bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PO-049: Inhibiting MNK kinases promotes macrophage immunosuppressive phenotype to limit anti-tumor immunity
Authors: Pham Thao N. D. , Spaulding Christina , Shields Mario A. , Khalafalla Mahmoud G. , Principe Daniel R. , Bentrem David J. , Munshi Hidayatullah G. 
Published: November 2021

Abstract
Background MAPK-interacting serine/threonine-protein kinase 1 and 2 (MNK1 and MNK2) are downstream effectors of the MEK/ERK and p38 MAPK pathways. Increased expression and activity of MNK kinases are linked to tumor growth and therapeutic resistance. Select MNK kinase inhibitors are currently being evaluated in clinical trials for different tumor types. Their immunomodulatory effects in tumors with low infiltrating CD8+ T have not been clearly defined. Methods: In vivo efficacy of MNK kinase inhibitors (CGP57380 and eFT508), either as a single agent or in combination with anti-PD-1 or anti-CSF-1R antibody, was tested in syngeneic mouse models of pancreatic cancer. Tumor-associated macrophages (TAMs) and murine bone marrow-derived macrophages (BMDMs) were evaluated in vitro for modulation of their polarization by MNK kinase inhibitors and their suppression of co-cultured T cells. Markers of M1/M2 polarization were measured by qRT-PCR. The effects of MNK kinase inhibitors on the expression of select M2 markers were also evaluated in ex vivo slice cultures of human pancreatic tumors. Results: We first found an inverse relationship between MNK kinase activity and CD8+ T cell abundance in human pancreatic tumors. In tumor-bearing mice, while pharmacological inhibition of MNK kinase activity increased CD8+ T cell infiltration, the tumor-infiltrating CD8+ T cells lacked effector function and failed to mount anti-tumor responses. Mechanistically, we showed that systemic inhibition of MNK kinases increased the expression of several anti-inflammatory genes in BMDMs and potentiated the ability of BMDMs and TAMs to suppress T cell proliferation. Reversal of T cell exhaustion either by an anti-PD-1 antibody or by TAM depletion with an anti-CSF-1R antibody enhanced the anti-tumor efficacy of MNK inhibitors and prolonged animal survival. Importantly, treating ex vivo human pancreatic cancer slice cultures with MNK inhibitors led to increased expression of known immunosuppressive markers in TAMs. Conclusion: Together, these findings provide new insights into the effects of MNK kinase inhibition on CD8+ T cell infiltration and TAM function and identify combination regimens with MNK kinase inhibitors to achieve effective anti-tumor responses in pancreatic cancer patients whose tumors have a low number of functional CD8+ T cells.
Citation Format: Thao N. D. Pham, Christina Spaulding, Mario A. Shields, Mahmoud G. Khalafalla, Daniel R. Principe, David J. Bentrem, Hidayatullah G. Munshi. Inhibiting MNK kinases promotes macrophage immunosuppressive phenotype to limit anti-tumor immunity [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-049.
Abstract PO-055: Phase II clinical trial of subtype directed neoadjuvant therapy in patients with localized pancreatic cancer
Authors: Tsai Susan , Borazanci Erkut , Gulley Margaret , Rashid Naim , Merker Jason , Khan Abdul H. , Chisholm Phillip , Hunt Bryan , Giorgadze Tamara , Hall William , Kamgar Mandana , Evans Douglas B. , Yeh Jen Jen 
Published: November 2021

