bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity from a Phase I Study of Simlukafusp Alfa (FAP-IL2v) in Advanced/Metastatic Solid Tumors
Authors: Steeghs Neeltje , Gomez-Roca Carlos , Rohrberg Kristoffer S. , Mau-Sørensen Morten , Robbrecht Debbie , Tabernero Josep , Ahmed Samreen , Rodríguez-Ruiz Maria E. , Ardeshir Caroline , Schmid Daniela , Sleiman Nassim , Watson Carl , Piper-Lepoutre Hanna , Dejardin David , Evers Stefan , Boetsch Christophe , Charo Jehad , Teichgräber Volker , Melero Ignacio 
Published: April 2024

Purpose:
Simlukafusp alfa [fibroblast activation protein α–targeted IL2 variant (FAP-IL2v)], a tumor-targeted immunocytokine, comprising an IL2 variant moiety with abolished CD25 binding fused to human IgG1, is directed against fibroblast activation protein α. This phase I, open-label, multicenter, dose-escalation, and extension study (NCT02627274) evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of FAP-IL2v in patients with advanced/metastatic solid tumors.

Patients and Methods:
Participants received FAP-IL2v intravenously once weekly. Dose escalation started at 5 mg; flat dosing (≤25 mg) and intraparticipant uptitration regimens (15/20, 20/25, 20/20/35, and 20/35/35 mg) were evaluated. Primary objectives were dose-limiting toxicities, maximum tolerated dose, recommended expansion dose, and pharmacokinetics.

Results:
Sixty-one participants were enrolled. Dose-limiting toxicities included fatigue (flat dose 20 mg: n = 1), asthenia (25 mg: n = 1), drug-induced liver injury (uptitration regimen 20/25 mg: n = 1), transaminase increase (20/25 mg: n = 1), and pneumonia (20/35/35 mg: n = 1). The uptitration regimen 15/20 mg was determined as the maximum tolerated dose and was selected as the recommended expansion dose. Increases in peripheral blood absolute immune cell counts were seen for all tested doses [NK cells, 13-fold; CD4+ T cells (including regulatory T cells), 2-fold; CD8+ T cells, 3.5-fold] but without any percentage change in regulatory T cells. Clinical activity was observed from 5 mg [objective response rate, 5.1% (n = 3); disease control rate, 27.1% (n = 16)]. Responses were durable [n = 3, 2.8 (censored), 6.3, and 43.4 months].

Conclusions:
FAP-IL2v had a manageable safety profile and showed initial signs of antitumor activity in advanced/metastatic solid tumors.
Low-Dose Ionizing γ-Radiation Elicits the Extrusion of Neutrophil Extracellular Traps
Authors: Teijeira Alvaro , Garasa Saray , Ochoa Maria C. , Sanchez-Gregorio Sandra , Gomis Gabriel , Luri-Rey Carlos , Martinez-Monge Rafael , Pinci Beatrice , Valencia Karmele , Palencia Belen , Barbés Benigno , Bolaños Elixabet , Azpilikueta Arantza , García-Cardosa Marina , Burguete Javier , Eguren-Santamaría Iñaki , Garate-Soraluze Eneko , Berraondo Pedro , Perez-Gracia Jose L. , de Andrea Carlos E. , Rodriguez-Ruiz Maria E. , Melero Ignacio 
Published: April 2024

Abstract

Purpose:
Patients with cancer frequently undergo radiotherapy in their clinical management with unintended irradiation of blood vessels and copiously irrigated organs in which polymorphonuclear leukocytes circulate. Following the observation that such low doses of ionizing radiation are able to induce neutrophils to extrude neutrophil extracellular traps (NET), we have investigated the mechanisms, consequences, and occurrence of such phenomena in patients undergoing radiotherapy.

