bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2985: Radiotherapy and αCD40 non-redundantly augment immunity to checkpoint blockade in refractory pancreatic ductal adenocarcinoma
Authors: Dada Hannah , Rech Andrew J. , Victor Christina Twyman-Saint , Minn Andy J. , Vonderheide Robert H. 
Published: August 2018

Abstract
Despite the success of cancer immunotherapy in many disease types, pancreatic ductal adenocarcinoma (PDA) is notably unresponsive to immune checkpoint blockade (ICB) with αPD1 and/or αCTLA4. The mechanism of resistance is poorly understood, but tumor epitopes and the microenvironment, which is immunosuppressive and excludes T cells, are thought to be contributory. To improve response to ICB, we used subcutaneous and orthotopic murine models of PDA to investigate the effect of combination therapy with ICB (CTLA-4 and PD-1 antagonist antibodies), CD40 agonist antibody and radiation therapy (RT). Combination therapy with CD40 agonist antibody, ICB and RT resulted in decrease tumor burden, increase overall survival, and generation of long-term immunity. Response is dependent on T and short-lived myeloid cells, while it is independent of innate activation pathways. Together, these results suggest a dual role for both the innate and adaptive immune response in treating PDA.
Citation Format: Hannah Dada, Andrew J. Rech, Christina Twyman-Saint Victor, Andy J. Minn, Robert H. Vonderheide. Radiotherapy and αCD40 non-redundantly augment immunity to checkpoint blockade in refractory pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2985.
Abstract 2989: BET inhibitors induce Rac1-dependent MNK and eIF4E phosphorylation in cancer cells
Authors: Pham Thao , Decant Brian T. , Kumar Krishan , Shang Meng , Matsangou Maria , Ebine Kazumi , Munshi Hidayatullah G. 
Published: August 2018

Abstract
Patients with recurrent differentiated thyroid cancers (DTCs) have poor prognosis and suffer from multiple complications from progressive symptomatic disease. Here we show that eukaryotic translation initiation factor 4E (eIF4E), an oncogene that is overexpressed in aggressive thyroid cancers, is required for growth of DTC cells in collagen microenvironment. We show that inhibitors targeting bromodomain and extra-terminal domain (BET) family of proteins also decrease growth of DTC cells in the collagen microenvironment. Unexpectedly, we have found that BET inhibitors induce MNK and eIF4E phosphorylation in cancer cells. Mechanistically, BET inhibitors induce Rac1-mediated cytoskeletal changes and targeting Rac1 blocks these changes as well as MNK and eIF4E phosphorylation. Functionally, we show that MNK inhibitors potentiate the effects of BET inhibitors at suppressing cancer cell proliferation and limiting sphere-forming ability. Together, these results demonstrate crosstalk between BET proteins and the MNK-eIF4E pathway, suggesting that combination therapy with BET and MNK inhibitors has the potential for synergistic inhibition of cancer cells.
Citation Format: Thao Pham, Brian T. Decant, Krishan Kumar, Meng Shang, Maria Matsangou, Kazumi Ebine, Hidayatullah G. Munshi. BET inhibitors induce Rac1-dependent MNK and eIF4E phosphorylation in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2989.
Abstract 2993: A switch in epigenetic silencing mechanisms of endogenous retroviruses during human genome evolution
Authors: Ohtani Hitoshi , Liu Minmin , Zhou Wanding , Liang Gangning , Jones Peter A. 
Published: August 2018

