bluuebunny/crossref_metadata_2025_split huggingface dataset:
PD-1 cis-targeted IL-2v in combination with radiotherapy inhibits lung cancer growth and remodels the immune microenvironment
Authors: Godfroid Céline , Romero Jackeline , Labiano Sara , Chuang Chia-Hsien , Kelemen Andrea , Wyss Tania , Roh Vincent , Verdeil Grégory , Klein Christian , Codarri Deak Laura , Umaña Pablo , Tolstonog Genrich V , Trumpfheller Christine , Vozenin Marie-Catherine , Romero Pedro J 
Published: January 2025

BackgroundMore efficient therapeutic options for non-small cell lung cancer (NSCLC) are needed as the survival at 5 years of metastatic disease is near zero. In this regard, we used a preclinical model of metastatic lung adenocarcinoma (SV2-OVA) to assess the safety and efficacy of novel radio-immunotherapy combining hypofractionated radiotherapy (HRT) with muPD1-IL2v immunocytokine and muFAP-CD40 bispecific antibody.MethodsWe evaluated the changes in the lung immune microenvironment at multiple timepoints following combination therapies and investigated their underlying antitumor mechanisms. Additionally, we analyzed the tumor clonal heterogeneity upon the combination treatments to explore potential mechanisms associated with the lack of complete response.ResultsThe combination of HRT with muPD1-IL2v had a potent antitumor effect and increased survival in the SV2-OVA lung cancer model. Importantly, this combination therapy was devoid of measurable toxicity. It induced remodeling of the immune contexture through the increase of CD8+T and natural killer (NK) cells. The addition of muFAP-CD40 to the combination treatment further increased infiltrating CD8+T cells, expressing high levels of effector molecules, both in the periphery and core tumor regions. An accumulation of CD8+PD-1+TOX+(exhausted) T cells, already at the ‘early’ timepoint, is consistent with the limited clinical benefits provided by the various combination treatments in this model. The study of the clonal dynamics of tumor cells during disease progression and therapy highlighted a clonal selection upon HRT+muPD1-IL2v therapy.ConclusionsWe demonstrated that HRT+muPD1-IL2v combination is a potent therapeutic strategy to delay tumor growth and increase survival in a metastatic lung cancer model, but additional studies are required to completely understand the resistance mechanisms associated with the lack of complete response in this model.
Computational study of the wake of a plane bluff body with a gap flow—mean velocity characteristics
Authors: Shinneeb A.-M. , Nasif G. , Balachandar R. 
Published: January 2025

This numerical study investigates the shallow wake characteristics behind a vertical flat plate with and without gap flow. It builds upon our prior experimental work on bluff wakes to gain deeper understanding of the flow. Using transient three-dimensional Navier–Stokes equations solved via finite-volume approach with improved delayed detached eddy simulation turbulence model, it provides spatial and temporal data for the wake volume. The bulk velocity was 0.45 m/s, yielded a Reynolds number of 45 000. This paper marks the initial phase of an extensive investigation aimed at characterizing the impact of gap flow on the mean velocity field. The results revealed the formation of a three-dimensional mean recirculation loop just behind the bluff body whose shape resembles a hairpin vortex loop. The gap flow reduces the vortex loop diameter and increases its spinning strength. Moreover, it hinders the secondary currents causing delayed wake spread near the bed but enhances the secondary flow in the upper velocity fields and hence, the growth rate.
How analogies helped novice students think about superposition states and collapse in quantum mechanics
Authors: Faletič Sergej 
Published: January 2025

