bluuebunny/crossref_metadata_2025_split huggingface dataset:
Disruption of the MYC Superenhancer Complex by Dual Targeting of FLT3 and LSD1 in Acute Myeloid Leukemia
Authors: Yashar William M. , Curtiss Brittany M. , Coleman Daniel J. , VanCampen Jake , Kong Garth , Macaraeg Jommel , Estabrook Joseph , Demir Emek , Long Nicola , Bottomly Daniel , McWeeney Shannon K. , Tyner Jeffrey W. , Druker Brian J. , Maxson Julia E. , Braun Theodore P. 
Published: April 2023

AbstractMutations in Fms-like tyrosine kinase 3 (FLT3) are common drivers in acute myeloid leukemia (AML) yet FLT3 inhibitors only provide modest clinical benefit. Prior work has shown that inhibitors of lysine-specific demethylase 1 (LSD1) enhance kinase inhibitor activity in AML. Here we show that combined LSD1 and FLT3 inhibition induces synergistic cell death in FLT3-mutant AML. Multi-omic profiling revealed that the drug combination disrupts STAT5, LSD1, and GFI1 binding at the MYC blood superenhancer, suppressing superenhancer accessibility as well as MYC expression and activity. The drug combination simultaneously results in the accumulation of repressive H3K9me1 methylation, an LSD1 substrate, at MYC target genes. We validated these findings in 72 primary AML samples with the nearly every sample demonstrating synergistic responses to the drug combination. Collectively, these studies reveal how epigenetic therapies augment the activity of kinase inhibitors in FLT3-ITD (internal tandem duplication) AML.Implications:This work establishes the synergistic efficacy of combined FLT3 and LSD1 inhibition in FLT3-ITD AML by disrupting STAT5 and GFI1 binding at the MYC blood-specific superenhancer complex.
MYC Induces Immunotherapy and IFNγ Resistance Through Downregulation of JAK2
Authors: Markovits Ettai , Harush Ortal , Baruch Erez N. , Shulman Eldad D. , Debby Assaf , Itzhaki Orit , Anafi Liat , Danilevsky Artem , Shomron Noam , Ben-Betzalel Guy , Asher Nethanel , Shapira-Frommer Ronnie , Schachter Jacob , Barshack Iris , Geiger Tamar , Elkon Ran , Besser Michal J. , Markel Gal 
Published: April 2023

Abstract
Immunotherapy has revolutionized the treatment of advanced melanoma. Because the pathways mediating resistance to immunotherapy are largely unknown, we conducted transcriptome profiling of preimmunotherapy tumor biopsies from patients with melanoma that received PD-1 blockade or adoptive cell therapy with tumor-infiltrating lymphocytes. We identified two melanoma-intrinsic, mutually exclusive gene programs, which were controlled by IFNγ and MYC, and the association with immunotherapy outcome. MYC-overexpressing melanoma cells exhibited lower IFNγ responsiveness, which was linked with JAK2 downregulation. Luciferase activity assays, under the control of JAK2 promoter, demonstrated reduced activity in MYC-overexpressing cells, which was partly reversible upon mutagenesis of a MYC E-box binding site in the JAK2 promoter. Moreover, silencing of MYC or its cofactor MAX with siRNA increased JAK2 expression and IFNγ responsiveness of melanomas, while concomitantly enhancing the effector functions of T cells coincubated with MYC-overexpressing cells. Thus, we propose that MYC plays a pivotal role in immunotherapy resistance through downregulation of JAK2.
mWTX-330, an IL-12 INDUKINE Molecule, Activates and Reshapes Tumor-Infiltrating CD8+ T and NK Cells to Generate Antitumor Immunity
Authors: Nirschl Christopher J. , Brodkin Heather R. , Domonkos Celesztina , Dwyer Connor J. , Hicklin Daniel J. , Ismail Nesreen , Seidel-Dugan Cynthia , Steiner Philipp , Steuert Zoe , Sullivan Jenna M. , Winston William M. , Salmeron Andres 
Published: April 2023

