bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 482: Atypical expression of βV-tubulin in secretory cells of the fallopian tube as a biomarker for early dysplasia
Authors: Mathew Deepti , Wang Yanhua , Van Arsdale Anne , Horwitz Susan Band , McDaid Hayley 
Published: July 2016

Abstract
Class V βeta tubulin isotype (βV-tubulin), was recently found to have a tissue-specific expression pattern in epithelial tissues with secretory function, and deregulated expression in certain tumors. The overall aim of this study was to define the localization of βV-tubulin in the fallopian tube and its expression in pre-malignant dysplasia. Fallopian tube epithelium (FTE) was obtained from patients undergoing salpingectomy for various reasons including familial history that comprised BRCA mutant cases. Additionally, βV-tubulin expression was also examined in serous ovarian neoplasms. Immunohistochemistry, using a novel antibody developed in our lab against human βV-tubulin, was used to evaluate expression in paraffin-embedded sections of the distal fallopian tube (n = 55) and tumors (n = 13), from prospectively selected cases, categorized according to reasons for salpingectomy. Staining with standard markers, Pax-8 and acetylated α-tubulin was done to demarcate the secretory and ciliated cells of the FTE, respectively. Pilot data indicate that in the FTE, βV-tubulin is present in secretory cells and essentially never in ciliated cells. Morphologically “normal” FTE had only rare, scattered βV-tubulin positive cells; whereas, percentage positivity was increased in cases with serous ovarian neoplasms, and BRCA-wildtype familial breast cancer. The highest expression was observed in FTE from patients with BRCA-mutant breast cancers. Four distinct types of FTE atypia were observed in patients with known BRCA mutations. βV-tubulin was highly expressed in serous ovarian neoplasms, with the extent and intensity of staining elevated in high-grade serous carcinomas, compared to serous borderline tumors. In summary, βV-tubulin was localized to secretory cells of the distal FTE and its expression varied according to the clinical diagnosis. The frequency of these cells, and thus expression of βV-tubulin was dramatically enriched in tissue obtained from BRCA mutant cases. BRCA mutants also exhibited pronounced histologic atypia indicative of early dysplasia. Furthermore, elevated expression of βV-tubulin correlated with poor differentiation status in serous ovarian neoplasms.
Citation Format: Deepti Mathew, Yanhua Wang, Anne Van Arsdale, Susan Band Horwitz, Hayley McDaid. Atypical expression of βV-tubulin in secretory cells of the fallopian tube as a biomarker for early dysplasia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 482.
Abstract 4870: A novel potential target for cancer immunotherapy
Authors: Campagnoli Susanna , Parri Matteo , Grandi Alberto , De Camilli Elisa , Viale Giuseppe , Grifantini Renata Maria , Pileri Piero 
Published: July 2016

Abstract
Suppression of the host's immune system plays a major role in cancer progression. The tumor microenvironment (TME) not only plays a pivotal role during cancer progression and metastasis but also has profound effects on therapeutic efficacy. Immune checkpoint therapy, which targets regulatory pathways in T cells to enhance antitumor immune responses, has led to important clinical advances and provided a new weapon against cancer. This therapy has elicited durable clinical responses and, in a fraction of patients, long-term remissions. Several immune checkpoint inhibitors have been approved by the Food and Drug Administration (FDA), whose therapeutic effect is due to blocking the activity of proteins expressed in T lymphocytes (CTLA4, PD-1) and the interaction with surface protein expressed on tumor cells (PD-L1 and PD-L2).
In our recent research activities we have identified 89 tumor-associated proteins by systematic immunohistochemistry analysis of tissue microarray (TMA) representing breast, colon, lung ovary and prostate cancer by using a large collection of polyclonal antibodies (approximately 1600) raised against membrane-associated and secreted proteins only marginally characterized. Among them, an interesting protein, which decorated the plasma membrane of breast cancer cells, was selected. This protein has been described to interact with the CD270/BTLA/CD160 pathway that regulates T-cell activation. It has also the capability to interfere with T-cell mediated allo-responses. Our characterization data showed that the protein is localized on the surface of several cancer cell lines. Moreover, it has the ability to stimulate cytokine production and secretion in PBMC from healthy donors. Several monoclonal antibodies have been generated in our lab against this protein and selected for the ability to bind the surface of cancer cells. Moreover, the ability of these monoclonal antibodies to interfere with the immune cells activity and to interfere with tumor growth in animal models is under evaluation. Results will be provided during the meeting.
The currently approved therapeutic targets regimens for triple negative breast cancer and ovarian cancer have limited efficacy. Therefore, the identification of other tumor-associated proteins targetable by specific mAbs is essential to improve patient survival.
Citation Format: Susanna Campagnoli, Matteo Parri, Alberto Grandi, Elisa De Camilli, Giuseppe Viale, Renata Maria Grifantini, Piero Pileri. A novel potential target for cancer immunotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4870.
Abstract 4881: CD300f-regulated efferocytosis by dendritic cells and macrophages controls the initiation and resolution of experimental colitis
Authors: Lee Ha-Na , Tian Linjie , Davis Jacquice , Quinones Mariam , Belkaid Yasmine , Krzewski Konrad , Coligan John E. 
Published: July 2016

