bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Single-Arm Phase 2 Trial of Trametinib in Patients with Locally Advanced or Metastatic Epithelioid Hemangioendothelioma
Authors: Schuetze Scott M. , Ballman Karla V. , Heise Rachel , Ganjoo Kristen N. , Davis Elizabeth J. , George Suzanne , Burgess Melissa A. , Choy Edwin , Shepard Dale R. , Tinoco Gabriel , Hirbe Angela , Kelly Ciara M. , Attia Steven , Deshpande Hari A. , Schwartz Gary K. , Siontis Brittany L. , Riedel Richard F. , von Mehren Margaret , Kozlowski Erin , Chen Helen X. , Astbury Caroline , Rubin Brian P. 
Published: March 2024

Abstract

Purpose:
Epithelioid hemangioendothelioma (EHE) is a rare vascular cancer with pathogenic TAZ–CAMTA1 (calmodulinbinding transcription activator 1) operating as an oncogenic driver through activation of the MAPK pathway. Trametinib is an inhibitor of MEK, a critical kinase in the MAPK pathway. We sought to evaluate the effect of trametinib in patients with EHE.

Patients and Methods:
A phase 2 trial of trametinib was conducted in patients with locally advanced or metastatic EHE. Eligibility requirements included evidence of tumor progression or presence of EHE-related pain requiring opiates for management before enrollment. The primary endpoint was objective response rate (ORR) as per RECIST1.1 in cases with TAZ– CAMTA1 confirmed by fusion-FISH. Secondary objectives were to estimate ORR for all patients, median progression-free survival (PFS), 2-year overall survival (OS) rate, patient safety, and change in patient-reported global health and pain scores per PROMIS questionnaires.

Results:
44 patients enrolled and 42 started trametinib. TAZ– CAMTA1 was detected in 27 tumor samples. TheORRwas 3.7%[95% confidence interval (CI), 0.094–19.0], median PFS was 10.4 months (95%CI, 7.1–NA), and 2-year OS rate was 33.3%(95%CI, 19.1–58.2) in the target population. Median pain intensity and interference scores improved significantly after 4 weeks of trametinib in patients using opiates. Common adverse events related to trametinib were rash, fatigue, nausea/vomiting, diarrhea/constipation, alopecia, and edema; one grade 5 ARDS/pneumonitis was related to trametinib.

Conclusions:
Trametinib was associated with reduction in EHE-related pain and median PFS of more than 6 months, providing palliative benefit in patients with advanced EHE, but the trial did not meet the ORR goal.
See related commentary by Van Tine and Haarberg, p. 4552
D-2-HG Inhibits IDH1mut Glioma Growth via FTO Inhibition and Resultant m6A Hypermethylation
Authors: Pianka Sean T. , Li Tie , Prins Terry J. , Eldred Blaine S.C. , Kevan Bryan M. , Liang Haowen , Zapanta Rinonos Serendipity , Kornblum Harley I. , Nathanson David A. , Pellegrini Matteo , Liau Linda M. , Nghiemphu Phioanh Leia , Cloughesy Timothy F. , Lai Albert 
Published: March 2024

Abstract

IDH1mut gliomas produce high levels of D-2-hydroxyglutarate (D-2-HG), an oncometabolite capable of inhibiting α-ketoglutarate–dependent dioxygenases critical to a range of cellular functions involved in gliomagenesis. IDH1mut gliomas also exhibit slower growth rates and improved treatment sensitivity compared with their IDH1wt counterparts. This study explores the mechanism driving apparent reduced growth in IDH1mut gliomas. Specifically, we investigated the relationship between IDH1mut and the RNA N6-methyladenosine (m6A) demethylases FTO and ALKBH5, and their potential for therapeutic targeting. We investigated the role of D-2-HG and m6A in tumor proliferation/viability using glioma patient tumor samples, patient-derived gliomaspheres, and U87 cells, as well as with mouse intracranial IDH1wt gliomasphere xenografts. Methylation RNA immunoprecipitation sequencing (MeRIP-seq) RNA sequencing was used to identify m6A-enriched transcripts in IDH1mut glioma. We show that IDH1mut production of D-2-HG is capable of reducing glioma cell growth via inhibition of the m6A epitranscriptomic regulator, FTO, with resultant m6A hypermethylation of a set of mRNA transcripts. On the basis of unbiased MeRIP-seq epitranscriptomic profiling, we identify ATF5 as a hypermethylated, downregulated transcript that potentially contributes to increased apoptosis. We further demonstrate how targeting this pathway genetically and pharmacologically reduces the proliferative potential of malignant IDH1wt gliomas, both in vitro and in vivo. Our work provides evidence that selective inhibition of the m6A epitranscriptomic regulator FTO attenuates growth in IDH1wt glioma, recapitulating the clinically favorable growth phenotype seen in the IDH1mut subtype.

