bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selectively Targeting Tumor Hypoxia With the Hypoxia-Activated Prodrug CP-506
Authors: van der Wiel Alexander M.A. , Jackson-Patel Victoria , Niemans Raymon , Yaromina Ala , Liu Emily , Marcus Damiënne , Mowday Alexandra M. , Lieuwes Natasja G. , Biemans Rianne , Lin Xiaojing , Fu Zhe , Kumara Sisira , Jochems Arthur , Ashoorzadeh Amir , Anderson Robert F. , Hicks Kevin O. , Bull Matthew R. , Abbattista Maria R. , Guise Christopher P. , Deschoemaeker Sofie , Thiolloy Sophie , Heyerick Arne , Solivio Morwena J. , Balbo Silvia , Smaill Jeff B. , Theys Jan , Dubois Ludwig J. , Patterson Adam V. , Lambin Philippe 
Published: October 2021

Abstract
Hypoxia-activated prodrugs (HAP) are a promising class of antineoplastic agents that can selectively eliminate hypoxic tumor cells. This study evaluates the hypoxia-selectivity and antitumor activity of CP-506, a DNA alkylating HAP with favorable pharmacologic properties. Stoichiometry of reduction, one-electron affinity, and back-oxidation rate of CP-506 were characterized by fast-reaction radiolytic methods with observed parameters fulfilling requirements for oxygen-sensitive bioactivation. Net reduction, metabolism, and cytotoxicity of CP-506 were maximally inhibited at oxygen concentrations above 1 μmol/L (0.1% O2). CP-506 demonstrated cytotoxicity selectively in hypoxic 2D and 3D cell cultures with normoxic/anoxic IC50 ratios up to 203. Complete resistance to aerobic (two-electron) metabolism by aldo-keto reductase 1C3 was confirmed through gain-of-function studies while retention of hypoxic (one-electron) bioactivation by various diflavin oxidoreductases was also demonstrated. In vivo, the antitumor effects of CP-506 were selective for hypoxic tumor cells and causally related to tumor oxygenation. CP-506 effectively decreased the hypoxic fraction and inhibited growth of a wide range of hypoxic xenografts. A multivariate regression analysis revealed baseline tumor hypoxia and in vitro sensitivity to CP-506 were significantly correlated with treatment response. Our results demonstrate that CP-506 selectively targets hypoxic tumor cells and has broad antitumor activity. Our data indicate that tumor hypoxia and cellular sensitivity to CP-506 are strong determinants of the antitumor effects of CP-506.
Molecular Characteristics of Repotrectinib That Enable Potent Inhibition of TRK Fusion Proteins and Resistant Mutations
Authors: Murray Brion W. , Rogers Evan , Zhai Dayong , Deng Wei , Chen Xi , Sprengeler Paul A. , Zhang Xin , Graber Armin , Reich Siegfried H. , Stopatschinskaja Shanna , Solomon Benjamin , Besse Benjamin , Drilon Alexander 
Published: October 2021

Abstract
NTRK chromosomal rearrangements yield oncogenic TRK fusion proteins that are sensitive to TRK inhibitors (larotrectinib and entrectinib) but often mutate, limiting the durability of response for NTRK+ patients. Next-generation inhibitors with compact macrocyclic structures (repotrectinib and selitrectinib) were designed to avoid resistance mutations. Head-to-head potency comparisons of TRK inhibitors and molecular characterization of binding interactions are incomplete, obscuring a detailed understanding of how molecular characteristics translate to potency. Larotrectinib, entrectinib, selitrectinib, and repotrectinib were characterized using cellular models of wild-type TRKA/B/C fusions and resistance mutant variants with a subset evaluated in xenograft tumor models. Crystal structures were determined for repotrectinib bound to TRKA (wild-type, solvent-front mutant). TKI-naïve and pretreated case studies are presented. Repotrectinib was the most potent inhibitor of wild-type TRKA/B/C fusions and was more potent than selitrectinib against all tested resistance mutations, underscoring the importance of distinct features of the macrocycle structures. Cocrystal structures of repotrectinib with wild-type TRKA and the TRKAG595R SFM variant elucidated how differences in macrocyclic inhibitor structure, binding orientation, and conformational flexibility affect potency and mutant selectivity. The SFM crystal structure revealed an unexpected intramolecular arginine sidechain interaction. Repotrectinib caused tumor regression in LMNA–NTRK1 xenograft models harboring GKM, SFM, xDFG, and GKM + SFM compound mutations. Durable responses were observed in TKI-naïve and -pretreated patients with NTRK+ cancers treated with repotrectinib (NCT03093116). This comprehensive analysis of first- and second-generation TRK inhibitors informs the clinical utility, structural determinants of inhibitor potency, and design of new generations of macrocyclic inhibitors.
Effect of Long-Term Marine ɷ-3 Fatty Acids Supplementation on the Risk of Atrial Fibrillation in Randomized Controlled Trials of Cardiovascular Outcomes: A Systematic Review and Meta-Analysis
Authors: Gencer Baris , Djousse Luc , Al-Ramady Omar T. , Cook Nancy R. , Manson JoAnn E. , Albert Christine M. 
Published: October 2021

