CBP/p300 is a cell type-specific modulator of CLOCK/BMAL1-mediated transcription

<p>Abstract</p> <p>Background</p> <p>Previous studies have demonstrated tissue-specific regulation of the rhythm of circadian transcription, suggesting that transcription factor complex CLOCK/BMAL1, essential for maintaining circadian rhythm, regulates transcription in a tissue-specific manner. To further elucidate the mechanism of the cell type-specific regulation of transcription by CLOCK/BMAL1 at the molecular level, we investigated roles of CBP/p300 and tissue-specific cofactors in CLOCK/BMAL1-mediated transcription.</p> <p>Results</p> <p>As shown previously, CBP/p300 stimulates CLOCK/BMAL1-mediated transcription in COS-1 cells. However, CBP/p300 repressed CLOCK/BMAL1-mediated transcription in NIH3T3 cells and knockdown of CBP or p300 expression by siRNA enhanced this transcription. Studies using GAL4-fusion proteins suggested that CBP represses CLOCK/BMAL1-mediated transcription by targeting CLOCK. We further investigated mechanisms of this cell type-specific modulation of CLOCK/BMAL1-mediated transcription by CBP by examining roles of co-repressor HDAC3 and co-activator pCAF, which are highly expressed in NIH3T3 and COS cells, respectively. CBP repressed CLOCK/BMAL1-mediated transcription in COS-1 cells when HDAC3 was overexpressed, but activated it in NIH3T3 cells when pCAF was overexpressed. CBP forms a complex with CLOCK by interacting with HDAC3 or pCAF; however, direct interaction of CBP with CLOCK was not observed.</p> <p>Conclusion</p> <p>Our findings indicate possible mechanisms by which CBP/p300 tissue-specifically acts cooperatively with pCAF and HDAC3 either as a co-activator or co-repressor, respectively, for CLOCK/BMAL1.</p

Long-term effectiveness of right septal pacing vs. right apical pacing in patients with atrioventricular block

AbstractBackgroundLong-term right ventricular apical (RVA) pacing increases the risk of heart failure (HF) by inducing ventricular dyssynchronization. Although recent studies suggest that right ventricular septal (RVS) pacing results in improved short-term outcomes, its long-term effectiveness remains unclear.Methods and resultsThis study investigated 149 consecutive patients who underwent implantation of a dual chamber pacemaker for atrioventricular block with either RVS-pacing between July 2007 and June 2010 or RVA-pacing between January 2003 and June 2007. The endpoint was defined as death and hospitalization due to heart failure (HF). The rates of mortality and hospitalization due to HF were significantly lower in the RVS-pacing group than that in the RVA-pacing group (event free RVS: 1 year, 98% and 2 years, 98%; RVA: 1 year, 85% and 2 years, 81%; p<0.05). None of the patients died from HF in the RVS-pacing group, while 4 patients died from HF in the RVA-pacing group within 2 years after pacemaker implantation. The paced QRS interval was significantly shorter with RVS pacing than with RVA pacing at different times after pacemaker implantation (RVS: immediately 157.8±24.0ms, after 3 months 157.3±17.5ms, after 6 months 153.6±21.7ms, after 12 months 153.6±19.4ms, after 24 months 149.3±24.0ms vs. RVA: immediately 168.3±23.7ms, after 3 months 168.7±26.0ms, after 6 months 168.0±22.8ms, after 12 months 171.2±22.3ms, after 24 months 176.1±25.5ms; p<0.05).ConclusionsRVS pacing is feasible and safe with more favorable clinical benefits than RVA pacing

LoCO: Local Cooperative Data Offloading System Based on Location Information, Journal of Telecommunications and Information Technology, 2019, nr 1

The development of high speed mobile networks and the widespread use of smartphones have enabled users to easily obtain large data volumes via the Internet. This causes a heavy consumption of network resources, a burden on the available bandwidth. To solve such problems, a data offloading method with a wireless LAN access point has been used to distribute traffic from mobile to fixed networks. However, the method using wireless LAN access points can only change the communication paths but cannot reduce the overall traffic. This paper proposes a local cooperative data offloading system (LoCO) that reduces the overall traffic by sharing data, with direct communication between neighbors based on their location-related information. Moreover, the authors implemented the LoCO system on Android smartphones and clarified its performance in comparison with a traditional client/server system through experiments to download data in a real-world environment

