Ten-year experiences and outcomes of bypass surgery and endovascular therapy in the management of infrarenal aortic occlusion: a single-center retrospective cohort study.

Background: Infrarenal aortic occlusion (IAO) is a life-threatening condition that often causes lower limb ischemia. Although open surgery is the current recommendation for first-line treatment, recent technological innovations have made endovascular treatment (EVT) a promising alternative. This study aims to compare the clinical outcomes of bypass surgery and EVT in the treatment of IAO. Methods: This study is a single-center retrospective observative study at Peking Union Medical College Hospital. Consecutive 92 patients with chronic and atherosclerotic IAO were treated with either EVT (n=40) or bypass surgery (n=52) between 2011 and 2021. The baseline clinical factors (including demographic data and comorbidities), perioperative data (including Rutherford classification changes, technical success) and complication rates were evaluated. The mid-term patency and overall survival of EVT and bypass were assessed. Follow-up was defined as the time from surgery to the last outpatient visit. Continuous variables and category variables were statistically compared, respectively. Kaplan-Meier survival analyses were conducted for vascular patency. Results: The study found that the demographics and pre-operative Rutherford classification were evenly distributed between the two groups (P>0.05). As for technical success, clinical success, comorbidities, mortality, complication rate, and Rutherford classification after procedures, no significant differences were observed (P>0.05). The average post-procedure hospital stay was 5.15 days in the EVT group and was significantly shorter than that of the bypass group, which was 11.83 days (P<0.0001). As for short-term and long-term results, the 1-, 3-, and 5-year primary patency rates were 81.8%, 73.1%, and 73.1% in the EVT group and 97.8%, 80.6%, and 80.6% in the bypass group. The bypass group had significantly better primary patency (P=0.034). There was a significant difference in the secondary patency rate (Bypass 100% vs. EVT 81.6%; P=0.005). Moreover, survival rates were higher in the bypass surgery group than in the EVT group (P=0.035). Conclusions: Although EVT's primary patency rate was lower than that with the bypass surgery, its safety and efficacy were still comparable to anatomic bypass surgery for IAO with less severe perioperative complications and shorter hospital stay. Therefore, EVT could be a feasible option for IAO.

A contrast-enhanced CT-based radiomic nomogram for the differential diagnosis of intravenous leiomyomatosis and uterine leiomyoma.

Objective: Uterine intravenous leiomyomatosis (IVL) is a rare and unique leiomyoma that is difficult to surgery due to its ability to extend into intra- and extra-uterine vasculature. And it is difficult to differentiate from uterine leiomyoma (LM) by conventional CT scanning, which results in a large number of missed diagnoses. This study aimed to evaluate the utility of a contrast-enhanced CT-based radiomic nomogram for preoperative differentiation of IVL and LM. Methods: 124 patients (37 IVL and 87 LM) were retrospectively enrolled in the study. Radiomic features were extracted from contrast-enhanced CT before surgery. Clinical, radiomic, and combined models were developed using LightGBM (Light Gradient Boosting Machine) algorithm to differentiate IVL and LM. The clinical and radiomic signatures were integrated into a nomogram. The diagnostic performance of the models was evaluated using the area under the curve (AUC) and decision curve analysis (DCA). Results: Clinical factors, such as symptoms, menopausal status, age, and selected imaging features, were found to have significant correlations with the differential diagnosis of IVL and LM. A total of 108 radiomic features were extracted from contrast-enhanced CT images and selected for analysis. 29 radiomics features were selected to establish the Rad-score. A clinical model was developed to discriminate IVL and LM (AUC=0.826). Radiomic models were used to effectively differentiate IVL and LM (AUC=0.980). This radiological nomogram combined the Rad-score with independent clinical factors showed better differentiation efficiency than the clinical model (AUC=0.985, p=0.046). Conclusion: This study provides evidence for the utility of a radiomic nomogram integrating clinical and radiomic signatures for differentiating IVL and LM with improved diagnostic accuracy. The nomogram may be useful in clinical decision-making and provide recommendations for clinical treatment.

