bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2753: The molecular basis of blocking the TIM-3 checkpoint with the LY3321367 mAb in cancer immunotherapy
Authors: Haidar Jaafar N. , Antonysamy Stephen , Mathew Sneha , Wu Lan , Zhang Yi , Kearins Margaret C. , Shen Leyi , Sauder J. Michael , Schaer David , Driscoll Kyla E. , Kalos Michael 
Published: August 2019

Abstract
The anti-T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) antibody LY3321367 is a promising immune-checkpoint inhibitor that is being clinically tested for the treatment of multiple solid tumors (NCT03099109). LY3321367 was phenotypically selected from a large set of phage library Fabs that are TIM-3 binders. Tim3 has multiple protein and non-protein binding partners; hence, we attempt in this study to deconvolute the molecular mechanism of action of LY3321367. Surprisingly, LY3321367 in ELISA assays partially blocks the TIM-3/GAL-9 complex but does not block the TIM-3/CEACAM-1 complex. We also utilized X-ray crystallography to solve the structure the LY3321367-Fab complex with the IgV domain of TIM-3 at 2.0Å resolution. After solving the unbound structure of the LY3321367-Fab, we demonstrated that its CDRs do not undergo any conformational changes upon binding human TIM-3. The structural alignment of the human TIM-3/LY3321367-Fab complex with the available murine TIM-3 structure unexpectedly suggests that the 6.0Å epitope of LY3321367 overlaps the phosphatidylserine (PS) binding site on TIM-3. Consequently, we developed a cell-based assay to demonstrate that LY3321367 completely blocks the binding of soluble human TIM-3 to PS displayed on the surface of Campothecin-treated DO11.10 cells.
Our structural results suggest an important role for PS in TIM-3 biology which is blocked by LY3321367. When combined with the partial blocking of GAL-9, the structural data of LY3321367 suggests that the binding sites of PS and GAL-9 may be proximal to each other on TIM-3.
Citation Format: Jaafar N. Haidar, Stephen Antonysamy, Sneha Mathew, Lan Wu, Yi Zhang, Margaret C. Kearins, Leyi Shen, J. Michael Sauder, David Schaer, Kyla E. Driscoll, Michael Kalos. The molecular basis of blocking the TIM-3 checkpoint with the LY3321367 mAb in cancer immunotherapy [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 2753.
Abstract 2754: Affinity-based probe reveal Bim negatively regulates the chaperone functions of Hsp70, a non-Bcl-2 BH3 receptor
Authors: Wang Ziqian , Zhang Zhichao , Song Ting , Guo Zongwei 
Published: August 2019

Abstract
The identification of novel non-Bcl-2 BH3 receptors is still challenge owing to frequently weak, transient and reversible binding character of the PPIs mediated by them. Herein, we designed and synthesized an affinity-based probe (AfBP), S1b-probe, by introducing a photo-crosslinker to an artificial BH3 mimetic. Hsp70 proteins were identified as novel BH3 receptors in situ. The PPIs between Bcl-2 proteins and Hsp70 proteins were further validated by fluorescent polarization (FP), isothermal titration calorimetry (ITC) and Co-immunoprecipitation (Co-IP) experiments. Structural and functional analysis by photo-crosslinking/LC-MS/MS sequencing, 1H-15N transverse relaxation optimized spectroscopy (TROSY-HSQC), trypsin proteolysis, single-turnover ATPase rates and denatured rhodanese aggregation measurement demonstrated that BimBH3 bind in the NBD domain of Hsp70 proteins to act as a co-chaperone that negatively regulates the ATPase activity and chaperone functions. S1g, derived from BH3 mimetics, was screened as a specific Hsp70 inhibitor in native physiological context by using S1b-probe.
Citation Format: Ziqian Wang, Zhichao Zhang, Ting Song, Zongwei Guo. Affinity-based probe reveal Bim negatively regulates the chaperone functions of Hsp70, a non-Bcl-2 BH3 receptor [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 2754.
Abstract 2758: Domain swapping and SMYD1 interactions with the PWWP domain of human hepatoma-derived growth factor
Authors: Chen Chun-Jung , Hsu Li-Jin 
Published: August 2019

