bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase 1 dose-escalation study of SEA-CD40: a non-fucosylated CD40 agonist, in advanced solid tumors and lymphomas
Authors: Coveler Andrew L , Smith David C , Phillips Tycel , Curti Brendan D , Goel Sanjay , Mehta Amitkumar N , Kuzel Timothy M , Markovic Svetomir N , Rixe Olivier , Bajor David L , Gajewski Thomas F , Gutierrez Martin , Lee Hun Ju , Gopal Ajay K , Caimi Paolo , Heath Elisabeth I , Thompson John A , Ansari Sahar , Jacquemont Celine , Topletz-Erickson Ariel , Zhou Peigen , Schmitt Michael W , Grilley-Olson Juneko E 
Published: June 2023

BackgroundSEA-CD40 is an investigational, non-fucosylated, humanized monoclonal IgG1antibody that activates CD40, an immune-activating tumor necrosis factor receptor superfamily member. SEA-CD40 exhibits enhanced binding to activating FcγRIIIa, possibly enabling greater immune stimulation than other CD40 agonists. A first-in-human phase 1 trial was conducted to examine safety, pharmacokinetics, and pharmacodynamics of SEA-CD40 monotherapy in patients with advanced solid tumors and lymphoma.MethodsSEA-CD40 was administered intravenously to patients with solid tumors or lymphoma in 21-day cycles with standard 3+3 dose escalation at 0.6, 3, 10, 30, 45, and 60 µg/kg. An intensified dosing regimen was also studied. The primary objectives of the study were to evaluate the safety and tolerability and identify the maximum tolerated dose of SEA-CD40. Secondary objectives included evaluation of the pharmacokinetic parameters, antitherapeutic antibodies, pharmacodynamic effects and biomarker response, and antitumor activity.ResultsA total of 67 patients received SEA-CD40 including 56 patients with solid tumors and 11 patients with lymphoma. A manageable safety profile was observed, with predominant adverse events of infusion/hypersensitivity reactions (IHRs) reported in 73% of patients. IHRs were primarily ≤grade 2 with an incidence associated with infusion rate. To mitigate IHRs, a standardized infusion approach was implemented with routine premedication and a slowed infusion rate. SEA-CD40 infusion resulted in potent immune activation, illustrated by dose dependent cytokine induction with associated activation and trafficking of innate and adaptive immune cells. Results suggested that doses of 10–30 µg/kg may result in optimal immune activation. SEA-CD40 monotherapy exhibited evidence of antitumor activity, with a partial response in a patient with basal cell carcinoma and a complete response in a patient with follicular lymphoma.ConclusionsSEA-CD40 was tolerable as monotherapy and induced potent dose dependent immune cell activation and trafficking consistent with immune activation. Evidence of monotherapy antitumor activity was observed in patients with solid tumors and lymphoma. Further evaluation of SEA-CD40 is warranted, potentially as a component of a combination regimen.Trial registration numberNCT02376699.
Intratumoral PPT1-positive macrophages determine immunosuppressive contexture and immunotherapy response in hepatocellular carcinoma
Authors: Weng Jialei , Liu Shaoqing , Zhou Qiang , Xu Wenxin , Xu Minghao , Gao Dongmei , Shen Yinghao , Yi Yong , Shi Yi , Dong Qiongzhu , Zhou Chenhao , Ren Ning 
Published: June 2023

BackgroundHepatocellular carcinoma (HCC) is a malignancy with limited treatment options and poor prognosis. Macrophages are enriched in the HCC microenvironment and have a significant impact on disease progression and therapy efficacy. We aim to identify critical macrophages subsets involved in HCC development.MethodsMacrophage-specific marker genes were identified through single-cell RNA sequencing analyses. The clinical significance of macrophages with palmitoyl-protein thioesterase 1 (PPT1) positive was investigated in 169 patients with HCC from Zhongshan Hospital using immunohistochemistry and immunofluorescence. The immune microenvironment of HCC and the functional phenotype of PPT1+macrophages were explored using cytometry by time-of-flight (CyTOF) and RNA sequencing.ResultsSingle-cell RNA sequencing analyses revealed that PPT1 was predominantly expressed in macrophages in HCC. Intratumoral PPT1+macrophages abundance was associated with inferior survival durations of patients and an independent risk factor of prognosis for HCC. High throughput analyses of immune infiltrates showed that PPT1+macrophage-enriched HCCs were characterized by high infiltration of CD8+T cells with increased programmed death-1 (PD-1) expression. PPT1+macrophages exhibited higher galectin-9, CD172a, and CCR2 levels but lower CD80 and CCR7 levels than PPT1−macrophages. Pharmacological inhibition of PPT1 by DC661 suppressed mitogen-activated protein kinase (MAPK) pathway activity but activated nuclear factor kappa B (NF-κB) pathway in macrophages. In addition, DC661 enhanced the therapeutic efficacy of anti-PD-1 antibody in the HCC mouse model.ConclusionsPPT1 is mainly expressed in macrophages in HCC and promotes immunosuppressive transformation of macrophages and tumor microenvironment. PPT1+macrophage infiltration is associated with poor prognosis of patients with HCC. Targeting PPT1 may potentiate the efficacy of immunotherapy for HCC.
Continuous long-term heart rate variability and risk assessment in pulmonary hypertension
Authors: Andersen Mads Ørbæk , Diederichsen Soren Zöga , Svendsen Jesper Hastrup , Carlsen Jørn 
Published: June 2023

