bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B056: Wild-type RAS/MAPK signaling complexes mediate adaptive resistance to KRAS inhibition in PDAC
Authors: Ge Xiangyu , Ruiz Christian F. , Li Wenxue , Quiñones-Avilés Yanixa , Muzumdar Mandar Deepak
Published: November 2022

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy and predicted to be the second most common cause of death in the US within the next decade. A striking hallmark of PDAC is the presence of activating KRAS mutations in >90% of all cases. Studies in animal models and cell lines have suggested that oncogenic KRAS is important for both the initiation and progression of PDAC, making KRAS an attractive target for therapy. Recent FDA approvals of KRAS mutant-specific inhibitors has advanced the clinical treatment of patients with cancers harboring mutant KRAS, yet resistance inevitably occurs through both genetic (second-site mutations, bypass pathways) and non-genetic (adaptive) mechanisms. Elucidating the adaptive mechanisms by which cancers evade KRAS inhibition in PDAC will enable the development of more efficacious and durable combinatorial therapeutic strategies with emerging KRAS inhibitors. To address this gap in knowledge, we used CRISPR/Cas-mediated gene knockout technology to model KRAS inhibition in PDAC and found that KRAS is dispensable in a subset of human and mouse PDAC cells, arguing that KRAS is not absolutely required for tumor maintenance. KRAS-deficient cells showed enhanced sensitivity to phosphoinositide 3-kinase (PI3K) inhibitors (PI3Ki), which functioned not only to block canonical AKT signaling but also, unexpectedly, to suppress mitogen-activated protein kinase (MAPK) signaling through rapid attenuation of wild-type RAS/MAPK activity in single cells. Importantly, we confirmed this novel regulatory role of PI3K in mediating RAS/MAPK activity across multiple wild-type KRAS-expressing malignant and non-malignant cell lines, supporting the generalizability of this signaling axis. Furthermore, unbiased proximity protein labeling (BioID) revealed that PI3K inhibition reduces the interaction of KRAS with canonical regulators, effectors, and scaffolds in RAS/MAPK signaling. Parallel genome-wide CRISPR screens comparing KRAS intact and isogenic KRAS-deficient PDAC cells revealed specific RAS/MAPK scaffold/docking proteins as essential for PDAC cell fitness following KRAS ablation. Together, our work sheds new light into the regulatory role of PI3K in wild-type RAS/MAPK signaling, highlights the importance of functional wild-type RAS/MAPK signaling complexes in adaptive resistance to KRAS inhibition, and nominates potential therapeutic targets to overcome resistance to KRAS inhibition in PDAC and possibly other KRAS mutant cancers.

Citation Format: Xiangyu Ge, Christian F. Ruiz, Wenxue Li, Yanixa Quiñones-Avilés, Mandar Deepak Muzumdar. Wild-type RAS/MAPK signaling complexes mediate adaptive resistance to KRAS inhibition in PDAC [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 B056.
Abstract B062: Activation of the MAPK pathway by altered RNA splicing in cancer
Authors: Zhang Yushan , Siraj Md Afjalus , Chakrabarty Prabir , Tseng Robert , Das Shamik , Bhattacharya Resham , Escobar-Hoyos Luisa , Mukherjee Priyabrata
Published: November 2022

Many cancers carry recurrent, change-of-function mutations affecting RNA splicing factors, however, less is known about the consequences of upregulated RNA splicing factors (SFs) in cancer. Here, we describe a role of survival motor neuron domain containing 1 (SMNDC1) protein, a poorly studied SF that we found to be upregulated in pancreatic ductal adenocarcinoma (PDAC) and high-grade serous ovarian cancers (HGSOCs) and associated with poor patient prognosis. By loss- and gain-of- function approaches we found that SMNDC1 promotes cancer cell proliferation, clonal expansion and tumor growth. Mechanistically, SMNDC1 promoted the retention of A/C-rich exons which otherwise would be excluded or less retained after RNA splicing in normal cells. Inclusion of exon 4 (E4) of MAPK3 (ERK1), which encodes both phosphorylation sites (Thr202/Tyr204) of the kinase, was among the promoted exons by SMNDC1. Forced exclusion of MAPK3 E4 using anti-sense oligos in vitro and in vivo, inhibited the phosphorylation of ERK1/2, the expression of downstream genes (Cyclin D1, Elk1) and increased proapoptotic proteins. These data provide a novel mechanism by which PDAC and HGSOC cells exploit a “splicing switch” that increases ERK1 phosphorylation, and offer a druggable alternative to target these cancer cells by jointly blocking oncogenic signaling and altered RNA splicing.

