eIF3 mRNA selectivity profiling reveals eIF3k as a cancer-relevant regulator of ribosome content.

eIF3, whose subunits are frequently overexpressed in cancer, regulates mRNA translation from initiation to termination, but mRNA-selective functions of individual subunits remain poorly defined. Using multiomic profiling upon acute depletion of eIF3 subunits, we observed that while eIF3a, b, e, and f markedly differed in their impact on eIF3 holo-complex formation and translation, they were each required for cancer cell proliferation and tumor growth. Remarkably, eIF3k showed the opposite pattern with depletion promoting global translation, cell proliferation, tumor growth, and stress resistance through repressing the synthesis of ribosomal proteins, especially RPS15A. Whereas ectopic expression of RPS15A mimicked the anabolic effects of eIF3k depletion, disruption of eIF3 binding to the 5'-UTR of RSP15A mRNA negated them. eIF3k and eIF3l are selectively downregulated in response to endoplasmic reticulum and oxidative stress. Supported by mathematical modeling, our data uncover eIF3k-l as a mRNA-specific module which, through controlling RPS15A translation, serves as a rheostat of ribosome content, possibly to secure spare translational capacity that can be mobilized during stress.

Transfemoral transcatheter aortic valve replacement with VitaFlowTM valve for pure native aortic regurgitation in patients with high surgical risk: Rationale and design of a prospective, multicenter, and randomized SEASON-AR trial.

BACKGROUND: Previous studies primarily demonstrated that transfemoral transcatheter aortic valve replacement (TAVR) with self-expanding valve appeared to be a safe and feasible treatment for patients with pure native aortic regurgitation (AR). However, the routine application of transfemoral TAVR for pure AR patients lacks support from randomized trials. TRIAL DESIGN: SEASON-AR trial is a prospective, multicenter, randomized, controlled, parallel-group, open-label trial, involving at least 20 sites in China, aiming to enroll 210 patients with pure native severe AR and high surgical risk. All enrolled patients are randomly assigned in a 1:1 fashion to undergo transfemoral TAVR with VitaFlowTM valve and receive guideline-directed medical therapy (GDMT) or to receive GDMT alone. The primary endpoint is the rate of major adverse cardiac events (MACE) at 12 months after the procedure, defined by the composite of all-cause mortality, disabling stroke, and rehospitalization for heart failure. The major secondary endpoints encompass various measures, including procedure-related complications, device success, 6-minute walk distance, and the occurrence of each individual component of the primary endpoint. After hospital discharge, follow-up was conducted through clinical visits or telephone contact at 1, 6, and 12 months. The follow-up will continue annually until 5 years after the index procedure to assess the long-term outcomes. CONCLUSION: SEASON-AR trial is the first study designed to investigate the clinical efficacy and safety of transfemoral TAVR with a self-expanding valve in patients with pure native severe AR with inoperable or high-risk, as compared to medical treatment only.

Single-center experience with self-expanding transcatheter aortic valve system for symptomatic high-risk patients with severe aortic regurgitation: One-year outcomes.

AIMS: To evaluate the safety and efficacy of transcatheter aortic valve implantation (TAVI) for the treatment of aortic regurgitation (AR). METHODS: From September 2019 to February 2022, 62 patients who underwent transfemoral TAVI procedure for pure, symptomatic severe AR with the VitaFlow system were enrolled in the current study. The outcomes were assessed according to the Valve Academic Research Consortium 3 criteria. Procedural results and clinical outcomes for 1 year were analyzed. RESULTS: The mean age was 71.56 ± 7.34 years and 58.1% were male. The mean Society of Thoracic Surgeons score was 5.44 ± 3.22%. The device success rate was 79.0%. Only one patient was converted to open surgery. The in-hospital mortality rate was 1.6%. The 1-year all-cause mortality rate was 6.5%. The new permanent pacemaker implantation rate was 29.0% in-hospital and 30.7% at 1-year follow-up. The second valve implantation rate was 14.5%. No patient developed more than moderate paravalvular leakage during follow-up. The mean ejection fraction improved from 54.05 ± 10.83% at baseline to 59.32 ± 8.70% (p < 0.001 compared with baseline) at 12 months. Left ventricular end-diastolic diameter decreased from 61.62 ± 5.58 mm at baseline to 55.20 ± 4.51 mm (p < 0.001 compared with the baseline) at 12 months. CONCLUSIONS: Transfemoral TAVI procedure shows efficacy in treating patients with severe pure native AR. The safety is improved with the development of the VitaFlow system.

