Hypercholesterolemia Is Associated With Dysregulation of Lipid Metabolism and Poor Prognosis in Primary Biliary Cholangitis.

BACKGROUND & AIMS: Hypercholesterolemia is frequently diagnosed in patients with primary biliary cholangitis (PBC). However, its association with the prognosis and lipid metabolism is unknown. In this study, we aimed to investigate the prognostic value of baseline total cholesterol (TC) levels in PBC and characterized the associated lipid metabolism. METHODS: Five hundred and thirty-one patients with PBC without prior cirrhosis-related complications were randomly divided into the derivation and validation cohorts at a ratio of 7:3. Complete clinical data were obtained and analyzed. The endpoints were defined as liver-related death, liver transplantation, and cirrhosis-related complications. Lipidomics was performed in 89 patients and 28 healthy controls. RESULTS: Baseline TC was independently associated with poor liver-related outcomes, and adjusted C-statistics were 0.80 (95% confidence interval [CI]: 0.74-0.85) and 0.88 (95% CI: 0.78-0.91) in the derivation and validation cohorts, respectively. The predictive ability of TC for disease outcomes was stable over time and comparable with the Globe score. The 200 mg/dL cut-off optimally divided patients into low- and high-TC groups. A combination of TC and Globe score provided a more accurate stratification of patients into risk subgroups. Lipidomics indicated an up-regulation of lipid families in high-TC patients. Pathway analysis of 66 up-regulated lipids revealed the dysregulation of glycerophospholipid and sphingolipid metabolism in high-TC patients, which were associated with poor liver-related outcomes. CONCLUSIONS: Our results indicate that patients with PBC having baseline TC levels above 200 mg/dL have unique lipidome characteristics and are at a higher risk of poor liver-related outcomes.

Early versus Late Recurrence of Hepatocellular Carcinoma after Microwave Ablation: Patterns, Treatments, and Post-Recurrence Survival.

INTRODUCTION: Recurrence after microwave ablation (MWA) has not been extensively studied. We aimed to investigate the patterns, treatments, and survival of patients with hepatocellular carcinoma (HCC) who experienced early and late recurrence after MWA. METHODS: This retrospective study included patients with HCC recurrence after MWA as the initial treatment from January 2008 to December 2021. Recurrence patterns, treatments, and outcomes between patients with early and late HCC recurrence were compared. Prognostic factors of post-recurrence survival (PRS) were identified by multivariable Cox regression analyses. RESULTS: Among 222 patients, 128 developed early recurrence (≤2 years after MWA) and 94 had late recurrence (>2 years). Majority of the recurrent HCC were intrahepatic-only recurrence, within the Milan criteria, and received potentially curative treatment. No significant differences in the recurrence patterns, vascular invasion, tumor staging, post-recurrence treatments, or median PRS (35.0 vs. 33.0 months, p = 0.523) were identified between patients with early and late recurrence. Multivariable analyses suggested that multiple tumor number (hazard ratio [HR]: 1.54; 95% CI: 1.03-2.30, p = 0.038), extrahepatic recurrence (HR: 2.14, 95% CI: 1.16-3.92, p = 0.015), vascular invasion (HR: 2.37, 95% CI: 1.18-4.76, p = 0.038), and higher ALBI grade (HR: 2.18, 95% CI: 1.54-3.08, p < 0.001) were independent risk factors of worse PRS, while curative treatment after recurrence (HR: 0.59, 95% CI: 0.38-0.92, p = 0.020) was associated with better PRS. CONCLUSIONS: No differences in recurrence patterns, post-recurrence treatments, or PRS were found between HCC patients with early and late recurrence following MWA. Tumor burden and patients' liver function reserve should be considered to decide the optimal post-recurrence treatment after MWA.

Glucocorticoid efficacy and treatment strategies for drug-induced liver injury: a literature review.

Drug-induced liver injury (DILI) is an adverse reaction to drugs and their metabolites. The activation of adaptive immune and inflammatory responses plays an important role in the pathogenesis of DILI. Glucocorticoids (GCs) have powerful anti-inflammatory and immunosuppressive effects and have been used to treat a variety of immune-mediated liver diseases. Due to the important role of the immune system in DILI, GCs are widely used in the clinical treatment of DILI; however, whether they are beneficial to patients remains controversial. There is no uniform standard for the timing, dosage, and population selection of GCs, which mainly depend on the clinician's experience. Therefore, elucidating whether GCs are beneficial for patients with DILI is an urgent clinical problem. Our review summarizes the recent literature and discusses the clinical efficacy, applicable population, application timing, and efficacy of GCs in special types of DILI, providing a reference for the clinical application of GCs.

