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Drug-coated balloons (DCB) have shown promising results for the treatment of in-stent restenosis (ISR) and small vessel disease (SVD). However, data comparing the treatment efficacy of different DCBs are limited.Methods and Results: AGENT Japan is a prospective randomized controlled trial that compares the Agent balloon coated with a low-dose formulation of paclitaxel (2 μg/mmData from this study demonstrate good clinical outcomes with the Agent DCB when used to treat patients with SVD or ISR.

The Task Force on Rotational Atherectomy of the Japanese Association of Cardiovascular Intervention and Therapeutics (CVIT) proposed the expert consensus document to summarize the techniques and evidences regarding rotational atherectomy (RA) in 2020. Because the revascularization strategy to severely calcified lesions is the hottest topic in contemporary percutaneous coronary intervention (PCI), many evidences related to RA have been published since 2020. Latest advancements have been incorporated in this updated expert consensus document.

There is a little datum about the impact of paclitaxel dosage in patients undergoing drug-coated balloons (DCB) in endovascular therapy (EVT) for femoropopliteal lesions. In the current study, the authors sought to compare the clinical outcomes of low-dose (LD) and high-dose (HD) paclitaxel DCBs for patients undergoing EVT for femoropopliteal lesions in a real-world setting.The study population was derived from a multicenter registry named "Evaluation of clinical outcome after endovascular therapy for femoropopliteal artery disease in Kanagawa" (LANDMARK registry). This registry consists of patients from 5 hospitals in Kanagawa, Japan. Overall, 1,378 patients with 1,777 lesions received treatment between July 2017 and June 2020. Among these, DCB angioplasty was performed in 477 patients (516 lesions). Propensity score matching analysis was performed to compare the clinical outcomes of LD-DCB (Lutonix; Becton Dickinson and Company, Franklin Lakes, New Jersey) and HD-DCB (IN.PACT Admiral; Medtronic Vascular, Santa Clara, CA, USA).A total of 160 matched pairs of lesions were analyzed. Primary patency and freedom from target lesion revascularization at 2 years were similar between the two groups (LD-DCB vs. HD-DCB: 72% vs. 70%, p = 0.53; and 75% vs. 73%, p = 0.59, respectively).No significant differences were found in the clinical outcomes between LD-DCB and HD-DCB angioplasty for femoropopliteal lesions.Level 3.

The original J-CTO score predicts the difficulty of percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) lesions, but the grade of calcification has not been fully evaluated. We examined 137 patients (141 CTO lesions) who underwent coronary computed tomography angiography (CTA) pre-PCI between October 2016 and October 2021. They were randomly divided into derivation (n = 94) and validation (n = 47) groups. The degree and distribution of calcification in the occluded segment were assessed using CTA. The calcified index was defined as calcium volume divided by the length of the occluded segment. We created the J-Calc-CTO score consisting of calcification parameters associated with 30-min wire crossing in the derivation group. The validity of the J-Calc-CTO score was compared with that of the original J-CTO score using c-statistics. The procedural success rate was 96%, and 30-min wire crossing during the procedure was achieved in 29%. Dense calcification (calcified-index12) (odds ratio [OR]: 4.63; 95% confidence interval [CI]: 1.24-22.2; p = 0.04) and calcification in the center of the lumen (OR: 7.25; 95% CI: 1.48-32.1; p = 0.02) were independently associated with 30-min wire crossing as variables evaluated using CTA. The J-Calc-CTO score was created by adding 1 point to the two parameters in place of "calcification" in the original J-CTO score. The J-Calc-CTO score showed a higher predictive value of 30-min wire crossing than the J-CTO score in the derivation (c-statistics; 0.836 vs. 0.670; p 0.01) and validation groups (c-statistics; 0.879 vs. 0.767, p 0.01). The degree and distribution of calcification evaluated using CTA refined the predictive value of the original J-CTO score for 30-min wire crossing.

Background Endovascular treatment (EVT) of superficial femoral artery (SFA) lesions that can be reached through transradial access (TRA) has often been performed due to its low invasiveness. For complex lesions such as chronic total occlusion (CTO) treated via TRA, EVT is still challenging due to poor device backup and guidewire operability. However, TRA might be preferred in patients with a high risk of bleeding or restricted access sites. Case series Both patients were diagnosed with peripheral artery disease and had an occlusion in one of their SFAs. They were treated using the balloon backed-up microcatheter technique (BBQ), a novel technique devised by us to treat patients with CTO through TRA. No complications were observed in either patient; therefore, we consider that both the procedures using this technique were successful. Conclusions We devised a technique that improved the backup of devices and maintained the torque response of the guidewire. This is because the 0.035-inch balloon catheter was anchored in the blood vessel and the microcatheter was trapped inside the monorail lumen of a 0.035-inch balloon catheter without crushing the lumen of the microcatheter. We introduce this technique in our report.

Supplementary Table 1 shows the differential expression analysis of RNA sequencing data. A list of genes that are differentially expressed upon TGF-beta treatment as well as upon RUNX3-Knockdown are shown.

This file contains Supplementary Figures 1-8. Fig.S1 shows Characterization of TGF-β-dependent EMT. Fig.S2 shows an analysis of endogenous DNA damage accumulation in the presence of TGF-β. Fig.S3 shows the Upregulation of NOX4 and downregulation of NRF-dependent genes upon TGF-β exposure.Fig.S4 displays that RNA-sequencing analysis unveils spontaneous EMT upon RUNX3 knockdown. Fig.S5 shows the regulation of HMOX1 expression by RUNX3. Figure.S6 shows how BACH1-KD in RUNX3-depleted cells rescues the accumulation of DNA damage. Fig.S7 displays RUNX1 depletion results in DNA damage accumulation and senescence in the presence of TGF-β. Fig.S8 shows HMOX1 depletion results in heightened ROS production and senescence in the presence of TGF-β.

