bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-151: A novel TGFβ 1/2 specific antibody suppresses 4T1 tumor growth by enhancing NK cell recruitment and function
Authors: Li Ou , Khan Shireen , Mendoza Nerissa , Vanegas Sandra , Tran Cat , Mirza Amer 
Published: May 2015

Abstract
TGFβ can play an important role in tumor progression. Whether expressed by the tumor, or the tumor microenvironment, it has a profound impact on not only the tumor itself but also the host immune system. There are three isoforms of TGFβ: TGFβ1, TGFβ2 and TGFβ3. The functions of TGFβ1 and 2 have been widely studied. However, little is known about how TGFβ3 affects both tumor growth and the host. Here we used a novel human antibody that neutralizes only TGFβ1 and 2, while leaving TGFβ3 activity untouched. By specifically blocking TGFβ1 and 2 functions, we were able to investigate the role of TGFβ3 in modulating the immune compartment, and its ability to combat tumor growth. We used the 4T1 murine breast carcinoma model, which secretes all three isoforms of TGFβ. Tumor-bearing mice were treated with 10mg/kg the novel anti-TGFβ1/2 antibody, which inhibited 25% of 4T1 tumor growth after 20 days. We evaluated the immune cells from tumors and found there was a significant increase (14%) in the NK cells that infiltrated the tumor site in the antibody-treated group. To explore the mechanism underlying this phenomenon, we evaluated the effect of tumor-secreted TGFβ isoforms on NK cells in vitro in a co-culture system. When 4T1 tumor cells were co-cultured with enriched NK cells, the TGFβ1/2 antibody elevated the levels of IFNγ, GzmB and perforin. However, the expression levels of NKG2D, CD69, Ly49A and C were unchanged. We also detected a significant upregulation of FasL on NK cells treated with the TGFβ1/2 antibody. Moreover, NK cells treated with the TGFβ1/2 antibody in the co-culture system showed improved killing activity towards Yac-1 cells, which was confirmed to be mediated by GzmB. In summary, a novel therapeutic antibody candidate that specifically neutralizes TGFβ1 and 2 inhibits 4T1 tumor growth by (i) changing the tumor microenvironment to attract NK cells to tumor sites; and (ii) by increasing NK cell function via upregulation of FasL and GzmB.
Citation Format: Ou Li, Shireen Khan, Nerissa Mendoza, Sandra Vanegas, Cat Tran, Amer Mirza. A novel TGFβ 1/2 specific antibody suppresses 4T1 tumor growth by enhancing NK cell recruitment and function. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-151. doi:10.1158/1538-7445.AM2014-LB-151
Abstract LB-155: Ovarian cancer-induced changes in the intestinal microbiota as potential biomarkers for early detection
Authors: Schmelz Eva M. , Roberts Paul C. , Ponder Monica A. 
Published: May 2015

Abstract
Early detection of cancer can drastically increase the survival rate of the patient. While tremendous efforts were devoted to developing early detection tools, especially cancers in the peritoneal cavity such as ovarian cancer are often detected late after the exfoliated cancer cells have spread throughout the peritoneal cavity and have formed metastases, leading to a high mortality. However, early detection can increase the 5-year survival rate of afflicted women from less than 30% to more than 80%, highlighting the importance of developing early detection tools. Ideally, these tools should be specific for ovarian cancer but include most histological sub-types, and be non-invasive. An attractive source of biomarkers lies within the complex gut microbiome- whose membership and functionality are tightly associated with the health of its host. Changes to the gut microbiota, a concept referred to as dysbiosis, are associated with disease in humans. Here we describe changes in the intestinal microbiota as a function of the presence of ovarian cancer metastases in the peritoneal cavity. We postulate that these might serve as useful markers for earlier detection of ovarian cancer or other peritoneal-associated cancers.
Citation Format: Eva M. Schmelz, Paul C. Roberts, Monica A. Ponder. Ovarian cancer-induced changes in the intestinal microbiota as potential biomarkers for early detection. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-155. doi:10.1158/1538-7445.AM2014-LB-155
Abstract LB-157: VISTA deficiency synergizes with a non-redundant immune checkpoint pathway and leads to enhanced immune activation
Authors: Wang Li , LeMercier Isabelle , Suriawinata Arief , Chen Wenna , Noelle Randolph J. , Li Jiannan 
Published: May 2015