Long-term survival analysis of ultrasound-guided percutaneous microwave ablation for hepatocellular carcinoma conforming to the Milan criteria: primary versus recurrent HCC.

BACKGROUND: This study compared long-term outcomes between patients with initial hepatocellular carcinoma (IHCC) and those with recurrent HCC (RHCC) treated with microwave ablation (MWA). METHODS: This retrospective study included 425 patients with HCCs (294 IHCCs and 131 RHCCs) within the Milan criteria who were treated with ultrasound-guided percutaneous MWA between January 2008 and November 2021. All patients with RHCC had previously undergone MWA for initial HCC. Overall survival (OS) and recurrence-free survival (RFS) rates were compared between the IHCC and RHCC groups before and after propensity score matching (PSM). RESULTS: Before matching, the 1-, 3-, 5-, and 10-year OS rates in the IHCC group were 95.9%, 78.5%, 60.2%, and 42.5%, respectively, which were significantly higher than those in the RHCC group (93.8%, 70.0%, 42.0%, and 6.6%, respectively). This difference remained significant after PSM. However, subgroup analyses suggested that there were no significant differences in OS rates between IHCC and RHCC in patients with solitary HCC ≤3.0 cm, AFP ≤200 ng/mL, ablative margins ≥0.5 cm, or Albumin-Bilirubin (ALBI) grade 1. RFS was significantly higher in IHCC than in RHCC before and after PSM, as well as in subgroup analyses. ALBI grade (hazard ratio (HR), 2.38; 95% CI: 1.46-3.86; p < 0.001), serum AFP level (HR, 2.07; 95% CI: 1.19-3.62; p = 0.010) and ablative margins (HR, 0.18; 95% CI: 0.06-0.59; p = 0.005) were independent prognostic factors for OS of RHCC. Serum AFP(HR, 1.29; 95% CI: 1.02-1.63, p = 0.036) level was the only factor associated with RFS in RHCC. CONCLUSIONS: MWA yielded comparable OS in IHCC and RHCC patients with solitary HCC ≤3.0 cm, AFP ≤200 ng/mL, ablative margins ≥0.5 cm, or ALBI grade 1.

Fenofibrate normalizes alkaline phosphatase and improves long-term outcomes in patients with advanced primary biliary cholangitis refractory to ursodeoxycholic acid.

BACKGROUND: Although patients with advanced liver disease have been included in studies evaluating fibrates for the treatment of primary biliary cholangitis (PBC), the frequency of biochemical responses and adverse effects for this group of patients was not reported separately and comprehensively. AIMS: to evaluate the efficacy and safety of additional fenofibrate therapy in patients with advanced and ursodeoxycholic acid (UDCA)-refractory PBC. METHODS: Patients were analyzed retrospectively to determine the clinical therapeutic effects of UDCA with additional fenofibrate therapy versus continued UDCA monotherapy. The liver transplantation (LT)-free survival and the alkaline phosphatase (ALP) normalization rates were estimated using Cox regression analyses and Kaplan-Meier plots with inverse probability of treatment weighting (IPTW). RESULTS: A total of 118 patients were included: 54 received UDCA alone and 64 received UDCA in combination with fenofibrate therapy. In the fenofibrate and UDCA groups, 37% and 11% of patients with advanced and UDCA-refractory PBC, respectively, achieved ALP normalization (P=0.001). Additional fenofibrate therapy improved both LT-free survival and ALP normalization rate after IPTW (hazard ratio [HR]: 0.23, 95% confidence interval [CI]: 0.07-0.75, P=0.015; and HR: 11.66, 95% CI: 5.02-27.06, P=0.001, respectively). These effects were supported by parallel changes in the rates of liver decompensation and histologic progression, and the United Kingdom (UK)-PBC and Globe risk scores. During the follow-up period, serum levels of ALP and aminotransferase decreased significantly, while total bilirubin, albumin, platelet, serum creatinine, and estimated glomerular filtration rate remained stable in fenofibrate-treated participants. No fenofibrate-related significant adverse events were observed in our cohort. CONCLUSIONS: Additional fenofibrate therapy significantly improved LT-free survival and ALP normalization in patients with advanced and UDCA-refractory PBC. Furthermore, adding-on fenofibrate therapy appeared to be safe and well tolerated in this population.

