bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C058: Remodeling the tumor microenvironment by targeting integrin alpha V beta 3 (αvβ3) expressing cells in pancreatic cancer
Authors: Dominguez Mayrel Palestino , Homan Philip , Zhang Xianyu , Reyes Sandra Navas , Guerin Theresa , Bassel Laura , Liu Zhi-ren , Kozlov Serguei , Alewine Christine 
Published: November 2022

Abstract
ProAgio is a therapeutic cytotoxin that targets and kills integrin αvβ3-expressing cells, resulting in reduced tumor collagen, decreased formation of new blood vessels in the tumor microenvironment (TME), and prolonged survival in mouse models of pancreatic ductal adenocarcinoma (PDAC). ProAgio is currently being tested in a Phase 1 dose-finding study in patients with solid tumors including pancreas cancers. The cell subsets within the PDAC TME that express integrin αvβ3 and could be subject to ProAgio-mediated killing have not been previously studied. Using the KPC genetically engineered mouse model of PDAC, we found that ProAgio (20 mg/kg daily, x7 days) restrained tumor growth by 20% compared to vehicle treatment without changing the cancer cell proliferation rate. We subsequently re-analyzed publicly available scRNA-seq PDAC datasets to identify cells present in human and mouse PDAC tumors that co-express integrins αv and β3 and could be targets of ProAgio. We found that specific subsets of cancer-associated fibroblasts (CAFs), monocytes and macrophages expressed both integrins. Flow cytometry was performed on cells dissociated from orthotopically implanted KPC-derived tumors treated for 15 days with ProAgio or vehicle to identify TME subsets affected by ProAgio treatment. There was no significant difference in the myofibroblast (myCAF) subset, but an increase in the percentage of inflammatory CAFs (iCAFs) was seen. ProAgio treatment also significantly increased the percentage of conventional dendritic cells which play a pivotal role in antigen recognition and T cell priming. T cell abundance was unchanged, but a decrease in B cells was observed. These data demonstrate that ProAgio treatment modifies specific immune and fibroblast subsets within the PDAC TME. Ongoing studies seek to further delineate the cell subtypes affected by ProAgio and the cytokine and chemokine mediators responsible for these changes.
Citation Format: Mayrel Palestino Dominguez, Philip Homan, Xianyu Zhang, Sandra Navas Reyes, Theresa Guerin, Laura Bassel, Zhi-ren Liu, Serguei Kozlov, Christine Alewine. Remodeling the tumor microenvironment by targeting integrin alpha V beta 3 (αvβ3) expressing cells in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C058.
Abstract C061: Alternative polyadenylation regulates gene expression within the pancreatic cancer tumor microenvironment
Authors: Chaubey Aditi H , Feigin Michael E 
Published: November 2022

Abstract
A characteristic of pancreatic ductal adenocarcinoma (PDAC) is that about 90% of its tumor volume can be made up of dense, fibrotic stroma. Multiple studies have shown that this dense stroma strongly influences disease progression and drug delivery. Amongst the cells that make up the stroma, Cancer Associated Fibroblasts (CAFs) are important regulators directly affecting cancer progression and therapeutic resistance. CAFs are a heterogeneous population, including inflammatory, myofibroblastic, and antigen-presenting CAFs, each with specific functional contributions to the cancer phenotype. While we have been able to define CAFs phenotypically, we lack a deeper understanding of the mechanisms underlying their transcriptional heterogeneity and ultimately their contribution in driving PDAC progression. Our lab has previously shown that 3’UTR-Alternative Polyadenylation (APA) is a key mechanism underlying gene dysregulation in PDAC. APA machinery makes use of multiple Poly A Sites (PAS) in a transcript and leads to the formation of distinct isoforms of mRNA with varying lengths, commonly referred to as short or long isoforms. This lengthening and shortening of mRNA modulates mRNA stability, protein expression, and localization, thus directly affecting cellular processes including proliferation, metastasis, and migration. We have now extended these findings to an analysis of APA events within the tumor microenvironment (TME). We find that 3’ UTR shortening is significantly associated with inflammatory CAFs (iCAFs), and that these APA events are correlated with gene expression changes in iCAF marker genes. We hypothesize that APA is a crucial driver of heterogeneity within the tumor microenvironment of PDAC. We have begun to elucidate the mechanisms underlying these gene regulatory changes in vitro using human-derived CAF cell lines via genetic and pharmacological inhibition of APA. Understanding these mechanisms may help us find druggable targets that may eventually affect the overall outcomes of PDAC patients.
Citation Format: Aditi H Chaubey, Michael E Feigin. Alternative polyadenylation regulates gene expression within the pancreatic cancer tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C061.
Abstract IA005: Generating T cell responses against pancreatic cancer
Authors: Byrne Katelyn T. 
Published: November 2022

