bluuebunny/crossref_metadata_2025_split huggingface dataset:
Macrophage Blockade Using CSF1R Inhibitors Reverses the Vascular Leakage Underlying Malignant Ascites in Late-Stage Epithelial Ovarian Cancer
Authors: Moughon Diana L. , He Huanhuan , Schokrpur Shiruyeh , Jiang Ziyue Karen , Yaqoob Madeeha , David John , Lin Crystal , Iruela-Arispe M. Luisa , Dorigo Oliver , Wu Lily 
Published: October 2015

Abstract
Malignant ascites is a common complication in the late stages of epithelial ovarian cancer (EOC) that greatly diminishes the quality of life of patients. Malignant ascites is a known consequence of vascular dysfunction, but current approved treatments are not effective in preventing fluid accumulation. In this study, we investigated an alternative strategy of targeting macrophage functions to reverse the vascular pathology of malignant ascites using fluid from human patients and an immunocompetent murine model (ID8) of EOC that mirrors human disease by developing progressive vascular disorganization and leakiness culminating in massive ascites. We demonstrate that the macrophage content in ascites fluid from human patients and the ID8 model directly correlates with vascular permeability. To further substantiate macrophages' role in the pathogenesis of malignant ascites, we blocked macrophage function in ID8 mice using a colony-stimulating factor 1 receptor kinase inhibitor (GW2580). Administration of GW2580 in the late stages of disease resulted in reduced infiltration of protumorigenic (M2) macrophages and dramatically decreased ascites volume. Moreover, the disorganized peritoneal vasculature became normalized and sera from GW2580-treated ascites protected against endothelial permeability. Therefore, our findings suggest that macrophage-targeted treatment may be a promising strategy toward a safe and effective means to control malignant ascites of EOC. Cancer Res; 75(22); 4742–52. ©2015 AACR.
ATDC/TRIM29 Drives Invasive Bladder Cancer Formation through miRNA-Mediated and Epigenetic Mechanisms
Authors: Palmbos Phillip L. , Wang Lidong , Yang Huibin , Wang Yin , Leflein Jacob , Ahmet McKenzie L. , Wilkinson John E. , Kumar-Sinha Chandan , Ney Gina M. , Tomlins Scott A. , Daignault Stephanie , Kunju Lakshmi. P. , Wu Xue-Ru , Lotan Yair , Liebert Monica , Ljungman Mats E. , Simeone Diane M. 
Published: October 2015

Abstract
Bladder cancer is a common and deadly malignancy but its treatment has advanced little due to poor understanding of the factors and pathways that promote disease. ATDC/TRIM29 is a highly expressed gene in several lethal tumor types, including bladder tumors, but its role as a pathogenic driver has not been established. Here we show that overexpression of ATDC in vivo is sufficient to drive both noninvasive and invasive bladder carcinoma development in transgenic mice. ATDC-driven bladder tumors were indistinguishable from human bladder cancers, which displayed similar gene expression signatures. Clinically, ATDC was highly expressed in bladder tumors in a manner associated with invasive growth behaviors. Mechanistically, ATDC exerted its oncogenic effects by suppressing miR-29 and subsequent upregulation of DNMT3A, leading to DNA methylation and silencing of the tumor suppressor PTEN. Taken together, our findings established a role for ATDC as a robust pathogenic driver of bladder cancer development, identified downstream effector pathways, and implicated ATDC as a candidate biomarker and therapeutic target. Cancer Res; 75(23); 5155–66. ©2015 AACR.
Identification of Cancer-Associated Fibroblasts in Circulating Blood from Patients with Metastatic Breast Cancer
Authors: Ao Zheng , Shah Sanket H. , Machlin Leah M. , Parajuli Ritesh , Miller Philip C. , Rawal Siddarth , Williams Anthony J. , Cote Richard J. , Lippman Marc E. , Datar Ram H. , El-Ashry Dorraya 
Published: October 2015