Effect of NPC1L1 polymorphism on warfarin stable dose in Chinese patients under heart valve replacement surgery.

Warfarin is the most often anticoagulant choice for preventable thromboembolism. Notably, vitamin K plays a vital role in the process of warfarin's anticoagulant effect. Therefore, we presume NPC1L1, a key transporter of vitamin K (VK) intestinal absorption, may modulate the anticoagulant effect of warfarin. Studies have shown that NPC1L1(-762T>C, rs2073548) and p53 (P72R, rs1042522) variations are implicated in influencing NPC1L1 expression. This study aimed to assess the association between these two variants and warfarin stable dose (WSD). A two-stage extreme phenotype design was used to explore the influence of these two variants (rs2073548, rs1042522) on WSD variance in 655 Chinese patients undergoing heart valve replacement surgery. NPC1L1 rs2073548, p53 rs1042522, VKORC1 rs9923231 and CYP2C9*1/*3 polymorphisms were genotyped by polymerase chain reaction-restriction fragment polymorphism (PCR-RFLP) or Sanger sequencing, respectively. WSD was identified when target monitoring international normalized ratio (INR) value at 2.0-3.0. In the discovery phase, NPC1L1 rs2073548 A allele carriers occupied a significantly higher rate in the low dose group (P = .019). However, in the validation group, warfarin dosage in patients with the rs2073548 AA, AG and GG genotypes were 2.91 ± 0.97 mg/day, 3.02 ± 1.00 mg/day and 3.00 ± 1.06 mg/day, respectively. Multiple linear regression analysis results suggested that CYP2C9*3 and VKORC1 rs9923231, but not NPC1L1 rs2073548, were independent predictors of WSD in Chinese heart valve replacement (HVR) surgical patients.

Adverse Effects of Esketamine for the Treatment of Major Depression Disorder: Findings from Randomized Controlled Trials.

Esketamine is a promising drug which can induce antidepressant effects in Major Depression Disorder (MDD). Several randomized controlled trials (RCTs) have been implemented to assess the efficacy and safety of esketamine for the treatment of MDD. Therefore, we carried out a meta-analysis to assess adverse effect profiles of esketamine for the treatment of MDD. We searched RCTs which were implemented from January 2010 to June 2020 by searching PubMed, Embase and Cochrane Library databases. Finally, four RCTs with 551 patients were included in our study. We pooled 551 patients from 4 RCTs. Compared with placebo, an increased risk of adverse effects was observed in our analysis. After using esketamine, the risk of nausea (RR = 2.34, 95% CI, 1.04 to 5.25, P = 0.04), dissociation (RR = 4.54, 95% CI, 2.36 to 8.73, P < 0.00001), dizziness (RR = 3.00, 95% CI, 1.80 to 5.00, P < 0.0001), vertigo (RR = 7.47, 95% CI, 2.55 to 21.86, P = 0.0002), hypoesthesia (RR = 5.68, 95% CI, 2.06 to 15.63, P = 0.0008), sedation (RR = 3.96, 95% CI, 1.29 to 12.15, P = 0.02) and paresthesia(RR = 3.05, 95% CI, 1.07 to 8.65, P = 0.04)were significantly increased compared with placebo. Our synthesized data analysis revealed drug specific risk profiles. The most frequent adverse effects under treatment with esketamine were nausea, dissociation, dizziness, vertigo, hypoesthesia,sedation and paresthesia.

RIP1/RIP3/MLKL-mediated necroptosis contributes to vinblastine-induced myocardial damage.

Vinblastine (VBL) has been considered as a first-line anti-tumor drug for many years. However, vinblastine-caused myocardial damage has been continually reported. The underlying molecular mechanism of the myocardial damage remains unknown. Here, we show that vinblastine induces myocardial damage and necroptosis is involved in the vinblastine-induced myocardial damage both in vitro and in vivo. The results of WST-8 and flow cytometry analysis show that vinblastine causes damage to H9c2 cells, and the results of animal experiments show that vinblastine causes myocardial cell damage. The necrosome components, receptor-interacting protein 1 (RIP1) receptor-interacting protein 3 (RIP3), are significantly increased in vinblastine-treated H9c2 cells, primary neonatal rat ventricular myocytes and rat heart tissues. And the downstream substrate of RIP3, mixed lineage kinase domain like protein (MLKL) was also increased. Pre-treatment with necroptosis inhibitors partially inhibits the necrosome components and MLKL levels and alleviates vinblastine-induced myocardial injury both in vitro and in vivo. This study indicates that necroptosis participated in vinblastine-evoked myocardial cell death partially, which would be a potential target for relieving the chemotherapy-related myocardial damage.

