bluuebunny/crossref_metadata_2025_split huggingface dataset:
Using a Mock Circulatory Loop as a Regulatory Science Tool to Simulate Different Heart Failure Conditions
Authors: D'Souza Gavin A. , Rinaldi Jean E. , Meki Moustafa , Crusan Annabelle , Richardson Eric , Shinnar Meir , Herbertson Luke H. 
Published: October 2023

Abstract
Mechanical circulatory support (MCS) device therapy is one of the primary treatment options for end-stage heart failure (HF), whereby a mechanical pump is integrated with the failing heart to maintain adequate tissue perfusion. The ISO 14708-5:2020 standard prescribes generic guidelines for nonclinical device evaluation and system performance testing of MCS devices using a mock circulatory loop (MCL). However, the utility of MCLs in premarket regulatory submissions of MCS devices is ambiguous, and the specific disease states that the device is intended to treat are not usually simulated. Hence, we aim to outline the potential of MCLs as a valuable regulatory science tool for characterizing MCS device systems by adequately representing target clinical-use HF conditions on the bench. Target pathophysiologic hemodynamics of HF conditions (i.e., cardiogenic shock (CS), left ventricular (LV) hypertrophy secondary to hypertension, and coronary artery disease), along with a healthy adult at rest and a healthy adult during exercise are provided as recommended test conditions. The conditions are characterized based on LV, aorta, and left atrium pressures using recommended cardiac hemodynamic indices such as systolic, diastolic, and mean arterial pressure, mean cardiac output (CO), cardiac cycle time, and systemic vascular resistance. This study is a first step toward standardizing MCLs to generate well-defined target HF conditions used to evaluate MCS devices.
Comparative metabolomics reveal key pathways associated with the synergistic activities of aztreonam and clavulanate combination against multidrug-resistant
Escherichia coli
Authors: Zhang Jiayuan , Yang Hai , Zhang Lei , Lv Zhihua , Yu Mingming , Sy Sherwin K. B. , Zhan Yuanchao 
Published: October 2023

ABSTRACT

The use of combination antibiotics has been useful in the treatment of multidrug-resistant bacterial infections. The synergistic effect of amoxicillin/clavulanate and aztreonam combination against
Escherichia coli
carrying New Delhi metallo-β-lactamase (NDM) was primarily due to clavulanate inhibiting aztreonam degradation. In the present study, we employed metabolomic analysis to investigate the downstream changes in
E. coli
after treatment with aztreonam and clavulanate.
E. coli
metabolomes were compared at 1 and 24 h following treatments with clavulanate (4 µg/mL) and aztreonam (4 µg/mL) alone and in combination. Excluding false positives, 198 metabolites were identified to be affected by antibiotic treatment. Aztreonam/clavulanate combination inhibited cell wall synthesis more aggressively at 1 h and 24 h than aztreonam alone. The purine and pyrimidine metabolism, the central carbon metabolism, and the amino acid metabolism were also disrupted resulting in a prolonged bactericidal effect. This study reveals the synergistic killing mechanism of clavulanate and aztreonam combination against
E. coli
harboring NDM and provides a theoretical basis for the combined use of aztreonam/clavulanate in the treatment of multidrug-resistant
E. coli
infection.

IMPORTANCE

Multidrug-resistant
Escherichia coli
is a major threat to the health care system and is associated with poor outcomes in infected patients. The combined use of antibiotics has become an important treatment method for multidrug-resistant bacteria. However, the mechanism for their synergism has yet to be explored.
Different Clinical Relevance of Anti-Citrullinated Protein Antibodies in RA Patients
Authors: Avdeeva A. S. , Cherkasova M. V. , Nasonov E. L. 
Published: October 2023

