bluuebunny/crossref_metadata_2025_split huggingface dataset:
Review of cardiac safety in onasemnogene abeparvovec gene replacement therapy: translation from preclinical to clinical findings
Authors: Chand Deepa H. , Sun Rui , Diab Karim A. , Kenny Damien , Tukov Francis Fonyuy 
Published: April 2023

AbstractHuman gene replacement therapies such as onasemnogene abeparvovec (OA) use recombinant adeno-associated virus (rAAV) vectors to treat monogenic disorders. The heart and liver are known target organs of toxicity in animals; with cardiac and hepatic monitoring recommended in humans after OA dosing. This manuscript provides a comprehensive description of cardiac data from preclinical studies and clinical sources including clinical trials, managed access programs and the post-marketing setting following intravenous OA administration through 23 May 2022. Single dose mouse GLP-Toxicology studies revealed dose-dependent cardiac findings including thrombi, myocardial inflammation and degeneration/regeneration, which were associated with early mortality (4-7 weeks) in the high dose groups. No such findings were documented in non-human primates (NHP) after 6 weeks or 6 months post-dose. No electrocardiogram or echocardiogram abnormalities were noted in NHP or humans. After OA dosing, some patients developed isolated elevations in troponin without associated signs/symptoms; the reported cardiac adverse events in patients were considered of secondary etiology (e.g. respiratory dysfunction or sepsis leading to cardiac events). Clinical data indicate cardiac toxicity observed in mice does not translate to humans. Cardiac abnormalities have been associated with SMA. Healthcare professionals should use medical judgment when evaluating the etiology and assessment of cardiac events post OA dosing so as to consider all possibilities and manage the patient accordingly.
Engineering α-carboxysomes into plant chloroplasts to support autotrophic photosynthesis
Authors: Chen Taiyu , Hojka Marta , Davey Philip , Sun Yaqi , Dykes Gregory F. , Zhou Fei , Lawson Tracy , Nixon Peter J. , Lin Yongjun , Liu Lu-Ning 
Published: April 2023

AbstractThe growth in world population, climate change, and resource scarcity necessitate a sustainable increase in crop productivity. Photosynthesis in major crops is limited by the inefficiency of the key CO2-fixing enzyme Rubisco, owing to its low carboxylation rate and poor ability to discriminate between CO2 and O2. In cyanobacteria and proteobacteria, carboxysomes function as the central CO2-fixing organelles that elevate CO2 levels around encapsulated Rubisco to enhance carboxylation. There is growing interest in engineering carboxysomes into crop chloroplasts as a potential route for improving photosynthesis and crop yields. Here, we generate morphologically correct carboxysomes in tobacco chloroplasts by transforming nine carboxysome genetic components derived from a proteobacterium. The chloroplast-expressed carboxysomes display a structural and functional integrity comparable to native carboxysomes and support autotrophic growth and photosynthesis of the transplastomic plants at elevated CO2. Our study provides proof-of-concept for a route to engineering fully functional CO2-fixing modules and entire CO2-concentrating mechanisms into chloroplasts to improve crop photosynthesis and productivity.
Anti-cancer pro-inflammatory effects of an IgE antibody targeting the melanoma-associated antigen chondroitin sulfate proteoglycan 4
Authors: Chauhan Jitesh , Grandits Melanie , Palhares Lais C. G. F. , Mele Silvia , Nakamura Mano , López-Abente Jacobo , Crescioli Silvia , Laddach Roman , Romero-Clavijo Pablo , Cheung Anthony , Stavraka Chara , Chenoweth Alicia M. , Sow Heng Sheng , Chiaruttini Giulia , Gilbert Amy E. , Dodev Tihomir , Koers Alexander , Pellizzari Giulia , Ilieva Kristina M. , Man Francis , Ali Niwa , Hobbs Carl , Lombardi Sara , Lionarons Daniël A. , Gould Hannah J. , Beavil Andrew J. , Geh Jenny L. C. , MacKenzie Ross Alastair D. , Healy Ciaran , Calonje Eduardo , Downward Julian , Nestle Frank O. , Tsoka Sophia , Josephs Debra H. , Blower Philip J. , Karagiannis Panagiotis , Lacy Katie E. , Spicer James , Karagiannis Sophia N. , Bax Heather J. 
Published: April 2023