Abstract
In my active learning course on quantum mechanics, students build their knowledge by following the scientific process as outlined by the Investigative Science Learning Environment. In this course, open-ended questions on the effect of measurement (collapse) failed to elicit meaningful responses from students. Meaningful responses are crucial for the next steps of testing students’ ideas using hypothetico-deductive reasoning. I wanted to help the students in this process with a pictorial representation. To arrive at a pictorial representation that would have meaning for students, I first asked them to provide their analogies for a superposition state. A common suggestion was the mixture of colours, but other, more inventive analogies were also suggested. I developed a pictorial representation based on the colour analogy. I reformulated the questions on collapse using this representation and a more concretized formulation. The ability of students to meaningfully answer the questions increased to the point where it was possible to complete also the testing part of the process. In the article, I discuss the analogies that students suggested and what underlying ideas known from literature they could represent. I provide the derived representation, the reformulated questions and evidence of how this helped students articulate their answers and helped identify students’ productive ideas that they could not clearly articulate in words. This enabled students to arrive at conclusions about the effect of measurement following the scientific process. This study contributes to the literature by providing student-generated analogies, using a pictorial representation derived from student-generated analogies, and showing an example of an efficiently formulated question on a difficult topic that is able to elicit meaningful responses.
First-in-Human Phase I Study of a CD16A Bispecific Innate Cell Engager, AFM24, Targeting EGFR-Expressing Solid Tumors
Authors: El-Khoueiry Anthony , Saavedra Omar , Thomas Jacob , Livings Claire , Garralda Elena , Hintzen Gabriele , Kohlhas Laura , Vanosmael Dessislava , Koch Joachim , Rajkovic Erich , Ravenstijn Paulien , Nuciforo Paolo , Fehniger Todd A. , Foster Mark , Berrien-Elliott Melissa M. , Wingert Susanne , Stäble Sina , Morales-Espinosa Daniela , Rivas Delcia , Emig Michael , Lopez Juanita 
Published: January 2025

Abstract

Purpose:
Innate immune cell–based therapies have shown promising antitumor activity against solid and hematologic malignancies. AFM24, a bispecific innate cell engager, binds CD16A on NK cells/macrophages and EGFR on tumor cells, redirecting antitumor activity toward tumors. The safety and tolerability of AFM24 were evaluated in this phase I/IIa dose-escalation/dose-expansion study in patients with recurrent or persistent, advanced solid tumors known to express EGFR.

Patients and Methods:
The main objective in phase I was to determine the MTD and/or recommended phase II dose. The primary endpoint was the incidence of dose-limiting toxicities during the observation period. Secondary endpoints included the incidence of treatment-emergent adverse events and pharmacokinetics.

Results:
In the dose-escalation phase, 35 patients received AFM24 weekly across seven dose cohorts (14–720 mg). One patient experienced a dose-limiting toxicity of grade 3 infusion-related reaction. Infusion-related reactions were mainly reported after the first infusion; these were manageable with premedication and a gradual increase in infusion rate. Pharmacokinetics was dose-proportional, and CD16A receptor occupancy on NK cells approached saturation between 320 and 480 mg. Paired tumor biopsies demonstrated the activation of innate and adaptive immune responses within the tumor. The best objective response was stable disease in 10/35 patients; four patients had stable disease for 4.3 to 7.1 months.

Conclusions:
AFM24 was well tolerated, with 480 mg established as the recommended phase II dose. AFM24 could be a novel therapy for patients with EGFR-expressing solid tumors, with suitable tolerability and appropriate pharmacokinetic properties for further development in combination with other immuno-oncology therapeutics.
МАРКЕТИНГОВИЙ АНАЛІЗ ЛІКАРСЬКИХ ЗАСОБІВ ВІД НУДОТИ ТА БЛЮВОТИ
Authors: Bobenchyk M. M. , Levytska O. R. , Hromovyk B.  P. , Chukhray I.  L. , Jarko N. B. 
Published: January 2025

