bluuebunny/crossref_metadata_2025_split huggingface dataset:
NOTCH1 signaling during CD4+ T-cell activation alters transcription factor networks and enhances antigen responsiveness
Authors: Wilkens Alec B. , Fulton Elena C. , Pont Margot J. , Cole Gabriel O. , Leung Isabel , Stull Sylvia M. , Hart Matthew R. , Bernstein Irwin D. , Furlan Scott N. , Riddell Stanley R. 
Published: May 2022

Abstract
Adoptive transfer of T cells expressing chimeric antigen receptors (CAR-T) effectively treats refractory hematologic malignancies in a subset of patients but can be limited by poor T-cell expansion and persistence in vivo. Less differentiated T-cell states correlate with the capacity of CAR-T to proliferate and mediate antitumor responses, and interventions that limit tumor-specific T-cell differentiation during ex vivo manufacturing enhance efficacy. NOTCH signaling is involved in fate decisions across diverse cell lineages and in memory CD8+ T cells was reported to upregulate the transcription factor FOXM1, attenuate differentiation, and enhance proliferation and antitumor efficacy in vivo. Here, we used a cell-free culture system to provide an agonistic NOTCH1 signal during naïve CD4+ T-cell activation and CAR-T production and studied the effects on differentiation, transcription factor expression, cytokine production, and responses to tumor. NOTCH1 agonism efficiently induced a stem cell memory phenotype in CAR-T derived from naïve but not memory CD4+ T cells and upregulated expression of AhR and c-MAF, driving heightened production of interleukin-22, interleukin-10, and granzyme B. NOTCH1-agonized CD4+ CAR-T demonstrated enhanced antigen responsiveness and proliferated to strikingly higher frequencies in mice bearing human lymphoma xenografts. NOTCH1-agonized CD4+ CAR-T also provided superior help to cotransferred CD8+ CAR-T, driving improved expansion and curative antitumor responses in vivo at low CAR-T doses. Our data expand the mechanisms by which NOTCH can shape CD4+ T-cell behavior and demonstrate that activating NOTCH1 signaling during genetic modification ex vivo is a potential strategy for enhancing the function of T cells engineered with tumor-targeting receptors.
CD19/22 CAR T cells in children and young adults with B-ALL: phase 1 results and development of a novel bicistronic CAR
Authors: Shalabi Haneen , Qin Haiying , Su Angela , Yates Bonnie , Wolters Pamela L. , Steinberg Seth M. , Ligon John A. , Silbert Sara , DéDé Kniya , Benzaoui Mehdi , Goldberg Sophia , Achar Sooraj , Schneider Dina , Shahani Shilpa A. , Little Lauren , Foley Toni , Molina John C. , Panch Sandhya , Mackall Crystal L. , Lee Daniel W. , Chien Christopher D. , Pouzolles Marie , Ahlman Mark , Yuan Constance M. , Wang Hao-Wei , Wang Yanyu , Inglefield Jon , Toledo-Tamula Mary Anne , Martin Staci , Highfill Steven L. , Altan-Bonnet Gregoire , Stroncek David , Fry Terry J. , Taylor Naomi , Shah Nirali N. 
Published: May 2022