Evaluation of the "safe multidisciplinary app-assisted remote patient-self-testing (SMART) model" for warfarin home management during the COVID-19 pandemic: study protocol of a multi-center randomized controlled trial.

BACKGROUND: Warfarin treatment requires frequent monitoring of INR (international normalized ratio) to adjust dosage in a therapeutic range. In China, patients living in small towns usually go to tertiary hospitals to get warfarin monitoring and dosing, resulting in low frequencies of follow-ups and high incidence of complications. Influenced by the COVID-19 pandemic, patients on warfarin have further reduced their visits to healthcare institutions. While patient self-testing (PST) via using a point-of-care testing device for INR measuring at home has been widely used in developed countries and demonstrated improved clinical outcomes compared to usual care in clinics, it is rarely applied in developing countries, including China. This proposed study will develop and assess the "Safe Multidisciplinary App-assisted Remote patient-self-Testing (SMART) model" for warfarin home management in China during the COVID-19 pandemic. METHODS: This is a multi-center randomized controlled trial. We will carry out the study in three county hospitals, three small tertiary hospitals and three large tertiary hospitals with anticoagulation clinics in Hunan province of China. Eligible patients will be randomly assigned to the SMART model group (n = 360) or the control group (usual care clinic group, n = 360; anticoagulation clinic group, n = 120). Patients in the SMART model group do PST at home once every two to 4 weeks. Controls receive usual care in the clinics. All the patients will be followed up through outpatient clinics, phone call or online interviews at the 3rd, 6th, 9th and 12th month. The percentage of time in therapeutic range (TTR), incidence of warfarin associated major bleeding and thromboembolic events and costs will be compared between the SMART model group and control groups. DISCUSSION: Patients in the SMART model group would show improved TTR, lower incidence of complications and better quality of life compared to the control groups. Our design, implementation and usage of the SMART model will provide experience and evidence in developing a novel model for chronic disease management to solve the problem of healthcare service maldistribution, an issue particularly obvious in developing countries during the COVID-19 pandemic. TRIAL REGISTRATION: ChiCTR, ChiCTR 2000038984 . Registered 11 October, 2020.

Surgical Management of a Giant Left Sinus of Valsalva Aneurysm with Coronary Artery Abnormality.

Coronary insufficiency caused by unruptured left sinus of Valsalva aneurysm (SVA) is exceedingly rare in the literature. Herein, we present a successful surgically treated case of giant left SVA with severe aortic regurgitation and coronary insufficiency, thus introducing a tailored valve-sparing aortic root repair technique.

Multiple Skin Bridging for No-Touch Saphenous-Vein Grafts Harvesting Can Reduce Wound Morbidity.

BACKGROUND: Reducing the leg wound morbidity is crucial for the patients undergoing coronary artery bypass grafting (CABG) with great saphenous vein (SV) grafts harvested by no-touch (NT) technique. This study was to summarize the experience of skin bridging technique for reducing wound morbidity and the influence of it on one-year bypass graft patency. METHODS: According to skin bridging or not, harvesting times, graft length, number of bleeding branches, postoperative subjective perception assessment scale (ASEPSIS) scores and one-year patency rate were analyzed. RESULTS: From June 2018 to February 2019, 60 patients underwent CABG with SV grafts either with open-incision NT or skin bridging NT (30 in each group). There were no significant differences in age (71.4 ± 5.1 years vs. 68.9 ± 5.5 years) or graft length (23.3 ± 1.1 cm vs. 23.9 ± 1.3 cm) between the two groups. The bridging/NT group had a significantly longer harvest time (38.5 ± 4.9 min vs. 18.5 ± 2.6 min; P < 0.001) and a significantly greater number of bleeding branches (1.9 ± 1.2 vs. 0.8 ± 0.8; P < 0.001) than the open NT group. The open NT group had a significantly higher ASEPSIS score (23.8 ± 2.0 vs. 15.7 ± 2.6; P < 0.001). There was no significant difference in patency rate at one-year follow-up. CONCLUSION: Obtaining the SV by the combined NT/discontinuous skin bridging technique is a satisfactory method for patients who underwent CABG. This method has important clinical significance in reducing wound morbidity in the harvest of NT grafts.