Significance:
We show that IDH1mut-generated D-2-HG can reduce glioma growth via inhibition of the m6A demethylase, FTO. FTO inhibition represents a potential therapeutic target for IDH1wt gliomas and possibly in conjunction with IDH1mut inhibitors for the treatment of IDH1mut glioma. Future studies are necessary to demonstrate the role of ATF5 downregulation in the indolent phenotype of IDH1mut gliomas, as well as to identify other involved gene transcripts deregulated by m6A hypermethylation.
Ovariectomy-Induced Arterial Stiffening Differs From Vascular Aging and Is Reversed by GPER Activation
Authors: Kilanowski-Doroh Isabella M. , McNally Alexandra B. , Wong Tristen , Visniauskas Bruna , Blessinger Sophia A. , Imulinde Sugi Ariane , Richard Chase , Diaz Zaidmara , Horton Alec , Natale Christopher A. , Ogola Benard O. , Lindsey Sarah H. 
Published: March 2024

BACKGROUND:
Arterial stiffness is a cardiovascular risk factor and dramatically increases as women transition through menopause. The current study assessed whether a mouse model of menopause increases arterial stiffness in a similar manner to aging and whether activation of the G-protein–coupled estrogen receptor could reverse stiffness.

METHODS:
Female C57Bl/6J mice were ovariectomized at 10 weeks of age or aged to 52 weeks, and some mice were treated with G-protein–coupled estrogen receptor agonists.

RESULTS:
Ovariectomy and aging increased pulse wave velocity to a similar extent independent of changes in blood pressure. Aging increased carotid wall thickness, while ovariectomy increased material stiffness without altering vascular geometry. RNA-sequencing analysis revealed that ovariectomy downregulated smooth muscle contractile genes. The enantiomerically pure G-protein–coupled estrogen receptor agonist, LNS8801, reversed stiffness in ovariectomy mice to a greater degree than the racemic agonist G-1. In summary, ovariectomy and aging induced arterial stiffening via potentially different mechanisms. Aging was associated with inward remodeling, while ovariectomy-induced material stiffness independent of geometry and a loss of the contractile phenotype.

CONCLUSIONS:
This study enhances our understanding of the impact of estrogen loss on vascular health in a murine model and warrants further studies to examine the ability of LNS8801 to improve vascular health in menopausal women.

REGISTRATION:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT04130516.
Diffusion deep learning for brain age prediction and longitudinal tracking in children through adulthood
Authors: Zapaishchykova Anna , Tak Divyanshu , Ye Zezhong , Liu Kevin X. , Likitlersuang Jirapat , Vajapeyam Sridhar , Chopra Rishi B. , Seidlitz Jakob , Bethlehem Richard A.I. , Mak Raymond H. , Mueller Sabine , Haas-Kogan Daphne A. , Poussaint Tina Y. , Aerts Hugo J.W.L. , Kann Benjamin H. 
Published: March 2024

Abstract
Deep learning (DL)-based prediction of biological age in the developing human from a brain magnetic resonance imaging (MRI) (“brain age”) may have important diagnostic and therapeutic applications as a non-invasive biomarker of brain health, aging, and neurocognition. While previous deep learning tools for predicting brain age have shown promising capabilities using single-institution, cross-sectional datasets, our work aims to advance the field by leveraging multi-site, longitudinal data with externally validated and independently implementable code to facilitate clinical translation and utility. This builds on prior foundational efforts in brain age modeling to enable broader generalization and individual’s longitudinal brain development. Here, we leveraged 32,851 T1-weighted MRI scans from healthy children and adolescents aged 3 to 30 from 16 multisite datasets to develop and evaluate several DL brain age frameworks, including a novel regression diffusion DL network (AgeDiffuse). In a multisite external validation (5 datasets), we found that AgeDiffuse outperformed conventional DL frameworks, with a mean absolute error (MAE) of 2.78 years (interquartile range [IQR]: [1.2-3.9]). In a second, separate external validation (3 datasets), AgeDiffuse yielded an MAE of 1.97 years (IQR: [0.8-2.8]). We found that AgeDiffuse brain age predictions reflected age-related brain structure volume changes better than biological age (R2 = 0.48 vs. R2 = 0.37). Finally, we found that longitudinal predicted brain age tracked closely with chronological age at the individual level. To enable independent validation and application, we made AgeDiffuse publicly available and usable for the research community.
Unexamined Zen: Challenges from Dōgen’s Zen Buddhism
Authors: Dunlap Rika 
Published: March 2024

