bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting Metabolic Dependencies Fueling the TCA Cycle to Circumvent Therapy Resistance in Acute Myeloid Leukemia
Authors: Boët Emeline , Sarry Jean-Emmanuel 
Published: April 2024

Abstract
Acute myeloid leukemia (AML) is one of the most prevalent blood cancers, characterized by a dismal survival rate. This poor outcome is largely attributed to AML cells that persist despite treatment and eventually result in relapse. Relapse-initiating cells exhibit diverse resistance mechanisms, encompassing genetic factors and, more recently discovered, nongenetic factors such as metabolic adaptations. Leukemic stem cells (LSC) rely on mitochondrial metabolism for their survival, whereas hematopoietic stem cells primarily depend on glycolysis. Furthermore, following treatments such as cytarabine, a standard in AML treatment for over four decades, drug-persisting leukemic cells exhibit an enhanced reliance on mitochondrial metabolism. In this issue of Cancer Research, two studies investigated dependencies of AML cells on two respiratory substrates, α-ketoglutarate and lactate-derived pyruvate, that support mitochondrial oxidative phosphorylation (OXPHOS) following treatment with the imipridone ONC-213 and the BET inhibitor INCB054329, respectively. Targeting lactate utilization by interfering with monocarboxylate transporter 1 (MCT1 or SLC16A1) or lactate dehydrogenase effectively sensitized cells to BET inhibition in vitro and in vivo. In addition, ONC-213 affected αKGDH, a pivotal NADH-producing enzyme of the TCA cycle, to induce a mitochondrial stress response through ATF4 activation that diminished the expression of the antiapoptotic protein MCL1, consequently promoting apoptosis of AML cells. In summary, targeting these mitochondrial dependencies might be a promising strategy to kill therapy-naïve and treatment-resistant OXPHOS-reliant LSCs and to delay or prevent relapse.
See related articles by Monteith et al., p. 1101 and Su et al., p. 1084
Engineering CD3/CD137 Dual Specificity into a DLL3-Targeted T-Cell Engager Enhances T-Cell Infiltration and Efficacy against Small-Cell Lung Cancer
Authors: Mikami Hirofumi , Feng Shu , Matsuda Yutaka , Ishii Shinya , Naoi Sotaro , Azuma Yumiko , Nagano Hiroaki , Asanuma Kentaro , Kayukawa Yoko , Tsunenari Toshiaki , Kamikawaji Shogo , Iwabuchi Ryutaro , Shinozuka Junko , Yamazaki Masaki , Kuroi Haruka , Ho Samantha Shu Wen , Gan Siok Wan , Chichili Priyanka , Pang Chai Ling , Yeo Chiew Ying , Shimizu Shun , Hironiwa Naoka , Kinoshita Yasuko , Shimizu Yuichiro , Sakamoto Akihisa , Muraoka Masaru , Takahashi Noriyuki , Kawa Tatsuya , Shiraiwa Hirotake , Mimoto Futa , Kashima Kenji , Kamata-Sakurai Mika , Ishikawa Shumpei , Aburatani Hiroyuki , Kitazawa Takehisa , Igawa Tomoyuki 
Published: April 2024

Abstract
Small-cell lung cancer (SCLC) is an aggressive cancer for which immune checkpoint inhibitors (ICI) have had only limited success. Bispecific T-cell engagers are promising therapeutic alternatives for ICI-resistant tumors, but not all patients with SCLC are responsive. Herein, to integrate CD137 costimulatory function into a T-cell engager format and thereby augment therapeutic efficacy, we generated a CD3/CD137 dual-specific Fab and engineered a DLL3-targeted trispecific antibody (DLL3 trispecific). The CD3/CD137 dual-specific Fab was generated to competitively bind to CD3 and CD137 to prevent DLL3-independent cross-linking of CD3 and CD137, which could lead to systemic T-cell activation. We demonstrated that DLL3 trispecific induced better tumor growth control and a marked increase in the number of intratumoral T cells compared with a conventional DLL3-targeted bispecific T-cell engager. These findings suggest that DLL3 trispecific can exert potent efficacy by inducing concurrent CD137 costimulation and provide a promising therapeutic option for SCLC.
LXRα Promotes Abdominal Aortic Aneurysm Formation Through UHRF1 Epigenetic Modification of miR-26b-3p
Authors: Guo Xiao , Zhong Jianmei , Zhao Yichao , Fu Yanan , Sun Ling-yue , Yuan Ancai , Liu Junling , Chen Alex F. , Pu Jun 
Published: April 2024

BACKGROUND:

Abdominal aortic aneurysm (AAA) is a severe aortic disease without effective pharmacological approaches. The nuclear hormone receptor LXRα (liver X receptor α), encoded by the
NR1H3
gene, serves as a critical transcriptional mediator linked to several vascular pathologies, but its role in AAA remains elusive.