Abstract
The human hepatoma-derived growth factor (HDGF), containing the chromatin-associated N-terminal PWWP domain capable of binding the SMYD1 promoter, participates in various cellular processes and is involved in human cancers, including hepatocellular carcinoma, pancreatic cancer, oral cancer, breast cancer and non-small cell lung cancer. However, the functional mechanisms of human HDGF had been puzzling because of a lack of essential knowledge of its intact structure in complex with DNA. We present the first crystal structures of the human HDGF PWWP domain (residues 1 - 100) in a complex with SMYD1 of 10 bp at 2.84 Å resolution and its apo form at 3.3 Å, respectively. The structure of the apo PWWP domain comprises mainly four β-strands and two α-helices. The PWWP domain undergoes domain swapping to dramatically transform its secondary structures, altering the overall conformation from monomeric globular folding into an extended dimeric structure upon DNA binding. The flexible loop2, as a hinge loop with the partially built structure in the apo PWWP domain, notably refolds into a visible and stable α-helix in the DNA complex. The swapped PWWP domain interacts with the minor grooves of the DNA through residues Lys19, Gly22, Arg79 and Lys80 in varied ways on loops 1 and 4 of the two chains, and the structure becomes more rigid than the apo form. These novel structural findings, together with physiological and activity assays of HDGF and the PWWP domain, provide new insights into the DNA-binding mechanism of HDGF during nucleosomal functions.
Note: This abstract was not presented at the meeting.
Citation Format: Chun-Jung Chen, Li-Jin Hsu. Domain swapping and SMYD1 interactions with the PWWP domain of human hepatoma-derived growth factor [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 2758.
Abstract 2773: Prognostic value of KRASP53PIK3CA in non-small cell lung cancer patients
Authors: Han Yiping 
Published: August 2019

Abstract
We explored the relationship of KRAS, PIK3CA, and TP53 mutations with the clinical features and survival prognosis in 50 non-small cell lung cancer (NSCLC) patients. The most common concurrent single gene mutation was TP53, followed by KRAS and PIK3CA. Coexisting mutations were found in 17 patients. KRAS, PIK3CA, and TP53 mutations were related to Ca19-9 expression, invasive growth, vacuolar signs, and margin lobulation in chest CT imaging. The incidence of distant metastasis (bone and adrenal) with KRAS and TP53 mutations was greater than that of local metastasis (pleura). Patients the wild-type gene had longer progression-free survival than those with KRAS, TP53, KRAS/TP53, or PIK3CA/TP53 mutations. Patients with KRAS/TP53 or PIK3CA/TP53 mutations had shorter progression free survival than those with a single KRAS or TP53 mutation. KRAS, PIK3CA, and TP53 mutations were associated with distant metastases and poor prognosis. NSCLC patients should receive routine KRAS, PIK3CA, and TP53 gene sequencing to determine mutations for the analysis of clinical characteristics and prognosis.
Note: This abstract was not presented at the meeting.
Citation Format: Yiping Han. Prognostic value of KRASP53PIK3CA in non-small cell lung 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 2773.
Abstract 2774: Pain signals oral cavity cancer metastasis
Authors: Bhattacharya Aditi , Janal Malvin N. , Kim Hyesung , Wang Susanna , Wu Angie K. , Hagiwara Mari , Kerr Alexander R. , Schmidt Brian L. , Albertson Donna G. 
Published: August 2019