Abstract
IL-12 is a pleotropic inflammatory cytokine, which has broad stimulatory effects on various immune cell populations, making it an attractive target for cancer immunotherapy. However, despite generating robust antitumor activity in syngeneic murine tumor models, clinical administration of IL-12 has been limited by severe toxicity. mWTX-330 is a selectively inducible INDUKINE molecule comprised of a half-life extension domain and an inactivation domain linked to chimeric IL-12 by tumor protease–sensitive linkers. Systemic administration of mWTX-330 in mice was well tolerated, resulted in robust antitumor immunity in multiple tumor models, and preferentially activated tumor-infiltrating immune cells rather than immune cells present in peripheral tissues. Antitumor activity was dependent on in vivo processing of the protease cleavable linkers and required CD8+ T cells for full efficacy. Within the tumor, mWTX-330 increased the frequency of cross-presenting dendritic cells (DC), activated natural killer (NK) cells, skewed conventional CD4+ T cells toward a T helper 1 (TH1) phenotype, drove regulatory T cells (Treg) fragility, and increased the frequency of polyfunctional CD8+ T cells. mWTX-330 treatment also increased the clonality of tumor-infiltrating T cells by expanding underrepresented T-cell receptor (TCR) clones, drove CD8+ T and NK cells towards increased mitochondrial respiration and fitness, and decreased the frequency of TOX+ exhausted CD8+ T cells within the tumor. A fully human version of this INDUKINE molecule was stable in human serum, was reliably and selectively processed by human tumor samples, and is currently in clinical development.
Adaptive c-Met-PLXDC2 Signaling Axis Mediates Cancer Stem Cell Plasticity to Confer Radioresistance-associated Aggressiveness in Head and Neck Cancer
Authors: Lang Liwei , Chen Fanghui , Li Yamin , Shay Chloe , Yang Fan , Dan Hancai , Chen Zhuo G. , Saba Nabil F. , Teng Yong 
Published: April 2023

Radiotherapy plays an essential role in the treatment of head and neck squamous cell carcinoma (HNSCC), yet radioresistance remains a major barrier to therapeutic efficacy. A better understanding of the predominant pathways determining radiotherapy response could help develop mechanism-informed therapies to improve cancer management. Here we report that radioresistant HNSCC cells exhibit increased tumor aggressiveness. Using unbiased proteome profiler antibody arrays, we identify that upregulation of c-Met phosphorylation is one of the critical mechanisms for radioresistance in HNSCC cells. We further uncover that radioresistance-associated HNSCC aggressiveness is effectively exacerbated by c-Met but is suppressed by its genetic knockdown and pharmacologic inactivation. Mechanistically, the resulting upregulation of c-Met promotes elevated expression of plexin domain containing 2 (PLXDC2) through activating ERK1/2-ELK1 signaling, which in turn modulates cancer cell plasticity by epithelial–mesenchymal transition (EMT) induction and enrichment of the cancer stem cell (CSC) subpopulation, leading to resistance of HNSCC cells to radiotherapy. Depletion of PLXDC2 overcomes c-Met–mediated radioresistance through reversing the EMT progress and blunting the self-renewal capacity of CSCs. Therapeutically, the addition of SU11274, a selective and potent c-Met inhibitor, to radiation induces tumor shrinkage and limits tumor metastasis to lymph nodes in an orthotopic mouse model. Collectively, these significant findings not only demonstrate a novel mechanism underpinning radioresistance-associated aggressiveness but also provide a possible therapeutic strategy to target radioresistance in patients with HNSCC.

Significance:
This work provides novel insights into c-Met-PLXDC2 signaling in radioresistance-associated aggressiveness and suggests a new mechanism-informed therapeutic strategy to overcome failure of radiotherapy in patients with HNSCC.
Association of Prenatal Depression With New Cardiovascular Disease Within 24 Months Postpartum
Authors: Ackerman‐Banks Christina M. , Lipkind Heather S. , Palmsten Kristin , Pfeiffer Mariah , Gelsinger Catherine , Ahrens Katherine A. 
Published: April 2023

Background
Although depression is well established as an independent risk factor for cardiovascular disease (CVD) in the nonpregnant population, this association has largely not been investigated in pregnant populations. We aimed to estimate the cumulative risk of new CVD in the first 24 months postpartum among pregnant individuals diagnosed with prenatal depression compared with patients without depression diagnosed during pregnancy.