Мета роботи. Розвідка асортименту і цінових пропозицій на вітчизняному фармацевтичному ринку лікарських засобів групи А04 Протиблювотні засоби та препарати, що усувають нудоту.
Матеріали та методи. Матеріали: Державний реєстр лікарських засобів України, інформація про величину визначеної добової дози, мінімальні та максимальні роздрібні ціни на лікарські засоби групи А04 в аптеках м. Львова станом на 30.11.2023 р. (період 1) та 28.02.2024 р. (період 2). Методи: інформаційного пошуку, аналізу, узагальнення, маркетингових досліджень.
Результати та обговорення. З’ясовано, що у періоді 1 в Україні було зареєстровано 46, а у періоді 2 – 49 асортиментних позицій лікарських засобів групи А04. Більшість з них були препаратами ондансетрону (65,2 % і 61,2 % відповідно). Число вітчизняних асортиментних позицій зменшилася з 56,5 % до 53,1 % внаслідок збільшення асортиментних позицій імпортного виробництва. За лікарськими формами в обидвох періодах переважали розчини для інфузій і таблетки.
На прикладі асортиментних позицій ондансетрону з’ясовано, що їх цінова пропозиція в аптеках м. Львів за час дослідження зменшилась на 17,7 % (з 3101 до 2552). При цьому були відсутні аптеки, які би пропонувати усі асортиментні позиції ондансетрону. Виявлено невисокий рівень конкуренції та недостатню економічну доступність більшості асортиментних позицій ондансетрону.
Висновки. Досліджено тенденції асортиментної та цінової характеристики лікарських засобів групи А04 Протиблювотні засоби та препарати, що усувають нудоту на вітчизняному фармацевтичному ринку.
Vascular HIF2 Signaling Prevents Cardiomegaly, Alveolar Congestion, and Capillary Remodeling During Chronic Hypoxia
Authors: Albendea-Gomez Teresa , Mendoza-Tamajon Susana , Castro-Mecinas Rosana , Escobar Beatriz , Ferreira Rocha Susana , Urra-Balduz Sonia , Nicolas-Avila Jose Angel , Oliver Eduardo , Villalba-Orero Maria , Martin-Puig Silvia 
Published: January 2025

BACKGROUND:
Hypoxia is associated with the onset of cardiovascular diseases including cardiac hypertrophy and pulmonary hypertension. HIF2 (hypoxia inducible factor 2) signaling in the endothelium mediates pulmonary arterial remodeling and subsequent elevation of the right ventricular systolic pressure during chronic hypoxia. Thus, novel therapeutic opportunities for pulmonary hypertension based on specific HIF2 inhibitors have been proposed. Nevertheless, HIF2 relevance beyond the pulmonary endothelium or in the cardiac adaptation to hypoxia remains elusive. Wt1 (Wilms tumor 1) lineage contributes to the heart and lung vascular compartments, including pericytes, endothelial cells, and smooth muscle cells.

METHODS:

Here, we describe the response to chronic hypoxia of a novel HIF2 mutant mouse model in the Wt1 lineage (
Hif2/Wt1
cKO [conditional knockout]), characterizing structural and functional aspects of the heart and lungs by means of classical histology, immunohistochemistry, flow cytometry, echocardiography, and lung ultrasound analysis.

RESULTS:

Hif2/Wt1
cKO is protected against pulmonary remodeling and increased right ventricular systolic pressure induced by hypoxia, but displays alveolar congestion, inflammation, and hemorrhages associated with microvascular instability. Furthermore, lack of HIF2 in the Wt1 lineage leads to cardiomegaly, capillary remodeling, right and left ventricular hypertrophy, systolic dysfunction, and left ventricular dilation, suggesting pulmonary-independent cardiac direct roles of HIF2 in hypoxia. These structural defects are partially restored upon reoxygenation, while cardiac functional parameters remain altered.