Abstract
Metastasis to the cervical (neck) lymph nodes is the primary determinant of survival for patients diagnosed with oral cavity cancer. Imaging (MRI, PET, CT) and clinical examination lack sensitivity to accurately detect cervical metastasis. Therefore most clinically node negative patients receive surgery to remove the cervical lymph nodes (elective neck dissection) at the time of surgical tumor removal. Half of these patients do not benefit from this additional surgery, highlighting the need for improved preoperative assessment in predicting metastatic risk. Oral cancer patients suffer severe chronic and mechanically-induced pain at the site of the cancer. We asked whether patient reported pain measured prior to surgery by a validated instrument, the University of California San Francisco Oral Cancer Pain Questionnaire (UCSFOCPQ), was an indicator of risk for lymph node metastasis. Seventy-two oral cancer patients were consented and enrolled, patients rated their pain using the UCSFOCPQ. Clinical and pathological characteristics of the patient cohorts were collected from pathology reports and medical records. Inclusion criteria included diagnosis of an oral squamous cell carcinoma, planned curative resection of the cancer and completion of the UCSFOCPQ within six weeks of surgery. Exclusion criteria included prior chemo- or radiation therapy for cancer, failure to complete or understand the UCSFOCPQ and less than one year post surgery follow-up. Sixty-six patients met the inclusion/exclusion criteria (35 node negative and 31 node positive). Patients with metastasis reported higher pain scores prior to surgery. Low pain score and depth of invasion each predicted low metastatic risk with high sensitivity and negative predictive values. Amongst patients who were clinically staged N0 by current standard of care imaging and physical exam prior to surgery, low pain scores correctly identified patients determined by pathology to be N0. Conclusions: Low pain scores assessed prior to surgery could identify patients at low risk for metastases who would not benefit from neck dissection. Pain score might be added to the standard of care preoperative assessments and decision making processes for determining whether to recommend an elective neck dissection.
Citation Format: Aditi Bhattacharya, Malvin N. Janal, Hyesung Kim, Susanna Wang, Angie K. Wu, Mari Hagiwara, Alexander R. Kerr, Brian L. Schmidt, Donna G. Albertson. Pain signals oral cavity cancer metastasis [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 2774.
Abstract 2775: Investigating myeloid-derived suppressor cells (MDSC) gene expression in predicting outcome in stage matched colorectal cancer patients
Authors: Heneidi Saleh G. , Bloomer Chance , Ahluwalia Pankaj , Mondal Ashis , Kolhe Ravindra 
Published: August 2019

Abstract
Colorectal cancer (CRC) has emerged as the third most commonly diagnosed cancer in males and second most common in females. Although surgery, chemotherapy, and emerging immunotherapies have reduced mortality rates, tools that can assist in tailoring individualized treatments are needed. MDSC are immune-suppressive cells that interfere with the functioning of T cells and immune-inflammatory pathways. An extensive literature search identified 8 MDSC-centric genes which were tested for their prognostic significance in CRC. These genes; CEBPB, IL10, NOS2, RORC, S100A8, SOCS1, SOCS3, and TGFB1, along with their expression in tumor microenvironments could give new insights when correlated with clinical-pathologic features of colon cancer patients. The aim of the study is to quantify MDSC gene signatures in colorectal cancer patients. Under an IRB approved protocol, a total of 750 colon cancer patients at the Medical College of Georgia with 5 years of follow-up were initially selected. A total of 88 patients fit in our inclusion criteria, on the basis of survival duration after diagnosis. The FFPE blocks were acquired and patients were stratified on the basis of overall survival in two groups, with higher (&gt;5 years) and lower survival (&lt;1 year), as well as AJCC staging (I to IV), grade, gender and age. Total RNA was isolated and quantified through Nanodrop method. The statistical analysis of data was performed using student t-test and Pearson correlation. SOCS1 (p = 0.00*) was expressed in higher levels in patients with high survival (&gt;5 years). Patients with low expression of TGFB1 survived longer compared to high expression group (p = 0.02*). On race comparison, CEBPA (p = 0.01*) showed significant expression in Caucasian population while NOS2 (p = 0.01*) expressed at higher levels in African Americans. These findings points to the clinical significance of MDSC based genes and tested the utility of a MDSC-related gene expression based prognostic biomarker panel for CRC patients.
Citation Format: Saleh G. Heneidi, Chance Bloomer, Pankaj Ahluwalia, Ashis Mondal, Ravindra Kolhe. Investigating myeloid-derived suppressor cells (MDSC) gene expression in predicting outcome in stage matched colorectal 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 2775.
Abstract 2783: OMICS analysis of breast cancer PDX tumors to determine CTC-cluster-specific signature in predicting breast cancer metastasis
Authors: Thangavel Hariprasad , Angelis Carmine De , Vasaikar Suhas , Bhat Raksha , Jolly Mohit Kumar , Dobrolecki Lacey Elizabeth , George Jason T. , Giuliano Mario , Lewis Michael , Levine Herbert , Zhang Bing , Schiff Rachel , Trivedi Meghana V. 
Published: August 2019