Abstract
The ultimate promise of tumor immunotherapy is dependent on the generation of an effective immune response against cancer, including CD4 and CD8 T cells. However, driving T cell responses in tumors such as pancreatic ductal adenocarcinoma (PDAC) requires overcoming significant hurdles in the tumor microenvironment (TME). Local and systemic suppression of dendritic cell function depresses endogenous T cell immunity against PDAC, which is further exacerbated by tumor cell intrinsic recruitment of suppressive myeloid cells and macrophages to the tumor site. To bypass these barriers, we’ve utilized agonistic anti-CD40 antibody, which mimics the endogenous CD40 ligand, to license and mature dendritic cells and re-educate tumor-associated myeloid cells towards a Th1/M1 phenotype in the PDAC TME. Using the KrasLSL-G12D/+,Trp53LSL-R172H/+,Pdx1-Cre (KPC) genetically engineered mouse model of pancreatic cancer, we show that combining standard-of-care chemotherapy with CD40 agonism promotes clonal T cell activation and expansion locally in the tumor site, resulting in regressions and cures of established tumors. This CD40-induced T cell response was further enhanced by the addition of dual immune checkpoint blockade (anti-PD-1 and anti-CTLA-4), but was independent of classical innate immune sensors such as Type I interferon receptor (IFNAR) and toll-like receptors (TLRs) previously thought to be critical for the generation of T cell immunity against tumors. These studies formed the preclinical rationale for trials investigating the use of agonistic CD40 therapy for patients with resectable or metastatic PDAC, and provided insight for immunological correlates of response in the clinical setting. More recently, we have reported on the negative impact of chemotherapy on the developing anti-tumor T cell response, emphasizing the need for additional investigations into the combination and sequencing of treatment modalities for enhanced outcomes in patients with PDAC. These studies reveal the potency of using an immunologically relevant mouse model to interrogate immune interventions in PDAC for patients with the greatest unmet clinical need.
Citation Format: Katelyn T. Byrne. Generating T cell responses against pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr IA005.
Abstract PR020: Cholinergic modulation of T lymphocytes in pancreatic adenocarcinoma
Authors: White Ruth A. , Waterbury Quin T. , Ochiai Yosuke , Zamechek Leah B. , Bates Susan E. , Wang Timothy C. 
Published: November 2022