Abstract
The objective of the study was to find a potential relationship between ACPAs and disease activity, bone destruction, and ACPA responses to various therapeutic regimens. The study included 232 patients with rheumatoid arthritis (RA); 90 patients had early RA, and 142 patients had an advanced stage of the disease. 77 (85.6%) patients with early RA were highly positive for anti-CCP, and 29 (70.7%) patients were highly positive for anti-MCV. A positive correlation was found between anti-MCV and DAS28 (r = 0.4; p = 0.04). As for advanced RA, 78 (80.4%) patients were high-positive for anti-CCP, and 70 (79.5%) were high-positive for anti-MCV. There was a positive correlation between anti-MCV concentration and SDAI (r = 0.4; p = 0.02), as well as CDAI (r = 0.4; p = 0.02). No significant correlations were found between the anti-CCP levels and activity indices, anti-CCP and acute-phase parameters in both early and advanced RA groups. Higher total Sharp scores (96.5 (65.0–122.0)) were found in pts highl-positive for anti-MCV (n = 79), compared to low-positive/negative (n = 27) patients (57.0 (31.0–88.0); p < 0.05). Anti-MCV levels dropped significantly in pts on rituximab and tocilizumab therapy at weeks 12 and 24 after initiation of treatment, while high anti-CCP concentration persisted throughout the treatment. Anti-MCV levels correlated with inflammatory activity and development of bone destruction and decreased in pts on treatment. Anti-CCP was less responsive and showed minor changes during treatment; therefore, its thorough monitoring was not feasible.
Interpretation and use of a decision support tool for multiple treatment options: a combined randomised controlled trial and survey of medical students
Authors: Stokke Hunskaar Birk , Løvsletten Per Olav , Muller Ashley , Vandvik Per Olav 
Published: October 2023

ObjectivesTo investigate medical students’ ability to interpret evidence, as well as their self-assessed understandability, perceived usefulness and preferences for design alternatives in an interactive decision support tool, displaying GRADE evidence summaries for multiple treatment options (Making Alternative Treatment CHoices Intuitive and Trustworthy, MATCH-IT).DesignA combined randomised controlled trial and survey. Participants were presented with a clinical scenario and randomised to one of two versions of the MATCH-IT tool (A/B), instructed to explore the evidence and decide on a recommendation. Participants answered a questionnaire assessing interpretation, treatment recommendation self-assessed understandability and perceived usefulness before exposure to the other MATCH-IT version and asked questions on design preferences.SettingOnline lecture in an evidence-based medicine (EBM) introductory course.Participants149 third-year medical students. 52% (n=77) had 6 months of clinical training and 48% (n=72) had preclinical training only.InterventionsThe MATCH-IT tool version A uses colour coding to categorise interventions by magnitude and direction of effects and displays all outcomes in a table on entry. Version B has no colour coding, and the user must decide which outcomes to display in the table.Main outcome measuresInterpretation of evidence, treatment recommendation, perceived usefulness and understandability, preference for format and design alternatives.Results82.5% (n=123) of medical students correctly answered ≥4 out of 5 multiple choice questions assessing interpretation of data. 75.8% (n=114) of students made a treatment recommendation in accordance with an expert panel for the same clinical scenario. 87.2% (n=130) found the tool understandable while 91.9% perceived the tool as useful in addressing the clinical scenario.ConclusionMedical students with no prior training in EBM can interpret and use the MATCH-IT tool. Certain design alternatives were preferred but had no bearing on interpretation of evidence or understandability of the tool.
Delivery versus Potency in Treating Brain Tumors: BI-907828, a MDM2-p53 Antagonist with Limited BBB Penetration but Significant In Vivo Efficacy in Glioblastoma
Authors: Zhang Wenjuan , Vaubel Rachael A. , Oh Ju-Hee , Mladek Ann C. , Talele Surabhi , Zhang Wenqiu , Waller Katie L. , Burgenske Danielle M. , Sarkaria Jann N. , Elmquist William F. 
Published: October 2023