Abstract
Background: Preoperative (neoadjuvant) therapy has become the preferred treatment sequencing strategy for patients with localized pancreatic cancer. During neoadjuvant therapy, approximately 30% of patients will experience metastatic disease progression while on treatment. Therefore, tools to aid clinicians to select efficacious first-line chemotherapeutic regimens is a critical unmet need. The most common neoadjuvant chemotherapy regimens used are 5-fluorouracil/irinotecan/oxaliplatin (mFOLFIRINOX) and gemcitabine/nab-paclitaxel (GnP). There is growing data to suggest an association of pancreatic cancer subtype (classical versus basal-like) with treatment response to therapy. Recently, the translation of tumor subtyping to the clinic has been successfully achieved using the Purity Independent Subtyping of Tumors (PurIST) single sample classifier. We aim to assess the clinical response to pancreatic cancer subtype-directed therapy in patients with localized pancreatic cancer. Methods: This is a phase II, multicenter, single-arm clinical trial for previously untreated patients with localized (resectable or borderline resectable) pancreatic cancer. Patients will undergo endoscopic ultrasound guided biopsy of the primary tumor and PurIST classifier to determine classical versus basal-like subtype. Patients with classical subtype will be assigned to mFOLFIRINOX and patients with basal-like tumors will be assigned to GnP. Following two months of therapy, patients will be restaged with a computed tomography scan, carbohydrate antigen (CA19-9) levels, performance status assessment, and a repeat endoscopic ultrasound guided biopsy for research. The primary endpoint is composite clinical response as measured by radiographic response, CA19-9 decline, and performance status following two months of treatment. Correlative endpoints include blood-based biomarkers for association with clinical response and stroma-specific response to therapy. The study has enrolled 4 of the anticipated 41 patients at the time of submission. Clinical Trial information: NCT 04683315.
Citation Format: Susan Tsai, Erkut Borazanci, Margaret Gulley, Naim Rashid, Jason Merker, Abdul H. Khan, Phillip Chisholm, Bryan Hunt, Tamara Giorgadze, William Hall, Mandana Kamgar, Douglas B. Evans, Jen Jen Yeh. Phase II clinical trial of subtype directed neoadjuvant therapy in patients with localized pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-055.
Abstract PO-060: N-terminal RHAMM cooperates with dysfunctional p53 to accelerate the progression of pancreatic cancer
Authors: Lin Anthony , Feng Jennifer , Chen Xiang , Wang Dunrui , Wong Megan , Zhang George , Na Joseph , Zhang Tiantian , Chen Zhengming , Chen Yao-Tseng , Du Yi-Chieh Nancy 
Published: November 2021

Abstract
Pancreatic cancer has the lowest survival rate in all types of cancer. Pancreatic cancer patients are often diagnosed at advanced stages. A better therapeutic development for this devastating disease is urgently needed. Receptor for hyaluronan-mediated motility (RHAMM), not expressed in adult normal pancreas, has been suggested as a prognostic factor and a potential therapeutic target for pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumor (PNET). In this study, we initially sought to determine whether genetic deletion of RHAMM would slow down pancreatic cancer progression using Rhamm−/− mice. However, we found that Rhamm−/− mice expressed a N-terminal RHAMM protein. While N-terminal RHAMM did not enable malignant progression of pancreatic intraepithelial neoplasia in p48-Cre; LSL-KRASG12D mice, it accelerated the formation of invasive PDAC and shortened the survival of p48-Cre; LSL-KRASG12D mice with heterozygous p53 knockout. KrasG12D PDAC mice with homozygous p53 knockout mice died around 10 weeks, and the effect of N-terminal RHAMM was not apparent in these mice with short life span. In addition, N-terminal RHAMM shortened the survival of PNET-bearing RIP-Tag mice, which had inactivated p53. In our analysis of TCGA dataset, pancreatic cancer patients with mutant TP53 or loss of one copy of TP53 had higher RHAMM expression, which, combined, predicted worse outcomes. Taken together, by collaborating with dysfunctional p53, N-terminal RHAMM that lacks the centrosome targeting domain and degrons for interaction with the Anaphase-Promoting Complex (APC) accelerated pancreatic cancer progression.
Citation Format: Anthony Lin, Jennifer Feng, Xiang Chen, Dunrui Wang, Megan Wong, George Zhang, Joseph Na, Tiantian Zhang, Zhengming Chen, Yao-Tseng Chen, Yi-Chieh Nancy Du. N-terminal RHAMM cooperates with dysfunctional p53 to accelerate the progression of pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-060.
Abstract PO-093: JNK2 suppresses the growth and invasion of pancreatic cancer and is opposed by JNK1
Authors: Shi Jingwei , Tian Xiaodong , Kornmann Marko , Traub Benno 
Published: November 2021