Abstract
Immunotherapy, which can produce durable responses in some cancers, has generally proven ineffective in PDAC, partially due to an immunosuppressive tumor immune microenvironment (TIME). Adjunctive therapies to sensitize PDAC to immunotherapy have the potential to greatly improve survival for patients with PDAC. We have shown that parasympathetic signaling via the vagus nerve inhibits PDAC by suppressing cancer stem cells. Cholinergic signaling through the Muscarinic Acetylcholine Receptor 1 (Chrm1) mediates this phenomenon. The effect of cholinergic signaling on the tumor immune microenvironment is unknown. Our objective is to investigate if loss of Chrm1 or cholinergic signaling impairs anti-tumor immune responses. We used two models of PDAC a) the KRasLSL G12D/+;Trp53R172H/+;Pdx1-Cre (KPC) autochthonous mouse model of PDAC crossed with Chrm1 knockout mice (KPCM) and b) orthotopic PDAC transplantation models. The composition of the TIME and tumor kinetics of these models were assessed, and the effect of genetic loss or pharmacological inhibition of CHRM1 on T lymphocytes function was examined. Inflammatory markers were analyzed in plasma samples from PDAC patients enrolled in a Phase 0/window of opportunity study of the cholinergic agonist, bethanechol, prior to surgery. Results show that loss of Chrm1 is associated with decreased T cell infiltration in the TIME of PDAC and increased tumor growth. CD8+ T cells deficient in Chrm1 demonstrate impaired proliferation, activation and suppression of TCF1, a transcription factor with well described roles in T cell development and maintenance of effector T cell function. Analysis of paired plasma samples obtained from patients treated with the cholinergic agonist, bethanechol show increased expression of CCL5, a chemokine with known roles in T cell migration in the TIME as well as suppression of a number of other inflammatory cytokines including TNF-alpha. These data suggest that cholinergic signaling via CHRM1 on T lymphocytes promotes CD8+ T cell infiltration into the TIME and maintenance of anti-tumor immune responses.
Citation Format: Ruth A. White, Quin T. Waterbury, Yosuke Ochiai, Leah B. Zamechek, Susan E. Bates, Timothy C. Wang. Cholinergic modulation of T lymphocytes in pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR020.
Race, Social Determinants of Health, and Length of Stay Among Hospitalized Patients With Heart Failure: An Analysis From the Get With The Guidelines-Heart Failure Registry
Authors: Segar Matthew W. , Keshvani Neil , Rao Shreya , Fonarow Gregg C. , Das Sandeep R. , Pandey Ambarish 
Published: November 2022

Background:
Racial disparities in heart failure hospitalization and mortality are well established; however, the association between different social determinants of health (SDOH) and length of stay (LOS) and the extent to which this association may differ across racial groups is not well established.

Methods:
We utilized data from the Get With The Guidelines-Heart Failure registry to evaluate the association between SDOH, as determined by patients’ residential ZIP Code and LOS among patients hospitalized with heart failure. We also assessed the race-specific contribution of the ZIP Code–level SDOH to LOS in patients of Black and non-Black races. Finally, we evaluated SDOH predictors of racial differences in LOS at the hospital level.

Results:
Among 301 500 patients (20.2% Black race), the median LOS was 4 days. In adjusted analysis accounting for patient-level and hospital-level factors, SDOH parameters of education, income, housing instability, and foreign-born were significantly associated with LOS after adjusting for clinical status and hospital-level factors. SDOH parameters accounted for 25.8% of the total attributable risk for prolonged LOS among Black patients compared with 10.1% in patients of non-Black race. Finally, hospitals with disproportionately longer LOS for Black versus non-Black patients were more likely to care for disadvantaged patients living in ZIP Codes with a higher percentage of foreign-born and non-English speaking areas.

Conclusions:
ZIP Code–level SDOH markers can identify patients at risk for prolonged LOS, and the effects of SDOH parameters are significantly greater among Black adults with heart failure as compared with non-Black adults.
Development and Piloting of a Community-Partnered Heart Failure Training Course for Home Health Care Workers
Authors: Sterling Madeline R. , Cho Jacklyn , Leung Peggy B. , Silva Ariel F. , Ringel Joanna , Wiggins Faith , Herring Natasha , Powell Alena , Toro Oscar , Lee Ann , Loughman Julia , Obodai Michael , Poon Anthony , Goyal Parag , Kern Lisa M. , Safford Monika M. 
Published: November 2022

Background:
Despite their unique contributions to heart failure (HF) care, home healthcare workers (HHWs) have unmet educational needs and many lack HF caregiving self-efficacy. To address this, we used a community-partnered approach to develop and pilot a HF training course for HHWs.

Methods:
We partnered with the Training and Employment Fund, a benefit fund of the largest healthcare union in the United States, to develop a 2-hour virtual HF training course that met HHWs’ job-specific needs. English and Spanish-speaking HHWs interested in HF training, with access to Zoom, were eligible. We used a mixed methods design with pre/postsurveys and semi-structured interviews to evaluate the course: (a) feasibility, (b) acceptability, and (c) effectiveness (change in knowledge [Dutch Heart Failure Knowledge Scale range 0−15] and caregiving self-efficacy [HF Caregiver Self-efficacy Scale range 0−100]).

