bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pressure-Electrochemistry as a Pathway to Novel Metal Hydrides
Authors: Sugano Karen , Phuthi Mgcini Keith , Guan Pinwen , Viswanathan Venkat , Chiang Yet-Ming 
Published: September 2023

We have developed a pressure-electrochemical cell apparatus to electrochemically insert hydrogen into metals at applied pressures of 1GPa. The coupling of pressure and potential (P^2) was motivated by our recent density functional theory calculations that predicted the stability of novel metal hydride phases when both pressure and potential are applied [1]. In this work, we adapted a traditional piston-cylinder pressure apparatus into a pressure-electrochemical cell by replacing the inert pressure transmitting medium with a proton-conducting liquid electrolyte (1M NaOH + polyvinyl alcohol) such that it not only provides hydrostatic pressure but also reduces into hydrogen, which is then absorbed into the metal cathode. The pressure being applied by the electrolyte was verified by measuring an increase in the electrical resistance of manganin alloy with pressure. We then electrochemically hydrogenated yttrium foil under varying pressures ranging from 0.25 to 1GPa, measuring the extent of hydrogenation post-mortem using x-ray diffraction. We find that the application of pressure suppresses hydrogen evolution, improving the current efficiency of hydrogenation of Y into YH3 from 45% at 0.25GPa to 75% at 1GPa. The development of the pressure-electrochemical apparatus unlocks a new pathway in potentially synthesizing novel metal hydrides.
[1] P.-W. Guan, R. J. Hemley, V. Viswanathan, Proceedings of the National Academy of Sciences. 118, e2110470118 (2021).
Bipropellant Enabled Solid Oxide Fuel Cell Stack Power Supply: Energy Agility for Space Vehicles
Authors: Plumley John Bryan , Benavidez Angelica , Jemison Noah , Spears Andre , Elangovan S , Pike Jenna , Hollist Michele , Larsen Dennis , Garzon Fernando H. , Peng Thomas 
Published: September 2023

Spacecraft often have instances where they are required to operate for long periods of time with significant power requirements and no access to solar power. While a battery system could be designed to meet these occasional, and possibly unexpected requirements, creating a power supply to meet these infrequent demands results in having a battery system that is excessively large, massive, and inefficient. A Solid Oxide Fuel Cell (SOFC) system capable of running on the same fuel and oxidizer as the onboard thruster of a bipropellant thruster equipped spacecraft can eliminate much of the added mass and volume needed to enable batteries to meet extreme power demands and create more operational flexibility on how the chemical energy in stowed bipropellants are used. If the spacecraft needs thrust, the bipropellant can be ignited to provide thrust. If the spacecraft needs electric power, the spacecraft can consume bipropellant to generate auxiliary power. In this work, the proven bipropellant pair ammonia (NH3) and nitrous oxide (N2O) are shown to be a viable fuel and oxidant for hydrogen (H2) consuming air breathing SOFCs, as spontaneous NH3 decomposition will generate H2 and spontaneous N2O decomposition will generate O2. A scale up to a 5-cell SOFC stack fed NH3 and N2O produced power up to ~89W. Higher power can be achieved by scaling up the number of cells in a stack to achieve required power demands. The results of this study demonstrate the potential and feasibility of integrating SOFCs with a bipropellant thruster to creating a dual functioning spacecraft system that can satisfy operational power requirements and on-orbit maneuverability.
This material is based on research sponsored by Air Force Research Laboratory under agreement number FA9453-21-C-0060. The views expressed are those of the authors and do not reflect the official guidance or position of the United States Government, the Department of Defense or of the United States Air Force. Approved for public release; distribution is unlimited. Public Affairs release approval #AFRL20230023.

Figure 1
The Next-Generation Oral Selective Estrogen Receptor Degrader Camizestrant (AZD9833) Suppresses ER+ Breast Cancer Growth and Overcomes Endocrine and CDK4/6 Inhibitor Resistance
Authors: Lawson Mandy , Cureton Natalie , Ros Susana , Cheraghchi-Bashi Azadeh , Urosevic Jelena , D'Arcy Sophie , Delpuech Oona , DuPont Michelle , Fisher David I. , Gangl Eric T. , Lewis Hilary , Trueman Dawn , Wali Neha , Williamson Stuart C. , Moss Jennifer , Montaudon Elodie , Derrien Heloise , Marangoni Elisabetta , Miragaia Ricardo J. , Gagrica Sladjana , Morentin-Gutierrez Pablo , Moss Thomas A. , Maglennon Gareth , Sutton Daniel , Polanski Radoslaw , Rosen Alan , Cairns Jonathan , Zhang Pei , Sánchez-Guixé Mònica , Serra Violeta , Critchlow Susan E. , Scott James S. , Lindemann Justin P.O. , Barry Simon T. , Klinowska Teresa , Morrow Christopher J. , Carnevalli Larissa S. 
Published: September 2023