Midterm Results of a Surgeon-Modified Device to Preserve the Flow of the Internal Iliac Artery During Endovascular Repair of Aneurysm: Single-Center Experiences.

BACKGROUND: During endovascular aneurysm repair (EVAR), commercial iliac branch devices (IBDs) have become an inescapable alternative for preserving antegrade internal iliac artery (IIA) blood flow. Due to the different morphological features of aneurysms, commercial IBDs may not be suitable for all patients. Reported experience with the implantation of the new surgeon-modified IBD (sm IBD) is limited. This investigation describes the indications, efficacy, and safety of the sm IBD. METHODS: Data from consecutive elective implantations of IBDs in patients between March 2011 and May 2021 in a single center were incorporated. The sm IBDs were indicated in patients with common iliac artery aneurysms (CIAAs) and with a challenging anatomy and in those patients with or without abdominal aortic aneurysm (AAA). RESULTS: Fifteen patients (15 male, mean age 67.6 ± 7.9 years) were included. Fifteen sm IBDs were implanted in 1 procedure (100%). Fourteen (93.3%) patients had simultaneous endovascular aneurysm repair (EVAR) and 1 (6.7%) patient previously had a bilateral CIAAs repair by EVAR. The mean common iliac artery (CIA) diameter was 36.6 ± 12.5 mm. Technical success was obtained in all patients (100%). The median operation time was 189.7 ± 78.6 min, with a median fluoroscopy time of 45.3 ± 15.9 min. Axillary artery access was used in 11 (73.3%) procedures. The mean total hospital stay was 5.6 ± 2.8 days, and the postoperative follow-up was 35.4 months (range 2-120). The estimated IIA bridge stent patency at 1 year after operation was 100% and 85.7% ± 13.2% 5 years postoperatively. One (6.7%) IIA branch was occluded, and this patient remained asymptomatic. One patient (6.7%) needed reintervention, and another (6.7%) patient had type II leakage, which is currently under close surveillance. CONCLUSIONS: Using an IBD to maintain the pelvic blood flow is an effective and feasible intravascular technique, especially for patients with an abnormal iliac artery anatomy. This novel technique has similar midterm procedural success rate compared to the use of commercial IBDs. Therefore, these devices are more suitable for patients with certain anatomic challenges and can be used as an alternative treatment.

Epicardial injection of allogeneic human-induced-pluripotent stem cell-derived cardiomyocytes in patients with advanced heart failure: protocol for a phase I/IIa dose-escalation clinical trial.

INTRODUCTION: Heart failure (HF) is a growing global public health burden. However, due to the very limited regenerative capacity of mature cardiomyocytes in the adult mammalian heart, conventional treatments can only improve the symptoms of HF but fail to restore cardiac function. Heart transplantation is limited by a severe shortage of donors. Cell-based transplantation for the treatment of HF has become a promising strategy. Human-induced-pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been tested in animal models to assess safety and efficacy. This study aims at evaluating the safety and efficacy of epicardial injection of hiPSC-CMs in patients with advanced HF during coronary artery bypass grafting (CABG) surgery. METHODS: This study is a dose-escalation, placebo-controlled, single-centre phase I/IIa clinical trial. Dose escalation will be guided by a modified 3+3 design for three doses (1×108, 2×108 and 4×108 cells, sequentially). Patients with advanced heart failure will be enrolled and randomly allocated to receive epicardial injection of hiPSC-CMs during CABG surgery or CABG surgery alone, followed by a 12-month follow-up investigation. The primary endpoint is to assess the safety of hiPSC-CMs transplantation, including haemodynamic compromised sustained ventricular arrhythmias and newly formed tumours during 6 months postoperatively. The secondary endpoint is to evaluate the efficacy of epicardial injection of hiPSC-CMs and CABG surgery combination by comparison with CABG surgery alone. ETHICS AND DISSEMINATION: The study protocol has been approved by the Institutional Ethical Committee of Nanjing Drum Tower Hospital (No. SC202000102) and approved by National Health Commission of the PRC (MR-32-21-014649). Findings will be disseminated to the academic community through peer-reviewed publications and presentation at national and international meetings. TRIAL REGISTRATION NUMBER: NCT03763136.