Supplementary Methods, Legends for Supplementary Figures,Legend for Table 1 and References

Supplementary Figure 3 from Role of RUNX3 in Bone Morphogenetic Protein Signaling in Colorectal Cancer

Supplementary Methods, Figures 1-5 from Role of RUNX3 in Bone Morphogenetic Protein Signaling in Colorectal Cancer

Supplementary Figure 1 from Role of RUNX3 in Bone Morphogenetic Protein Signaling in Colorectal Cancer

Supplementary Figure 4 from Role of RUNX3 in Bone Morphogenetic Protein Signaling in Colorectal Cancer

Bone morphogenetic proteins (BMPs), members of the transforming growth factor-β (TGF-β) superfamily, are multifunctional cytokines regulating a broad spectrum of biological functions. Recent studies show the presence of BMP receptor 1a mutations in juvenile polyposis and frequent Smad4 mutations in colon cancer, suggesting that aberrations in BMP signaling play an important role in intestinal cancer pathogenesis. However, the exact molecular mechanisms remain poorly understood. The Runt domain transcription factor RUNX3 is an integral component of signaling pathways mediated by TGF-β and BMPs. RUNX3 is a gastric and colon tumor suppressor, functioning downstream of TGF-β. Recently, we showed the tumor-suppressive effects of RUNX3 by its ability to attenuate β-catenin/T-cell factors (TCFs) transactivation in intestinal tumorigenesis. Here, we explore the molecular basis of the tumor-suppressive function of the BMP pathway through RUNX3 in colorectal carcinogenesis. BMP exerted a growth-suppressive effect in HT-29, a human colorectal cancer cell line. c-Myc oncogene was found to be downregulated by BMP and/or RUNX3. We show that upregulation of RUNX3 by BMP reduces c-Myc expression. Evidence is presented suggesting that RUNX3 downregulates c-Myc expression by two parallel pathways—directly at the transcriptional level and through attenuation of β-catenin/TCFs, downstream of BMPs in colorectal cancer cells. Cancer Res; 70(10); 4243–52. ©2010 AACR.

Supplementary Figure 2 from Role of RUNX3 in Bone Morphogenetic Protein Signaling in Colorectal Cancer

Supplementary Figure 5 from Role of RUNX3 in Bone Morphogenetic Protein Signaling in Colorectal Cancer

Kα,β X-ray lines from photon excitation were measured in selected elements from Mg to Cu using a high-resolution double-crystal X-ray spectrometer with a proportional counter, and the Kβ/Kα intensity ratio for each element was obtained, after correcting for self-absorption, detection efficiency, and crystal reflectance. This intensity ratio increases rapidly from Mg to Ca but, in the 3d elements region, the increase becomes slower. This is related to the intensity of the Kβ line involving valence electrons. The slow increase of this ratio in the 3d elements region is thought to be due to the correlation between 3d and 4s electrons. Moreover, the chemical shifts, FWHM, asymmetry indices, and Kβ/Kα intensity ratios of the Cr compounds, due to different valences, were also investigated using the same double-crystal X-ray spectrometer. The chemical effects were clearly observed, and the Kβ/Kα intensity ratio was found to be compound-dependent for Cr.

Y. Ito acknowledges the financial support for the measurements of a part of the data by the REXDAB Collaboration that was initiated within the International Fundamental Parameter Initiative. This research was supported in part by FCT (Portugal) under research center grants UID/FIS/04559/2020 (LIBPhys). This work was also supported by the National Science Centre, Poland under grant number 2017/25/B/ST2/00901 and grant number 2021/05/X/ST2/01664, and by the Slovenian Research Agency (P1-0112). A. Kahoul and A. Hamidani acknowledge the support of the DGRSDT, Ministry of Higher Education and Scientific Research, Algeria, and of Mohamed El Bachir El Ibrahimi University, under project (PRFU) No. B00L02UN340120220001. Paul Indelicato is a member of the Allianz Program of the Helmholtz Association, contract n° EMMI HA-216 “Extremes of Density and Temperature: Cosmic Matter in the Laboratory”. P.I. acknowledge support from the PESSOA Hubert Curien Program 2022, Number 47863UE. Publisher Copyright: © 2023 by the authors. (Formula presented.) X-ray lines from photon excitation were measured in selected elements from Mg to Cu using a high-resolution double-crystal X-ray spectrometer with a proportional counter, and the (Formula presented.) intensity ratio for each element was obtained, after correcting for self-absorption, detection efficiency, and crystal reflectance. This intensity ratio increases rapidly from Mg to Ca but, in the (Formula presented.) elements region, the increase becomes slower. This is related to the intensity of the (Formula presented.) line involving valence electrons. The slow increase of this ratio in the (Formula presented.) elements region is thought to be due to the correlation between (Formula presented.) and (Formula presented.) electrons. Moreover, the chemical shifts, FWHM, asymmetry indices, and (Formula presented.) intensity ratios of the Cr compounds, due to different valences, were also investigated using the same double-crystal X-ray spectrometer. The chemical effects were clearly observed, and the (Formula presented.) intensity ratio was found to be compound-dependent for Cr. publishersversion published