Abstract

Oral selective estrogen receptor degraders (SERD) could become the backbone of endocrine therapy (ET) for estrogen receptor–positive (ER+) breast cancer, as they achieve greater inhibition of ER-driven cancers than current ETs and overcome key resistance mechanisms. In this study, we evaluated the preclinical pharmacology and efficacy of the next-generation oral SERD camizestrant (AZD9833) and assessed ER–co-targeting strategies by combining camizestrant with CDK4/6 inhibitors (CDK4/6i) and PI3K/AKT/mTOR-targeted therapy in models of progression on CDK4/6i and/or ET. Camizestrant demonstrated robust and selective ER degradation, modulated ER-regulated gene expression, and induced complete ER antagonism and significant antiproliferation activity in ESR1 wild-type (ESR1wt) and mutant (ESR1m) breast cancer cell lines and patient-derived xenograft (PDX) models. Camizestrant also delivered strong antitumor activity in fulvestrant-resistant ESR1wt and ESR1m PDX models. Evaluation of camizestrant in combination with CDK4/6i (palbociclib or abemaciclib) in CDK4/6-naive and -resistant models, as well as in combination with PI3Kαi (alpelisib), mTORi (everolimus), or AKTi (capivasertib), indicated that camizestrant was active with CDK4/6i or PI3K/AKT/mTORi and that antitumor activity was further increased by the triple combination. The response was observed independently of PI3K pathway mutation status. Overall, camizestrant shows strong and broad antitumor activity in ER+ breast cancer as a monotherapy and when combined with CDK4/6i and PI3K/AKT/mTORi.

Significance:
Camizestrant, a next-generation oral SERD, shows promise in preclinical models of ER+ breast cancer alone and in combination with CDK4/6 and PI3K/AKT/mTOR inhibitors to address endocrine resistance, a current barrier to treatment.
Integration of Genomic Sequencing Drives Therapeutic Targeting of PDGFRA in T-Cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma
Authors: Paolino Jonathan , Dimitrov Boris , Apsel Winger Beth , Sandoval-Perez Angelica , Rangarajan Amith Vikram , Ocasio-Martinez Nicole , Tsai Harrison K. , Li Yuting , Robichaud Amanda L. , Khalid Delan , Hatton Charlie , Gillani Riaz , Polonen Petri , Dilig Anthony , Gotti Giacomo , Kavanagh Julia , Adhav Asmani A. , Gow Sean , Tsai Jonathan , Li Yen Der , Ebert Benjamin L. , Van Allen Eliezer M. , Bledsoe Jacob , Kim Annette S. , Tasian Sarah K. , Cooper Stacy L. , Cooper Todd M. , Hijiya Nobuko , Sulis Maria Luisa , Shukla Neerav N. , Magee Jeffrey A. , Mullighan Charles G. , Burke Michael J. , Luskin Marlise R. , Mar Brenton G. , Jacobson Matthew P. , Harris Marian H. , Stegmaier Kimberly , Place Andrew E. , Pikman Yana 
Published: September 2023

Abstract

Purpose:
Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) or lymphoblastic lymphoma (T-LBL) have limited therapeutic options. Clinical use of genomic profiling provides an opportunity to identify targetable alterations to inform therapy.

Experimental Design:
We describe a cohort of 14 pediatric patients with relapsed or refractory T-ALL enrolled on the Leukemia Precision-based Therapy (LEAP) Consortium trial (NCT02670525) and a patient with T-LBL, discovering alterations in platelet-derived growth factor receptor-α (PDGFRA) in 3 of these patients. We identified a novel mutation in PDGFRA, p.D842N, and used an integrated structural modeling and molecular biology approach to characterize mutations at D842 to guide therapeutic targeting. We conducted a preclinical study of avapritinib in a mouse patient-derived xenograft (PDX) model of FIP1L1-PDGFRA and PDGFRA p.D842N leukemia.