Results:

Of the 210 HHWs approached, 100 were eligible and agreed, and 70 enrolled. Of them, 53 (employed by 15 different home care agencies) participated. Posttraining data showed significant improvements (pretraining mean [SD] versus posttraining mean [SD];
P
value) in HF knowledge (11.21 [1.90] versus 12.21 [1.85];
P
=0.0000) and HF caregiving self-efficacy (75.21 [16.57] versus 82.29 [16.49];
P
=0.0017); the greatest gains occurred among those with the lowest pre-training scores. Participants found the course engaging, technically feasible, and highly relevant to their scope of care.

Conclusions:
We developed and piloted the first HF training course for HHWs, which was feasible, acceptable, and improved their HF knowledge and caregiving self-efficacy. Our findings warrant scalability to the workforce at large with a train-the-trainer model.
Increasing Uptake of Depression Screening and Treatment Guidelines in Cardiac Patients: A Behavioral and Implementation Science Approach to Developing a Theory-Informed, Multilevel Implementation Strategy
Authors: Reuter Katja , Genao Kirali , Callanan Emily M. , Cannone Diane E. , Giardina Elsa-Grace , Rollman Bruce L. , Singer Jessica , Slutzky Amy R. , Ye Siqin , Duran Andrea T. , Moise Nathalie 
Published: November 2022

Background:
Depression leads to poor health outcomes in patients with coronary heart disease (CHD). Despite guidelines recommending screening and treatment of depressed patients with CHD, few patients receive optimal care. We applied behavioral and implementation science methods to (1) identify generalizable, multilevel barriers to depression screening and treatment in patients with CHD and (2) develop a theory-informed, multilevel implementation strategy for promoting guideline adoption.

Methods:
We conducted a narrative review of barriers to depression screening and treatment in patients with CHD (ie, medications, exercise, cardiac rehabilitation, or therapy) comprising data from 748 study participants. Informed by the behavior change wheel framework and Expert Recommendations for Implementing Change, we defined multilevel target behaviors, characterized determinants (capability, opportunity, motivation), and mapped barriers to feasible, acceptable, and equitable intervention functions and behavior change techniques to develop a multilevel implementation strategy, targeting health care systems/providers and patients.

Results:
We identified implementation barriers at the system/provider level (eg, Capability: knowledge; Opportunity: workflow integration; Motivation: ownership) and patient level (eg, Capability: knowledge; Opportunity: mobility; Motivation: symptom denial). Acceptable, feasible, and equitable intervention functions included education, persuasion, environmental restructuring, and enablement. Expert Recommendations for Implementing Change strategies included learning collaborative, audit, feedback, and educational materials. The final multicomponent strategy (iHeart DepCare) for promoting depression screening/treatment included problem-solving meetings with clinic staff (system); educational/motivational videos, electronic health record reminders/decisional support (provider); and a shared decision-making (electronic shared decision-making) tool with several functions for patients, for example, patient activation, patient treatment selection support.

Conclusions:
We applied implementation and behavioral science methods to identify implementation barriers and to develop a multilevel implementation strategy for increasing uptake of depression screening and treatment in patients with CHD as a use case. The multilevel implementation strategy will be evaluated in a future hybrid II effectiveness-implementation trial.
When a Sunny Day Gives You Butterflies: An Electrophysiological Investigation of Concreteness and Context Effects in Semantic Word Processing
Authors: Bechtold Laura , Bellebaum Christian , Ghio Marta 
Published: November 2022