Irisin Suppresses Nicotine-Mediated Atherosclerosis by Attenuating Endothelial Cell Migration, Proliferation, Cell Cycle Arrest, and Cell Senescence.

Atherosclerotic disease has become the major cause of death worldwide. Smoking, as a widespread independent risk factor, further strengthens the health burden of atherosclerosis. Irisin is a cytokine that increases after physical activity and shows an atheroprotective effect, while its specific mechanism in the process of atherosclerosis is little known. The reversal effect of irisin on intimal thickening induced by smoking-mediated atherosclerosis was identified in Apoe -/- mice through the integrin αVß5 receptor. Endothelial cells treated with nicotine and irisin were further subjected to RNA-seq for further illustrating the potential mechanism of irisin in atherosclerosis, as well as the wound healing assays, CCK-8 assays, ß-gal staining and cell cycle determination to confirm phenotypic alterations. Endothelial differential expressed gene enrichment showed focal adhesion for migration and proliferation, as well as the P53 signaling pathway for cell senescence and cell cycle control. Irisin exerts antagonistic effects on nicotine-mediated migration and proliferation via the integrin αVß5/PI3K pathway. In addition, irisin inhibits nicotine-mediated endothelial senescence and cell cycle arrest in G0/G1 phase via P53/P21 pathway. This study further illustrates the molecular mechanism of irisin in atherosclerosis and stresses its potential as an anti-atherosclerotic therapy.

Mechanisms of peripheral neurotoxicity associated with four chemotherapy drugs using human induced pluripotent stem cell-derived peripheral neurons.

The awareness of the long-term toxicities of cancer survivors after chemotherapy treatment has been gradually strengthened as the population of cancer survivors grows. Generally, chemotherapy-induced peripheral neurotoxicity (CIPN) is studied by animal models which are not only expensive and time-consuming, but also species-specific differences. The generation of human induced pluripotent stem cells (hiPSCs) and differentiation of peripheral neurons have provided an in vitro model to elucidate the risk of CIPN. Here, we developed a drug-induced peripheral neurotoxicity model using hiPSC-derived peripheral neurons (hiPSC-PNs) to study the mechanisms of different chemotherapeutic agents on neuronal viability using LDH assay, a cell apoptosis assay determined by caspase 3/7 activation, neurite outgrowth, ion channel expression and neurotransmitter release following treatment of cisplatin, bortezomib, ixabepilone, or pomalidomide. Our data showed that the multiple endpoints of the hiPSC-PNs model had different sensitivity to various chemotherapeutic agents. Furthermore, the chemotherapeutics separated cell viability from the decrease in neurite lengthand changed levels of ion channels and neurotransmitters to a certain extent. Thus, we study the mechanisms of peripheral neurotoxicity induced by chemotherapeutic agents through changes in these indicators.

Correction to: Transplantation of human induced pluripotent stem cell-derived cardiomyocytes improves myocardial function and reverses ventricular remodeling in infarcted rat hearts.

The original article omits an affiliation for authors, He Zhang and Dongjin Wang. The omitted affiliation can be viewed in this Correction article.

Transplantation of human induced pluripotent stem cell-derived cardiomyocytes improves myocardial function and reverses ventricular remodeling in infarcted rat hearts.