NRP2 promotes atherosclerosis by upregulating PARP1 expression and enhancing low shear stress-induced endothelial cell apoptosis.

Atherosclerosis-related cardiovascular diseases are leading causes of mortality worldwide, characterized by the development of endothelial cell dysfunction, increased oxidized low-density lipoprotein uptake by macrophages, and the ensuing formation of atherosclerotic plaque. Local blood flow patterns cause uneven atherosclerotic lesion distribution, and endothelial dysfunction caused by disturbed flow is an early step in the development of atherosclerosis. The present research aims to elucidate the mechanism underlying the regulation of Neuropilin 2 (NRP2) under low shear stress (LSS) in the atheroprone phenotype of endothelial cells. We observed that NRP2 expression was significantly upregulated in LSS-stimulated human umbilical vein endothelial cells (HUVECs) and in mouse aortic endothelial cells. Knockdown of NRP2 in HUVECs significantly ameliorated cell apoptosis induced by LSS. Conversely, overexpression of NRP2 had the opposite effect on HUVEC apoptosis. Animal experiments suggest that NRP2 knockdown markedly mitigated the development of atherosclerosis in Apoe-/- mice. Mechanistically, NRP2 knockdown and overexpression regulated PARP1 protein expression in the condition of LSS, which in turn affected the expression of apoptosis-related genes. Moreover, the upstream transcription factor GATA2 was found to regulate NRP2 expression in the progression of atherosclerosis. These findings suggest that NRP2 plays an essential proatherosclerotic role through the regulation of cell apoptosis, and the results reveal that NRP2 is a promising therapeutic target for the treatment of atherosclerotic disorders.

Comparison of one-month versus twelve-month dual antiplatelet therapy after implantation of drug-eluting stents guided by either intravascular ultrasound or angiography in patients with acute coronary syndrome: rationale and design of prospective, multicenter, randomized, controlled IVUS-ACS and ULTIMATE-DAPT trial.

BACKGROUND: Current guidelines recommend administering dual antiplatelet therapy (DAPT) for 12 months to patients with acute coronary syndromes (ACS) and without contraindications after drug-eluting stent (DES) implantation. A recent study reported that 3 months of DAPT followed by ticagrelor monotherapy is effective and safe in ACS patients undergoing DES implantation compared with the standard duration of DAPT. However, it is unclear whether antiplatelet monotherapy with ticagrelor alone versus ticagrelor plus aspirin reduces the incidence of clinically relevant bleeding without increasing the risk of major adverse cardiovascular and cerebrovascular events (MACCEs) in ACS patients undergoing percutaneous coronary intervention (PCI) with DES implantation guided by either intravascular ultrasound (IVUS) or angiography who have completed a 1-month course of DAPT with aspirin plus ticagrelor. METHODS: The IVUS-ACS and ULTIMATE-DAPT is a prospective, multicenter, randomized, controlled trial designed to determine (1) whether IVUS-guided versus angiography-guided DES implantation in patients with ACS reduces the risk of target vessel failure (TVF) at 12 months and (2) whether ticagrelor alone versus ticagrelor plus aspirin reduces the risk of clinically relevant bleeding without increasing the risk of MACCE 1-12 months after the index PCI in ACS patients undergoing DES implantation guided by either IVUS or angiography. This study will enroll 3486 ACS patients eligible for DES implantation, as confirmed by angiographic studies. The patients who meet the inclusion criteria and none of the exclusion criteria will be randomly assigned in a 1:1 fashion to the IVUS- or angiography-guided group (first randomization). All enrolled patients will complete a 1-month course of DAPT with aspirin plus ticagrelor after the index PCI. Patients with no MACCEs or major bleeding (≥Bleeding Academic Research Consortium (BARC) 3b) within 30 days will be randomized in a 1:1 fashion to either the ticagrelor plus matching placebo (SAPT)group or ticagrelor plus aspirin (DAPT)group for an additional 11 months (second randomization). The primary endpoint of the IVUS-ACS trial is TVF at 12 months, including cardiac death, target vessel myocardial infarction (TVMI), or clinically driven target vessel revascularization (CD-TVR). The primary superiority endpoint of the ULTIMATE-DAPT trial is clinically relevant bleeding, defined as BARC Types 2, 3, or 5 bleeding, and the primary non-inferiority endpoint of the ULTIMATE-DAPT trial is MACCE, defined as cardiac death, myocardial infarction, ischemic stroke, CD-TVR, or definite stent thrombosis occurring 1-12 months in the second randomized population. CONCLUSION: The IVUS-ACS and ULTIMATE-DAPT trial is designed to test the efficacy and safety of 2 different antiplatelet strategies in ACS patients undergoing PCI with DES implantation guided by either IVUS or angiography. This study will provide novel insights into the optimal DAPT duration in ACS patients undergoing PCI and provide evidence on the clinical benefits of IVUS-guided PCI in ACS patients.