Methods and Results

Our longitudinal population‐based study included pregnant individuals with deliveries during 2007 to 2019 in the Maine Health Data Organization's All Payer Claims Data. We excluded those with prepregnancy CVD, multifetal gestations, or no continuous health insurance during pregnancy. Prenatal depression and CVD (heart failure, ischemic heart disease, arrhythmia/cardiac arrest, cardiomyopathy, cerebrovascular disease, and chronic hypertension) were identified by
International Classification of Diseases, Ninth Revision
(
ICD‐9
)/
International Classification of Diseases, Tenth Revision
(
ICD‐10
) codes. Cox models were used to estimate hazard ratios (HRs), adjusting for potential confounding factors. Analyses were stratified by hypertensive disorder of pregnancy. A total of 119 422 pregnancies were examined. Pregnant individuals with prenatal depression had an increased risk of ischemic heart disease, arrhythmia/cardiac arrest, cardiomyopathy, and new hypertension (adjusted HR [aHR], 1.83 [95% CI, 1.20–2.80], aHR, 1.60 [95% CI, 1.10–2.31], aHR, 1.61 [95% CI, 1.15–2.24], and aHR, 1.32 [95% CI, 1.17–1.50], respectively). When the analyses were stratified by co‐occurring hypertensive disorders of pregnancy, several of these associations persisted.

Conclusions
The cumulative risk of a new CVD diagnosis postpartum was elevated among individuals with prenatal depression and persists even in the absence of co‐occurring hypertensive disorders of pregnancy. Further research to determine the causal pathway can inform postpartum CVD preventive measures.
Neutrophil Extracellular Traps in Ischemic Stroke Thrombi Are Associated Wth Poor Clinical Outcome
Authors: Lapostolle Arnaud , Loyer Chloé , Elhorany Mahmoud , Chaigneau Thomas , Bielle Franck , Alamowitch Sonia , Clarençon Frédéric , Elbim Carole 
Published: April 2023

Background
Acute ischemic stroke is a neurologic emergency associated with severe disability and death. There is growing evidence that neutrophil extracellular traps (NETs) contribute to the pathogenesis of acute stroke. By mechanical removal of the occluding thrombus from the patient's vasculature, endovascular thrombectomy enables the collection of thrombus material for immunohistologic analysis. The aim of our study was to strengthen the association of NET content in ischemic thrombi with clinical outcome and guide future therapeutics.

Methods
We performed an immunohistologic analysis of thrombi from 101 patients with acute ischemic stroke, focusing on the association between NET content and clinical and interventional indicators.

Results
NETs were present in every patient with acute ischemic stroke. Their abundance in thrombi was associated with interventional markers of thrombus stability. NET‐rich thrombi were associated with unsuccessful recanalization (modified Thrombolysis in Cerebral Infarction <2B) and longer procedure time, and NET abundance in acute ischemic stroke thrombi was associated with outcomes evaluated by patients’ postassessment National Institutes of Health Stroke Scale and modified Rankin Scale scores.

Conclusion
These findings suggest that NET content is critically important to thrombus stability and clinical outcome in acute stroke. They should open new perspectives for innovative immunotherapy strategies based on neutrophil modulation.
Improvements in task performance after practice are associated with scale-free dynamics of brain activity
Authors: Kardan Omid , Stier Andrew J. , Layden Elliot A. , Choe Kyoung Whan , Lyu Muxuan , Zhang Xihan , Beilock Sian L. , Rosenberg Monica D. , Berman Marc G. 
Published: April 2023

Abstract
Although practicing a task generally benefits later performance on that same task, there are individual differences in practice effects. One avenue to model such differences comes from research showing that brain networks extract functional advantages from operating in the vicinity of criticality, a state in which brain network activity is more scale-free. We hypothesized that higher scale-free signal from fMRI data, measured with the Hurst exponent (H), indicates closer proximity to critical states. We tested whether individuals with higher H during repeated task performance would show greater practice effects. In Study 1, participants performed a dual-n-back task (DNB) twice during MRI (n = 56). In Study 2, we used two runs of n-back task (NBK) data from the Human Connectome Project sample (n = 599). In Study 3, participants performed a word completion task (CAST) across six runs (n = 44). In all three studies, multivariate analysis was used to test whether higher H was related to greater practice-related performance improvement. Supporting our hypothesis, we found patterns of higher H that reliably correlated with greater performance improvement across participants in all three studies. However, the predictive brain regions were distinct, suggesting that the specific spatial H↑ patterns are not task-general.
Remote sensing and citizen science to characterize the ecological niche of an endemic and endangered Costa Rican poison frog
Authors: Garrido-Priego Marina , Aragonés David , Liedtke H. Christoph , Whitworth Andrew , Gomez-Mestre Ivan 
Published: April 2023