Background:
Some, but not all, large-scale randomized controlled trials (RCTs) investigating the effects of marine ɷ-3 fatty acids supplementation on cardiovascular outcomes have reported increased risks of atrial fibrillation (AF). The potential reasons for disparate findings may be dose-related.

Methods:
The MEDLINE and Embase databases were searched for articles and abstracts published between January 1, 2012, and December 31, 2020, in addition to a meta-analysis of large cardiovascular RCTs published in 2019. RCTs of cardiovascular outcomes of marine ɷ-3 fatty acids that reported results for AF, either as a prespecified outcome, an adverse event, or a cause for hospitalization, with a minimum sample size of 500 patients and a median follow-up of at least 1 year were included. RCTs specifically examining shorter-term effects of ɷ-3 fatty acids on recurrent AF in patients with established AF or postoperative AF were not included. The hazard ratio (HR) for the reported AF outcomes within each trial was meta-analyzed using random effects model with Knapp-Hartung adjustment and evaluated a dose-response relationship with a meta-regression model.

Results:

Of 4049 screened records, 7 studies were included in the meta-analysis. Of those, 5 were already detected in a previous meta-analysis of cardiovascular RCTs. Among the 81 210 patients from 7 trials, 58 939 (72.6%) were enrolled in trials testing ≤1 g/d and 22 271 (27.4%) in trials testing >1 g/d of ɷ-3 fatty acids. The mean age was 65 years, and 31 842 (39%) were female. The weighted average follow-up was 4.9 years. In meta-analysis, the use of marine ɷ-3 fatty acid supplements was associated with an increased risk of AF (n=2905; HR, 1.25 [95% CI, 1.07–1.46];
P
=0.013). In analyses stratified by dose, the HR was greater in the trials testing >1 g/d (HR, 1.49 [95% CI, 1.04–2.15];
P
=0.042) compared with those testing ≤1 g/d (HR, 1.12 [95% CI, 1.03–1.22];
P
=0.024;
P
for interaction <0.001). In meta-regression, the HR for AF increased per 1 g higher dosage of ɷ-3 fatty acids dosage (HR, 1.11 [95% CI, 1.06–1.15];
P
=0.001).

Conclusions:
In RCTs examining cardiovascular outcomes, marine ɷ-3 supplementation was associated with an increased risk of AF. The risk appeared to be greater in trials testing >1 g/d.
Inpatient Versus Outpatient Acute Venous Thromboembolism Management: Trends and Postacute Healthcare Utilization From 2011 to 2018
Authors: Lutsey Pamela L. , Walker Rob F. , MacLehose Richard F. , Norby Faye L. , Evensen Line H. , Alonso Alvaro , Zakai Neil A. 
Published: October 2021

Background
Acute outpatient management of venous thromboembolism (VTE), which includes pulmonary embolism (PE) and deep vein thrombosis (DVT), is perceived to be as safe as inpatient management in some settings. How widely this strategy is used is not well documented.

Methods and Results

Using MarketScan administrative claims databases for years 2011 through 2018, we identified patients with
International Classification of Diseases
(
ICD
) codes indicating incident VTE and trends in the use of acute outpatient management. We also evaluated healthcare utilization and hospitalized bleeding events in the 6 months following the incident VTE event. A total of 200 346 patients with VTE were included, of whom 50% had evidence of PE. Acute outpatient management was used for 18% of those with PE and 57% of those with DVT only, and for both DVT and PE its use increased from 2011 to 2018. Outpatient management was less prevalent among patients with cancer, higher Charlson comorbidity index scores, and whose primary treatment was warfarin as compared with a direct oral anticoagulant. Healthcare utilization in the 6 months following the incident VTE event was generally lower among patients managed acutely as outpatients, regardless of initial presentation. Acute outpatient management was associated with lower hazard ratios of incident bleeding risk for both patients who initially presented with PE (0.71 [95% CI, 0.61, 0.82]) and DVT only (0.59 [95% CI, 0.54, 0.64]).