Abstract
Approximately 9% of the human genome is derived from Endogenous Retroviruses (ERVs), which are a type of transposable element. ERVs started to become integrated into the ancestral human genome about 100 million years ago. Recent studies have reported that silencing mechanisms of long terminal repeats regions (LTRs), which are the putative promoters of ERVs, depend on DNA methylation, heterochromatin conformation (H3K9me3) and the PRC2 complex (H3K27me3). However, extensive maps of LTR distribution and the associated epigenetic marks have not yet been provided in human cancer cells. Here we report a switch in epigenetic silencing mechanisms of the approximately 450,000 LTR elements present in the non-genic regions of human DNA. Total RNA-seq in human colon cancer HCT116 cells following DNA methylation inhibitor treatment or knockdown of individual H3K9me2/3 histone methyltransferases (G9a, SETDB1, SETDB2, SUV39H1 and SUV39H2), H3K27me3 (EZH2) or a scaffold protein TRIM28 revealed that about 1,000 of evolutionary young LTRs were predominantly silenced by DNA methylation, whereas about 800 of intermediate age LTRs were silenced by histone methylation. They therefore have undergone an “epigenetic switch” in silencing mechanism during host genome evolution. Eventually, evolutionary old LTRs become inactive by accumulation of loss-of-function mutations. Consistent with these results, CpG sites in evolutionary young LTRs were methylated at higher levels than in intermediate age LTRs, whereas H3K9me2 and H3K9me3 marks were enriched on intermediate age LTRs. Interestingly, knockdowns of EZH2 showed limited upregulation of LTRs by itself, but multiple LTRs were upregulated by combination treatment with DNA methylation inhibitor. This is probably due to a process, in which removal of DNA methylation leads to the subsequent recruitment of EZH2 resulting in suppression by the polycomb repressive complex PRC2. Our earlier studies showed that LTR expressions lead to activation of viral defense pathways and apoptosis, however the species of LTRs was not characterized. We found that the activation of viral defense pathway was correlated with the upregulation of evolutionary young, but not intermediate age LTRs. Dual inhibition of DNA methylation and histone modifications by knockdown of G9a, SUV39H1 and EZH2 showed further upregulation of evolutionary young LTRs. Therefore, combination treatment targeting DNA methylation and the histone methyltransferases (G9a, SUV39H1 and EZH2) inhibitor may be useful in epigenetic therapy for cancer patients.
Citation Format: Hitoshi Ohtani, Minmin Liu, Wanding Zhou, Gangning Liang, Peter A. Jones. A switch in epigenetic silencing mechanisms of endogenous retroviruses during human genome evolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2993.
Abstract 302: Selective Mcl-1 inhibition by AZD5991 induces on-target cell death and achieves antitumor activity in multiple myeloma and acute myeloid leukemia
Authors: Tron Adriana E. , Belmonte Matthew A. , Criscione Steven , Clark Edwin A. , Gangl Eric , Gibbons Francis D. , Tyner Jeffrey W. , Kurtz Stephen E. , Ye Qing , Hird Alexander W. , Schuller Alwin , Secrist J. Paul 
Published: August 2018

Abstract
Mcl-1 is a member of the Bcl/Mcl family of proteins that promotes cell survival by preventing induction of apoptosis in a broad range of cancers. High expression of Mcl-1 has been linked to tumor development and resistance to anticancer therapies, underscoring the potential of Mcl-1 inhibitors as anticancer drugs. We have previously shown that AZD5991, a rationally designed macrocycle with sub-nanomolar affinity for Mcl-1 and high selectivity, induces rapid and irreversible commitment to apoptosis in Mcl-1-dependent cancer cells in a manner dependent on proapoptotic BAK. Here, we demonstrate that AZD5991 exhibits cytotoxic activity (GI50&lt;100nM) in various MM and AML cell lines in vitro with an activity profile distinct from the selective Bcl2 inhibitor venetoclax. In vivo, AZD5991 shows potent antitumor activity with complete (100%) tumor regression in several mouse MM and AML xenograft models after a single tolerated dose. AZD5991 shows enhanced efficacy in vivo when combined with standard-of-care agents. Pharmacodynamic studies confirmed that AZD5991 kills cancer cells by activation of the mitochondrial apoptotic pathway. Ex vivo analysis indicates that AZD5991 has single agent activity in primary AML patient samples with LC50 values in the low nanomolar range. Consistent with our findings in AML cell lines, the activity profile for AZD5991 in AML primary samples was distinct from venetoclax, highlighting the unique therapeutic opportunity for AZD5991. Based on these data a phase I clinical trial has been launched for evaluation of AZD5991 in patients with MM and other hematologic malignancies (NCT03218683).
Citation Format: Adriana E. Tron, Matthew A. Belmonte, Steven Criscione, Edwin A. Clark, Eric Gangl, Francis D. Gibbons, Jeffrey W. Tyner, Stephen E. Kurtz, Qing Ye, Alexander W. Hird, Alwin Schuller, J. Paul Secrist. Selective Mcl-1 inhibition by AZD5991 induces on-target cell death and achieves antitumor activity in multiple myeloma and acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 302.
Abstract 3021: Plexin-B3 regulates cellular motility, invasiveness and metastasis in pancreatic cancer
Authors: Saxena Sugandha , Hayashi Yuri , Rachagani Satyanarayana , Batra Surinder Kumar , Singh Rakesh Kumar 
Published: August 2018