Experimental Design:
NETosis was analyzed in cultures of neutrophils isolated from healthy donors, patients with cancer, and cancer-bearing mice under confocal microscopy. Cocultures of radiation-induced NETs, immune effector lymphocytes, and tumor cells were used to study the effects of irradiation-induced NETs on immune cytotoxicity. Radiation-induced NETs were intravenously injected to mice for assessing their effects on metastasis. Circulating NETs in irradiated patients with cancer were measured using ELISA methods for detecting MPO–DNA complexes and citrullinated histone 3.

Results:
Irradiation of neutrophils with very low γ-radiation doses (0.5–1 Gy) elicits NET formation in a manner dependent on oxidative stress, NADPH oxidase activity, and autocrine IL8. Radiation-induced NETs interfere with NK cell and T-cell cytotoxicity. As a consequence, preinjection of irradiation-induced NETs increases the number of successful metastases in mouse tumor models. Increases in circulating NETs were readily detected in two prospective series of patients following the first fraction of their radiotherapy courses.

Conclusions:
NETosis is induced by low-dose ionizing irradiation in a neutrophil-intrinsic fashion, and radiation-induced NETs are able to interfere with immune-mediated cytotoxicity. Radiation-induced NETs foster metastasis in mouse models and can be detected in the circulation of patients undergoing conventional radiotherapy treatments.
See related commentary by Mowery and Luke, p. 3965
Spatially Preserved Multi-Region Transcriptomic Subtyping and Biomarkers of Chemoimmunotherapy Outcome in Extensive-Stage Small Cell Lung Cancer
Authors: Peressini Melina , Garcia-Campelo Rosario , Massuti Bartomeu , Martí Cristina , Cobo Manuel , Gutiérrez Vanesa , Dómine Manuel , Fuentes José , Majem Margarita , de Castro Javier , Córdoba Juan F. , Diz María P. , Isla Dolores , Esteban Emilio , Carcereny Enric , Vila Laia , Moreno-Vega Alberto , Ros Silverio , Moreno Amaia , García Francisco J. , Huidobro Gerardo , Aguado Carlos , Cebey-López Victor , Valdivia Javier , Palmero Ramón , Lianes Pilar , López-Brea Marta , Vidal Oscar J. , Provencio Mariano , Arriola Edurne , Baena Javier , Herrera Mercedes , Bote Helena , Molero Magdalena , Adradas Vera , Ponce-Aix Santiago , Nuñez-Buiza Angel , Ucero Álvaro , Hernandez Susana , Lopez-Rios Fernando , Conde Esther , Paz-Ares Luis , Zugazagoitia Jon 
Published: April 2024

AbstractPurpose:Transcriptomic subtyping holds promise for personalized therapy in extensive-stage small cell lung cancer (ES-SCLC). In this study, we aimed to assess intratumoral transcriptomic subtype diversity and to identify biomarkers of long-term chemoimmunotherapy benefit in human ES-SCLC.Experimental Design:We analyzed tumor samples from 58 patients with ES-SCLC enrolled in two multicenter single-arm phase IIIb studies evaluating frontline chemoimmunotherapy in Spain: n = 32 from the IMfirst trial and n = 26 from the CANTABRICO trial. We used the GeoMx Digital Spatial Profiler system to perform multi-region transcriptomic analysis. For subtype classification, we performed hierarchical clustering using the relative expression of ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POU2F3 (SCLC-P), and YAP1 (SCLC-Y).Results:Subtype distribution was found to be similar between bothcohorts, except for SCLC-P, which was not identified in the CANTABRICO_DSP cohort. A total of 44% of the patients in both cohorts had tumors with multiple coexisting transcriptional subtypes. Transcriptional subtypes or subtype heterogeneity was not associated with outcomes. Most potential targets did not show subtype-specific expression. Consistently in both cohorts, tumors from patients with long-term benefit (time to progression ≥12 months) contained an IFNγ-dominated mRNA profile, including enhanced capacity for antigen presentation. Hypoxia and glycolytic pathways were associated with resistance to chemoimmunotherapy.Conclusions:This work suggests that intratumoral heterogeneity, inconsistent association with outcome, and unclear subtype-specific target expression might be significant challenges for subtype-based precision oncology in SCLC. Preexisting IFNγ-driven immunity and mitochondrial metabolism seem to be correlates of long-term efficacy in this study, although the absence of a chemotherapy control arm precludes concluding that these are predictive features specific for immunotherapy.
A experiência do trabalho de campo no universo da comunicação
Authors: Travancas Isabel Siqueira 
Published: April 2024