Purpose To compare the sensitivity of the hyperdense middle cerebral artery (MCA) sign between maximum intensity projection (MIP) and conventional averaged images in patients with acute focal neurological deficits with acute thromboembolic MCA occlusion (MCA occlusion group) and patients with acute focal neurological deficits without MCA occlusion (control group). Materials and methods Initial computed tomography (CT) scans on admission were reconstructed with 5 mm thickness at every 3 mm interval for averaged and MIP images from 1 mm thickness non-contrast axial source images. Images were obtained from 30 cases each in the MCA occlusion and control groups. The CT values in the region of interests (ROIs) on the affected and unaffected sides of the MCA were compared. To compare CT values among subjects, the CT values were normalized by obtaining a ratio on the affected and unaffected sides, and the normalized CT values were analyzed using the receiver operating characteristic (ROC) curve. Results The hyperdense MCA sign was visually detected on MIP images in 90% cases and on 5 mm averaged images in only 57% cases in the MCA occlusion group. Based on the ROC analysis of the normalized ratio on the affected and unaffected sides, area under the curve of MIP image and averaged image was 0.941 and 0.655, respectively. On MIP images, the optimal threshold of the ratio on the affected and unaffected sides was 1.152 (sensitivity: 90.0%, and specificity: 93.3%). Conclusion The hyperdense MCA sign sensitivity on 5 mm MIP images was significantly higher than that on conventional 5 mm averaged CT images. This could be useful for the early initiation of proper therapy for patients with acute focal neurological deficits.

SUMMARY The Japan forearc plays a crucial role in modulating the post-seismic deformation in response to the enormous stress perturbation induced by the 2011 Tohoku-oki earthquake. Dense geodetic observations across Japan have revealed coupled interactions between afterslip on the subducting plate interface and viscous deformation within the mantle wedge, and detailed numerical models can provide further profound insights into the forearc rheology. Recent studies have revealed the presence of a stagnant section in the forearc mantle of the Tohoku subduction zone, and here we investigate the associated along-arc variation of the stagnant part of the mantle wedge (cold nose) across Japan. We utilize a newly deployed geodetic network along a corridor in the Fukushima–Niigata region and compare the surface deformation pattern to that of the Miyagi–Yamagata corridor close to the main rupture area. We present a 3-D rheological model using laboratory-derived constitutive laws to simulate the geodetic observations including displacement fields and their time-series. Our results suggest along-arc heterogeneity in the forearc mantle rheology; specifically, we find a narrower cold nose in the Miyagi region and a wider one in the Fukushima forearc. The geodetic inferences on the forearc variation are consistent with along-arc spatial heterogeneity in the cut-off depth for shallow earthquakes as well as comparative measurements of the respective geothermal gradients between the Miyagi and Fukushima regions.

Mammary gland homeostasis is maintained by adult tissue stem-progenitor cells residing within the luminal and basal epithelia. Dysregulation of mammary stem cells is a key mechanism for cancer development. However, stem cell characterization is challenging because reporter models using cell-specific promoters do not fully recapitulate the mammary stem cell populations. We previously found that a 270-basepair Runx1 enhancer element, named eR1, marked stem cells in the blood and stomach. Here, we identified eR1 activity in a rare subpopulation of the ERα-negative luminal epithelium in mouse mammary glands. Lineage-tracing using an eR1-CreERT2 mouse model revealed that eR1+ luminal cells generated the entire luminal lineage and milk-secreting alveoli—eR1 therefore specifically marks lineage-restricted luminal stem cells. eR1-targeted-conditional knockout of Runx1 led to the expansion of luminal epithelial cells, accompanied by elevated ERα expression. Our findings demonstrate a definitive role for Runx1 in the regulation of the eR1-positive luminal stem cell proliferation during mammary homeostasis. Our findings identify a mechanistic link for Runx1 in stem cell proliferation and its dysregulation in breast cancer. Runx1 inactivation is therefore likely to be an early hit in the cell-of-origin of ERα+ luminal type breast cancer.

RUNX transcription factors play pivotal roles in embryonic development and neoplasia. We previously identified the single missense mutation R122C in RUNX3 from human gastric cancer. However, how RUNX3To understand the oncogenic nature of this mutation in vivo, we generated the RUNX3The corpus tissue of RUNX3RUNX3

Purpose The relationship between severity of calcification and clinical outcomes after endovascular therapy (EVT) for femoropopliteal lesions is well known. We often encounter dense calcifications in our daily practice, which are darker than normal calcifications on angiography. Accordingly, we named it “black rock” (BR), and investigated its impact on clinical outcomes after EVT. Materials and methods We retrospectively analyzed 677 lesions in 495 patients who underwent EVT for de novo calcified femoropopliteal lesions at our hospital between April 2007 and June 2020. BR is defined as a calcification which is 1 cm or more in length, occupies more than half of the vessel diameter, and appears darker than the body of the femur on angiography. Propensity score matching analysis was performed to compare clinical outcomes between lesions with BR [BR (+) group] and without BR [BR (−) group]. Results A total of 124 matched pairs of lesions were analyzed. Primary patency at 2 years was significantly lower in the BR (+) group than in the BR (−) group (48% vs. 75%, p = .0007). Multivariate analysis revealed that BR [hazard ratio (HR) = 2.23, 95% confidence interval (CI); 1.48–3.38, p = .0001], lesion length (HR = 1.03, 95%CI; 1.00–1.06, p = .0244), and scaffold use (HR = 0.63, 95%CI; 0.42–0.94, p = .0246) were predictors of restenosis. Conclusion BR is independently associated with clinical outcomes after EVT for de novo calcified femoropopliteal lesions. Level of Evidence: Level 4

A novel 2,3-epoxy naphthoquinol, named (6R,7R,8R)-theissenone A (1), possessing an oxatricyclo[5.4.0.03,5]undeca-trien-2-one skeleton, together with two known compounds, (6S,7R,8R)-theissenone (2) and arthrinone (3), were produced by an endophytic fungus, Arthrinium marii M-211, which was isolated from mangrove plants. The structure of 1, including the absolute stereochemistry, was elucidated by analysis of nuclear magnetic resonance (NMR) and mass spectrometry (MS) data and time-dependent density functional theory (TDDFT) calculations of electronic circular dichroism (ECD) spectra. Additionally, the absolute structure of 2 was deduced as a diastereomer of 1 using ECD spectral data analysis. Compounds 1, 2 and 3 exhibited cytotoxic activity against the H4IIE rat hepatoma cells, with IC50 values of 67.5, 46.6 and 13.4 µM, respectively.