ObjectiveCurrent multimodal risk assessment for pulmonary hypertension (PH) has been redefined with a simplified assessment for follow-up in the new European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines. Follow-up risk assessment parameters include WHO functional class, 6 min walk test and N-terminal pro-brain natriuretic peptide. Although these parameters have prognostic implications assessment reflect data relating to specific time points.MethodsPatients diagnosed with PH received an implantable loop recorder (ILR) to monitor daytime and night-time heart rate (HR), HR variability (HRV) and daily physical activity. Associations between the ILR measurements and established risk parameters were analysed using correlations, linear mixed models as well as logistical mixed models for addressing the ESC/ERS risk-score.Results41 patients (median age: 56 years, range: 44–61.5 years) were included. Continuous monitoring had a median duration of 755 days (range: 343–1138 days), totalling 96 patient-years. In the linear mixed models, HRV and physical activity indexed by daytime HR (PAiHR) were significantly associated with the ERS/ERC risk parameters. In a logistical mixed model, HRV revealed a significant difference between 1-year mortality (<5% vs >5%) (p=0.027) with an OR of 0.82 for being in the group with 1-year mortality >5% for every increase by one HRV unit.ConclusionsRisk assessment in PH can be refined with continuous monitoring of HRV and PAiHR. These markers were associated with the ESC/ERC parameters. Our study with continuous risk stratification in PH demonstrated that a lower HRV predict worse prognosis.
Dual ultrasound-guided totally implantable venous access ports via the right internal jugular vein in pediatric patients with cancer: a preliminary experience in a single institution
Authors: Deng Xiao Bin , Peng Liang , Zhang Jun , Kong Xiangru , Zhao Zhenzhen , Wang Shan , Li Changchun , Du Yifei , Zhou Jianwu , Liu Lifei , Yang Chao 
Published: June 2023

ObjectiveTo assess the efficacy and safety of dual ultrasound-guided (DUG) totally implantable venous access port (TIVAP) implantation (namely, using ultrasound-guided percutaneous puncture with transesophageal echocardiography-guided catheterization) via the right internal jugular vein (IJV) in pediatric patients with cancer.MethodsFifty-five children with cancer requiring chemotherapy underwent DUG-TIVAP implantation via the right IJV. Clinical data were recorded, including the procedure success rate, first attempt success rate, and perioperative and postoperative complications.ResultsAll 55 cases were successfully operated on. The first puncture success rate was 100%. The operation time was 22–41 min, with a mean time of 30.8±5.5 min. The mean TIVAP implantation time was 253±145 days (range 42–520 days). There were no perioperative complications. The postoperative complication rate was 5.4% (3/55), including skin infections around the port in one case, catheter-related infection in one case, and fibrin sheath formation in one case. The ports were all preserved after anti-infection or thrombolytic therapy. No unplanned port withdrawal was recorded in this study.ConclusionsDUG-TIVAP implantation is a technique with a high success rate and a low complication rate; therefore, it provides an alternative for children with cancer. Further randomized controlled studies are needed to confirm the efficacy and safety of DUG-TIVAP via the right IJV in children.
Charge gap in SU(3) Yang–Mills-plus-nonlinear-spinor-field theory
Authors: Dzhunushaliev Vladimir , Folomeev Vladimir , Berkimbayev Daulet 
Published: June 2023