Abstract
The traditional narrative of Zen Buddhism focuses on a religious experience that goes beyond words and concepts. I argue that Dōgen’s understanding of enlightenment is not limited to a religious experience, as it involves a creative process of Buddha-making that demands the flexibility to present a novel expression of the Buddha way with the transiency of the impermanent world. In arguing for the processual understanding of the Buddha way and enlightenment, I refer to the fluidity of dao in Chinese philosophy to shed light upon the significance of creativity in authentic practice. By doing so, I explain why an unexamined Zen is problematic for Dōgen.
Consumption as a Demarcation of Social and Economic Status: The Case of Beyhan Sultan
Authors: Nizri Michael 
Published: March 2024

Abstract
Beyhan Sultan (1765–1824) was an Ottoman princess, the daughter of Sultan Mustafa III (r. 1757–1774) and his consort Adilşah Kadın. She was part of a group of high-born Ottoman women who led entirely separate lives with their own households during the last quarter of the eighteenth and the first quarter of the nineteenth century. However, very few studies have examined the lives and experiences of Ottoman princesses. In this article, I discuss issues such as consumption patterns, the freedom and privileges enjoyed by the princess and the composition and social networks of her household. I argue that Ottoman princesses, such as Beyhan Sultan, were able to extend their agency and visibility through the management of their households and consumption.
No Outcome Is Good, Bad, or Evaluatively Neutral for Anyone
Authors: Rabenberg Michael 
Published: March 2024

Abstract
I argue that no outcome is good, bad, or evaluatively neutral for anyone. My argument concerns non-comparative personal evaluative properties alone; it does not support (say) the conclusion that no outcome is better for anyone than any other outcome. First I argue that there is a sequence of outcomes with the following properties, and that the existence of such a sequence supports the conclusion that no outcome is good for anyone: (i) the first member of the sequence is good for you if any outcome is good for you, (ii) any two adjacent members of the sequence are on a par for you, and (iii) the last member of the sequence is not good for you. I then defend similar arguments that no outcome is bad or evaluatively neutral for anyone. Thus, I conclude that no outcome is good, bad, or evaluatively neutral for anyone.
Enhancing reproducibility in black soldier fly research
Authors: Wiklicky Viktoria , Guidini Lopes Ivã , Lalander Cecilia 
Published: March 2024

Abstract
Over the past decade, there has been a steady increase in research focused on insects as food and feed, integrated with waste management and fertiliser production, with notable attention given to the black soldier fly (Hermetia illucens, BSF). Extensive knowledge has been developed regarding waste bioconversion and characterisation of the products generated (larval biomass and frass). However, the diverse range of rearing methods for BSF larvae (BSFL) has led to equally diverse outcomes. This confusion can lead to new research in the field of BSF being conducted using sub-optimal BSFL treatment conditions. In this editorial we propose that calibration procedures within distinct research areas should be considered when planning new BSFL experiments.
Territorial Peace Five Years After the Peace Agreement in Colombia: An Analysis of the Discourse of the Former FARC-EP
Authors: Ríos Jerónimo 
Published: March 2024