Citation Format: Yushan Zhang, Md Afjalus Siraj, Prabir Chakrabarty, Robert Tseng, Shamik Das, Resham Bhattacharya, Luisa Escobar-Hoyos, Priyabrata Mukherjee. Activation of the MAPK pathway by altered RNA splicing in 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 B062.
Abstract B071: Preclinical evaluation of RM-042, an orally bioavailable inhibitor of GTP-RAS, in models of pancreatic ductal adenocarcinoma
Authors: Wasko Urszula N. , Sastra Stephen A. , Palermo Carmine F. , Wildes David , Singh Mallika , Olive Kenneth P.
Published: November 2022

Approximately 95% of pancreatic ductal adenocarcinoma (PDAC) cases are driven by activating mutations in KRAS, accounting for over 45,000 deaths per year in the United States. In KRAS-mutant cells, KRAS protein exists predominantly in an active, GTP-bound state, leading to excessive oncogenic signaling via RAF/MEK/ERK and other effector pathways. After decades of anticipation, the first therapeutic inhibitors of this oncoprotein target a specific mutant allele (KRASG12C) and have shown promising results in this rare subset of human PDAC patients (1-2% of cases). While these encouraging clinical results bolster support for targeting RAS in human PDAC, most patients harbor KRASG12D and KRASG12V mutations and remain unserved by targeted therapies. Here we report preclinical studies of RM-042, a first-in-class, potent, oral, small molecule inhibitor of GTP-bound RAS proteins, designed to treat cancers driven by a variety of RAS mutations. RMC-6236, a clinical candidate and RM-042, a tool compound, both act through non-covalent binding to an abundant intracellular chaperone protein, cyclophilin A (CypA), resulting in a binary complex that engages GTP-bound RAS to form a high-affinity, RAS-selective tri-complex that sterically inhibits RAS binding to effectors. We examined the anti-tumor activity of RM-042 in two complementary preclinical model systems of PDAC. Using primary human PDAC explant cultures (tissue slices cultured intact in optimized media for up to one week), we found that RM-042 potently inhibits phospho-ERK expression (a marker of KRAS/RAF/MEK pathway activity), in a concentration-dependent manner. Loss of pERK expression in tumors was also associated with reduced viability, and altered stromal content. Pilot studies in the K-rasLSL.G12D/+, p53LSL.R172H/+, Pdx1Cretg/+ (KPC) mouse model of PDAC found that RM-042 induced tumor stabilizations and regressions associated with loss of pERK expression, and alterations in apoptosis and proliferation, at tolerated doses. Ongoing studies will determine the duration of tumor responses and assess the mechanisms by which RM-042 may impact both epithelial and stromal cell populations. Together, these studies provide complementary evidence from in vivo murine and ex vivo human models for anti-tumor activity in response to GTP-Ras inhibition, supporting the inclusion of PDAC patients in future clinical trials of RMC-6236.

Citation Format: Urszula N. Wasko, Stephen A. Sastra, Carmine F. Palermo, David Wildes, Mallika Singh, Kenneth P. Olive. Preclinical evaluation of RM-042, an orally bioavailable inhibitor of GTP-RAS, in models of pancreatic ductal 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 B071.
Abstract B081: Synergistic paracrine action of Vitamin D and mesenchymal stem cell secretome in targeting pancreatic cancer stem cells
Authors: Choudhury Sangeeta , Chopra Neha , Jain Kriti , Yadav Poonam , Singh Surinder P. , Charla Yashika
Published: November 2022

The knowledge of immunomodulatory and reparative properties of Mesenchymal Stem cells (MSCs) are rapidly advancing and could be best suited as a therapeutic option for inflammatory or adverse immunological conditions such as cancer. In the last decade, Mesenchymal stem cells have attracted significant attention because of their accessibility, tumor-oriented homing capacity and the transplantation feasibility. Until date, MSC-based therapy for pancreatic cancer has not been demonstrated. As per the current understanding of the potentials of MSCs in regenerative medicine, we hypothesized their inhibitory influence on pancreatic cancer cells. For experimentation purposes, we have used human Wharton’s jelly derived MSCs (hWJ-MSCs) and pancreatic cell line models. Our findings show that secretion of soluble biologically active factors from hWJ-MSCs (secretome) had a greater impact on induction of anergy and apoptosis of pancreatic tumor cells. The mechanistic approach directed to influence the tumor microenvironment appear to be two pronged: one, via modulation of tumor glycoproteins (MUC-1 and EpCAM) and second, via GSK3β/Stat3/HIF1-α axis. Treatment with calcitriol, an analogue of Vitamin D known to regulate cell cycle, cell differentiation ca also reduce side effects of chemo-drugs, one of the mainstay of therapy in pancreatic cancer. Yet, the potential mechanism to exert anti-cancer effect remains underexplored. We attempted to elicit the involvement of VitD in one of the crucial stem-cell related embryonic pathway, the Sonic Hedgehog (SHH) pathway. Our data showed enhanced apoptosis of calcitirol treated-pCSCs cells when treated with salinomycin (SHH inhibitor). Further combinatorial treatment with secretome + VitD decreased copy numbers of transcription factors C-myc, SMO, PTCH1, PTCH2, and hypoxia-induced factor (HIF1-α) demonstrating the potential mechanism of action. In conclusion, our experimental evidence postulates a potential mechanism by which VitD-analogue regulate sHH-mTOR axis and in combination with mesenchymal stem cell secretome can affect the proliferation and migratory (oncogenic) capabilities of pancreatic cancer stem cells. So, what next? Do we have the evidence to suggest secretome as a novel cell-free therapeutic candidate!!