Results:
Two patients with T-ALL in the LEAP cohort (14%) had targetable genomic alterations affecting PDGFRA, a FIP1-like 1 protein/PDGFRA (FIP1L1-PDGFRA) fusion and a novel mutation in PDGFRA, p.D842N. The D842N mutation resulted in PDGFRA activation and sensitivity to tested PDGFRA inhibitors. In a T-ALL PDX model, avapritinib treatment led to decreased leukemia burden, significantly prolonged survival, and even cured a subset of mice. Avapritinib treatment was well tolerated and yielded clinical benefit in a patient with refractory T-ALL.

Conclusions:
Refractory T-ALL has not been fully characterized. Alterations in PDGFRA or other targetable kinases may inform therapy for patients with refractory T-ALL who otherwise have limited treatment options. Clinical genomic profiling, in real time, is needed for fully informed therapeutic decision making.
Advanced Age in Humans and Mouse Models of Glioblastoma Show Decreased Survival from Extratumoral Influence
Authors: Johnson Margaret , Bell April , Lauing Kristen L. , Ladomersky Erik , Zhai Lijie , Penco-Campillo Manon , Shah Yajas , Mauer Elizabeth , Xiu Joanne , Nicolaides Theodore , Drumm Michael , McCortney Kathleen , Elemento Olivier , Kim Miri , Bommi Prashant , Low Justin T. , Memon Ruba , Wu Jennifer , Zhao Junfei , Mi Xinlei , Glantz Michael J. , Sengupta Soma , Castro Brandyn , Yamini Bakhtiar , Horbinski Craig , Baker Darren J. , Walunas Theresa L. , Schiltz Gary E. , Lukas Rimas V. , Wainwright Derek A. 
Published: September 2023

Abstract

Purpose:
Glioblastoma (GBM) is the most common aggressive primary malignant brain tumor in adults with a median age of onset of 68 to 70 years old. Although advanced age is often associated with poorer GBM patient survival, the predominant source(s) of maladaptive aging effects remains to be established. Here, we studied intratumoral and extratumoral relationships between adult patients with GBM and mice with brain tumors across the lifespan.

Experimental Design:
Electronic health records at Northwestern Medicine and the NCI SEER databases were evaluated for GBM patient age and overall survival. The commercial Tempus and Caris databases, as well as The Cancer Genome Atlas were profiled for gene expression, DNA methylation, and mutational changes with varying GBM patient age. In addition, gene expression analysis was performed on the extratumoral brain of younger and older adult mice with or without a brain tumor. The survival of young and old wild-type or transgenic (INK-ATTAC) mice with a brain tumor was evaluated after treatment with or without senolytics and/or immunotherapy.

Results:
Human patients with GBM ≥65 years of age had a significantly decreased survival compared with their younger counterparts. While the intra-GBM molecular profiles were similar between younger and older patients with GBM, non-tumor brain tissue had a significantly different gene expression profile between young and old mice with a brain tumor and the eradication of senescent cells improved immunotherapy-dependent survival of old but not young mice.

Conclusions:
This work suggests a potential benefit for combining senolytics with immunotherapy in older patients with GBM.
Novel Thienoduocarmycin–Trastuzumab ADC Demonstrates Strong Antitumor Efficacy with Favorable Safety Profile in Preclinical Studies
Authors: Valsasina Barbara , Orsini Paolo , Caruso Michele , Albanese Clara , Ciavolella Antonella , Cucchi Ulisse , Fraietta Ivan , Melillo Nicola , Fiorentini Francesco , Rizzi Simona , Salsa Matteo , Isacchi Antonella , Gasparri Fabio 
Published: September 2023

Abstract
New antibodies–drug conjugate (ADC) payloads overcoming chemoresistance and killing also poorly proliferating tumors at well-tolerated doses are much desired. Duocarmycins are a well-known class of highly potent cytotoxic agents, with DNA minor groove-binding and alkylation properties, active also in chemoresistant tumors. Although different duocarmycin derivatives have been used during the years as payloads for ADC production, unfavorable physicochemical properties impaired the production of ADCs with optimal features. Optimization of the toxin to balance reactivity and stability features and best linker selection allowed us to develop the novel duocarmycin-like payload–linker NMS-P945 suitable for conjugation to mAbs with reproducible drug–antibody ratio (DAR) &gt;3.5. When conjugated to trastuzumab, it generated an ADC with good internalization properties, ability to induce bystander effect and immunogenic cell death. Moreover, it showed strong target-driven activity in cells and cytotoxic activity superior to trastuzumab deruxtecan tested, in parallel, in cell lines with HER2 expression. High in vivo efficacy with cured mice at well-tolerated doses in HER2-driven models was also observed. A developed pharmacokinetic/pharmacodynamic (PK/PD) model based on efficacy in mice and cynomolgus monkey PK data, predicted tumor regression in patients upon administration of 2 doses of trastuzumab–NMS-P945–ADC at 0.5 mg/kg. Thus, considering the superior physicochemical features for ADC production and preclinical results obtained with the model trastuzumab ADC, including bystander effect, immunogenic cell death and activity in chemoresistant tumors, NMS-P945 represents a highly effective, innovative payload for the creation of novel, next-generation ADCs.
Adoption and Diffusion of Transcarotid Artery Revascularization in Contemporary Practice
Authors: Columbo Jesse A. , Stone David H. , Martinez-Camblor Pablo , Goodney Philip P. , O’Malley A. James 
Published: September 2023