Conclusions
Outpatient management of VTE is increasing. In the present analysis, it was associated with lower subsequent healthcare utilization and fewer bleeding events. However, this may be because healthier patients were managed on an outpatient basis.
Association of Global Coagulation Profiles With Cardiovascular Risk Factors and Atherosclerosis: A Sex Disaggregated Analysis From the BioHEART‐CT Study
Authors: Kott Katharine A. , Morel‐Kopp Marie‐Christine , Vernon Stephen T. , Takagi Yuki , Di Bartolo Belinda A. , Peter Karlheinz , Yang Jean Y. , Grieve Stuart M. , Ward Christopher , Figtree Gemma A. 
Published: October 2021

Background
Although the association between dysregulated coagulation and atherosclerosis is well recognized, individual assays have been of minimal value in understanding disease susceptibility. Here we investigated the association of global coagulation profiles with coronary artery disease with consideration of sex differences.

Methods and Results
The study included patients from the BioHEART‐CT (The BioHEART Study: Assessing Patients With Suspected Cardiovascular Disease for New Disease Markers and Risk Factors) biobank who had computed tomography coronary angiograms scored for coronary artery calcium score (CACS) and Gensini score. The cohort included 206 adult patients who were referred for clinically indicated computed tomography coronary angiography and had a median of 2 major cardiac risk factors; 50% were women and the average age was 62.6 years (±9.9 years). The overall hemostatic potential (OHP) and calibrated automated thrombography generation assays were performed on platelet‐poor plasma. CACS and Gensini score in men were significantly correlated in bivariate analysis with measures from the OHP assay, and regression models predicting disease severity by CACS or Gensini score were improved by adding the OHP assay variables in men but not in women. The calibrated automated thrombography generation assay demonstrated a more hypercoagulable profile in women than in men. The OHP assay showed hypercoagulable profiles in women with hyperlipidemia and men with obesity.

Conclusions
The OHP assay identified hypercoagulable profiles associated with different risk factors for each sex and was associated with CACS and Gensini score severity in men, emphasizing the associations between increased fibrin generation and reduced fibrinolysis with cardiac risk factors and early atherosclerosis.

Registration Information

www.anzctr.org.au
. Identifier: ACTRN12618001322224.
Impact of Center Volume on Outcomes in Myocardial Infarction Complicated by Cardiogenic Shock: A CULPRIT‐SHOCK Substudy
Authors: Schrage Benedikt , Zeymer Uwe , Montalescot Gilles , Windecker Stephan , Serpytis Pranas , Vrints Christiaan , Stepinska Janina , Savonitto Stefano , Oldroyd Keith G. , Desch Steffen , Fuernau Georg , Huber Kurt , Noc Marko , Schneider Steffen , Ouarrak Taoufik , Blankenberg Stefan , Thiele Holger , Clemmensen Peter 
Published: October 2021

Background
Little is known about the impact of center volume on outcomes in acute myocardial infarction complicated by cardiogenic shock. The aim of this study was to investigate the association between center volume, treatment strategies, and subsequent outcome in patients with acute myocardial infarction complicated by cardiogenic shock.

Methods and Results

In this subanalysis of the randomized CULPRIT‐SHOCK (Culprit Lesion Only PCI Versus Multivessel PCI in Cardiogenic Shock) trial, study sites were categorized based on the annual volume of acute myocardial infarction complicated by cardiogenic shock into low‐/intermediate‐/high‐volume centers (<50; 50–100; and >100 cases/y). Subjects from the study/compulsory registry with available volume data were included. Baseline/procedural characteristics, overall treatment, and 1‐year all‐cause mortality were compared across categories. n=1032 patients were included in this study (537 treated at low‐volume, 240 at intermediate‐volume, and 255 at high‐volume centers). Baseline risk profile of patients across the volume categories was similar, although high‐volume centers included a larger number of older patients. Low‐/intermediate‐volume centers had more resuscitated patients (57.5%/58.8% versus 42.2%;
P
<0.01), and more patients on mechanical ventilation in comparison to high‐volume centers. There were no differences in reperfusion success despite considerable differences in adjunctive pharmacological/device therapies. There was no difference in 1‐year all‐cause mortality across volume categories (51.1% versus 56.5% versus 54.4%;
P
=0.34).