Abstract
Introduction: Pancreatic cancer cells are exposed to multiple stressors with both endogenous (proliferation, metabolism and nutrient deprivation) and exogenous (medical treatment) origins. The c-Jun N-terminal protein kinases (JNKs) JNK1 and JNK2 are important stress-activated kinases, responsible for the cellular response to these stressors. Both were demonstrated to exert both tumor-suppressing and tumor-promoting effects in human cancers Most previous studies rely on nonspecific pharmacological JNK inhibition. In this study, we planned to determine the isoform-specific roles in PDAC. Methods: Specific JNK1- and JNK2-knockdown (KD) clones were established in cultured human pancreatic cancer cell lines MIA PaCa-2 and PANC-1 by using specific shRNA plasmids. Anchorage dependent and independent growth, as well as migration and invasion, were analyzed in JNK-1/2 KD clones and compared to pharmacological JNK inhibition using SP600125. Xenograft growth was assessed using an orthotopic mouse model. Mechanistically, we assessed changes in EMT markers both in vitro and in vivo. Results: JNKs were expressed in both cultured pancreatic cancer cell lines as well as in resected human pancreatic cancer samples. Specific downregulation of JNK2 resulted in an overall increase in cell proliferation, invasion and alterations in cytoskeleton structure, while JNK1-KD revealed opposite effects. Nonspecific JNK-inhibition using SP600125 inhibited cell growth of all cell lines except PANC-1. Conclusion: JNK1 and JNK2 play opposing roles in human pancreatic cancer. Specifically targeting JNK1 with the retained function of JNK2 may provide a potential, individualized approach for targeting pancreatic cancer progression.
Citation Format: Jingwei Shi, Xiaodong Tian, Marko Kornmann, Benno Traub. JNK2 suppresses the growth and invasion of pancreatic cancer and is opposed by JNK1 [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-093.
Abstract PO-125: The role of KDM6A in pancreatic cancer immune microenvironment
Authors: Jin Lin , Yang Jing , Yi Zhujun , Kim Hong S. , Tian Feng , Shi Jiaqi 
Published: November 2021

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States, with a 10% 5-year survival rate. Immunosuppressive myeloid cells, including tumor-associated neutrophils (TANs), contribute to tumor development and treatment resistance. Lysine (K)-specific demethylase 6A (KDM6A) is one of the most frequently mutated epigenetic genes and a tumor suppressor in PDAC. However, the molecular mechanisms by which KDM6A contributes to PDAC development and whether KDM6A impacts the tumor immune microenvironment are unknown. This study established a genetically engineered pancreas-specific Kdm6a-knockout Ptf1aCre;LSL-KrasG12D/+;LSL-p53R172H/+ (KPC) PDAC mouse model to investigate the influence of KDM6A loss on PDAC development and tumor immune microenvironment. We found that KDM6A loss accelerated PDAC progression and increased metastases. Pancreata of mice with Kdm6a deficiency developed aggressive undifferentiated PDACs. Additionally, KDM6A loss led to increased infiltration of TANs and neutrophil extracellular traps (NETs) formation. Mechanistically, we used Bru-seq technology to investigate the impact of KDM6A on nascent RNA transcription. We demonstrated that many chemotactic cytokines related to neutrophil recruitment, specifically CXCL1, were upregulated in KDM6A-knockout PDAC cells. We further confirmed increased CXCL1 mRNA and protein levels in KDM6A-deficient human and mouse PDAC cells. In addition, immunohistochemical staining also confirmed the upregulated CXCL1 expression in both human and murine PDAC cells with KDM6A loss. TANs were found to express CXCR2, the receptor of CXCL1, by immunofluorescent analysis. To further confirm that cancer cells with KDM6A loss can attract neutrophils in vitro, we performed chemotaxis assays using both human neutrophils derived from PLB-985 cells and mouse primary neutrophils isolated from bone marrow and conditioned media from KDM6A- knockout or knockdown PDAC cells. We found that PDAC cells with KDM6A loss promoted neutrophil recruitment in vitro compared to KDM6A-retained PDAC cells. Furthermore, the CXCL1 neutralizing antibody reversed the chemotactic property of KDM6A-deficient PDAC cells, confirming that CXCL1 is the primary chemokine mediating the neutrophil recruitment. In summary, these findings shed light on the mechanism by which KDM6A loss promotes PDAC development, regulates tumor immune microenvironment, and suggests that the CXCL1-CXCR2 axis may be a candidate target for the treatment of PDAC, especially those with KDM6A mutations.
Citation Format: Lin Jin, Jing Yang, Zhujun Yi, Hong S. Kim, Feng Tian, Jiaqi Shi. The role of KDM6A in pancreatic cancer immune microenvironment [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-125.
Abstract PO-130: Macropinocytosis at the nexus of crosstalk in the pancreatic tumor microenvironment
Authors: Zhang Yijuan , Recouvreux M. Victoria , Jung Michael , Galencamp Koen , Li Yunbo , Zagnitko Olga , Scott David , Lowy Andrew , Commisso Cosimo 
Published: November 2021