AbstractOutcomes for half of patients with melanoma remain poor despite standard-of-care checkpoint inhibitor therapies. The prevalence of the melanoma-associated antigen chondroitin sulfate proteoglycan 4 (CSPG4) expression is ~70%, therefore effective immunotherapies directed at CSPG4 could benefit many patients. Since IgE exerts potent immune-activating functions in tissues, we engineer a monoclonal IgE antibody with human constant domains recognizing CSPG4 to target melanoma. CSPG4 IgE binds to human melanomas including metastases, mediates tumoricidal antibody-dependent cellular cytotoxicity and stimulates human IgE Fc-receptor-expressing monocytes towards pro-inflammatory phenotypes. IgE demonstrates anti-tumor activity in human melanoma xenograft models engrafted with human effector cells and is associated with enhanced macrophage infiltration, enriched monocyte and macrophage gene signatures and pro-inflammatory signaling pathways in the tumor microenvironment. IgE prolongs the survival of patient-derived xenograft-bearing mice reconstituted with autologous immune cells. No ex vivo activation of basophils in patient blood is measured in the presence of CSPG4 IgE. Our findings support a promising IgE-based immunotherapy for melanoma.
Surface hydroxide promotes CO2 electrolysis to ethylene in acidic conditions
Authors: Cao Yufei , Chen Zhu , Li Peihao , Ozden Adnan , Ou Pengfei , Ni Weiyan , Abed Jehad , Shirzadi Erfan , Zhang Jinqiang , Sinton David , Ge Jun , Sargent Edward H. 
Published: April 2023

AbstractPerforming CO2 reduction in acidic conditions enables high single-pass CO2 conversion efficiency. However, a faster kinetics of the hydrogen evolution reaction compared to CO2 reduction limits the selectivity toward multicarbon products. Prior studies have shown that adsorbed hydroxide on the Cu surface promotes CO2 reduction in neutral and alkaline conditions. We posited that limited adsorbed hydroxide species in acidic CO2 reduction could contribute to a low selectivity to multicarbon products. Here we report an electrodeposited Cu catalyst that suppresses hydrogen formation and promotes selective CO2 reduction in acidic conditions. Using in situ time-resolved Raman spectroscopy, we show that a high concentration of CO and OH on the catalyst surface promotes C-C coupling, a finding that we correlate with evidence of increased CO residence time. The optimized electrodeposited Cu catalyst achieves a 60% faradaic efficiency for ethylene and 90% for multicarbon products. When deployed in a slim flow cell, the catalyst attains a 20% energy efficiency to ethylene, and 30% to multicarbon products.
A machine learning model identifies patients in need of autoimmune disease testing using electronic health records
Authors: Forrest Iain S. , Petrazzini Ben O. , Duffy Áine , Park Joshua K. , O’Neal Anya J. , Jordan Daniel M. , Rocheleau Ghislain , Nadkarni Girish N. , Cho Judy H. , Blazer Ashira D. , Do Ron 
Published: April 2023

AbstractSystemic autoimmune rheumatic diseases (SARDs) can lead to irreversible damage if left untreated, yet these patients often endure long diagnostic journeys before being diagnosed and treated. Machine learning may help overcome the challenges of diagnosing SARDs and inform clinical decision-making. Here, we developed and tested a machine learning model to identify patients who should receive rheumatological evaluation for SARDs using longitudinal electronic health records of 161,584 individuals from two institutions. The model demonstrated high performance for predicting cases of autoantibody-tested individuals in a validation set, an external test set, and an independent cohort with a broader case definition. This approach identified more individuals for autoantibody testing compared with current clinical standards and a greater proportion of autoantibody carriers among those tested. Diagnoses of SARDs and other autoimmune conditions increased with higher model probabilities. The model detected a need for autoantibody testing and rheumatology encounters up to five years before the test date and assessment date, respectively. Altogether, these findings illustrate that the clinical manifestations of a diverse array of autoimmune conditions are detectable in electronic health records using machine learning, which may help systematize and accelerate autoimmune testing.
Epigenetic landscape reveals MECOM as an endothelial lineage regulator
Authors: Lv Jie , Meng Shu , Gu Qilin , Zheng Rongbin , Gao Xinlei , Kim Jun-dae , Chen Min , Xia Bo , Zuo Yihan , Zhu Sen , Zhao Dongyu , Li Yanqiang , Wang Guangyu , Wang Xin , Meng Qingshu , Cao Qi , Cooke John P. , Fang Longhou , Chen Kaifu , Zhang Lili 
Published: April 2023

