bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract C009: Disruption of tumor-promoting desmoplasia by adoptive transfer of fibroblast activation protein targeted chimeric antigen receptor (CAR) T cells enhances anti-tumor immunity and immunotherapy
Authors: Xiao Zebin , Hopper Leslie A. , Kopp Meghan C. , McMillan Emily , Li Yue , Barrett Richard L , Puré Ellen
Published: November 2022

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease due to the poor response to current therapeutic treatments. A major barrier to effective treatment of PDAC is the extensive remodeling of tumor stroma characterized by accumulation of cancer associated fibroblasts (CAFs) and extracellular matrix which forms a physical barrier that limits access of the drugs to the cancer cells, suppresses the immune system, and attenuates efficacy of immunotherapies. Fibroblast activation protein (FAP) is highly expressed in a pro-tumorigenic subset of CAFs in PDAC. We hypothesized that depletion of FAP+-CAFs would deplete extracellular matrix (ECM) and reduce the immune suppressive function of the stroma and thereby enhance the efficacy of tumor antigen targeted CAR T cell therapy in PDAC. Using real-time tumor fragment-based 2-photon microscopy, multiparametric flow cytometry and multiplexed immunofluorescence staining, we showed that FAP targeted CAR T cells (FAP-CAR T) efficiently traffic into tumors compared with tumor-antigen (mesothelin) targeted CAR (Meso-CAR) T cells which were trapped in the stroma-rich or matrix-dense areas and led to depletion of immunosuppressive FAP+ cells and reprogrammed the fibrillar collagen network surrounding tumor nests, advancing the infiltration of FAP-CAR T cells into tumor nests. Strikingly, FAP-CAR T cell-mediated depletion for FAP+ cells also rendered the tumor microenvironment permissive to the infiltration and anti-tumor activity of tumor antigen meso-CAR T cells. Moreover, ablation of FAP+ cells markedly enhanced endogenous T cell infiltration which further enhanced anti-tumor immunity and immunotherapy in PDAC models. Thus, our findings established that FAP-CAR T cell-mediated ablation of immunosuppressive FAP+-CAFs and disruption of the desmoplastic stroma they generate, can enhance accumulation and functionality of endogenous anti-tumor immunity and CAR-T cell therapy in the context of highly desmoplastic solid tumors.

Citation Format: Zebin Xiao, Leslie A. Hopper, Meghan C. Kopp, Emily McMillan, Yue Li, Richard L Barrett, Ellen Puré. Disruption of tumor-promoting desmoplasia by adoptive transfer of fibroblast activation protein targeted chimeric antigen receptor (CAR) T cells enhances anti-tumor immunity and immunotherapy [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 C009.
Abstract C029: Chemotherapy backbone alters the mechanism of action of TGFb blockade in pancreatic cancer
Authors: Qiang Li , Ali Lestat , Hoffman Meggie , Silva Jaime Ivan Castillo , Lenehan Patrick , Bello Elisa , Pelletier Marc , Cremasco Viviana , Dougan Stephanie
Published: November 2022

TGFβ plays a critical role in promoting pancreatic tumor progression, attenuating CD8 T cell proliferation and cytokine production, enhancing the differentiation of myofibroblasts and the deposition of extracellular matrix. However, single agent TGFβ blockade has shown limited efficacy in mouse models of pancreatic cancer. Here we showed that in combination with chemotherapy, using either gemcitabine/n(ab)-paclitaxel or FOLFIRINOX, neutralization of TGFβ can reduce tumor burden in the poorly immunogenic 6694c2 orthotopic pancreatic cancer mouse model, without affecting the metastatic rate of cancer cells. As expected, anti-TGFβ with combination chemotherapy significantly increased the mean survival time of the orthotopic mouse models. Surprisingly, the efficacy of both combinational therapies is not dependent on CD8 T cells in either immunogenic or non-immunogenic models, as CD8 depleted or RAG2 knockout mice are responsive to the treatments to similar levels. Instead, comparing to chemotherapy single treatment, in the presence of TGFβ blocking antibody, tumor cells are more vulnerable to chemotherapy-induced cell death, both in vitro and in vivo. Recent studies from Raghavan et al. demonstrated that the plasticity of the classical and basal lineage of pancreatic cancer can be regulated by TGFβ ligand. Consistently, here we show that single-cell analysis and limited bulk RNAseq on tumor cells sorted ex vivo revealed 6694c2 tumor cells treated with TGFβ blockade maintain classical lineage, the state of pancreatic cancer with more sensitivity to chemotherapy and better prognosis. FOLFIRINOX treatments have largely modified tumor stromal landscape, with a unique CAF population presented expressing high levels of PTX3, which further verified by immunohistochemistry. This study provides the scientific rationale for the evaluation of TGFβ with both chemotherapy backbone in the clinical setting, as well as supports the concept of plasticity of pancreatic cancer cell state and plasticity of stromal cell landscape in tumors, providing foundations for future investigations on the mechanisms of TGFβ with different chemotherapy backbone in regulating the crosstalk among fibroblast subsets, immune cells and pancreatic cancer cells.