CONCLUSIONS:
Our results indicate that cardiopulmonary HIF2 signaling prevents excessive vascular proliferation during chronic hypoxia and define novel protective roles of HIF2 to warrant stable microvasculature and organ function.
Classifying Race in Out-of-Hospital Cardiac Arrest and Potential Disparities: A Retrospective Cohort Study
Authors: Shin Jenny , Liu Jennifer , Parayil Megin , Counts Catherine R. , Drucker Christopher J. , Coult Jason , Blackwood Jennifer , Guan Sally , Kudenchuk Peter J. , Sayre Michael R. , Rea Thomas 
Published: January 2025

BACKGROUND:
Although racial disparities have been described in resuscitation, little is known about potential bias in race classification of out-of-hospital cardiac arrest (OHCA).

METHODS:
We conducted a retrospective cohort study of adults treated by emergency medical services (EMS) for nontraumatic OHCA in King County, WA between January 1, 2018, and December 31, 2021. We assessed agreement using κ and evaluated patterns of missingness between EMS-assessed race versus comprehensive race classification from hospital and death records. Using multivariable logistic regression adjusting for Utstein data elements, we analyzed the association between race and OHCA survival across different sources.

RESULTS:
Among 5909 eligible OHCA patients, the average age was 64.0 years, 35.4% were female, and 16.1% survived to hospital discharge. Based on comprehensive race classification, 68.7% were White, 12.8% Black, 12.1% Asian, 2.5% multiracial, 2.3% Native Hawaiian/other Pacific Islander, and 1.6% American Indian/Alaska Native. EMS did not classify race in 43.7%. The κ coefficient between EMS and comprehensive race classification was 0.88 (95% CI, 0.86–0.90), though agreement varied substantially by specific race and was lowest among American Indian/Alaska Native (39.5%). Missingness in EMS records varied according to race and was greater among those classified as American Indian/Alaska Native (60.8%), Native Hawaiian/other Pacific Islander (58.8%), Asian (57.8%), or multiracial (54.1%) compared with White (40.6%) or Black (40.4%). In multivariable models using EMS-classified race, the odds ratio (OR) of survival was not significantly different for any race group compared with the White race, that is, OR. However, when using comprehensive race classification, OR of survival was significantly lower among Native Hawaiian/other Pacific Islander (OR, 0.57 [95% CI, 0.33–0.97]) and among multiracial (OR, 0.40 [95% CI, 0.20–0.75]) compared with White race.

CONCLUSIONS:
In adult OHCA, race misclassification and missingness influenced its association with survival. Efforts should continue to evaluate best practices to classify race correctly and comprehensively.
NEDD4–Mediated GSNOR Degradation Aggravates Cardiac Hypertrophy and Dysfunction
Authors: Tang Xin , Liu Xiameng , Sha Xinqi , Zhang Yan , Zu Yan , Fan Qiyao , Hu Lulu , Sun Shixiu , Zhang Zhiren , Chen Feng , Yan ChengHui , Chen Xin , Xu Yueyue , Chen Wen , Shao Yongfeng , Gu Jiaxi , Pu Jun , Yu Bo , Han Yaling , Xie Liping , Han Yi , Ji Yong 
Published: January 2025

BACKGROUND:
The decrease in S-nitrosoglutathione reductase (GSNOR) leads to an elevation of S-nitrosylation, thereby exacerbating the progression of cardiomyopathy in response to hemodynamic stress. However, the mechanisms under GSNOR decrease remain unclear. Here, we identify NEDD4 (neuronal precursor cell expressed developmentally downregulated 4) as a novel molecule that plays a crucial role in the pathogenesis of pressure overload–induced cardiac hypertrophy, by modulating GSNOR levels, thereby demonstrating significant therapeutic potential.

METHODS:
Protein synthesis and degradation inhibitors were used to verify the reasons for the decrease in GSNOR. Mass spectrometry and database filtering were used to uncover NEDD4, the E3 Ub (ubiquitin) ligase, involved in GSNOR decrease. NEDD4 cardiomyocyte-specific deficiency mice were used to evaluate the role of NEDD4 and NEDD4–induced ubiquitination of GSNOR in cardiac hypertrophy in vivo. Both IBM (indolebutenate methyl ester derivatives), a highly specific NEDD4 inhibitor, and indole-3-carbinol, a NEDD4 inhibitor currently undergoing phase 2 clinical trial, were used to effectively suppress the NEDD4/GSNOR axis.

