bluuebunny/crossref_metadata_2025_split huggingface dataset:
Learning from alcohol (policy) reforms in the Northern Territory (LEARNT): protocol for a mixed-methods study examining the impacts of the banned drinker register
Authors: Miller Peter , Coomber Kerri , Smith James , Livingston Michael , Stevens Matthew , Guthridge Steven , Room Robin , Wright Cassandra J C , Rung Daile , Clifford Sarah , Baldwin Ryan , Das Sumon , Paradies Yin , Scott Debbie , Griffiths Kalinda E , Farmer Clare , Mayshak Richelle , Silver Bronwyn , Moore Sam , Mack Jordan , Mithen Vincent , Dyall Danielle , Ward J , Boffa John , Chikritzhs Tanya 
Published: April 2022

IntroductionThe Banned Drinker Register (BDR) was reintroduced in the Northern Territory (NT) in September 2017. The BDR is a supply reduction measure and involves placing people who consume alcohol at harmful levels on a register prohibiting the purchase, possession and consumption of alcohol. The current study aims to evaluate the impacts of the reintroduction of the BDR, in the context of other major alcohol policy initiatives introduced across the NT such as Police Auxiliary Liquor Inspectors and a minimum unit price for alcohol of US$1.30 per standard drink.Methods and analysesThe Learning from Alcohol (policy) Reforms in the Northern Territory project will use a mixed-methods approach and contain four major components: epidemiological analysis of trends over time (outcomes include health, justice and social welfare data); individual-level data linkage including those on the BDR (outcomes include health and justice data); qualitative interviews with key stakeholders in the NT (n≥50); and qualitative interviews among people who are, or were previously, on the BDR, as well as the families and communities connected to those on the BDR (n=150). The impacts of the BDR on epidemiological data will be examined using time series analysis. Linked data will use generalised mixed models to analyse the relationship between outcomes and exposures, utilising appropriate distributions. Qualitative data will be analysed using thematic analysis.Ethics and disseminationEthics approvals have been obtained from NT Department of Health and Menzies School of Health Research Human Research Ethics Committee (HREC), Central Australia HREC and Deakin University HREC. In addition to peer-reviewed publications, we will report our findings to key organisational, policy, government and community stakeholders via conferences, briefings and lay summaries.
NFATc1 signaling drives chronic ER stress responses to promote NAFLD progression
Authors: Latif Muhammad Umair , Schmidt Geske Elisabeth , Mercan Sercan , Rahman Raza , Gibhardt Christine Silvia , Stejerean-Todoran Ioana , Reutlinger Kristina , Hessmann Elisabeth , Singh Shiv K , Moeed Abdul , Rehman Abdul , Butt Umer Javed , Bohnenberger Hanibal , Stroebel Philipp , Bremer Sebastian Christopher , Neesse Albrecht , Bogeski Ivan , Ellenrieder Volker 
Published: April 2022

ObjectivesNon-alcoholic fatty liver disease (NAFLD) can persist in the stage of simple hepatic steatosis or progress to steatohepatitis (NASH) with an increased risk for cirrhosis and cancer. We examined the mechanisms controlling the progression to severe NASH in order to develop future treatment strategies for this disease.DesignNFATc1 activation and regulation was examined in livers from patients with NAFLD, cultured and primary hepatocytes and in transgenic mice with differential hepatocyte-specific expression of the transcription factor (Alb-cre, NFATc1c.a. andNFATc1Δ/Δ). Animals were fed with high-fat western diet (WD) alone or in combination with tauroursodeoxycholic acid (TUDCA), a candidate drug for NAFLD treatment. NFATc1-dependent ER stress-responses, NLRP3 inflammasome activation and disease progression were assessed both in vitro and in vivo.ResultsNFATc1 expression was weak in healthy livers but strongly induced in advanced NAFLD stages, where it correlates with liver enzyme values as well as hepatic inflammation and fibrosis. Moreover, high-fat WD increased NFATc1 expression, nuclear localisation and activation to promote NAFLD progression, whereas hepatocyte-specific depletion of the transcription factor can prevent mice from disease acceleration. Mechanistically, NFATc1 drives liver cell damage and inflammation through ER stress sensing and activation of the PERK-CHOP unfolded protein response (UPR). Finally, NFATc1-induced disease progression towards NASH can be blocked by TUDCA administration.ConclusionNFATc1 stimulates NAFLD progression through chronic ER stress sensing and subsequent activation of terminal UPR signalling in hepatocytes. Interfering with ER stress-responses, for example, by TUDCA, protects fatty livers from progression towards manifest NASH.
Design and implementation of information extraction system for scientific literature using fine-tuned deep learning models
Authors: Won Kwanghee , Jang Youngsun , Choi Hyung-do , Shin Sung 
Published: April 2022