Abstract
Cancer metastasis significantly worsens the survival of pancreatic cancer (PC) patients. Currently, semaphorins and their high-affinity receptors plexins are considered versatile regulators of cancer cell migration, angiogenesis, invasion and metastasis. Our group identified semaphorin-5A (SEMA5A) as a putative cell adhesion molecule involved in organ-specific homing of PC cells and playing a significant role in PC angiogenesis and metastasis. Thus, SEMA5A and its receptor plexin-B3 represents an attractive targetable axis in PC metastasis. However, for a better understanding of the SEMA5A-initiated downstream signaling events and regulation of cellular phenotypes, it is necessary to delineate the function of its receptor plexin-B3 in PC as well. Thus, understanding the pathologic expression and functional role of plexin-B3 is essential for characterization of SEMA5A/plexin-B3 axis in PC. In the present study, we analyzed plexin-B3 expression in PC disease progression model of PDX-Cre-Kras(G12D) (KC) mice and evaluated the functional role by utilizing plexin-B3 knockdown T3M-4 and CD18/HPAF cells. We observed a reduction of plexin-B3 expression with disease progression in KC mice model and also the poor survival of pancreatic adenocarcinoma stage II patients (n = 24) with lower plexin-B3 expression. Functionally, knockdown of plexin-B3 enhanced in vitro cellular migration and invasiveness of PC cells. Furthermore, plexin-B3 knockdown cells showed a significant increase in cellular size with impaired colony formation in three-dimensional culture. Cell proliferation analysis demonstrated that plexin-B3 knockdown cells showed lower proliferation in comparison with the control cells. We also observed higher metastasis with lower tumor burden in nude mice injected with CD18/HPAF-sh plexin-B3 cells than CD18/HPAF-control cells. Furthermore, the tumors formed by CD18/HPAF-plexin-B3 cells showed higher fibrosis, a higher number of vimentin-positive cells, and lower number of proliferation marker Ki-67-positive cells in comparison with the CD18/HPAF-control tumors. In addition, we observed similar phenotypic changes in PC cells with loss of SEMA5A-ligand of plexin-B3. In summary, our data demonstrate that impairment in SEMA5A/plexin-B3 axis enhances cellular motility and invasiveness of PC cells, thereby resulting in higher metastasis.
Citation Format: Sugandha Saxena, Yuri Hayashi, Satyanarayana Rachagani, Surinder Kumar Batra, Rakesh Kumar Singh. Plexin-B3 regulates cellular motility, invasiveness and metastasis in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3021.
Abstract 303: Novel role of nuclear BH3-only protein BNIP3 in regulation of cellular proliferation
Authors: Singh Amandeep , Azad Meghan , Gibson Spencer 
Published: August 2018

Abstract
The objective of this study is to investigate the role of Bcl-2 nineteen kilodalton interacting protein 3 (BNIP3) in regulating cellular proliferation and identifying the proliferation pathways mediated by BNIP3. BNIP3 is a BH3-only proapoptotic member of Bcl-2 family of cell death regulating proteins. The function of BNIP3 is dependent on its localization and expression levels. Under normal conditions, low levels of BNIP3 are present in the nucleus of cells. Low oxygen or hypoxic conditions lead to increased expression of BNIP3, and high levels of BNIP3 are found in the cytoplasm. Cytoplasmic BNIP3 is associated with caspase-independent apoptotic cell death through mitochondria. If, however, BNIP3 levels are increased in the nucleus, it promotes survival of cells by transcriptionally inhibiting several apoptosis-inducing factors. High levels of BNIP3 in nucleus are seen in majority of glioblastoma tumors, where hypoxic environment of tumor core causes an increase in expression of BNIP3 but high amounts of BNIP3 localize to the nucleus, possibly aiding in the survival of the tumor cells. In this study, we found that BNIP3 knockout mice brains have increased cellularity compared to wild-type brains. We also found that both mouse primary astrocytes and embryonic fibroblasts (MEFs) lacking BNIP3 expression have an increased capacity for proliferation compared to wild-type MEFs. Overexpressing BNIP3 in the nucleus of HEK 293 cells also resulted in reduced proliferation. In contrast, both astrocytes and MEFs lacking BNIP3 failed to show differences in cell death compared to wild-type cells. This reveals a novel function for BNIP3 in regulating cellular proliferation that may lead to new targets for cancer therapy. In future studies, we will identity genes regulated by nuclear BNIP3 that may lead to suppression of cellular proliferation in cancer cells.
Citation Format: Amandeep Singh, Meghan Azad, Spencer Gibson. Novel role of nuclear BH3-only protein BNIP3 in regulation of cellular proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 303.
Abstract 3049: Dexamethasone pretreatment impairs the TS inhibition-mediated flare in thymidine salvage pathway activity
Authors: Katz Sharyn I. , Chen Xiao , Yang Yizeng 
Published: August 2018

