Following the publication of the above article, an interested reader drew to the attention of the Editorial Office that the immunofluorescence images shown in Fig. 3B on p. 214 to represent the 'HCT116 SiP' and 'HCT116+3 SiP' experiments (top row of data) were strikingly similar. Upon examining their data, the authors have realized that the data in Fig. 3B were presented incorrectly; specifically, the data shown in the 'HCT116+3 SiP' panel were erroneously duplicated from the data shown correctly in the 'HCT116 SiP' panel. The authors have now submitted a revised version of Fig. 3, containing the corrected version of the 'HCT116+3 SiP' data panel in Fig. 3B, and this is shown on the next page. Note that this error did not affect the overall conclusions reported in the study. The authors are grateful to the Editor of International Journal of Oncology for allowing them this opportunity to publish a Corrigendum, and all the authors agree with its publication. Furthermore, the authors apologize to the readership for any inconvenience caused. [International Journal of Oncology 43: 210‑218, 2013; DOI: 10.3892/ijo.2013.1932].

Abstract Background In transcatheter mitral valve edge-to-edge repair (M-TEER), the goal of optimizing post-procedural residual mitral regurgitation inadvertently carries the risk of generating relevant mitral stenosis, resulting in an elevated mean mitral valve pressure gradient (MPG). In patients with primary mitral regurgitation, an elevated post-procedural MPG has been found to independently predict impaired outcomes. However, the effect of elevated post-procedural MPG on outcome after M-TEER in patients with secondary mitral regurgitation (SMR) has yet to be fully elucidated. This study investigated the impact of elevated MPG on outcome in the EuroSMR registry, a large, multi-center real-world cohort of patients with SMR. Methods This retrospective study included patients who underwent M-TEER for SMR between 2009 and 2021 in 12 centers. Patients were stratified into two groups based on SMR etiology: (1) ventricular SMR (vSMR), and (2) atrial SMR (aSMR). The etiology was considered as vSMR in patients with a left ventricular ejection fraction (LV-EF) <50% and aSMR in subjects with preserved left ventricular function (LV-EF ≥50%) and a markedly dilated left atrium (Left Atrial Volume Index [LAVi] ≥40ml/m2). According to the proposed M-VARC threshold, post-procedural MPG was assessed by discharge transthoracic echocardiography and was considered elevated if >5 mmHg. The primary endpoint was all-cause mortality after 5 years, with statistical analysis conducted using Kaplan-Meier and uni- and multivariable Cox Regression analysis. Results Among the 1703 patients in the study (vSMR: n=1420; aSMR: n=283), elevated post-procedural MPG was observed in 9.4% (n=133) of vSMR and 19.1% (n=54) of aSMR patients. Atrial fibrillation was significantly more prevalent in aSMR (78.4% vs. 57.1%, p<0.001). Patients with vSMR had a higher median surgical risk assessed by the EuroScore II (aSMR vs. vSMR: 7.0% [IQR 4.0, 13.1] vs. 4.9% [IQR 2.9, 8.5], p<0.001). Kaplan-Meier analyses for all-cause mortality after 5 years demonstrated significant differences in aSMR patients (low vs. elevated MPG: 48.9% vs. 69.8%, log-rank p<0.01), while there was no difference in vSMR patients (55.7% vs. 60.8%, log-rank p=0.66) (Figure 1). This observed effect remained significant even after accounting for common confounding factors: elevated MPG was an independent predictor for all-cause mortality in aSMR patients (HR=1.86; 95%-CI: 1.14-3.02, p=0.013) but not in vSMR patients (HR=1.00; 95%-CI: 0.74-1.35, p=0.99). Conclusion Our findings suggest that elevated post-procedural MPG is an independent predictor of adverse outcomes in patients with aSMR, but not in those with vSMR. This effect may partially be explained by a reduced left atrial function and higher rates of atrial fibrillation.Figure 1.Study flowchart

