bluuebunny/crossref_metadata_2025_split huggingface dataset:
In situ vaccination with cowpea mosaic virus elicits systemic antitumor immunity and potentiates immune checkpoint blockade
Authors: Mao Chenkai , Beiss Veronique , Ho Gregory W , Fields Jennifer , Steinmetz Nicole F , Fiering Steven 
Published: December 2022

BackgroundIn situ vaccination (ISV) is a cancer immunotherapy strategy in which immunostimulatory reagents are introduced directly into a tumor to stimulate antitumor immunity both against the treated tumor and systemically against untreated tumors. Recently, we showed that cowpea mosaic virus (CPMV) is a potent multi-toll-like receptor (TLR) agonist with potent efficacy for treating tumors in mice and dogs by ISV. However, ISV with CPMV alone does not uniformly treat all mouse tumor models tested, however this can be overcome through strategic combinations. More insight is needed to delineate potency and mechanism of systemic antitumor immunity and abscopal effect.MethodWe investigated the systemic efficacy (abscopal effect) of CPMV ISV with a two-tumor mouse model using murine tumor lines B16F10, 4T1, CT26 and MC38. Flow cytometry identified changes in cell populations responsible for systemic efficacy of CPMV. Transgenic knockout mice and depleting antibodies validated the role of relevant candidate cell populations and cytokines. We evaluated these findings and engineered a multicomponent combination therapy to specifically target the candidate cell population and investigated its systemic efficacy, acquired resistance and immunological memory in mouse models.ResultsISV with CPMV induces systemic antitumor T-cell-mediated immunity that inhibits growth of untreated tumors and requires conventional type-1 dendritic cells (cDC1s). Furthermore, using multiple tumor mouse models resistant to anti-programmed death 1 (PD-1) therapy, we tested the hypothesis that CPMV along with local activation of antigen-presenting cells with agonistic anti-CD40 can synergize and strengthen antitumor efficacy. Indeed, this combination ISV strategy induces an influx of CD8+T cells, triggers regression in both treated local and untreated distant tumors and potentiates tumor responses to anti-PD-1 therapy. Moreover, serial ISV overcomes resistance to anti-PD-1 therapy and establishes tumor-specific immunological memory.ConclusionsThese findings provide new insights into in situ TLR activation and cDC1 recruitment as effective strategies to overcome resistance to immunotherapy in treated and untreated tumors.
Exploring the utility of assistive artificial intelligence for ultrasound scanning in regional anesthesia
Authors: Bowness James Simeon , El-Boghdadly Kariem , Woodworth Glenn , Noble J Alison , Higham Helen , Burckett-St Laurent David 
Published: December 2022

IntroductionUltrasound-guided regional anesthesia (UGRA) involves the acquisition and interpretation of ultrasound images to delineate sonoanatomy. This study explores the utility of a novel artificial intelligence (AI) device designed to assist in this task (ScanNav Anatomy Peripheral Nerve Block; ScanNav), which applies a color overlay on real-time ultrasound to highlight key anatomical structures.MethodsThirty anesthesiologists, 15 non-experts and 15 experts in UGRA, performed 240 ultrasound scans across nine peripheral nerve block regions. Half were performed with ScanNav. After scanning each block region, participants completed a questionnaire on the utility of the device in relation to training, teaching, and clinical practice in ultrasound scanning for UGRA. Ultrasound and color overlay output were recorded from scans performed with ScanNav. Experts present during the scans (real-time experts) were asked to assess potential for increased risk associated with use of the device (eg, needle trauma to safety structures). This was compared with experts who viewed the AI scans remotely.ResultsNon-experts were more likely to provide positive and less likely to provide negative feedback than experts (p=0.001). Positive feedback was provided most frequently by non-experts on the potential role for training (37/60, 61.7%); for experts, it was for its utility in teaching (30/60, 50%). Real-time and remote experts reported a potentially increased risk in 12/254 (4.7%) vs 8/254 (3.1%, p=0.362) scans, respectively.DiscussionScanNav shows potential to support non-experts in training and clinical practice, and experts in teaching UGRA. Such technology may aid the uptake and generalizability of UGRA.Trial registration numberNCT04918693.
Nontrivial Limit Cycles in a Kind of Piecewise Smooth Generalized Abel Equation
Authors: Zhao Qianqian , Yu Jiang , Wang Cheng 
Published: December 2022