Abstract
A feature of tumor cells is the acquisition of nutrients via macropinocytosis, an endocytic form of protein scavenging that functions to support metabolism and proliferation in the context of a nutrient-depleted tumor microenvironment. Here, we provide evidence that macropinocytosis is also operational in the tumor stroma. We find that glutamine deficiency triggers macropinocytic uptake in patient-derived cancer-associated fibroblasts (CAFs) from pancreatic ductal adenocarcinoma (PDAC) tumors. Mechanistically, stromal macropinocytosis is dependent on a CaMKK2-AMPK signaling axis that activates Rac1. We find that these signaling events are potentiated via an enhancement of cytosolic Ca2+ caused by glutamine limitation. Interestingly, glucose deprivation, which robustly enhances AMPK activation, does not activate Rac1 and fails to induce uptake in CAFs. We determine that the selectivity of the observed macropinocytic response is mediated by the glutamine depletion-induced upregulation of ARHGEF2, a Rho/Rac guanine nucleotide exchange factor. We elucidate that macropinocytosis has dual function in CAFs – it serves as a source of intracellular amino acids that sustain CAF viability, and it provides extracellular amino acids that promote tumor cell survival. By specifically ablating macropinocytosis in the stroma, we demonstrate that macropinocytosis-deficient CAFs are unable to enhance PDAC tumor growth. Current efforts are focused on how different metabolic inputs in the tumor microenviroment can differentially regulate the CaMKK2-AMPK signaling axis in stromal cells. These results highlight the functional role of macropinocytosis in the tumor stroma and provide a mechanistic understanding of how nutrient deficiency can control stromal protein scavenging.
Citation Format: Yijuan Zhang, M. Victoria Recouvreux, Michael Jung, Koen Galencamp, Yunbo Li, Olga Zagnitko, David Scott, Andrew Lowy, Cosimo Commisso. Macropinocytosis at the nexus of crosstalk in the pancreatic tumor microenvironment [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-130.
Abstract PR-008: Kdm6 demethylases are critical regulators of pancreatic cancer initiation, progression and subtype specification
Authors: Leonhardt Laura , Li Lucia Y. , Berrios David I. , Ashe Sudipta , Hendley Audrey M. , Kim Grace E. , Hebrok Matthias 
Published: November 2021

Abstract
Aberrant epigenetic regulation is a hallmark of pancreatic cancer. Since changes in histone methylation are potentially reversible, they present an attractive target for therapeutic intervention. Kdm6a and Kdm6b belong to a family of histone demethylases specific for lysine 27 of histone 3 and have been implicated in multiple types of cancer, including pancreatic ductal adenocarcinoma (PDA). We have gathered data from the extensive investigation of a mouse model of PDA in which either Kdm6b or both Kdm6a and Kdm6b have been deleted with concomitant activation of oncogenic KrasG12D restricted to adult acinar cells. While prior work had demonstrated an important role for Kdm6a in PDA formation, our data now show that the closely related Kdm6b is implicated in PDA tumorigenesis as well. Partial or complete loss of Kdm6b results in accelerated acinar-to-ductal metaplasia (ADM) and formation of pancreatic intraepithelial neoplasia (PanIN) with increased inflammation and fibrosis. Accelerated ADM formation was also observed ex vivo upon culturing acinar cells in the absence of oncogenic Kras, indicating that Kdm6b activity is critical for the maintenance of acinar identity and suppresses the early stages of pancreatic neoplasia development. However, only mice heterozygous for Kdm6b continue to exhibit a reduced overall median survival compared to KrasG12D alone, while complete loss of Kdm6b results in a similar overall median survival compared to KrasG12D. This suggests a requirement for oncogenic Kdm6b function during later progression of PanIN to invasive cancer. Conversely, concomitant loss of Kdm6a and Kdm6b protects against ADM and PanIN formation in vivo and ex vivo and double mutants display a trend towards an increased overall median survival compared to mice carrying only the KrasG12D mutation. Strikingly, the resulting tumors of Kdm6a/Kdm6b deficient mice exhibit features of an extremely rare subtype of sarcomatoid pancreatic cancer found in human patients. Taken together, this suggests that Kdm6 demethylase function is required during the initiation and progression of PDA. Furthermore, targeting Kdm6a/Kdm6b with specific inhibitors at distinct stages might provide opportunities for novel treatment avenues for pancreatic cancer.
Citation Format: Laura Leonhardt, Lucia Y. Li, David I. Berrios, Sudipta Ashe, Audrey M. Hendley, Grace E. Kim, Matthias Hebrok. Kdm6 demethylases are critical regulators of pancreatic cancer initiation, progression and subtype specification [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PR-008.
An Enduring Covenant: The Past and the Present in Contemporary African Christian Practice
Authors: Nwadialor Kanayo L. 
Published: November 2021