Two new octahydronaphthalene derivatives, trichodermic acid C (1) and trichodermic acid D (2), along with known analogs, trichodermic acid (3), trichodermic acid A (4) and trichodermic acid B (5), were isolated from an ethyl acetate extract of endophytic strain Trichoderma sp. HN-1.1. The structures of compounds 1 and 2 were elucidated using spectroscopic methods including UV, IR, HRESITOFMS, ECD, 1 D and 2 D NMR. The cytotoxic activity of the isolated compounds was evaluated on the rat hepatoma cell line H4IIE, using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. According to the results, only compound 3 showed a significant reduction of H4IIE cells from 75 to 21% (p

OBJECTIVE: Tumors evade immune surveillance by expressing Programmed Death-Ligand 1 (PD-L1), subsequently inhibiting CD8+ cytotoxic T lymphocyte function. Response of gastric cancer to immunotherapy is relatively low. Our laboratory has reported that Helicobacter pylori-induced PD-L1 expression within the gastric epithelium is mediated by the Hedgehog (Hh) signaling pathway. The PI3K/AKT/mTOR pathway is activated in gastric cancer and may have immunomodulatory potential. We hypothesize that Hh signaling mediates mTOR-induced PD-L1 expression. DESIGN: Patient-derived organoids (PDOs) were generated from gastric biopsies and resected tumor tissues. Autologous organoid/immune cell co-cultures were used to study the immunosuppressive function of MDSCs. NanoString Digital Spatial Profiling (DSP) of immune-related protein markers using FFPE slide-mounted tissues from gastric cancer patients was performed. RESULTS: DSP analysis showed infiltration of immunosuppressive MDSCs expressing Arg1, CD66b, VISTA and IDO1 within cancer tissues. Orthotopic transplantation of patient derived organoids (PDOs) resulted in the engraftment of organoids and the development of histology similar to that observed in the patient’s tumor tissue. PDO/immune cell co-cultures revealed that PD-L1-expressing organoids were unresponsive to nivolumab in vitro in the presence of PMN-MDSCs. Depletion of PMN-MDSCs within these co-cultures sensitized the organoids to anti-PD-1/PD-L1-induced cancer cell death. Rapamycin decreased phosphorylated S6K, Gli2 and PD-L1 expression in PDO/immune cell co-cultures. Transcriptional regulation of PD-L1 by GLI1 and GLI2 was blocked by rapamycin. CONCLUSIONS: The PDO/immune cell co-cultures may be used to to study immunosuppressive MDSC function within the gastric tumor microenvironment. The mTOR signaling pathway mediates GLI-induced PD-L1 expression in gastric cancer.

High-degree atrioventricular block (HAVB) or complete heart block (CHB) is a common complication associated with transcatheter aortic valve replacement (TAVR). However, some patients with HAVB/CHB recover with time. The results of electrophysiological studies (EPSs) using permanent pacemaker implantation (PPI) in patients with suspicious HAVB/CHB are considered controversial.This study aimed to evaluate whether HAVB/CHB induction at the bedside using a temporary pacemaker can predict recurrence in patients who had recovered from HAVB/CHB after TAVR.We enrolled a total of 11 patients who had recovered from HAVB/CHB and evaluated their electrophysiology using right ventricular pacing and/or procainamide administration.HAVB/CHB induction was positive. Three patients tested positive for HAVB/CHB, whereas 8 tested negative. The ejection fraction and the interval between HAVB/CHB onset and EPS were found to be significant. HAVB/CHB positive patients underwent PPI. A patient with a balloon-expandable valve tested positive just before recovery of CHB, but tested negative 5 days later and was included in the negative group. The 4 patients who tested negative received a cardiovascular implantable electric device (CIED). We observed HAVB/CHB in 2 patients who had previously tested positive after 3 months. Among those who tested negative, those with CIED had no HAVB/CHB, and others showed neither HAVB/CHB on electrocardiogram nor experienced syncope or sudden death.Our EPS revealed that HAVB/CHB induction may predict HAVB/CHB recurrence after TAVR. Valve type and EPS timing may affect the results.

Hypoxia-inducible factor 1α (HIF1α) is a transcription factor that regulates angiogenesis under hypoxic conditions. To investigate the posttranscriptional regulatory mechanism of HIF1α, we performed a cell-based screening to reveal potential cis-elements and the regulatory RNA-binding proteins that act as trans-factors. We found that LIN28A promoted HIF1α protein expression independently of the downregulation of microRNA let-7, which is also directly mediated by LIN28A. Transcriptome analysis and evaluation of RNA stability using RNA-seq and SLAM-seq analyses, respectively, revealed that LIN28A upregulates HIF1A expression via mRNA stabilization. To investigate the physical association of LIN28A with HIF1A mRNA, we performed enhanced crosslinking immunoprecipitation in 293FT cells and integrally analyzed the transcriptome. We observed that LIN28A associates with HIF1A mRNA via its cis-element motif "UGAU". The "UGAU" motifs are recognized by the cold shock domain of LIN28A, and the introduction of a loss-of-function mutation to the cold shock domain diminished the upregulatory activities performed by LIN28A. Finally, the microvessel density assay showed that the expression of LIN28A promoted angiogenesis in vivo. In conclusion, our study elucidated the role of LIN28A in enhancing the HIF1α axis at the posttranscription layer.

