Safety and efficacy of steerable versus non-steerable sheaths for catheter ablation of atrial fibrillation systematic review and meta-analysis.

OBJECTIVES: With the development of radiofrequency (RF) ablation technology. In recent years, more and more patients with atrial fibrillation (AF) have been treated with RF ablation. Steerable sheaths (SS) have been widely used in RF ablation of AF. The aim of this meta-analysis was to compare the efficacy and safety of AF ablation using SS and non-steerable sheaths (NSS). METHODS: From the beginning to March 2022, we conducted a comprehensive, systematic search of the databases PubMed, MEDLINE, EMBASE, Web of Science and the Cochrane Library to finish the study. For categorical and continuous data, we used ORs and mean difference to calculate the effect. We also estimated the 95% CI. RESULTS: Five studies of RF ablation of AF were selected, three prospective and two retrospective, involving 282 SS and 236 NSS ablation patients. The rate of recurrence of AF or atrial arrhythmias was 27.3% versus 42.8% (OR: 0.52, 95% CI 0.36, 0.76, z=3.41, p=0.0006) and acute pulmonary vein (PV) reconnection (8.7% vs 17.4%, OR: 0.47, 95% CI 0.23, 0.95, z=2.10, p=0.04). In the SS group and the NSS group, the total ablation time (p=0.25), fluoroscopy time (p=0.26) and total operative time (p=0.35) were not significantly different. CONCLUSIONS: Compared with the use of NSS, the use of SS for RF ablation of AF can effectively reduce the recurrence rate of AF and the occurrence of acute PVs reconnection events. However, there is no advantage in shortening the total RF time, fluoroscopy time, total surgical time and reducing complications.

Association of serum PCSK9 levels with platelet function in patients with acute coronary syndromes.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates low-density lipoprotein (LDL) homeostasis and plays a key role in acute coronary syndrome (ACS). The cardioprotective effect of PCSK9 inhibition extends beyond LDL cholesterol reduction, involving regulation of platelet function by not yet unraveled mechanisms. Oxidized-LDL (ox-LDL) is increased during ACS and induces platelet activation via binding to platelet surface. We will evaluate serum PCSK9 and its correlation with platelet reactivity and platelet-ox-LDL binding in Chinese ACS patients. METHOD AND DESIGN: In this pilot cross-sectional study, we will enroll 115 Chinese participants aged 30 to 75 years with ACS. Blood sample will be obtained after the first maintenance dose of aspirin and clopidogrel during morning time. Serum PCSK9 will be measured by an enzyme-linked immunoadsorbent assay. Platelet reactivity will be assessed by; Platelet activation (P-selectin and GPIIbIIIa expression using flow cytometry) and; Platelet aggregation using light transmission aggregometry in response to various stimuli. On-treatment platelet reactivity is measured by adenosine diphosphate-induced platelet aggregation. Binding of ox-LDL to platelet will be evaluated by flow cytometry. Spearman correlations will be used to determine association of serum PCSK9 with platelet functional parameters and platelet-ox-LDL binding. Additionally, continuous PCSK9 levels will be categorized into tertiles of equal size to investigate its association with on-treatment platelet reactivity. DISCUSSION: This study will reveal possible relationship between serum PCSK9 and platelet reactivity in the setting of ACS which may shed light on therapeutic potential in platelet inhibition by targeting PCSK9. The study will also explore the association of serum PCSK9 and platelet-ox-LDL binding, an important mechanism for platelet-LDL interplay, to provide mechanistic insight into PCSK9-mediated regulation of platelet reactivity.

Combined modality therapy for patients with esophageal squamous cell carcinoma: Radiation dose and survival analyses.