The following paper examines the notion of territorial peace associated with the Peace Agreement signed in 2016 between the Colombian government and the FARC-EP. More specifically, the political discourse of the FARC-EP is analyzed through nine in-depth interviews with prominent members of the organization, who, in addition, have held or hold positions of political relevance in the formation heir to the armed group – today the political party known as Comunes. The relevance, contradictions, tensions and problems that have accompanied the difficult process of implementation of the Agreement in Colombia will be addressed. The responses given by interviewees reveal a common narrative regarding the failures of the Iván Duque government’s commitment and implementation but differ on the scope and significance of the dissident groups or the role that the Comunes party should play in defending the Peace Agreement. Additionally, the territorial dimension emergesas an underlying aspect that requires special attention in all the testimonies. El siguiente artículo examina la noción de paz territorial asociada al Acuerdo de Paz firmado en 2016 entre el gobierno colombiano y las FARC-EP. Más concretamente, se analiza el discurso político de las FARC-EP a través de nueve entrevistas en profundidad a destacados miembros de la organización, quienes, además, han ocupado o ocupan cargos de relevancia política en la formación heredera del grupo armado -hoy el partido político conocido como Comunes. Se abordará la relevancia, contradicciones, tensiones y problemas que han acompañado el difícil proceso de implementación del Acuerdo en Colombia. Las respuestas dadas por los entrevistados revelan una narrativa común sobre los fracasos del compromiso y la implementación del gobierno de Iván Duque, pero difieren sobre el alcance y la importancia de los grupos disidentes o el papel que debería desempeñar el partido Comunes en la defensa del Acuerdo de Paz. Además, la dimensión territorial emerge como un aspecto subyacente que requiere especial atención en todos los testimonios.
Ecofriendly quince peel powder incorporated Polylactic acid biocomposite film
Authors: Şen İbrahim , Eroğlu Murat , Severgün Olcay , Kızıl Demet 
Published: March 2024

This study aims to develop sustainable, renewable and biodegradable biocomposite films from environmentally friendly materials. For this purpose, completely biodegradable polymer composites were prepared by mixing polylactic acid (PLA) with a new source, quince peel (QP), by solvent casting method, and their structural, mechanical and thermal properties were examined. The tensile strengths of the composites prepared using QP in proportions varying between 5% (P5Q) and 30% (P30Q) by weight vary between 21.13 ± 0.80 and 12.01 ± 0.10 MPa, and their elongations at break vary between 11.33 ± 0.38 and 4.08 ± 1.06 %. As the QP contribution increased, the tensile strength and breaking elongation of these composites generally decreased, while the elastic modulus also increased. Among these composites, whose elastic modulus varies between 1040.00 ± 140.01 and 811.33 ± 13.31 MPa, it was determined that the elastic modulus (1040.00 ± 140.01 MPa) of the 20% QP added composite (P20Q) was higher than the others. When the thermal analysis of PLA/QP films were examined, it was observed that the glass transition temperatures (Tg) were between 58.54 and 51.45°C and the melting temperatures (Tm) were between 167.71 and 164.28°C, and these temperatures generally decreased with increasing QP doping. When the T50 values, which represent the temperature at which 50% of the composite materials decompose, were examined, it was found that the QP-added ones were higher than the pure composites. While this value was 317.96°C in pure PLA composite, T50 values varied between 327.92 and 340.80°C depending on the varying QP ratios. According to the XRD results performed to evaluate the crystalline properties of PLA composites containing quince bark, the crystallinity of pure PLA was determined as 19.5% and the crystallinity of composites containing 5, 10, 20 and 30 wt % QP additives was determined as 19.3, 18.3, 16.4 and 14.6%, respectively.
The potential mechanism of ursolic acid in the treatment of bladder cancer based on network pharmacology and molecular docking
Authors: Huang Xiao-Long , Sun Yan , Wen Peng , Pan Jun-Cheng , He Wei-Yang 
Published: March 2024

Objective This study explored the potential molecular mechanisms of ursolic acid (UA) in bladder cancer treatment using network pharmacology and molecular docking. Methods The Traditional Chinese Medicine Systems Pharmacology and UniProt databases were used to screen potential targets of UA. Relevant bladder cancer target genes were extracted using the GeneCards database. All data were pooled and intercrossed to obtain common target genes of UA and bladder cancer. Gene Ontology functional annotation and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed. Molecular docking was conducted to verify the possible binding conformation between UA and bladder cancer cells. Then, in vitro experiments were performed to further validate the predicted results. Results UA exerts anti-tumor effects on bladder cancer through multiple targets and pathways. Molecular docking indicated that UA undergoes stable binding with the proteins encoded by the top six core genes ( STAT3, VEGFA, CASP3, TP53, IL1B, and CCND1). The in vitro experiments verified that UA can induce bladder cancer cell apoptosis by regulating the PI3K/Akt signaling pathway. Conclusions Our study illustrated the potential mechanism of UA in bladder cancer based on network pharmacology and molecular docking. The results will provide scientific references for follow-up studies and clinical treatment.
Physical Exercise for Treating the Anxiety and Depression Symptoms of Parkinson’s Disease: Systematic Review and Meta-Analysis
Authors: Costa Valton , Prati José Mario , de Oliveira Barreto Suassuna Alice , Souza Silva Brito Thanielle , Frigo da Rocha Thalita , Gianlorenço Anna Carolyna 
Published: March 2024