METHODS:

Through integrated analyses of human and murine AAA gene expression microarray data sets, we identified
NR1H3
as a candidate gene regulating AAA formation. To investigate the role of LXRα in AAA formation, we used global
Nr1h3
-knockout and vascular smooth muscle cell–specific
Nr1h3
-knockout mice in 2 AAA mouse models induced with angiotensin II (1000 ng·kg·min; 28 days) or calcium chloride (CaCl
2
; 0.5 mol/L; 42 days).

RESULTS:

Upregulated LXRα was observed in the aortas of patients with AAA and in angiotensin II– or CaCl
2
-treated mice. Global or vascular smooth muscle cell–specific
Nr1h3
knockout inhibited AAA formation in 2 mouse models. Loss of LXRα function prevented extracellular matrix degeneration, inflammation, and vascular smooth muscle cell phenotypic switching.
Uhrf1
, an epigenetic master regulator, was identified as a direct target gene of LXRα by integrated analysis of transcriptome sequencing and chromatin immunoprecipitation sequencing. Susceptibility to AAA development was consistently enhanced by UHRF1 (ubiquitin-like containing PHD and RING finger domains 1) in both angiotensin II– and CaCl
2
-induced mouse models. We then determined the CpG methylation status and promoter accessibility of UHRF1-mediated genes using CUT&Tag (cleavage under targets and tagmentation), RRBS (reduced representation bisulfite sequencing), and ATAC-seq (assay for transposase-accessible chromatin with sequencing) in vascular smooth muscle cells, which revealed that the recruitment of UHRF1 to the promoter of miR-26b led to DNA hypermethylation accompanied by relatively closed chromatin states, and caused downregulation of miR-26b expression in AAA. Regarding clinical significance, we found that underexpression of miR-26b-3p correlated with high risk in patients with AAA. Maintaining miR-26b-3p expression prevented AAA progression and alleviated the overall pathological process.

CONCLUSIONS:
Our study reveals a pivotal role of the LXRα/UHRF1/miR-26b-3p axis in AAA and provides potential biomarkers and therapeutic targets for AAA.
BRCC3 Regulation of ALK2 in Vascular Smooth Muscle Cells: Implication in Pulmonary Hypertension
Authors: Shen Hui , Gao Ya , Ge Dedong , Tan Meng , Yin Qing , Wei Tong-You Wade , He Fangzhou , Lee Tzong-Yi , Li Zhongyan , Chen Yuqin , Yang Qifeng , Liu Zhangyu , Li Xinxin , Chen Zixuan , Yang Yi , Zhang Zhengang , Thistlethwaite Patricia A. , Wang Jian , Malhotra Atul , Yuan Jason X.-J. , Shyy John Y.-J. , Gong Kaizheng 
Published: April 2024

BACKGROUND:
An imbalance of antiproliferative BMP (bone morphogenetic protein) signaling and proliferative TGF-β (transforming growth factor-β) signaling is implicated in the development of pulmonary arterial hypertension (PAH). The posttranslational modification (eg, phosphorylation and ubiquitination) of TGF-β family receptors, including BMPR2 (bone morphogenetic protein type 2 receptor)/ALK2 (activin receptor-like kinase-2) and TGF-βR2/R1, and receptor-regulated Smads significantly affects their activity and thus regulates the target cell fate. BRCC3 modifies the activity and stability of its substrate proteins through K63-dependent deubiquitination. By modulating the posttranslational modifications of the BMP/TGF-β–PPARγ pathway, BRCC3 may play a role in pulmonary vascular remodeling, hence the pathogenesis of PAH.