The study aim was to evaluate the impact of extravascular ultrasound-guided (EVUSG) wiring on achieving optimal vessel preparation and patency in endovascular therapy (EVT) for superficial femoral artery (SFA) chronic total occlusion (CTO).Between April 2007 and January 2019, a total of 239 SFA-CTO limbs were successfully treated with EVT and bailout implantation of self-expandable nitinol stents at our hospital. The study subjects were divided into 2 groups according to the type of guidance strategy used during CTO wiring, ie, the EVUSG group and the conventional angiography guidance (AG) group. Immediately after the initial balloon angioplasty and successful passage of the wire through the SFA-CTO lesions, the EVUSG (65 limbs) and AG groups (174 limbs) were retrospectively evaluated for angiographic dissection patterns. The primary patency rate was also compared between the 2 groups.No significant difference was observed in the balloon diameter at the initial dilation immediately after successful wire passing (3.7 ± 0.5 mm in the EVUSG group vs 3.8 ± 0.5 mm in the AG group; P=.17). The incidence of severe dissection was significantly lower (Plt;.001) in the EVUSG group (28/65; 43%) than in the AG group (137/174; 79%). The 3-year primary patency rates in the EVUSG and AG groups were 84.5% and 68.4%, respectively (Plt;.001).EVUSG for SFA-CTO may achieve optimal vessel preparation, defined as an initial balloon angioplasty without severe dissection, and subsequent implantation of self-expandable stents may lead to a better patency rate.

Evaluation of in-stent restenosis (ISR) by computed tomography coronary angiography (CTCA) is less invasive but often impossible. We aimed to create a scoring model for predicting which drug-eluting stents (DES) cannot be evaluated with CTCA. We enrolled 757 consecutive implanted DES assessed with CTCA. Non-diagnostic evaluation was defined as poor/not evaluative by two different observers. These stents were randomly divided into a derivation (n = 379) and validation (n = 378) group. In the derivation group, we assessed predictors using logistic regression analysis and created a scoring model that would stratify non-diagnostic evaluation of DES-ISR. The validity of this scoring model was evaluated in the validation group using receiver-operating characteristic analysis. The percentage of non-diagnostic stents was 19/21% in the derivation/validation group (p = 0.71). Non-diagnostic evaluation was independently associated with implanted stent diameter (2.25–2.5. vs. 2.5–3 vs. > 3.0 mm), severe calcification, stent-in-stent lesion, and type of DES (stainless vs. CoCr vs. PtCr) in the derivation group. The predicting system of implanted DES non-diagnostic by CTCA (PIDENT) for non-diagnostic evaluation, including these four baseline factors, was derived (C-statistic = 0.86 in derivation group, cutoff: 8 points). The PIDENT score had a high predictive value for non-diagnostic DES in the validation model (C-statistic = 0.87, sensitivity 86%, specificity 74%, cutoff 8 points, p

Background This analysis aimed to evaluate the clinical impact of high bleeding risk (HBR) on adverse events after percutaneous coronary intervention (PCI). Methods We retrospectively analyzed 1695 patients in the MODEL U-SES study, which was a multicenter, open-label, prospective observational study evaluating safety of 3-month dual antiplatelet therapy (DAPT) after Ultimaster stent (Terumo Corporation, Tokyo, Japan) implantation at 65 sites in Japan. Patients were divided into 2 groups (HBR/Non-HBR) according to modified Academic Research Consortium-HBR criteria. Ischemic/thrombotic event (cardiovascular death, myocardial infarction, ischemic stroke, and stent thrombosis) and bleeding event (Bleeding Academic Research Consortium 3 or 5) at 1 year were evaluated. Results Of 1695 patients, 840 patients were categorized as HBR and 855 patients were Non-HBR. One-year follow-up was completed in 95.3%. During 1-year follow-up, ischemic/thrombotic events were observed in 31 cases (1.8%) and bleeding events occurred in 21 cases (1.2%). Presence of HBR was significantly associated with higher incidence of ischemic/thrombotic events as compared to Non-HBR (adjusted hazard ratio, 0.16; 95% confidence interval, 0.05 to 0.50), whereas the incidence of bleeding events did not reach statistical significance between HBR and Non-HBR. In comparison of monotherapy after DAPT, P2Y12 inhibitor monotherapy after DAPT had comparable ischemic/thrombotic and bleeding events with aspirin monotherapy after DAPT in both HBR and Non-HBR. Conclusion In contemporary PCI practice, nearly half of patients had HBR and presence of HBR significantly increased risk of ischemic/thrombotic events. Both aspirin and P2Y12 inhibitor monotherapy following short DAPT had low and comparable ischemic/bleeding events.

In-situ X-ray diffraction measurements of ScOOH were conducted under high pressure and temperature conditions up to 11 GPa and 900 K to understand its phase transitions. As the pressure increased, ...

