bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 491: NLG919, a novel indoleamine-2,3-dioxygenase (IDO)-pathway inhibitor drug candidate for cancer therapy.
Authors: Mautino Mario R. , Jaipuri Firoz A. , Waldo Jesse , Kumar Sanjeev , Adams James , Van Allen Clarissa , Marcinowicz-Flick Agnieszka , Munn David , Vahanian Nicholas , Link Charles J. 
Published: August 2014

Abstract
The IDO pathway mediates immunosuppressive effects through the metabolization of tryptophan (Trp) to kynurenine (Kyn), triggering downstream signaling through GCN2, mTOR and AHR that can affect differentiation and proliferation of T cells. Expression of the IDO1 gene by tumor cells or host APCs can inhibit tumor-specific effector CD8+ T cells and enhance the suppressor activity of Tregs, and high expression of IDO correlates with worse clinical prognosis in patients with a variety of malignancies. Therefore, targeting the IDO pathway via inhibition of the IDO enzyme or blocking its downstream signaling effects is a prime target for small-molecule immunomodulatory drugs in cancer.
Here we describe the pharmacological and biological properties of NLG919, a novel small-molecule IDO-pathway inhibitor. NLG919 potently inhibits this pathway in vitro and in cell based assays (Ki=7 nM; EC50 =75 nM). It is orally bioavailable (F&gt;70%); and has a favorable pharmacokinetic and toxicity profile. In mice, a single oral administration of NLG919 reduces the concentration of plasma and tissue Kyn by ∼ 50%. Using IDO-expressing human monocyte-derived DCs in allogeneic MLR reactions, NLG919 potently blocked IDO-induced T cell suppression and restored robust T cell responses with an ED50=80 nM. Similarly, using IDO-expressing mouse DCs from tumor-draining lymph nodes, NLG919 abrogated IDO-induced suppression of antigen-specific T cells (OT-I) in vitro, with ED50=120 nM. In vivo, in mice bearing large established B16F10 tumors, administration of NLG919 markedly enhanced the anti-tumor responses of naïve, resting pmel-1 cells to vaccination with cognate hgp100 peptide plus CpG-1826 in IFA. In this stringent established-tumor model, NLG919 plus pmel 1/vaccine produced a dramatic collapse of tumor size within 4 days of vaccination (∼95% reduction in tumor volume compared to control animals receiving pmel-1/vaccine alone without NLG919).
In conclusion, NLG919 is a potent IDO pathway inhibitor with desirable pharmacological properties, suitable for the treatment of immunosuppression associated with cancer.
Citation Format: Mario R. Mautino, Firoz A. Jaipuri, Jesse Waldo, Sanjeev Kumar, James Adams, Clarissa Van Allen, Agnieszka Marcinowicz-Flick, David Munn, Nicholas Vahanian, Charles J. Link. NLG919, a novel indoleamine-2,3-dioxygenase (IDO)-pathway inhibitor drug candidate for cancer therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 491. doi:10.1158/1538-7445.AM2013-491
Abstract 4921: Essential role of MMP-2 in carbon nanotube-induced invasion of human pleural mesothelial cells.
Authors: Lohcharoenkal Warangkana , Liu Yuxin , Stueckle Todd A. , Dinu Cerasela-Zoica , Wang Liying , Rojanasakul Yon 
Published: August 2014

Abstract
Carbon nanotubes (CNTs) have increasingly been used in a wide variety of applications. However, because of their needle-shape morphology, biopersistence and mode of exposure similar to those of asbestos which is a known carcinogen causing lung mesothelioma, there has been a great concern about their potential carcinogenicity. In this study, we investigated the effect of long-term exposure of CNT on proliferative and invasive properties of human pleural mesothelial cells. We found that chronic exposure of human mesothelial Met5A cells to low-dose non-cytotoxic concentration of single-walled CNT (0.02 μg/cm2 for 25 weeks) in culture induced malignant transformation of the cells as indicated by their increased cell invasion and migration. Analysis of gene expression by real-time PCR array showed a 50-fold increase in MMP-2 expression in CNT-transformed cells as compared to passage-matched control cells. Western blot analysis of the protein expression confirmed the upregulation of MMP-2 in the transformed cells. Downregulation of MMP-2 in the transformed cells by short-hairpin RNA stable transfection effectively inhibited the MMP-2 activity in these cells as well as their invasive and migratory activities. These results indicate MMP-2 as a key regulator of the aggressive phenotype of mesothelial cells after chronic CNT exposure. This study fortifies the carcinogenic potential of CNT and reveals a novel mechanism that may be important in CNT-induced mesothelioma.
Citation Format: Warangkana Lohcharoenkal, Yuxin Liu, Todd A. Stueckle, Cerasela-Zoica Dinu, Liying Wang, Yon Rojanasakul. Essential role of MMP-2 in carbon nanotube-induced invasion of human pleural mesothelial cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4921. doi:10.1158/1538-7445.AM2013-4921
Abstract 4942: Deletion of the asymmetry regulator Lgl1 contributes to tumor stemness and invasiveness.
Authors: Lerner Robin G. , Nguyen Loan , Petritsch Claudia 
Published: August 2014