This paper presents an overview of a quality scoring system that utilizes pre-trained deep neural network models. Two types of DL models, a classification and extractive question answering (EQA) models are used to implement components of the system. The abstracts of the scientific literature are classified into two groups, in-vivo and in-vitro, and a question and answering model architecture is constructed for extracting the following types of information (animal type, the number of animals, exposure dose, and signal frequency). The Bidirectional Encoder Representations of Transformers (BERT) model pre-trained with a large text corpus is used as our baseline model for classification and EQA tasks. The models are fine-tuned with 455 EMF-related research papers.
In our experiments, the fine-tuned model showed improved performance on EQA tasks for the four-categories of questions compared to the baseline, and it also showed improvements on similar questions that were not used in training. This suggests the importance of retraining of deep learning model specifically in some areas requiring domain expertise such as scientific papers. However, additional research is needed on some implementation issues, in such cases where there are still multiple answers, or where there is no answer given in a context.
Substance Misuse Decreases Heart Rate Variability
Authors: Lu Ming-Kuei , Chou Li-Wei , Chang Kang-Ming , Lee Hsin-Yi , Kang Hui-Jen 
Published: April 2022

There are few biomarkers to reflect the physiological conditions for substance misuse. In this study, autonomic nervous and cardiovascular parameters were measured for participants in deferred prosecution programs. The goal of this study is to develop significant biomarkers of the above subjects and enhance their motivation to join further substance misuse disorder treatment program. This study recruited 34 participants with a mean age of 35.1 years. The participants spent approximately five minutes filling in the basic information form and another five minutes filling in the Pittsburgh Sleep Quality Index (PSQI). Blood pressure, heart rate, and heart rate variability data were also measured. Their sleep quality was measured by the Pittsburgh Sleep Quality Inventory (PSQI) with an average score of 8.6 and average systolic and diastolic pressure measured of 116.1 (

standard

deviation

SD

=
13.7

) and 77.9 mmHg (

SD
=
8.1

) during resting, respectively. Average heartbeat rates are 90.4 beats per minute (

SD
=
17.0

); and average low-frequency power ratio is 56.4% (

SD
=
19.8

%). Of the participants, 35% exhibited a low-frequency power rate below 30% and above 70%. The average biological HRV age of the participants was 46.0 years (

SD
=
22.9

), which was significantly older than their average actual age (

p
=

0.002

∗

∗

). The biological HRV age of the participants is 10 years older than their own actual age, and it effectively reflects the physiological conditions of participants in deferred prosecution programs. These physiological parameters, especially the biological HRV age, can be used in future treatment for substance use disorder counseling programs to increase the illness insight of program participants and increase their motivation to join further substance misuse disorder treatment program.
Simulación remota con feedback asincrónico como estrategia de enseñanza para entrenar habilidades prácticas en kinesiología
Authors: Villagrán -Gutierrez Ignacio , Antúnez Marcela , Fuentes-Cimma Javiera , Del Valle Javiera , Gregorio de las Heras Sofía , Pozo Liliana , Rammsy Francisca , Torres Gustavo , Escalona Gabriel , Varas Julián 
Published: April 2022