Abstract
Remission durability following single-antigen targeted chimeric antigen receptor (CAR) T-cells is limited by antigen modulation, which may be overcome with combinatorial targeting. Building upon our experiences targeting CD19 and CD22 in B-cell acute lymphoblastic leukemia (B-ALL), we report on our phase 1 dose-escalation study of a novel murine stem cell virus (MSCV)-CD19/CD22-4-1BB bivalent CAR T-cell (CD19.22.BBζ) for children and young adults (CAYA) with B-cell malignancies. Primary objectives included toxicity and dose finding. Secondary objectives included response rates and relapse-free survival (RFS). Biologic correlatives included laboratory investigations, CAR T-cell expansion and cytokine profiling. Twenty patients, ages 5.4 to 34.6 years, with B-ALL received CD19.22.BBζ. The complete response (CR) rate was 60% (12 of 20) in the full cohort and 71.4% (10 of 14) in CAR-naïve patients. Ten (50%) developed cytokine release syndrome (CRS), with 3 (15%) having ≥ grade 3 CRS and only 1 experiencing neurotoxicity (grade 3). The 6- and 12-month RFS in those achieving CR was 80.8% (95% confidence interval [CI]: 42.4%-94.9%) and 57.7% (95% CI: 22.1%-81.9%), respectively. Limited CAR T-cell expansion and persistence of MSCV-CD19.22.BBζ compared with EF1α-CD22.BBζ prompted laboratory investigations comparing EF1α vs MSCV promoters, which did not reveal major differences. Limited CD22 targeting with CD19.22.BBζ, as evaluated by ex vivo cytokine secretion and leukemia eradication in humanized mice, led to development of a novel bicistronic CD19.28ζ/CD22.BBζ construct with enhanced cytokine production against CD22. With demonstrated safety and efficacy of CD19.22.BBζ in a heavily pretreated CAYA B-ALL cohort, further optimization of combinatorial antigen targeting serves to overcome identified limitations (www.clinicaltrials.gov #NCT03448393).
Impact of MRD status in patients with AML undergoing allogeneic stem cell transplantation in the first vs the second remission
Authors: Jentzsch Madlen , Bischof Lara , Backhaus Donata , Brauer Dominic , Schulz Julia , Franke Georg-Nikolaus , Vucinic Vladan , Niederwieser Dietger , Platzbecker Uwe , Schwind Sebastian 
Published: May 2022

Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) offers the best chance for relapse-free survival to most patients with acute myeloid leukemia (AML). It may be performed during complete remission or delayed until after the first relapse because of relevant treatment-related morbidity and mortality. The measurable residual disease (MRD) status at HSCT adds refined prognostic information to the assigned European LeukemiaNet (ELN) 2017 genetic risk at diagnosis. We analyzed 580 patients with AML who underwent allogeneic HSCT during either the first (79%) or second (21%) remission. Although, because of common treatment strategies, some adverse risk characteristics, such as monosomal or complex karyotypes, were less frequent in patients who underwent transplant in the second remission, those patients had worse outcomes compared with patients who had transplant in the first remission. The MRD status at HSCT was an independent prognostic factor, irrespective of the number of remissions at HSCT. Notably, patients who were MRD+ who underwent HSCT in the first remission and those who were MRD− and underwent transplant in the second remission had similar outcomes. In the clinically highly relevant group of individuals who had ELN2017 intermediate risk, the MRD status provided the highest prognostic value with very dismal outcomes for patients who were MRD+ and underwent second-remission transplants. The adverse outcomes of patients who are MRD+ and of those who undergo transplant in the second remission should be considered when planning consolidation treatment, to avert an allogeneic HSCT in MRD+ second remission when possible.
The miR528-D3 Module Regulates Plant Height in Rice by Modulating the Gibberellin and Abscisic Acid Metabolisms
Authors: Zhao Juan , Liu Xing , Wang Mei , Xie Lingjuan , Wu Zhengxin , Yu Jiuming , Wang Yuchen , Zhang Zhiqiao , Jia Yufang , Liu Qingpo 
Published: May 2022