BACKGROUND: We aimed to analyze the radiation dose and compare survival among combined modality therapy using modern radiation techniques for patients with esophageal squamous cell carcinoma (ESCC). METHODS: This retrospective study included patients with clinically staged T1-4N0-3M0 ESCC from 2014 to 2018. Patients who received combined modality therapies with curative intent were enrolled. The overall survival (OS) rates among combined modality therapy were compared. The clinical variables and impacts of radiation dose on survival were analyzed by the Kaplan-Meier method and Cox regression model. RESULTS: Of the 259 patients, 141 (54.4%) received definitive concurrent chemoradiotherapy (DCCRT); 67 (25.9%) underwent neoadjuvant chemoradiotherapy followed by surgery (NCRT+S); 51 (19.7%) obtained surgery followed by adjuvant chemoradiotherapy (S+ACRT). Two-year OS rates of the DCCRT, NCRT+S and S+ACRT group were 48.9, 61.5 and 51.2%. In the subgroup analysis of DCCRT group, the 2-year OS of patients receiving radiation dose 55-60 Gy was 57.1%. Multivariate analyses showed that clinical stage (p = 0.004), DCCRT with 55-60 Gy (p = 0.043) and NCRT+S with pathological complete response (pCR) (p = 0.014) were significant prognostic factors for better OS. The radiation dose-survival curve demonstrated a highly positive correlation between higher radiation dose and better survival. CONCLUSION: Our results suggest that NCRT+S can provide a favorable survival for patients with ESCC, especially in patients who achieved pCR. The optimal radiation dose might be 55-60 Gy for patients receiving DCCRT via modern radiation techniques. Further randomized clinical studies are required to confirm the survival benefits between NCRT+S and DCCRT with escalated dose.

Offline Selective Extraction Combined with Online Enrichment for Sensitive Analysis of Chondroitin Sulfate by Capillary Electrophoresis.

A capillary electrophoresis (CE) method combined with online and offline enrichment for improving the detection sensitivity of chondroitin sulfate (CS) is established. The online enrichment method is based on the field-amplified sample stacking and large volume electrokinetic injection, and offline enrichment is based on the association between cetyltrimethylammonium chloride and CS. Experimental parameters affecting CE method such as the type and pH of background electrolyte, the injection mode and time and the steps of offline enrichment were optimized. Under optimum conditions, the calibration plot between CS concentration and peak area was linear in the range of 1 ~ 100 µg/mL. The enrichment factor was 130 times and the limit of detection was 50 ng/mL. The average recovery was 103.5% and the relative standard deviation of peak area was <2.0%. The method was successfully applied to the quantitative analysis of CS in drugs.

The effect of esomeprazole vs famotidine on aspirin/clopidogrel dual therapy after percutaneous coronary intervention.

BACKGROUND: Regarding drug interactions between proton pump inhibitors (PPIs) and dual antiplatelet therapy (DAPT), controversies have arisen over the possibility that PPIs may interfere with the antiplatelet effect of DAPT. However, whether this interaction is drug-specific or a class effect needs to be determined. It is not clear whether famotidine, an H2-receptor antagonist (H2RA), interacts with DAPT. OBJECTIVES: The aim of this study was to assess the impact of esomeprazole and famotidine on the efficacy of DAPT. MATERIAL AND METHODS: The study involved 160 patients undergoing elective percutaneous coronary interventions and treated with DAPT and concomitant use of esomeprazole (40 mg/d) or famotidine (40 mg/d). Platelet reactivity was measured with adenosine diphosphate (ADP)-induced light transmittance aggregometry (LTA) and vasodilator-stimulated phosphoprotein phosphorylation-platelet reactivity index (VASP-PRI) at baseline, 14 and 30 days after applying randomized acid-suppressing agents. RESULTS: No significance differences were observed in treatment-by-period interactions with LTA values (p = 0.298) and VASP-PRI values (p = 0.867), which suggested no carryover effect in either regimen over the 30-day treatment period. Intergroup comparisons were done between the 2 groups at 3 times, and similar findings were observed at each time (all p > 0.05). As for intragroup measurements among the separate times, significantly lower LTA and VASP-PRI values existed on day 14 for both agents (both p < 0.05). CONCLUSIONS: The antiplatelet effect of DAPT was not affected by concomitant use of esomeprazole or famotidine. These 2 agents were much less likely than CYP2C19 polymorphisms to influence aspirin/clopidogrel therapy, supporting the assertion that the pharmacodynamic interaction between aspirin/clopidogrel and acid-suppressing agents is a drug-specific rather than a class effect.