Abstract
Metastasis is facilitated by cancer-associated fibroblasts (CAF) in the tumor microenvironment through mechanisms yet to be elucidated. In this study, we used a size-based microfilter technology developed by our group to examine whether circulating CAF identified by FAP and α-SMA co-expression (cCAF) could be distinguished in the peripheral blood of patients with metastatic breast cancer. In a pilot study of patients with breast cancer, we detected the presence of cCAFs in 30/34 (88%) patients with metastatic disease (MET group) and in 3/13 (23%) patients with localized breast cancer (LOC group) with long-term disease-free survival. No cCAFs as defined were detected in healthy donors. Further, both cCAF and circulating tumor cells (CTC) were significantly greater in the MET group compared with the LOC group. Thus, the presence of cCAF was associated with clinical metastasis, suggesting that cCAF may complement CTC as a clinically relevant biomarker in metastatic breast cancer. Cancer Res; 75(22); 4681–7. ©2015 AACR.
Phase Ib Randomized, Double-Blinded, Placebo-Controlled, Dose Escalation Study of Polyphenon E in Patients with Barrett's Esophagus
Authors: Joe Andrew K. , Schnoll-Sussman Felice , Bresalier Robert S. , Abrams Julian A. , Hibshoosh Hanina , Cheung Ken , Friedman Richard A. , Yang Chung S. , Milne Ginger L. , Liu Diane D. , Lee J. Jack , Abdul Kazeem , Bigg Michelle , Foreman Jessica , Su Tao , Wang Xiaomei , Ahmed Aqeel , Neugut Alfred I. , Akpa Esther , Lippman Scott M. , Perloff Marjorie , Brown Powel H. , Lightdale Charles J. 
Published: October 2015

AbstractThis study was conducted to determine the safety and efficacy of the green tea–derived Polyphenon E (Poly E) in patients with Barrett's Esophagus (BE). Subjects were randomized to a 6-month, twice daily (BID) oral treatment of placebo or Poly E (200, 400, or 600 mg). Endoscopic evaluation, including biopsies, was performed before and after treatment. The primary objective was to demonstrate safety; secondary objectives investigated catechin accumulation and effects in clinical specimens. Of the 44 enrolled subjects, 11 received placebo, and 33 received Poly E. No dose-limiting toxicities were encountered, and a maximum tolerated dose (MTD) was not reached. The recommended phase II dose was 600 mg twice daily. The most common treatment-related adverse events (AE) in Poly E–treated subjects were grade I and II nausea, grade I belching, and grade I lactate dehydrogenase (LDH) elevation. No treatment-related AEs were reported in placebo-treated subjects, aside from grade I laboratory abnormalities. Pill counts and subject diaries were not consistently collected, and compliance was difficult to determine. However, on the basis of an intention-to-treat analysis, there was a significant relationship between Poly E dose and esophageal EGCG level—mean changes (pmol/g) of 0.79 (placebo), 6.06 (200 mg), 35.67 (400 mg), and 34.95 (600 mg); P = 0.005. There was a possible relationship between Poly E dose and urine PGE-M concentration. In conclusion, Poly E was well-tolerated, and treatment with Poly E (400 and 600 mg) but not Poly E (200 mg) or placebo resulted in clinically relevant and detectable EGCG accumulation in the target organ, esophageal mucosa. Cancer Prev Res; 8(12); 1131–7. ©2015 AACR.
Abstract A14: Overcoming therapeutic MAb resistance in agressive HER2 positive breast carcinomas by adoptive immunotherapy using optizimed effectors cells
Authors: Valsesia-Wittmann Sandrine , Clemenceau Beatrice , Jallas Anne-Catherine , Blay Jean-Yves , Marabelle Aurelien , Caux Christophe , Vie Henri 
Published: October 2015