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

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

Assessment of the expression and response of PD-1, LAG-3, and TIM-3 after neoadjuvant radiotherapy in rectal cancer.

Many studies have verified the safety of combined radiotherapy and immune checkpoint blockades (ICBs) without the specific radiation dose or sequencing of combination. We aimed to evaluate the expression and response of PD-1, TIM-3, LAG-3 after neoadjuvant radiotherapy (NRT) and explore the possibility and optimal schedule of combining immunotherapy with radiotherapy in treating rectal cancer. Immunohistochemistry was performed to detect the expression of PD-1, TIM-3, LAG-3, CD8, and CD3. These molecules' expression was detected on the specimens of 76 rectal cancer patients following NRT and 13 of these patients before NRT. The expression of ICBs was assessed by the percentage of positive cells. The levels of PD-1 and immune cells (ICs) LAG-3 in rectal cancer increased after NRT (0% vs. 3%, p=0.043 and 5% vs. 45%, p=0.039, respectively). However, TIM-3 in ICs and tumor cells (TCs) were both decreased (80% vs. 50%, p=0.011, 90% vs. 0%, p=0.000, respectively). The LAG-3 expression was higher in patients treated with short-course RT than long-course RT (22.5% vs. 8.0%, p=0.0440 in ICs; 0% vs. 70%, p<0.001 in TCs). On the contrary, CD8 was higher after long-course RT (15% vs. 8%, p=0.0146). Interestingly, the level of ICs TIM-3 was low in > eight weeks after long-course RT (p=0.045). The expressions of PD-1, ICs TIM-3, ICs LAG-3, CD3, and CD8 were associated with the disease-free survival (DFS) in univariate analysis (p=0.036, 0.008, 0.018, 0.025, and 0.004, respectively). Adjusted by the relevant variables, PD-1 (HR 0.274; 95% CI 0.089-0.840; p=0.024) and ICs TIM-3 (HR 0.425; 95% CI 0.203-0.890; p=0.023) were independent prognostic factors of DFS in rectal cancer patients following NRT. In conclusion, we have identified that PD-1 and ICs LAG-3 presented a trend towards increased expression after NRT, supporting the ICBs and NRT combination as a potential treatment option for local advanced rectal cancer patients. The radiotherapeutic mode and timing of the treatment might significantly affect the expression of ICBs, which indicated that the sequencing and time window of ICBs immunotherapy utility might deserve a high value.

AMP-activated protein kinase regulates glycocalyx impairment and macrophage recruitment in response to low shear stress.

