. There were no significant differences in the overall image quality, arterial anatomy and venous overlap (chi2 = 0.004, P = 0.947; chi2 = 0.000, P = 1; chi2 = 0.681, P = 0.409). The CEMRA motion artifacts were less than FBI (chi2 = 8.744, P = 0.03). CONCLUSION: The FBI technique, which shows the vascular disease in lower extremity without contrast medium with ECG gating, is considered clinically useful.

[Non-contrast-enhanced MR angiography for selective visualization of the hepatic vein].

OBJECTIVE: To evaluate the diagnostic performance of non-contrast-enhanced MR angiography (NCE-MRA) in the preoperative assessment of hepatic vein. MATERIALS AND METHODS: Contrast-enhanced MR angiography (CE-MRA)and NCE-MRA were performed on ten patients with hepatic cirrhosis and twelve potential living liver donors with the same 1. 5T MR scanner. The anatomic angiographic images were reconstructed and reviewed by two radiologists independently. The quality of the images of hepatic vein vessels was rated with a four point scale. RESULTS: After consensus reading, 19 NCE-MRA images (86.4%) and 20 CE-MRA images (90.9%) scored more than 3 point, respectively. The segmental branch vessels were visualized on MR angiography in the majority of cases. Both NCE-MRA and CE-MRA correctly characterized 20 out of 22 hepatic veins without false positive reporting. The NCE-MRA reported two false negative cases. There were no statistically significant differences between NCE-MRA and CE-MRA for the characterization of hepatic vasculature (P > 0.05). High consistency was achieved between the two reviewers, with Kappa values over 0.75. CONCLUSION: NCE-MRA is a non-invasive and effective method for the comprehensive assessment of hepatic vein.

BUB1B promotes extrahepatic cholangiocarcinoma progression via JNK/c-Jun pathways.

Currently, the controversy regarding the expression profile and function of BUB1B in different malignancies still exist. In this project, we aimed to explore the role and molecular mechanism of BUB1B in the progression of extrahepatic cholangiocarcinoma (ECC). The expression levels of BUB1B in human ECC were evaluated by immunohistochemistry, western blot, and real-time PCR. The role and mechanism of BUB1B in CCA cell proliferation and invasion were investigated in both in vitro and in vivo functional studies. To indicate the clinical significance, a tissue microarray was performed on 113 ECC patients, followed by univariate and multivariate analyses. The expression of BUB1B was increased in both human CCA tissues and CCA cells. Results from loss-of-function and gain-of-function experiments suggested that the inhibition of BUB1B decreased the proliferation and invasiveness of CCA cells in vitro and in vivo, while overexpression of BUB1B achieved the opposite effect. Furthermore, the activation of c-Jun N-terminal kinase-c-Jun (JNK)-c-Jun pathway was regulated by BUB1B. BUB1B regulated the proliferation and invasiveness of CAA cells in a JNK-c-Jun-dependent manner. Clinically, ECC patients with BUB1B high expression had worse overall survival and recurrence-free survival than those with BUB1B low expression. Multivariate analysis identified that BUB1B was an independent predictor for postoperative recurrence and overall survival of ECC patients. In conclusion, BUB1B promoted ECC progression via JNK/c-Jun pathways. These findings suggested that BUB1B could be a potential therapeutic target and a biomarker for predicting prognosis for ECC patients.

[MR angiograph of peripheral arterial injury in patients with diabetic feet].

OBJECTIVE: To explore the diagnostic value of MRI blood vessel imaging in diagnosing peripheral arterial injury in diabetic patients. METHODS: Nineteen diabetic patients with suspected peripheral artery injuries underwent MRI blood vessel imaging. 3D contrast enhanced-MRA (CE-MRA) was performed in the area from the articular genu to the ankle mortise to identify peripheral artery injury. The extent of blood vessel stenosis was graded. The correlation between blood vessel stenosis and clinical features was analyzed. RESULTS: All target arteries were well demonstrated. Out of a total of 152 arterial segments, 121 segments showed normal or mild stenosis, 17 showed moderate stenosis, 9 showed severe stenosis, and 6 showed occlusion. The extent of stenosis was correlated with clinical features. CONCLUSION: MRI blood vessel imaging is a promising and valuable method for examining peripheral arterial changes in patients with diabetic foot problems.

[Nonenhanced renal artery MR angiography with time spatial labeling inversion pulse technology and its clinical values].

OBJECTIVE: To evaluate the feasibility of nonenhanced renal artery MR angiography (MRA) with respiratory-gated time spatial labeling inversion pulse (time-slip) and its clinical application. METHODS: Thirty-two consecutive patients underwent the 1.5 T MRI (TOSHIBA EXCELART Vantage) examination to visualize renal artery with contrast-enhanced MRA (CEMRA) and the examination with time-slip technology. Signal to noise ratio (SNR) and contrast to noise ratio (CNR) were measured on CEMRA and Time-slip images, respectively. Two experienced radiologists assessed the imaging quality of renal artery MRA on 3D-MIPs reconstructed images. RESULTS: Sixty-four renal arteries and 3 accessory renal arteries in 32 patients were visualized on both time-slip and CEMRA. SNR values on Time-slip and CEMRA were 102.7 +/- 16.2 and 83.9 +/- 17.7 (t = -4.625, P < 0.001); CNR were 97.8 +/- 16.1 and 78.8 +/- 18.3 (t = -4.554, P < 0.001), respectively. Time-slip MIP images obtained higher quality than CEMRA did (Z = -2.318, P = 0.02), and venous contamination was sharply reduced on Time-slip technology when compared with CEMRA (Z = -4.895, P = 0.001). CONCLUSION: Non-enhanced renal artery MRA with respiratory-gated time-slip technology can provide higher SNR images of renal artery than conventional CEMRA, which can provide more information for clinical decision-making.