Effect of Aqueous Extract from Descurainia sophia (L.) Webb ex Prantl on Ventricular Remodeling in Chronic Heart Failure Rats.

OBJECTIVE: Descurainia sophia (L.) Webb ex Prantl (DS) is a traditional Chinese medicine. Our current study was to evaluate the effect of DS on ventricular remodeling in chronic heart failure (HF) rats and its underlying mechanism. METHODS: The rat chronic heart failure model induced by suprarenal abdominal aortic coarctation surgery. The survival rats were randomly divided into 3 groups: the sham group (n=6), the HF group (n=6), and the HF+DS group (n=6). After 3 months of drug intervention, we examined the effects of DS by Sirius Red staining, electron microscopy, echocardiography, hemodynamic measurement, and TUNEL and explored the underlying mechanism by Western blotting. RESULTS: We found that rats treated with DS showed improved cardiac function and less tissue damage compared to untreated group. Additionally, DS could reduce the cardiomyocytes apoptosis, decrease the ratio of Bax/bcl-2 and Caspase-3 expression, and enhance the phosphorylation of Akt protein expression. CONCLUSION: Our study suggested that rats treated with DS after suprarenal abdominal aortic coarctation surgery showed attenuated cardiac fibrosis and apoptosis, and the protective effect may be correlated with the activation of PI3k/Akt/mTOR dependent manner.

Gold nanomaterials based pseudostationary phases in capillary electrophoresis: a brand-new attempt at chondroitin sulfate isomers separation.

In this work, a CE method with bare gold nanorods (GNRs) based pseudostationary phase was developed and applied for the separation of chondroitin sulfate (CS) isomers, CS, and dermatan sulfate (DS). The separation efficiency was investigated by varying the experimental parameters such as concentration and pH of the BGE, separation voltage, internal diameter of capillary, different size, and morphology of gold nanomaterials. Results showed that different size and morphology of gold nanomaterials had different effects on the separation of CS and DS. The best separation of CS and DS was achieved in the BGE composed of aqueous 150 mmol/L (mM) ethylenediamine + 20 mM sodium dihydrogen phosphate + 30% v/v GNRs, pH 4.5, at the separation voltage of -10 kV. Capillary was 59.2 cm in length (effective length 49 cm), 50 µm id capillary thermostated at 25°C. CE with bare GNRs used as pseudostationary phase was shown to be a suitable technique for the separation of CS and DS mixtures with wider peaks. RSD of migration time and peak area of CS and DS were 0.13, 0.14 and 0.86, 1.07%, respectively.

Overexpression of GOLPH3 protein is associated with worse prognosis in patients with epithelial ovarian cancer.

Golgi phosphoprotein 3 (GOLPH3) has important roles in the pathogenesis of cancer, and overexpression of GOLPH3 has been found in several kinds of cancers. However, the relationship between GOLPH3 overexpression and prognosis in patients with epithelial ovarian cancer remains unknown. This study aimed to investigate the relationship between GOLPH3 overexpression and overall survival in patients with epithelial ovarian cancer. The expression of GOLPH3 protein in tumor tissue was evaluated using immunohistochemistry. Seventy-five patients with epithelial ovarian cancer with the data of GOLPH3 expression and follow-up were included. GOLPH3 overexpression was significantly associated with advanced stage, histology, high grade, and lymph node metastases (P < 0.05). Kaplan-Meier analysis showed that patients with GOLPH3 overexpression had significantly poorer overall survival than those with low expression of GOLPH3 (log-rank P < 0.001). In the multivariate Cox proportional hazards analysis, GOLPH3 overexpression was independently associated with poorer overall survival (hazard ratio [HR] = 3.60; 95 % confidence interval (CI0 1.14-11.33, P = 0.03). Therefore, overexpression of GOLPH3 protein is closely related to poorer prognosis in patients with epithelial ovarian cancer.

STAT3 interacts with Skp2/p27/p21 pathway to regulate the motility and invasion of gastric cancer cells.

