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Background: The diagnosis of cardiac syncope remains a challenge. This study sought to develop and validate a diagnostic model for the early identification of individuals likely to have a cardiac cause. Methods: 877 syncope patients with a determined cause were retrospectively enrolled at a tertiary heart center. They were randomly divided into the training set and validation set at a 7:3 ratio. We analyzed the demographic information, medical history, laboratory tests, electrocardiogram, and echocardiogram by the least absolute shrinkage and selection operator (LASSO) regression for selection of key features. Then a multivariable logistic regression analysis was performed to identify independent predictors and construct a diagnostic model. The receiver operating characteristic curves, area under the curve (AUC), calibration curves, and decision curve analysis were used to evaluate the predictive accuracy and clinical value of this nomogram. Results: Five independent predictors for cardiac syncope were selected: BMI (OR 1.088; 95% CI 1.022– 1.158; P =0.008), chest symptoms preceding syncope (OR 5.251; 95% CI 3.326– 8.288; P < 0.001), logarithmic NT-proBNP (OR 1.463; 95% CI 1.240– 1.727; P < 0.001), left ventricular ejection fraction (OR 0.940; 95% CI 0.908– 0.973; P < 0.001), and abnormal electrocardiogram (OR 6.171; 95% CI 3.966– 9.600; P < 0.001). Subsequently, a nomogram based on a multivariate logistic regression model was developed and validated, yielding AUC of 0.873 (95% CI 0.845– 0.902) and 0.856 (95% CI 0.809– 0.903), respectively. The calibration curves showcased the nomogram's reasonable calibration, and the decision curve analysis demonstrated good clinical utility. Conclusion: A diagnostic tool providing individualized probability predictions for cardiac syncope was developed and validated, which may potentially serve as an effective tool to facilitate early identification of such patients. [ABSTRACT FROM AUTHOR]

Irreversible perturbations in Langevin dynamics have been widely recognized for their role in accelerating convergence in simulations of multi-modal distributions π (θ) . A commonly used and easily computed standard irreversible perturbation is J ∇ log π (θ) , where J is a skew-symmetric matrix. However, Langevin dynamics employing a fixed-scale standard irreversible perturbation encounter a trade-off between local exploitation and global exploration, associated with small and large scales of standard irreversible perturbation, respectively. To address this trade-off, we introduce the adaptive irreversible perturbations Langevin dynamics, where the scale of the standard irreversible perturbation changes adaptively. Through numerical examples, we demonstrate that adaptive irreversible perturbations in Langevin dynamics can enhance performance compared to fixed-scale irreversible perturbations. [ABSTRACT FROM AUTHOR]

Chronic stress triggers activation of the sympathetic nervous system and drives malignancy. Using an immunodeficient murine system, we showed that chronic stress-induced epinephrine promoted breast cancer stem-like properties via lactate dehydrogenase A-dependent (LDHA-dependent) metabolic rewiring. Chronic stress- induced epinephrine activated LDHA to generate lactate, and the adjusted pH directed USP28-mediated deubiquitination and stabilization of MYC. The SLUG promoter was then activated by MYC, which promoted development of breast cancer stem-like traits. Using a drug screen that targeted LDHA, we found that a chronic stress-induced cancer stem-like phenotype could be reversed by vitamin C. These findings demonstrated the critical importance of psychological factors in promoting stem-like properties in breast cancer cells. Thus, the LDHA-lowering agent vitamin C can be a potential approach for combating stress-associated breast cancer., Introduction Patients suffering from cancer often experience a variety of chronic emotional stressors (1), including depression, anxiety, and fear (2, 3). These serve as risk factors by facilitating tumor growth [...]