In this paper, we focus on the number of nontrivial limit cycles in a kind of piecewise smooth generalized Abel equation [Formula: see text] where [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text] and [Formula: see text]. Under the condition [Formula: see text], employing Melnikov functions of any order and using properties of Chebyshev systems, we prove that if [Formula: see text] is odd, then the maximum number of nontrivial limit cycles bifurcating from the periodic annulus of the unperturbed system is 6 and it is attainable, and if [Formula: see text] is even, then the maximum number is 3, and it can be attained too.
Abstract IA003: Catalytic and noncatalytic mechanisms of chromatin modifiers
Authors: Armache Karim-Jean 
Published: December 2022

Abstract
Many mechanisms regulate chromatin structure to ensure that genes are active or silent. Some are considered epigenetic, ensuring the heritable transmission of a specific chromatin state. One of the mechanisms of chromatin regulation is based on posttranslational modifications of histones. Chemical groups are deposited, read, and removed by protein complexes that regulate chromatin structure. Histone modifications correlate with and sometimes directly affect critical processes such as transcription, replication, recombination, and repair. They are the subject of many clinical studies, as aberrant histone modifications and deregulation of enzymes responsible for their deposition occur in many cancers. These modifications rarely function in isolation, and there is often crosstalk between them that results in a coordinated transcriptional output. The central question in the field is to understand the regulation of histone modifications and associated molecular complexes, their role in gene expression, and their pathology in cancer. Another critical question is to discover and characterize the intricate relationships between different histone modifications and histone modifying enzymes at the mechanistic level. I will discuss our progress in understanding the roles of histone methylation and how it interfaces with other chromatin modifications that play critical roles in gene regulation.
Citation Format: Karim-Jean Armache. Catalytic and noncatalytic mechanisms of chromatin modifiers. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA003.
Abstract IA006: Systematic functional screening of chromatin factors identifies strong lineage and disease dependencies in normal and malignant haematopoiesis
Authors: Huntly Brian 
Published: December 2022

Abstract
Interactions between transcription factors (TF) and chromatin factors (CF) regulate gene expression programmes to determine cellular fate. However, unlike for TF, the exact role of CF in this process is poorly understood. Using haematopoiesis as a model system, we address this fundamental question in lineage choice of normal haematopoiesis and the maintenance of acute myeloid leukaemia (AML). To do this, we have functionally characterized the requirement ex vivo of 550 CFs in normal lineage differentiation and further dissected, with single-cell resolution, the roles of 40 CFs during in vivo lineage commitment (using Perturb-seq). Further, utilizing epigenetic profiling (ATAC-seq and ChIP-seq) we have probed TF-CF interactions that have lineage regulatory potential. Finally, we compare the functions of key CFs and their TF-associations between normal and malignant haematopoiesis. These studies demonstrate, both ex vivo and in vivo, that similar complexes, including three MLL-H3K4 COMPASS methyltransferases (KMTs) and non-canonical (nc-BAF) and canonical BAF (c-BAF) complexes, regulate disparate lineage decisions across haematopoiesis. However, somewhat paradoxically, we demonstrate that unrelated Repressive complexes function similarly, but non-redundantly, to restrain excessive myeloid differentiation and protect lineage diversity. We identify interactions between CF and TF that explain the regulatory function of CF and demonstrate that KO of the nc-BAF member Brd9 leads to a premalignant accumulation of myeloid progenitors, related to impaired recruitment of late myeloid TFs. Finally, utilizing similar experiments in a relevant murine AML model, we identify perturbations of MLL-, BAF- and Repressive CF that trigger partial differentiation and loss of leukaemia potential. Our data also highlight opposing functions for the same CF in normal and malignant haematopoiesis. CFs such as COMPASS members and cBAF remodelers are critical for the balanced differentiation of specific normal haematopoietic lineages, however the same CF are critical for the maintenance of leukaemia fitness, where they act predominantly to maintain differentiation blockade. Finally, we demonstrate that this altered effect occurs through the differential utilization of TF by CF complexes between normal and malignant haematopoiesis, such as corrupted Stat5a-CF interactions, potentially identifying specific CF-TF complexes as therapeutic targets in AML. Taken all together, our work greatly elucidates the role of CF and their TF partners across normal and malignant haematopoiesis.
Citation Format: Brian Huntly. Systematic functional screening of chromatin factors identifies strong lineage and disease dependencies in normal and malignant haematopoiesis. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA006.
Abstract A02: MEK-CDK4/6 inhibition induces plasma cell tumor infiltration and sensitizes de novo MPNSTs to immune checkpoint blockade
Authors: Lingo Joshua , Kohlmeyer Jordan , Kaemmer Courtney , Scherer Amanda , Voigt Ellen , Chimenti Michael , Tanas Munir , Monga Varun , Darbro Ben , Meyerholz David , Dodd Rebecca , Quelle Dawn 
Published: December 2022

Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) are deadly, Ras-driven sarcomas that lack effective therapies. Many tumors are unresectable and toxic chemotherapies are ineffectual. The sensitivity of MPNSTs to immune checkpoint blockade (ICB) therapies is not known, although sarcomas are generally unresponsive. Patient tumor analyses comparing MPNSTs to benign precursors identified Ras effectors, MEK and CDK4/6 kinases, as rational targets for therapy. We tested the efficacy of dual MEK-CDK4/6 inhibition versus single drug therapy using preclinical MPNST models. In MPNST cells, low-dose drug combinations synergistically reactivated the retinoblastoma (RB1) tumor suppressor, induced cell death and decreased clonogenic survival. In de novo MPNSTs in immune competent mice, combination therapy caused tumors to shrink, substantially delayed resistant tumor outgrowth and improved survival relative to monotherapies. Tumor regression was associated with an immune activation gene expression profile featuring plasma cell infiltration, an event not previously observed with MEK-CDK4/6 inhibitor therapy. In other human tumor types, intratumoral plasma cells prognose better overall survival and improved response to ICB therapies. Excitingly, MEK-CDK4/6 therapy sensitized de novo MPNSTs to anti-programmed death ligand 1 (PD-L1) therapy with the combination achieving complete tumor ablation and apparent cure in 10% of mice. These findings implicate a critical role for plasma cells in mediating MPNST regression in response to kinase inhibitor therapy and sensitizing tumors to PD-L1 targeting. This novel therapeutic combination is a promising option for MPNST therapy that could improve ICB efficacy in other solid tumors.
Citation Format: Joshua Lingo, Jordan Kohlmeyer, Courtney Kaemmer, Amanda Scherer, Ellen Voigt, Michael Chimenti, Munir Tanas, Varun Monga, Ben Darbro, David Meyerholz, Rebecca Dodd, Dawn Quelle. MEK-CDK4/6 inhibition induces plasma cell tumor infiltration and sensitizes de novo MPNSTs to immune checkpoint blockade [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A02.
Abstract A18: In vivo CRISPR screening in syngeneic tumor models to identify novel combinations for cancer immunotherapy
Authors: Sa Qila , Liang Hongyu , Kostadinov Rumen , Yu Jong , Waight Jeremy , Van Horn Stephanie , Xie Qing , Griffin Sue , Hopson Chris , Sun Ning 
Published: December 2022

Abstract
Inducible T cell Co-Stimulator (ICOS, CD278) is a receptor belonging to the CD28/CTLA-4 superfamily that is predominantly expressed on T cells following T cell receptor (TCR) activation and plays an important role in regulating adaptive immune response. ICOS represents possible node of therapeutic intervention for cancer, and as such, is under clinical evaluation. Although ICOS agonists have been shown to promote significant monotherapeutic efficacy in non-clinical studies, most patients do not respond to the single-agent approaches. Therefore, it is crucial to better understand the potential mechanisms of action as well as to develop novel combination strategies and biomarkers to best position therapeutic in the clinic. In an effort to identify novel combination partners and/or biomarkers for ICOS agonist, we utilized pooled in vivo genetic screening via CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 genome editing in the syngeneic CT26 colorectal mouse tumor model alongside agonist treatment for the target. We evaluated 509 druggable genes with four sgRNAs targeting each gene to identify genes where loss in CT26 tumor cells can increase sensitivity or resistance to this treatment. With a false discovery rate (FDR) &lt;0.05, we were able to identify 38 sensitizing hits for ICOS agonist. To our knowledge, this is the first in vivo genetic screening in mouse models aiming to uncover potential combinational targets for anti-ICOS agonist. Importantly, this screening strategy can be adapted to orthogonal tumor types to confirm current hits or identify undescribed combination targets for a range of other immunotherapeutic approaches.
Citation Format: Qila Sa, Hongyu Liang, Rumen Kostadinov, Jong Yu, Jeremy Waight, Stephanie Van Horn, Qing Xie, Sue Griffin, Chris Hopson, Ning Sun. In vivo CRISPR screening in syngeneic tumor models to identify novel combinations for cancer immunotherapy [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A18.
Abstract IA24: The evolution of neoadjuvant immunotherapy in bladder cancer
Authors: Galsky Matthew D. 
Published: December 2022