BACKGROUND:
In 2015, the FDA approved transcarotid artery revascularization (TCAR) as an alternative to carotid endarterectomy (CEA) and transfemoral carotid artery stenting (TF-CAS) for high-risk patients with carotid stenosis. This was granted in the absence of level 1 evidence to support TCAR. We aimed to document trends in TCAR utilization, its diffusion over time, and the clinical phenotypes of patients undergoing TCAR, CEA, and TF-CAS.

METHODS:
We used the Vascular Quality Initiative to study patients who underwent TCAR. We calculated the number of TCARs performed and the percent of TCAR utilization versus CEA/TF-CAS. Using data from before TCAR was widespread, we calculated propensity scores for patients to receive CEA. We applied this model to patients undergoing carotid revascularization from 2016 to 2022 and grouped patients by the procedure they ultimately underwent, examining overlap in score distribution to measure patient similarity. We measured the trend of in-hospital stroke/death after TCAR.

RESULTS:

We studied 31 447 patients who underwent TCAR from January 1, 2016 to March 31, 2022. The number of centers performing TCAR increased from 29 to 606. In 2021, TCAR represented 22.5% of carotid revascularizations at centers offering all 3 procedures. The percentage of patients that underwent TCAR who met approved high-risk criteria decreased from 88.5% to 80.9% (
P
<0.001). Those with a prior ipsilateral carotid procedure decreased from 20.6% in 2016 to 12.0% in 2021 (
P
<0.001). Patients undergoing TCAR after stroke increased from 19.7% to 30.7% (
P
<0.001). Propensity-score overlap was 55.4% for TCAR/CEA, and 58.6% for TCAR/TF-CAS, demonstrating that TCAR patients have a clinical phenotype mixed between those who undergo CEA and TF-CAS. The average in-hospital stroke/death risk after TCAR was 2.3% in 2016 and 1.7% in 2022 (
P
trend: 0.954).

CONCLUSIONS:
TCAR now represents nearly 1-in-4 procedures at centers offering it. TCAR was increasingly performed among standard-risk patients and as a first-line procedural option after stroke. The absence of level 1 evidence underscores the importance of high-quality registry-based analyses to document TCAR’s real-world outcomes and durability.
Complete Revascularization Versus Culprit-Lesion-Only PCI in STEMI Patients With Diabetes and Multivessel Coronary Artery Disease: Results From the COMPLETE Trial
Authors: Oqab Zardasht , Kunadian Vijay , Wood David A. , Storey Robert F. , Rao Sunil V. , Mehran Roxana , Pinilla-Echeverri Natalia , Mani Thenmozhi , Boone Robert H. , Kassam Saleem , Bossard Matthias , Mansour Samer , Ball Warren , Sibbald Matthew , Valettas Nicholas , Moreno Raul , Steg Philippe Gabriel , Cairns John A. , Mehta Shamir R. 
Published: September 2023

BACKGROUND:
In the COMPLETE trial (Complete Versus Culprit-Only Revascularization to Treat Multivessel Disease After Early PCI for STEMI), a strategy of complete revascularization reduced the risk of major cardiovascular events compared with culprit-lesion-only percutaneous coronary intervention in patients presenting with ST-segment–elevation myocardial infarction (STEMI) and multivessel coronary artery disease. Patients with diabetes have a worse prognosis following STEMI. We evaluated the consistency of the effects of complete revascularization in patients with and without diabetes.