Incidence and Etiology of Drug-Induced Liver Injury in Mainland China.

BACKGROUND & AIMS: We performed a nationwide, retrospective study to determine the incidence and causes of drug-induced liver injury (DILI) in mainland China. METHODS: We collected data on a total of 25,927 confirmed DILI cases, hospitalized from 2012 through 2014 at 308 medical centers in mainland China. We collected demographic, medical history, treatment, laboratory, disease severity, and mortality data from all patients. Investigators at each site were asked to complete causality assessments for each case whose diagnosis at discharge was DILI (n = 29,478) according to the Roussel Uclaf Causality Assessment Method. RESULTS: Most cases of DILI presented with hepatocellular injury (51.39%; 95% confidence interval [CI] 50.76-52.03), followed by mixed injury (28.30%; 95% CI 27.73-28.87) and cholestatic injury (20.31%; 95% CI 19.80-20.82). The leading single classes of implicated drugs were traditional Chinese medicines or herbal and dietary supplements (26.81%) and antituberculosis medications (21.99%). Chronic DILI occurred in 13.00% of the cases and, although 44.40% of the hepatocellular DILI cases fulfilled Hy's Law criteria, only 280 cases (1.08%) progressed to hepatic failure, 2 cases underwent liver transplantation (0.01%), and 102 patients died (0.39%). Among deaths, DILI was judged to have a primary role in 72 (70.59%), a contributory role in 21 (20.59%), and no role in 9 (8.82%). Assuming the proportion of DILI in the entire hospitalized population of China was represented by that observed in the 66 centers where DILI capture was complete, we estimated the annual incidence in the general population to be 23.80 per 100,000 persons (95% CI 20.86-26.74). Only hospitalized patients were included in this analysis, so the true incidence is likely to be higher. CONCLUSIONS: In a retrospective study to determine the incidence and causes of DILI in mainland China, the annual incidence in the general population was estimated to be 23.80 per 100,000 persons; higher than that reported from Western countries. Traditional Chinese medicines, herbal and dietary supplements, and antituberculosis drugs were the leading causes of DILI in mainland China.

MicroRNA-132 suppresses migration and invasion of renal carcinoma cells.

BACKGROUND: The aim of this study was to explain the effects of microRNA-132 in renal cell carcinoma by regulating FOXM1 expression. METHODS: Thirty patients with renal cell carcinoma admitted to our hospital were enrolled, and their adjacent normal tissues and cancer tissues were taken. The expression of microRNA-132 was measured by in situ hybridization (ISH) and RT-PCR, and the expression of FOXM1 was evaluated by RT-PCR and immunohistochemistry (IHC), and the correlation between microRNA-132 and FOXM1 was analyzed. In the cell experiment, the KETR-3 cells were divided into three groups: Negative control (NC) group were treated with nothing; blank (BL) group were transfected with empty vector; and microRNA-132 (miRNA) group were transfected with microRNA-132. The cell invasion and migration abilities among groups were assessed by transwell and wound healing assays. The expression levels of related proteins (FOXM1, MMP-2, MMP-9, VEGF-alpha, and uPAR) were determined by Western blot. RESULTS: Depending on clinical data, we found that FOXM1 protein expression of renal cell carcinoma tissues was higher than that in adjacent normal tissues. MiRNA-132 was negative correlation with FOXM1. In vitro, the number of invasive cells and wound healing rate in the microRNA group were significantly suppressed than those in the NC group (P < 0.05, respectively). In the Western blot assay, the results showed that the protein expression levels of FOXM1, MMP-2, MMP-9, VEGF-α, and uPAR were significantly inhibited in the miRNA group compared with the NC group (P < 0.05, respectively). CONCLUSION: miRNA-132 had anti-tumor effects in renal cell carcinoma by suppressing FOXM1 expression.

A nomogram based on pretreatment clinical parameters for the prediction of inadequate biochemical response in primary biliary cholangitis.