El objetivo de esta comunicación es discutir de la experiencia del trabajo de campo a partir de dos investigaciones distintas: la primeira realizada con periodistas y la otra con jóvenes universitarios. La idea es problematizar las particularidades de la investigación antropológica y del método cualitativo, el cual incluye la observación participante, la realización de entrevistas abiertas en profundidad y la producción de un diario de campo. También se analizará la dificultad de trabajar de forma simultánea con los métodos cuantativos que aportan nuevas perspectivas y que muchas veces son vistos como herramientas menores. En cada uno de estos trabajos surgieron dificultades diferentes. Las dos experiencias de trabajo dentro del campo de la comunicación permiten ahondar en la discusión sobre la utilización de distintos métodos de investigación y evaluar las contribuciones de la metodología antropológica.
Informação pró-ativa na valorização dos direitos fundamentais garantidos pelo Estado de Direito
Authors: Haswani Mariângela Furlan 
Published: April 2024

A carta constitucional da maioria dos países latino americanos define o Estado como democrático de direito e, portanto, tutor dos direitos fundamentais (individuais, sociais e difusos) dos seus cidadãos. A informação pró ativa e amplamente disseminada do Estado se constitui em garantia desses direitos, especialmente aqueles de preservação da vida. A publicidade estatal, portanto, deveria ser positivada nas constituições como garantia dos direitos fundamentais, conforme se trata no artigo.
La salud en los medios de comunicación brasileños: en busa de la superación de las semejanzas entre el local y lo nacional
Authors: Bortoliero Simone Terezinha 
Published: April 2024

This article aims to address the "state of art" for research that focus on how health is linked in the Brazilian media produced in the last decade by the Federal University of Bahia. The results of three surveys addressed: 1) the knowledge of journalists on health and its representation in the newspaper "The Evening" (2008); coverage on the use of human embryos ins stem cell research which culminated in the in the judgment of the direct action of unconstitutionality (ADI 3150), the Supreme Court - STF (2010) in spreading the use of stem cells for the treatment of Chagas disease in Bahia, Bahia bound by the TV and in the newspaper "The Evening" (2006), which showed similiarities despite the use of different methodologies, with other surveys in this field undertaken in Brazil since the 80s. Researchers pioneers of this Bahia thematic point to the need to overcome the biomedical model that pays attention to disease, so that the science among the national media can effectively treat health.
Outcomes of Transcatheter Tricuspid Edge-to-Edge Repair in Patients With Right Ventricular Dysfunction
Authors: Vogelhuber Johanna , Tanaka Tetsu , Kavsur Refik , Goto Tadahiro , Öztürk Can , Silaschi Miriam , Nickenig Georg , Zimmer Sebastian , Weber Marcel , Sugiura Atsushi 
Published: April 2024

BACKGROUND:
We assessed the safety profile of tricuspid transcatheter edge-to-edge repair (TEER) in patients with right ventricular (RV) dysfunction.

METHODS:
We identified patients undergoing TEER to treat tricuspid regurgitation from June 2015 to October 2021 and assessed tricuspid annular plane systolic excursion (TAPSE) and RV fractional area change (RVFAC). RV dysfunction was defined as TAPSE <17 mm and RVFAC <35%. The primary end point was 30-day mortality after TEER. We also investigated the change in the RV function in the early phase and clinical outcomes at 2 years.