Abstract
V-domain Ig suppressor of T cell activation (VISTA) is a novel negative checkpoint ligand that suppresses T-cell mediated immune responses. Previous studies using VISTA-neutralizing monoclonal antibody show that VISTA-blockade enhances T cell-activation in an inflammatory disease model EAE, as well as in murine tumor models. Current study describes a comprehensive characterization of VISTA knockout (KO) mice. We show that despite the apparent normal hematopoietic development in young ko mice, VISTA genetic deficiency leads to a pro-inflammatory phenotype in aged animals, as well as enhanced T-cell activation in response to acute antigen immunization. In addition, we show that VISTA deficiency significantly enhanced disease development in a spontaneous model of autoimmune disease, which is correlated with the spontaneous activation of auto-antigen specific CD4+ T cells. Lastly, when combined with the genetic deficiency of another checkpoint molecule, synergistic or additive immune activation was observed. The implication of such enhanced immunity in cancer development and treatment will be discussed.
Citation Format: Li Wang, Isabelle LeMercier, Arief Suriawinata, Wenna Chen, Randolph J. Noelle, Jiannan Li. VISTA deficiency synergizes with a non-redundant immune checkpoint pathway and leads to enhanced immune activation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-157. doi:10.1158/1538-7445.AM2014-LB-157
Abstract LB-16: Discovery of novel SGK1 inhibitors by a fragment-based approach: Generating patentable, chemically tractable and ligand efficient leads
Authors: Alton Gordon , Wade Warren , Lingardo Laura , Batova Ayse , Smart Tom , Buhr Chris , Zapf James W. , Pallai Peter 
Published: May 2015

Abstract
Triple negative (ER, PR and HER2/neu negative) breast cancer (TNBC) can have an unfavorable prognosis compared to other breast cancers. TNBC is more difficult to treat since most targeted breast cancer therapies are directed at one of the three receptors. Aggressive combinatorial therapies are usually required and the cytotoxic agents used in these regimens frequently loose effectiveness with time. Serum and glucocorticoid-regulated kinase 1 (SGK1) (a serine/threonine protein kinase), promotes the growth and invasiveness of breast cancer cells. SGK1 is a key protein regulated by the glucocorticoid receptor (GR). In TNBC tumors, high expression/activity in the GR/SGK axis correlates with shorter survival times and resistance to chemotherapy. The small numbers of SGK1 inhibitors reported in the literature have resulted from screening against other kinases (such as CHK1/azaindoles) and thus are not selective and lack patentable chemical diversity. We describe the identification of novel SGK1 inhibitors using a fragment-based library screening approach. The BioBlocks Leap-To-Lead platform contains a library of novel fragment-like compounds that span a range of polarities and sizes without compromising on flexibility. For example, this 275 compound library has an average molecule weight of 160 Da; AlogP, 1.1; hydrogen bond donors, 1.1; hydrogen bond acceptors, 2.2, and rotatable bonds, 0.7 yet still contains 114 unique rings. The library was screened against fully activated human SGK1 in an ADP-Glo assay using physiologically relevant peptide substrate and an optimal ATP concentration to also identify non-classical kinase inhibitor mode binders. The fragment library was screened at 2 mM and hits were profiled in IC50 dose response. From these, several novel chemical matter hit compounds were selected that had ligand efficiency values greater than 0.3 and spanned IC50 values from 75 µM to 2000 µM.
In summary, a fragment-based screening approach was used to identify several novel scaffolds that represent both classical and non-classical kinase inhibitor binding modes as hit-to-lead starting points for the optimization of novel, potent and selective SGK1 inhibitors.
Citation Format: Gordon Alton, Warren Wade, Laura Lingardo, Ayse Batova, Tom Smart, Chris Buhr, James W. Zapf, Peter Pallai. Discovery of novel SGK1 inhibitors by a fragment-based approach: Generating patentable, chemically tractable and ligand efficient leads. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-16. doi:10.1158/1538-7445.AM2014-LB-16
Abstract LB-164: Towards operative in vivo fluorescence imaging of c-Met proto-oncogene for personalization of therapy in ovarian cancer
Authors: Liu Shujuan , Zheng Yong , Volpi Davide , El-Kasti Muna , Klotz Daniel , Tullis Iain , Henricks Andrea , Campo Leticia , Myers Kevin , Laios Alex , Thomas Peter , Ng Tony , Dhar Sunanda , Becker Christian , Vojnovic Borivoj , Ahmed Ahmed A. 
Published: May 2015