Aims Left bundle branch area pacing (LBBAP) is a novel approach for cardiac resynchronization therapy (CRT), but the impact of myocardial substrate on its effect is poorly understood. This study aims to assess the association of cardiac magnetic resonance (CMR)–derived scar burden and the response of CRT via LBBAP. Methods and results Consecutive patients with CRT indications who underwent CMR examination and successful LBBAP-CRT were retrospectively analysed. Cardiac magnetic resonance late gadolinium enhancement was used for scar assessment. Echocardiographic reverse remodelling and composite outcomes (defined as all-cause death or heart failure hospitalization) were evaluated. The echocardiographic response was defined as a ≥15% reduction of left ventricular end-systolic volume. Among the 54 patients included, LBBAP-CRT resulted in a 74.1% response rate. The non-responders had higher global, septal, and lateral scar burden (all P < 0.001). Global, septal, and lateral scar percentage all predicted echocardiographic response [area under the curve (AUC): 0.857, 0.864, and 0.822; positive likelihood ratio (+LR): 9.859, 5.594, and 3.059; and negative likelihood ratio (−LR): 0.323, 0.233, and 0.175 respectively], which was superior to QRS morphology criteria (Strauss left bundle branch abnormality: AUC: 0.696, +LR 2.101, and −LR 0.389). After a median follow-up time of 20.3 (11.5–38.7) months, higher global, lateral and septal scar burdens were all predictive of the composite outcome (hazard ratios: 4.996, 7.019, and 4.741, respectively; P 's < 0.05). Conclusion Lower scar burden was associated with higher response rate of LBBAP-CRT. The pre-procedure CMR scar evaluation provides further useful information to identify potential responders and clinical outcomes. [ABSTRACT FROM AUTHOR]

Hemophagocytic syndrome (HPS) is a fatal hyperinflammatory disease with a poorly understood mechanism that occurs most frequently in extranodal natural killer/T cell lymphoma (ENKTL). Through exome sequencing of ENKTL tumor-normal samples, we have identified a hotspot mutation (c.419T [greater than] C) in the evolutionarily conserved signaling intermediate in Toll pathway (ECSIT) gene, encoding a V140A variant of ECSIT. ECSIT-V140A activated NF-[kappa]B more potently than the wild-type protein owing to its increased affinity for the S100A8 and S100A9 heterodimer, which promotes NADPH oxidase activity. ECSIT-T419C knock-in mice showed higher peritoneal NADPH oxidase activity than mice with wild-type ECSIT in response to LPS. ECSIT-T419C-transfected ENKTL cell lines produced tumor necrosis factor (TNF)-[alpha] and interferon (IFN)-[gamma], which induced macrophage activation and massive cytokine secretion in cell culture and mouse xenografts. In individuals with ENKTL, ECSIT-V140A was associated with activation of NF-[kappa]B, higher HPS incidence, and poor prognosis. The immunosuppressive drug thalidomide prevented NF-[kappa]B from binding to the promoters of its target genes (including TNF and IFNG), and combination treatment with thalidomide and dexamethasone extended survival of mice engrafted with ECSIT-T419C-transfected ENKTL cells. We added thalidomide to the conventional dexamethasone-containing therapy regimen for two patients with HPS who expressed ECSIT-V140A, and we observed reversal of their HPS and disease-free survival for longer than 3 years. These findings provide mechanistic insights and a potential therapeutic strategy for ENKTL-associated HPS., Author(s): Haijun Wen [1, 2, 3]; Huajuan Ma [1, 4]; Qichun Cai [1, 5, 6]; Suxia Lin [1, 7]; Xinxing Lei [1]; Bin He [1]; Sijin Wu [8]; Zifeng Wang [...]