RESULTS:
GSNOR protein levels were reduced, while mRNA levels remained unchanged in myocardium samples from hypertrophic patients and transverse aortic constriction–induced mice, indicating GSNOR is regulated by ubiquitination. NEDD4, an E3 Ub ligase, was associated with GSNOR ubiquitination, which exhibited significantly higher expression levels in hypertrophic myocardial samples. Moreover, either the NEDD4 enzyme-dead mutant or GSNOR nonubiquitylated mutant decreased GSNOR ubiquitination and inhibited cardiac hypertrophic growth. Cardiomyocyte-specific NEDD4 deficiency inhibited cardiac hypertrophy in vitro and in vivo. NEDD4 inhibitor IBM effectively suppressed GSNOR ubiquitination and cardiac hypertrophy. Clinically, indole-3-carbinol, a NEDD4 inhibitor in phase II clinical trials used as an antitumor drug, demonstrated comparable efficacy.

CONCLUSIONS:
Our findings showed that upregulated NEDD4 leads to GSNOR ubiquitination and subsequent degradation, thereby facilitating the progression of cardiac hypertrophy. NEDD4 inhibitors may serve as a potential therapeutic strategy for the treatment of cardiac hypertrophy and heart failure.
Impact of Acute Myocardial Injury on Short‐ and Long‐Term Outcomes in Patients With Primary Intracerebral Hemorrhage
Authors: Ma Shenghui , Li Jiawen , Kong Qi , Xu Zhiming , Wu Haojie , Jin Yujia , Ye Xianghua , Luo Dong , Tong Lusha , Gao Feng 
Published: January 2025

Background
Myocardial injury is common after brain injury; however, few studies have reported serial cardiac troponin (cTn) measurements to distinguish whether the myocardial injury is acute or chronic. The fourth Universal Definition of Myocardial Infarction introduced for the first time the criteria for acute myocardial injury (AMI). We aimed to investigate the prevalence and prognostic implications of AMI in primary intracerebral hemorrhage.

Methods and Results
We retrospectively analyzed patients with primary intracerebral hemorrhage within 48 hours after symptom onset. All patients included had at least 2 cTn measurements: 1 obtained at the time of emergency admission and at least 1 more within the first 2 days of hospitalization. AMI was defined as an elevated cTn above the upper‐reference limit (14 ng/L) along with a rise/fall >20%. Patients were followed for up to 5 years. Outcomes included major adverse cardiac events (MACEs; a composite of vascular death, nonfatal coronary events, and nonfatal stroke) and 90‐day unfavorable outcomes (modified Rankin scale score ≥4). Cox proportional hazards models, multivariable logistic regression models, and Kaplan–Meier analyses were used to evaluate the association between AMI and outcomes. Of 600 patients included, 115 had AMI (19.2%). AMI independently conferred an increased risk for major adverse cardiac events (adjusted hazard ratio, 1.69 [95% CI, 1.12–2.53]) and 90‐day unfavorable outcomes (adjusted odds ratio, 2.15 [95% CI, 1.26–3.67]) compared with patients without AMI.

Conclusions
AMI is relatively common in patients with intracerebral hemorrhage and is associated with both long‐term major adverse cardiac events and 90‐day unfavorable outcomes.
Monocyte to High‐Density Lipoprotein Ratio Is Associated With Carotid Plaque: A Retrospective Cohort Study
Authors: Liu Shuang , Miao Xinlei , Hu Manling , Song Ziping , Xie Xiaoling , Sun Yuting , Li Meng , Tang Guimin , Leng Song 
Published: January 2025

Background
The level of monocyte to high‐density lipoprotein ratio (MHR) is associated with cardiovascular diseases. Carotid plaque (CP) is an independent risk factor for cardiovascular diseases. However, evidence for association of MHR with risk of CP is scarce.

