bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4434: Th1 cytokines promotes E3 ubiquitin ligase Cullin 5 expression via STAT1 signaling cascade and enhance cul5 mediated proteasomal degradation of HER2 in HER2+/ER- breast cancer
Authors: Jia Yongsheng , Ramamoorthi Ganesan , Kodumudi Krithika , Basu Amrita , Wiener Doris , Czerniecki Brian 
Published: August 2019

Abstract
The proto-oncogene HER2/ErbB2 overexpression occurs in 30% of invasive breast cancer patients and its critically associated with aggressive disease, metastasis and tumor recurrence. Despite advances in the treatment of HER2+ breast cancers, resistance and metastatic disease are potential obstacles. Cullin 5 (Cul 5), a scaffold protein mediates formation of the Cullin 5-RING E3 ubiquitin ligase functional complex. This complex acts on protective molecular chaperone heat shock protein (HSP90) complex and subsequently leads to polyubiquitination and proteasomal degradation of its client protein HER2/ErbB2. Reduced expression of Cul 5 in breast cancer patients can abrogates its inhibitory function and favor HSP90 mediated stabilization of HER2/ErbB2. More recently, we showed that Th1 cytokines (IFN-γ and TNF-α) decreased HER2 expression and induced senescence and apoptosis in HER2 overexpressing breast cancer cell lines. However, the role of Th1 cytokines on Cul 5 mediated regulation of HER2/ErbB2 remains unknown. In the present study, low level expression of Cul 5 was observed in various human (SKBR3, HCC1419 and JIMT1) and mouse (Tubo) HER2+/ER- breast cancer cell lines. Interestingly, treatment of HER2+/ER- breast cancer cells with Th1 cytokines increased the expression of Cul 5 and downregulated the expression of HER2. We knocked-down Cul 5 expression by specific siRNA found that treatment of Th1 cytokines failed to decrease HER2 expression in HER2+/ER- breast cancer cells. To investigate whether the mechanism of Th1 cytokines on Cul5 is via downstream signaling molecule STAT-1, we knock-down STAT-1. Silencing of STAT-1 expression prevented Th1 cytokines mediated activation of Cul 5. We also observed no effect on the inhibition of HER2 expression after Th1 cytokines treatment in HER2+/ER- breast cancer cells in which the expression of STAT-1 was knocked-down. Collectively, our findings demonstrate a novel mechanism that Th1 cytokines promote Cul 5 expression via STAT1 signaling and enhance Cul 5 mediated proteasomal degradation of HER2 in HER2+/ER- breast cancer. Enhancing Cul 5 levels may represent a new therapeutic avenue for the inhibition of HER2 overexpression and prevention of metastasis and tumor relapse.
Citation Format: Yongsheng Jia, Ganesan Ramamoorthi, Krithika Kodumudi, Amrita Basu, Doris Wiener, Brian Czerniecki. Th1 cytokines promotes E3 ubiquitin ligase Cullin 5 expression via STAT1 signaling cascade and enhance cul5 mediated proteasomal degradation of HER2 in HER2+/ER- breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4434.