Abstract Background Little is known about acute changes in right ventricular (RV) function and geometry following transcatheter tricuspid edge-to-edge repair (T-TEER) or transcatheter tricuspid valve replacement (TTVR). Pressure-strain-volume loop-derived myocardial work metrics showed associations with myocardial energetics and contractility in conditions accompanied by volume overload, suggesting their potential utility in patients with tricuspid regurgitation (TR). Purpose To define acute changes in RV volumes and RV myocardial work following T-TEER and TTVR using conventional and pressure-strain-volume derived RV work metrics. Methods In this multicenter, observational study, 3D echocardiographic datasets and invasively acquired RV pressures were collected before and after transcatheter tricuspid valve procedure. Using dedicated software (ReVISION, Argus Cognitive) 3D RV volumes and strains were quantified and decomposed to longitudinal, radial and anterio-posterior motion. Forward stroke volume (SV) was calculated by subtracting TR volumes from RV 3D end-diastolic volume (EDV) and end-systolic volume (ESV) difference. Three-dimensional pressure-strain-volume loops were constructed and global RV work-index (RV-Wi) was calculated. Changes in RV parameters before and after the intervention were compared using paired-samples t test. Results Of 37 patients included in this study (65% male), 20 underwent T-TEER and 17 underwent TTVR. Compared to T-TEER patients, patients undergoing TTVR had higher prevalence of torrential TR at baseline but also achieved a higher reduction in TR volumes after the intervention (44 ± 11 ml vs 60 ± 16ml; p = 0,001). Following T-TEER there was a significant reduction in RV EDV (240 ± 93 ml vs 200 ± 80 ml; p < 0.001) and increase in SV (55 ± 34 ml vs 68 ± 26 ml; p = 0.036). Following TTVR there was a significant increase in RV ESV (121 ± 46 vs 146 ± 48, p = 0.003) and no significant change in SV (47 ± 24 ml vs 55 ± 20 ml; p = 0.143). There was significant reduction in RV strain and ejection fraction (EF) (all p < 0.001) primarily driven by reduction of radial motion component in both groups. RV-Wi increased in 35% (7/20) of T-TEER patients and in 18% of (3/17) TTVR patients. Conclusion An acute reduction in RV EF was observed in all patients and was mainly caused by decrease in RV EDV in T-TEER patients and increase in RV ESV in TTVR patients. Despite decrease of conventional metrics of RV function in both groups, an increase in RV-Wi was observed in 27% of all patients.Baseline and follow-up characteristicsCentral Figure

Abstract Background Hemodynamic outcomes in patients undergoing transcatheter edge-to-edge-repair of the mitral valve (M-TEER) are difficult to predict. Computational functional dynamic (CFD) is frequently used in biomedical engineering to simulate blood flow patterns under various conditions. The authors developed a standardized workflow for individualized analyses and investigated the hemodynamic of mitral regurgitation volumes and gradients by using CFD. Methods 20 patients from two high volume centers who suffered from severe mitral regurgitation (MR) and underwent full cycle cardiac computed tomography (CT) prior procedure were enrolled. Baseline computed tomography and intraprocedural data were analyzed. Based on the specific valve morphology, individualized CFD-simulations were performed to calculate MR volumes prior to intervention and estimate hemodynamics after M-TEER. Results CFD-analyses of 20 patients (mean age 80±4 years, 60% male) showed excellent correlation between baseline PISA method-based MR volumes (45±23ml) measured in transesophageal echocardiography (TEE) and CFD-based calculation (45±26ml; R=0.917; P<0.001) as well as between TEE-measured mean baseline effective regurgitant orifice area (EROA; 27±16mm²) and CFD-measured EROA (24±18mm²; R=0.869; P<0.001)). After device implantation, correlation between intraprocedural TEE-measured and CFD-estimated correlation for residual MR volumes (R=0.949; P<0.001) and EROA (R=0.841; P<0.001) remained robust. Post-interventional mean diastolic pressure gradient (TEE) was 3.6±2.8mmHg which was in close correlation with the CFD estimated gradient (3.0±1.8mmHg, R=0.905; P<0.001). Conclusions This is the first study to use a CFD-standardized workflow for predicting hemodynamic changes in patients undergoing M-TEER using data from two different centers. In the future, CFD-based analyses might serve as a key-diagnostic tool for predicting residual MR volumes and gradients for M-TEER-procedures.Comparison of TEE and CFD flow patternBland-Altman-Blots