BACKGROUND: Human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have shed great light on cardiac regenerative medicine and specifically myocardial repair in heart failure patients. However, the treatment efficacy and the survival of iPSC-CMs in vivo after transplantation have yielded inconsistent results. OBJECTIVES: The objective of this study was to evaluate the ability of human iPSC-CMs to improve myocardial function in a rat postinfarction heart failure model. METHODS: Eight-week-old male Sprague-Dawley rats were randomly selected to receive an intramyocardial injection of 5% albumin solution with or without 1 × 107 human iPSC-CMs 10 days after undergoing left anterior descending (LAD) coronary artery ligation. Cyclosporine A and methylprednisolone were administered before iPSC-CM injection and until the rats were killed to prevent graft rejection. Cardiac function was evaluated by echocardiography. The survival of grafted cardiomyocytes was confirmed by observing the fluorescent cell tracer Vybrant™ CM-DiI or expression of the enhanced green fluorescent protein (eGFP) in transplanted cells, or survival was demonstrated by polymerase chain reaction (PCR)-based detection of human mitochondrial DNA. Sirius red stain was used to evaluate the fibrosis ratio. Hematoxylin-eosin staining was used to observe the formation of teratomas. RESULTS: Four weeks after intramyocardial injection of iPSC-CMs, animals undergoing iPSC-CM transplantation had lower mortality than the control group. Animals injected with cell-free solution (control group) demonstrated significant left ventricular (LV) functional deterioration, whereas grafting of iPSC-CMs attenuated this remodeling process. In the control group, the ejection fraction deteriorated by 10.11% (from 46.36 to 41.67%), and fractional shortening deteriorated by 9.23% (from 24.37 to 22.12%) by 4 weeks. In the iPSC-CM injection group, the ejection fraction improved by 18.86% (from 44.09 to 52.41%), and fractional shortening improved by 23.69% (from 23.08 to 28.54%). Cell labeling, tracking, and molecular biology techniques indicated that the grafted cardiomyocytes survived in the rat heart 1 month after iPSC-CM transplantation. Myocardial fibrosis was also attenuated in the iPSC-CM treatment group. CONCLUSIONS: Human iPSC-CM grafts survived in infarcted rat hearts and restored myocardial function 4 weeks after transplantation. Cell replacement therapy also reversed ventricular remodeling, indicating the potential of iPSC-CMs for cardiac repair strategies.

Idiopathic isolated fibrotic atrial cardiomyopathy underlies unexplained scar-related atrial tachycardia in younger patients.

Aims: Unexplained scar-related atrial tachycardia (AT) has been frequently encountered in clinical practice. We hypothesized that idiopathic, isolated fibrotic atrial cardiomyopathy (ACM) underlies this rhythm disorder. This study was aimed to characterize the underlying substrate and to explore the aetiology of this unexplained scar-related AT. Methods and results: Twenty-six (11 men, aged 46 ± 13 years) of 52 non-surgical scar-related AT patients identified by three-dimensional voltage mapping were enrolled in this prospective observational study. Multimodality image examinations (echocardiography, cardiac magnetic resonance, 99Tc single-photon emission computed tomography), ventricular voltage mapping, and intracardiac pressure curve recording ruled out ventricular involvement. Catheter ablation was acutely successful for all the patients, and pacemaker implantation was performed in seven patients who presented sinus node dysfunction or atrial standstill after termination of the AT. In three patients with multiple AT recurrences, the diseased areas of the right atrium were resected and dechannelled via mini-invasive surgical interventions. Histological examinations revealed profound fibrosis without amyloidosis or adipose deposition. Viral and familial investigations yielded negative results. Fibrosis progression over a median of 45 (5-109) months of follow-up manifested as atrial arrhythmia recurrence in seven patients and atrial lead non-capture due to newly developed atrial standstill in two patients. Two patients suffered four ischaemic stroke events before receiving anticoagulation treatment. Conclusion: Isolated, fibrotic ACM may underlie the idiopathic scar-related ATs. This novel cardiomyopathy has unique clinical characteristics with high morbidity including stroke and warrants specific therapeutic strategies. Further investigations are required to determine the aetiology and mechanism.

Niclosamide induced cell apoptosis via upregulation of ATF3 and activation of PERK in Hepatocellular carcinoma cells.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of most common and aggressive human malignancies in the world, especially, in eastern Asia, and its mortality is very high at any phase. We want to investigate mechanism of niclosamide inducing cell apoptosis in HCC. METHODS: Two hepatoma cell lines were used to evaluate activity of niclosamide inducing cell apoptosis and study its mechanism. Quantitative real-time PCR and western blotting were used in analysis of genes expression or protein active regulated by niclosamide. RESULTS: Niclosamide remarkably induced cell apoptosis in hepatoma cells. Furthermore, our study revealed that RNA-dependent protein kinase-like kinase (PERK) is activated and its expression is up-regulated in HCC cells which are exposed to niclosamide. niclosamide also significantly increase activating transcription factor 3 (ATF3), activating transcription factor 4 (ATF4) and CCAAT/enhancer-binding protein-homologous protein (CHOP) expression in HCC cells. It's suggested that the function of niclosamide was abrogated by PERK inhibitor or absent ATF3. Expression of PERK and CHOP is correlated with ATF3 level in the cells. CONCLUSION: Taken together, our results indicate that ATF3 plays an integral role in ER stress activated and cell apoptosis induced by niclosamide in HCC cells. In this study, the new mechanism of niclosamide as anti-cancer we investigated, too.