AbstractA comprehensive understanding of endothelial cell lineage specification will advance cardiovascular regenerative medicine. Recent studies found that unique epigenetic signatures preferentially regulate cell identity genes. We thus systematically investigate the epigenetic landscape of endothelial cell lineage and identify MECOM to be the leading candidate as an endothelial cell lineage regulator. Single-cell RNA-Seq analysis verifies that MECOM-positive cells are exclusively enriched in the cell cluster of bona fide endothelial cells derived from induced pluripotent stem cells. Our experiments demonstrate that MECOM depletion impairs human endothelial cell differentiation, functions, and Zebrafish angiogenesis. Through integrative analysis of Hi-C, DNase-Seq, ChIP-Seq, and RNA-Seq data, we find MECOM binds enhancers that form chromatin loops to regulate endothelial cell identity genes. Further, we identify and verify the VEGF signaling pathway to be a key target of MECOM. Our work provides important insights into epigenetic regulation of cell identity and uncovered MECOM as an endothelial cell lineage regulator.
Self-recovering passive cooling utilizing endothermic reaction of NH4NO3/H2O driven by water sorption for photovoltaic cell
Authors: Kim Seonggon , Park Jong Ha , Lee Jae Won , Kim Yongchan , Kang Yong Tae 
Published: April 2023

AbstractPower efficiency of photovoltaic cell is significantly affected by the cell temperature. Here, a self-recovering passive cooling unit is developed. The water-saturated zeolite 13X is coated on the back side of photovoltaic cell, and ammonium nitrate is dispersed as a layer to form a thin film. When heat is supplied, water is desorbed from zeolite 13X (latent cooling), and dissolves ammonium nitrate to induce endothermic reaction cooling. It is a reversible process that recovers itself at night. The unit works on the basis that the water sorption performance of porous materials is inversely proportional to temperature, and the solubility of endothermic reaction pairs increases proportionally with temperature. The average temperature of photovoltaic cell can be reduced by 15.1 °C, and the cooling energy density reaches 2,876 kJ/kg with average cooling power of 403 W/m2. We show that highly efficient passive cooling comprising inexpensive materials for photovoltaic cell could be achieved.
Extended adjuvant endocrine therapy in a longitudinal cohort of young breast cancer survivors
Authors: Sella Tal , Zheng Yue , Rosenberg Shoshana M. , Ruddy Kathryn J. , Gelber Shari I. , Tamimi Rulla M. , Peppercorn Jeffrey M. , Schapira Lidia , Borges Virginia F. , Come Steven E. , Carey Lisa A. , Winer Eric P. , Partridge Ann H. 
Published: April 2023

AbstractExtended adjuvant endocrine therapy (eET) improves outcomes in breast cancer survivors. Most studies however have been limited to postmenopausal women, and optimal eET for young survivors is uncertain. We report eET use among participants in the Young Women’s Breast Cancer Study (YWS), a multicenter prospective cohort of women age ≤40 newly diagnosed with breast cancer enrolled between 2006–2016. Women with stage I–III hormone receptor-positive breast cancer, ≥6 years from diagnosis without recurrence were considered eET candidates. Use of eET was elicited from annual surveys sent years 6–8 after diagnosis, censoring for recurrence/death. 663 women were identified as eET candidates with 73.9% (490/663) having surveys eligible for analysis. Among eligible participants, mean age was 35.5 (±3.9), 85.9% were non-Hispanic white, and 59.6% reported eET use. Tamoxifen monotherapy was the most reported eET (77.4%), followed by aromatase inhibitor (AI) monotherapy (21.9%), AI-ovarian function suppression (AI-OFS) (6.8%) and tamoxifen-OFS (3.1%). In multivariable analysis, increasing age (per year odds ratio [OR]: 1.10, 95% confidence interval [CI]: 1.04–1.16), stage (II v. I: OR: 2.86, 95% CI: 1.81–4.51; III v. I: OR: 3.73, 95%CI: 1.87–7.44) and receipt of chemotherapy (OR: 3.66, 95% CI: 2.16–6.21) were significantly associated with eET use. Many young breast cancer survivors receive eET despite limited data regarding utility in this population. While some factors associated with eET use reflect appropriate risk-based care, potential sociodemographic disparities in uptake warrants further investigation in more diverse populations.
Genomic profiles of IDH-mutant gliomas: MYCN-amplified IDH-mutant astrocytoma had the worst prognosis
Authors: Lee Kwanghoon , Kim Seong-Ik , Kim Eric Eunshik , Shim Yu-Mi , Won Jae-Kyung , Park Chul-Kee , Choi Seung Hong , Yun Hongseok , Lee Hyunju , Park Sung-Hye 
Published: April 2023