Abstract
Phagocytic clearance of apoptotic cells (efferocytosis) is critical for resolution of inflammation and prevention of chronic inflammatory disorders, including inflammatory bowel diseases, and inflammation-associated cancer. CD300f (CLM-1), a cell surface receptor that recognizes phosphatidylserine exposed on apoptotic cells, has been shown to promote efferocytosis by macrophages. In the present study, we found that CD300f plays a critical role in controlling the severity and duration of dextran sulfate sodium (DSS)-induced colitis, and CD300f-expressing macrophages and dendritic cells (DC) were identified as key players controlling disease pathogenesis. Compared to Cd300f+/+ mice, Cd300f-/- mice showed increased susceptibility to DSS-induced colitis and impaired resolution of inflammation. In Cd300f-/- mice, macrophage-mediated efferocytosis was reduced, resulting in apoptotic cell accumulation in the gut mucosa. In contrast, Cd300f-/- DC engulfed apoptotic cells more efficiently than Cd300f+/+ DC. CD300f-deficient DC transfer exacerbated DSS-induced inflammation and delayed its resolution, whereas CD300f-expressing macrophage transfer attenuated DSS-induced inflammation. Hyperactive efferocytosis by CD300f-deficient gut DC resulted in excessive tumor necrosis factor-á (TNF-á) secretion, which induced secondary interferon-ã (IFN-ã) over-production, both of which impaired the resolution of colitis. TNF-á neutralization resulted in decreased levels of gut pro-inflammatory cytokines and significant disease amelioration. Collectively, these results suggest that CD300f is important for preventing chronic inflammation by enhancing macrophage efferocytosis and inhibiting TNF-á production induced by DC efferocytosis. From these findings, it is conceivable that increasing macrophage-mediated efferocytosis and suppressing DC-mediated efferocytosis through upregulation of CD300f expression would provide a new therapeutic strategy for inflammatory bowel disease patients.
Citation Format: Ha-Na Lee, Linjie Tian, Jacquice Davis, Mariam Quinones, Yasmine Belkaid, Konrad Krzewski, John E. Coligan. CD300f-regulated efferocytosis by dendritic cells and macrophages controls the initiation and resolution of experimental colitis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4881.
Abstract 4882: Identification of potential immune targets in controlling endometrioid endometrial carcinoma metastatic progression
Authors: Billaud Jean-Noel , Tugendreich Stuart , Toburen Debra 
Published: July 2016

Abstract
Endometrial adenocarcinoma is a common cause of gynecological cancer death in Europe and North America. The most dominant subtype, Endometrioid Endometrial Cancer (EEC) accounts for &gt;80% of this cancer and is estrogen-dependent. At diagnosis, 75% of women have the disease confined to the uterus, which is considered Stage One. Five-year survival for Stage One patients is 80%, however, about 15-20% develop metastasis.
Total RNA extracted from tissues obtained after surgical resection from three women at stage one EEC was subjected to RNA-sequencing. The publicly available dataset (SRP045645) was downloaded directly from the Sequence Read Archive and the FASTQ files were processed with Biomedical Genomics Workbench for secondary analysis including mapping, quantification and differential expression analysis. Through streamlined integration the data was uploaded to Ingenuity Pathway Analysis (IPA) for biological interpretation.
We show how in silico solutions developed by QIAGEN Bioinformatics enable us to analyze the biological parameters involved in EEC metastatic progression from an early stage in the three patients diagnosed at Stage One. By comparing these patients’ RNA-seq results, we determined that key Canonical Pathways and other biological processes differentiated the three patients from one other. In particular, the predicted transcriptional program allowed us to visualize key upstream drivers. Three of these transcriptional drivers are immune related molecules (two cytokines: CXCL14 and GDF15 and one growth factor FGF3). They have been predicted to be potential master regulators of a Causal Network that drives increase of EEC, metastasis, epithelial-to-mesenchymal-transition (EMT), and cellular invasion in one of the three patients. Based on these results we propose these three immune molecules as possible therapeutic targets to counteract the metastatic processes in EEC.
Citation Format: Jean-Noel Billaud, Stuart Tugendreich, Debra Toburen. Identification of potential immune targets in controlling endometrioid endometrial carcinoma metastatic progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4882.
Abstract 4885: Intratumoral injection of G100 (TLR4 agonist glycopyranosyl lipid A) modulates tumor microenvironment and induces CD8 T cell-dependent, systemic anti-tumor immunity
Authors: Lu Hailing , Hewitt Jessica , Meulen. Jan ter 
Published: July 2016