Low shear stress (LSS) increases degradation of the endothelial glycocalyx, leading to production of endothelial inflammation and atherosclerosis. However, the underlying mechanisms of how LSS diminishes the endothelial glycocalyx remain unclear. We showed that LSS inactivated AMPK, enhanced Na+-H+ exchanger (NHE)1 activity, and induced glycocalyx degradation. Activation of AMPK prevented LSS-induced NHE1 activity and endothelial glycocalyx impairment. We further identified hyaluronidase 2 (HYAL2) as a mediator of endothelial glycocalyx impairment in HUVECs exposed to LSS. Inactivation of AMPK by LSS up-regulates the activity of HYAL2, which acts downstream of NHE1. We characterized a left common carotid artery partial ligation (PL) model of LSS in C57BL/6 mice. The results showed decreased expression of hyaluronan (HA) in the endothelial glycocalyx and decreased thickness of the endothelial glycocalyx in PL mice. Pharmacological activation of AMPK by ampkinone not only attenuated glycocalyx impairment due to HA degradation but also blocked vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 expression increase and macrophage recruitment in the endothelia of PL mice. Our results revealed that AMPK dephosphorylation induced by LSS activates NHE1 and HYAL2 to promote HA degradation and glycocalyx injury, which may contribute to endothelial inflammatory reaction and macrophage recruitment.-Zhang, J., Kong, X., Wang, Z., Gao, X., Ge, Z., Gu, Y., Ye, P., Chao, Y., Zhu, L., Li, X., Chen, S. AMP-activated protein kinase regulates glycocalyx impairment and macrophage recruitment in response to low shear stress.

Oscillatory Shear Stress Induces Oxidative Stress via TLR4 Activation in Endothelial Cells.

BACKGROUND: Oscillatory shear stress (OSS) disrupts endothelial homeostasis and promotes oxidative stress, which can lead to atherosclerosis. In atherosclerotic lesions, Toll-like receptor 4 (TLR4) is highly expressed. However, the molecular mechanism by which TLR4 modulates oxidative changes and the cell signaling transudation upon OSS is yet to be determined. METHODS AND RESULTS: Carotid artery constriction (CAC) surgery and a parallel-plate flow chamber were used to modulate shear stress. The results showed that OSS significantly increased the oxidative burden, and this was partly due to TLR4 activation. OSS activated NOX2 and had no significant influence to NOX1 or NOX4 in endothelial cells (ECs). OSS phosphorylated caveolin-1, promoted its binding with endothelial nitric oxide synthase (eNOS), and resulted in deactivation of eNOS. TLR4 inhibition restored levels of nitric oxide (NO) and superoxide dismutase (SOD) in OSS-exposed cells. CONCLUSION: TLR4 modulates OSS-induced oxidative stress by activating NOX2 and suppressing eNOS.

Clinical Outcomes of Antithrombotic Strategies for Patients with Atrial Fibrillation After Percutaneous Coronary Intervention.

Antithrombotic strategies for patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) remain challenging. This study aims to explore the best antithrombotic strategy for AF patients after PCI based on a network meta-analysis. This study was registered in PROSPERO (CRD42018093928). The PubMed, Cochrane, and EMBASE databases were searched to identify clinical trials concerning antithrombotic therapy for AF patients with PCI from inception to April 2018. Pairwise and network meta-analysis were conducted to compare clinical outcomes of different antithrombotic therapy. The primary endpoint was major bleeding. Fifteen studies including 16,382 patients were identified with follow-up ranging from 3 to 12 months. Non-vitamin K oral anticoagulants (NOAC) plus P2Y12 inhibitor ranked first with a reduced risk of major bleeding compared with vitamin K antagonist (VKA) plus dual antiplatelet therapy (OR: 0.57, 95% CI: 0.43-0.75) but with no significant difference compared with VKA plus single platelet therapy (OR: 0.85, 95% CI: 0.62-1.16). Similar thrombotic events were evident among these groups. Subgroup analysis showed that VKA plus aspirin exhibited a similar risk of major bleeding compared with VKA plus clopidogrel (OR: 0.94, 95% CI: 0.73-1.23) but was associated with increased risks of ischaemic stroke (OR: 2.10, 95% CI: 1.33-3.32) and all-cause death (OR: 1.77, 95% CI: 1.15-2.74) versus VKA plus clopidogrel. In AF patients undergoing PCI, NOAC plus P2Y12 inhibitor and VKA plus clopidogrel, but not VKA plus aspirin, were associated with reduced risk of major bleeding compared with the recommended VKA-based triple therapy, while thrombotic events were similar among these treatments.