Abstract
The arrival of Christianity in Africa witnessed varieties of African response. Each of the patterns of the response has received attention from scholars of various milieus. Missionary historiographers for instance see African initial resistance as the battle of Satan to keep the gospel from invading his so called kingdom; this led to an alliance between the missionaries and European colonial forces that caused Africans’ acceptance of Christianity through imposition. Many scholars have interpreted this imposition to mean that “pagandom” has been defeated and African primal religion has retreated. However, a series of movements emerged for religious independence, manifesting Africa’s attempts to forge a new identity. This paper adopts evolutionist theory and the culture lag theory to provide insight into the interface of this great encounter that produced a movement for social and religious change; a reflection of the echoes of African religio-cultural heritage and a manifestation of an enduring covenant.
Covid-19 and the Celebration of the Fetu Afahye Festival in Ghana
Authors: Assanful Vincent , Boakye Peter 
Published: November 2021

Abstract
Festivals are important occasions that African societies have used to bring members together to foster unity and forge development of the communities. Traditional leaders also use festival to propitiate the ancestral spirits and deities to help dispel evil in the society. Throughout the year, festivals and durbars are held in various parts of the country for reunions and developmental purposes, and to the strengthen beliefs of the society. Festivals help the community and people to forge a closer bond with their ancestors and to ask for their protection. Festivals are also held in order to purify the whole state so that people can enter the New Year with confidence and hope. This paper, uses newspapers, interviews, major secondary works and articles on the internet as a source of data. It also uses qualitative and phenomenological methods to assess the impact of the Covid-19 pandemic on the celebration of the Fetu Afahye festival among the people of Cape Coast (Oguaa) in Ghana. The advent of the pandemic in Ghana altered the lives of the people in the traditional society since it led to the cancellation of the celebration of their festivals. The paper also examines how the non-observance of such festivals, especially the Fetu Afahye, impacted the ritual lives of the people. The paper concludes that even though a ban was placed on the celebration of festivals, due to its significance the traditional leaders found a way to perform the rituals associated with them in the face of the pandemic. This was done in order to avoid incurring the wrath of the sacred and to give the members in the community a sense of identity.
Cities, Migration and the Historiography of Post-war Europe
Authors: Shaev Brian , Hackett Sarah 
Published: November 2021

Abstract
The role of municipalities in migrant integration in post-war European history has largely slipped below the radar in previous migration research. Our special issue presents case studies on how Bristol, Dortmund, Malmö, Mannheim, Stuttgart and Utrecht managed migrant influxes from the mid-1940s to 1960s. Following interdisciplinary advances in local migration studies, our urban histories take a diversity of approaches, present diverse temporalities, and uncover municipal responses that range from generosity to indifference and to outright hostility. In all six cities, despite such diversity in local attitudes and municipal policies, municipal authorities had significant impacts on migrants’ lives. The introductory article explores how our urban perspectives contribute to scholarship on reconstruction and the post-war boom; welfare; democracy and citizenship; and European integration. Using local migration as a lens into postwar European history, we argue, provides important new insights for the historiography of postwar Europe.