Two new oleanane-type triterpene saponins, named polythosides A and B (1 and 2), together with a known compound, silphioside E (3), were isolated from the roots of Acacia polyacantha. Their structures were elucidated by analysis of 1D and 2D-NMR experiments, and mass spectrometry (HR-ESITOF-MS) as oleanolic acid 3-O-β- d -galactopyranosyl-(1→2)-β- d -xylopyranosyl-(1→6)-[β- d -xylopyranosyl-(1→4)]-[β- d -xylopyranosyl-(1→2)]-β- d -galactopyranoside (1), 3-O-[β- d -galactopyranosyl-(1→2)-β- d -xylopyranosyl-(1→6)-[β- d -xylopyranosyl-(1→4)]-[β- d -xylopyranosyl-(1→2)]-β- d -galactopyranosyl] oleanolic acid-28-O-β- d -glucopyranosyl ester (2) and 3-O-β- d -glucopyranosyl-(1→2)-β- d -glucopyranosyl] oleanolic acid 28-O-β- d -glucopyranosyl ester (3). The cytotoxic effect of isolated saponins was evaluated on the H4IIE rat hepatoma cell line. The results show that none of the compounds (assayed at 100 μM) showed cytotoxicity against H4IIE cells.

Background Sedation during cardiac catheter examination in neonates with complex congenital heart disease is challenging, as even the slightest change in the circulatory or respiratory status can lead to hemodynamic collapse. Here, we report a case wherein we achieved adequate sedation with a high-flow nasal cannula (HFNC) for catheter examination in a neonate with a congenital cardiac anomaly. Case presentation An 11-day-old boy with hypoplastic left heart syndrome was scheduled for a cardiac catheter examination prior to the Norwood procedure. He underwent bilateral pulmonary artery banding (PAB) on day 1 and was receiving dobutamine, milrinone, alprostadil, and dexmedetomidine in addition to air and nitrogen insufflation via HFNC, which was applied following extubation on day 3 and nitrogen therapy on day 6 owing to persistent pulmonary overcirculation symptoms (tachypnea and low arterial blood pressure) despite bilateral PAB. A catheter examination was performed on day 11 with careful monitoring of expired carbon dioxide and observation of chest wall motion. Adequate sedation was provided with supplemental midazolam and fentanyl along with HFNC without tracheal intubation. Conclusions The findings from this case suggest that HFNC is a safe and effective tool for oxygenation during cardiac catheter examination under sedation in neonates.

Purpose To compare the impact of Chocolate and conventional balloons on vessel preparation in percutaneous transluminal angioplasty. Materials and methods This single-center retrospective study included 111 endovascular therapy consecutive cases of femoropopliteal lesions using drug-coated balloon strategy with a 1:1 pre-dilation balloon diameter between February 2020 and August 2021, divided into the Chocolate percutaneous transluminal angioplasty (n = 48) and conventional (n = 63) groups. Before the availability of Chocolate balloons in Japan (December 2020), a standard semi-compliant or non-compliant balloon was used for vessel preparation. The primary endpoint was rate of severe dissection after pre-dilatation. Secondary endpoints were angiographic percent diameter stenosis, bailout stent rate, primary patency rate, and freedom from target-lesion-revascularization rate at six months. Results There was no significant difference in patient and lesion characteristics. The procedural characteristics comprised balloon length 90 ± 37 and 149 ± 95 mm (P = 0.004) and inflation pressure 11 ± 3 and 16 ± 7 atm (P P = 0.003); regarding secondary endpoints, percent diameter stenosis was 18 ± 15% and 20 ± 17% (P = 0.409), and the rate of bailout stenting was 2.1% and 15.9% (P = 0.016) in the Chocolate and conventional groups, respectively. The primary patency rates at six months were 89.1% and 85.2% (P = 0.670), and freedom from target-lesion-revascularization rate at six months was 100% and 92.8% (P = 0.691) in the Chocolate and conventional groups, respectively. Conclusion Chocolate percutaneous transluminal angioplasty balloons reduce the rate of severe dissection while maintaining a sufficient dilatation effect during drug-coated balloon vessel preparation.

Scaffold protein IQ motif-containing GTPase-activating protein 3 (IQGAP3; IQ3) is a member of the multifunctional IQGAP family. The interaction between IQ3 and Ras-ERK signaling has been reported, but how IQ3 regulates Ras-ERK signaling in malignancies is still unclear. The purpose of this study is to elucidate the role of IQ3 in coordinating diverse pathways, such as ERK-Ras and TGFβ in gastric cancer (GC).According to Stomach Adenocarcinoma of TCGA Pan-Cancer Atlas, the frequency of gene mutations is high in TP53 (60.1%), RTK-Ras (51.8%), and TGFβ pathways (36.4%). Gene Set Enrichment Analysis (GSEA) indicated that KRAS signaling was significantly downregulated after IQ3 knockdown (KD) in three GC cell lines (AGS, NUGC3, Hs746T). Ingenuity upstream regulator analysis (IPA) of RNA sequencing data revealed that TGFβ1, the top-ranked growth factor, is significantly inhibited after IQ3 KD. Immunoblot analysis showed that IQ3 KD led to suppression of TGFβ-induced phosphorylation of MEK/ERK in three GC cell lines, particularly NUGC3. While TGFβ treatment promoted invasion and migration in transwell migration assays, IQ3 KD significantly diminished TGFβ-mediated cell migration. In vivo, the size and volume of subcutaneous tumors from IQ3 KD NUGC3 cells were significantly smaller than that from Control (Ctrl) cells. According to RNA sequencing using bulk tumors, mouse stromal cells in Ctrl tumors showed significantly higher expression of acta2, fap, pdgfa, which are the markers of cancer-associated fibroblasts, than in IQ3 KD tumors. The TGFβ1 expression levels in the NUGC3 xenograft and mouse stromal cells harvested from Ctrl were significantly higher than that from IQ3 KD, respectively. Additionally, digital spatial profiler (DSP) GeoMx evaluation of the intra-tumoral expressions from the human xenograft and mouse stromal cells showed that the mouse stromal cells from Ctrl expressed significantly higher acta2 and tgfβ1 than that from IQ3 KD. Furthermore, metastasis assays via tail vein injection in vivo showed dramatically lesser lung metastases from IQ3 KD cells than that from Ctrl cells. This study shows that IQ3 KD suppressed Ras signaling and blocked upstream regulator TGFβ1 in vitro. The stromal cells in the IQ3 KD xenografts showed a reduced population of cancer-associated fibroblasts in vivo. Consequently, tumorigenesis and metastasis were strongly suppressed after IQ3 KD. IQ3 is thus a highly relevant therapy target in GC. Citation Format: Mitsuhiro Shimura, Pang SHUCHIN, Junichi Matsuo, Linda Shyue Chuang, Yoshiaki Ito. IQGAP3 regulates intra-cellular Ras signaling and intra-tumoral malignant cycles via TGFβ signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2618.