RESULTS:

The study participants (n=262) were at high surgical risk (EuroSCORE II, 6.2% [interquartile range, 4.0%–10.3%]). Among them, 44 patients met the criteria of RV dysfunction. Thirty-day mortality was 3.2% in patients with normal RV function and 2.3% in patients with RV dysfunction (
P
=0.99). Tricuspid regurgitation reduction to ≤2+ was consistently achieved irrespective of RV dysfunction (76.5% versus 70.5%;
P
=0.44). TAPSE and RVFAC declined after TEER in patients with normal RV function (TAPSE, 19.0±4.7 to 17.9±4.5 mm;
P
=0.001; RVFAC, 46.2%±8.1% to 40.3%±9.7%;
P
<0.001). In contrast, those parameters were unchanged or tended to increase in patients with RV dysfunction (TAPSE, 13.2±2.3 to 15.3±4.7 mm;
P
=0.011; RVFAC, 29.6%±4.1% to 31.6%±8.3%;
P
=0.14). Two years after TEER, compared with patients with normal RV function, patients with RV dysfunction had significantly higher mortality (27.0% versus 56.3%;
P
<0.001).

CONCLUSIONS:
TEER was safe and feasible to treat tricuspid regurgitation in patients with RV dysfunction. The decline in the RV function was observed in patients with normal RV function but not in patients with RV dysfunction.
Orphan Nuclear Receptor NR4A3 Promotes Vascular Calcification via Histone Lactylation
Authors: Ma Wenqi , Jia Kangni , Cheng Haomai , Xu Hong , Li Zhigang , Zhang Hang , Xie Hongyang , Sun Hang , Yi Lei , Chen Zhiyong , Duan Shengzhong , Sano Motoaki , Fukuda Keiichi , Lu Lin , Gao Fei , Zhang Ruiyan , Yan Xiaoxiang 
Published: April 2024

BACKGROUND:
Medial arterial calcification is a chronic systemic vascular disorder distinct from atherosclerosis and is commonly observed in patients with chronic kidney disease, diabetes, and aging individuals. We previously showed that NR4A3 (nuclear receptor subfamily 4 group A member 3), an orphan nuclear receptor, is a key regulator in apo (apolipoprotein) A-IV-induced atherosclerosis progression; however, its role in vascular calcification is poorly understood.

METHODS:

We generated NR4A3
−/−
mice and 2 different types of medial arterial calcification models to investigate the biological roles of NR4A3 in vascular calcification. RNA-seq was performed to determine the transcriptional profile of NR4A3
−/−
vascular smooth muscle cells under β-glycerophosphate treatment. We integrated Cleavage Under Targets and Tagmentation analysis and RNA-seq data to further investigate the gene regulatory mechanisms of NR4A3 in arterial calcification and target genes regulated by histone lactylation.

RESULTS:

NR4A3 expression was upregulated in calcified aortic tissues from chronic kidney disease mice, 1,25(OH)
2
VitD
3
overload–induced mice, and human calcified aorta. NR4A3 deficiency preserved the vascular smooth muscle cell contractile phenotype, inhibited osteoblast differentiation-related gene expression, and reduced calcium deposition in the vasculature. Further, NR4A3 deficiency lowered the glycolytic rate and lactate production during the calcification process and decreased histone lactylation. Mechanistic studies further showed that NR4A3 enhanced glycolysis activity by directly binding to the promoter regions of the 2 glycolysis genes
ALDOA
and
PFKL
and driving their transcriptional initiation. Furthermore, histone lactylation promoted medial calcification both in vivo and in vitro. NR4A3 deficiency inhibited the transcription activation and expression of Phospho1 (phosphatase orphan 1). Consistently, pharmacological inhibition of Phospho1 attenuated calcium deposition in NR4A3-overexpressed vascular smooth muscle cells, whereas overexpression of Phospho1 reversed the anticalcific effect of NR4A3 deficiency in vascular smooth muscle cells.