AbstractPlant height, as one of the important agronomic traits of rice, is closely related to yield. In recent years, plant height-related genes have been characterized and identified, among which the DWARF3 (D3) gene is one of the target genes of miR528, and regulates rice plant height and tillering mainly by affecting strigolactone (SL) signal transduction. However, it remains unknown whether the miR528 and D3 interaction functions in controlling plant height, and the underlying regulatory mechanism in rice. In this study, we found that the plant height, internode length, and cell length of internodes of d3 mutants and miR528-overexpressing (OE-miR528) lines were greatly shorter than WT, D3-overexpressing (OE-D3), and miR528 target mimicry (OE-MIM528) transgenic plants. Knockout of D3 gene (d3 mutants) or miR528-overexpressing (OE-miR528) triggers a substantial reduction of gibberellin (GA) content, but a significant increase of abscisic acid (ABA) accumulation than in WT. The d3 and OE-miR528 transgenic plants were much more sensitive to GA, but less sensitive to ABA than WT. Moreover, the expression level of GA biosynthesis-related key genes, including OsCPS1, OsCPS2, OsKO2 and OsKAO was remarkably higher in OE-D3 plants, while the NECD2 expression, a key gene involved in ABA biosynthesis, was significantly higher in d3 mutants than in WT and OE-D3 plants. The results indicate that the miR528-D3 module negatively regulates plant height in rice by modulating the GA and ABA homeostasis, thereby further affecting the elongation of internodes, and resulting in lower plant height, which adds a new regulatory role to the D3-mediated plant height controlling in rice.
Alanine-specific appetite in slow growing chickens is associated with impaired glucose transport and TCA cycle
Authors: Niknafs Shahram , Fortes Marina R. S. , Cho Sungbo , Black John L. , Roura Eugeni 
Published: May 2022

Abstract
Background
The rate of protein accretion and growth affect amino acid requirements in young animals. Differences in amino acid metabolism contribute to individual variations in growth rate. This study aimed at determining how amino acid needs may change with growth rates in broiler chickens. Experiment 1 consisted of testing amino acid choices in two chicken groups with extreme growth rates (the slowest –SG- or fastest –FG- growing birds in a flock). Essential (EAA) (methionine, lysine and threonine) or non-essential (NEAA) (alanine, aspartic acid and asparagine) amino acids were added to a standard control feed (13.2 MJ/kg; 21.6% crude protein). The chickens were offered simultaneous access to the control feed and a feed supplemented with one of the two amino acid mixes added at 73% above standard dietary levels. Experiment 2 consisted of the selection of the bottom 5 SG and top 5 FG chickens from a flock of 580 to study differences in amino acid metabolism using the proventriculus representing gut sensing mechanism. In this experiment, transcriptomic, proteomic, and genomic analyses were used to compare the two groups of chickens.

Results
SG preferred NEAA, while they rejected EAA supplemented feeds (P < 0.05). However, FG rejected NEAA (P < 0.05), and they were indifferent to EAA supplemented feed (P > 0.05). Transcriptomic and proteomic analyses identified 909 differentially expressed genes and 146 differentially abundant proteins associated with differences in growth rate (P < 0.05). The integration of gene expression and protein abundance patterns showed the downregulation of sensing and transport of alanine and glucose associated with increased alanine catabolism to pyruvate in SG chickens.

Conclusion
Dietary preferences for NEAA in the SG group are associated with a potential cytosolic depletion of alanine following an upregulation of the catabolism into TCA cycle intermediates.
The effects of dual antiplatelet therapy (DAPT) adherence on survival in patients undergoing revascularization and the determinants of DAPT adherence
Authors: Zhang Shuqi , Chourase Mithlesh , Sharma Nupur , Saunik Sujata , Duggal Mona , Danaei Goodarz , Duggal Bhanu 
Published: May 2022

Abstract
Background
The prevalence and burden of coronary heart disease (CHD) has increased substantially in India, accompanied with increasing need for percutaneous coronary interventions (PCI). Although a large government-funded insurance scheme in Maharashtra, India covered the cost of PCI for low-income patients, the high cost of post-PCI treatment, especially Dual Antiplatelet Therapy (DAPT), still caused many patients to prematurely discontinue the secondary prevention. Our study aimed to investigate the effectiveness of DAPT adherence on all-cause mortality among post-PCI patients and explore the potential determinants of DAPT adherence in India.

Method
We collected clinical data of 4,595 patients undergoing PCI in 110 participating medical centers in Maharashtra, India from 2012 to 2015 by electronic medical records. We surveyed 2527 adult patients who were under the insurance scheme by telephone interview, usually between 6 to 12 months after their revascularization. Patients reporting DAPT continuation in the telephone survey were categorized as DAPT adherence. The outcome of the interest was all-cause mortality within 1 year after the index procedure. Multivariate Cox proportional hazard (PH) model with adjustment of potential confounders and standardization were used to explore the effects of DAPT adherence on all-cause mortality. We further used a multivariate logistic model to investigate the potential determinants of DAPT adherence.