Introducción: en los escenarios de reducción de la presencialidad como los provocados por la pandemia de COVID-19, la carrera de kinesiología incorporó la metodología de simulación remota con feedback asincrónico con una plataforma que considera la práctica remota de habilidades prácticas, y un proceso de retroalimentación con el propósito de mejorar el desempeño y aprendizaje de los estudiantes. El objetivo del estudio es describir la implementación y resultados de esta metodología. Métodos: se realizó un entrenamiento remoto piloto con estudiantes de kinesiología de la Pontificia Universidad Católica de Chile, el cuál consistió en 7 etapas de diferentes técnicas manuales musculoesqueléticas. Se aplicó una encuesta final para conocer la percepción de los estudiantes y se realizó un análisis descriptivo de los resultados. Resultados: se evaluaron 468 videos de 78 estudiantes a través de 4040 inputs de retroalimentación. La mayoría de los estudiantes reportó una percepción positiva respecto a la metodología (92,7%) y feedback recibido (71,4%). Un 60% de los estudiantes reportó sentir seguridad al realizar las técnicas por última vez. Un porcentaje (%) bajo de estudiantes reportó haber tenido dificultades con el entrenamiento. Conclusión: la implementación de la metodología propuesta permitió que los estudiantes siguieran adquiriendo habilidades prácticas en técnicas manuales musculoesqueléticas en un contexto donde el aprendizaje presencial no era posible, con una alta valoración. Esta metodología, relevó la existencia de un entrenamiento oculto previo a la evaluación del instructor, lo que permitiría que los estudiantes transiten hacia una curva de aprendizaje autónoma para una posterior transferencia en contexto real.
Ovarian Cancers with Low CIP2A Tumor Expression Constitute an APR-246–Sensitive Disease Subtype
Authors: Cvrljevic Anna N. , Butt Umar , Huhtinen Kaisa , Grönroos Tove J. , Böckelman Camilla , Lassus Heini , Butzow Ralf , Haglund Caj , Kaipio Katja , Arsiola Tiina , Laajala Teemu D. , Connolly Denise C. , Ristimäki Ari , Carpen Olli , Pouwels Jeroen , Westermarck Jukka 
Published: April 2022

Abstract
Identification of ovarian cancer patient subpopulations with increased sensitivity to targeted therapies could offer significant clinical benefit. We report that 22% of the high-grade ovarian cancer tumors at diagnosis express CIP2A oncoprotein at low levels. Furthermore, regardless of their significantly lower likelihood of disease relapse after standard chemotherapy, a portion of relapsed tumors retain their CIP2A-deficient phenotype. Through a screen for therapeutics that would preferentially kill CIP2A-deficient ovarian cancer cells, we identified reactive oxygen species inducer APR-246, tested previously in ovarian cancer clinical trials. Consistent with CIP2A-deficient ovarian cancer subtype in humans, CIP2A is dispensable for development of MISIIR-Tag–driven mouse ovarian cancer tumors. Nevertheless, CIP2A-null ovarian cancer tumor cells from MISIIR-Tag mice displayed APR-246 hypersensitivity both in vitro and in vivo. Mechanistically, the lack of CIP2A expression hypersensitizes the ovarian cancer cells to APR-246 by inhibition of NF-κB activity. Accordingly, combination of APR-246 and NF-κB inhibitor compounds strongly synergized in killing of CIP2A-positive ovarian cancer cells. Collectively, the results warrant consideration of clinical testing of APR-246 for CIP2A-deficient ovarian cancer tumor subtype patients. Results also reveal CIP2A as a candidate APR-246 combination therapy target for ovarian cancer.
Maximal Activation of Apoptosis Signaling by Cotargeting Antiapoptotic Proteins in BH3 Mimetic–Resistant AML and AML Stem Cells
Authors: Carter Bing Z. , Mak Po Yee , Tao Wenjing , Zhang Qi , Ruvolo Vivian , Kuruvilla Vinitha M. , Wang Xiangmeng , Mak Duncan H. , Battula Venkata L. , Konopleva Marina , Jabbour Elias J. , Hughes Paul E. , Chen Xiaoyue , Morrow Phuong K. , Andreeff Michael 
Published: April 2022

Abstract
MCL-1 is known to play a major role in resistance to BCL-2 inhibition, but the contribution of other BCL-2 family proteins has not been fully explored. We, here, demonstrate the ineffectiveness of MCL-1 inhibitor AMG176 in venetoclax-resistant, and conversely, of venetoclax in AMG176-resistant acute myelogenous leukemia (AML). Like cells with acquired resistance to venetoclax, cells with acquired resistance to AMG176 express increased MCL-1. Both cells with acquired resistance to venetoclax and to AMG176 express increased levels of BCL-2 and BCL-2A1, decreased BAX, and/or altered levels of other BCL-2 proteins. Cotargeting BCL-2 and MCL-1 was highly synergistic in AML cell lines with intrinsic or acquired resistance to BH3 mimetics or engineered to genetically overexpress BCL-2 or BCL-2A1 or downregulate BAX. The combination effectively eliminated primary AML blasts and stem/progenitor cells resistant to or relapsed after venetoclax-based therapy irrespective of mutations and cytogenetic abnormalities. Venetoclax and AMG176 combination markedly suppressed antiapoptotic BCL-2 proteins and AML stem/progenitor cells and dramatically extended mouse survival (median 336 vs. control 126 days; P &lt; 0.0001) in a patient-derived xenograft (PDX) model developed from a venetoclax/hypomethylating agent therapy-resistant patient with AML. However, decreased BAX levels in the bone marrow residual leukemia cells after 4-week combination treatment may represent a resistance mechanism that contributed to their survival. Enhanced antileukemia activity was also observed in a PDX model of monocytic AML, known to be resistant to venetoclax therapy. Our results support codependence on multiple antiapoptotic BCL-2 proteins and suppression of BAX as mechanisms of AML resistance to individual BH3 mimetics. Cotargeting of MCL-1 and BCL-2 eliminates otherwise apoptosis-resistant cells.
Noxious Combination of Tobacco Smoke Nitrosamines with Bile, Deoxycholic Acid, Promotes Hypopharyngeal Squamous Cell Carcinoma, via NFκB, In Vivo
Authors: Vageli Dimitra P. , Doukas Panagiotis G. , Doukas Sotirios G. , Tsatsakis Aristidis , Judson Benjamin L. 
Published: April 2022