The interleukin-6 (IL-6)/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway mediates cell proliferation and migration. S-phase kinase-associated protein-2 (Skp2) catalyzes the ubiquitylation of p27 and p21. Here we investigated that the cross-talk of the two pathways regulates motility and invasion of gastric cancer SGC7901 and MGC803 cells. Both cell lines endogenously secret IL-6, and blockage of IL-6 or JAK2 inhibited the activation of JAK2 and STAT3. Depletion of STAT3 downregulated Skp2 expression, and thereby increased the expression of p27 and p21. The depletion of STAT3 inhibited the ability of cells to migrate and invade, and impaired the cellular cytoskeleton mainly microtubules; while the depletion of p27 partially restored the impaired ability to migrate, and reversed the impaired microfilaments, further inhibited the ability to invade, but had little effect on microtubules and cellular adhering ability of STAT3-depleted cells. STAT3 depletion inhibited the activity of RhoA and the interaction with stathmin, downregulated the expression of pFAK (phosphorylated focal adhesion kinase), acetylated-tubulin, RECK (reversion-inducing-cysteine-rich protein with kazal motifs) and Sp1, upregulated E-cadherin, and reduced the activities of MMP (matrix metalloproteinase)-2 and -9. The depletion of p27 increased RhoA (Ras homolog family member A) activity, upregulated RECK, and downregulated E-cadherin and Sp1 in STAT3-depleted cells. The results indicate that the interaction between STAT3 and Skp2/p27/p21 pathway plays an important role in mediating the motility, migration and invasion of gastric cancer cells, and inhibition of STAT3 may be a useful therapeutic approach for metastasis of gastric cancer, but caution needs to be taken for its effects on Skp2/p27/p21 pathway.

Hypoxic switch in mitochondrial myeloid cell leukemia factor-1/Mtd apoptotic rheostat contributes to human trophoblast cell death in preeclampsia.

Preeclampsia, a disorder of pregnancy, is characterized by increased trophoblast cell death and altered trophoblast-mediated remodeling of myometrial spiral arteries resulting in reduced uteroplacental perfusion. Mitochondria-associated Bcl-2 family members are important regulators of programed cell death. The mechanism whereby hypoxia alters the mitochondrial apoptotic rheostat is essential to our understanding of placental disease. Herein, myeloid cell leukemia factor-1 (Mcl-1) isoform expression was examined in physiological/pathological models of placental hypoxia. Preeclamptic placentae were characterized by caspase-dependent cleavage of death-suppressing Mcl-1L and switch toward cell death-inducing Mcl-1S. In vitro, Mcl-1L cleavage was induced by hypoxia-reoxygenation in villous explants, whereas Mcl-1L overexpression under hypoxia-reoxygenation rescued trophoblast cells from undergoing apoptosis. Cleavage was mediated by caspase-3/-7 because pharmacological caspase inhibition prevented this process. Altitude-induced chronic hypoxia was characterized by expression of Mcl-1L; resulting in a reduction of apoptotic markers (cleaved caspase-3/-8 and p85 poly-ADP-ribose polymerase). Moreover, in both physiological (explants and high altitude) and pathological (preeclampsia) placental hypoxia, decreased trophoblast syncytin expression was observed. Hence, although both pathological and physiological placental hypoxia are associated with slowed trophoblast differentiation, trophoblast apoptosis is only up-regulated in preeclampsia, because of a hypoxia-reoxygenation-induced switch in generation of proapoptotic Mcl-1 isoforms.

Human placental hypoxia-inducible factor-1alpha expression correlates with clinical outcomes in chronic hypoxia in vivo.