The chemokine CXCL9 exacerbates chemotherapy-induced acute intestinal damage through inhibition of mucosal restitution.

PURPOSE: Acute intestinal damage induced by chemotherapeutic agent is often a dose-limiting factor in clinical cancer therapy. The aim of this study was to investigate the effect of chemokine CXCL9 on the intestinal damage after chemotherapy and explore the therapeutic potential of anti-CXCL9 agents. METHODS: In vitro cell proliferation assay was performed with a non-tumorigenic human epithelial cell line MCF10A. Multiple pathway analysis was carried out to explore the pathway that mediated the effect of CXCL9, and the corresponding downstream effector was identified with enzyme-linked immunosorbent assays. Chemotherapy-induced mouse model of intestinal mucositis was prepared by a single injection of the chemotherapeutic agent 5-fluorouracil (5-FU). In vivo expression of cxcl9 and its receptor cxcr3 in intestinal mucosa after chemotherapy was determined by quantitative real-time PCR. Therapeutic treatment with anti-CXCL9 antibodies was investigated to confirm the hypothesis that CXCL9 can contribute to the intestinal epithelium damage induced by chemotherapy. RESULTS: CXCL9 inhibited the proliferation of MCF10A cells by activating phosphorylation of p70 ribosomal S6 kinase (p70S6K), which further promotes the secretion of transforming growth factor beta (TGF-ß) as the downstream effector. A blockade of phospho-p70S6K with inhibitor abolished the effect of CXCL9 on MCF10A cells and reduced the secretion of TGF-ß. The expression levels of cxcl9 and cxcr3 were significantly up-regulated in intestinal mucosa after 5-FU injection. Neutralizing elevated CXCL9 with anti-CXCR9 antibodies successfully enhanced reconstitution of intestinal mucosa and improved the survival rate of mice that received high-dose chemotherapy. CONCLUSIONS: CXCL9 inhibits the proliferation of epithelial cells via phosphorylation of p70S6K, resulting in the excretion of TGF-ß as downstream mediator. CXCL9/CXCR3 interaction can exacerbate chemotherapeutic agent-induced intestinal damage, and anti-CXCL9 agents are potential novel therapeutic candidates for promoting mucosal restitution.

Small molecule-mediated directed differentiation of human embryonic stem cells toward ventricular cardiomyocytes.

The generation of human ventricular cardiomyocytes from human embryonic stem cells and/or induced pluripotent stem cells could fulfill the demand for therapeutic applications and in vitro pharmacological research; however, the production of a homogeneous population of ventricular cardiomyocytes remains a major limitation. By combining small molecules and growth factors, we developed a fully chemically defined, directed differentiation system to generate ventricular-like cardiomyocytes (VCMs) from human embryonic stem cells and induced pluripotent stem cells with high efficiency and reproducibility. Molecular characterization revealed that the differentiation recapitulated the developmental steps of cardiovascular fate specification. Electrophysiological analyses further illustrated the generation of a highly enriched population of VCMs. These chemically induced VCMs exhibited the expected cardiac electrophysiological and calcium handling properties as well as the appropriate chronotropic responses to cardioactive compounds. In addition, using an integrated computational and experimental systems biology approach, we demonstrated that the modulation of the canonical Wnt pathway by the small molecule IWR-1 plays a key role in cardiomyocyte subtype specification. In summary, we developed a reproducible and efficient experimental platform that facilitates a chemical genetics-based interrogation of signaling pathways during cardiogenesis that bypasses the limitations of genetic approaches and provides a valuable source of ventricular cardiomyocytes for pharmacological screenings as well as cell replacement therapies.