Abstract
MDM2–p53 inhibition may be effective in glioblastoma (GBM). This study evaluates the pharmacokinetics/pharmacodynamics of BI-907828, a potent antagonist of MDM2, in GBM, and demonstrates a translational paradigm with a focus on a unified “Delivery – Potency – Efficacy” relationship in drug development for central nervous system(CNS) tumors. BI-907828 was tested for cytotoxicity and MDM2–p53 pathway inhibition. Systemic pharmacokinetics and transport mechanisms controlling CNS distribution were evaluated in mice. BI-907828 free fractions in cell media, mouse and human specimens were measured to determine “active” unbound concentrations. Efficacy measures, including overall survival and target expression were assessed in mouse orthotopic GBM xenografts. BI-907828 exhibited potent inhibition of MDM2–p53 pathway and promoted cell death in GBM TP53 wild-type cells. MDM2-amplified cells are highly sensitive to BI-907828, with an effective unbound concentration of 0.1 nmol/L. The CNS distribution of BI-907828 is limited by blood–brain barrier (BBB) efflux mediated by P-gp, resulting in a Kp,uu_brain of 0.002. Despite this seemingly “poor” BBB penetration, weekly administration of 10 mg/kg BI-907828 extended median survival of orthotopic GBM108 xenografts from 28 to 218 days (P &lt; 0.0001). This excellent efficacy can be attributed to high potency, resulting in a limited, yet effective, exposure in the CNS. These studies show that efficacy of BI-907828 in orthotopic models is related to high potency even though its CNS distribution is limited by BBB efflux. Therefore, a comprehensive understanding of all aspects of the “Delivery – Potency – Efficacy” relationship is warranted in drug discovery and development, especially for treatment of CNS tumors.
Design and Evaluation of Phosphonamidate-Linked Exatecan Constructs for Highly Loaded, Stable, and Efficacious Antibody–Drug Conjugates
Authors: Schmitt Saskia , Machui Paul , Mai Isabelle , Herterich Sarah , Wunder Swetlana , Cyprys Philipp , Gerlach Marcus , Ochtrop Philipp , Hackenberger Christian P.R. , Schumacher Dominik , Helma Jonas , Vogl Annette M. , Kasper Marc-André 
Published: October 2023

Abstract
Topoisomerase I (TOP1) Inhibitors constitute an emerging payload class to engineer antibody–drug conjugates (ADC) as next-generation biopharmaceutical for cancer treatment. Existing ADCs are using camptothecin payloads with lower potency and suffer from limited stability in circulation. With this study, we introduce a novel camptothecin-based linker–payload platform based on the highly potent camptothecin derivative exatecan. First, we describe general challenges that arise from the hydrophobic combination of exatecan and established dipeptidyl p-aminobenzyl-carbamate (PAB) cleavage sites such as reduced antibody conjugation yields and ADC aggregation. After evaluating several linker–payload structures, we identified ethynyl-phosphonamidates in combination with a discrete PEG24 chain to compensate for the hydrophobic PAB–exatecan moiety. Furthermore, we demonstrate that the identified linker–payload structure enables the construction of highly loaded DAR8 ADCs with excellent solubility properties. Head-to-head comparison with Enhertu, an approved camptothecin-based ADC, revealed improved target-mediated killing of tumor cells, excellent bystander killing, drastically improved linker stability in vitro and in vivo and superior in vivo efficacy over four tested dose levels in a xenograft model. Moreover, we show that ADCs based on the novel exatecan linker–payload platform exhibit antibody-like pharmacokinetic properties, even when the ADCs are highly loaded with eight drug molecules per antibody. This ADC platform constitutes a new and general solution to deliver TOP1 inhibitors with highest efficiency to the site of the tumor, independent of the antibody and its target, and is thereby broadly applicable to various cancer indications.
RNF185 Control of COL3A1 Expression Limits Prostate Cancer Migration and Metastatic Potential
Authors: Van Espen Benjamin , Oo Htoo Zarni , Collins Colin , Fazli Ladan , Molinolo Alfredo , Yip Kevin , Murad Rabi , Gleave Martin , Ronai Ze'ev A. 
Published: October 2023

Abstract

RNF185 is a RING finger domain-containing ubiquitin ligase implicated in ER-associated degradation. Prostate tumor patient data analysis revealed a negative correlation between RNF185 expression and prostate cancer progression and metastasis. Likewise, several prostate cancer cell lines exhibited greater migration and invasion capabilities in culture upon RNF185 depletion. Subcutaneous inoculation of mouse prostate cancer MPC3 cells stably expressing short hairpin RNA against RNF185 into mice resulted in larger tumors and more frequent lung metastases. RNA-sequencing and Ingenuity Pathway Analysis identified wound-healing and cellular movement among the most significant pathways upregulated in RNF185-depleted lines, compared with control prostate cancer cells. Gene Set Enrichment Analyses performed in samples from patients harboring low RNF185 expression and in RNF185-depleted lines confirmed the deregulation of genes implicated in epithelial-to-mesenchymal transition. Among those, COL3A1 was identified as the primary mediator of RNF185’s ability to impact migration phenotypes. Correspondingly, enhanced migration and metastasis of RNF185 knockdown (KD) prostate cancer cells were attenuated upon co-inhibition of COL3A1. Our results identify RNF185 as a gatekeeper of prostate cancer metastasis, partly via its control of COL3A1 availability.