Abstract
Circulating tumor cell clusters (CTCcl) have been shown to have a significantly higher metastatic potential compared to single CTCs and to predict long-term outcomes in breast cancer patients. A characterization of primary tumors that give rise to CTCcl hold significant promises for better diagnosis and may uncover targets for prevention and treatment of metastatic breast cancer. In our study, we utilized the available transcriptomic and proteomic data (RNA-Seq and RPPA) of 10 triple-negative breast cancer patient-derived xenograft (TNBC-PDX) transplantable models. The sample set consisted of 6 CTCcl-negative (-) and 4 CTCcl-positive (+) models. Genome-wide transcriptomic analysis revealed 549 differentially expressed genes in CTCcl+ TNBC-PDX models vs. CTCcl- models (316 up-regulated and 233 down-regulated, p&lt;0.05). Gene set enrichment analysis (GSEA) terms significantly enriched (FDR&lt;0.05) in CTCcl+ TNBC-PDXs included Cytoplasmic Ribosomal Proteins (NES=2.53), Angiogenesis (NES=1.95), Type II Interferon signaling (NES=-2.52), Antigen processing and presentation (NES=-2.38), TNF signaling pathway (NES=-2.04), Jak-STAT signaling pathway (NES=-1.91), and apoptosis (NES=-1.69). The proteomic analysis revealed elevated levels of Bcl2 expression in PDX tumors associated with CTCcl positivity, which substantiated the inhibited apoptosis pathway as seen in GSEA analysis. The increase in Bcl2 was also validated independently by IHC staining in primary PDX tumors that were CTCcl+. The distribution of EMT score based on the inferential EMT metric using canonical epithelial and mesenchymal markers was not significantly different between CTCcl+ and CTCcl- TNBC-PDX tumors suggesting no differential regulation of EMT in tumors that give rise to clusters versus only single cells. In summary, our results suggest that primary tumors with active anti-apoptotic and/or survival pathways may promote CTC clusters formation and increase the risk of distant metastasis.
Citation Format: Hariprasad Thangavel, Carmine De Angelis, Suhas Vasaikar, Raksha Bhat, Mohit Kumar Jolly, Lacey Elizabeth Dobrolecki, Jason T. George, Mario Giuliano, Michael Lewis, Herbert Levine, Bing Zhang, Rachel Schiff, Meghana V. Trivedi. OMICS analysis of breast cancer PDX tumors to determine CTC-cluster-specific signature in predicting breast cancer metastasis [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 2783.
Abstract 2792: PD-1 modulates CD8+ T cell function in prostate tumor microenvironment
Authors: Stokes James , Berry Eric , Singh Rajesh , Manne Upender , Mishra Manoj K. 
Published: August 2019

Abstract
In general, the Regulatory T (Treg) suppresses the immune response. However, their role and immunosuppressive mechanism(s) in context to programmed death 1 (PD-1) are not completely understood. This study aims to determine the role of PD-1 on Treg cells and their impact on CD8+ T cell function in prostatic tumor microenvironment using transgenic adenocarcinoma of the mouse prostate (TRAMP) cells (TRAMP C1, C2, and C3) as a model system. To execute the above aim, tumor induction studies were performed. Briefly, the C57BL/6 mice were administered with serial log concentrations of TRAMP (C1-3) cells. Interestingly, the TRAMP-C3 cells do not form a tumor, however, TRAMP-C1 and TRAMP-C2 cells do form a tumor. After tumor development, mice were sacrificed by cervical dislocation; tumor, lung, spleen, and draining lymph nodes were harvested when the tumor size reached approximately 20mm. Single cell suspensions were prepared from different organs, cells were then stained with specific antibodies, and flow analyzed for the expression of different immune markers. Our preliminary findings demonstrated that PD-1 expression on Foxp3+ Treg cells displayed greater suppressive capacity against CD8+ T cell function in tumor, lung, spleen, and draining lymph node when compared to the control. More importantly, Foxp3+ Treg(high) PD-1(high) interaction with PDL-1 induced immunosuppression by blocking CD8+ T cells function in the prostatic tumor microenvironment. Our data suggest that the expression of Foxp3 and PD-1 may enhance tumor progression; thus, targeting the PD-1 on Treg cells may be a possible therapy to treat prostate cancer.
Note: This abstract was not presented at the meeting.
Citation Format: James Stokes, Eric Berry, Rajesh Singh, Upender Manne, Manoj K. Mishra. PD-1 modulates CD8+ T cell function in prostate tumor microenvironment [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 2792.
Abstract 28: Dihydrolipoyl dehydrogenase is a key molecule inducing ferroptotic cell death
Authors: Lee Jaewang , Shin Daiha , Roh Jong-Lyel 
Published: August 2019