Citation Format: Sangeeta Choudhury, Neha Chopra, Kriti Jain, Poonam Yadav, Surinder P. Singh, Yashika Charla. Synergistic paracrine action of Vitamin D and mesenchymal stem cell secretome in targeting pancreatic cancer stem cells [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 B081.
Abstract C070: Investigation of the roles of BDKRB1 in pancreatic cancer progression and tumor microenvironment modulation
Authors: Li Ching-Fei , Fu Jie , Lee Heng-Huan , Wang Ying-Nai , Chu Yu-Yi , Chiao Paul J. , Hung Mien-Chie
Published: November 2022

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with features of early metastasis and extensive desmoplasia which is the growth of fibrous or connective tissue. The PDAC patient outcomes have not improved in decades, albeit a plenty of therapies that target PDAC have been tested but failed. It could be due to most research focused on tumor cells, whereas the effect of the stroma and immune cells during tumor progression has been largely ignored. Bradykinin receptor B1 (BDKRB1), one of the cell-surface G protein-coupled receptors plays a crucial role in the physiological process associated with coagulation, vasodilation and promotes fibrotic diseases and inflammation in pathological conditions. Based on the analyzed results of Cancer Genome Atlas (TCGA) database, BDKRB1 mRNA is upregulated in PDAC patients. Of note, BDKRB1 mRNA level positively associates with several activated human pancreatic stellate cells (HPSCs; the main fibroblastic cells of the pancreas)-related genes such as CTGF (connective tissue growth factor), IL6 (interleukin 6), and PDGFB (platelet derived growth factor subunit B) in PDAC patients. Interestingly, the conditioned medium from des-Arg9-bradykinin treated-HPSCs can induce M2-like macrophages polarization which dictate clinically relevant immunosuppression in metastatic tumors and express immunosuppressive cytokines such as IL-10, CCL17 and CCL18, implying that activation of BDKRB1 not only stimulates PDAC growth, but also causes HPSCs activation, desmoplasia and immune suppression, followed by exacerbating tumor progression. Moreover, a chemotherapy gemcitabine remains a cornerstone of PDAC treatment in all stages of PDAC despite of the low therapeutic efficacy, we demonstrated that treatment of gemcitabine increases the expression of BDKRB1 in HPSCs and PDAC, indicating that activation of BDKRB1 could be one of the mechanisms involved in gemcitabine resistance. Here, we hypothesize BDKRB1 activation may orchestrate the tumor microenvironment which promotes PDAC progression by inducing tumor cells survival, HPSCs activation, immune suppression, and may contribute to chemotherapy resistance. The outcomes of this proposal will provide not only a novel cellular and molecular mechanism involved in progression of PDAC, but also highlight a potential therapeutic approach to improve PDAC treatment.

Citation Format: Ching-Fei Li, Jie Fu, Heng-Huan Lee, Ying-Nai Wang, Yu-Yi Chu, Paul J. Chiao, Mien-Chie Hung. Investigation of the roles of BDKRB1 in pancreatic cancer progression and tumor microenvironment modulation [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 C070.
Abstract C072: Cytokine modulation can suppress an EMT-like phenotype in pancreatic cancer
Authors: Bell Whitney , Kren Nancy , Wang Yan , Pylayeva-Gupta Yuliya
Published: November 2022

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers with a 5-year survival rate of only 11% and approximately half of patients present with distant metastasis at the time of diagnosis. PDAC is accompanied by pronounced alterations in stromal responses and immune surveillance programs, which are now recognized as some of the major drivers in PDAC tumor evolution. The role of immune modulators in driving metastatic potential in PDAC is poorly understood. We find that low expression levels of cytokine IL-23 in patients with PDAC correlate with poor differentiation status of these tumors, and thus predict poor outcomes. Consistent with this observation, we have found that a loss of host-derived IL-23 in a mouse model of pancreatic cancer promotes an EMT-like phenotype. The tumor morphology is altered and appears to be less differentiated. Additionally, we see a significant increase in the number of tumor cells expressing Zeb1 and a decrease in E-cadherin expression. We also find an increase in metastatic capacity in the absence of IL-23 in the tumor stroma. Single cell RNA sequencing of tumors injected orthotopically into IL-23 knockout mice reveals clusters of tumor cells with increases in EMT-associated genes such as Zeb1 and Vimentin and concurrent decreases in gastric identity genes. Overall, our findings indicate that IL-23 plays a role in suppressing an EMT-like phenotype in pancreatic cancer with one mechanism being through regulation of gastric lineage genes.

Citation Format: Whitney Bell, Nancy Kren, Yan Wang, Yuliya Pylayeva-Gupta. Cytokine modulation can suppress an EMT-like phenotype 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 C072.
Abstract IA007: Does cancer cell state matter? Moving from DNA genotype to RNA phenotype-directed therapies in cancer
Authors: Shalek Alex K.
Published: November 2022