Conclusions
In this study of patients with acute myocardial infarction complicated by cardiogenic shock, considerable differences in adjunctive medical and mechanical support therapies were observed. However, we could not detect an impact of center volume on reperfusion success or mortality.
Angiostatic Peptide, Endostatin, Predicts Severity in Pediatric Congenital Heart Disease–Associated Pulmonary Hypertension
Authors: Daly Caroline M. , Griffiths Megan , Simpson Catherine E. , Yang Jun , Damico Rachel L. , Vaidya R. Dhananjay , Williams Monica , Brandal Stephanie , Jone Pei‐Ni , Polsen Cassandra , Ivy D. Dunbar , Austin Eric D. , Nichols William C. , Pauciulo Michael W. , Lutz Katie , Nies Melanie K. , Rosenzweig Erika B. , Hirsch Russel , Yung Delphine , Everett Allen D. 
Published: October 2021

Background
Endostatin, an angiogenic inhibitor, is associated with worse pulmonary arterial hypertension (PAH) outcomes in adults and poor lung growth in children. This study sought to assess whether endostatin is associated with disease severity and outcomes in pediatric PAH.

Methods and Results
Serum endostatin was measured in cross‐sectional (N=160) and longitudinal cohorts (N=64) of pediatric subjects with PAH, healthy pediatric controls and pediatric controls with congenital heart disease (CHD) (N=54, N=15), and adults with CHD associated PAH (APAH‐CHD, N=185). Outcomes, assessed by regression and Kaplan‐Meier analysis, included hemodynamics, change in endostatin over time, and transplant‐free survival. Endostatin secretion was evaluated in pulmonary artery endothelial and smooth muscle cells. Endostatin was higher in those with PAH compared with healthy controls and controls with CHD and was highest in those with APAH‐CHD. In APAH‐CHD, endostatin was associated with a shorter 6‐minute walk distance and increased mean right atrial pressure. Over time, endostatin was associated with higher pulmonary artery pressure and pulmonary vascular resistance index, right ventricular dilation, and dysfunction. Endostatin decreased with improved hemodynamics over time. Endostatin was associated with worse transplant‐free survival. Addition of endostatin to an NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) based survival analysis improved risk stratification, reclassifying subjects with adverse outcomes. Endostatin was secreted primarily by pulmonary artery endothelial cells.

Conclusions
Endostatin is associated with disease severity, disease improvement, and worse survival in APAH‐CHD. Endostatin with NT‐proBNP improves risk stratification, better predicting adverse outcomes. The association of elevated endostatin with shunt lesions suggests that endostatin could be driven by both pulmonary artery flow and pressure. Endostatin could be studied as a noninvasive prognostic marker, particularly in APAH‐CHD.
Effect of Religious Fasting in Ramadan on Blood Pressure: Results From LORANS (London Ramadan Study) and a Meta‐Analysis
Authors: Al‐Jafar Rami , Zografou Themeli Maria , Zaman Sadia , Akbar Sharmin , Lhoste Victor , Khamliche Ahlam , Elliott Paul , Tsilidis Konstantinos K. , Dehghan Abbas 
Published: October 2021

Background
Ramadan fasting is practiced by hundreds of millions every year. This ritual practice changes diet and lifestyle dramatically; thus, the effect of Ramadan fasting on blood pressure must be determined.

Methods and Results

LORANS (London Ramadan Study) is an observational study, systematic review, and meta‐analysis. In LORANS, we measured systolic blood pressure (SBP) and diastolic blood pressure (DBP) of 85 participants before and right after Ramadan. In the systematic review, studies were retrieved from PubMed, Embase, and Scopus from inception to March 3, 2020. We meta‐analyzed the effect from these studies and unpublished data from LORANS. We included observational studies that measured SBP and/or DBP before Ramadan and during the last 2 weeks of Ramadan or the first 2 weeks of the month after. Data appraisal and extraction were conducted by at least 2 reviewers in parallel. We pooled SBP and DBP using a random‐effects model. The systematic review is registered with PROSPERO (International Prospective Register of Systematic Reviews; CRD42019159477). In LORANS, 85 participants were recruited; mean age was 45.6±15.9 years, and 52.9% (
n
=45) of participants were men. SBP and DBP after Ramadan fasting were lower by 7.29 mm Hg (−4.74 to −9.84) and 3.42 mm Hg (−1.73 to −5.09), even after adjustment for potential confounders. We identified 2778 studies of which 33 with 3213 participants were included. SBP and DBP after/before Ramadan were lower by 3.19 mm Hg (−4.43 to −1.96, I
2
=48%) and 2.26 mm Hg (−3.19 to −1.34, I
2
=66%), respectively. In subgroup analyses, lower blood pressures were observed in the groups who are healthy or have hypertension or diabetes but not in patients with chronic kidney disease.