AbstractParticlelike solutions in SU(3) gauge Yang–Mills theory with color magnetic and electric fields sourced by a nonlinear spinor field are obtained. The asymptotic behavior of these fields is studied. It is shown that the electric field exhibits the Coulomb asymptotic behavior, and one of the color components of the magnetic field behaves asymptotically as the field of a magnetic dipole. This allows one to determine the corresponding charge and magnetic moment. It is shown that profiles of the color charge and magnetic moment have global minima, which may be called charge and magnetic moment gaps. The relationship between the total energy of the system and the color charge is obtained. The physical reason for the appearance of the mass, charge, and magnetic moment gaps in the theory under consideration is discussed.
Spinor domain wall and test fermions on an arbitrary domain wall
Authors: Dzhunushaliev Vladimir , Folomeev Vladimir , Zholdakhmet Dina 
Published: June 2023

AbstractWe consider a spinor domain wall embedded in a five-dimensional spacetime with a nondiagonal metric. The corresponding plane symmetric solutions for linear and nonlinear spinor fields with different parameters are obtained. It is shown that in the general case the metric functions and spinor fields do not possess $$Z_2$$

Z
2

symmetry with respect to the domain wall. We study the angular momentum density of the domain wall arising because of the presence of the spinor field creating the wall. The properties of test fermions located on an arbitrary domain wall are considered. The concepts of the “second spin” (arising due to the properties of the Lorentz group generators in a five-dimensional spacetime) and of the “second magnetic field” (representing the components $$F_{i 5}$$

F

i
5

of the electromagnetic field five-tensor) are introduced. We find eigenspinors of the “second spin” and show that some of them represent the Bell states. In the nonrelativistic limit we derive the Pauli equation for the test fermions on the domain wall which contains an extra term describing the interaction of a spin-1/2 particle with the “second magnetic field”; this allows the possibility of an experimental verification of the existence of extra dimensions.
Nimbus++: Revisiting Efficient Function Signature Recovery with Depth Data Analysis
Authors: Chen Ligeng , Qian Yi , Wang Yuyang , Mao Bing 
Published: June 2023

Function signature recovery is vital for many binary analysis tasks, led by control-flow integrity enhancement. To minimize human effort, existing works attempt to replace rule-based methods with learning-based methods. These works put a lot of work into improving the system’s performance, but this had the unintended consequence of increasing resource usage. However, recovering the function signature is more about providing information for subsequent tasks, e.g. reverse engineering, so both efficiency and performance are significant. To identify the fundamental factors that increase efficiency, we attempt to optimize data-driven systems throughout their lifecycle from a data perspective. To this end, we perform detailed data analysis on a carefully collected dataset. After analysis and exploration, selective input is adopted and a multi-task learning (MTL) structure is introduced for function feature recovery to make full use of mutual information, and the computing resource overhead is optimized based on the observation of information deviation and sub-task relationship. The resource usage of the entire process is significantly reduced by our suggested solution, named Nimbus++ for efficient function signature recovery, without sacrificing performance. Our test findings demonstrate that we even surpass the state-of-the-art method’s prediction accuracy across all function signature recovery tasks by about 1% with just about 12.5% of the processing time.
INVESTIGATION OF MICROSTRUCTURE AND MECHANICAL PROPERTIES OF MAGNESIUM ALLOY COATED WITH INCONEL 625/WC COMPOSITES BY HVOF METHOD
Authors: SOMER MEDENI , GURGENC TURAN , ILKILIC CUMALI , MACIT CEVHER KURSAT 
Published: June 2023

In this study, Inconel 625 (IN625) alloy and tungsten carbide (WC) with additive ratios of 10%, 30% and 50% by weight were coated on the magnesium alloy surface. The coating process was carried out with the High Speed Oxy-Fuel Spray (HVOF) technique. Microstructure characterizations were performed by profilometry, optical microscope (OM), scanning electron microscope (SEM), energy distribution X-ray spectroscopy (EDS) and X-ray diffraction (XRD) analysis. Microhardness measurements and wear tests were also used to determine mechanical properties. Dry sliding wear tests were carried out at loads of 2, 6 and 10 N and at a sliding distance of 150 m. It has been observed that powder mixtures with different additive ratios form different microstructures. It was observed that the Surface Centric Cubic Structure (FCC) [Formula: see text] (gamma) matrix and WC carbide as well as W2C, W6C[Formula: see text], M6C and M[Formula: see text]C6 carbides were formed on the obtained coating layers. Depending on the increase in WC additive ratio, the surface roughness values increased. The microhardness values in the coating layers varied between 392 and 508 HV[Formula: see text]WC additive to Inconel 625 improved its hardness and wear resistance. While 0.64, 0.97 and 1.19 mg weight loss was measured for 2, 6 and 10 N in the pure AZ91 sample, these values were 0.12, 0.2 and 0.31 mg in the IN625WC-50 sample measured. The coating with the highest hardness and wear resistance was obtained with a high WC ratio.
Absolutely pure covers of sheaves
Authors: Hosseini Esmaeil , Zarei Zahra 
Published: June 2023