Abstract

Tobacco smoking is the most known risk factor for hypopharyngeal cancer. Bile reflux has recently been documented as an independent risk factor for NFκB-mediated hypopharyngeal squamous cell carcinoma. However, the carcinogenic effect of tobacco smoke on the hypopharynx and its combination with bile has not yet been proven by direct evidence. We investigated whether in vivo chronic exposure (12–14 weeks) of murine (C57Bl/6J) hypopharyngeal epithelium to tobacco smoke components (TSC) [N-nitrosamines; 4-(N-Methyl-N-Nitrosamino)-1-(3-pyridyl)-1-butanone (0.2 mmol/L), N-nitrosodiethylamine (0.004 mmol/L)], as the sole drinking fluid 5 days per week, along with topically applied (two times/day) bile [deoxycholic acid (0.28 mmol/L)], can accelerate a possible TSC-induced neoplastic process, by enhancing NFκB activation and the associated oncogenic profile, using histologic, IHC, and qPCR analyses. We provide direct evidence of TSC-induced premalignant lesions, which can be exacerbated by the presence of bile, causing invasive carcinoma. The combined chronic exposure of the hypopharynx to TSC with bile causes advanced NFκB activation and profound overexpression of Il6, Tnf, Stat3, Egfr, Wnt5a, composing an aggressive phenotype. We document for the first time the noxious combination of bile with a known risk factor, such as tobacco smoke nitrosamines, in the development and progression of hypopharyngeal cancer, via NFκB, in vivo. The data presented here encourage further investigation into the incidence of upper aerodigestive tract cancers in smokers with bile reflux and the early identification of high-risk individuals in clinical practice. This in vivo model is also suitable for large-scale studies to reveal the nature of inflammatory-associated aerodigestive tract carcinogenesis and its targeted therapy.

Prevention Relevance:
Early assessment of bile components in refluxate of tobacco users can prevent the chronic silent progression of upper aerodigestive tract carcinogenesis. This in vivo model indicates that bile reflux might have an additive effect on the tobacco-smoke N-nitrosamines effect and could be suitable for large-scale studies of diagnostic and therapeutic interventions.
IFNγ Helps CBLB-Deficient CD8+ T Cells to Put Up Resistance to Tregs
Authors: Wolf Dominik , Baier Gottfried 
Published: April 2022

Abstract
In this issue, Han and colleagues demonstrate in preclinical cancer models that genetic deletion of the E3 ubiquitin ligase Cbl proto-oncogene B (CBLB) in adoptively transferred CD8+ T cells induces resistance to regulatory T cells. CBLB deletion induces IFNγ and downmodulates TGFβ/SMAD signaling. This ultimately enforces these cells to be way more effective against various cancers.
See related article by Han et al., p. 437 (4).
Associations of Dietary Cholesterol, Serum Cholesterol, and Egg Consumption With Overall and Cause-Specific Mortality: Systematic Review and Updated Meta-Analysis
Authors: Zhao Bin , Gan Lu , Graubard Barry I. , Männistö Satu , Albanes Demetrius , Huang Jiaqi 
Published: April 2022

Background:
Despite substantial research highlighting the importance of exogenous dietary cholesterol intake and endogenous serum cholesterol level in human health, a thorough evaluation of the associations is lacking. Our study objective was to examine overall and cause-specific mortality in relation to dietary and serum cholesterol, as well as egg consumption, and conduct an updated meta-regression analysis of cohort studies.