Implications:
RNF185 is identified as an important regulator of prostate cancer migration and metastasis, in part due to its regulation of COL3A1. Both RNF185 and COL3A1 may serve as novel markers for prostate tumors.
Statistical Assessment of Drug Synergy from In Vivo Combination Studies Using Mouse Tumor Models
Authors: Mao Binchen , Guo Sheng 
Published: October 2023

Abstract

Drug combination therapy is a promising strategy for treating cancer; however, its efficacy and synergy require rigorous evaluation in preclinical studies before going to clinical trials. Existing methods have limited power to detect synergy in animal studies. Here, we introduce a novel approach to assess in vivo drug synergy with high sensitivity and low false discovery rate. It can accurately estimate combination index and synergy score under the Bliss independence model and the highest single agent (HSA) model without any assumption on tumor growth kinetics, study duration, data completeness and balance for tumor volume measurement. We show that our method can effectively validate in vitro drug synergy discovered from cell line assays in in vivo xenograft experiments, and can help to elucidate the mechanism of action for immune checkpoint inhibitors in syngeneic mouse models by combining an anti-PD-1 antibody and several tumor-infiltrating leukocytes depletion treatments. We provide a unified view of in vitro and in vivo synergy by presenting a parallelism between the fixed-dose in vitro and the 4-group in vivo combination studies, so they can be better designed, analyzed, and compared. We emphasize that combination index, when defined here via relative survival of tumor cells, is both dose and time dependent, and give guidelines on designing informative in vivo combination studies. We explain how to interpret and apply Bliss and HSA synergies. Finally, we provide an open-source software package named invivoSyn that enables automated analysis of in vivo synergy using our method and several other existing methods.

Significance:
This work presents a general solution to reliably determine in vivo drug synergy in single-dose 4-group animal combination studies.
Comparative Discrimination of Life’s Simple 7 and Life’s Essential 8 to Stratify Cardiovascular Risk: Is the Added Complexity Worth It?
Authors: Howard George , Cushman Mary , Blair Jessica , Wilson Nicole R. , Yuan Ya , Safford Monika M. , Levitan Emily B. , Judd Suzanne E. , Howard Virginia J. 
Published: October 2023

BACKGROUND:
Life’s Simple 7 (LS7) is an easily calculated and interpreted metric of cardiovascular health based on 7 domains: smoking, diet, physical activity, body mass index, blood pressure, cholesterol, and fasting glucose. The Life’s Essential 8 (LE8) metric was subsequently introduced, adding sleep metrics and revisions of the previous 7 domains. Although calculating LE8 requires additional information, we hypothesized that it would be a more reliable index of cardiovascular health.

METHODS:
Both the LS7 and LE8 metrics yield scores with higher values indicating lower risk. These were calculated among 11 609 Black and White participants free of baseline cardiovascular disease (CVD) in the Reasons for Geographic and Racial Differences in Stroke study, enrolled in 2003 to 2007, and followed for a median of 13 years. Differences in 10-year risk of incident CVD (coronary heart disease or stroke) were calculated as a function LS7, and LE8 scores were calculated using Kaplan-Meier and proportional hazards analyses. Differences in incident CVD discrimination were quantified by difference in the c-statistic.

RESULTS:

For both LS7 and LE8, the 10-year risk was approximately 5% for participants around the 99th percentile of scores, and a 4× higher 20% risk for participants around the first percentile. Comparing LS7 to LE8, 10-year risk was nearly identical for individuals at the same relative position in score distribution. For example, the “cluster” of 2013 participants with an LS7 score of 7 was at the 35.8th percentile in distribution of LS7 scores, and had an estimated 10-year CVD risk of 8.4% (95% CI, 7.2%–9.8%). In a similar location in the LE8 distribution, the 1457 participants with an LE8 score of 60±2.5 at the 39.4th percentile of LE8 scores had a 10-year risk of CVD of 8.5% (95% CI, 7.1%–10.1%), similar to the cluster defined by LS7. The age-race-sex adjusted c-statistic of the LS7 model was 0.691 (95% CI, 0.667–0.705), and 0.695 for LE8 (95% CI, 0.681–0.709) (
P
for difference, 0.12).