Aims Data on the prognostic impact of residual tricuspid regurgitation (TR) after tricuspid transcatheter edge‐to‐edge repair (T‐TEER) are scarce. The aim of this analysis was to evaluate 2‐year survival and symptomatic outcomes of patients in relation to residual TR after T‐TEER. Methods and results Using the large European Registry of Transcatheter Repair for Tricuspid Regurgitation (EuroTR registry) we investigated the impact of residual TR on 2‐year all‐cause mortality and New York Heart Association (NYHA) functional class at follow‐up. The study further identified predictors for residual TR ≥3+ using a logistic regression model. The study included a total of 1286 T‐TEER patients (mean age 78.0 ± 8.9 years, 53.6% female). TR was successfully reduced to ≤1+ in 42.4%, 2+ in 40.0% and 3+ in 14.9% of patients at discharge, while 2.8% remained with TR ≥4+ after the procedure. Residual TR ≥3+ was an independent multivariable predictor of 2‐year all‐cause mortality (hazard ratio 2.06, 95% confidence interval 1.30–3.26, p = 0.002). The prevalence of residual TR ≥3+ was four times higher in patients with higher baseline TR (vena contracta >11.1 mm) and more severe tricuspid valve tenting (tenting area >1.92 cm 2 ). Of note, no survival difference was observed in patients with residual TR ≤1+ versus 2+ (76.2% vs. 73.1%, p = 0.461). The rate of NYHA functional class ≥III at follow‐up was significantly higher in patients with residual TR ≥3+ (52.4% vs. 40.5%, p < 0.001). Of note, the degree of TR reduction significantly correlated with the extent of symptomatic improvement ( p = 0.012). Conclusions T‐TEER effectively reduced TR severity in the majority of patients. While residual TR ≥3+ was associated with worse outcomes, no differences were observed for residual TR 1+ versus 2+. Symptomatic improvement correlated with the degree of TR reduction.

<p>Supplementary Tables S1-S5 - PDF file 94K, Clinicopathologic characteristics of patients with HCC (S1); Pharmacological inhibitors (S2); Antibodies for Western blot and immunofluorescence (S3); Primer pairs for qualitative and quantitative PCR (S4); Correlations between IR-A and splicing factor mRNA levels in human HCC tumours (S5)</p>

Supplementary Figure S1 - PDF file 573K, IR status in human HCC tumours

Supplementary Figure S4 - PDF file 227K, CUGBP1, hnRNPH, hnRNPA2B1 and S2/ASF mRNA levels are controlled by EGFR in HuH7 cells

Supplementary Figure S3 - PDF file 53K, Basal and EGFR-activated ERK levels in HCC cell lines

Abstract Objectives To investigate the long-term clinical impact of prosthesis-patient mismatch (PPM) in patients undergoing transcatheter aortic valve implantation(TAVI). Background Both measured and predicted effective orifice area indexed to the body surface area (EOAi) have been suggested to define PPM in patients undergoing TAVI. The impact of PPM on clinical outcomes may accumulate with extended follow-up and vary according to the definition used. Methods Patients included in a prospective TAVI registry were stratified by the presence of moderate (0.65-0.85 cm2/m2 or 0.55-0.70 cm2/m2 if obese) or severe (≤0.65 cm2/m2 or ≤0.55 cm2/m2 if obese) PPM according to echocardiographically measured EOAi (measured PPM) prior to discharge, predicted EOAi based on published EOA reference values for each valve model and size (predicted PPMTHV), or predicted EOAi based on EOA reference derived from computed tomography measurements of aortic annulus dimension (predicted PPMCT). Results In an analysis of 2,463 patients, the incidence of measured PPM (moderate: 27.0%; severe: 8.7%) was higher than the incidence of predicted PPMTHV (moderate: 11.3%; severe: 1.2%) or predicted PPMCT (moderate: 12.0%; severe: 0.1%). During a median time to death of 843 days, mortality rates at 10 years were comparable in patients with versus without measured PPM or predicted PPMCT. In contrast, patients with moderate predicted PPMTHV had a lower risk of 10-year all-cause mortality compared with those without PPM (HR: 0.69; 95% CI: 0.52-0.90). Conclusions The use of predicted as compared to measured EOAi results in a lower estimate of PPM severity in TAVI ptients. We observed no increased risk of death in patients with PPM throughout 10-year of follow-up.Incidence of PPM after TAVIImpact of Measured an Predicted PPM