DNA topoisomerase IIα (TOP2A) plays a vital role in replication and cell division by catalytically altering DNA topology. It is a prominent target for anticancer drugs, but clinical efficacy is often compromised due to chemoresistance. In this study, we investigate the role of TOP2A O‐GlcNAcylation in breast cancer cells and patient tumor tissues. Our results demonstrate that elevated TOP2A, especially its O‐GlcNAcylation, promotes breast cancer malignant progression and resistance to adriamycin (Adm). O‐GlcNAcylation at Ser1469 enhances TOP2A chromatin DNA binding and catalytic activity, leading to resistance to Adm in breast cancer cells and xenograft models. Mechanistically, O‐GlcNAcylation‐modulated interactions between TOP2A and cell cycle regulators influence downstream gene expression and contribute to breast cancer drug resistance. These results reveal a previously unrecognized mechanistic role for TOP2A O‐GlcNAcylation in breast cancer chemotherapy resistance and provide support for targeting TOP2A O‐GlcNAcylation in cancer therapy. Synopsis: O‐GlcNAcylation at Ser1469 enhances chromatin binding and catalytic activity of TOP2A. O‐GlcNAcylation also enhances the interaction between TOP2A and cell cycle regulators, thereby playing a crucial role in breast cancer progression and Adm resistance. TOP2A can be O‐GlcNAcylated by OGT at Ser1469 in vitro and in vivo.O‐GlcNAcylation promotes TOP2A chromatin binding.TOP2A O‐GlcNAcylation elevates its DNA cleavage and decatenation activity.O‐GlcNAcylation of TOP2A drives breast cancer progression and drug resistance. [ABSTRACT FROM AUTHOR]

Failure to achieve complete elimination of triple negative breast cancer (TNBC) stem cells after adjuvant therapy is associated with poor outcomes. Aldehyde dehydrogenase 1 (ALDH1) is a marker of breast cancer stem cells (BCSCs), and its enzymatic activity regulates tumor stemness. Identifying upstream targets to control ALDH+ cells may facilitate TNBC tumor suppression. Here, we show that KK-LC-1 determines the stemness of TNBC ALDH+ cells via binding with FAT1 and subsequently promoting its ubiquitination and degradation. This compromises the Hippo pathway and leads to nuclear translocation of YAP1 and ALDH1A1 transcription. These findings identify the KK-LC-1-FAT1-Hippo-ALDH1A1 pathway in TNBC ALDH+ cells as a therapeutic target. To reverse the malignancy due to KK-LC-1 expression, we employ a computational approach and discover Z839878730 (Z8) as an small-molecule inhibitor which may disrupt KK-LC-1 and FAT1 binding. We demonstrate that Z8 suppresses TNBC tumor growth via a mechanism that reactivates the Hippo pathway and decreases TNBC ALDH+ cell stemness and viability. The presence of breast cancer stem cells is associated with therapy resistance in patients with triple-negative breast cancer (TNBC). Here, the authors identify KK-LC-1-mediated YAP signaling as a driver of TNBC stemness and develop a therapeutic molecule to target this axis in preclinical models of TNBC. [ABSTRACT FROM AUTHOR]

Leadless pacemakers with an atrioventricular synchrony algorithm represent a novel technology for patients qualified for VDD pacing. The current evidence of their performance is limited to several small-scale observational studies. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of this new technology. We systematically searched the PubMed, Embase, and Cochrane library databases from their inception to 12 September 2022. The primary efficacy outcome was atrioventricular synchrony after implantation, whereas the secondary efficacy outcome was the change in cardiac output represented by the left ventricular outflow tract velocity time integral (LVOT-VTI). The primary safety outcome was major complications related to the procedures and the algorithm. Means or mean differences with 95% confidence interval (95% CI) were combined using a random-effects model or a fixed-effects model. Finally, 8 published studies with 464 participants were included in the qualitative analysis. The pooled atrioventricular synchrony proportion was 78.9% (95% CI 71.9–86.0%), and a further meta-regression did not screen factors that contributed significantly to the heterogeneity. Additionally, a significant increase in atrioventricular synchrony of 11.3% (95% CI 7.0–15.7%, p < 0.01) was achieved in patients experiencing programming optimization. LVOT-VTI was significantly increased by 1.9 cm (95% CI 1.2–2.6, p < 0.01), compared with the VVI pacing mode. The overall incidence of complications was approximately 6.3%, with major complications related to the algorithm being extremely low. Overall, leadless pacemakers with atrioventricular synchronous pacing demonstrated favorable safety and efficacy. Future data on their long-term performance are required to facilitate their widespread adoption in clinical practice. [ABSTRACT FROM AUTHOR]