METHODS:

The COMPLETE trial randomized a strategy of complete revascularization, consisting of angiography-guided percutaneous coronary intervention of all suitable nonculprit lesions, versus a strategy of culprit-lesion-only percutaneous coronary intervention (guideline-directed medical therapy alone). In prespecified analyses, treatment effects were determined in patients with and without diabetes on the first coprimary outcome of cardiovascular death or new myocardial infarction and the second coprimary outcome of cardiovascular death, new myocardial infarction, or ischemia-driven revascularization. Interaction
P
values were calculated to evaluate whether there was a differential treatment effect in patients with and without diabetes.

RESULTS:

Of the 4041 patients enrolled in the COMPLETE trial, 787 patients (19.5%) had diabetes. The median HbA1c (glycated hemoglobin) was 7.7% in the diabetes group and 5.7% in the nondiabetes group. Complete revascularization consistently reduced the first coprimary outcome in patients with diabetes (hazard ratio, 0.87 [95% CI, 0.59–1.29]) and without diabetes (hazard ratio, 0.70 [95% CI, 0.55–0.90]), with no evidence of a differential treatment effect (interaction
P
=0.36). Similarly, for the second coprimary outcome, no differential treatment effect (interaction
P
=0.27) of complete revascularization was found in patients with diabetes (hazard ratio, 0.61 [95% CI, 0.43–0.87]) and without diabetes (hazard ratio, 0.48 [95% CI, 0.39–0.60]).

CONCLUSIONS:
Among patients presenting with STEMI and multivessel disease, the benefit of complete revascularization over a culprit-lesion-only percutaneous coronary intervention strategy was consistent regardless of the presence or absence of diabetes.
Noisy Omens and Enslaved Gods
Authors: Réal Matthieu 
Published: September 2023

Abstract
I offer a reconsideration of Zoilus’ treatise Against Homer’s Poetry. Two fragments of this work, F9a and F14 Fogagnolo, especially showcase Zoilus’ significance in the context of ancient literary criticism. F9a is usually considered a sarcastic comment on Homer’s lack of realism. I propose instead that it is a critique of the way the poet crafted the bird omen of Il. 10.174-177: Zoilus regarded the omen as a symbolic device and focused on the details of the analogical relationship between interpretandum and the interpretamentum. I also suggest that Aristotle F369 Gigon may have originated as a defense of Homer against one of Zoilus’ criticisms. Through a new translation of F14, I show that Zoilus did not content himself with analyzing problematic lines of Homer in isolation, but also assessed passages of the poem in light of other relevant passages within the same poem. In short, he criticized Homer from Homer.
Valuing the Dental Caries Utility Index in Australia
Authors: Hettiarachchi Ruvini M. , Kularatna Sanjeewa , Byrnes Joshua , Mulhern Brendan , Chen Gang , Scuffham Paul A. 
Published: September 2023

Introduction The Dental Caries Utility Index (DCUI) is a new oral health–specific health state classification system for adolescents, consisting of 5 domains: pain/discomfort, difficulty eating food/drinking, worried, ability to participate in activities, and appearance. Each domain has 4 response levels. This study aims to generate an Australian-specific utility algorithm for the DCUI. Methods An online survey was conducted using a representative sample of the adult Australian general population. The discrete choice experiment (DCE) was used to elicit the preferences on 5 domains. Then, the latent utilities were anchored onto the full health-dead scale using the visual analogue scale (VAS). DCE data were modeled using conditional logit, and 2 anchoring procedures were considered: anchor based on the worst health state and a mapping approach. The optimal anchoring procedure was selected based on the model parsimony and the mean absolute error (MAE). Results A total of 995 adults from the Australian general population completed the survey. The conditional logit estimates on 5 dimensions and levels were monotonic and statistically significant, except for the second level of the “worried” and “appearance” domains. The mapping approach was selected based on a smaller MAE between the 2 anchoring procedures. The Australian-specific tariff of DCUI ranges from 0.1681 to 1. Conclusion This study developed a utility algorithm for the DCUI. This value set will facilitate utility value calculations from the participants’ responses for DCUI in economic evaluations of dental caries interventions targeted for adolescents. Highlights Preference-based quality-of-life measures (PBMs), which consist of a health state classification system and a set of utility values (a scoring algorithm), are used to generate utility weights for economic evaluations. This study is the first to develop an Australian utility value set for the Dental Caries Utility Index (DCUI), a new oral health–specific classification system for adolescents. The availability of a utility value set will enable using DCUI in economic evaluations of oral health interventions targeted for adolescents and may ultimately lead to more effective and efficient planning of oral health care services.