Abstract 444: Continuous, high throughput microfluidic device to monitor circulating tumor cells in cancer patients
Authors: Smith Kaylee , Kim Tae Hyun , Paoletti Costanza , Thamm Douglas H. , Hayes Daniel F. , Nagrath Sunitha 
Published: August 2019

Abstract
Analysis of circulating tumor biomarkers, designated “liquid biopsies” are less invasive and lower risk to the patient and might replace or complement standard tissue biopsies to determine prognosis, predict benefit from specific therapies, or monitor patients with cancer. Circulating tumor cells (CTCs) are extremely rare, with only 1-10 CTCs per mL of blood. Current technologies typically process 1-10 mL of blood ex vivo. We report an in vivo, indwelling CTC-capture device that is analogous to a Holter monitor used to interrogate cardiac rhythm abnormalities over long periods of time. The system incorporates a dual lumen intravenous catheter that directs blood from the vein into a small (~ the size of a wristwatch) capture carriage by virtue of a peristaltic pump. The carriage contains a CTC capture chip which separates CTCs from whole blood based on flow differences and solid phase anti-EpCAM capture, while the remaining whole blood is returned to the venous system via the dual lumen catheter. The chip is then removed from the carriage for further enumeration and characterization of the CTCs. In a proof of principle set of experiments, the system was placed into investigational canines into which fluorescently labeled human breast cancer cells were injected intravenously. Although the vast majority of these xeno-cancer cells were rapidly removed from circulation, the system captured “CTCs” over a 2 hour time period more successfully than was seen in simultaneous blood draws for ex vivo enumeration over the same time. No adverse effects were observed in the subjects at the time of the experiments or over the succeeding 48 hours after removal of the IV system.Our system permits interrogation of a much larger volume of blood than can be processed with standard blood draws. The larger processed volume will drastically increase the number of cells isolated which in turn increases the number of downstream assays that can be performed. This study is focused on developing a high throughput microfluidic device that can detect CTCs and implementing it in a canine model.
Citation Format: Kaylee Smith, Tae Hyun Kim, Costanza Paoletti, Douglas H. Thamm, Daniel F. Hayes, Sunitha Nagrath. Continuous, high throughput microfluidic device to monitor circulating tumor cells in cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 444.
Abstract 4495: Role of base excision repair (BER) pathway in regulation of KRAS expression in pancreatic cancer
Authors: Pramanik Suravi , Roychoudhury Shrabasti , Harris Hannah , Song Heyu , Bhakat Kishor K. 
Published: August 2019

Abstract
Activating mutations in KRAS proto-oncogene, a signature event driving the development, progression and therapeutic resistance of pancreatic ductal adenocarcinoma (PDAC), remains undruggable. The occurrence of guanine oxidation (8-oxoguanine) in the KRAS promoter and up-regulation of KRAS gene transcription under oxidative stress has been shown to be associated with KRAS expression and cancer development and progression. However, the molecular mechanism by which 8-oxoguanine damage regulates KRAS expression is largely unknown. Here, we show that the base excision repair (BER) pathway, a fundamental DNA damage repair pathway that processes most of the endogenous damages including oxidative base damage is involved in regulation of KRAS expression and survival of PDAC. We show that Apurinic/apyrimidinic endonuclease (APE1), a key enzyme of the BER pathway, is highly elevated in pancreatic cancer tissue samples. To elucidate the role of active BER pathway in the regulation of KRAS expression, we used real-time PCR (RT-PCR) analysis. Inflicting cells with oxidative damage using glucose oxidase increased KRAS gene expression in control cells but not in APE1 downregulated cells. ChIP assay showed enhanced occupancy of APE1 in KRAS promoter upon oxidative stress. Consistent with this, using synthetic oligonucleotide containing the KRAS promoter region, we showed that APE1 could bind and cleave AP site in KRAS promoter. Further, ChIP-qPCR analysis showed decreased occupancy of MAZ, a transcription factor, to the KRAS promoter in APE1 downregulated cells. Down-regulation of APE1 also resulted in decreased KRAS expression and increased sensitivity of pancreatic cancer cells to routinely used chemotherapeutic agents such as Gemcitabine, 5-Fluorouracil, Oxaliplatin, etc., suggesting that targeting APE1 and in turn, BER can sensitize pancreatic cancer cells. Our study suggests that BER pathway or APE1 plays a significant role in the tumor-selective regulation of gene expression and sensitization of cancer cells to chemotherapy, and supports the further investigation of novel treatments that target this pathway for cancer therapy.
Citation Format: Suravi Pramanik, Shrabasti Roychoudhury, Hannah Harris, Heyu Song, Kishor K. Bhakat. Role of base excision repair (BER) pathway in regulation of KRAS expression in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4495.