Abstract
Introduction: Inhibition of thymidylate synthase (TS) by pemetrexed, an inhibitor of thymidylate synthase, results in an early transient burst or “flare” in thymidine salvage pathway activity at 2 hrs of therapy, which, we have demonstrated in prior publications, can be measurable with FLT ([18F]thymidine)-positron emission tomography (PET) in non-small cell lung cancer (NSCLC). Administration of dexamethasone with pemetrexed-based therapy, as typically practiced in the clinic, could potentially confound this imaging approach since dexamethasone is known to inhibit expression of thymidine kinase 1, a key enzyme in the thymidine salvage pathway. Here we examine the potential impact of dexamethasone on the TS inhibition-mediated thymidine salvage pathway “flare” in NSCLC.
Materials and Methods: In order to determine NSCLC cell line sensitivity to dexamethasone and pemetrexed, IC50 studies were performed on NSCLC cell lines H23, H1975, H460, H1299. TS inhibition-mediated “flare” in thymidine salvage pathway activity was then measured at 2hrs of exposure to pemetrexed and cisplatin in NSCLC cells lines following using 3H-thymidine incorporation assays under the following conditions: control (no chemotherapy or dexamethasone), treated with pemetrexed and cisplatin without dexamethasone, with 24 pretreatment of dexamethasone, or with dexamethasone administered together with chemotherapy. These conditions were chosen to model the delivery of pemetrexed-based therapy in the clinic.
Results: The IC50 of H23, H1975, H460, H1299 for dexamethasone and pemetrexed were 40, 5.9, 718, 362 uM and 0.22, 0.73, 0.14 and 0.66 uM, respectively. Significant blunting of the thymidine salvage pathway “flare” is observed at 2hrs of pemetrexed-based therapy when dexamethasone-sensitive cell lines H23 and H1975 were pretreated with dexamethasone but not when dexamethasone was given together with pemetrexed therapy or in the setting of dexamethasone resistance (H460 and H1299).
Conclusion: Imaging of TS inhibition may be impacted by pretreatment with dexamethasone but not administration of dexamethasone on the same day of therapy delivery.
Citation Format: Sharyn I. Katz, Xiao Chen, Yizeng Yang. Dexamethasone pretreatment impairs the TS inhibition-mediated flare in thymidine salvage pathway activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3049.
Abstract 3050: Imaging tissue extracellular pH for the differential diagnosis of coccidioidomycosis and lung cancer
Authors: Lindeman Leila Renee , Randtke Edward A. , Shubitz Lisa F. , Howison Christine M. , Jones Kyle M. , Pagel Mark D. 
Published: August 2018