Abstract
In the developing and adult brain asymmetric cell division (ACD) maintains a balance between self-renewing and differentiated progeny of neural stem and progenitor cells. The WD protein lethal giant larvae 1 (Lgl1) regulates the distribution of polarity proteins in dividing cells and thereby establishes an axis of polarity, which is crucial for proper asymmetric divisions to occur (Baek et al. Mutat Res. 1999; 436; 131-6). Lgl, along with other asymmetry regulators, have been identified as a putative tumor suppressor gene in Drosophila.
There remains debate as to whether disrupting ACD by itself is sufficient to cause tumor initiation by mammalian stem and progenitor cells. We have previously shown that expression of multiple asymmetry regulators is disrupted in human glioma (Sugiarto et al. Cancer Cell; 2011; 20; 320-340). Here we address our hypothesis that ACD defects are crucial for tumorigenesis, by delineating the role of Lgl1 in tumor initiation and progression.
Using mouse neural stem cells (NSCs) isolated from genetically modified Lgl1lox/lox mice (Klezovitch et al. Genes Dev. 2004; 18; 559-71) we investigated the contribution of Lgl1 to various hallmarks of cancer in vitro and in vivo.
We demonstrate that loss of Lgl1 in mouse NSC and oligodendrocyte precursor cells disrupts ACD and increases the expression of early-stage precursor cell markers. Deletion of Lgl1 does not increase proliferation in vitro and deletion of Lgl1 alone does not transform cells transplanted into immunocompromised mice. However properties associated with a high-grade tumor, including invasiveness and stem cell marker expression, are increased when Lgl1 is deleted in the context of oncogenic EgfrVIII expression.
Increase in tumor invasiveness has previously been demonstrated to be associated with an increase in stem cell marker expression (Molina et al. Neoplasia. 2010; 12; 453-63). Our data suggest that loss of asymmetry in tumor precursor cells blocks differentiation and contributes to tumor progression by increasing stemness and hence invasiveness.
Citation Format: Robin G. Lerner, Loan Nguyen, Claudia Petritsch. Deletion of the asymmetry regulator Lgl1 contributes to tumor stemness and invasiveness. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4942. doi:10.1158/1538-7445.AM2013-4942
Abstract 4949: Combined immunochemotherapy for poor prognosis breast cancer.
Authors: Wasiuk Anna , Rugo Hope , Coussens Lisa M. 
Published: August 2014

Abstract
Using preclinical mouse models of luminal B-type mammary adenocarcinoma (e.g., MMTV-PyMT mice), we, and others have reported that immune microenvironments of mammary tumors can be therapeutically manipulated to enhance responses to chemotherapy (CTX)(1). To determine the degree to which other subtypes of mammary carcinoma are similarly susceptible to immune reprogramming, we evaluated transgenic models of basal-like/triple negative (TN), e.g., C3(1)-Tag (2), and erbB2-amplified, e.g., Erbb2f/f/MMTV-Cre (3), mammary adenocarcinoma, with clinical/preclinical agents acting to either deplete or re-educate tumor-associated macrophages, in combination with taxol-based CTX, e.g., paclitaxel, nab-paclitaxel or eribulin mesylate. Our preliminary studies reveal similar complexity of immune cells infiltrating basal-like/TN tumors as what we previously reported for luminal B-type tumors where macrophages, as opposed to monocytes, are the predominate myeloid cells present. Significantly, mammary tumors in C3(1)-TAg mice exhibit improved responses to taxol-based CTX when given in combination with either colony stimulating factor-1 (CSF1) or CSF1 receptor (CSF1R) antagonists, as compared to either therapy alone, with no evident liver (ALT, AST, ALP) or kidney (Cre, BUN, CPK) toxicity. These studies reveal a synergistic benefit of combination macrophage-targeting immunotherapy with standard-of-care CTX regardless of mammary tumor subtype or form of taxol-based CTX. Thus, macrophage-targeting immunotherapy remains as an encouraging new neo-adjuvant strategy for slowing primary tumors and minimizing early metastasis. It remains to be determined if similar results will be realized with this class of agents in the metastatic setting.
1. DeNardo D, et al. Cancer Discov 1, 54-67 (2011)
2. Maroulakou I, et al., PNAS 91, 11236-11240 (1994)
3. Andrechek E, et al. PNAS 97, 3444-3449 (2000)
Support provided from the NCI/NIH (R01CA15531), the DoD (W81XWH-11-1-0702) and the Susan G Komen Foundation (KG110560, KG111084).
Citation Format: Anna Wasiuk, Hope Rugo, Lisa M. Coussens. Combined immunochemotherapy for poor prognosis breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4949. doi:10.1158/1538-7445.AM2013-4949
Abstract 496: Inflammatory responses with infiltrating DC and functional cytotoxic T lymphocytes in the dermal vaccination sites of GVAX/ipilimumab treated prostate cancer patients.
Authors: Santegoets Saskia J. , van Mens Leonieke JJ , Beliën Jeroen AM , Stam Anita GM , Lougheed Sinead M. , Scheper Rik J. , Samiei Shabnam , Gall Helen , Jooss Karin , Cuillerot Jean-Marie , Sacks Natalie , Hege Kirsten , Gerritsen Winald R. , van den Eertwegh Alfons JM , de Gruijl Tanja D. 
Published: August 2014

