Nanog regulates Pou3f1 expression at the exit from pluripotency during gastrulation.

Pluripotency is regulated by a network of transcription factors that maintain early embryonic cells in an undifferentiated state while allowing them to proliferate. NANOG is a critical factor for maintaining pluripotency and its role in primordial germ cell differentiation has been well described. However, Nanog is expressed during gastrulation across all the posterior epiblast, and only later in development is its expression restricted to primordial germ cells. In this work, we unveiled a previously unknown mechanism by which Nanog specifically represses genes involved in anterior epiblast lineage. Analysis of transcriptional data from both embryonic stem cells and gastrulating mouse embryos revealed Pou3f1 expression to be negatively correlated with that of Nanog during the early stages of differentiation. We have functionally demonstrated Pou3f1 to be a direct target of NANOG by using a dual transgene system for the controlled expression of Nanog Use of Nanog null ES cells further demonstrated a role for Nanog in repressing a subset of anterior neural genes. Deletion of a NANOG binding site (BS) located nine kilobases downstream of the transcription start site of Pou3f1 revealed this BS to have a specific role in the regionalization of the expression of this gene in the embryo. Our results indicate an active role of Nanog inhibiting neural regulatory networks by repressing Pou3f1 at the onset of gastrulation.This article has an associated First Person interview with the joint first authors of the paper.This work was funded by the Spanish government [grant BFU2017-84914-P to M.M.]. The Gottgens laboratory is supported by core funding from the Wellcome Trust and Medical Research Council to the Wellcome and Medical Research Council Cambridge Stem Cell Institute. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia, Innovación y Universidades (MCNU) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence [SEV-2015-0505]

Amphilimus- vs. zotarolimus-eluting stents in patients with diabetes mellitus and coronary artery disease: the SUGAR trial

Aim: Patients with diabetes mellitus are at high risk of adverse events after percutaneous revascularization, with no differences in outcomes between most contemporary drug-eluting stents. The Cre8 EVO stent releases a formulation of sirolimus with an amphiphilic carrier from laser-dug wells, and has shown clinical benefits in diabetes. We aimed to compare Cre8 EVO stents to Resolute Onyx stents (a contemporary polymer-based zotarolimus-eluting stent) in patients with diabetes. Methods and results: We did an investigator-initiated, randomized, controlled, assessor-blinded trial at 23 sites in Spain. Eligible patients had diabetes and required percutaneous coronary intervention. A total of 1175 patients were randomly assigned (1:1) to receive Cre8 EVO or Resolute Onyx stents. The primary endpoint was target-lesion failure, defined as a composite of cardiac death, target-vessel myocardial infarction, and clinically indicated target-lesion revascularization at 1-year follow-up. The trial had a non-inferiority design with a 4% margin for the primary endpoint. A superiority analysis was planned if non-inferiority was confirmed. There were 106 primary events, 42 (7.2%) in the Cre8 EVO group and 64 (10.9%) in the Resolute Onyx group [hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.44 to 0.96; pnon-inferiority <0.001; psuperiority = 0.030]. Among the secondary endpoints, Cre8 EVO stents had significantly lower rate than Resolute Onyx stents of target-vessel failure (7.5% vs 11.1%, HR 0.67, 95% CI 0.46 to 0.99; p = 0.042). Probable or definite stent thrombosis and all-cause death were not significantly different between groups. Conclusions: In patients with diabetes, Cre8 EVO stents were non-inferior to Resolute Onyx stents with regard to target-lesion failure composite outcome. An exploratory analysis for superiority at 1 year suggests that the Cre8 EVO stents might be superior to Resolute Onyx stents with regard to the same outcome

Amphilimus- vs. zotarolimus-eluting stents in patients with diabetes mellitus and coronary artery disease: the SUGAR trial.

AIM: Patients with diabetes mellitus are at high risk of adverse events after percutaneous revascularization, with no differences in outcomes between most contemporary drug-eluting stents. The Cre8 EVO stent releases a formulation of sirolimus with an amphiphilic carrier from laser-dug wells, and has shown clinical benefits in diabetes. We aimed to compare Cre8 EVO stents to Resolute Onyx stents (a contemporary polymer-based zotarolimus-eluting stent) in patients with diabetes. METHODS AND RESULTS: We did an investigator-initiated, randomized, controlled, assessor-blinded trial at 23 sites in Spain. Eligible patients had diabetes and required percutaneous coronary intervention. A total of 1175 patients were randomly assigned (1:1) to receive Cre8 EVO or Resolute Onyx stents. The primary endpoint was target-lesion failure, defined as a composite of cardiac death, target-vessel myocardial infarction, and clinically indicated target-lesion revascularization at 1-year follow-up. The trial had a non-inferiority design with a 4% margin for the primary endpoint. A superiority analysis was planned if non-inferiority was confirmed. There were 106 primary events, 42 (7.2%) in the Cre8 EVO group and 64 (10.9%) in the Resolute Onyx group [hazard ratio (HR): 0.65, 95% confidence interval (CI): 0.44-0.96; Pnon-inferiority < 0.001; Psuperiority = 0.030]. Among the secondary endpoints, Cre8 EVO stents had significantly lower rate than Resolute Onyx stents of target-vessel failure (7.5% vs. 11.1%, HR: 0.67, 95% CI: 0.46-0.99; P = 0.042). Probable or definite stent thrombosis and all-cause death were not significantly different between groups. CONCLUSION: In patients with diabetes, Cre8 EVO stents were non-inferior to Resolute Onyx stents with regard to target-lesion failure composite outcome. An exploratory analysis for superiority at 1 year suggests that the Cre8 EVO stents might be superior to Resolute Onyx stents with regard to the same outcome. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT03321032

Safety and effectiveness of self-adhesive mesh in laparoscopic ventral hernia repair using transabdominal preperitoneal route (vol 31, pg 1213, 2017)

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Subclavian angioplasty during coronary interventions using radial approach.