Recent advances in high throughput genomic sequencing technologies have led to a detailed understanding of the genetic alterations that underlie human tumors. However, evidence increasingly indicates that using mutations alone to assign therapies has its limitations, even for cancers with actionable mutational heterogeneity. The advent of single-cell genomic technologies has confirmed extensive mutational heterogeneity in human tumors but also revealed that the complexity of cancer extends to variation in cell transcriptional state. Deciphering whether transcriptional variation informs treatment response heterogeneity represents a new but poorly understood frontier in cancer therapeutics. In pancreatic ductal adenocarcinoma (PDAC), clinically relevant RNA expression states exist but our understanding of their drivers, stability, and relationship to therapeutic response is limited. To examine these attributes systematically, we profiled metastatic biopsies and matched organoid models at single-cell resolution. We identify a new intermediate PDAC transcriptional cell state and uncover distinct site- and state-specific tumor microenvironments. Moreover, we reveal strong organoid culture-specific biases in cancer cell transcriptional state representation and nominate critical factors missing from the ex vivo microenvironment. By adding back specific factors, we restore in vivo expression state heterogeneity and show plasticity in culture models, demonstrating that microenvironmental signals are critical regulators of cell state. Importantly, we prove that non-genetic modulation of cell state can significantly influence drug responses and uncover state-specific vulnerabilities. Our work provides a broadly applicable framework for mapping cell states across in vivo and ex vivo settings, identifying drivers of transcriptional plasticity, and manipulating cell state to target its associated vulnerabilities.

Citation Format: Alex K. Shalek. Does cancer cell state matter? Moving from DNA genotype to RNA phenotype-directed therapies in 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 IA007.
Abstract IA010: Meeting the challenge of pancreatic cancer
Authors: Philip Philip A.
Published: November 2022

Approximately one third of patients (pts) with pancreatic adenocarcinoma (PDA) present with locally advanced unresectable disease (LAPC). Majority of pts with LAPC have micrometastatic disease at presentation. However, median survival times exceed those of pts with radiologically visible metastases and is currently around 14-16 months (versus less than 1 year). Initial treatment strategies in LAPC focused on radiation that did not improve survival. With improvements in systemic therapies, current treatments of LAPC are based on cytotoxic combinations similar to ones used in metastatic PDA. However, benefits of cytotoxic therapy remain very modest. Unfortunately, the development of systemic therapy for PDA was plagued by repeated failures of randomized clinical trials of a range of targeted and other agents. In recent years, we exponentially advanced knowledge of PDA’s molecular biology and are attempting to learn from our clinical failures. One thing that stood out, with very few exceptions, is lack of success in single target/pathway strategies, especially in the absence of predictive biomarkers and lack of targetable “driver” mutations. Immune checkpoint inhibitors were ineffective unlike successes in other cancers. Focus has therefore shifted to rational strategies based on biology that defines phenotype along with ongoing attempts to refine molecular characterizations of PDA. Major research strategies include targeting the stroma to enhance drug delivery (e.g., CEND-1), reversing the immune suppressive microenvironment (combinatorial immunotherapy), exploiting DNA repair defects (e.g., BRCA mutations), and most importantly tackling KRAS oncogene. KRASG12C, KRASwt, BRCAmutated, and microsatellite instability provide additional treatment opportunities in up to 10% of PDA patients. The goal of new therapy developments in LAPC must address the locoregional morbidity of the primary tumor with the ultimate goal of prolonging survival. Examples of ongoing research in locoregionally directed therapy include ablative radiation and tumor treating fields (TTF) that attempt to control its growth, reduce the tumor bulk, and improve possibilities of tumor resection. As our systemic therapies improve, locoregional therapy becomes more relevant. Improvements in molecular classifications of PDA, refinements in the use of organoids to predict drug and radiation effect, and use of liquid biopsies are examples of measures that will provide foundations for personalized treatment approaches. Collectively, we have endless opportunities for translational research based on advances in PDA’s basic science and our experiences from the many “negative” clinical trials.

Citation Format: Philip A. Philip. Meeting the challenge of 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 IA010.
Abstract IA014: Collagen cleavage controls PDAC metabolism and malignancy via a DDR1-NRF2 cascade and mitochondrial biogenesis
Authors: Karin Michael , Su Hua
Published: November 2022

PDAC is distinct by being highly desmoplastic, due to the activation and eventual infiltration of cancer associated fibroblasts (CAF) and the extracellular matrix (ECM) they produce, which is mainly composed of collagen type I (Col I). The role of fibroblasts and collagen in PDAC pathology is highly contentious, ranging from tumor stimulatory to tumor inhibitory. Using mouse models and human specimens we found that the way in which Col I affects PDAC progression, metabolism and its response to therapy is highly dependent on its cleavage by matrix metalloproteases (MMP). Whereas noncleaved Col I inhibits PDAC metabolism, inhibits human and mouse PDAC growth in mice and is correlated with improved survival after surgical resection, MMP generated Col I fragments stimulate tumor metabolism and growth and correlate with poor post-resection survival. These differential activities of cleaved and noncleaved Col I depend on its interactions with the receptor tyrosine kinase DDR1. Whereas MMP-generated Col I binds DDR1 and activates it, intact Col I induces DDR1 degradation. By activating DDR1, cleaved Col I triggers an NF-kB-p62-NRF2 signaling cascade, whose major efferent, NRF2, controls many aspects of PDAC metabolism, including macropinocytosis, aerobic glycolysis, respiration and mitochondrial biogenesis. Inhibitors of NRF2 and mitochondrial biogenesis induce regression of established PDAC in-vivo and compromise its growth and survival in-vitro.