Abstract
Habitat encroachment can have devastating effects upon biodiversity, especially amphibians. Phyllobates vittatus is an endemic frog from Costa Rica, where land cover has seen significant changes over recent decades. Here we use remote sensing to create a land cover map of the region and carry out ecological niche modelling to identify the main abiotic factors associated to the distribution of this species. We have informed our models based on our own field observations, those from other researchers, and citizen science participants to obtain a comprehensive database of P. vittatus occurrences. Elevation, forest percentage, distance to lakes and rivers, annual temperature range and precipitation variables were found to shape the ecological niche of P. vittatus, which is mostly located within protected areas. Prior knowledge of the habitat of the species was key to interpret the model output. We identify populations that might be isolated, and areas where presence has not yet been verified or that have not been occupied by the species, thus, identifying potential areas for reintroductions. We also calculated the area of occupancy and recommend that P. vittatus’ status be adjusted to “Endangered”. Future surveys and evaluation of population health and connectivity would help to better ensure the protection of the species in the long-term.
1600 BC: Fårdrup and Valsømagle-Type Axes and the First Evidence of Southern Alpine Metal
Authors: Nørgaard Heide W. , Pernicka Ernst , Vandkilde Helle 
Published: April 2023

Abstract
This article presents the results of a comprehensive investigation of Fårdrup and Valsømagle-type shafthole axes from Denmark and southern Sweden. The combination of artefact style and typology with trace element and lead isotope data in the analysis has provided new insights into the chronological relationship between these two axe types. This way, we open a new window to long-standing debates surrounding these artefact types. Did Fårdrup and Valsømagle type axes evolve parallel, or did they replace each other chronologically in evolutionary progression? The archaeometallurgical dataset presented in this article includes more than 70 axes. Four axes have been analysed for this article. This large set of data is then assessed against a background of metal analyses which trace the long and winding evolution of the use of bronze in Scandinavia c.2300–1400 BC. Combining these two datasets shows the provenance of the metals and, thus, provides insights into metallurgical developments at the onset of the Nordic Bronze Age (NBA, c.1600 BC). In particular, the shafthole axes offer new evidence of the use of a novel type of copper from the East Alpine region based on chalcopyrite ores. The first occurrences of this low-impurity copper in southern Scandinavia appeared around 1700 BC. However, it would eventually become dominant in c.1600 BC, when the local production of shafthole axes began. Significantly, a fraction of the shafthole axes – Fårdrup and Valsømagle-types alike – consist of low impurity copper most likely derived from the Italian Alps (Trentino), which was absent in earlier periods. By NBA II 1500–1300 BC, most metal objects can be related to this northern Italian copper. We interpret this in terms of chronology: Fårdrup (⁓Koszider) and Valsømagle (⁓Tumulus B1) consisted of similar types of copper, which had declined by the onset of NBA II, all indicating that Fårdrup and Valsømagle style objects flourished before the beginning of NBA II (c.1500 BC). The small influx of north Italian copper in the axes indicates that its arrival began before the breakthrough of NBA II. Therefore, while the results of the metal analyses cannot exclude chronological differences between the two shafthole axe types over the 16th century BC, it is probable that their timelines coincided. In summary, our results display correlations between societal developments and thresholds on the one hand and metal provenances and trade routes on the other.
Discrepancy between Intention and Realization in an Implementation Research Perspective: When Researcher and Teachers Talk Past Each Other
Authors: Østergaard Maria Kirstine 
Published: April 2023