In the past years, the percentage of percutaneous coronary angiography and coronary interventions using radial access had significantly increased due to its higher safety, lower risk of major bleeding, and hence lower cardiovascular mortality. Subclavian artery stenosis is one of the challenges that may be met during transradial coronary interventions, which may necessitate femoral access crossover or conversion. To evaluate the feasibility and safety of performing subclavian angioplasty via radial access during complex coronary interventions using the forearm approach. A series of patients with complex radial approach due to subclavian stenosis received subclavian angioplasty during the procedure. We included 48 patients out of 22 500 procedures performed from February 2009 to February 2020. All patients did not have alternative vascular access due to extensive peripheral arterial disease (previous history of iliac stenting or distal aortic occlusion, which makes femoral access crossover difficult; also the contralateral radial/ulnar artery was very faint or not detectable at all). Mean age was 72 (10) years and 67% of patients were males. Subclavian angioplasty was successfully done in all patients via ipsilateral radial access; 44 patients (91.7%) required subclavian stenting, and 4 patients were treated by subclavian angioplasty without stenting. Coronary angiography or intervention was perfectly achieved through the revascularized subclavian artery; coronary stenting was successfully done in 36 patients as indicated. It can be concluded that percutaneous subclavian artery angioplasty can be done safely and effectively to facilitate complex transradial coronary procedures with an acceptable immediate technical success, especially in patients without alternative vascular access. Also, we may conclude that subclavian angioplasty may be successfully performed in patients with symptomatic upper limb ischemia, via the radial approach

Subclavian angioplasty during coronary interventions using radial approach

BACKGROUND: In the past years, the percentage of percutaneous coronary angiography and interventions using the radial access had significantly increased due to its higher safety, lower risk of major bleeding and hence lower cardiovascular mortality. Subclavian artery stenosis is one of the challenges that may be met during transradial coronary interventions, which may necessitate femoral access crossover or conversion. AIMS: To evaluate the feasibility and safety of performing subclavian angioplasty via the radial access, during complex coronary interventions using forearm approach. METHODS: A series of patients with complex radial approach due to subclavian stenosis, for which subclavian angioplasty was performed during the procedure. Forty-eight patients out of 22 500 procedures performed, from February 2009 to February 2020, were included. All patients did not have alternative vascular access due to extensive peripheral arterial disease (previous history of iliac stenting or distal aortic occlusion which makes femoral access crossover difficult, also the contralateral radial/ulnar artery was very faint or not felt at all). RESULTS: Mean age was 72 (10) years and 67% were males. Subclavian angioplasty was successfully done in all patients via the ipsilateral radial access; 91.7% (44 patients) required subclavian stenting and 4 patients were treated by subclavian angioplasty without stenting. Coronary angiography or intervention was perfectly done through the revascularized subclavian artery; coronary stenting was successfully done in 36 patients as indicated. CONCLUSIONS: It can be concluded that percutaneous subclavian artery angioplasty can be done safely and effectively to facilitate complex transradial coronary procedures, with an acceptable immediate technical success, especially in patients without alternative vascular access. Also, we may conclude that subclavian angioplasty may be successfully performed in patients with symptomatic upper limb ischemia, via the radial approac

Nanog regulates Pou3f1 expression at the exit from pluripotency during gastrulation

Pluripotency is regulated by a network of transcription factors that maintain early embryonic cells in an undifferentiated state while allowing them to proliferate. NANOG is a critical factor for maintaining pluripotency and its role in primordial germ cell differentiation has been well described. However, Nanog is expressed during gastrulation across all the posterior epiblast, and only later in development is its expression restricted to primordial germ cells. In this work, we unveiled a previously unknown mechanism by which Nanog specifically represses genes involved in anterior epiblast lineage. Analysis of transcriptional data from both embryonic stem cells and gastrulating mouse embryos revealed Pou3f1 expression to be negatively correlated with that of Nanog during the early stages of differentiation. We have functionally demonstrated Pou3f1 to be a direct target of NANOG by using a dual transgene system for the controlled expression of Nanog Use of Nanog null ES cells further demonstrated a role for Nanog in repressing a subset of anterior neural genes. Deletion of a NANOG binding site (BS) located nine kilobases downstream of the transcription start site of Pou3f1 revealed this BS to have a specific role in the regionalization of the expression of this gene in the embryo. Our results indicate an active role of Nanog inhibiting neural regulatory networks by repressing Pou3f1 at the onset of gastrulation.This article has an associated First Person interview with the joint first authors of the paper.This work was funded by the Spanish government [grant BFU2017-84914-P to M.M.]. The Gottgens laboratory is supported by core funding from the Wellcome Trust and Medical Research Council to theWellcome and Medical Research Council Cambridge Stem Cell Institute. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia, Innovación y Universidades MCNU) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence [SEV-2015-0505].S