Abstract
Trastuzumab, a monoclonal antibody targeting HER2 has been demonstrated to improve survival of HER2 overexpressing metastatic breast cancer. However, half of patients who initially respond to Trastuzumab develop resistance within one year of treatment initiation. Alteration of Antibodies Dependant Cellular Cytotoxicity (ADCC) mechanisms is one of the rational mechanisms for resistance to therapeutic Mab.
The goal of this project is to overcome this resistance by adoptive transfer using genetically engineered optimized NK cells. We thus compare efficacy of two different approaches: (i) NK cells armed with a high affinity Fc domain (FcγRIIIα/CD16) linked to its transduction chain FCεRIγ to generate NK-CD16/γ cells that allow recognition and interaction with Mab, inducing ADCC and (ii) NK cells expressing Trastuzumab sequence fused to the transduction chain FCεRIγ to generate NK-Her/γ that directly kill the HER2 positively cells.
In vitro, both strategies demonstrated high cytotoxic efficacy against HER2 positive cells, with direct killing systematically more efficient (reaching up to 95% with ratio E:T 5:1). Interestingly, two steps killing with NK-CD16/γ enabled a very specific cytotoxicity only in the presence of specific antibody. We demonstrated that efficacy of lysis is linked (i) to effector dose, (ii) levels of CD16/γ expression on effectors cells, (iii) HER2 expression but not level on target cells
In vivo, in Trastuzumab resistant HER2+ xenograft immunodeficient NSG mice model, complete regression was obtained only when using NK-CD16/γ in the presence of Trastuzumab. Even if the NK-Her/γ was found by IF or FACS in the tumor after IV or IP injection, they could not induce tumor regression. Analyses of NK dysfunction will be presented.
Restoration or improvement of effectors cells might be considerate as an issue in therapeutic Mab resistance treatment. Successful immune-based therapies will likely ultimately integrate strategies that combine immunotherapy approaches and immune-modulating drugs, in order to maximize their antitumor activity.
Citation Format: Sandrine Valsesia-Wittmann, Beatrice Clemenceau, Anne-Catherine Jallas, Jean-Yves Blay, Aurelien Marabelle, Christophe Caux, Henri Vie. Overcoming therapeutic MAb resistance in agressive HER2 positive breast carcinomas by adoptive immunotherapy using optizimed effectors cells. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A14.
Abstract A23: Potentiating immunological memory in mice using aptamer targeted siRNA delivery to inhibit mediators of effector differentiation in CD8+ cytotoxic T lymphocytes
Authors: Berezhnoy Alexey , Anugraha Rajagopalan , Malek Thomas , Gilboa Eli 
Published: October 2015

Abstract
This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR11) of the Conference Proceedings.
Citation Format: Alexey Berezhnoy, Rajagopalan Anugraha, Thomas Malek, Eli Gilboa. Potentiating immunological memory in mice using aptamer targeted siRNA delivery to inhibit mediators of effector differentiation in CD8+ cytotoxic T lymphocytes. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A23.
Abstract A33: Preparation of local anti-wart and anti-inflammatory rub of polyglycidol based saturated lipid (DDP-PG) with HPMC containing curcumin
Authors: Shaheen Sharif Mohammad , Bakardzhiev Pavel , Momekova Denitsa , Koseva Neli S. , Rangelov Stanislav 
Published: October 2015

Abstract
Curcumin is absorbed poorly and has a limited bioavailability to work promptly as an anti-cancer drug or as an anti-inflammatory agent. If curcumin could be delivered directly into the cell, it might be a potential therapeutic against the inflammation and thereby cancer signaling cascades. In order to reach this goal here a topical medicament (rub) containing curcumin has been developed as an alternative therapeutic especially for skin inflammation and cancer thereby. We synthesized polyglycidol based block copolymers DDP-PG (MW 2700), which was incorporated into HPMC (7%) to prepare the rub containing curcumin. One more formulation containing monoolein rac glycerol (MO) with DDP-PG was incorporated. The diffusion of curcumin was evaluated in vitro using a biomembrane (fish swim bladder). The diffusion of curcumin form DDP-PG based formulation did not differ from that of MO, which is the indication of their suitability as biomaterials for the preparation of a transdermal penetrating vehicle. Subsequently, curcumin containing DDP-PG was evaluated directly for therapeutic purposes treating local apoptotic skin, inflammatory sites and benign tumor mass (wart). It showed skin cured very promisingly from apoptosis, which might be worst if not treated in time. It cleared the inflammation perfectly and reduced dramatically the size of the wart (a benign tumor) as well.
Citation Format: Sharif Mohammad Shaheen, Pavel Bakardzhiev, Denitsa Momekova, Neli S. Koseva, Stanislav Rangelov. Preparation of local anti-wart and anti-inflammatory rub of polyglycidol based saturated lipid (DDP-PG) with HPMC containing curcumin. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A33.
Abstract A41: Galectin-9 has tumor promoting properties that may be targetable in metastatic melanoma
Authors: Enninga Elizabeth Ann L. , Nevala Wendy K. , Markovic Svetomir N. 
Published: October 2015