CONCLUSIONS:
Both LS7 and LE8 were associated with incident CVD, with discrimination of the 2 indices practically indistinguishable. As a simpler metric, LS7 may be favored for use by the general population and clinicians.
Abstract P3045: MicroRNA-31-5p Is Upregulated During Neointima Formation And Promotes Smooth Muscle Cell Proliferation And Migration By Regulating Krüppel-like Factor 4 (KLF4)
Authors: Gürlach Simon , Kalies Katrin , Daniel Fiene , Köster Jan Michael , Boettcher Solveig , Hehl Laura , Knoepp Kai , Dutzmann Jochen , Daniel Jan-Marcus , Sedding Daniel 
Published: October 2023

In the context of CVDs, microRNAs (miRs) have emerged as potential therapeutic targets for preventing adverse vascular remodeling and restenosis, given their ability to modulate multiple signaling pathways and cellular processes. Here, we propose that targeting miR-31-5p might be an effective approach to enhance vascular healing and regeneration in a cell-specific manner, thereby limiting angioplasty-related complications.
A screening of murine neointimal tissue for differentially regulated miRs revealed robustly increased expression levels of miR-31-5p over time. Subsequently, expression levels of miR-31-5p were confirmed by qRT-PCR in human coronary artery endothelial cells (EC) and -smooth muscle cells (SMC). Further, the effect of miR-31-5p on cellular function was investigated and possible targets were identified and confirmed on mRNA and protein level.

Expression analysis revealed a significant upregulation of miR-31-5p (p<0.0001) in C57BL/6J mice following wire-induced injury of the femoral artery at 7 and 21 days. In vitro, miR-31-5p was significantly upregulated in SMC (p<0,05
)
following serum stimulation, whereas only a slightly enhanced expression was observed in EC. On a functional level, miR-31-5p revealed dissenting effects on EC and SMC: Migration and proliferation were not altered in EC (p>0.05). In contrast, knockdown of miR-31-5p significantly reduced the migration (p<0,05) and proliferation in SMC (p<0,01) without detectable apoptotic effects. Systematic
in silico
target screens suggested KLF4 as potential target. Knock down of miR-31-5p resulted in a significant upregulation of KLF4 in SMC (p<0,01), whereas overexpression resulted in a significant downregulation of KLF4 in SMC (p<0,05) on mRNA- and protein level.

Here, we report that miR-31-5p is robustly upregulated during neointima formation and seems to exert a functional role in SMC rather than EC since knockdown of miR-31-5p was able to prevent SMC proliferation and migration. Mechanistically, KLF4 identified as a direct target of miR-31-5p can mediate the observed effects. Thus, miR-31-5p might represent an attractive target to selectively modulate SMC dysfunction following vascular intervention, limiting neointima formation in treated vessels.
THE ROLE OF PERCEIVED QUALITY, CUSTOMER SATISFACTION AND BRAND PARITY IN DEVELOPING BRAND LOYALTY IN GLOBAL E-COMMERCE SITES
Authors: MANİSA Rabia , SARI Sema 
Published: October 2023

E-commerce has changed shopping habits and increased the competition of businesses while expanding consumers' options. Therefore, e-commerce businesses have begun to actively seek ways to increase brand loyalty in order to survive and differentiate themselves in a highly competitive environment. In this context, this study investigates the role of perceived quality, customer satisfaction, and brand parity in cultivating brand loyalty within the realm of global e-commerce.
In this study, an online survey has been conducted on the customers of Amazon, Global JD (JoyBuy) and Aliexpress e-commerce sites. SPSS 25 program was used for validity, reliability and frequency analysis in the research, and the AMOS 21 software was utilized to assess the structural soundness of the scales and conduct confirmatory factor analysis. The findings suggest that customer satisfaction and brand parity positively affect brand loyalty. In addition, the empirical evidences have revealed a favorable impact of perceived quality on customer satisfaction.