Abstract
PD-1/PD-L1 blockade has transformed the treatment landscape for advanced bladder cancer. Based on the durable disease control achieved in a subset of patients with such therapy, in the context of a relatively favorable tolerability profile, a logical progression of the clinical development of PD-1/PD-L1 blockade in bladder cancer is to move these treatments to earlier disease states. The neoadjuvant, or pre-surgical, treatment platform affords a number of potential opportunities for clinical drug development which encompass scientific, pragmatic, patient-centered, and regulatory domains. However, this platform may serve to both advance the development of drugs and also advance the development of treatment paradigms and no single trial is likely poised to fully address these related, but distinct, goals. Neoadjuvant trials incorporating immune checkpoint blockade in bladder cancer have already demonstrated sufficient signals of activity to support the initiation of multiple large definitive phase 3 trials, generate novel immunobiologic insights, and even provide a new path for curative-intent bladder-sparing treatment.
Citation Format: Matthew D. Galsky. The evolution of neoadjuvant immunotherapy in bladder cancer [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr IA24.
Assessing Heuristic Bias During Care for Patients Hospitalized for Heart Failure: Get With The Guidelines-Heart Failure
Authors: Selvaraj Senthil , Greene Stephen J. , Ayodele Iyanuoluwa , Alhanti Brooke , Allen Larry A. , Lewsey Sabra C. , Adusumalli Srinath , Reza Nosheen , Hernandez Adrian F. , Yancy Clyde W. , Jena Anupam B. , Fonarow Gregg C. , Bhatt Deepak L. 
Published: December 2022

Background:
Heuristic biases are increasingly recognized, and potentially modifiable, contributors to patient care and outcomes. Left digit bias is a cognitive bias where continuous variables are categorized by their left-most digit. The impact of this heuristic bias applied to patient age on quality of care in heart failure has not been explored.

Methods:
We examined participants admitted from 2005 to 2021 in the Get With The Guidelines-Heart Failure registry. To create 2 naturally randomized groups, isolating the effect of left digit bias, we dichotomized patients into those discharged within 60 days prior to their 80th birthday (N=4238) and those discharged within 60 days after their 80th birthday (N=4329). We performed multivariable logistic regression to assess the association between discharge date relative to 80th birthday and several in-hospital quality metrics and in-hospital outcomes. Among Medicare participants (N=2759), we performed adjusted Cox regression to analyze the relationship between discharge date and risk of 1-year mortality or readmission.

Results:

Among 8567 patients, 50.4% were female, 73% were non-Hispanic White, and 42.9% had an ejection fraction ≤40%. Discharge date relative to 80th birthday was not associated with numerous in-hospital quality metrics or in-hospital outcomes on unadjusted or adjusted logistic regression. Among Medicare beneficiaries, there was no association between discharge date and risk of mortality or readmission at 1-year postdischarge (hazard ratio, 1.03 [95% CI, 0.95–1.12];
P
=0.52).