Abstract
Introduction: Galectin-9 (Gal-9) is a carbohydrate-binding protein that interacts with T-cell immunoglobulin mucin 3 (TIM3) to modulate immune homeostasis. The Gal-9/TIM3 interaction down regulates activated T cells which promotes tumor growth, much like program death 1 (PD-1) and its ligand (PD-L1). Still, the effect Gal-9 has on the immune environment of melanoma patients is weakly understood. This study focuses on the role of Gal-9 in immunoregulation of healthy persons and metastatic melanoma patients.
Methods: Soluble Gal-9 levels were determined from plasma collected from patients and healthy persons using standard ELISA methods. Proliferation and apoptosis of cells in the presence and absence of Gal-9 was determined by mixed lymphocyte reactions and Tunnel staining. Supernatants from these reactions were collected and run using a cytokine bead assay to determine changes in immune parameters with and without Gal-9.
Results: Soluble Gal-9 was significantly higher in metastatic melanoma patients compared to healthy controls (3929 vs. 877 pg/mL, p=0.0003 respectively). In the presence of Gal-9, the proliferative effect of an allostimulus could be overridden until the level of responder cells to stimulator cells was 4:1. Using an apoptosis assay, Gal-9 was found to increase the level of cellular apoptosis; however, apoptosis was decreased as the allostimulus increased. Healthy cells incubated with Gal-9 were found to increase secretion of growth factors (EGF and FGF-2), chemokines (CXCL1, CXCL8, CCL2 and CCL3), T helper 1 cytokines (IFN-g and IL-7) which have shown tumor promoting affects and T helper 2 cytokines (IL-13 and IL-4).
Conclusions: Gal-9 may potentially play a role in suppressing anti-tumor immunity. This suggests the use of a Gal-9 neutralizing antibody for therapeutic benefit in melanoma.
Citation Format: Elizabeth Ann L. Enninga, Wendy K. Nevala, Svetomir N. Markovic. Galectin-9 has tumor promoting properties that may be targetable in metastatic melanoma. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A41.
Abstract A55: PD-1 blockade synergizes with cisplatin radiation therapy aiding in clearance of murine HPV+ oropharyngeal carcinoma
Authors: Vermeer Daniel W. , Powell Steven , Spanos William C. , Lee John H. 
Published: October 2015