Abstract
Ferroptosis is iron-dependent, non-apoptotic cell death from lipid peroxidation. Cystine-glutamate transporter (xCT) and glutathione peroxidase 4 (GPX4) are recognized as the key regulators of ferroptosis. Glutathione depletion via cystine deficiency or inhibition of xCT or GPX4 accumulates cellular lipid peroxidation and ferrous iron, resulting in ferroptosis. Glutamine is an amino acid essential for growth of cancer cells as well as induction of ferroptotic cell death via the production of alpha-ketoglutarate (αKG) from glutaminolysis. However, it is still unclear whether αKG or its relevant metabolic process is engaged in ferroptotic cell death. Therefore, we examined the role of αKG dehydrogenase (αKGDH) in induction of ferroptosis in head and neck cancer (HNC) cells. Cystine-deficient conditioned medium or xCT inhibition with sulfasalazine induced typical ferroptotic cell death, which was prevented by the inhibition of glutaminolysis or αKG production. Next, we focused the dihydrolipoyl dehydrogenase (DLD) and dihydrolipoyl succinyltransferase (DLST), consisting of the E3 and E2 components of αKGDH respectively. Ferroptosis was significantly prevented by genetic inhibition of the DLD but not the DLST, which was rescued by re-insertion of the DLD gene. Cellular reactive oxygen, lipid peroxidation, and ferrous iron accumulation were induced by the increased function of αKGDH, that is mainly the DLD, when αKG was converted to succinate in the tricarboxylic acid cycle. Sulfasalazine did not significantly suppress the in vivo growth of the shDLD-transfected HNC cells but vector control transplanted in nude mice. Taken together, our data support that the DLD is a key molecule inducing ferroptosis in cancer cells.
Note: This abstract was not presented at the meeting.
Citation Format: Jaewang Lee, Daiha Shin, Jong-Lyel Roh. Dihydrolipoyl dehydrogenase is a key molecule inducing ferroptotic cell death [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 28.
Abstract 2803: CSF-1 receptor-mediated macrophage depletion can induce immunomodulatory resistance mechanisms in murine tumor models
Authors: O'Brien Sarah A. , Skrzypczynska Katarzyna , Orf Jessica , Belmontes Brian , Tan Hong , Lu Daniel , Driver Ian , Egen Jackson 
Published: August 2019

Abstract
Tumor associated macrophages (TAMs) are present within the stroma of most solid tumors where they can act to inhibit immune responses and promote disease progression through expression of immunosuppressive factors and modulation of tumor stroma. Tumor immunotherapies aimed at depletion of TAMs, for instance through the use of blocking antibodies against the CSF1 receptor (CSF1R), have been widely explored, with multiple studies demonstrating that blocking TAM function can inhibit tumor growth/metastasis and stimulate anti-tumor immunity. In order to further dissect the functions of TAM populations and define conditions under which antiCSF1R immunotherapy may have benefit, we evaluated the effect of antiCSF1R treatment on multiple subcutaneous murine tumor models with varying dosing parameters. Despite robust macrophage depletion, some tumor models, such as Renca renal cell adenocarcinoma, showed only a modest change in tumor volume and minimal effector T cell recruitment or activation in response to anti-CSF1R therapy. Comprehensive flow cytometry-based immunophenotyping and single-cell RNA sequencing on immune cells isolated from antiCSF1R and isotype control-treated Renca tumors revealed shifts in gene expression patterns related to vascular remodeling, hypoxic responses, and enhanced regulatory T cell activity. These studies indicate macrophage depletion may, under some conditions, result in compensatory anti-tumor immune responses that could limit the clinical benefit of this therapeutic approach.
Citation Format: Sarah A. O'Brien, Katarzyna Skrzypczynska, Jessica Orf, Brian Belmontes, Hong Tan, Daniel Lu, Ian Driver, Jackson Egen. CSF-1 receptor-mediated macrophage depletion can induce immunomodulatory resistance mechanisms in murine tumor models [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 2803.