Abstract 4563: Profiling the tumor immune microenvironment of adenocarcinoma and squamous cell NSCLC
Authors: Harmeyer Kayla , Deng Jiehui , Shah Suhagi , Bagdatlioglu Ece , Ahsan Aarif , Reid Christopher , Thennavan Aatish , Perou Charles , Wong Kwok-Kin , Pass Harvey 
Published: August 2019

Abstract
The emergence of immune checkpoint inhibitors has changed the treatment paradigm for NSCLC. Recently, immunotherapy in combination with chemotherapy was shown to be a promising first-line treatment strategy for patients with squamous cell lung cancer, where targeted therapy has had little efficacy due to the pathological driver mutations for this disease being poorly understood. However, for both adenocarcinoma and squamous cell NSCLC, use of such immune checkpoint inhibitors has shown to improve the outcome for only a subset of patients with advanced or metastatic disease. Understanding the diversity in the tumor immune microenvironment will be critical to not only advance immune oncology research but to also determine potential clinical distinctions that dictate therapeutic response. Here, we take a multifaceted approach to compare the tumor immune microenvironments of over 50 patients diagnosed with either adenocarcinoma or squamous cell NSCLC. To this end, we performed a comprehensive multicolor flow cytometry analysis to compare tumor immune infiltrates and expression of suppressive markers to adjacent normal lung tissue as well as peripheral blood immune cells from the same patient. This analysis showed differences in the CD4+ and CD8+ T cell, CD19+ B cell, NK cell, and CD14+/CD16+ myeloid cell populations between the tumor and matched tissue and blood. These immune profiles were then compared between adenocarcinoma and squamous cell carcinoma subtypes as well as early versus late stage disease. We then integrated these findings with multiplexed immunofluorescence analysis on a panel of immune cell markers. Finally, 10x genomics single-cell RNA sequencing (scRNAseq) data were used to analyze single-cell transcriptomes from both adenocarcinoma and squamous cell lung tumors. Our result showed great heterogeneity of immune infiltrates across different patient samples, including different subtypes and different disease stages. This detailed comparative analysis will help us further understand the involvement of tumor infiltrating immune cells for different subtypes of lung cancer.
Citation Format: Kayla Harmeyer, Jiehui Deng, Suhagi Shah, Ece Bagdatlioglu, Aarif Ahsan, Christopher Reid, Aatish Thennavan, Charles Perou, Kwok-Kin Wong, Harvey Pass. Profiling the tumor immune microenvironment of adenocarcinoma and squamous cell NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4563.
Abstract 4577: Anti-tumor immunity is a key determinant of small cell lung cancer survivorship
Authors: Kosari Farhad , Muppa Prasuna , Terra Simone , Sharma Anurag , Mansfield Aaron , Aubry Marie Christine , Janaki Nafiseh , Nasir Aqsa , Peikert Tobias 
Published: August 2019

Abstract
Introduction: While most small cell lung cancer (SCLC) patients die within a few months, a sub-group of patients survive for many years. Factors determining long-term survivorship remain largely unknown. We present the first comprehensive comparative genomic and tumor microenvironment analyses of small cell lung cancer (SCLC) between patients with long term (LTS) and expected (EXS) survival times.
Methods: We compared surgically resected tumors of 23 LTS (survival &gt; 4 years) and 18 EXS (survival ≤ 2 years). There were no differences in clinical variables including TNM staging and curative versus non-curative intend surgery between the groups. Gene expression profiling was performed by microarrays and tumor microenvironment analyses were by IHC of prominent immune related markers.
Results: Immune related genes and pathways represented the majority of the differentially overexpressed genes in LTS compared to the EXS. The differences in the immunological tumor-microenvironment were confirmed by quantitative immuno-staining. Increased numbers of tumor infiltrating and associated lymphocytes were present throughout tumors of LTS. Several differentiating patterns of enhanced anti-tumor immunity were identified. While some areas of LTS tumors also harbored higher numbers of suppressive immune cells (monocytes, regulatory lymphocytes, and macrophages), ratios of these suppressive cells to CD3+ lymphocytes were generally lower in LTS tumors indicating a more tumor suppressive microenvironment.