Citation Format: Li Qiang, Lestat Ali, Meggie Hoffman, Jaime Ivan Castillo Silva, Patrick Lenehan, Elisa Bello, Marc Pelletier, Viviana Cremasco, Stephanie Dougan. Chemotherapy backbone alters the mechanism of action of TGFb blockade 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 C029.
Abstract C043: Addition of losartan to FOLFORINOX and chemoradiation downregulates pro-invasion and immunosuppression-associated genes in locally advanced pancreatic cancer
Authors: Boucher Yves , Posada Jessica M. , Subudhi Sonu , Rosario Spencer R. , Gu Liqun , Kumar Ashwin S. , Kumra Heena , Mino-Kenudson Mari , Talele Nilesh P. , Duda Dan G. , Fukumura Dai , Wo Jennifer Y. , Clark Jeffrey W. , Ryan David P. , Castillo Carlos Fernandez-Del , Hong Theodore S. , Pittet Mikael J. , Jain Rakesh K.
Published: November 2022

Purpose: Adding losartan to FOLFIRINOX (FFX) chemotherapy followed by chemoradiation (CRT) resulted in 61% R0 surgical resection in our phase II trial in patients with locally advanced pancreatic cancer. Here we identify potential mechanisms of benefit by assessing the effects of neoadjuvant losartan+FFX+CRT versus FFX+CRT on the stromal tumor microenvironment. Experimental Design: We performed a gene expression analysis of RNA extracted from pancreatic cancer tissue sections and immunofluorescence for cancer cells and immune cells using archived surgical samples from patients treated with losartan+FFX+CRT (NCT01591733), FFX+CRT (NCT01591733) or surgery upfront, without any neoadjuvant therapy. We then assessed whether certain gene sets could stratify the overall survival of patients. Results: Neoadjuvant losartan+FFX+CRT and FFX+CRT increased the expression of genes linked to vascular normalization, transendothelial migration of leukocytes, T cell activation and cytolytic activity, and dendritic cell related genes versus no neoadjuvant treatment. In comparison to FFX+CRT, losartan+FFX+CRT downregulated pro-invasion, immunosuppression, and M2 macrophages related genes, and upregulated genes associated with tumor suppression, including the p53 pathway. Furthermore, immunostaining revealed significantly less residual disease in lesions treated with losartan+FFX+CRT versus FFX+CRT. Losartan+FFX+CRT also reduced CD4+FOXP3+ regulatory T cells in pancreatic cancer lesions with a complete/near complete response. Overall survival was associated with dendritic cell and antigen presentation genes for patients treated with FFX+CRT, and with immunosuppression and invasion genes or dendritic cell- and blood vessel-related genes for those treated with losartan+FFX+CRT. Conclusions: Adding losartan to FFX+CRT reduced pro-invasion and immunosuppression related genes, which were associated with improved treatment outcomes in patients with locally advanced pancreatic cancer.

Citation Format: Yves Boucher, Jessica M. Posada, Sonu Subudhi, Spencer R. Rosario, Liqun Gu, Ashwin S. Kumar, Heena Kumra, Mari Mino-Kenudson, Nilesh P. Talele, Dan G. Duda, Dai Fukumura, Jennifer Y. Wo, Jeffrey W. Clark, David P. Ryan, Carlos Fernandez-Del Castillo, Theodore S. Hong, Mikael J. Pittet, Rakesh K. Jain. Addition of losartan to FOLFORINOX and chemoradiation downregulates pro-invasion and immunosuppression-associated genes in locally advanced 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 C043.
Abstract C050: Elucidating mechanisms of endocrine-exocrine signaling in obesity-driven pancreatic cancer
Authors: Garcia Cathy C. , Lawres Lauren , Agabiti Sherry , Singh Jaffarguriqbal , Tong Alex , Venkat Aarthi , Burkhardt Daniel B. , Cardone Rebecca , Kibbey Richard G. , Krishnaswamy Smita , Muzumdar Mandar D.
Published: November 2022