CONCLUSIONS:
Taken together, our findings reveal that NR4A3-mediated histone lactylation is a novel metabolome-epigenome signaling cascade mechanism that participates in the pathogenesis of medial arterial calcification.
Geographic Adaptation of Pretrained Language Models
Authors: Hofmann Valentin , Glavaš Goran , Ljubešić Nikola , Pierrehumbert Janet B. , Schütze Hinrich 
Published: April 2024

AbstractWhile pretrained language models (PLMs) have been shown to possess a plethora of linguistic knowledge, the existing body of research has largely neglected extralinguistic knowledge, which is generally difficult to obtain by pretraining on text alone. Here, we contribute to closing this gap by examining geolinguistic knowledge, i.e., knowledge about geographic variation in language. We introduce geoadaptation, an intermediate training step that couples language modeling with geolocation prediction in a multi-task learning setup. We geoadapt four PLMs, covering language groups from three geographic areas, and evaluate them on five different tasks: fine-tuned (i.e., supervised) geolocation prediction, zero-shot (i.e., unsupervised) geolocation prediction, fine-tuned language identification, zero-shot language identification, and zero-shot prediction of dialect features. Geoadaptation is very successful at injecting geolinguistic knowledge into the PLMs: The geoadapted PLMs consistently outperform PLMs adapted using only language modeling (by especially wide margins on zero-shot prediction tasks), and we obtain new state-of-the-art results on two benchmarks for geolocation prediction and language identification. Furthermore, we show that the effectiveness of geoadaptation stems from its ability to geographically retrofit the representation space of the PLMs.
Black soldier fly larvae meal in an extruded food: effects on nutritional quality and health parameters in healthy adult cats
Authors: Bosch G. , Loureiro B.A. , Schokker D. , Kar S.K. , Paul A. , Sluczanowski N. 
Published: April 2024

Abstract
We aimed to evaluate the effects of including black soldier fly larvae meal (BSFL) meal in a dry extruded food on nutritional quality and some health aspects in healthy adult cats. Two dry extruded foods with either poultry meal (control) or 37.5% BSFL meal were fed to eight (3.8-5.2 kg BW; 2.3-y.o.) cats in a cross-over design with two 28-day periods. Food acceptance was recorded throughout the study and samples were collected during the last 7 days of each period for assessment of apparent total tract nutrient digestibility, faecal consistency, fermentation products and microbiota, and blood biochemistry and haematology. Foods were well-accepted and faeces were well-formed with optimal consistency scores. Digestibility values for dry matter, organic matter, nitrogen and gross energy were considered high for the BSFL meal-based food but lower than for the control food (). Unexpectedly, inclusion of BSFL meal had a profound impact on the intestinal microbial activity and composition as illustrated by increased faecal short-chain fatty acids () and biogenic amines concentrations () and reduced bacterial diversity () and shifts in multiple genera (e.g. more Bifidobacterium) in the faeces (). Minor changes in haematology and serum biochemistry parameters were found and deemed not clinically relevant. Overall, this study showed that a BSFL meal-based extruded dry food is readily accepted by healthy adult cats, yields optimal faecal consistency, had suitable nutrient digestibilities and can support their health when fed for 28 days with new leads for impact on feline gut health.
A taxonomy of regulatory and policy matters relevant to psychedelic-assisted therapy in Australia
Authors: Hatfield Samuel P , Thornton Nicollette LR , Greenstien Kayla , Glozier Nick 
Published: April 2024