Hyaluronidase2 (Hyal2) modulates low shear stress-induced glycocalyx impairment via the LKB1/AMPK/NADPH oxidase-dependent pathway.

The endothelium glycocalyx layer (ECL), presents on the apical surface of endothelial cells, creates a barrier between circulating blood and the vessel wall. Low shear stress (LSS) may accelerate the degradation of the glycocalyx via hyaluronidase2 (Hyal2) and then alter the cell polarity. Yet the liver kinase B1 (LKB1) signaling pathway plays an important role in regulating cell polarity. However, the relationship between LKB1 and glycocalyx during LSS is not clear. In the current study, we demonstrate that LSS attenuates LKB1 and AMP-activated protein kinase activation as well as activated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (p47phox ) and Hyal2 in the human umbilical vein endothelial cell (HUVEC). Pretreatment with 5-Aminoimidazole-4-carboxamide1-ß-D-ribofuranoside (AICAR), or diphenyleneiodonium (DPI chloride) and transfection with LKB1 overexpression vector and p47phox small interfering RNA downregulated LSS-induced Hyal2 activation. By coimmunoprecipitation, we discovered the existence of p47phox /Hyal2 complex. LSS induced the dissociation of p47phox /Hyal2 complex, which was inhibited by LKB1 overexpression and AICAR. Furthermore, knockdown of Hyal2 performed a positive feedback on LKB1 activity. In addition, we also show that LSS enhanced LKB1 translocation from the cytosol to the nucleus. Taken together, these data indicate that Hyal2 regulates LSS-induced injury of the glycocalyx via LKB1/AMPK/NADPH oxidase signaling cascades.

Low shear stress induces endothelial reactive oxygen species via the AT1R/eNOS/NO pathway.

Reactive oxygen species (ROS) contribute to many aspects of physiological and pathological cardiovascular processes. However, the underlying mechanism of ROS induction by low shear stress (LSS) remains unclear. Accumulating evidence has shown that the angiotensin II type 1 receptor (AT1R) is involved in inflammation, apoptosis, and ROS production. Our aim was to explore the role of AT1R in LSS-mediated ROS induction. We exposed human umbilical vein endothelial cells (HUVECs) to LSS (3 dyn/cm2 ) for different periods of time. Western blotting and immunofluorescence showed that LSS significantly induced AT1R expression in a time-dependent manner. Using immunohistochemistry, we also noted a similar increase in AT1R expression in the inner curvature of the aortic arch compared to the descending aorta in C57BL/6 mice. Additionally, HUVECs were cultured with a fluorescent probe, either DCFH, DHE or DAF, after being subjected to LSS. Cell chemiluminescence and flow cytometry results revealed that LSS stimulated ROS levels and suppressed nitric oxide (NO) generation in a time-dependent manner, which was reversed by the AT1R antagonist Losartan. We also found that Losartan markedly increased endothelial NO synthase (eNOS) phosphorylation at Ser(633,1177) and dephosphorylation at Thr(495), which involved AKT and ERK. Moreover, the ROS level was significantly reduced by endogenous and exogenous NO donors (L-arginine, SNP) and increased by the eNOS inhibitor L-NAME. Overall, we conclude that LSS induces ROS via AT1R/eNOS/NO.

Exogenous hydrogen sulfide attenuates the development of diabetic cardiomyopathy via the FoxO1 pathway.