Results
Out of the 2527 patients interviewed, 2064 patients were included in the analysis, of whom 470 (22.8%) discontinued DAPT prematurely within a year. After adjustment for baseline confounders, DAPT adherence was associated with lower one-year all-cause mortality compared to premature discontinuation (less than 6-month), with an adjusted hazard ratio (HR) of 0.52 (95% Confidence Interval (CI) = (0.36, 0.67)). We also found younger patients (OR per year was 0.99 (0.97, 1.00)) and male (vs. female, OR of 1.30 (0.99, 1.70)) had higher adherence to DAPT at one year as did patients taking antihypertensive medications (vs. non medication, OR of 1.57 (1.25, 1.95)).

Conclusion
These findings suggest the protective effects of DAPT adherence on 1-year mortality among post-PCI patients in a low-income setting and indicate younger age, male sex and use of other preventive treatments were predictors of higher DAPT adherence.
Description of organizational and clinician characteristics of primary dementia care in Canada: a multi-method study
Authors: Henein Mary , Arsenault-Lapierre Geneviève , Sourial Nadia , Godard-Sebillotte Claire , Bergman Howard , Vedel Isabelle ,   Research on Organization of Healthcare Services for Alzheimer’s (ROSA) Team
Published: May 2022

Abstract
Background
Organizational and clinician characteristics are important considerations for the implementation of evidence-based recommendations into primary care practice. The introduction of Canadian dementia practice guidelines and Alzheimer strategies offers a unique context to study which of the organizational and clinician characteristics align with good quality care in primary care practices.

Methods
To evaluate the quality of dementia care, we carried out a retrospective chart review in randomly selected patients with a diagnosis of dementia and who had a visit during a 9-month period in 33 primary care practices. We collected data on indicators that were based on existing Canadian evidence-based recommendations to measure a quality of dementia care score. In addition, four questionnaires were administered: two questionnaires to evaluate the organizational characteristics of the practices (dementia-specific and general organization) and two to evaluate the clinician characteristics (one for family physicians and one for nurses). Primary care practices were stratified into tertiles based on their average quality of dementia care score (low, moderate, high). The differences between the groups organizational and clinician questionnaires scores were analyzed descriptively and visually.

Results
The mean overall scores for each questionnaire were higher in the high quality of dementia care group. When looking at the breakdown of the overall score into each characteristic, the high-quality group had a higher average score for the dementia-specific organizational characteristics of “access to and coordination with home and community services”, “financial support”, “training”, “coordination and continuity within the practice”, and “caregiver support and involvement”. The characteristic “Leadership” showed a higher average score for the moderate and high-quality groups than the low-quality group. In both clinician questionnaires, the high group scored better in “attitudes towards the Alzheimer’s plan” than the other two groups.

Conclusions
These results suggest that investing in organizational characteristics specifically aimed at dementia care is a promising avenue to improve quality of dementia care in primary care. These results may be useful to enhance the implementation of evidence-based practices and improve the quality of dementia care.
Correlation analysis of physical fitness and its impact on falls in 2130 community- dwelling older adults: a retrospective cross-sectional study
Authors: Lin Wang-Sheng , Hsu Nai-Wei , Lee Meng-Jer , Lin You-Yuan , Tsai Chih-Chun , Pan Po-Jung 
Published: May 2022