Methods:

We conducted a prospective analysis of 27 078 men in the ATBC Study (Alpha-Tocopherol, Beta-Carotene Cancer Prevention). Multivariable-controlled cause-specific Cox proportional hazards regression models were used to calculate hazard ratios and 31-year absolute mortality risk differences. A systematic review and meta-analysis of cohort studies was also performed (PROSPERO [URL:
https://www.crd.york.ac.uk/prospero/
; Unique identifier: CRD42021272756]).

Results:

Based on 482 316 person-years of follow-up, we identified 22 035 deaths, including 9110 deaths from cardiovascular disease (CVD). Greater dietary cholesterol and egg consumption were associated with increased risk of overall and CVD-related mortality. Hazard ratios for each additional 300 mg cholesterol intake per day were 1.10 and 1.13 for overall and CVD-related mortality, respectively; for each additional 50-g egg consumed daily, hazard ratios were 1.06 and 1.09, respectively, for overall and CVD-related mortality (all
P
values<0.0001). After multivariable adjustment, higher serum total cholesterol concentrations were associated with increased risk of CVD-related mortality (hazard ratios per 1 SD increment, 1.14;
P
<0.0001). The observed associations were generally similar across cohort subgroups. The updated meta-analysis of cohort studies on the basis of 49 risk estimates, 3 601 401 participants, and 255 479 events showed consumption of 1 additional 50-g egg daily was associated with significantly increased CVD risk (pooled relative risk, 1.04 [95% CI, 1.00–1.08]; I
2
=80.1%). In the subgroup analysis of geographic regions (
P
interaction
=0.02), an increase of 50-g egg consumed daily was associated with a higher risk of CVD in US cohorts (pooled relative risk, 1.08 [95% CI, 1.02–1.14]) and appeared related to a higher CVD risk in European cohorts with borderline significance (pooled relative risk, 1.05), but was not associated with CVD risk in Asian cohorts.

Conclusions:
In this prospective cohort study and updated meta-analysis, greater dietary cholesterol and egg consumption were associated with increased risk of overall and CVD-related mortality. Our findings support restricted consumption of dietary cholesterol as a means to improve long-term health and longevity.
Longitudinal Progression of Magnetic Resonance Imaging Markers and Cognition in Dutch-Type Hereditary Cerebral Amyloid Angiopathy
Authors: van Dijk Suzanne E. , van der Grond Jeroen , Lak Jessie , van den Berg-Huysmans Annette , Labadie Gerda , Terwindt Gisela M. , Wermer Marieke J.H. , Gurol M. Edip , van Buchem Mark A. , Greenberg Steven M. , van Rooden Sanneke 
Published: April 2022

Background:
Hemorrhagic and ischemic magnetic resonance imaging lesions as well as the more recently described decrease in vasomotor reactivity have been suggested as possible biomarkers for cerebral amyloid angiopathy (CAA). Analyses of these markers have been primarily cross-sectional during the symptomatic phase of the disease, with little data on their longitudinal progression, particularly in the presymptomatic phase of the disease when it may be most responsive to treatment. We used the unique opportunity provided by studying Dutch-type hereditary cerebral amyloid angiopathy (D-CAA) to determine longitudinal progression of CAA biomarkers during the presymptomatic as well as the symptomatic phase of the disease.

Methods:
In this longitudinal case-control study, magnetic resonance imaging markers and cognitive performance were assessed at baseline and after ≈4 years in 10 presymptomatic and 6 symptomatic D-CAA mutation carriers and 20 control subjects. These magnetic resonance imaging markers included hemorrhagic and ischemic manifestations, measurements of cerebral blood flow, and vasomotor reactivity to visual stimulation.

Results:

In presymptomatic D-CAA mutations carriers, vasomotor reactivity showed a decline over time for blood-oxygen-level–dependent amplitude (
P
=0.011) and prolongation of time to peak (
P
<0.001). In contrast, no significant changes in hemorrhagic markers, ischemic markers, cerebral blood flow, and cognition were found. In symptomatic D-CAA mutation carriers, the number of intracerebral hemorrhages increased over the 4-year period (
P
=0.007).

Conclusions:
Our findings indicate that in the presymptomatic phase of D-CAA, cerebrovascular reactivity measured by the blood-oxygen-level–dependent amplitude and time to peak to visual stimulation progressively worsens and can thus be regarded as a disease progression marker. In the symptomatic phase, the most salient marker of progression appears to be recurrent intracerebral hemorrhage.