Citation Format: Michael Karin, Hua Su. Collagen cleavage controls PDAC metabolism and malignancy via a DDR1-NRF2 cascade and mitochondrial biogenesis [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 IA014.
Abstract IA016: Determinants of B cell fate and function in cancer
Authors: Pylayeva-Gupta Yuliya
Published: November 2022

Effector B cell responses in solid malignancies are associated with anti-tumor immunity and favorable response to immunotherapy. B cells can amplify anti-tumor immune responses through antibody production, antigen presentation, and pro-inflammatory cytokine release; yet B cells in cancer patients and tumor-bearing mice often fail to support these effector cell functions. The determinants of B cell fate and function in cancer are still not clear. We find that systemic exposure to STING agonists potentiates expansion of immunosuppressive regulatory human and mouse IL-35+ B lymphocytes in an IRF3 dependent manner. Mechanistically, the loss of STING signaling in B cells or treatment with cGAMP combined with ablation of IL-35 facilitates increases NK cell proliferation and enhances NK cell dependent anti-tumor response. Further, we identify dysregulated transcriptional programs activated in pancreatic cancer-associated B cells that promote differentiation of naïve into immunosuppressive B cells and inhibit differentiation of anti-tumor plasma cells. The signaling network that contributes to this dysfunction is driven by IL35-mediated formation of STAT3-PAX5 complex that upregulates the transcriptional factor BCL6 in B cells. Transient inhibition of BCL6 in naïve B cells is sufficient to stimulate the intratumoral accumulation of plasma cells and effector T cells and renders pancreatic tumors sensitive to anti-PD-1 immune checkpoint blockade therapy. Our findings reveal that systemic STING signaling can expand immunosuppressive B cells and show that B cell differentiation can be re-routed towards anti-tumor plasma cell response, suggesting novel combinatorial strategies to facilitate anti-tumor immune activity.

Citation Format: Yuliya Pylayeva-Gupta. Determinants of B cell fate and function in 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 IA016.
Abstract PR003: Race plays a role on the rate of transdifferentiation in human pancreatic acinar ductal metaplasia and its' drug response
Authors: Perkins Corey , Jiang Jinmai , Hakimjavadi Hesam , Quashie David , Mao Yating , Ali Jamel , Schmittgen Thomas D.
Published: November 2022

Pancreatic diseases (acute/chronic pancreatitis, type 2 diabetes, pancreatic cancer) disproportionately affect the Black/African American community in comparison to non-White Hispanics and Whites. Acinar to ductal metaplasia (ADM), the process by which pancreatic acinar cells transdifferentiate into ductal epithelial cells, is believed to be an initiating event of pancreatic ductal adenocarcinoma. Our lab has developed a 3D organoid assay to display ADM using primary, human pancreatic acinar cells to study the rate of transdifferentiation among these three different races. Preliminary data shows that the rate of ADM is occurring significantly faster (p < 0.05) in Blacks/African Americans (White=11, Hispanic=10, Black/African American=5), which may explain the disproportionately behind the incidence and mortality rates for this race in pancreatic diseases. We additionally use nanoparticles to study the biomechanical properties (I.e., viscoelasticity, storage modulus) of the ADM microenvironment which shows a stiffer microenvironment in Blacks/African Americans than for the other races (White=4, Hispanic=4, Black/African American=1). Furthermore, I study the use of histone deacetylase (HDAC) inhibitors in reversing the process of ADM, which has consequently shown race-related outcomes, with Blacks/African Americans displaying a significant chemoresistance (p < 0.05) to HDAC treatment (White=6, Hispanic=6, Black/AA=3) by utilizing an ADM reversal index (ADMRI). Through further analysis, the plan is to continue procuring human samples from these three races to isolate an ADM-specific biomarker in relation race and drug reversal by studying the expression/activity of pancreatic associated genes by bulk-RNA and single-cell sequencing.

Citation Format: Corey Perkins, Jinmai Jiang, Hesam Hakimjavadi, David Quashie Jr, Yating Mao, Jamel Ali, Thomas D. Schmittgen. Race plays a role on the rate of transdifferentiation in human pancreatic acinar ductal metaplasia and its' drug response [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 PR003.
Abstract PR009: An epigenetic memory of inflammation controls context-dependent lineage plasticity in the pancreas
Authors: Falvo David J. , Grimont Adrien , Zumbo Paul , Yang Julie L. , Osterhoudt Alexa , Pan Grace , Rendeiro Andre F. , Wilkinson John E. , Dündar Friederike , Elemento Olivier , Yantiss Rhonda K. , Betel Doron , Koch Richard , Chandwani Rohit
Published: November 2022