Conclusions:
In a large registry of patients hospitalized for heart failure, we did not detect a left digit bias‚ with respect to age at discharge, which resulted in differential quality of care or outcomes.
TSPAN12 (Tetraspanin 12) Is a Novel Negative Regulator of Aldosterone Production in Adrenal Physiology and Aldosterone-Producing Adenomas
Authors: Gong Siyuan , Tetti Martina , Kemter Elisabeth , Peitzsch Mirko , Mulatero Paolo , Bidlingmaier Martin , Eisenhofer Graeme , Wolf Eckhard , Reincke Martin , Williams Tracy Ann 
Published: December 2022

Background:

Aldosterone-producing adenomas (APAs) are a major cause of primary aldosteronism, a condition of low-renin hypertension, in which aldosterone overproduction is usually driven by a somatic activating mutation in an ion pump or channel.
TSPAN12
is differentially expressed in different subgroups of APAs suggesting a role in APA pathophysiology. Our objective was to determine the function of TSPAN12 (tetraspanin 12) in adrenal physiology and pathophysiology.

Methods:
APA specimens, pig adrenals under dietary sodium modulation, and a human adrenocortical cell line HAC15 were used for functional characterization of TSPAN12 in vivo and in vitro.

Results:

Gene ontology analysis of 21 APA transcriptomes dichotomized according to high versus low
TSPAN12
transcript levels highlighted a function for
TSPAN12
related to the renin-angiotensin system.
TSPAN12
expression levels in a cohort of 30 APAs were inversely correlated with baseline plasma aldosterone concentrations (
R
=−0.47;
P
=0.009). In a pig model of renin-angiotensin system activation by dietary salt restriction,
TSPAN12
mRNA levels and TSPAN12 immunostaining were markedly increased in the zona glomerulosa layer of the adrenal cortex. In vitro stimulation of human adrenocortical human adrenocortical cells with 10 nM angiotensin II for 6 hours caused a 1.6-fold±0.13 increase in
TSPAN12
expression, which was ablated by 10 μM nifedipine (
P
=0.0097) or 30 μM W-7 (
P
=0.0022). Gene silencing of
TSPAN12
in human adrenocortical cells demonstrated its inverse effect on aldosterone secretion under basal and angiotensin II stimulated conditions.

Conclusions:
Our findings show that TSPAN12 is a negative regulator of aldosterone production and could contribute to aldosterone overproduction in primary aldosteronism.
Representations of Abstract Relations in Infancy
Authors: Hochmann Jean-Rémy 
Published: December 2022

Abstract
Abstract relations are considered the pinnacle of human cognition, allowing for analogical and logical reasoning, and possibly setting humans apart from other animal species. Recent experimental evidence showed that infants are capable of representing the abstract relations same and different, prompting the question of the format of such representations. In a propositional language of thought, abstract relations would be represented in the form of discrete symbols. Is this format available to pre-lexical infants? We report six experiments (N = 192) relying on pupillometry and investigating how preverbal 10- to 12-month-old infants represent the relation same. We found that infants’ ability to represent the relation same is impacted by the number of individual entities taking part in the relation. Infants could represent that four syllables were the same and generalized that relation to novel sequences (Experiments 1 and 4). However, they failed to generalize the relation same when it involved 5 or 6 syllables (Experiments 2–3), showing that infants’ representation of the relation same is constrained by the limits of working memory capacity. Infants also failed to form a representation equivalent to all the same, which could apply to a varying number of same syllables (Experiments 5–6). These results highlight important discontinuities along cognitive development. Contrary to adults, preverbal infants lack a discrete symbol for the relation same, and rather build a representation of the relation by assembling symbols for individual entities.
Modeling Individual Differences in Children’s Information Integration During Pragmatic Word Learning
Authors: Bohn Manuel , Schmidt Louisa S. , Schulze Cornelia , Frank Michael C. , Tessler Michael Henry 
Published: December 2022

Abstract
Pragmatics is foundational to language use and learning. Computational cognitive models have been successfully used to predict pragmatic phenomena in adults and children – on an aggregate level. It is unclear if they can be used to predict behavior on an individual level. We address this question in children (N = 60, 3- to 5-year-olds), taking advantage of recent work on pragmatic cue integration. In Part 1, we use data from four independent tasks to estimate child-specific sensitivity parameters to three information sources: semantic knowledge, expectations about speaker informativeness, and sensitivity to common ground. In Part 2, we use these parameters to generate participant-specific trial-by-trial predictions for a new task that jointly manipulated all three information sources. The model accurately predicted children’s behavior in the majority of trials. This work advances a substantive theory of individual differences in which the primary locus of developmental variation is sensitivity to individual information sources.