BACKGROUND: Previous studies have suggested that exogenous hydrogen sulfide can alleviate the development of diabetic cardiomyopathy (DCM) by inhibiting oxidative stress, inflammation, and apoptosis. However, the underlying mechanism is not fully understood. Nuclear expression and function of the transcription factor Forkhead box protein O (FoxO1) have been associated with cardiovascular diseases, and thus, the importance of FoxO1 in DCM has gained increasing attention. This study was designed to investigate the interactions between hydrogen sulfide (H2 S) and nuclear FoxO1 in DCM. METHODS: Diabetes was induced in adult male C57BL/6J mice by intraperitoneal injection of streptozotocin and was treated with H2 S donor sodium hydrosulfide for 12 weeks. The H9C2 cardiomyoblast cell line and neonatal rat cardiomyocytes (NRCMs) were treated with the slow-releasing H2 S donor GYY4137 before high-glucose (HG) exposure with or without pretreatment with the Akt inhibitor MK-2206 2HCl. Changes in FoxO1 protein phosphorylation and subcellular localization were determined in H9C2 cells, NRCMs, and cardiac tissues from normal and diabetic mice. Cardiac structure and function in the diabetic mice were evaluated by echocardiography and histological analysis and compared with those in control animals. RESULTS: The echocardiographic and histopathological data indicated that exogenous H2 S improved cardiac function and attenuated cardiac hypertrophy and myocardial fibrosis in diabetic mice. H2 S also improved HG-induced oxidative stress and apoptosis in cardiac tissue and NRCMs. In addition, H2 S induced FoxO1 phosphorylation and nuclear exclusion in vitro and in vivo, and this function was not inhibited by MK-2206 2HCl. Alanine substitution mutation of three sites in FoxO1-enhanced FoxO1 transcriptional activity, and subsequent treatment with exogenous H2 S could not prevent HG-induced nuclear retention. CONCLUSIONS: Our data indicate that H2 S is a novel regulator of FoxO1 in cardiac cells and provide evidence supporting the potential of H2 S in inhibiting the progression of DCM.

Relationship between high platelet reactivity on clopidogrel and long-term clinical outcomes after drug-eluting stents implantation (PAINT-DES): a prospective, propensity score-matched cohort study.

BACKGROUND: The relationship between platelet reactivity and long-term clinical outcomes remains controversial. The present prospective study was designed to explore the association between high platelet reactivity (HPR) on clopidogrel and long-term clinical outcomes following implantation of drug eluting stents (DES). METHODS: A total of 1769 consecutive patients assessed by Aggrestar (PL-11) were enrolled at our center from February 2011 to December 2017. The primary end point was major adverse cardiovascular and cerebrovascular events (MACCE), defined as definite or probable stent thrombosis, spontaneous myocardial infarction, all cause death, clinically driven target vessel revascularization (TVR), or ischemic stroke. Bleeding served as the safety endpoint. Propensity score matching (PSM) analysis was performed to adjust for baseline differences in the overall cohort. RESULTS: Finally, 409 patients (23.1%) were identified with HPR on clopidogrel. At a median follow-up of 4.1 years (interquartile range, 1.8 years), the occurrence of MACCE was significantly higher in HPR on clopidogrel group than normal platelet reactivity (NPR) on clopidogrel group (15.6% vs. 5.4%, p < 0.001). After PSM, 395 paired patients were matched, and the difference in MACCE between HPR (15.7%) versus NPR (9.4%) on clopidogrel groups remained significant (P < 0.001), mainly driven by increased all cause death (5.3% vs. 1.8%, p < 0.001), and clinically driven TVR (8.1% vs. 6.3%, p = 0.019) in the HPR group. The risk of bleeding between two groups was similar. CONCLUSIONS: This prospective study confirms the relationship between HPR on clopidogrel and long-term adverse cardiovascular events after coronary stenting.

Inhibition of angiotension II type 1 receptor reduced human endothelial inflammation induced by low shear stress.