Inflammation is essential to the disruption of tissue homeostasis, and, in the pancreas, can destabilize the identity of terminally differentiated acinar cells. A longstanding question has been whether a history of past injuries instructs subsequent homeostatic responses to future stimuli – despite being distantly separated in time. Thus, we employ here Mist1-CreERT2; LSL-tdTomato lineage-tracing mice to investigate the long-term effects of a transient inflammatory episode on pancreatic tissue homeostasis. We delineate the chromatin dynamics that accompany the cycle of metaplasia and regeneration following pancreatitis, and reveal that the pancreatic acinar cell compartment durably retains specific inflammation-induced epigenetic changes even 18-weeks after exposure to the original inflammatory stimulus. We observe that despite histologic resolution of pancreatitis, acinar cells fail to return to their molecular baseline after several months, representing an incomplete cell fate decision. Motif analysis demonstrates the enrichment of AP-1/Fra1 motifs at these persistently accessible memory regions—a transcriptional effector activated downstream of the Ras/MAPK pathway. This epigenetic memory controls lineage plasticity, with diminished metaplasia in response to a second inflammatory insult but increased tumorigenesis with an oncogenic Kras mutation. We demonstrate that pancreatic acinar cells exhibit rapid malignant transformation upon re-challenge with oncogenic stress via inflammatory memory recall, with robust reactivation of genes associated with differentially accessible memory regions. Together, our findings define the dynamics and recall of an epigenetic memory of inflammation that impacts cell fate decisions in a context-dependent manner.

Citation Format: David J. Falvo, Adrien Grimont, Paul Zumbo, Julie L. Yang, Alexa Osterhoudt, Grace Pan, Andre F. Rendeiro, John E. Wilkinson, Friederike Dündar, Olivier Elemento, Rhonda K. Yantiss, Doron Betel, Richard Koch, Rohit Chandwani. An epigenetic memory of inflammation controls context-dependent lineage plasticity in the pancreas [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 PR009.
Abstract PR023: Targeting gemcitabine resistance in pancreatic cancer
Authors: Beutel Alica Katrin , Singh Rima , Anaraki Cecily , Tong Gregory , Martinez Thomas , Kleger Alexander , Jutric Zeljka , Halbrook Christopher James
Published: November 2022

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with a devastating 5-year survival rate of 11%. A lack of durable responses to standard-of-care chemotherapy combinations renders its treatment particularly challenging and largely contributes to the devastating prognosis. Gemcitabine, a pyrimidine anti-metabolite, is a cornerstone in PDAC therapy, but resistance remains a major hurdle. Multiple mechanisms of chemoresistance have been suggested to be mediated by rewired metabolism in PDAC cells. Accordingly, we hypothesize that metabolic reprogramming can be targeted to re-sensitize PDAC tumors to anti-metabolite chemotherapy. To define the spectrum of targetable metabolic and transcriptomic programs that drive cell-intrinsic resistance to gemcitabine, we established organoids from treatment-naïve PDAC patients. Gemcitabine high versus low responders, as assessed by dose response viability assays, were selected for metabolomic profiling and RNA sequencing. To define real-time reprogramming during the acquisition of resistance, we generated gemcitabine resistant murine pancreatic cancer cell lines and collected a time course series of metabolomic and transcriptomic datasets of sensitive, intermediate resistant and resistant cells. Integration of these dataset through a systems biology approach to define primary and de novo resistance is being used to characterize metabolic gemcitabine resistance mechanisms. These are functionally validated to provide novel approaches to re-sensitize resistant PDAC cells to gemcitabine in vitro and in vivo. The improvement of current chemotherapy combinations represents a promising approach, with potential to immediately translate into a clinical benefit and improve survival in this deadly disease.

Citation Format: Alica Katrin Beutel, Rima Singh, Cecily Anaraki, Gregory Tong, Thomas Martinez, Alexander Kleger, Zeljka Jutric, Christopher James Halbrook. Targeting gemcitabine resistance 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 PR023.
Prediction Model for Contractile Function of Circulatory Death Donor Hearts Based on Microvascular Flow Shifts During Ex Situ Hypothermic Cardioplegic Machine Perfusion
Authors: Saemann Lars , Kohl Matthias , Veres Gábor , Korkmaz‐Icöz Sevil , Großkopf Anne , Karck Matthias , Simm Andreas , Wenzel Folker , Szabó Gábor
Published: November 2022

Background

Hearts procured from circulatory death donors (DCD) are predominantly maintained by machine perfusion (MP) with normothermic donor blood. Currently, DCD heart function is evaluated by lactate and visual inspection. We have shown that MP with the cardioplegic, crystalloid Custodiol‐N solution is superior to blood perfusion to maintain porcine DCD hearts. However, no method has been developed yet to predict the contractility of DCD hearts after cardioplegic MP. We hypothesize that the shift of microvascular flow during continuous MP with a cardioplegic preservation solution predicts the contractility of DCD hearts.

Methods and Results

In a pig model, DCD hearts were harvested and maintained by MP with hypothermic, oxygenated Custodiol‐N for 4 hours while myocardial microvascular flow was measured by Laser Doppler Flow (LDF) technology. Subsequently, hearts were perfused with blood for 2 hours, and left ventricular contractility was measured after 30 and 120 minutes. Various novel parameters which represent the LDF shift were computed. We used 2 combined LDF shift parameters to identify bivariate prediction models. Using the new prediction models based on LDF shifts, highest
r
2
for end‐systolic pressure was 0.77 (
P
=0.027), for maximal slope of pressure increment was 0.73 (
P
=0.037), and for maximal slope of pressure decrement was 0.75 (
P
=0.032) after 30 minutes of reperfusion. After 120 minutes of reperfusion, highest
r
2
for end‐systolic pressure was 0.81 (
P
=0.016), for maximal slope of pressure increment was 0.90 (
P
=0.004), and for maximal slope of pressure decrement was 0.58 (
P
=0.115). Identical prediction models were identified for maximal slope of pressure increment and for maximal slope of pressure decrement at both time points. Lactate remained constant and therefore was unsuitable for prediction.