We reported earlier that heterozygous deletion of RUNX3 in the mouse induces adenoma in small intestine, mammary gland (1) and lung (2) and a precancerous stomach epithelium that is highly sensitive to a chemical carcinogen (3). We therefore propose that RUNX3 is a gatekeeper of cancer development (1). In our recent study on how RUNX3 inhibits early-stage cancer development in multiple tissues, we uncovered a previously unknown mode of MYC destabilization by RUNX3. From RNA sequencing, knockdown experiments, tumorigenic assays, protein interaction and ubiquitination studies, we show that the strong inhibitory effects of RUNX3 on proliferation and tumor growth may, in part, be attributed to its ability to promote MYC degradation. The evolutionarily conserved Runt domain of RUNX3 interacts directly with the basic helix-loop-helix leucine zipper of MYC, resulting in the disruption of MYC/MAX interaction, enhanced GSK3β-mediated phosphorylation of MYC protein at threonine-58 and its subsequent degradation via the ubiquitin-proteasomal pathway (4). MYC inhibitor Omomyc, a short peptide comprising the b HLH LZ domain of MYC with 4 amino acid substitutions, is extremely effective in disrupting MYC/MAX interaction (5). RUNX3 appears to function similarly to Omomyc: is RUNX3 a Nature-designed Omomyc? References:(1) Ito K et al, Cancer Cell 14;226-237, 2008; (2) Lee YS et al, Cancer Cell 24: 603-616, 2013; (3) Ito K et al, Gastroenterol 140:1536-1546, 2011; (4) Oei V, Chuang LSH, et al, Submitted; (5) Soucek et al, Nature 455:679-683, 2008 Citation Format: Yoshiaki Ito, Vincent Oei, Linda Chuang, Junichi Matsuo, Supriya Srivastava, Ming Teh. RUNX3 disrupts MYC/MAX complex and promotes MYC degradation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5753.

Recently, antegrade dissection re-entry (ADR) with re-entry device for chronic total occlusion (CTO) percutaneous coronary intervention (PCI) has evolved to become one of the pillar techniques of the hybrid algorithm. Although the success rate of the device is high, it could be improved. We sought to evaluate the current trends and issues associated with ADR in Japan and evaluate the potential of cardiac computed tomography angiography (CCTA) for ADR procedure. A total 48 patients with CTO suitable for ADR evaluated by baseline conventional angiography and CCTA were enrolled. Procedural success and technical success were evaluated as the primary and secondary observations. Furthermore, all puncture points were analyzed by CCTA. CT score at each punctured site depended on the location of plaque deposition (none; + 0, at isolated myocardial site; + 1, at epicardial site; + 2) and the presence of calcification (none; + 0, presence; + 1) was analyzed and calculated (score 0–3). Overall procedure success rate was 95.8%. Thirty-two cases were attempted with the ADR procedure and 25 cases of them were successful. The technical success rate was 78.1% and myocardial infarction or other major complications were not observed in any cases. CT score at 60 puncture sites in 32 cases were analyzed and the score at technical success points was significantly smaller compared to that at technical failure points (0.68 ± 1.09 vs 1.77 ± 1.09, p

Background: SYNERGY is a thin-strut, platinum-chromium metal alloy stent with an ultrathin abluminal everolimus-eluting bioabsorbable polymer. EVOLVE II was a global randomized controlled trial that enrolled 1,684 patients treated with either a SYNERGY or durable polymer PROMUS Element Plus (PE+) everolimus-eluting stent, including 155 patients from Japanese sites. This substudy analyzed 5-year clinical outcomes in the Japanese and non-Japanese cohorts. Methods and Results: Patients aged ≥18 years with ≤3 native coronary artery lesions (reference vessel diameter ≥2.25–≤4.00 mm; length ≤34 mm) in ≤2 major vessels were randomized 1 : 1 to receive either SYNERGY (n=74 patients in Japan) or PE+ (n=81 patients in Japan). Five-year target lesion failure (TLF) was observed in 8.3% SYNERGY- and 11.2% PE+-treated patients (P=0.54). There were no cardiac deaths, and rates of target lesion revascularization and myocardial infarction were comparable between treatment arms. One patient in the SYNERGY arm experienced a very late definite stent thrombosis (ST); no ST occurred in the PE+ arm (P=0.30). Despite differences in baseline clinical and lesion characteristics, the 5-year TLF rates were not significantly different in SYNERGY-treated patients either in (8.3%) or outside (14.8%) Japan (P=0.14). Conclusions: In Japanese patients with coronary artery disease, SYNERGY showed comparable efficacy to PE+, with low rates of adverse events over 5 years. Similarly, 5-year clinical outcomes were favorable in Japanese vs. non-Japanese patients implanted with SYNERGY.