Low shear stress (LSS)-induced endothelial inflammation is the basis for the development of atherosclerosis. However, the mechanism underlying LSS-induced inflammation is not well understood. The angiotensin II type 1 receptor (AT1R), a component of the renin-angiotensin system, participates in atherosclerotic plaque progression. The aim of this study was to investigate the role of AT1R in LSS-induced endothelial activation. Using immunohistochemistry, we noted significant increases in AT1R, vascular endothelial adhesion cell-1 (VCAM1), and intercellular adhesion molecule-1 (ICAM1) expression in the inner curvature of the aortic arch in C57BL/6 mice compared to the descending aorta in these mice. Moreover, western blotting revealed that these LSS-induced increases in AT1R, ICAM1 and VCAM1 expression were time dependent. However, the expression of these proteins was significantly abolished by treatment with the AT1R antagonist Losartan (1µM) or AT1R small interfering RNA (siRNA). AT1R inhibition significantly suppressed extracellular signal-regulated kinase 1/2 (ERK) upregulation, which also resulted in decreases in ICAM1 and VCAM1 protein expression. These findings demonstrate that LSS induces endothelial inflammation via AT1R/ERK signaling and that Losartan has beneficial effects on endothelial inflammation.

Two DNA repair gene polymorphisms on the risk of gastrointestinal cancers: a meta-analysis.

PARP-1 and MGMT play an important role in the DNA repair system and therefore have been implicated in human carcinogenesis. However, the association between the most studied PARP-1 rs1136410: T > C and MGMT rs12917: C > T polymorphism and risk of gastrointestinal (GI) cancers was reported with inconclusive results. Accordingly, a meta-analysis of 23 published case-control studies was conducted to assess the strength of association using crude odds ratios (ORs) with 95% confidence intervals (CIs). Overall, the C allele of PARP-1 rs1136410: T > C polymorphism was significantly associated with increased susceptibility of GI cancers (homozygote comparison: OR = 1.43, 95% CI 1.14-1.81; heterozygote comparison: OR = 1.18, 95% CI 1.07-1.29; dominant model: OR = 1.23, 95% CI 1.12-1.35; recessive model: OR = 1.30, 95% CI 1.04-1.62; allelic comparison: OR = 1.19, 95% CI 1.07-1.32). In the subgroup analysis, still obvious associations were found in the Asian population, gastric cancer, and high-quality studies. For MGMT rs12917: C > T polymorphism, no obvious associations were found for all genetic models overall. However, in the subgroup analysis, we found that the T allele was significantly associated with reduced colorectal cancer risk for heterozygote (OR = 0.83, 95% CI 0.70-0.97) and dominant model (OR = 0.84, 95% CI 0.72-0.98). In conclusion, this meta-analysis suggests that the PARP-1 rs1136410: T > C polymorphism is a susceptibility factor for GI cancers, but the variant allele of MGMT rs12917: C > T polymorphism appears to be a protective factor for colorectal cancer. Large-scale and well-designed case-control studies are necessary to validate the risk identified in the present meta-analysis.

The correlation between the comprehensive nutrition index and quality of life of patients with nasopharyngeal carcinoma treated by intensity-modulated radiotherapy.

The purpose of this study was to compare the changing tendency of nutrition with 54 nasopharyngeal carcinoma patients during intensity-modulated radiation therapy (IMRT), and to investigate the correlation between comprehensive nutritional status and quality of life (QoL), which was assessed by the European Organization for Research and Treatment of Cancer Core Quality-of-Life Questionnaire. The nutritional index, including body mass index, ideal body weight percentage, usual body weight percentage, albumin, hemoglobin, and total lymphocyte count (TLC), was evaluated at 2 time points: within 48 h after admission (T1) and at the end of treatment with IMRT (T2). A statistically significant downgrade of every index was observed during IMRT. A comprehensive nutritional model was established by principal components analysis at T2. QoL scores of functional (P = 0.002) and the global QoL scales (P = 0.001) existed a positive correlation with comprehensive nutritional status. QoL scores of symptom scales (P = 0.002) and 6 single items (P = 0.005) had a negative correlation with it. The scores of global QoL scales in comprehensive nutrition of normal (20.4%), moderate (55.6%), and severe malnutrition (24.1%) were 69.70 ± 17.98, 48.33 ± 19.25, and 37.18 ± 24.67, respectively. Patients with different nutritional status had different QoL (B = 10.405, SE = 2.828, t = 3.680, P = 0.001). Multiaspect nutritional supports should be enhanced to improve patients' comprehensive nutritional status during treatment.