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States. Various epidemiologic studies have shown that obesity increases the risk of PDAC. With rising rates of obesity worldwide, it is imperative that we understand the mechanisms by which obesity promotes PDAC progression. Therefore, to study the effect of obesity on PDAC, we combined a well-established genetic model of obesity (Lepob/ob) with a faithful oncogenic Kras-driven pancreatic cancer model (KC: Pdx1-Cre; KrasLSL-G12D/+) and showed that obese mice had both increased tumor burden and shortened survival compared to their lean counterparts. Strikingly, weight loss (via AAV-leptin rescue or caloric restriction), decreased tumor development, demonstrating that the tumor-promoting effects of obesity can be reversed. Bulk-RNA sequencing of tumors from obese mice exhibited aberrant expression of islet beta-cell genes, including those coding for the peptide hormones cholecystokinin (CCK) and amylin (Iapp). Single-cell RNA sequencing of islet beta-cells from wild-type, high fat diet-fed, and Lepob/ob mice revealed a trajectory of beta-cell adaptation to obesity with dysregulated hormone expression, including downregulation of insulin expression and upregulation of CCK and Iapp, concordant with loss of beta-cell identity transcription factors and beta-cell dysfunction. In silico analyses using dynamic optimal transport (TrajectoryNet) demonstrate that CCK-expressing beta-cells arise from pre-existing insulin low-expressing beta-cells, arguing for baseline beta-cell heterogeneity as a determinant of aberrant hormone expression. Lastly, transgenic expression of CCK or Iapp in beta-cells was sufficient to promote oncogenic Kras-driven pancreatic tumorigenesis, while converse beta-cell ablation impeded tumor progression in mice. Together, these results uncover a novel mechanism of obesity driven PDAC by local hormonal signaling between endocrine islets and exocrine acinar cells and reveal pancreatic endocrine adaptations that could be targeted to halt exocrine tumorigenesis.

Citation Format: Cathy C. Garcia, Lauren Lawres, Sherry Agabiti, Jaffarguriqbal Singh, Alex Tong, Aarthi Venkat, Daniel B. Burkhardt, Rebecca Cardone, Richard G. Kibbey, Smita Krishnaswamy, Mandar D. Muzumdar. Elucidating mechanisms of endocrine-exocrine signaling in obesity-driven 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 C050.
Abstract C054: Hypoxia promotes a durable epithelial-mesenchymal transition in pancreas cancer through a histone methylation-MAPK signaling axis
Authors: Brown Brooke A. , Myers Paul J. , Adair Sara J. , Pitarresi Jason R. , Teli Shiv Sah , Karppinen Peppi , Stanger Ben Z. , Bauer Todd W. , Lazzara Matthew J.
Published: November 2022

Pancreatic ductal adenocarcinoma (PDAC) tumors are poorly vascularized and exhibit regions of hypoxia. Here, we demonstrate that this feature of the tumor microenvironment promotes epithelial-mesenchymal transition (EMT), which occurs early in PDAC and drives chemoresistance, and we identify the underlying signaling mechanism. Analysis of publicly-available human transcriptomics and proteomics demonstrated that PDAC cells or tumors enriched in mesenchymal markers were also enriched in markers of hypoxia or HIF activity. Furthermore, in lineage-traced autochthonous, orthotopic patient-derived xenograft, and orthotopic or subcutaneous implanted cell line models of PDAC, hypoxic tumor tissue regions were enriched for neoplastic cells that had undergone EMT. In cell culture experiments, PDAC cells from human and mouse tumors exhibited an ability to undergo EMT in response to 1% O2, with loss of membranous E-cadherin, increased vimentin protein expression, and transcriptional changes indicative of both hypoxia and EMT. Moreover, EMT in response to hypoxia was substantially more persistent than that observed in response to growth factors, and a hypoxia fate mapping system revealed that once-hypoxic cells could retain mesenchymal characteristics outside hypoxic tumor regions. To understand the mechanism for EMT in response to low oxygen tension, we constructed a multivariable linear regression model of the dependence of the hypoxic gene signature on different gene sets in PDAC ductal cells, which identified MAPK signaling as the most important feature. Consistent with the model inference, in both in vitro and in vivo settings, hypoxic cells showing evidence of EMT displayed elevated MAPK signaling. We further demonstrated that MAPK activation in hypoxia was potentiated by suppressed activity of a histone demethylase and concomitant loss of protein phosphatase expression, which reinforced the mechanism by stabilizing the expression of a histone methyltransferase. Thus, this study identifies a tumor microenvironment-initiated mechanism leading to EMT and nominates several potential drug targets whose antagonism may promote PDAC chemoresponse.