Abstract
The recent recognition of the scale of the problem of tumour heterogeneity has made it clear that standard biomarker testing of a single macroscopic disease sites is unlikely to be sufficient. A focus on examining global biomarker expression or activity is needed for appropriate selection of targeted therapies. A particular attention to microscopic residual chemotherapy-residual disease (MRCD) would ensure appropriate targeting of chemotherapy resistance. However, the techniques for global assessment of biomarkers in patients with MRCD have not established.
Using an in-house developed fluorescent imaging device we show that it is possible to identify global c-Met expression in submillimeter peritoneal metastases that were freshly excised from a human high-grade serous ovarian cancer. We evaluated a modified Cy5-tagged peptide (GE137) that selectively binds to the c-Met tyrosine kinase and demonstrated the feasibility of detecting submillimeter ovarian cancer cell peritoneal metastases in vivo following intravenous injection of this peptide. GE137 specifically accumulated in cells that express c-Met via clathrin-mediated endocytosis and emitted a fluorescent signal that lasted for at least 8 hours in tumour xenografts in vivo with a sustained high signal to noise ratio. Thus, intraoperative optical imaging could provide a new paradigm for selecting cancer patients with MRCD for appropriate targeted therapies following initial chemotherapy.
Citation Format: Shujuan Liu, Yong Zheng, Davide Volpi, Muna El-Kasti, Daniel Klotz, Iain Tullis, Andrea Henricks, Leticia Campo, Kevin Myers, Alex Laios, Peter Thomas, Tony Ng, Sunanda Dhar, Christian Becker, Borivoj Vojnovic, Ahmed A. Ahmed. Towards operative in vivo fluorescence imaging of c-Met proto-oncogene for personalization of therapy in ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-164. doi:10.1158/1538-7445.AM2014-LB-164
Abstract LB-168: Perivascular, CXCR4-expressing macrophages in tumors promote relapse following chemotherapy
Authors: Lewis Claire E. 
Published: May 2015