Abstract
The tumor microenvironment (TME) plays a critical role in controlling the balance between tumor progression and immune surveillance. Increased infiltration of T cells, especially CD8 T cells has been associated with a good prognosis. We hypothesized that G100, a novel synthetic TLR4 agonist, can modulate TME when directly injected into the tumor and trigger both a local and systemic effective immune response. Balb/c mice with implanted syngeneic A20 lymphoma received intratumoral (IT) injection of G100 (10 ìg) or control PBS three times a week. This treatment significantly inhibited tumor growth and resulted in complete tumor regression in approximately 60% of treated mice. To investigate the effects of G100 on TME, tumors were collected after three IT G100 injections for gene expression analysis by Nanostring and immune phenotyping analysis by FACS. Out of the 770 immune response genes included in the mouse PanCancer Immune Profiling panel, 295 genes were significantly upregulated in G100 treated tumors. The upregulated genes include DC function-related genes (CD40, CD83, CD86, and Ly96) and T cell and NK cell function genes and multiple chemokines and cytokines (IL1b, IL12A, IL18, IL6, IFNã, FcãR4, ICOS, GZMB, CCL3, CCL5, CCL7, CXCL1, CXCL2, CXCL11, CCR5, CCR6, and CCR7). T cell exhaustion markers (CTLA4 and LAG3) and CD274 (PD-L1) were also induced. G100-induced inflammation is also reflected at the cellular level as shown by increased T cells and NK cells in tumor via FACS analysis. To determine the immune cells that mediated tumor rejection, mice were selectively depleted of CD4 or CD8 T cells during G100 treatment. Results showed that the anti-tumor effect of G100 is dependent on CD8 T cells. G100-induced tumor protection was durable as mice surviving the first tumor challenge rejected a secondary tumor challenge without additional G100 treatment. Altogether, our results showed that IT G100 induces a proinflammatory cytokine and chemokine milieu that changes a “cold” tumor to a “hot” tumor, which facilitates the development of a CD8 T cell-dependent potent and durable anti-tumor effect. The induction of PD-L1 also suggests the potential synergy between G100 and checkpoint blockade therapy. These preclinical data support an on-going clinical trial of IT G100 in patients with follicular non-Hodgkin's lymphoma (NCT02501473), alone and in combination with anti-PD-1 therapy (pembrolizumab).
Citation Format: Hailing Lu, Jessica Hewitt, Jan ter Meulen. Intratumoral injection of G100 (TLR4 agonist glycopyranosyl lipid A) modulates tumor microenvironment and induces CD8 T cell-dependent, systemic anti-tumor immunity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4885.
Abstract 489: NGS analysis of the single CTC or DTC isolated and subtyped by the integrated subtraction enrichment and immunostaining-FISH
Authors: Lin Peter 
Published: July 2016

Abstract
Majority of the circulating or disseminated tumor cell (CTC or DTC) detection methodologies rely on existence of epithelial markers (such as EpCAM and/or cytokeratins) on tumor cells. However, highly heterogeneous expression or even absence of EpCAM, and down-regulation of both EpCAM and cytokeratins in CTCs/DTCs during epithelial-mesenchymal transition (EMT) has been reported elsewhere, resulting in significant false negative detection of those uncatchable and invisible CTCs/DTCs. A novel strategy integrating subtraction enrichment which efficiently enriches non-hematopoietic tumor cells shed from various types of solid tumor into biofluid including peripheral blood, bone marrow, ascites, pleural effusion, and cerebrospinal fluid (CSF), with immunostaining-FISH (iFISH), which enables in situ phenotypic immunofluorescent staining of tumor biomarker and chromosomal FISH on the identical tumor cell, has shown its unique advantage in terms of detecting CTCs/DTCs with higher sensitivity and specificity. Diversified CTCs/DTCs could be identified and subtyped upon specific chromosome ploidy and tumor biomarker expression, and each subtype of CTCs/DTCs respectively correlate with therapeutic drug sensitivity or resistance, tumor metastasis or relapse. Whole genome amplification and subsequent next generation sequencing (NGS) analysis performed on the single subtyped breast, pancreatic, gastric and NSCLC cancer CTC or DTC targeted by iFISH, and collected by means of a microscopic cell manipulator is able to reveal ploidy of all the chromosomes and status of either unknown genes or a series of known oncogenes including HER2, Kras, BRAF, etc. It is anticipated that SE-iFISH could guide and promote more significant single cell based genomic and functional analyses of CTCs and/or DTCs.
Citation Format: Peter Lin. NGS analysis of the single CTC or DTC isolated and subtyped by the integrated subtraction enrichment and immunostaining-FISH. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 489.
Abstract 4890: Preclinical analysis of combination therapy using radiation and cellular immunotherapy
Authors: Wada Satoshi 
Published: July 2016