AbstractThis study aimed to find any ambiguous genetic outlier for “oligodendroglioma, IDH-mutant and 1p/19q-codeleted (O_IDH_mut)” and “astrocytoma, IDH-mutant (A_IDH_mut)” and to redefine the genetic landscape and prognostic factors of IDH-mutant gliomas. Next-generation sequencing (NGS) using a brain tumor-targeted gene panel, methylation profiles, and clinicopathological features were analyzed for O_IDH_mut (n = 74) in 70 patients and for A_IDH_mut (n = 95) in 90 patients. 97.3% of O_IDH_mut and 98.9% of A_IDH_mut displayed a classic genomic landscape. Combined CIC (75.7%) and/or FUBP1 (45.9%) mutations were detected in 93.2% and MGMTp methylation in 95.9% of O_IDH_mut patients. In A_IDH_mut, TP53 mutations were found in 86.3% and combined ATRX (82.1%) and TERTp (6.3%) mutations in 88.4%. Although there were 3 confusing cases, NOS (not otherwise specified) category, based on genetic profiles, but they were clearly classified by combining histopathology and DKFZ methylation classifier algorithms. The patients with MYCN amplification and/or CDKN2A/2B homozygous deletion in the A_IDH_mut category had a worse prognosis than those without these gene alterations and MYCN-amplified A_IDH_mut showed the worst prognosis. However, there was no prognostic genetic marker in O_IDH_mut. In histopathologically or genetically ambiguous cases, methylation profiles can be used as an objective tool to avoid a diagnosis of NOS or NEC (not elsewhere classified), as well as for tumor classification. The authors have not encountered a case of true mixed oligoastrocytoma using an integrated diagnosis of histopathological, genetic and methylation profiles. MYCN amplification, in addition to CDKN2A/2B homozygous deletion, should be included in the genetic criteria for CNS WHO grade 4 A_IDH_mut.
Multi-center retrospective study of children with sickle cell disease admitted to pediatric intensive care units in the United States
Authors: Ettinger Nicholas A. , Guffey Danielle , Anum Shaniqua J. , Fasipe Titilope , Katkin Julie , Bhar Saleh , Airewele Gladstone , Saini Arun , Tubman Venée N. 
Published: April 2023

AbstractData on outcomes and interventions for children with sickle cell disease (SCD) admitted to a pediatric intensive care units (PICU) are unknown. We provide the first comprehensive multi-center report on PICU interventions associated with death, the need for invasive respiratory support or stroke among critically ill children with SCD. We collected retrospective multi-center cohort data from January 1, 2012 to December 31, 2019 utilizing the Virtual Pediatric Systems, LLC database. We identified 3388 unique children with SCD, accounting for a total of 5264 PICU admissions from 138 PICUs. The overall mortality rate for the PICU admissions cohort was 1.8% (95/5264 PICU admissions, 95/3388 [2.8%] of all unique patients), the rate of needing of needing Invasive Respiratory Support (IRS, a composite category of exposure) was 21.3% (872/4093 PICU admissions with complete data) and the overall rate of stroke (ischemic or hemorrhagic) was 12.5% (657/5264 PICU admissions). In multivariable analysis adjusting for admission age category, sex, race/ethnicity, PRISM-3 score at admission, exposure to IRS, quartile of unit volume of patients with SCD, and patient origin, admitted children who needed invasive respiratory support (IRS) had higher adjusted odds ratios for mortality (adjusted odds ratio [aOR], 19.72; 95% confidence interval [CI] 8.98–43.29; p < 0.001), although admitted children > 2 years old had decreased aOR for needing IRS (aOR 0.25–0.62; 95% CI 0.16–0.94; p < 0.001–0.025). By contrast, admitted children > 2 years old had a strikingly increased aOR for stroke (aOR 7.57–16.32; 95% CI 2.25–52.15; p < 0.001). These groups may represent PICU-specific subsets of patients with SCD who are at higher risk for more serious illness and should deserve early consideration for referral to a pediatric institution providing comprehensive care for patients with SCD.
Lectin-based carbohydrate profile of megakaryocytes in murine fetal liver during development
Authors: Bomfim Barbara Cristina Marcollino , Azevedo-Silva Jessyca , Caminha Giulia , Santos João Paulo Rodrigues , Pelajo-Machado Marcelo , de Paula Ayres-Silva Jackline 
Published: April 2023