BACKGROUND: Ursodeoxycholic acid (UDCA) has been widely recommended as the first-line drug for primary biliary cholangitis (PBC) in the current guidelines. However, its therapeutic effects are poor in nearly one-third of patients. The early identification and intervention of these patients is crucial for delaying disease progression. Therefore, we explored risk factors for inadequate biochemical response and constructed a nomogram to predict the potential risk. METHODS: We enrolled 356 patients and randomly divided them into training (70%) and validation groups (30%). We defined inadequate biochemical response as the study endpoint. Logistic analysis was used to identify the independent predictors of poor biochemical response. Based on these factors, a predictive nomogram was finally constructed. Then, discrimination and calibration were evaluated by internal validation. Additionally, the association between the model predictions and prognosis was further analyzed. RESULTS: Female sex, and albumin and bilirubin concentrations were identified as risk factors, and a nomogram was built based on these factors. The areas under the ROC curves of the training and validation groups were 0.809 and 0.791, respectively. Moreover, calibration curves showed that predictions of the nomogram had good concordance with the actual outcomes. The correlation analysis demonstrated that PBC patients with a high probability of a suboptimal biochemical response were more likely to have adverse outcomes. CONCLUSION: We constructed a nomogram, which can accurately predict the risk of inadequate biochemical response to UDCA, facilitating the early screening of high-risk patients with PBC who should be prioritized for additional therapy.

Percutaneous gallbladder drainage as a bridge to concomitant coronary artery bypass grafting and laparoscopic cholecystectomy.

A 74-year-old woman with left main and three-vessel coronary artery disease was scheduled for off-pump coronary artery bypass grafting and developed acute severe cholecystitis preoperatively. Percutaneous gallbladder drainage was placed to achieve gallbladder decompression and infection control. Two weeks later, CABG and laparoscopic cholecystectomy were successfully performed at the same time.

Mesenchymal stem cell-derived conditioned medium attenuate angiotensin II-induced aortic aneurysm growth by modulating macrophage polarization.

Mesenchymal stem cells (MSCs) exhibit therapeutic benefits on aortic aneurysm (AA); however, the molecular mechanisms are not fully understood. The current study aimed to investigate the therapeutic effects and potential mechanisms of murine bone marrow MSC (BM-MSCs)-derived conditioned medium (MSCs-CM) on angiotensin II (AngII)-induced AA in apolipoprotein E-deficient (apoE-/- ) mice. Murine BM-MSCs, MSCs-CM or control medium were intravenously administrated into AngII-induced AA in apoE-/- mice. Mice were sacrificed at 2 weeks after injection. BM-MSCs and MSCs-CM significantly attenuated matrix metalloproteinase (MMP)-2 and MMP-9 expression, aortic elastin degradation and AA growth at the site of AA. These treatments with BM-MSCs and MSCs-CM also decreased Ly6chigh monocytes in peripheral blood on day 7 and M1 macrophage infiltration in AA tissues on day 14, whereas they increased M2 macrophages. In addition, BM-MSCs and MSCs-CM reduced MCP-1, IL-1Ra and IL-6 expression and increased IL-10 expression in AA tissues. In vitro, peritoneal macrophages were co-cultured with BM-MSCs or fibroblasts as control in a transwell system. The mRNA and protein expression of M2 macrophage markers were evaluated. IL-6 and IL-1ß were reduced, while IL-10 was increased in the BM-MSC systems. The mRNA and protein expression of M2 markers were up-regulated in the BM-MSC systems. Furthermore, high concentration of IGF1, VEGF and TGF-ß1 was detected in MSCs-CM. Our results suggest that MSCs-CM could prevent AA growth potentially through regulating macrophage polarization. These results may provide a new insight into the mechanisms of BM-MSCs in the therapy of AA.

The methylation of Notch1 promoter mediates the osteogenesis differentiation in human aortic valve interstitial cells through Wnt/ß-catenin signaling.