METHODS:
Bioinformatic analyses were used to explore the mechanism by which BRCC3 deubiquitinates ALK2. Cultured pulmonary artery smooth muscle cells (PASMCs), mouse models, and specimens from patients with idiopathic PAH were used to investigate the rebalance between BMP and TGF-β signaling in regulating ALK2 phosphorylation and ubiquitination in the context of pulmonary hypertension.

RESULTS:

BRCC3 was significantly downregulated in PASMCs from patients with PAH and animals with experimental pulmonary hypertension. BRCC3, by de-ubiquitinating ALK2 at Lys-472 and Lys-475, activated receptor-regulated Smad1/5/9, which resulted in transcriptional activation of BMP-regulated PPARγ, p53, and Id1. Overexpression of BRCC3 also attenuated TGF-β signaling by downregulating TGF-β expression and inhibiting phosphorylation of Smad3. Experiments in vitro indicated that overexpression of BRCC3 or the de-ubiquitin–mimetic ALK2-K472/475R attenuated PASMC proliferation and migration and enhanced PASMC apoptosis. In SM22α-BRCC3-Tg mice, pulmonary hypertension was ameliorated because of activation of the ALK2-Smad1/5-PPARγ axis in PASMCs. In contrast,
Brcc3
-/-
mice showed increased susceptibility of experimental pulmonary hypertension because of inhibition of the ALK2-Smad1/5 signaling.

CONCLUSIONS:
These results suggest a pivotal role of BRCC3 in sustaining pulmonary vascular homeostasis by maintaining the integrity of the BMP signaling (ie, the ALK2-Smad1/5-PPARγ axis) while suppressing TGF-β signaling in PASMCs. Such rebalance of BMP/TGF-β pathways is translationally important for PAH alleviation.
Development of a Full-Scale Connected U-Net for Reflectivity Inpainting in Spaceborne Radar Blind Zones
Authors: King Fraser , Pettersen Claire , Fletcher Christopher G. , Geiss Andrew 
Published: April 2024

Abstract
CloudSat’s Cloud Profiling Radar is a valuable tool for remotely monitoring high-latitude snowfall, but its ability to observe hydrometeor activity near the Earth’s surface is limited by a radar blind zone caused by ground clutter contamination. This study presents the development of a deeply supervised U-Net-style convolutional neural network to predict cold season reflectivity profiles within the blind zone at two Arctic locations. The network learns to predict the presence and intensity of near-surface hydrometeors by coupling latent features encoded in blind zone-aloft clouds with additional context from collocated atmospheric state variables (i.e., temperature, specific humidity, and wind speed). Results show that the U-Net predictions outperform traditional linear extrapolation methods, with low mean absolute error, a 38% higher Sørensen–Dice coefficient, and vertical reflectivity distributions 60% closer to observed values. The U-Net is also able to detect the presence of near-surface cloud with a critical success index (CSI) of 72% and cases of shallow cumuliform snowfall and virga with 18% higher CSI values compared to linear methods. An explainability analysis shows that reflectivity information throughout the scene, especially at cloud edges and at the 1.2-km blind zone threshold, along with atmospheric state variables near the tropopause, are the most significant contributors to model skill. This surface-trained generative inpainting technique has the potential to enhance current and future remote sensing precipitation missions by providing a better understanding of the nonlinear relationship between blind zone reflectivity values and the surrounding atmospheric state.

Significance Statement
Snowfall is a critical contributor to the global water–energy budget, with important connections to water resource management, flood mitigation, and ecosystem sustainability. However, traditional spaceborne remote monitoring of snowfall faces challenges due to a near-surface radar blind zone, which masks a portion of the atmosphere. In this study, a deep learning model was developed to fill in missing data across these regions using surface radar and atmospheric state variables. The model accurately predicts reflectivity, with significant improvements over conventional methods. This innovative approach enhances our understanding of reflectivity patterns and atmospheric interactions, bolstering advances in remote snowfall prediction.
Vertical Energy Fluxes Driven by the Interaction between Wave Groups and Langmuir Turbulence
Authors: Scully Malcolm E. , Zippel Seth F. 
Published: April 2024