Conclusions: Our data demonstrate that long-term survivorship of SCLC patients is strongly influenced by the presence of anti-tumor immune cells in the tumor microenvironment. Characterization of the anti-tumor immune responses may identify opportunities for individualized immunotherapies for SCLC.
Citation Format: Farhad Kosari, Prasuna Muppa, Simone Terra, Anurag Sharma, Aaron Mansfield, Marie Christine Aubry, Nafiseh Janaki, Aqsa Nasir, Tobias Peikert. Anti-tumor immunity is a key determinant of small cell lung cancer survivorship [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4577.
Abstract 4580: Primary tumor-induced immunity eradicates disseminated tumor cells in syngeneic mouse model
Authors: Piranlioglu Raziye , Lee Eunmi , Ouzuonova Maria , Rodier Riley , Greer Adam , Bayraktar Feyzanur , Durmus Omer Can , Arbab Ali S. , Thangaraju Muthushamy , Wicha Max S. , Celis Esteban , Korkaya Hasan 
Published: August 2019

Abstract
Although clinically apparent metastasis is associated with late stages of cancer development, micro-metastatic dissemination may be an early event. However, the fate of these early disseminated tumor cells (DTC) remains elusive.
Using the syngeneic mouse models, we demonstrated that although both orthotopically-implanted murine 4T1 and EMT6 tumors are capable of disseminating into secondary organs, only 4T1 tumors develop overt metastasis. However, EMT6 tumors induce an anti-tumor immunity in syngeneic mice and that eradicates disseminated tumor cells (DTC) in distant organs. Following the complete removal of primary EMT6 tumors, mice do not develop detectable metastasis and generate an immunological memory that leads to complete elimination of repeatedly injected tumor cells via tail vein. Conversely, these cells readily grow and metastasize in immuno-deficient athymic or Rag2- mice, and when g-MDSCs from 4T1 tumor-bearing mice were co-injected into immunocompetent EMT6 primed mice. In contrast to complete resection, mice with residual tumors following surgery exhibited an enhanced growth of local and concomitant growth of DTCs at metastatic site with increased g-MDSCs accumulation in lung and spleen.
Together, our results suggest that some tumors are capable of inducing anti-tumor immunity against the DTCs when complete resection of primary tumor cures animals. However, in the presence of residual tumors, inflammation induced by surgical procedure promote the growth of DTCs.
Citation Format: Raziye Piranlioglu, Eunmi Lee, Maria Ouzuonova, Riley Rodier, Adam Greer, Feyzanur Bayraktar, Omer Can Durmus, Ali S. Arbab, Muthushamy Thangaraju, Max S. Wicha, Esteban Celis, Hasan Korkaya. Primary tumor-induced immunity eradicates disseminated tumor cells in syngeneic mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4580.