Anxiety disorders are associated with increased plasma adrenomedullin level and left ventricular hypertrophy in patients with hypertension.

OBJECTIVE: To investigate the association between anxiety disorders and left ventricular hypertrophy in patients with essential hypertension. METHODS: Left ventricular structure and function were assessed with echocardiography in 56 patients with essential hypertension and anxiety disorder (study group) and in 56 patients with hypertension only (control group). Serum adrenomedullin levels were also measured in these patients. RESULTS: There was no statistically significant difference in the left ventricular ejection fraction between the study and the control group (54.21 ± 88.81% versus 56.01 ± 7.85%, p>0.05). The left ventricular mass index (LVMI) in study group was higher than in control group (137.05 ± 9.42 versus 123.57 ± 7.01 g/m(2), p=0.001). The plasma levels of adrenomedullin in study group was higher than in control group (25.97 ± 5.48 versus 18.32 ± 6.97 ng/L, p=0.001). Levels of plasma adrenomedullin were positively correlated with LVMI in the study (r=0.734, p<0.05) and control group (r=0.592, p<0.05). CONCLUSION: Anxiety disorders are associated with elevated plasma adrenomedullin levels and increased left ventricular hypertrophy in patients with essential hypertension. The clinical significance of these changes requires further investigation.

Pathological Mechanism and Treatment of Calcified Aortic Stenosis.

Calcified aortic stenosis (AS) is one of the most common valvular heart diseases worldwide, characterized by progressive fibrocalcific remodeling and thickening of the leaflets, which ultimately leads to obstruction of blood flow. Its pathobiology is an active and complicated process, involving endothelial cell dysfunction, lipoprotein deposition and oxidation, chronic inflammation, phenotypic transformation of valve interstitial cells, neovascularization, and intravalvular hemorrhage. To date, no targeted drug has been proven to slow down or prevent disease progression. Aortic valve replacement is still the optimal treatment of AS. This article reviews the etiology, diagnosis, and management of calcified aortic stenosis and proposes novel potential therapeutic targets.

Intravascular Ultrasound vs Angiography-Guided Drug-Coated Balloon Angioplasty: The ULTIMATE â ¢ Trial.

BACKGROUND: Drug-coated balloon (DCB) angioplasty seems a safe and effective option for specific de novo coronary lesions. However, the beneficial effect of intravascular ultrasound (IVUS)-guided DCB angioplasty in de novo lesions remains uncertain. OBJECTIVES: This study aimed to assess the benefits of IVUS guidance over angiography guidance during DCB angioplasty in de novo coronary lesions. METHODS: A total of 260 patients with high bleeding risk who had a de novo coronary lesion (reference vessel diameter 2.0-4.0 mm, and lesion length ≤15 mm) were randomly assigned to either an IVUS-guided or an angioplasty-guided DCB angioplasty group. The primary endpoint was in-segment late lumen loss (LLL) at 7 months after procedure. The secondary endpoint was target vessel failure at 6 months. RESULTS: A total of 2 patients in the angiography-guided group and 7 patients in the IVUS-guided group underwent bailout stent implantation (P = 0.172). The primary endpoint of 7-month LLL was 0.03 ± 0.52 mm with angiography guidance vs -0.10 ± 0.34 mm with IVUS guidance (mean difference 0.14 mm; 95% CI: 0.02-0.26; P = 0.025). IVUS guidance was also associated with a larger 7-month minimal lumen diameter (2.06 ± 0.62 mm vs 1.75 ± 0.63 mm; P < 0.001) and a smaller diameter stenosis (28.15% ± 13.88% vs 35.83% ± 17.69%; P = 0.001) compared with angiography guidance. Five target vessel failures occurred at 6 months, with 4 (3.1%) in the angiography-guided group and 1 (0.8%) in the IVUS-guided group (P = 0.370). CONCLUSIONS: This study demonstrated that IVUS-guided DCB angioplasty is associated with a lower LLL in patients with a de novo coronary lesion compared with angiography guidance. (Intravascular Ultrasound Versus Angiography Guided Drug-Coated Balloon [ULTIMATE-III]; NCT04255043).