Abstract
The relapse of cancer after frontline therapies like chemotherapy is a major clinical problem as tumors often grow back at the site of surgical removal and/or as metastases. Tumor-associated macrophages (TAMs) are a major cellular component of both primary and metastatic tumors, and promote such key processes in tumor progression as angiogenesis, immunosuppression, invasion, and metastasis. Gene expression profiling and immunostaining studies have identified both classically (M1) and alternatively (M2) activated TAMs in human and mouse tumors. Heavily M2-skewed TAMs - those expressing the angiopoietin receptor, TIE2 - have been shown to be important for angiogenesis and immunosuppression in mouse tumors. Moreover, high levels of TAMs expressing another M2 marker, CD163, correlate with poor prognosis in various forms of human cancer. TAMs have been shown recently to reduce the sensitivity of mouse mammary tumors to cytotoxic agents like paclitaxel (PTX) and doxorubicin. Here, we report on our use of various mouse tumor models to investigate the role of TAMs in tumor relapse after chemotherapy. Our studies show that a distinct subset of M2-skewed, CXCR4hi VEGF+ TAMs cluster around blood vessels after administration of various cytotoxic agents. This correlated with increased tumor CXCL12 levels - and the selective depletion of this perivascular TAM subset, using the CXCR4 antagonist, AMD3100 (Plerixafor), revealed an important role for these cells in driving revascularisation and regrowth in post-chemotherapy tumors. Additionally, adoptive transfer of this TAM subset into tumor-bearing mice after chemotherapy accelerated tumor regrowth. No such effect was seen with non-M2 skewed TAMs isolated from the same tumors. These studies suggest that combining chemotherapy with inhibitors of the CXCL12-CXCR4 axis could delay tumor relapse in cancer patients.
Citation Format: Claire E. Lewis. Perivascular, CXCR4-expressing macrophages in tumors promote relapse following chemotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-168. doi:10.1158/1538-7445.AM2014-LB-168
Abstract LB-17: Oral delivery of taurocholic acid-linked heparin-docetaxel conjugates for tumor and its angiogenesis therapy
Authors: Khatun Zehedina , Nurunnabi MD , Huh Kang Moo , Lee Yong-kyu 
Published: May 2015

Abstract
Oral delivery is the preferred route to deliver therapeutics via nanoparticles due to ease of administration and patient acceptance. Here, we report on the findings of the absorption pathway of taurocholic acid (TCA)-linked heparin and docetaxel (DTX) conjugate, which we refer to as HDTA. The ternary biomolecular conjugates formed self-assembly nanoparticles where docetaxel was located inside the core and taurocholic acid was located on the surface of the nanoparticles. The oral absorption profile demonstrated that the concentration of the conjugates in plasma is about 6 fold higher than heparin alone. An anti-tumor study in MDA-MB231 and KB tumor bearing mice showed significant tumor growth inhibition activity by the ternary biomolecular conjugates. We studied the oral absorption of HDTA using a Caco-2 cell transport system and an animal model. We have also used other absorption enhancers, such as ethylene glycol tetraacetic acid (EGTA), or inhibitors, such as sodium azide, to compare the relative permeability of HDTA conjugates. In vivo comparative studies were conducted using free TCA as a pre-administration and exhibited the maximum absorption site of the organ after oral administration of HDTA conjugates. HDTA was found to be absorbed mainly in the ileum and Caco-2 cell monolayer through passive diffusion and bile acid transporters. High fluorescence intensity of HDTA in mice came from the ileum, and it was eliminated from the body through colon. This novel formulation could be further investigated by clinical trials to find the prospect of oral anti-cancer drug delivery through anti-angiogenic treatment strategies.
Citation Format: Zehedina Khatun, MD Nurunnabi, Kang Moo Huh, Yong-kyu Lee. Oral delivery of taurocholic acid-linked heparin-docetaxel conjugates for tumor and its angiogenesis therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-17. doi:10.1158/1538-7445.AM2014-LB-17
Abstract LB-178: In vivo validation of candidate radiosensitizers that target ionizing radiation induced foci
Authors: Efimova Elena V. , Mauceri Helena J. , Labay Edwardine , Sutton Harold , Haraf Ashly , Kron Stehen J. , Weichselbaum Ralph 
Published: May 2015