Placental hypoxia is causally implicated in fetal growth restriction and preeclampsia, with both occurring more frequently at high altitude (>2700 m; HA). The nuclear transcription factor hypoxia-inducible factor (HIF) may facilitate placental oxygen transport at HA by increasing erythropoiesis and placental angiogenesis. We therefore investigated HIF expression and its regulatory mechanisms in placentas from normal pregnancies at high (3100 m), moderate (1600 m), and sea level (75 m) altitudes. Moderate-altitude and sea level placentas did not differ, but HIF-1alpha and the von Hippel-Lindau tumor suppressor protein were overexpressed in HA placentas. The ability of von Hippel-Lindau tumor suppressor protein to form the E3 ubiquitin protein ligase complex, required for HIF-1alpha degradation, was unaltered in HA placentas. mRNA for factor-inhibiting HIF, a negative modulator of HIF-1alpha transactivation, was increased, but protein levels were diminished. Elevated HIF-1alpha likely contributed to the significant increase we report in HIF-1alpha downstream target proteins, transforming growth factor beta3 in the placenta, and vascular endothelial growth factor and erythropoietin in the maternal circulation. These circulating markers and lowered birth to placental weight ratios correlated with increased HIF-1alpha, thereby linking molecular and systemic physiological data. The HA response to chronic hypoxia resembles preeclampsia in several aspects, illustrating the utility of the HA model in understanding placental pathologies.

Oxygen regulation of macrophage migration inhibitory factor in human placenta.

Macrophage migration inhibitory factor (MIF) is an important proinflammatory cytokine involved in regulation of macrophage function. In addition, MIF may also play a role in murine and human reproduction. Although both first trimester trophoblast and decidua express MIF, the regulation and functional significance of this cytokine during human placental development remains unclear. We assessed MIF expression throughout normal human placental development, as well as in in vitro (chorionic villous explants) and in vivo (high altitude placentae) models of human placental hypoxia. Dimethyloxalylglycine (DMOG), which stabilizes hypoxia inducible factor-1 under normoxic conditions, was also used to mimic the effects of hypoxia on MIF expression. Quantitative real-time PCR and Western blot analysis showed high MIF protein and mRNA expression at 7-10 wk and lower levels at 11-12 wk until term. Exposure of villous explants to 3% O(2) resulted in increased MIF expression and secretion relative to standard conditions (20% O(2)). DMOG treatment under 20% O(2) increased MIF expression. In situ hybridization and immunohistochemistry showed elevated MIF expression in low oxygen-induced extravillous trophoblast cells. Finally, a significant increase in MIF transcript was observed in placental tissues from high-altitude pregnancies. Hence, three experimental models of placental hypoxia (early gestation, DMOG treatment, and high altitude) converge in stimulating increased MIF, supporting the conclusion that placental-derived MIF is an oxygen-responsive cytokine highly expressed in physiological in vivo and in in vitro low oxygen conditions.

Dynamic HIF1A regulation during human placental development.

The human placenta is a unique organ in terms of oxygenation as it undergoes a transition from a low to a more oxygenated environment. This physiological switch in oxygen tension is a prerequisite for proper placental development and involves the hypoxia inducible factor (HIF). HIF is stable and initiates gene transcription under hypoxia, whereas in normoxia, interaction with the von Hippel-Lindau tumor suppressor protein (VHL) leads to rapid degradation of the HIF1A subunit. The degradation requires formation of a multiprotein complex (VHLCBC) and hydroxylation of HIF1A proline residues via members of the egg-laying-defective nine (EGLN) family. Herein, we have investigated the regulatory mechanisms of HIF1A expression during human placental development. Expression of HIF1A and VHL was high at 7-9 wk of gestation, when oxygen tension is low, and decreased when placental oxygen tension increases (10-12 wk of gestation). During early placentation, HIF1A localized in cytotrophoblasts, while VHL was present in syncytiotrophoblasts. At 10-12 wk, VHL appeared in cytotrophoblast cells, which coincided with the disappearance of HIF1A. At the same time the association of VHL and Cullin 2 as well as ubiquitination of HIF1A was maximal. EGLN1, EGLN2, and EGLN3 were also temporally expressed in an oxygen-dependent fashion, with greatest mRNA expression at 10-12 wk of gestation. Inhibition of EGLN activity increased HIF1A stability in villous explants and stimulated transforming growth factor beta 3 (TGFB3) expression consistent with promoter analyses showing that HIF1A transactivates TGFB3. These data demonstrate that during placental development, HIF1A is regulated by temporal and spatial changes in expression and association of molecules forming the multi-protein VHLCBC complex as well as prolyl hydroxylase activities.