Conclusions

Contractility of DCD hearts after continuous MP with a cardioplegic preservation solution can be predicted by the shift of LDF during MP.
Thermal Performance on Radiative and Ohmic Dissipative Magneto-Nanoliquid Over Moving Flat Porous Plate Suspended by Single Wall Carbon Nanotubes and Multi Wall Carbon Nanotubes
Authors: Kumar T. Kiran , Shamshuddin MD.
Published: November 2022

This investigation examines heat transport in the flow of magnetized Blasius flow suspended by carbon nanotubes (CNTs) on an accelerated by moving flat porous plate that contains water and ethylene glycol as base fluids. The transfer of heat has been contemplated in the company of suspended
CNTs above a plane plate. The flow simulations are carried by utilizing the impact of magnetic field and uniform porous medium. The transport of thermal is controlled by the significant influence of thermal radiation, heat source, heat and Joule dissipation. Utilizing scaling analysis flow
governing problem is converted into a set of higher order nonlinear ordinary differential equations which afterwards are tackled numerically by employing Runge-Kutta Fehlberg 45 method with shooting quadrature. Quantities of flow physical significance are portrayed through graphically. Verification
of attained numerical results with available literature under certain limitations are presented and found excellent agreement. With elevation in convective term flow profiles of SWCNTs and MWCNTs are reduced. A reduction of flow characteristic dimensions is observed with increasing magnetic
field and porosity terms. Finally, SWCNTs and MWCNTs are positively influenced by Joule dissipation and negatively by thermal radiation.
Intolerance of Uncertainty, Acculturative Stress, Gratitude, and Distress: A Moderated Mediation Model
Authors: Liao Kelly Yu-Hsin , Wei Meifen
Published: November 2022

Based on Berry’s (1997) model of acculturation, the current study examined whether gratitude would moderate the association between intolerance of uncertainty (IU) and acculturative stress (i.e., moderation hypothesis), and mitigate the positive association between IU and psychological distress through acculturative stress (i.e., moderated mediation hypothesis). Participants were 171 international students with Chinese heritage from a Midwest public university. Results from PROCESS supported these hypotheses. First, the positive association between IU and acculturative stress was attenuated to a greater extent at higher compared to lower levels of gratitude. Second, the mediation effect of IU on psychological distress through acculturative stress was weaker among those with higher compared to lower levels of gratitude. Findings demonstrate the protective role of gratitude and the role of IU as a risk factor for psychological distress through acculturative stress. Implications for practice, training, and research are discussed.
Toward Decolonizing Our Scholarship and Discourses: Lessons From the Special Issue on Decoloniality for EAQ
Authors: Bainazarov Talgat , Gilzene Alounso A. , Kim Taeyeon , López Gerardo R. , Louis Lawrence , Oh Soon-young , Taylor Emma K.
Published: November 2022

Members of the Educational Administration Quarterly (EAQ) internal editorial team took a critical look at the publication record of our journal with respect to epistemological plurality over the past 10 years. Our goal was to identify international publication trends and highlight how pluralized the research frames are within EAQ. Data overwhelmingly show that EAQ is a largely U.S.-centric publication, even when the topics explored touch on critical or epistemological concerns. The implications of these findings are discussed.
The feelings of living in poverty and depending on social assistance: An exploratory study on gender differences in Dibao families in China
Authors: Zhang Haomiao , Tan Hong
Published: November 2022

Little is known about the differences in feelings of poverty and social assistance receipt among the different genders of heads of Chinese Dibao families. This article makes a preliminary analysis of the feelings of Chinese female heads of Dibao families about living in poverty and depending on social assistance and compares them with those of male heads. It finds that there are gender differences in the experiences between the female and male heads of Dibao families in China. The article argues that social assistance policies should be constructed or correspondingly adjusted in a targeted manner to become gender-sensitive.
Fighting the Pandemic with “Shields”: Successful COVID-19 Securitization and Mask Policy in Taiwan
Authors: Chang Chia-Chien , Yen Wei-Ting , Liu Li-Yin
Published: November 2022

Facemasks have been proven an effective non-pharmaceutical measure against coronavirus disease-19. Against the backdrop of global mask shortages, Taiwan distinguished herself from other countries in that Taiwan took a whole-of-nation approach to masks and mobilized the society quickly to become self-sufficient in masks. This paper argues that successful virus securitization as a threat to national security was what enabled Taiwan to effectively mobilize the private sector to carry out the state’s will in ensuring adequate mask supply. Moreover, Taiwan securitized the virus more successfully than many other countries because the virus was connected to China, the nation’s existing security threat.
The influence factors of interprovincial power transmission on China's CO2 emissions
Authors: Li Wenchao , Xu Lingyu , Jin Yi
Published: November 2022