Abstract
Purpose:
To optimize the combination of ionizing radiation and cellular immunotherapy using a preclinical autochthonous model of prostate cancer.
Methods and Materials:
Transgenic mice expressing a model antigen under a prostate-specific promoter were treated using a platform that integrates cone-beam CT imaging with 3-dimensional conformal therapy. Using this technology we investigated the immunologic and therapeutic effects of combining ionizing radiation with granulocyte/macrophage colonystimulating factor-secreting cellular immunotherapy for prostate cancer in mice bearing autochthonous prostate tumors.
Results:
The combination of ionizing radiation and immunotherapy resulted in a significant decrease in pathologic tumor grade and gross tumor bulk that was not evident with either single-modality therapy. Furthermore, combinatorial therapy resulted in improved overall survival in a preventive metastasis model and in the setting of established micrometastases. Mechanistically, combined therapy resulted in an increase of the ratio of effector-to regulatory T cells for both CD4 and CD8 tumor-infiltrating lymphocytes.
Conclusions:
Our preclinical model establishes a potential role for the use of combined radiation-immunotherapy in locally advanced prostate cancer, which warrants further exploration
in a clinical setting.
Citation Format: Satoshi Wada. Preclinical analysis of combination therapy using radiation and cellular immunotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4890.
Abstract 4901: Short-course enzalutamide reveals immune activating properties in patients with biochemically recurrent prostate cancer
Authors: Donahue Renee N. , Madan Ravi A. , Richards Jacob , Grenga Italia , Lepone Lauren M. , Heery Christopher R. , Gulley James L. , Schlom Jeffrey 
Published: July 2016

Abstract
Background: Enazalutamide (enz) is an androgen receptor signaling molecule approved by the FDA for the treatment of patients with metastatic castration-resistant prostate cancer; however, trials are evaluating this agent in earlier stages of disease. Here, we have investigated the effect of enz on peripheral immunity in patients with biochemically recurrent prostate cancer enrolled in a clinical trial of enz with/without a therapeutic vaccine (NCT01875250).
Methods: Patients from the arm receiving enz alone (160 mg daily for 84 days, without ADT) were assessed in this study. Peripheral blood mononuclear cells (PBMCs) collected from 12 patients pre and post enz (days 14, 28, 84, and 100) were analyzed by flow cytometry to identify 123 immune cell subsets, including 9 standard subsets (CD4+ and CD8+ T cells, T-regulatory cells (Treg), B cells, conventional and plasmacytoid dendritic cells (cDC, pDC), natural killer cells (NK), natural killer T cells (NKT), and myeloid derived suppressor cell (MDSC)), and 114 subsets relating to maturation and function. PBMCs were also assessed for T-cell receptor excision circles (TREC) to identify recent thymic emigrants, and by microarray to determine changes in global gene expression.
Results: Treatment with enz induced several notable alterations in peripheral immune cells, suggesting that it has potential immune activating properties. These changes occurred early following treatment, and included an increase of NK cells, decreased frequencies of MDSCs with a suppressive phenotype (e.g. PDL1+ MDSC, gMDSC, and CD16+ MDSC), and decreased frequencies of both CD4+ and CD8+ T-lymphocytes expressing the immune inhibitory checkpoint molecule CTLA4. Additionally, treatment with enz increased TREC levels by &gt;75% in 7 out of 12 patients compared to pre-therapy levels (p = 0.012); naïve CD4+ and CD8+ T-lymphocytes were also elevated by &gt;25% in those patients demonstrating the greatest increase in TREC. Gene expression analysis of PBMCs corroborated these findings, showing that enz increased activation of interferon-gamma signaling and related immune activating pathways.
Conclusions. These findings show that short-course enz has immune activating properties in cancer patients, and support the combination of enz with immunotherapy.
Citation Format: Renee N. Donahue, Ravi A. Madan, Jacob Richards, Italia Grenga, Lauren M. Lepone, Christopher R. Heery, James L. Gulley, Jeffrey Schlom. Short-course enzalutamide reveals immune activating properties in patients with biochemically recurrent prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4901.