Abstract
Squamous cell carcinomas of the head and neck (SCCHN) are the 6th most common malignancy world-wide with approximately 650,000 diagnoses per year. Human papillomavirus (HPV) causes up to 80% of oropharyngeal (tonsil/base of tongue) SCCHN. Despite presenting at an advanced stage, multiple studies show that HPV+ SCCHN are more curable relative to their HPV- counterparts. Clearance of SCCHN during treatment with cisplatin radiation therapy (CRT) is not only related to direct cytotoxicity, but is also dependent on immune mediated clearance. This immune clearance is strongly dependent on an intact CD4+ and CD8+ cellular response to tumor cells harboring these viral oncogenes. Furthermore, the immune system recognizes and clears HPV + SCCHN only after the start of CRT. The immunologic tolerance to these cancers prior to treatment could be explained by immune checkpoints aimed at preventing unregulated immune activity. The programmed death 1 receptor (PD-1) and its ligand, PD-L1, are one such checkpoint axis. Recent data suggests that the PD-1:PD-L1 pathway may play an important role in immune resistance in head and neck cancer. We evaluated PD-1 in combination with CRT in an immune competent HPV+ SCCHN mouse model. HPV + mouse SCCHN cells were injected subcutaneously into immune competent mice and tumors were treated after growing to palpable size. Using the mouse analog to the human PD-1 blocker, pembrolizumab, we determined that while single-agent therapy does not have significant activity on primary disease or distant metastasis, PD-1 blockade strongly synergizes with CRT. An overall survival of 58% was evident in mice treated with combination PD-1 and CRT versus 8% in mice treated with isotype control (IgG1) in combination with CRT (p = 0.006). These studies provide the impetus for future work investigating less toxic induction of immune responses in combination with blockade of immune checkpoint pathways.
Citation Format: Daniel W. Vermeer, Steven Powell, William C. Spanos, John H. Lee. PD-1 blockade synergizes with cisplatin radiation therapy aiding in clearance of murine HPV+ oropharyngeal carcinoma. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A55.
Abstract A71: Modulation of macrophages in breast tumors towards an anti-tumor phenotype
Authors: Guerriero Jennifer L. , Letai Anthony 
Published: October 2015

Abstract
While several avenues of manipulating the adaptive immune response have met with striking clinical success in recent years, there is also a growing appreciation of the innate immune system in mediating tumor reduction and elimination. In fact, tumor associated macrophages (TAMs) are the most abundant immune population in a breast tumor. Although M1 macrophages have potent anti-tumor activity, TAMs are phenotypically polarized to M2 macrophages, which support tumors. Clinically, a high tumor density of TAMs has been associated with chemoresistance and a worse clinical outcome. Using a tool, BH3 profiling, that is unique to the Letai Laboratory, we have identified that macrophage phenotype can alter the sensitivity of neighboring tumor cells to apoptotic signaling, and enhance their response to chemotherapy.
The Letai Laboratory has developed a unique and novel assay to predict a cancer cell's response to chemotherapy called BH3 profiling. BH3 profiling is used to determine whether a cell is relatively close to the threshold of apoptosis (“primed” for death), or relatively far from the threshold (“unprimed”). We have found that the priming of cancer cells, as measured by BH3 profiling, is by itself a predictor of clinical response to conventional chemotherapy. Using the BH3 profiling strategy, we show for the first time that M1 macrophages “prime” breast tumor cells for apoptosis, which correlates to their increased chemosensitivity. Interestingly, we have found some breast tumor cells to be resistant to M1 macrophage induced priming. We have performed gene expression analysis on these two phenotypes of breast tumor cells, to uncover why some, but not others, are sensitive to M1 macrophages. We also have identified how M1 macrophages increase the priming of tumor cells, making them more chemosensitive. These results suggest modulating TAMs towards an anti-tumor phenotype may have great promise for cancer therapy. To this end, we are investigating strategies to convert M2 TAMs to a M1 phenotype. We have conducted a high throughput screen (HTS) at the Institute of Chemistry and Cell Biology (ICCB) – Longwood, at Harvard Medical School, to identify small molecules that polarize macrophages to an anti-tumor phenotype. We have identified several interesting small molecules and are working to validate their clinical significance.
Citation Format: Jennifer L. Guerriero, Anthony Letai. Modulation of macrophages in breast tumors towards an anti-tumor phenotype. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A71.
Abstract B20: Enhanced affinity T cell receptor based therapy can surmount immune and physical barriers to treat pancreatic ductal adenocarcinoma
Authors: Stromnes Ingunn M. , Brockenbrough Scott J. , Schmitt Thomas M. , Hingorani Sunil R. , Greenberg Philip D. 
Published: October 2015

Abstract
This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR08) of the Conference Proceedings.
Citation Format: Ingunn M. Stromnes, Scott J. Brockenbrough, Thomas M. Schmitt, Sunil R. Hingorani, Philip D. Greenberg. Enhanced affinity T cell receptor based therapy can surmount immune and physical barriers to treat pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B20.