As a guide rail is the basic motion unit of precision equipment, the measurement of and compensation for its motion errors are important preconditions for precision machining and manufacturing. A targetless and simultaneous measurement method of three-degree-of-freedom (3-DOF) angular motion errors using digital speckle pattern interferometry (DSPI) is introduced in this paper. Based on the analysis of the sensitivity mechanism of DSPI to DOF errors and the formation mechanism of the phase fringes, the relationship between the angular motion errors and the distribution of the interferometric phases was established, and a new simultaneous measurement model of 3-DOF angular motion errors was further proposed. An optical setup based on a three-dimensional spatial-carrier DSPI with a right-angle symmetrical layout was used in the measurement system. Furthermore, repetitive tests, noise tests, and precision analysis were carried out to verify the performance of the system. The test results showed that the measurement resolution of the system was <1 μrad, which is capable of measuring the pitch angle, yaw angle, and roll angle at the submicron arc level simultaneously without target mirrors. The method has the advantages of no need to install cooperative targets and high measurement resolution, showing broad application prospects in many fields, including mechanical manufacturing, laser detection, aerospace, etc. [ABSTRACT FROM AUTHOR]

The thermal deactivation of diesel soot particles exerts a significant influence on the control strategy for the regeneration of diesel particulate filters (DPFs). This work focused on the changes in the surface functional groups, carbon chemical state, and graphitization degree during thermal treatment in an inert gas environment at intermediate temperatures of 600°C, 800°C, and 1000°C and explore the chemical species that were desorbed from the diesel soot surface during thermal treatment using a thermogravimetric analyser coupled with a gas-chromatograph mass spectrometer (TGA-GC/MS). The surface functional groups and carbon chemical state were characterized using Fourier transform infrared spectroscopy (FT-IR) and X-ray photoelectron spectroscopy (XPS). The graphitization degree was evaluated by means of Raman spectroscopy (RS). The concentrations of aliphatic C–H, C–OH, C=O, and O–C=O groups are reduced for diesel soot and carbon black when increasing the thermal treatment temperature, while the sp2/sp3 hybridized ratio and graphitization degree enhance. These results provide comprehensive evidence of the decreased reactivity of soot samples. Among oxygenated functional groups, the percentage reduction during thermal treatment is the largest for the O–C=O groups owing to its worst thermodynamic stability. TGA-GC/MS results show that the aliphatic and aromatic chains and oxygenated species would be desorbed from the soot surface during 1000°C thermal treatment of diesel soot. [ABSTRACT FROM AUTHOR]

Cell lysates were subjected to immunoblotting. gl We next examined the biological consequences of dp53m-RA-mediated p53-R175H degradation in cancer cells. dp53m-RA treatment dramatically inhibited the proliferation of p53-R175H-expressing H1299 cells and SKBR3 cells. Moreover, the proteasome inhibitor MG132 completely blocked dp53m-RA-induced p53-R175H degradation (Figure 2J), and dp53m-RA treatment increased polyubiquitination of p53-R175H over p53-WT (Figure 2K). To the Editor: I TP53 i encodes the tumour suppressor protein p53, a master regulator of genomic integrity and cell survival, and is the most frequently mutated gene.[1] p53 mutant proteins are stabilised and can acquire dominant-negative or oncogenic gain-of-function activities, thereby promoting malignant transformation, metastasis and chemoresistance.[[2]] Proteolysis targeting chimeras (PROTACs) that hijack cellular ubiquitin-proteasome machinery for targeted protein degradation have shown considerable promise in targeting previously undruggable proteins.[[4]] However, PROTACs targeting p53 mutants have not yet been reported, probably due to difficulty in identifying a suitable binder for these mutants. [Extracted from the article]