Abstract
Even after several decades of use, radiation therapy (RT) remains an important tool in the treatment of different types of cancers. Discovery of novel non-toxic radiosensitizers that halt tumor growth and/or restore senescence checkpoint growth arrest are highly desirable. Our work, along with other studies, has revealed that disrupting the repair of DNA double strand breaks (DSBs) can sensitize cancer cells to genotoxic stress. In our prior work we used GFP-53BP1 expressed in the MCF-7 breast cancer cell line as a sensor to screen small molecules that affect radiation-induced foci (IRIF) persistence. The screening of libraries of approved and investigational drugs identified several “hits”, a surprising number of which were compounds without known connections to the DNA damage response or to chromatin alteration. Significantly, several compounds that promote IRIF persistence also restore the senescence checkpoint in irradiated cancer cells. To validate the candidate radiosensitizers we demonstrated that selected hits induced IRIF persistence and senescence in a variety of different cell lines, including HNSCC, and pancreatic and melanoma cells. Based on in vitro analysis, we identified the most promising compounds/”hits” for testing in tumor growth studies. Combining selected “hits” with radiation treatment (RT) induced IRIF persistence and increased senescence induction in MCF7-GFP-53BP1 xenografts growing in nude mice. We report that drug “hits” combined with RT induced senescence and suppressed tumor regrowth in highly radioresistant B16-SIY melanoma tumors growing in syngeneic C57BL/6 mice. Our data suggest that the use of nontoxic radiation sensitizers which enhance the effects of DNA damage and overcome intrinsic tumor radioresistance may be employed to enhance the therapeutic ratio of radiotherapy.
Citation Format: Elena V. Efimova, Helena J. Mauceri, Edwardine Labay, Harold Sutton, Ashly Haraf, Stehen J. Kron, Ralph Weichselbaum. In vivo validation of candidate radiosensitizers that target ionizing radiation induced foci. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-178. doi:10.1158/1538-7445.AM2014-LB-178
Abstract LB-180: Prognostic analysis of invasive circulating tumor cells (iCTCs) to monitor epithelial ovarian cancer
Authors: Chen Wen-Tien , Dong Huan , Zhao Qiang , Yang Jie , ZHANG QIAO , Zucker Stanley , Pearl Michael L. 
Published: May 2015

Abstract
Purpose:
Cancer antigen 125 (CA125) is recognized as the leading biomarker in monitoring Epithelial Ovarian Cancer (EOC). More recently, invasive circulating tumor cells (iCTCs) have been introduced as a biomarker for metastatic potential. The goal of this research is to compare this biomarker with CA125 to determine the response to surgery and chemotherapy.
Experimental Design:
We compared clinical parameters with serial assays for iCTCs and CA125 in 129 fresh blood and 169 serum samples, respectively, from 31 patients who were receiving surgery and chemotherapy. iCTCs were capable of ingesting matrices (Cell Adhesion Matrix CAM+) and identified using positive tumor markers, Epi (EPCAM and CA125 or seprase and CD44), and negative selection markers, which exclude Epi-positive hematopoietic lineage (HL) cells, and enumerated by flow cytometry. iCTCs and CA125 levels were measured at time point less than 3-days apart.
Results:
A significant correlation was identified between changes in iCTC counts and CA125 levels (r=0.67, P&lt;0.001) in the 83 samples collected prior to and after surgery and therapy. CA125 levels, but not iCTCs, were significantly reduced after surgery. During therapy, a significantly stronger concordance with clinical status was noted for decreasing values (specificity, 93.8% CA128; 90.6% iCTCs) compared with increasing values (sensitivity, 61.3% CA125; 83.9% iCTCs). Notably, increases in iCTCs, not CA125, were associated with increased risks for progressive disease (P&lt;0.001). In the 8 patients who had &gt;4 serial samples during therapy, changes in iCTC counts provided earlier measure of therapy response than CA125.
Conclusion:
This analysis showed that iCTC assay compared favorably with CA125 to monitor the response of chemotherapy in EOC patients, whereas changes of CA125 correlated better with reduced tumor burden after surgery.
Citation Format: Wen-Tien Chen, Huan Dong, Qiang Zhao, Jie Yang, QIAO ZHANG, Stanley Zucker, Michael L. Pearl. Prognostic analysis of invasive circulating tumor cells (iCTCs) to monitor epithelial ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-180. doi:10.1158/1538-7445.AM2014-LB-180