Abstract 4581: High endothelial venules are associated with immune evasion and hereditary background in mismatch repair-deficient colorectal cancers
Authors: Ahadova Aysel , Pfuderer Pauline , Ballhausen Alexej , Frayling Ian , Ager Ann , Doeberitz Magnus von Knebel , Kloor Matthias 
Published: August 2019

Abstract
DNA mismatch repair (MMR)-deficient cancers can develop in the context of Lynch syndrome or sporadically. MMR-deficient cancers accumulate a high load of immunogenic frameshift peptide neoantigens as a consequence of insertion/deletion mutations at coding microsatellites (microsatellite instability, MSI). Whether enhanced lymphocyte recruitment contributes to the high immune infiltration and the pronounced local immune response typically observed in MSI colorectal cancers (CRCs) is not known. Here we analyzed the density of high endothelial venules (HEVs), postcapillary blood vessels specialized for lymphocyte trafficking, in MSI CRC of sporadic and hereditary origin. Immunohistochemical staining with rat monoclonal MECA-79 antibody was used to detect HEVs in tumor specimens from MSI (hereditary, n=20 and sporadic, n=28) and MSS CRCs (n=35). Lymph follicle-associated HEVs were normalized per mm2 of tumor and peritumoral area. Mutations of the B2M gene were determined by Sanger sequencing. Significantly elevated HEV densities were detected in MSI (n=48) compared to MSS CRCs (n=35) (0.09 vs 0.02 counts per mm2, p=0.0002). Lynch syndrome-associated MSI CRCs presented with significantly higher HEV densities compared to sporadic counterparts (0.15 vs 0.05 counts per mm2, p=0.025). This difference remained significant when age-matched groups of hereditary and sporadic MSI CRCs were compared. MSI CRCs with B2M mutations (n=12) presented with significantly higher HEV densities than their B2M-wild type counterparts (n=14, p=0.016). Our results demonstrate that a high density of HEVs correlates with the MSI phenotype in CRC, underlining the elevated local immune activation in these tumors. Within MSI CRC, Lynch syndrome was a predictor of high HEV counts, suggesting a likely role of lymphocyte recruitment in immune surveillance of Lynch syndrome CRCs. The observation of high HEV counts particularly in MSI CRCs harboring B2M mutations supports the model that immune evasion occurs particularly in an activated local immune environment. The prognostic value of HEVs in MSI CRCs should be addressed in the future studies.
Citation Format: Aysel Ahadova, Pauline Pfuderer, Alexej Ballhausen, Ian Frayling, Ann Ager, Magnus von Knebel Doeberitz, Matthias Kloor. High endothelial venules are associated with immune evasion and hereditary background in mismatch repair-deficient colorectal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4581.
Abstract 4582: Mannose receptor positive macrophage infiltrate correlates with prostate cancer onset and metastatic castration-resistant disease
Authors: Zarif Jelani C. , Valle Javier A. Baena-Del , Hicks Jessica L. , Heaphy Christopher M. , Vidal Igor , Luo Jacob , Lotan Tamara L. , Hooper Jody E. , Isaacs William B. , Pienta Kenneth J. , Marzo Angelo M. De 
Published: August 2019

Abstract
M2-Tumor Associated macrophages (M2-TAMs) can suppress inflammation within the tumor microenvironment and have been reported to modulate cancer progression. We and others have previously reported infiltration of M2 macrophages in metastatic castrate-resistant prostate cancers (mCRPC). The objective of this study was to determine whether the extent of M2 macrophage infiltration correlates with prostate cancer aggressiveness, we applied immunohistochemistry to normal prostatic tissue, localized prostate cancer and metastatic castrate-resistant prostate cancer (mCRPC) from 192 patients. To assess M2 macrophage involvement, we analytically validated an IHC assay to detect the human mannose receptor (CD206). Also, we used multiplex immunofluorescent staining to show that a small fraction of CD206 staining co-localizes with endothelial cells of lymphatic vessels, while the vast majority of staining occurs in CD68-positive macrophages. The area fraction of staining for CD206-positive macrophages increased in a stepwise fashion going from normal (i.e. non-inflammation) prostatic tissue, to primary untreated carcinomas, to hormone naive regional lymph node metastases to castration resistant prostate cancer. Complimentary studies using flow cytometry confirmed CD206-positive M2-TAM infiltration. Altogether, this study revealed a progressive increase in CD206-positive macrophages from normal prostate to metastatic CRPC. Given the immunosuppressive nature of these cells and lack of clinical success of immunotherapy for prostate cancer patients, our results provide a rationale for therapeutic development to deplete these cells in the prostate cancer microenvironment as a potential method to augment immunotherapeutic approaches in prostate cancer.
Citation Format: Jelani C. Zarif, Javier A. Baena-Del Valle, Jessica L. Hicks, Christopher M. Heaphy, Igor Vidal, Jacob Luo, Tamara L. Lotan, Jody E. Hooper, William B. Isaacs, Kenneth J. Pienta, Angelo M. De Marzo. Mannose receptor positive macrophage infiltrate correlates with prostate cancer onset and metastatic castration-resistant disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4582.