Abstract
Theories on controlled semantic cognition assume that word concreteness and linguistic context interact during semantic word processing. Methodological approaches and findings on how this interaction manifests at the electrophysiological and behavioral levels are heterogeneous. We measured ERPs and RTs applying a validated cueing paradigm with 19 healthy participants, who performed similarity judgments on concrete or abstract words (e.g., “butterfly” or “tolerance”) after reading contextual and irrelevant sentential cues. Data-driven analyses showed that concreteness increased and context decreased negative-going deflections in broadly distributed bilateral clusters covering the N400 and N700/late positive component time range, whereas both reduced RTs. Crucially, within a frontotemporal cluster in the N400 time range, contextual (vs. irrelevant) information reduced negative-going amplitudes in response to concrete but not abstract words, whereas a contextual cue reduced RTs only in response to abstract but not concrete words. The N400 amplitudes did not explain additional variance in the RT data, which showed a stronger contextual facilitation for abstract than concrete words. Our results support separate but interacting effects of concreteness and context on automatic and controlled stages of contextual semantic processing and suggest that effects on the electrophysiological versus behavioral level obtained with this paradigm are dissociated.
The Role of the Angular Gyrus in Goal-directed Behavior—Two Transcranial Magnetic Stimulation Studies Examining Response Outcome Learning and Outcome Anticipation
Authors: Jargow Janine , Zwosta Katharina , Treu Svenja , Korb Franziska M. , Ruge Hannes , Wolfensteller Uta 
Published: November 2022

Abstract
Learning the contingencies between a situational context (S), one's own responses (R), and their outcomes (O) and selecting responses according to their anticipated outcomes is the basis of a goal-directed behavior. Previous imaging studies found the angular gyrus (AG) to be correlated to both the representation of R-O associations and outcome-based response selection. Based on this correlational relationship, we investigated the causal link between AG function and goal-directed behavior in offline and online TMS experiments. To this end, we employed an experimental R-O compatibility paradigm testing outcome anticipation during response selection and S-R-O knowledge to probe S-R-O learning. In Experiment 1, we applied 1-Hz rTMS offline to the AG or the vertex before participants performed the experimental tasks. In Experiment 2, we applied online 10-Hz pulse trains to the AG or used sham stimulation during an early action selection stage in half of the trials. In both experiments, the R-O compatibility effect was unaltered when response selection was outcome-based, suggesting no causal role of the AG in outcome anticipation during response selection. However, in both experiments, groups with AG stimulation showed significantly modulated knowledge of S-R-O associations in a posttest. Additionally, in an explorative analysis, we found an induced R-O compatibility effect later in the experiment when response selection was guided by stimulus–response rules, suggesting reduced selectivity of outcome anticipation. We discuss possible compensatory behavioral and brain mechanism as well as specific TMS-related methodical considerations demonstrating important implications for further studies investigating cognitive function by means of TMS.
Examining Shared Reading and White Matter Organization in Kindergarten in Relation to Subsequent Language and Reading Abilities: A Longitudinal Investigation
Authors: Davison Kelsey E. , Zuk Jennifer , Mullin Lindsay J. , Ozernov-Palchik Ola , Norton Elizabeth , Gabrieli John D. E. , Yu Xi , Gaab Nadine 
Published: November 2022

Abstract
Parent–child language interaction in early childhood carries long-term implications for children's language and reading development. Conversational interaction, in particular, has been linked to white matter organization of neural pathways critical for language and reading. However, shared book reading serves an important role for language interaction as it exposes children to sophisticated vocabulary and syntax. Despite this, it remains unclear whether shared reading also relates to white matter characteristics subserving language and reading development. If so, to what extent do these environmentally associated changes in white matter organization relate to subsequent reading outcomes? This longitudinal study examined shared reading and white matter organization in kindergarten in relation to subsequent language and reading outcomes among 77 typically developing children. Findings reveal positive associations between the number of hours children are read to weekly (shared reading time) and the fractional anisotropy of the left arcuate fasciculus, as well as left lateralization of the superior longitudinal fasciculus (SLF). Furthermore, left lateralization of the SLF in these kindergarteners is associated with subsequent reading abilities in second grade. Mediation analyses reveal that left lateralization of the SLF fully mediates the relationship between shared reading time and second-grade reading abilities. Results are significant when controlling for age and socioeconomic status. This is the first evidence demonstrating how white matter structure, in relation to shared reading in kindergarten, is associated with school-age reading outcomes. Results illuminate shared reading as a key proxy for the home language and literacy environment and further our understanding of how language interaction may support neurocognitive development.