Abstract Background Staging classification to quantify the extent of extra-aortic valve cardiac damage is recognized as a useful prognostic tool in patients undergoing transcatheter aortic implantation (TAVI) for aortic stenosis (AS). However, this classification has not been validated in each AS subtype. Objectives The present study aimed to investigate the prognostic impact of staging classification in patients with four major AS subtypes. Methods In a prospective TAVI registry, patients were classified into high gradient AS (HG-AS), classical low flow low gradient AS (LFLG-AS), paradoxical LFLG-AS, and normal flow low gradient AS (NFLG-AS). Five-year mortality was compared between early stage (stage 0, 1, or 2) and advanced stage (stage 3 or 4). Results Among 1,507 patients undergoing TAVI, 812 patients had HG-AS, 186 patients had classical LFLG-AS, 277 patients had paradoxical LFLG-AS, and 232 patients had NFLG-AS. There were much difference in the distribution of cardiac stage among AS subtypes; advanced stage accounting for 54.3% in HG-AS, 58.6% in NFLG-AS, 62.5% in paradoxical LFLG-AS, and 80.6% in classical LFLG-AS. Patients with advanced stage had higher all-cause mortality compared with early stage in HG-AS and paradoxical LFLG-AS (HRadjusted 2.00; 95% CI 1.44-2.78 and HRadjusted 2.15; 95% CI 1.43-3.21), but not in classical LFLG-AS and NFLG-AS (HRadjusted 1.17; 95% CI 0.70-1.95 and HRadjusted 1.43; 95% CI 0.90-2.27). Conclusions Early stage was associated with a reduced risk for five-year mortality in patients with HG-AS and paradoxical LFLG-AS, while there was comparable mortality between early and advanced stages in patients with classical LFLG-AS and NFLG-AS.

Abstract Background Atrial fibrillation (AF) has been associated with adverse clinical outcomes after transcatheter aortic valve implantation (TAVI). However, the impact of AF on post-TAVI flow status and clinical outcomes in patients with paradoxical low-flow low-gradient aortic stenosis (PLFLG-AS) is still unclear. Objectives The present study aimed to investigate the effect of AF on post-TAVI flow status and clinical outcomes in patients with PLFLG-AS undergoing TAVI. Methods In a prospective TAVI registry, patients with preserved left ventricular ejection fraction (LVEF ≥50%) were stratified according to the flow-gradient status and presence of AF. Results Among 2,259 TAVI patients with preserved LVEF between August 2007 and June 2021, 765 had high-gradient AS (HG-AS) (mean gradient ≥40 mmHg) and 444 had PLFLG-AS (mean gradient <40 mmHg and stroke volume index [SVi] <35 ml/m2). AF was observed in 199 patients with HG-AS (26.0%) and 190 patients with PLFLG-AS (42.8%). At 1 year after TAVI, SVi was significantly improved in PLFLG-AS patients with no AF, whereas those with AF remained low-flow status (from 25.9 ± 8.5 mL/m2 to 37.2 ± 9.9 mL/m2 and from 26.8 ± 5.1 mL/m2 to 26.1 ± 9.1 mL/m2, respectively). PLFLG-AS patients had an increased risk of all-cause mortality at 1 year after TAVI compared with those without AF (HRadjust 2.79; 95% CI 1.58-4.93). Whereas PLFLG-AS patients with no AF had a similar mortality compared with HG-AS patients with no AF (HRadjust 0.84; 95% CI 0.49-1.44). Conclusions AF was associated with worse flow status and impaired prognosis after TAVI in patients with PLFLG-AS.

Background: Transcatheter mitral valve replacement (TMVR) using dedicated devices is an alternative therapy for high-risk patients with mitral regurgitation (MR). This study aimed to assess 2-year outcomes and predictors of mortality in patients undergoing TMVR from the CHOICE-MI multicenter registry.