Abstract
Data from an air–sea interaction tower are used to close the turbulent kinetic energy (TKE) budget in the wave-affected surface layer of the upper ocean. Under energetic wind forcing with active wave breaking, the dominant balance is between the dissipation rate of TKE and the downward convergence in vertical energy flux. The downward energy flux is driven by pressure work, and the TKE transport is upward, opposite to the downgradient assumption in most turbulence closure models. The sign and the relative magnitude of these energy fluxes are hypothesized to be driven by an interaction between the vertical velocity of Langmuir circulation (LC) and the kinetic energy and pressure of wave groups, which is the result of small-scale wave–current interaction. Consistent with previous modeling studies, the data suggest that the horizontal velocity anomaly associated with LC refracts wave energy away from downwelling regions and into upwelling regions, resulting in negative covariance between the vertical velocity of LC and the pressure anomaly associated with the wave groups. The asymmetry between downward pressure work and upward TKE flux is explained by the Bernoulli response of the sea surface, which results in groups of waves having a larger pressure anomaly than the corresponding kinetic energy anomaly, consistent with group-bound long-wave theory.
How Being Inside or Outside of Buildings Affects the Causal Relationship between Weather and Pain among People Living with Chronic Pain
Authors: Little Claire L. , Schultz David M. , Yimer Belay B. , Beukenhorst Anna L. 
Published: April 2024

Abstract
Although many people believe their pain fluctuates with weather conditions, both weather and pain may be associated with time spent outside. For example, pleasant weather may mean that people spend more time outside doing physical activity and are exposed to the weather, leading to more (or less) pain, and poor weather or severe pain may keep people inside, sedentary, and not exposed to the weather. We conducted a smartphone study where participants with chronic pain reported daily pain severity, as well as time spent outside. We address the relationship between four weather variables (temperature, dewpoint temperature, pressure, and wind speed) and pain by proposing a three-step approach to untangle their effects: (i) propose a set of plausible directed acyclic graphs (DAGs) that account for potential roles of time spent outside (e.g., collider, effect modifier, mediator); (ii) analyze the compatibility of the observed data with the assumed model; and (iii) identify the most plausible model by combining evidence from the observed data and domain-specific knowledge. We found that the data do not support time spent outside as a collider or mediator of the relationship between weather variables and pain. On the other hand, time spent outside modifies the effect between temperature and pain, as well as wind speed and pain, with the effect being absent on days that participants spent inside and present if they spent some or all of the day outside. Our results show the utility of using directed acyclic graphs for studying causal inference.

Significance Statement
Three-quarters of people living with chronic pain believe that weather influences their pain. However, people staying inside would not be exposed to the weather outside, and good weather may mean that people are more active outside, leading to more or less pain. To obtain data to calculate how the amount of time spent outside affects the weather–pain relationship, we conducted a 15-month smartphone study collecting daily pain reports and nearby weather for nearly 5000 participants in the United Kingdom. We found that time spent outside modifies the relationship between temperature/wind speed and pain, showing the importance of accounting for other factors when investigating the association between weather and chronic pain, which could guide future research into pain mitigation and management.
Management of Choledocholithiasis in a Community Hospital: Laparoscopic Common Bile Duct Exploration Versus Endoscopic Retrograde Cholangiopancreatography
Authors: McNamee Molly M. , Stolz Michael P. , Harvell Robert Tyler , Staley Christopher A. , Green Emilie E. , Othman Hedaya D. , Gibson Brian H. 
Published: April 2024