Citation Format: Brooke A. Brown, Paul J. Myers, Sara J. Adair, Jason R. Pitarresi, Shiv Sah Teli, Peppi Karppinen, Ben Z. Stanger, Todd W. Bauer, Matthew J. Lazzara. Hypoxia promotes a durable epithelial-mesenchymal transition in pancreas cancer through a histone methylation-MAPK signaling axis [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 C054.
Abstract C056: The prolyl isomerase PIN1 controls fibroblast state plasticity to impact pancreatic cancer
Authors: Langer Ellen M. , Shah Vidhi , Farrell Amy , Daniel Colin , Wang Xiaoyan , MacPherson Kevin , Allen-Petersen Brittany L. , Tsuda Motoyuki , Sherman Mara , Adey Andrew , Sears Rosalie C.
Published: November 2022

Pancreatic cancer associated fibroblasts (CAFs) have been described to play multiple, often conflicting, roles to support or restrict tumor growth. Recent work suggests that heterogeneous differentiation states of fibroblasts contribute to these diverse functions and that reprogramming of fibroblast states can influence tumor outcomes. The impact of distinct fibroblast subpopulations on heterogeneous tumor development and growth, however, remain incompletely understood. PIN1 is a phosphorylation-directed prolyl isomerase that alters the conformation and, therefore, the function of many proteins. PIN1 is overexpressed in cancer and contributes to cancer cell-intrinsic pro-tumorigenic behaviors including cellular proliferation and migration. While its pro-tumor functions have generated interest in therapeutic targeting of PIN1 for cancer treatment, the direct effects of PIN1 inhibition on tumor-associated stromal phenotypes are poorly understood. We have found that PIN1 loss or inhibition results in decreased tumor growth in vivo in transplant or genetically engineered mouse models. Moreover, in syngeneic orthotopic allograft models in which loss of PIN1 is restricted to the tumor host, we observed that KPC tumor cells still have decreased growth, suggesting a critical role for PIN1 in the tumor microenvironment. We observed that PIN1 loss or inhibition in vivo was accompanied by decreased expression of alpha-SMA, a marker of myofibroblast-like CAFs, and have identified a role for PIN1 in the phenotypic and epigenetic response to TGF-beta, a major driver of the myCAF state. PIN1low pancreatic stellate cells or CAFs display altered cell morphology, decreased proliferation, decreased ECM deposition, as well as altered paracrine signaling to cancer cells and other stromal cells. We are currently using 2D co-cultures, heterotypic 3D bioprinted tissues, and in vivo mouse models to interrogate the molecular mechanisms by which PIN1 controls fibroblast phenotypes and functional impact of altering fibroblast state on tumor phenotypes and outcomes. In addition, we are defining PIN1-dependent mechanisms of crosstalk between neoplastic and non-neoplastic cells and are investigating the requirements for specific fibroblast states to support in vivo growth of heterogeneous pancreatic cancer cells.

Citation Format: Ellen M. Langer, Vidhi Shah, Amy Farrell, Colin Daniel, Xiaoyan Wang, Kevin MacPherson, Brittany L. Allen-Petersen, Motoyuki Tsuda, Mara Sherman, Andrew Adey, Rosalie C. Sears. The prolyl isomerase PIN1 controls fibroblast state plasticity to impact 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 C056.
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

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

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

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

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.
Prospective Test Performance of Nonfasting Biomarkers to Identify Dysglycemia in Children and Adolescents
Authors: Vajravelu Mary Ellen , Hirschfeld Emily , Gebremariam Acham , Burant Charles F. , Herman William H. , Peterson Karen E. , Meijer Jennifer L. , Lee Joyce M.
Published: November 2022