Abstract
This article (an extension of a conference paper presented at CERME12; Østergaard & Jankvist, 2022) discusses influential factors in the longitudinal implementation of an innovation concerning students’ beliefs, especially reflection, in mathematics education. Here, the researcher constantly found herself “talking past” the two involved teachers. In the search for a deeper understanding of the discrepancy between the intended and the realized outcome, qualitative data collected in planning sessions and classroom observations are analyzed by applying theoretical constructs from implementation research. In particular, three influential factors appeared to play a central role in the case presented in the paper: characteristics of the end-users, attributes of the innovation, and implementation support strategies. The findings suggest that some of these factors may even have been contradictive to the intentions of the innovation. Furthermore, the article also contributes to the discussion of whether small-scale, qualitative studies have a role to play in implementation research, illustrating how a deeper understanding of the processes involved can be achieved.
The impact sheet to this article can be accessed at 10.6084/m9.figshare.22304629.
Correcting Subseasonal Forecast Errors with an Explainable ANN to Understand Misrepresented Sources of Predictability of European Summer Temperatures
Authors: van Straaten Chiem , Whan Kirien , Coumou Dim , van den Hurk Bart , Schmeits Maurice 
Published: April 2023

Abstract
Subseasonal forecasts are challenging for numerical weather prediction (NWP) and machine learning models alike. Forecasting 2-m temperature (t2m) with a lead time of 2 or more weeks requires a forward model to integrate multiple complex interactions, like oceanic and land surface conditions leading to predictable weather patterns. NWP models represent these interactions imperfectly, meaning that in certain conditions, errors accumulate and model predictability deviates from real predictability, often for poorly understood reasons. To advance that understanding, this paper corrects conditional errors in NWP forecasts with an artificial neural network (ANN). The ANN postprocesses ECMWF extended-range summer temperature forecasts by learning to correct the ECMWF-predicted probability that monthly t2m in western and central Europe exceeds the climatological median. Predictors are objectively selected from ECMWF forecasts themselves, and from states at initialization, i.e., the ERA5 reanalysis. The latter allows the ANN to account for sources of predictability that are biased in the NWP model itself. We attribute ANN corrections with two explainable artificial intelligence (AI) tools. This reveals that certain erroneous forecasts relate to tropical western Pacific Ocean sea surface temperatures at initialization. We conjecture that the atmospheric teleconnection following this source of predictability is imperfectly represented by the ECMWF model. Correcting the associated conditional errors with the ANN improves forecast skill.

Significance Statement
We want to understand occasions in which a numerical weather prediction (NWP) model fails to forecast a predictable event existing in the real world. For forecasts of European summer weather more than 2 weeks in advance, real predictable events are rare. When misrepresented by the model, predicted future states become needlessly biased. We diagnose these missed opportunities with an explainable neural network. The neural network is aware of the initial state and learns to correct the NWP forecast on occasions when it misrepresents a teleconnection from the western tropical Pacific Ocean to Europe. The explainable architecture can be useful for other applications in which conditional model errors need to be understood and corrected.
Exploring the Symmetries of Pantropical Connections between the Tropical Atlantic and Pacific Basins
Authors: Naha Rajashree , McGregor Shayne , Singh Martin 
Published: April 2023

Abstract
Recent analysis of pantropical interactions suggests that after 1980 the tropical Atlantic Ocean’s (TAO) influence on the tropical Pacific Ocean (TPO) appears to have become much more pronounced while the tropical Indian Ocean’s (TIO) influence appears to have weakened. This study explores whether and how decadal changes in TAO and TPO SSTs modulate these pantropical connections in an attempt to explain the recent dominance of the TAO. To this end, we carry out a series of idealized atmosphere-only experiments using the ACCESS atmospheric general circulation model where the magnitude and sign of the decadal TAO SST signal are varied, presenting various warm and cool Atlantic scenarios. To understand further if these pantropical connections are influenced by changes in TPO SST, we carry out the above TAO experiments with both warm and cool phases of Pacific decadal variability (PDV). We find that an imposed TAO warming leads to increases in TPO atmospheric temperature and stability, which lead to a decrease in average TPO precipitation, with the most prominent changes occurring in June–August. These changes in TPO precipitation induced by TAO warming are largely mirrored when TAO cooling is added, whereas the TPO rainfall response to TAO anomalies remains relatively unchanged for the different phases of PDV. In contrast to the precipitation response, the wind response did display some asymmetries between different phases of TAO SST variability. Specifically, surface winds in the western half of the Niño-4 region exhibited a significantly different response to positive versus negative Atlantic multidecadal variability (AMV), whereas the surface winds in the western equatorial Pacific were significantly stronger (roughly 40% larger) in the positive phase of PDV than in the negative phase. These results suggest that the phases of PDV and AMV may modulate pantropical interactions through their effect on zonal wind stress.