Electric power system is a major source of CO2 emission in China. Understanding the evolution of power-related CO2 emission is an important step to both emission reduction and a sustainable energy transition. Here, we assess the CO2 emission of power production in China, finding that it increased by 47% from 2008 to 2017 despite a significant decrease in CO2 emission intensity of power production. The CO2 emission intensity of power production differs greatly across provinces, with the highest provincial CO2 emission intensity 11 times the lowest. To understand the evolution of power-related CO2 emission, this study quantified the embodied CO2 emissions of power transmission, and then use decomposition analysis to explore the influencing factors of it. We found that China's embodied CO2 emissions from power transmission increased from 315 to 523 Mt between 2008 and 2017, and the increase in electricity consumption and the dependence on power transmission networks are the important reasons for the increase in embodied CO2 emissions. Nationally, power transmission reduced CO2 emission by 78 Mt. because, compared to the east, the west generally has a larger CO2 emission factor. These dynamics will become important for policymakers and energy planners to achieve carbon neutrality.
Diagnostic challenge: Diffuse large B-cell lymphoma masquerading as orbital cellulitis
Authors: Wen Lim Yi , Mohamad Nor Fadhilah , Ramli Norlina Mohd
Published: November 2022

We report a clinical case of orbital lymphoma masquerading as orbital cellulitis. Orbital lymphoma and lymphoma of the orbital adnexa are relatively rare types of lymphoma. They represent the malignant end of a spectrum of lymphoproliferative lesions that occur in the orbit, conjunctiva and eyelid. Diffuse large B-cell lymphomas (DLBCL) with variable clinical presentations have a relatively poor prognosis with rapid visual loss. Therefore, thorough evaluation and assessment with a multi-specialty effort are warranted for earlier diagnosis and initiation of treatment to save life and prevent sight loss.
Drug-Induced Rhinitis: Narrative Review
Authors: Alromaih Saud , Alsagaf Lamya , Aloraini Nouf , Alrasheed Abdulaziz , Alroqi Ahmad , Aloulah Mohammad , Alsaleh Saad , Alhawassi Tariq
Published: November 2022

Objectives

Rhinitis, one of the most common inflammatory conditions of the nasal mucosa, is known to affect a large proportion of people worldwide. It is generally classified into allergic and non-allergic types and both are associated with several unpleasant symptoms. Several medications prescribed for different medical conditions can cause unpleasant rhinitis as an adverse effect, which is known as drug-induced non-allergic rhinitis. The aims of this article were to review the literature to identify drugs that could induce rhinitis, prevalence of drug-induced rhinitis, and the associated pathogenic mechanisms if known.

Methods

Literature search screening for eligible papers published up to December 31st, 2021, in Medline (via PubMed) and Embase was conducted. The search included the following combination of keywords and terms: rhinitis, sneezing, congestion, allergic, non-allergic, rhinorrhea, vasomotor, medication, drug-induced.

Results

The review findings suggest that 12 subtypes of drugs potentially could induce rhinitis. Based on their mechanisms of action, the pathogenic causes for the induction of rhinitis have been recognized for some drugs, while others remain unknown.

Conclusion

Awareness of the list of drugs that reportedly induce non-allergic nasal symptoms, along with taking the patient’s medication history, is important in the diagnosis of rhinitis.
Restricting Human Movement During the COVID-19 Pandemic: New Research Avenues in the Study of Mobility, Migration, and Citizenship
Authors: Piccoli Lorenzo , Dzankic Jelena , Ruedin Didier , Jacob-Owens Timothy
Published: November 2022

Every government in the world introduced restrictions to human mobility – that is, the movement of persons across and within state borders – in response to the COVID-19 pandemic. Such restrictions thus constituted a global phenomenon, but they were by no means globally uniform; rather, they varied significantly between and within states, as well as over time. This research note presents different data sources for studying the drivers and outcomes of mobility restrictions, highlighting specific ways in which the data can be used. We begin by surveying seven new databases capturing various aspects of the regulation of human movement during the COVID-19 pandemic. Drawing inspiration from research on previous pandemics, we then outline five possible research avenues prompted by these data. We suggest that explaining the causes and consequences of such restrictions, as well as the differences between them, can significantly advance research on the governance of mobility, migration, and citizenship.
Ethics, virtues and xenotransplantation
Authors: George Andrew JT
Published: November 2022

Early in 2022 the first pig to human cardiac xenotransplant was performed. The graft initially performed well, and rejection was well controlled. However, the graft failed, and the patient died 60 days after the procedure. The ethical issues relating to xenotransplantation include the risk/benefit to the individual, the risk of porcine-derived infectious agents crossing into humans, animal welfare and rights, issues of human and animal identity and concerns relating to fair allocation of organs and appropriate use of resources.

These ethical issues are often addressed using emotional arguments, or through consequentialist or deontological lens. An alternative is to use approaches based on virtue ethics to understand the moral purpose ( telos) of the research and the virtues (character traits) needed to be a good research clinician. In this review we will consider the virtues of justice, courage, temperance and practical wisdom, as well as the role of clinical curiosity, and their application to xenotransplantation. This provides an alternative approach for the clinical academic and others involved in the research to reflect on their practice.