BACKGROUND This study evaluated the safety of 3-month dual antiplatelet therapy (DAPT) after implantation of a bioresorbable polymer sirolimus-eluting stent (BP-SES) and compared P2Y12inhibitor with aspirin monotherapy 3 months after DAPT.Methods and Results:Patients who underwent percutaneous coronary intervention using BP-SES were enrolled and followed for 1 year. Patients with a history of stent thrombosis were excluded. The primary endpoint was a composite of all-cause death, myocardial infarction, stroke (ischemic and hemorrhagic), definite or probable stent thrombosis, and severe bleeding at 12 months. The BP-SES arm of the CENTURY II trial was used as a conventional DAPT group for comparison. After DAPT, patients were maintained on either aspirin (n=846) or a P2Y12inhibitor (n=674 patients).In all, 1,695 patients were enrolled in the study across 65 centers. The primary endpoint occurred in 4.3% of patients at 1 year. After propensity score adjustment, the incidence of the primary endpoint was not inferior in those receiving DAPT for 3 months compared with conventional DAPT (5.5%; Pnon-inferiority

The aim of this study is to evaluate the long-term safety and efficacy of the 2.25 mm bioresorbable-polymer sirolimus-eluting Ultimaster stent in a Japanese patient population. Treatment of coronary artery disease in very small vessels is associated with an increased risk for cardiac events. The CENTURY JSV study is a prospective, multicenter, single-arm study. Seventy patients with stable and unstable coronary artery disease with a coronary lesion eligible for implantation with a 2.25 mm stent were enrolled in this study. Patients underwent clinical follow-up through 5-year after the PCI procedure. The mean age was 70.4 ± 9.2 years. The prevalence of diabetes mellitus was 37.1%, all not insulin dependent. The incidence of major adverse cardiac events, defined as cardiac death, target vessel myocardial infarction (MI), and clinically driven target lesion revascularization (CD-TLR) at 5 years was 5.7%. A non-Q wave MI was noted in 1.4% and 4.3% underwent a CD-TLR. There was no stent thrombosis during the entire follow-up period. No cardiac events were reported between 2 and 5 years. This is the first study to demonstrate safety and effectiveness for 5 years after treatment of very small coronary disease with 2.25 mm-diameter DES.Clinical trial registration: UMIN000012928

To evaluate the procedural results and in-hospital outcomes of percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) in patients with reduced left ventricular ejection fraction (LVEF).While the technical success of general CTO-PCI has improved, CTO-PCI patients with reduced LVEF remain at high-risk for adverse events.The data of 820 patients with LVEF ≤ 35% (Group 1), 1816 patients with LVEF = 35%-50% (Group 2), and 5503 patients with LVEF ≥ 50% (Group 3), registered in the Japanese CTO-PCI Expert Registry from January 2014 to December 2019, were retrospectively analyzed. The primary endpoint was in-hospital major adverse cardiac or cerebrovascular events (MACCEs), including death, myocardial infarction, stent thrombosis, stroke, and emergent revascularization. Secondary endpoints included procedural details, guidewire success, and technical success.There were no differences in guidewire and technical success rates between the groups. In-hospital MACCEs was significantly higher in Group 1 (Group 1 vs. Group 2 vs. Group 3: 3.4% vs. 1.7% vs. 1.5%, p = 0.001) and was especially driven by death (1.3% vs. 0.3% vs. 0.1%, p 0.001) and stroke (0.7% vs. 0.2% vs. 0.2%, p = 0.007). Multivariate analysis showed that LVEF ≤ 35% (odds ratio [OR]; 1.58, 95% confidence interval [CI]; 1.04-2.41, p = 0.03) and New York Heart Association (NYHA) class ≥ 3 (OR; 2.01, 95% CI; 1.03-3.93, p = 0.04) were predictors of in-hospital MACCEs.In-hospital MACCEs were significantly higher in patients with LVEF ≤ 35%. LVEF ≤;35% and NYHA class ≥ 3 were predictors of in-hospital MACCEs after CTO-PCI.

BACKGROUND Second-generation drug-eluting stents (DES) reduce the incidence of stent thrombosis, even in patients with ST-segment elevated myocardial infarction (STEMI). However, the early local vascular healing after DES implantation in STEMI lesions, which mainly concerns stent thrombosis, is still unclear.Methods and Results:We attempted to determine early local vascular healing 3 months after cobalt-chromium everolimus-eluting stent (CoCr-EES) implantation in STEMI lesions relative to stable coronary artery disease (CAD) lesions. This prospective, multicenter study analyzed 96 total lesions (STEMI=49, stable CAD=51) by frequency domain-optical coherence tomography (FD-OCT) performed post-procedure and at the 3-month follow-up. Although CoCr-EES implanted in STEMI were almost entirely covered at 3 months, they had a relatively high incidence of uncovered struts compared with stable CAD (5.5% vs. 1.6%, P

Rotational atherectomy (RA) has been widely used for percutaneous coronary intervention (PCI) to severely calcified lesions. As compared to other countries, RA in Japan has uniquely developed with the aid of greater usage of intravascular imaging devices such as intravascular ultrasound (IVUS) or optical coherence tomography (OCT). IVUS has been used to understand the guidewire bias and to decide appropriate burr sizes during RA, whereas OCT can also provide the thickness of calcification. Owing to such abundant experiences, Japanese RA operators modified RA techniques and reported unique evidences regarding RA. The Task Force on Rotational Atherectomy of the J apanese Association of Cardiovascular Intervention and Therapeutics (CVIT) has now proposed the expert consensus document to summarize the contemporary techniques and evidences regarding RA.