Objectives: The Australian government recently rescheduled psilocybin and 3,4-methylenedioxymethamphetamine for limited clinical uses. This change has raised various regulatory concerns and challenges for the field of psychedelic-assisted therapy. To provide clarity, we aimed to comprehensively catalogue the matters relating to psychedelic-assisted therapy that are or could be regulated. Methods: We conducted a desktop review of the literature and current regulatory sources, semi-structured interviews with professionals who had expertise in fields relating to psychedelic-assisted therapy and a framework analysis to generate a taxonomy of relevant regulatory matters. In relation to each matter, we further identified what type of regulation (if any) currently applies to that matter, any uncertainty as to how the matter should be addressed in clinical practice in the context of current regulation and whether there are conflicting views as to how the matter could or should be further regulated. Results: The taxonomy is structured into six main regulatory domains, three of which have a substantial proportion of matters with uncertainty or conflicting views: Service Establishment, Practitioner, and Treatment Delivery. Key examples of such matters include the location of services and facilities required, which professionals are eligible to become psychedelic therapists, and with what qualifications and experience. Matters in the remaining three domains, Patient Evaluation, Drug Supply and Service Oversight, appear by comparison relatively settled, with regulation either well-established or thought unnecessary. Conclusions: The taxonomy provides a roadmap for health services establishing and implementing a psychedelic-assisted therapy program, or for government and other policymakers when determining areas that may require further regulation.
People’s Participation and Impact  of Micro Watershed Project: An Analysis of the Beneficiary Farmer’s Perceived Impact of Jalyukt Shivar  of Maharashtra, India
Authors: Chavan Pravin 
Published: April 2024

Despite being one of India’s wealthiest states, Maharashtra has the highest number of farmer suicides. Research links farmer suicides to monsoon failure, drought and a lack of social security. To make the state drought-free by 2019, the state government launched the ‘Jalyukt Shivar Scheme’ on 26 January 2015. According to the State Economic Survey 2019–20, the programme has spent ₹9,488 crore on 6.28 lakh works in the 5 years since its inception, has eliminated drought in 19,655 villages, and has stored 26.52 TMC of water. However, regardless of the government’s assertions, experts and non-government organisations question the scheme’s efficacy and scientific validity. After the 2019 state assembly elections, the new Maharashtra Vikas Aghadi Government discontinued the scheme. Nevertheless, examining the scheme’s implementation and effectiveness would shape future policy and watershed project execution. The study has assessed the farmer’s perceived effectiveness of the scheme. To assess the beneficiary farmer’s perceived impact of the scheme, the Jalyukt Shivar impact assessment scale was developed. Confirmatory factor analysis and Cronbach’s alpha ensured the validity and reliability of the scale. Structural equation modelling shows that public participation is a significant predictor of the irrigation impact of the scheme, and irrigation impact mediates the outcome of agriculture and environmental impact, socio-economic impact and impact on women. The findings reveal that the programme remained a supply-side initiative in the absence of people’s participation. For the watershed project to achieve its goals, the study advocated active public participation at all stages of its implementation. JEL Codes: Q15, Q18, Q25, Q28, R58
Psychometric Support and Measurement Invariance of a Turkish Version of the Transformational Parenting Questionnaire
Authors: Yıldırım Sinan , Sarıkaya Serap 
Published: April 2024

Our primary objective in this study was to psychometrically evaluate the Transformational Parenting Questionnaire (TPQ) within the Turkish context. Secondarily, we aimed to determine whether the questionnaire demonstrated measurement invariance across children’s genders and grade levels. We included 950 participants, aged 11–18 years (446 girls, 498 boys, 6 unspecified gender identity; Mage = 14.73, SD = 1.85 years). Confirmatory factor analysis provided support for the original 4-factor structure of the TPQ, and there was satisfactory criterion-related correlational validity between this instrument and the Satisfaction with Life Scale. The TPQ exhibited robust internal item reliability coefficients, and respondent’s test-retest correlations over a 15-day interval suggested adequate item response consistency. Importantly, we confirmed measurement invariance of the scale across participants gender and educational grade levels. In summary, we found that the TPQ was a valid and reliable tool for assessing Turkish children’s perceptions of transformative parenting behaviors.