Background Approximately 10% of intraoperative cholangiograms identify choledocholithiasis (CDL), stones in the common bile duct. Choledocholithiasis management options include endoscopic retrograde cholangiopancreatography (ERCP) followed by cholecystectomy, laparoscopic cholecystectomy (LC) followed by ERCP (LC + ERCP), cholecystectomy with open common bile duct exploration, or laparoscopic cholecystectomy with laparoscopic common bile duct exploration (LC + LCBDE). The goal of these interventions is to clear the obstruction from CDL. Methods Patients from a single-center community hospital undergoing LC with intraoperative cholangiogram (LC + IOC) progressing to LC + LCBDE from July 2020 to August 2022 were evaluated for hospital length of stay (LOS), operative times, and complications. These were compared to the prior standard practice of pre/post-operative ERCP. Results The results were evaluated using ANOVA, Student-Newman-Keuls, and chi square analysis. In comparison of LC + CBDE to ERCP + cholecystectomy, LOS was reduced (1.8 vs 4.6 days P < .0001). No difference in LOS between LC + IOC and LC + CBDE (1.4 vs 1.8 days, P > .05) was found. No difference in complication rates was found. Mean operative time differed between LC + IOC and LC + CBDE (63 vs 113 minutes, P < .0001). Fifty-five attempts of LC + CBDE were performed with only 10 requiring post-operative ERCP. Discussion Since implementation of LC + CBDE, there has been reduced LOS without increasing complication rates. Operative times are increased with LC + CBDE but offset by reduced LOS, additional anesthesia events, and procedures. Our institution will continue to pursue LC + CBDE when indicated with efforts to improve resource allocation.
5-year Follow-up of Reimplanted Parathyroid Glands in Forearm Subcutaneous Tissue During Thyroidectomy. A Confirmation of Graft Vitality in a Large Series of Patients
Authors: Lelli Giulio , Micalizzi Alessandra , Gurrado Angela , Bononi Marco , Iossa Angelo , De Angelis Francesco , Di Meo Diletta , Fassari Alessia , Testini Mario , Cavallaro Giuseppe 
Published: April 2024

Introduction The aim of this study is to assess the outcomes of parathyroid gland reimplantation with PR-FaST technique in patients undergoing thyroid surgery, focusing on graft functionality over a 5-year follow-up period. Materials and Methods We analyzed data from 131 patients who underwent parathyroid reimplantation using the PR-FaST technique during thyroid surgery due to inadvertent parathyroid removal or evident vascular damage. Postoperative evaluations included serum calcium (Ca), magnesium (Mg), and phosphorus (P) analyses on the 1st and 2nd postoperative days, at 10 days, and at 1, 3, 6 months, 1 year, and 5 years of follow-up. Additionally, the mean values of serum intact parathyroid hormone (iPTH) concentration were measured from blood samples collected from both the reimplanted arm (iPTH RA) and non-reimplanted arm (iPTH NRA) within the same period. Results Among 131 patients, at 10 days post-surgery, only 46 patients (35.1%) out of 131 exhibited graft viability (iPTH ratio >1.5). This percentage increased to 72.8% (94 patients) after 1 month and further to 87.8% (108 patients) after 3 months post-surgery. At 1 year, 84.7% of patients showed good graft functionality. After 5 years, the percentage remained stable, with graft viability observed in 81.3% of patients. Only 91 of the initial 131 patients completed follow-up up to 5 years, with a dropout rate of 30.5 %. Conclusions Parathyroid reimplantation using the PR-FaST technique is a viable option for patients undergoing thyroidectomy and has been shown to be a reproducible and effective technique in most patients, with sustained graft functionality and parathyroid hormone production over a 5-year follow-up period.
Youth Violence Does not Discriminate: Inclusive Violence Prevention Support Services Focused on Counseling and Peer Support are Essential for Youth and Young Adults
Authors: Puppalla Pravarakhya , Pick Carly , Graves Justin , Harfouche Melike 
Published: April 2024

Background Violence disproportionately affects individuals of low socioeconomic status, and rates of injury amongst youth and young adults (YYAs) are rising. Little is known about how the social needs of this high-risk subgroup compared to the overall violently injured population. Methods This is a retrospective review of an intake assessment of violently injured victims admitted to a level I trauma center (Jan 2022-Aug 2023). Data collected include race, age, mechanism of injury, and protective and predisposing factors for violent injury. We compared the risk factors of YYAs (=≤ 24 years) to those of adults (>24) and evaluated rates and types of violence prevention services requested by age group. Results Of 350 individuals surveyed, 94 (27%) were <= 24 years and 256 (73%) were >24 years. Younger patients were less likely to be male (77% vs 86%, P = .03) and experienced more firearm injury (76% vs 51%, P < .001). They reported less alcohol use (20% vs 38%, P < .001), similar rates of mental illness (25% vs 26%, P = .62), less housing instability (5% vs 22%, P < .001), and similar access to government benefits (20% vs 29%, P = .2) compared to the older cohort. Services were requested by 41% of the study population (N = 142); the younger cohort was 2.9 times more likely to request non-financial services ( P = .042). Discussion Violently injured youth and young adults (YYAs) experience disproportionately high rates of gun violence. Efforts should be made to prioritize legal, peer support, and mental health services over financial services for this population.