Aortic valve interstitial cells (AVICs) have the potential to undergo calcification, which has been regarded as a critical issue during the pathology of calcific aortic valve disease (CAVD). In the past decade, epigenetics, in particular, DNA methylation dysregulation, has been reported to play a vital role in the occurrence and development of CAVD. In the present study, the expression of Notch1, which can inhibit the osteogenesis differentiation of valve interstitial cells, was downregulated whereas the expression of methyltransferases was upregulated in CAVD tissues, suggesting the potential role of DNA methylation in Notch1 expression and CAVD progression. As revealed by DNA extraction and bisulfite sequencing polymerase chain reaction (PCR), the methylation level in Notch1 promoter was much higher in CAVD tissues and human AVICs on Day 14 of osteogenesis differentiation induction. The silence of Notch1 intercellular domain (NICD) promoted while the treatment of demethylation agent, 5-Aza-dC, inhibited the osteogenesis differentiation. Moreover, NICD overexpression significantly suppressed the transcriptional activity of ß-catenin on TCF4, and the expression of osteogenesis differentiation factors, indicating the involvement of Wnt/ß-catenin signaling in Notch1 modulating the osteogenesis differentiation in human AVICs (hAVICs). Taken together, Notch1 promoter methylation leads to a decreased Notch1 expression and subsequent decreased release of NICD in the nucleus of hAVICs, therefore promoting the activation of Wnt/ß-catenin signaling and the expression of osteogenesis differentiation factors, finally promoting the osteogenesis differentiation in hAVICs. DNA methylation might act as an important bridge to link epigenetic variation and CAVD progression.

Long-term Outcomes of Autologous Peripheral Blood Stem Cell Transplantation in Patients With Cirrhosis.

BACKGROUND & AIMS: Peripheral blood stem cells (PBSCs) mobilized with colony-stimulating factor can promote liver regeneration and increase liver function in patients with liver diseases. However, the long-term effects of stem cell treatments on survival and risk of hepatocellular carcinoma (HCC) in patients with cirrhosis have not been determined. We investigated the long-term effects of autologous stem cell transplantation and risk of HCC in patients with cirrhosis. METHODS: We performed a retrospective analysis of 2 cohorts of patients with decompensated cirrhosis who received transplantations of autologous PBSCs (n = 282) or standard medical treatment (SMT, n = 286) in China from January 1, 2006, through December 31, 2016. Patients were followed up until death or liver transplantation. Mortality data were obtained by case records and confirmed by telephone calls. Survival time was calculated and HCC was confirmed by computed tomography or ultrasound. We used propensity score matching to adjust the differences between the 2 groups. Survival and incidence of HCC were analyzed and Cox proportional hazard regression was used to determine the prognostic factors. RESULTS: After propensity score matching, time of survival was significantly higher in the PBSC group than the SMT group (P = .001). The adjusted rate of 5-year survival was 71.2% in the PBSC group and 52.1% in the SMT group. The overall incidence of HCC did not differ significantly between the PBSC and SMT groups (21.1% vs 20.4%; P = .999). Significant improvement of liver functions was observed at 1 year, 2 years, 3 years, and 5 years after PBSC transplantation compared with the SMT group. CONCLUSIONS: In a long-term analysis of patients with decompensated cirrhosis, autologous transplants of PBSCs significantly improved long-term survival compared with a control group. PBSC transplant did not appear to increase the risk of HCC.

Diverse roles of macrophage polarization in aortic aneurysm: destruction and repair.

Aortic aneurysm (AA) is defined as an enlargement of the aorta greater than 1.5 times its normal size. Early diagnosis of AA is challenging and mortality of AA is high. Curative pharmacological treatments for AA are still lacking, highlighting the need for better understanding of the underlying mechanisms of AA progression. Accumulating studies have proven that the polarization state of circulating monocyte-derived macrophages plays a crucial role in regulating the development of AA. Distinct macrophage subtypes display different functions. Several studies targeting macrophage polarization during AA formation and progression showed potential treatment effects. In this review, we focus on the recent advances of research on macrophage polarization in the progression of AA and propose that targeting macrophage polarization could hold great promise for preventing and treating AA.

Severe Pulmonary Embolism was Secondary to Cement Inferior Vena Cava Embolism after Percutaneous Vertebroplasty.

Cement pulmonary embolism (cPE) and inferior vena cava embolism (cIE) are rare but potentially life-threatening complications of percutaneous vertebroplasty (PVP). Most cPE and cIE occurred simultaneously. In this case, a 65-year-old woman complained of dyspnea after PVP for 4 days. Patient's symptom and image tests manifest that the cPE was secondary to cIE. Although cIE was found at the first day after PVP, the local surgeons treat the patient with a regular anticoagulant without another more effective therapeutic measure. Eventually, the long cement inferior vena cava embolus was broken and result in left pulmonary embolism via the systemic circulation. She was admitted to our hospital and performed with embolectomy surgery by cardiopulmonary bypass and discharged after 7 days. We report this case to show that cIE embolism is still underestimated by some spine surgeons in China, and cIE may be developed to severe cPE during conservation management with anticoagulation.