Conclusions
Our study suggests beneficial effects of Ramadan fasting on blood pressure independent of changes in weight, total body water, and fat mass and supports recommendations for some governmental guidelines that describe Ramadan fasting as a safe religious practice with respect to blood pressure.
Impact of Diastolic Interventricular Septal Flattening on Clinical Outcome in Patients With Severe Tricuspid Regurgitation
Authors: Omori Taku , Maeda Mika , Kagawa Shunsuke , Uno Goki , Rader Florian , Siegel Robert J. , Shiota Takahiro 
Published: October 2021

Background
Little is known about the impact of diastolic interventricular septal flattening on the clinical outcome in patients with severe tricuspid regurgitation. This study sought to evaluate the association of diastolic interventricular septal flattening with clinical outcome in patients with severe tricuspid regurgitation.

Methods and Results

We retrospectively studied 407 patients who underwent 2‐dimensional transthoracic echocardiography and were diagnosed with severe tricuspid regurgitation between January 2014 and December 2015. Cardiovascular events were defined as cardiovascular death or admission for heart failure. The magnitude of interventricular septal flattening was calculated by the eccentricity index (EI) of the left ventricle, and hemodynamic parameters were obtained from transthoracic echocardiography. During follow‐up (median, 200 days; interquartile range, 35–1059), 117 of the patients experienced cardiovascular events. By multivariate analysis including potential covariates, EI at end‐diastole and left ventricular ejection fraction were independent predictors of cardiovascular events (hazard ratio, 5.33 [1.63–17.41]; hazard ratio, 0.98 [0.97–0.99], respectively). An EI of 1.2 at end‐diastole was the optimal cutoff value for identifying poor hemodynamic status defined as cardiac index ≤2.2 L/min per m
2
and right atrial pressure 15 mm Hg, both on transthoracic echocardiography. Patients with D‐shaped left ventricle defined as EI ≥1.2 at end‐diastole showed worse outcomes than those without (adjusted hazard ratio, 1.80 [1.18–2.74]).

Conclusions
Increasing EI at end‐diastole was strongly associated with worse outcomes in patients with severe tricuspid regurgitation. Furthermore, the presence of D‐shaped left ventricle defined as EI ≥1.2 at end‐diastole provides prognostic value for cardiovascular events.
Factors affecting the fitness of an entomopathogenic nematode (Heterorhabditis bacteriophora SUP strain) for use in biocontrol in a horticultural area of Argentina
Authors: Eliceche Daiana P. , Rosales Matias N. , Achinelly María F. 
Published: October 2021

Summary
The optimum conditions for storage, infectivity and multiplication of the nematode Heterorhabditis bacteriophora SUP strain, isolated from horticultural soils in Argentina, were determined for later use in biocontrol. This strain was able to kill Tenebrio molitor larvae (over 90%) at 16 and 25°C, after 7 and 4 days, respectively, with mortality being significantly higher at 25°C. No infectivity was reported at 4 and 11°C. Higher concentrations (over 150 infective juveniles (IJ) insect−1) produced higher percentages of mortality. However, increasing inoculum density reduced offspring production and increased emergence time. Storage density between 2500 and 7500 IJ ml−1 had no effect on survival of IJ. Survival of IJ maintained at 4 and 16°C was around 80% after 4 weeks storage and 30% after 32 weeks. However, at 25°C, a 60% IJ survival was observed at 4 weeks, decreasing to around 10% after 16 weeks and with no survival at 24 weeks. An overall significant decrease in virulence was observed after 90 and 120 days of storage but this was more pronounced at a storage temperature of 4°C than at 16 and 25°C. IJ stored at 4°C had reduced virulence after 90 and 120 days, but not after 60 days. This study provides useful information about some fundamental environmental conditions influencing important nematode traits of the species H. bacteriophora.