Let [Formula: see text] be a scheme and [Formula: see text] be the category of all sheaves of [Formula: see text]-modules. Enochs’ conjecture states that any covering class in [Formula: see text] is closed under directed colimits. In this work, if Abs[Formula: see text] is the class of all absolutely pure objects in [Formula: see text], then we prove the validity of the conjecture for Abs[Formula: see text]. This gives a characterization of locally coherent schemes. In addition, we study some homological properties of absolutely pure sheaves of [Formula: see text]-modules and answer a question raised in [P. Rothmaler, When are pure injective envelopes of flat modules flat? Comm. Algebra 30(6) (2002) 3077–3085].
MAGT1 Deficiency Dysregulates Platelet Cation Homeostasis and Accelerates Arterial Thrombosis and Ischemic Stroke in Mice
Authors: Gotru Sanjeev Kiran , Mammadova-Bach Elmina , Sogkas Georgios , Schuhmann Michael K. , Schmitt Karen , Kraft Peter , Herterich Sabine , Mamtimin Medina , Pinarci Akif , Beck Sarah , Stritt Simon , Han Chao , Ren Pengxuan , Freund Jean-Noël , Klemann Christian , Ringshausen Felix C. , Heemskerk Johan W.M. , Dietrich Alexander , Nieswandt Bernhard , Stoll Guido , Gudermann Thomas , Braun Attila 
Published: June 2023

BACKGROUND:
MAGT1 (magnesium transporter 1) is a subunit of the oligosaccharide protein complex with thiol-disulfide oxidoreductase activity, supporting the process of N-glycosylation. MAGT1 deficiency was detected in human patients with X-linked immunodeficiency with magnesium defect syndrome and congenital disorders of glycosylation, resulting in decreased cation responses in lymphocytes, thereby inhibiting the immune response against viral infections. Curative hematopoietic stem cell transplantation of patients with X-linked immunodeficiency with magnesium defect causes fatal bleeding and thrombotic complications.

METHODS:
We studied the role of MAGT1 deficiency in platelet function in relation to arterial thrombosis and hemostasis using several in vitro experimental settings and in vivo models of arterial thrombosis and transient middle cerebral artery occlusion model of ischemic stroke.

RESULTS:

MAGT1-deficient mice (

Magt1
−/y

) displayed accelerated occlusive arterial thrombus formation in vivo, a shortened bleeding time, and profound brain damage upon focal cerebral ischemia. These defects resulted in increased calcium influx and enhanced second wave mediator release, which further reinforced platelet reactivity and aggregation responses. Supplementation of MgCl
2
or pharmacological blockade of TRPC6 (transient receptor potential cation channel, subfamily C, member 6) channel, but not inhibition of store-operated calcium entry, normalized the aggregation responses of

Magt1
−/y

platelets to the control level. GP (glycoprotein) VI activation of

Magt1
−/y

platelets resulted in hyperphosphorylation of Syk (spleen tyrosine kinase), LAT (linker for activation of T cells), and PLC (phospholipase C) γ2, whereas the inhibitory loop regulated by PKC (protein kinase C) was impaired. A hyperaggregation response to the GPVI agonist was confirmed in human platelets isolated from a MAGT1-deficient (X-linked immunodeficiency with magnesium defect) patient. Haploinsufficiency of TRPC6 in

Magt1
−/y

mice could normalize GPVI signaling, platelet aggregation, and thrombus formation in vivo.

CONCLUSIONS:
These results suggest that MAGT1 and TRPC6 are functionally linked. Therefore, deficiency or impaired functionality of MAGT1 could be a potential risk factor for arterial thrombosis and stroke.
Spatially Resolved Metabolites in Stable and Unstable Human Atherosclerotic Plaques Identified by Mass Spectrometry Imaging
Authors: Seeley Erin H. , Liu Zhipeng , Yuan Shuai , Stroope Chad , Cockerham Elizabeth , Rashdan Nabil A. , Delgadillo Luisa F. , Finney Alexandra C. , Kumar Dhananjay , Das Sandeep , Razani Babak , Liu Wanqing , Traylor James , Orr A. Wayne , Rom Oren , Pattillo Christopher B. , Yurdagul Arif 
Published: June 2023

Background:
Impairments in carbohydrate, lipid, and amino acid metabolism drive features of plaque instability. However, where these impairments occur within the atheroma remains largely unknown. Therefore, we sought to characterize the spatial distribution of metabolites within stable and unstable atherosclerosis in both the fibrous cap and necrotic core.