Background Depression and anxiety are non-motor symptoms of Parkinson’s disease (PD). Physical exercise is a promising approach to reducing neuropsychological burden. We aimed to comprehensively synthesize evidence regarding the use of exercise for treating depression and anxiety symptoms in PD. Methods Systematic review and meta-analysis following PRISMA recommendations. Searches on PubMed, Cochrane Library, Scopus, Web of Science, Embase, and Physiotherapy Evidence Database (PEDro) was conducted. The random-effects model was employed for all analyses with the standardized mean difference as the effect estimate. Results Fifty records were retrieved, but only 17 studies met the criteria for the meta-analyses. A moderate to large effect was observed for depression (−.71 [95% CI = −.96 to −.46], 11 studies, 728 individuals), and a small to moderate effect for anxiety (−.39 [95% CI = −.65 to −.14], 6 studies, 241 individuals), when comparing exercise to non-exercise controls. Subgroup analysis revealed significant effects from aerobic (−.95 [95% CI = −1.60, −.31]), mind-body (−1.85 [95% CI = −2.63, −1.07]), and resistance modalities (−1.61 [95% CI = −2.40, −.83]) for depression, and from mind-body (−.67 [95% CI = −1.19 to −.15]) and resistance exercises (−1.00 [95% CI = −1.70 to −.30]) for anxiety. Conclusion Physical exercise has a relevant clinical impact on depression and anxiety in PD. We discuss the level of the evidence, the methodological limitations of the studies, and give recommendations.
Preclinical Dementia and Economic Well-Being Trajectories of Racially Diverse Older Adults
Authors: Mudrazija Stipica , Palms Jordan , Lee Ji Hyun , Maher Amanda , Zahodne Laura B. , Chopik William J. 
Published: March 2024

Objectives This study examined the magnitude, changes, and racial/ethnic disparities in the economic costs of the 16-year preclinical phase of dementia—a period of cognitive decline without significant impact on daily activities. Methods: The study utilized two dementia algorithms to classify individuals with incident dementia in the Health and Retirement Study. These cases were compared to matched controls in terms of poverty status, labor force participation, and unsecured debts. Results: Older adults classified with dementia were more likely to drop out of the labor force and become poor than similar older adults without dementia. Racial/ethnic disparities in poverty persisted during the preclinical period, with non-Hispanic Black older adults more likely to leave the labor force and Hispanic older adults more likely to have unsecured debt. Discussion: Findings highlight the economic costs during prodromal phase of dementia, emphasizing need for early interventions to reduce financial strain across diverse older adults.
Sleep Quality as a Critical Pathway Between Adverse Childhood Experiences and Multimorbidity and the Impact of Lifestyle
Authors: Sheffler Julia L. , Meng Zhuo , Sachs-Ericsson Natalie , Caimary Viviana G. , Patel Juhi , Pickett Scott 
Published: March 2024

Objectives This study aims to establish the effects of ACEs on multimorbidity through sleep quality and investigate whether lifestyle factors (e.g., eating habits and exercise) may influence this relationship among middle-aged and older adults. Methods Participants were drawn from a cross-sectional sample of community dwelling older adults ( N = 276, 55+) and three waves of data from the Midlife in the United States study (MIDUS, N = 843). We examined the direct and indirect effects of ACEs, sleep quality, and health conditions, as well as the conditional effects of physical activity and eating habits. Results Across both samples, sleep quality mediated the relationship between ACEs and chronic health conditions. Moderating effects of unhealthy eating and physical activity differed between samples. Discussion Sleep quality is an important pathway connecting ACEs and adult multimorbidity, and health behaviors may provide targets for intervention particularly in older adults.
Silent reflections remain unheard
Authors: Higgins Matthew , Palepu Radhika , Little John 
Published: March 2024

Objective To consider the contribution of non-clinical factors in the rising rate of mental health presentations and explore the associated silence within the psychiatric profession. Conclusion Medicalisation, concept creep and group think, alongside societal demand and expectations, have collectively contributed toward a distorted view of mental health and illness. Equitable service provision has been hindered by the silence of important perspectives.