Recurrent, Tumor Mutation Burden-High, Cutaneous Angiosarcoma of the Scalp Treated with Pembrolizumab

Introduction: Chemoradiotherapy with taxanes is well-recognized as a first-line therapy for cutaneous angiosarcoma (CAS), but second-line therapy for CAS is still controversial. Case Presentation: In this report, we described a 75-year-old Japanese case of recurrent, tumor mutation burden-high CAS on the scalp treated with pembrolizumab. Our present case survived for 1 year despite of taxane refractory CAS with mediastinal lymph node metastasis, though the administration of anti-PD-1 Abs alone could not fully suppress the tumor progression of CAS. Conclusion: Since various factors such as pro-angiogenic molecules are correlated with the tumor progression in CAS, the administration of anti-PD-1 Abs alone could not fully suppress the tumor progression of CAS. Further novel anticancer drugs are needed in the future for the treatment of CAS

Possible involvement of iron-induced oxidative insults in neurodegeneration.

Involvement of iron in the development of neurodegenerative disorders has long been suggested, and iron that cannot be stored properly is suggested to induce iron toxicity. To enhance iron uptake and suppress iron storage in neurons, we generated transgenic (Tg) mice expressing iron regulatory protein 2 (IRP2), a major regulator of iron metabolism, in a neuron-specific manner. Although very subtle, IRP2 was expressed in all regions of brain examined. In the Tg mice, mitochondrial oxidative insults were observed including generation of 4-hydroxynonenal modified proteins, which appeared to be removed by a mitochondrial quality control protein Parkin. Inter-crossing of the Tg mice to Parkin knockout mice perturbed the integrity of neurons in the substantia nigra and provoked motor symptoms. These results suggest that a subtle, but chronic increase in IRP2 induces mitochondrial oxidative insults and accelerates neurodegeneration in a mouse model of Parkinson's disease. Thus, the IRP2 Tg may be a useful tool to probe the roles of iron-induced mitochondrial damages in neurodegeraration research

Late thrombotic events after bioresorbable scaffold implantation: a systematic review and meta-analysis of randomized clinical trials

To compare the long-term safety and efficacy of bioresorbable vascular scaffold (BVS) with everolimus-eluting stent (EES) after percutaneous coronary interventions.Methods and Results: A systematic review and meta-analysis of randomized clinical trials comparing clinical outcomes of patients treated with BVS and EES with at least 24 months follow-up was performed. Adjusted random-effect model by the Knapp–Hartung method was used to compute odds ratios (OR) and 95% confidence intervals (CI). The primary safety outcome of interest was the risk of definite/probable device thrombosis (DT). The primary efficacy outcome of interest was the risk of target lesion failure (TLF). Five randomized clinical trials (n = 1730) were included. Patients treated with Absorb BVS had a higher risk of definite/probable DT compared with patients treated with EES (OR 2.93, 95%CI 1.37–6.26, P = 0.01). Very late DT (VLDT) occurred in 13 patients [12/996 (1.4%, 95%CI: 0.08–2.5) Absorb BVS vs. 1/701 (0.5%, 95%CI: 0.2–1.6) EES; OR 3.04; 95%CI 1.2–7.68, P = 0.03], 92% of the VLDT in the BVS group occurred in the absence of dual antiplatelet therapy (DAPT). Patients treated with Absorb BVS had a trend towards higher risk of TLF (OR 1.48, 95%CI 0.90–2.42, P = 0.09), driven by a higher risk of target vessel myocardial infarction and ischaemia-driven target lesion revascularization. No difference was found in the risk of cardiac death.Conclusion: Compared with EES, the use of Absorb BVS was associated with a higher rate of DT and a trend towards higher risk of TLF. VLDT occurred in 1.4% of the patients, the majority of these events occurred in the absence of DAPT

Right Atrial Volume Calculated by Multi-detector Computed Tomography: Useful Predictor of Atrial Fibrillation Recurrence after Pulmonary Vein Catheter Ablation