Abstract
Introduction: Our objective was to determine whether acidoCEST MRI—a novel, non-invasive MRI method that measures extracellular pH (pHe)—can differentiate between lung tumors and coccidioidomycosis (valley fever) granulomas within in vivo mouse models of lung cancer and valley fever.
Methods: To develop a spontaneous murine lung tumor model, A/J mice received orthotopic injections of urethane to induce formation of lung adenocarcinomas. The Valley Fever Center for Excellence at the University of Arizona infected SW mice with a BSL 2-compatible mutant Coccidioides strain, Δcps1, to develop our preclinical valley fever model. All scans were performed with a Bruker BioSpin 7T MRI system. For all MRI scans, mice were anesthetized with 2.0% isofluorane, respiration and body temperature were monitoreduring scans, and body temperature was maintained at 37 °C. Respiration-triggering (gating) was used in all imaging sequences to compensate for motion artifacts in the lung. For optimal gating, the mouse's respiration rate was maintained at &lt; 50 breaths per minute. Each mouse was scanned with acidoCEST MRI using 370 mg/mL Iopamidol (200 μL IV bolus, 400 μL/hr IV infusion). AcidoCEST MRI (3.5 μT, 300 ms imaging time, 6000 ms presaturation pulse) was performed according to previously published methods, updated with improved respiration gating. For acidoCEST MRI, the saturation pulse continued until terminated by the gating trigger. Spatial pHe maps of tumor and granuloma ROI were produced using Bloch fitting in Matlab 2014a. Average lesion pHe and iopamidol concentration we also recorded.
Results: AcidoCEST MRI was successfully applied to the in vivo imaging of murine lung tumors and coccidioidomycosis granulomas. Lung tumors demonstrated successful uptake of the iopamidol contrast agent, with an average concentration of approximately 40 mM. pHe values in the tumor ROI ranged from 6.5 to 7.2 with an average value of 6.64. Granulomas demonstrated successful uptake of iopamidol with an average concentration of about 75 mM. pHe values in granulomas ranged from 7.2 to 7.4 with an average value of 7.29.
Conclusion: AcidoCEST MRI may be used to quantify the pHe of murine lung tumors and coccidioidomycosis granulomas in vivo. Our results show that pHe is a promising biomarker for the differential diagnosis of coccidioidomycosis and lung cancer.
Citation Format: Leila Renee Lindeman, Edward A. Randtke, Lisa F. Shubitz, Christine M. Howison, Kyle M. Jones, Mark D. Pagel. Imaging tissue extracellular pH for the differential diagnosis of coccidioidomycosis and lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3050.
Abstract 3054: High-throughput microfluidic Labyrinth for the label-free isolation of circulating tumor cells
Authors: Lin Eric 
Published: August 2018

Abstract
Circulating tumor cells (CTCs) present in the blood are the instruments of metastasis and are of high biologic and clinical relevance. Single-cell technologies are playing an increasing role in profiling CTCs in the peripheral blood for detection and real-time monitoring of cancer metastasis. CTCs also help in identifying its distinct drivers. However, current approaches are limited to manual selection of CTCs, which hinders the unbiased comprehensive study of CTCs on a single-cell level. We present a unique label-free microfluidic “Labyrinth” device to isolate CTCs at a high throughput of 2.5mL/min, offering the first biomarker-independent single-cell isolation and genomic characterization platform to study heterogeneous CTC subpopulations in cancer patients. The Labyrinth takes advantage of inertial forces on the microscale in curved geometries to differentially focus cells based on their size. This novel strategy of multicourse path traversing across inner loops to outer loops yielding highest hydrodynamic path length enables focusing of white blood cells (WBCs), leading to high recoveries (&gt; 90%) and efficient separation of WBCs from CTCs, resulting in high purity (~ 200 WBCs/mL), even in whole blood samples without any preprocessing. CTCs were successfully isolated from 56 breast cancer (9.1 CTCs/mL average, range 2-31/mL) and 20 pancreatic cancer (51.6 CTCs/mL average, range 11-115/mL) patients. We detected not only CTCs typically defined by epithelial markers, but also significant numbers of CTCs (&gt;50%) lacking epithelial markers but expressing mesenchymal and cancer stem cell (CSC) markers. Patient samples were then analyzed using single-cell multiplex gene expression. Seventy single cells were successfully recovered and used to identify different subpopulations of CTCs based on their genetic signature, unlike other methods where a positive or negative selection based on protein expression is used. Interestingly, both inter- and intrapatient molecular heterogeneity at the single-cell level in CTCs were observed with cells expressing genes uniquely related to epithelial, MET, and EMT phenotypes. The Labyrinth platform allows a thorough molecular understanding of the heterogeneity among CTCs. This platform also shows CTCs' potential as a biomarker to noninvasively evaluate tumor progression and response to treatment in cancer patients.
Citation Format: Eric Lin. High-throughput microfluidic Labyrinth for the label-free isolation of circulating tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3054.