Methods:
Atherosclerotic tissue specimens from 9 unmatched individuals were scored based on the Stary classification scale and subdivided into stable and unstable atheromas. After performing mass spectrometry imaging on these samples, we identified over 850 metabolite-related peaks. Using MetaboScape, METASPACE, and Human Metabolome Database, we confidently annotated 170 of these metabolites and found over 60 of these were different between stable and unstable atheromas. We then integrated these results with an RNA-sequencing data set comparing stable and unstable human atherosclerosis.

Results:
Upon integrating our mass spectrometry imaging results with the RNA-sequencing data set, we discovered that pathways related to lipid metabolism and long-chain fatty acids were enriched in stable plaques, whereas reactive oxygen species, aromatic amino acid, and tryptophan metabolism were increased in unstable plaques. In addition, acylcarnitines and acylglycines were increased in stable plaques whereas tryptophan metabolites were enriched in unstable plaques. Evaluating spatial differences in stable plaques revealed lactic acid in the necrotic core, whereas pyruvic acid was elevated in the fibrous cap. In unstable plaques, 5-hydroxyindoleacetic acid was enriched in the fibrous cap.

Conclusions:
Our work here represents the first step to defining an atlas of metabolic pathways involved in plaque destabilization in human atherosclerosis. We anticipate this will be a valuable resource and open new avenues of research in cardiovascular disease.
Association Between Electrocardiographic Age and Cardiovascular Events in Community Settings: The Framingham Heart Study
Authors: Brant Luisa C.C. , Ribeiro Antônio H. , Pinto-Filho Marcelo M. , Kornej Jelena , Preis Sarah R. , Fetterman Jessica L. , Eromosele Oseiwe B. , Magnani Jared W. , Murabito Joanne M. , Larson Martin G. , Benjamin Emelia J. , Ribeiro Antonio L.P. , Lin Honghuang 
Published: June 2023

BACKGROUND:
Deep neural networks have been used to estimate age from ECGs, the electrocardiographic age (ECG-age), which predicts adverse outcomes. However, this prediction ability has been restricted to clinical settings or relatively short periods. We hypothesized that ECG-age is associated with death and cardiovascular outcomes in the long-standing community-based FHS (Framingham Heart Study).

METHODS:
We tested the association of ECG-age with chronological age in the FHS cohorts in ECGs from 1986 to 2021. We calculated the gap between chronological and ECG-age (Δage) and classified individuals as having normal, accelerated, or decelerated aging, if Δage was within, higher, or lower than the mean absolute error of the model, respectively. We assessed the associations of Δage, accelerated and decelerated aging with death or cardiovascular outcomes (atrial fibrillation, myocardial infarction, and heart failure) using Cox proportional hazards models adjusted for age, sex, and clinical factors.

RESULTS:
The study population included 9877 FHS participants (mean age, 55±13 years; 54.9% women) with 34 948 ECGs. ECG-age was correlated to chronological age (r=0.81; mean absolute error, 9±7 years). After 17±8 years of follow-up, every 10-year increase of Δage was associated with 18% increase in all-cause mortality (hazard ratio [HR], 1.18 [95% CI, 1.12–1.23]), 23% increase in atrial fibrillation risk (HR, 1.23 [95% CI, 1.17–1.29]), 14% increase in myocardial infarction risk (HR, 1.14 [95% CI, 1.05–1.23]), and 40% increase in heart failure risk (HR, 1.40 [95% CI, 1.30–1.52]), in multivariable models. In addition, accelerated aging was associated with a 28% increase in all-cause mortality (HR, 1.28 [95% CI, 1.14–1.45]), whereas decelerated aging was associated with a 16% decrease (HR, 0.84 [95% CI, 0.74–0.95]).

CONCLUSIONS:
ECG-age was highly correlated with chronological age in FHS. The difference between ECG-age and chronological age was associated with death, myocardial infarction, atrial fibrillation, and heart failure. Given the wide availability and low cost of ECG, ECG-age could be a scalable biomarker of cardiovascular risk.