Aims The impact of the cardio‐hepatic syndrome (CHS) on outcomes in patients undergoing mitral valve transcatheter edge‐to‐edge repair (M‐TEER) for relevant mitral regurgitation (MR) is unknown. The objectives of this study were three‐fold: (i) to characterize the pattern of hepatic impairment, (ii) to investigate the prognostic value of CHS, and (iii) to evaluate the changes in hepatic function after M‐TEER. Methods and results Hepatic impairment was quantified by laboratory parameters of liver function. In accordance with existing literature, two types of CHS were distinguished: ischaemic type I CHS (elevation of both transaminases) and cholestatic type II CHS (elevation of two out of three parameters of hepatic cholestasis). The impact of CHS on 2‐year mortality was evaluated using a Cox model. The change in hepatic function after M‐TEER was assessed by laboratory testing at follow‐up. We analysed 1083 patients who underwent M‐TEER for relevant primary or secondary MR at four European centres between 2008 and 2019. Ischaemic type I and cholestatic type II CHS were observed in 11.1% and 23.0% of patients, respectively. Predictors for 2‐year all‐cause mortality differed by MR aetiology. While in primary MR cholestatic type II CHS was independently associated with 2‐year mortality, ischaemic CHS type I was an independent mortality predictor in secondary MR patients. At follow‐up, patients with MR reduction ≤2+ (obtained in 90.7% of patients) presented with improved parameters of hepatic function (median reduction of 0.2 mg/dl, 0.2 U/L and 21 U/L for bilirubin, alanine aminotransferase and gamma‐glutamyl transferase, respectively, p < 0.01). Conclusions The CHS is frequently observed in patients undergoing M‐TEER and significantly impairs 2‐year survival. Successful M‐TEER may have beneficial effects on CHS.

Supplementary Figure S5 - PDF file 190K, The blockage of EGFR signalling does not alter the subcellular localization of splicing factors in HCC cells

Supplementary Figure S2 - PDF file 640K, EGFR-dependent signalling increases IR-A mRNA splicing in HCC cells

Background: Transapical transcatheter mitral valve implantation (TMVI) provides treatment for severely ill patients with symptomatic mitral regurgitation (MR) deemed poor candidates for conventional surgery. A prospective, multi-center, single-arm, post-market follow-up (PMCF) study is enrolling to confirm safety and efficacy of a tethered transapical (TA) transcatheter heart valve (THV) in patients with severe symptomatic MR at high risk for surgery.

Supplementary Table 1. Human primers used for quantitative real-time PCR. Supplementary Table 2. Mouse primers used for quantitative real-time PCR. Supplementary Table 3. Human primers used for analysis of IR-A and IR-B isoforms by PCR visualized on gel electrophoresis. Supplementary Table 4. Primary antibodies used for immunodetection. Supplementary Table 5. Clinical and pathological characteristics of patients with CCA (n=10) Supplementary Table 6. Cancer stem cell-associated gene sets significantly enriched in the gene profiles of erlotinib-resistant cell lines. Supplementary Figure S1. Resistant CCA cells to EGFR inhibition display a down-regulation of activated EGFR and a lower sensitivity to erlotinib. Supplementary Figure S2. EGI-1 cells resistant to EGFR inhibition display increased migratory properties. Supplementary Figure S3. IGF2/IR/IGF1R axis is an escape route upregulated in CCA cells resistant to EGFR inhibition. Supplementary Figure S4. IR/IGF1R blockage regulates viability and cell plasticity of cholangiocarcinoma cells resistant to EGFR inhibition. Supplementary Figure S5. IR/IGF1R downregulation regulates viability and cell plasticity of cholangiocarcinoma cells resistant to EGFR inhibition. Supplementary Figure S6. Cholangiocarcinoma cells resistant to EGFR inhibition show increased tumorigenic potential and higher tumor stroma content. Supplementary Figure S7. Tumor cells and CAFs express IGF2 and IGF1R in human intrahepatic CCA. Supplementary Figure S8. IGF2/IR/IGF1R signaling regulates proliferation of hepatic myofibroblasts.

Supplementary Figure Legends - PDF file 119K, Legend for Supplementary Figures S1-S6