AbstractHematopoiesis is the process by which blood cells are generated. During embryonic development, these cells migrate through different organs until they reach the bone marrow, their definitive place in adulthood. Around E10.5, the fetal liver starts budding from the gut, where first hematopoietic cells arrive and expand. Hematopoietic cell migration occurs through cytokine stimulation, receptor expression, and glycosylation patterns on the cell surface. In addition, carbohydrates can modulate different cell activation states. For this reason, we aimed to characterize and quantify fetal megakaryocytic cells in mouse fetal liver according to their glycan residues at different gestational ages through lectins. Mouse fetuses between E11.5 and E18.5 were formalin-fixed and, paraffin-embedded, for immunofluorescence analysis using confocal microscopy. The results showed that the following sugar residues were expressed in proliferating and differentiating megakaryocytes in the fetal liver at different gestational ages: α-mannose, α-glucose, galactose, GlcNAc, and two types of complex oligosaccharides. Megakaryocytes also showed three proliferation waves during liver development at E12.5, E14.5, and E18.5. Additionally, the lectins that exhibited high and specific pattern intensities at liver capsules and vessels were shown to be a less time-consuming and robust alternative alternative to conventional antibodies for displaying liver structures such as capsules and vessels, as well as for megakaryocyte differentiation in the fetal liver.
Early Aptian marine incursions in the interior of northeastern Brazil following the Gondwana breakup
Authors: Fauth Gerson , Kern Henrique Parisi , Villegas-Martín Jorge , De Lira Mota Marcelo Augusto , dos Santos Filho Marcos Antonio Batista , Santa Catharina Amanda , Leandro Lilian Maia , Luft-Souza Fernanda , Strohschoen Oscar , Nauter-Alves Andressa , Tungo Edna de Jesus Francisco , Bruno Mauro Daniel Rodrigues , Ceolin Daiane , Baecker-Fauth Simone , Bom Marlone Heliara Hünnig , Lima Francisco Henrique de Oliveira , Santos Alessandra , Assine Mario Luis 
Published: April 2023

AbstractThis study reports a set of primeval marine incursions identified in two drill cores, 1PS-06-CE, and 1PS-10-CE, which recovered the Barbalha Formation, Araripe Basin, Brazil. Based on a multi-proxy approach involving stratigraphy, microbiofacies, ichnofossils, and microfossils, three short-lived marine incursions were identified, designated Araripe Marine Incursions (AMI) 1–3. AMI-1 and AMI-2, which occur within the shales of the Batateira Beds (lower part of the Barbalha Formation), were identified by the occurrence of benthonic foraminifera, calcareous nannofossils, dinocysts, and a mass mortality event of non-marine ostracods. AMI-3 was recognized in the upper part of the Barbalha Formation, based on the occurrence of ichnofossils and planktonic foraminifera. The observation of the planktonic foraminifera genus Leupoldina for the first time in the basin indicates early Aptian/early late Aptian age for these deposits, and the first opportunity of correlation with global foraminifera biozonation. Our findings have implications for the breakup of the Gondwana Supercontinent, as these incursions represent the earliest marine-derived flooding events in the inland basins of northeastern Brazil.
Detrusor underactivity is associated with metabolic syndrome in aged primates
Authors: Biscola Natalia P. , Bartmeyer Petra M. , Christe Kari L. , Colman Ricki J. , Havton Leif A. 
Published: April 2023

AbstractLower urinary tract (LUT) dysfunction is prevalent in the elderly population, and clinical manifestations include urinary retention, incontinence, and recurrent urinary tract infections. Age-associated LUT dysfunction is responsible for significant morbidity, compromised quality of life, and rising healthcare costs in older adults, but its pathophysiology is not well understood. We aimed to investigate the effects of aging on LUT function by urodynamic studies and metabolic markers in non-human primates. Adult (n = 27) and aged (n = 20) female rhesus macaques were evaluated by urodynamic and metabolic studies. Cystometry showed detrusor underactivity (DU) with increased bladder capacity and compliance in aged subjects. Metabolic syndrome indicators were present in the aged subjects, including increased weight, triglycerides, lactate dehydrogenase (LDH), alanine aminotransferase (ALT), and high sensitivity C-reactive protein (hsCRP), whereas aspartate aminotransferase (AST) was unaffected and the AST/ALT ratio reduced. Principal component analysis and paired correlations showed a strong association between DU and metabolic syndrome markers in aged primates with DU but not in aged primates without DU. The findings were unaffected by prior pregnancies, parity, and menopause. Our findings provide insights into possible mechanisms for age-associated DU and may guide new strategies to prevent and treat LUT dysfunction in older adults.