Methods and Results

This study involved 5260 participants aged >18 years old from the Dalian health management cohort in 2014 to 2022. The subjects were stratified into 4 groups based on the quartile of the MHR at baseline. Multivariable‐adjusted Cox regression models were used to calculate the MHR‐associated risk of incident CP. The mean age of the population was 46.14 years and 58.8% (n=3093) of the participants were male. Seven hundred fifty‐nine (14.4%) of participants developed new‐onset CP. During the follow‐up of 9725 person‐years, the MHR at quartile 4 group experienced a significantly higher incidence of CP than the MHR at quartile 1 group (56.9 versus 101.5 per 1000 person‐years; log‐rank
P
<0.001). Compared with the MHR at quartile 1 group, the MHR at quartile 4 group had the highest CP risk (hazard ratio. 1.389 [95% CI, 1.059–1.823]) and 10‐year cardiovascular risk (China‐PAR Project score: odds ratio, 1.975 [95% CI, 1441–2.708 in men]; odds ratio, 6.015 [95% CI, 1.949–18.564 in women) (
P
<0.001). Meanwhile, similar results were observed in multiple sensitivity analyses.

Conclusions
Elevated MHR was associated with the risk of CP. The assessment and management of MHR is helpful for the early detection of patients with CP and the primary prevention of cardiovascular diseases.
Association Between Triglyceride–Glucose Index and Carotid Plaque Stability in Different Glycemic Status: A Single‐Center Retrospective Study
Authors: Huo Guijun , Zheng Jin , Cao Junjie , Zhang Lili , Yao Zhichao , Zeng Yuqi , Tang Yao , Liu Zhanao , Tan Ziyi , Zhou Dayong 
Published: January 2025

Background
The triglyceride–glucose (TyG) index has been proposed as a reliable marker of insulin resistance. However, its value in patients with carotid plaque stability remains unclear. This study investigated the association between the TyG index and unstable carotid plaque.

Methods
A total of 12 068 participants were enrolled. Carotid ultrasound was used to determine the stability of carotid plaque. Logistic regression was used to analyze the relationship between the TyG index and unstable carotid plaque. The relationship between the TyG index and unstable carotid plaque was evaluated according to sex, age, and glucose metabolism states. Further, the dose–response relationship between the TyG index and unstable carotid plaque was also determined by restrictive cubic splines.

Results
Of the 12 068 participants, 11 601 had stable carotid plaque and 467 had unstable carotid plaque. In several different adjustment models, the TyG index is significantly related to the risk of unstable carotid plaque. The association between the TyG index and an unstable carotid plaque was similar between men and women, despite the fact that the odds ratio (OR) tended to be higher in men (OR, 2.80 [95% CI, 2.04–3.83]) than women (OR, 2.07 [95% CI, 1.51–2.82]), and higher in older patients (aged >60 years; (OR, 3.59 [95% CI, 2.74–4.70]) than middle‐aged patients (aged ≤60 years) (OR, 2.00 [95% CI, 1.36–2.95]). The TyG index of patients with different glycemic status was significantly correlated with the risk of unstable carotid plaque, among which the OR value of diabetes (OR, 2.51 [95% CI, 1.87–3.36]) was the highest. The restrictive cubic spline analysis indicated a nonlinear relationship between the TyG index and unstable carotid plaque, with TyG index >8.63 identified as an independent risk factor for unstable carotid plaque.

Conclusions
The TyG index has a significant association with unstable carotid plaque. The association between the TyG index and unstable carotid plaque is similar between men and women, and the association in older patients is higher than that in middle‐aged patients. In different glycemic status, the association between the TyG index and unstable carotid plaque is highest in patients with diabetes.