We investigated whether right atrial (RA) volume could be used to predict the recurrence of atrial fibrillation (AF) after pulmonary vein catheter ablation (CA). We evaluated 65 patients with paroxysmal AF (mean age, 60+10 years, 81.5% male) and normal volunteers (57 ± 14 years, 41.7% male). Sixty-four-slice multi-detector computed tomography was performed for left atrial (LA) and RA volume estimations before CA. The recurrence of AF was assessed for 6 months after the ablation. Both left and right atrial volumes were larger in the AF patients than the normal volunteers (LA: 99.7+33.2ml vs. 59.7+17.4ml; RA: 82.9+35.7ml vs. 43.9+12ml; P100ml) for predicting the recurrence of AF was 81.3% in 13 of 16 patients with AF recurrence, and the specificity was 69.4% in 34 of 49 patients without recurrence. The sensitivity with large RA volumes (>87ml) was 81.3% in 13 of 16 patients with AF recurrence, and the specificity was 75.5% in 37 of 49 patients without recurrence. RA volume is a useful predictor of the recurrence of AF, similar to LA volume

Accuracy of coronary computed tomography angiography for bioresorbable scaffold luminal investigation: a comparison with optical coherence tomography

To establish the accuracy of coronary computed tomography angiography (CTA) for in-scaffold quantitative evaluation with opt

The impact of plaque type on strut embedment/protrusion and shear stress distribution in bioresorbable scaffold

AIMS: Scaffold design and plaque characteristics influence implantation outcomes and local flow dynamics in treated coronary segments. Our aim is to assess the impact of strut embedment/protrusion of bioresorbable scaffold on local shear stress distribution in different atherosclerotic plaque types. METHODS AND RESULTS: Fifteen Absorb everolimus-eluting Bioresorbable Vascular Scaffolds were implanted in human epicardial coronary arteries. Optical coherence tomography (OCT) was performed post-scaffold implantation and strut embedment/protrusion were analysed using a dedicated software. OCT data were fused with angiography to reconstruct 3D coronary anatomy. Blood flow simulation was performed and wall shear stress (WSS) was estimated in each scaffolded surface and the relationship between strut embedment/protrusion and WSS was evaluated. There were 9083 struts analysed. Ninety-seven percent of the struts (n = 8840) were well-apposed and 243 (3%) were malapposed. At cross-section level (n = 1289), strut embedment was significantly increased in fibroatheromatous plaques (76 ± 48 µm) and decreased in fibrocalcific plaques (35 ± 52 µm). Compatible with strut embedment, WSS was significantly higher in lipid-rich fibroatheromatous plaques (1.50 ± 0.81 Pa), whereas significantly decreased in fibrocalcified plaques (1.05 ± 0.91 Pa). After categorization of WSS as low (<1.0 Pa) and normal/high WSS (≥1.0 Pa), the percent of low WSS in the plaque subgroups were 30.1%, 31.1%, 25.4%, and 36.2% for non-diseased vessel wall, fibrous plaque, fibroatheromatous plaque, and fibrocalcific plaque, respectively (P-overall < 0.001). CONCLUSION: The composition of the underlying plaque influences strut embedment which seems to have effect on WSS. The struts deeply embedded in lipid-rich fibroatheromas plaques resulted in higher WSS compared with the other plaque types

Recurrence of Atrial Fibrillation within Three Months after Pulmonary Vein Isolation in Patients with Paroxysmal Atrial Fibrillation : Analysis Using an External Loop Recorder with Auto-trigger Function

Pulmonary vein isolation (PVI) via catheter ablation has been shown to be a highly effective option for patients with symptomatic paroxysmal atrial brillation (AF). The recurrence of AF within 3 months after PVI is not considered a failure of the ablation procedure because early recurrence of AF is not always associated with late recurrence. We examined the usefulness of an external loop recorder with auto-trigger function (ELR-AUTO) to detect AF following PVI to characterize early recurrence and determine the implication of AF within 3 months after PVI. The study included 53 consecutive patients with symptomatic paroxysmal AF (age, 61.6 ± 12.6 years ; 77％ male) who underwent PVI, and were fitted with an ELR-AUTO for 7 ± 2 days within 3 months after PVI. Of the 33 patients(62.2％) who did not have AF within the 3-month period, only 1 patient had AF recurrence at 12 months. Seven of 20 patients (35％) who experienced AF within 3 months had symptomatic AF recurrence at 12 months. The sensitivity, specificity, positive predictive value, and negative predictive value of early AF recurrence for late recurrence was 87.5％, 71.1％, 35.0％, and 96.9％, respectively. Thus, AF recurrence detected by ELR-AUTO within 3 months after PVI can predict late AF recurrence. Freedom from AF in the firrst 3 months following ablation significantly predicts long-term freedom from AF. An ELR-AUTO is useful for detecting symptomatic and asymptomatic AF