AbstractBackgroundAs the community-dwelling population ages in Taiwan, concerns regarding long-term care have grown more urgent. Physical fitness plays a key role in enabling community-dwelling older adults to independently complete daily tasks and avoid falling accidents. However, the effect of physical fitness on falls and other fitness-related factors remains poorly understood.MethodsIn this retrospective cross-sectional study, 2130 community-dwelling older adults were recruited from a rural region of Taiwan. Each of these participants completed a demographics interview and frailty questionnaire and reported their history of falls. We evaluated each participant’s height and body weight measurements, calf circumference, bone mass density, and results on the grip strength, single-leg standing, chair sit-and-reach, 8-ft up-and-go, 30-second chair stand, 2-minute step, 30-second arm curl, 6-m walk, and back scratch tests to determine their overall physical fitness, which consisted of their body composition, muscular strength and endurance, flexibility, and cardiopulmonary fitness.ResultsThe prevalence of falls in the preceding year among the older adults surveyed was 20.8%, and the resultant hospitalization rate was 10.9%. The older adults who were more physically active in the past week, had regular exercise habits, lived with family, and had no history of hospitalization due to falls, exhibited greater performance on the physical fitness tests. Three time fallers exhibited lower levels of overall physical fitness than did those who had not fallen. The nonfallers outperformed the fallers in grip strength (participants who had not fallen and those who had fallen once, twice, or three times in the preceding year: 24.66 ± 0.19 vs. 23.66 ± 0.35 vs. 20.62 ± 0.71 vs. 22.20 ± 0.90 kg) and single-leg standing duration (19.38 ± 0.39 vs. 16.33 ± 0.78 vs. 13.95 ± 1.67 vs. 12.34 ± 1.82 seconds).ConclusionsExercise habits, living status, hospitalization due to falls, and amount of exercise were all associated with physical fitness in community-dwelling older adults. The results of all of the assessments indicated that the participants who had fallen three times exhibited lower levels of physical fitness than did those who had not fallen in the previous year. Physical measurements, including grip strength and single-leg standing duration, are associated with an individual’s risk of falling, which indicates that they should be considered in the development of geriatric physical fitness and fall-prevention programs.
Adapting strategies for effective and efficient pediatric HIV case finding in low prevalence countries: risk screening tool for testing children presenting at high-risk entry points in Ethiopia
Authors: Teferi Wondimu , Gutreuter Steve , Bekele Alemayehu , Ahmed Jelaludin , Ayalew Jemal , Gross Jessica , Kumsa Hanna , Antefe Tenagnework , Mengistu Semegnew , Mirkovic Kelsey , Dziuban Eric J. , Ross Christine , Belay Zena , Tilahun Tsegaye , Kassa Desta , Hrapcak Susan 
Published: May 2022

Abstract
Background
Implementing effective and efficient case-finding strategies is crucial to increasing pediatric antiretroviral therapy coverage. In Ethiopia, universal HIV testing is conducted for children presenting at high-risk entry points including malnutrition treatment, inpatient wards, tuberculosis (TB) clinics, index testing for children of positive adults, and referral of orphans and vulnerable children (OVC); however, low positivity rates observed at inpatient, malnutrition and OVC entry points warrant re-assessing current case-finding strategies. The aim of this study is to develop HIV risk screening tool applicable for testing children presenting at inpatient, malnutrition and OVC entry points in low-HIV prevalence settings.

Methods
The study was conducted from May 2017–March 2018 at 29 public health facilities in Amhara and Addis Ababa regions of Ethiopia. All children 2–14 years presenting to five high-risk entry points including malnutrition treatment, inpatient wards, tuberculosis (TB) clinics, index testing for children of positive adults, and referral of orphans and vulnerable children (OVC) were enrolled after consent. Data were collected from registers, medical records, and caregiver interviews. Screening tools were constructed using predictors of HIV positivity as screening items by applying both logistic regression and an unweighted method. Sensitivity, specificity and number needed to test (NNT) to identify one new child living with HIV (CLHIV) were estimated for each tool.

Results
The screening tools had similar sensitivity of 95%. However, the specificities of tools produced by logistic regression methods (61.4 and 65.6%) which are practically applicable were higher than those achieved by the unweighted method (53.6). Applying these tools could result in 58‒63% reduction in the NNT compared to universal testing approach while maintaining the overall number of CLHIV identified.

Conclusion
The screening tools developed using logistic regression method could significantly improve HIV testing efficiency among children presenting to malnutrition, inpatient, and OVC entry points in Ethiopia while maintaining case identification. These tools are simplified to practically implement and can potentially be validated for use at various entry points. HIV programs in low-prevalence countries can also further investigate and optimize these tools in their settings.