Introduction: Test performance screening measures for dysglycemia have not been evaluated prospectively in youth. This study evaluated the prospective test performance of random glucose (RG), 1-h nonfasting glucose challenge test (1-h GCT), hemoglobin A1c (HbA1c), fructosamine (FA), and 1,5-anhydroglucitol (1,5-AG) for identifying dysglycemia. Methods: Youth ages 8–17 years with overweight or obesity (body mass index, BMI, ≥85th percentile) without known diabetes completed nonfasting tests at baseline (n = 176) and returned an average of 1.1 years later for two formal fasting 2-h oral glucose tolerance tests. Outcomes included glucose-defined dysglycemia (fasting plasma glucose ≥100 mg/dL or 2-h plasma glucose ≥140 mg/dL) or elevated HbA1c (≥5.7%). Longitudinal test performance was evaluated using receiver-operating characteristic (ROC) curves and calculation of area under the curve (AUC). Results: Glucose-defined dysglycemia, elevated HbA1c, and either dysglycemia or elevated HbA1c were present in 15 (8.5%), 11 (6.3%), and 23 (13.1%) participants at baseline, and 16 (9.1%), 18 (10.3%), and 28 (15.9%) participants at follow-up. For prediction of glucose-defined dysglycemia at follow-up, RG, 1-h GCT, and HbA1c had similar performance (0.68 (95% CI: 0.55–0.80), 0.76 (95% CI: 0.64–0.89), and 0.70 (95% CI: 0.56–0.84)), while FA and 1,5-AG performed poorly. For prediction of HbA1c at follow-up, baseline HbA1c had strong performance (AUC 0.93 [95% CI: 0.88–0.98]), RG had moderate performance (AUC 0.67 [95% CI: 0.54–0.79]), while 1-h GCT, FA, and 1,5-AG performed poorly. Conclusion: HbA1c and nonfasting glucose tests had reasonable longitudinal discrimination identifying adolescents at risk for dysglycemia, but performance depended on outcome definition.
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

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

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

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.
AI for AI: Using AI methods for classifying AI science documents
Authors: Sachini Evi , Sioumalas-Christodoulou Konstantinos , Christopoulos Stefanos , Karampekios Nikolaos
Published: November 2022

Subject area classification is an important first phase in the entire process involved in bibliometrics. In this paper, we explore the possibility of using automated algorithms for classifying scientific papers related to Artificial Intelligence at the document level. The current process is semimanual and journal based, a realization that, we argue, opens up the potential for inaccuracies. To counter this, our proposed automated approach makes use of neural networks, specifically BERT. The classification accuracy of our model reaches 96.5%. In addition, the model was used for further classifying documents from 26 different subject areas from the Scopus database. Our findings indicate that a significant subset of existing Computer Science, Decision Science, and Mathematics publications could potentially be classified as AI-related. The same holds in particular cases in other science fields such as Medicine and Psychology or Arts and Humanities. The above indicate that in subject area classification processes, there is room for automatic approaches to be utilized in a complementary manner with traditional manual procedures.
Wikinformetrics: Construction and description of an open Wikipedia knowledge graph data set for informetric purposes
Authors: Arroyo-Machado Wenceslao , Torres-Salinas Daniel , Costas Rodrigo
Published: November 2022

Wikipedia is one of the most visited websites in the world and is also a frequent subject of scientific research. However, the analytical possibilities of Wikipedia information have not yet been analyzed considering at the same time both a large volume of pages and attributes. The main objective of this work is to offer a methodological framework and an open knowledge graph for the informetric large-scale study of Wikipedia. Features of Wikipedia pages are compared with those of scientific publications to highlight the (dis)similarities between the two types of documents. Based on this comparison, different analytical possibilities that Wikipedia and its various data sources offer are explored, ultimately offering a set of metrics meant to study Wikipedia from different analytical dimensions. In parallel, a complete dedicated data set of the English Wikipedia was built (and shared) following a relational model. Finally, a descriptive case study is carried out on the English Wikipedia data set to illustrate the analytical potential of the knowledge graph and its metrics.
Recitation and Performance in Late Antique Hebrew
Authors: Kantor Benjamin
Published: November 2022

Significant linguistic research has been carried out in the field of language register and its relevance for speech patterns. In various contexts, language users tend to employ different linguistic features, especially but not limited to the realm of pronunciation. In many linguistic communities, there is a higher register of language associated with more formal settings, a lower register of language associated with less formal settings, and a wide spectrum of variation in between. In the context of reading traditions that develop around a sacred text, the same principles may apply. While the pronunciation (or phonology) of the reading tradition often interacts with and is influenced by the vernacular, tradents of the reading tradition often try to preserve a more “archaic,” conservative, and/or simply distinct pronunciation. There appears to be evidence that such a phenomenon was already at play in Biblical Hebrew reading traditions of late antiquity. By comparing Greek and Latin transcriptions of the Biblical Hebrew reading traditions of late antiquity to transcriptions of Hebrew taken from non-biblical sources, we can actually isolate multiple features that demonstrate a distinct difference in pronunciation between biblical and non-biblical sources. The collection of linguistic features characteristic of the reading tradition may properly be termed a “performance register,” the societal implications of which for Jewish communities of late antiquity will be explored in closing.