Abstract
We have been studying the safety and clinical efficacy of the Prostate GVAX vaccine (consisting of two allogeneic GM-CSF secreting tumor cell lines: LNCaP and PC3) and the CTLA-4 blocking antibody ipilimumab in prostate cancer patients in a phase I/II dose escalation/expansion trial. To assess immune reactivity against the GVAX vaccine, immune infiltrate analysis of the vaccination sites was performed. Punch biopsies of the vaccination site were taken 48 hours after the 1st, 5th, and 11th injections and analyzed by immunohistochemical staining. Injection of the GVAX vaccine evoked striking local reactions that were characterized by local erythema, induration and swelling in all patients. Analysis of the vaccination site biopsies revealed that the GVAX/ipilimumab combination resulted in an inflammatory response in the skin with intradermal infiltrates of CD1a+ dendritic cells (DC), DC-SIGN+/CD68+ immature DC/macrophages, CD14+ monocyte-like cells, eosinophils, and of CD4+, CD8+, and Granzyme-B+ T lymphocytes. Strikingly, CD56+ NK cells were completely absent. The inflammatory response significantly increased over the course of treatment and resulted in accelerated clearance of the vaccine in vivo. Moreover, analysis revealed that the PC3 vaccine was more immunogenic, and induced a more potent anti-vaccine T cell response. The latter was confirmed in an in vitro cytotoxicity assay. Upon multiple vaccinations T cell reactivity to PC3 was significantly enhanced in the PC3 but not in the LNCaP vaccination sites, whereas reactivity to LNCaP was not enhanced in either vaccination site. We conclude that the GVAX/ipilimumab combination elicits a local immune infiltrate that increases over time, consistent with an induced CD8+ effector T cell mediated cytolytic response, only in vaccination sites of the PC3 component of the vaccine.
Citation Format: Saskia J. Santegoets, Leonieke JJ van Mens, Jeroen AM Beliën, Anita GM Stam, Sinead M. Lougheed, Rik J. Scheper, Shabnam Samiei, Helen Gall, Karin Jooss, Jean-Marie Cuillerot, Natalie Sacks, Kirsten Hege, Winald R. Gerritsen, Alfons JM van den Eertwegh, Tanja D. de Gruijl. Inflammatory responses with infiltrating DC and functional cytotoxic T lymphocytes in the dermal vaccination sites of GVAX/ipilimumab treated prostate cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 496. doi:10.1158/1538-7445.AM2013-496
Abstract 5001: Cachexia induced different tumor microenvironment.
Authors: Matsuyama Tatsuzo 
Published: August 2014

Abstract
Back ground and aim
Cancer cachexia affects up to 80% of patients with advanced cancers and accounts for nearly 30% of cancer-related deaths.Cachexia is pointed out of loss of fat mass, wasting of skeletal muscle, and cardiac atrophy. The mechanism by which the degree of cachexia is induced by the different local cancer environment has not been studied. In this study, we investigated the mechanism of cachexia in the different local tcarcinoma such as between subcutaneous tumor model and intraperitoneal tumor model.
Materials and Methods
Cachexia was induced by subcutaneous grafting and intraperitoneal administration using colon cancer cells, (colon 26cells 1 × 10 ˆ 6/ 100μL each) in7-week-old BALB/c mice. Two weeks after the tumor-bearing, we measured adipose tissue (around epididymis), gastrocnemius muscle, heart, and cytokines in serum.
Result
The body weight, heart, fat, muscle weight of each mice was decreased gradually as of significant difference in subcutaneous tumor model, and intraperitoneal tumor model compared with normal mice . We have a significant difference in IL-1a, IL-4, IL-6, IL-9, IL-10, IL-12 (p40), IL-12 (p70), IL-13, G-CSF, IFN-γ, KC, MCP-1, MIP I-1a in the serum cytokine of tumor models compared with normal models. IL-12(p40), IL-13, G-CSF, KC has significant differences in subcutaneous tumor model compared with intraperitoneal tumor model.
Conclusion
In addition to the skeletal muscle and fat, in the state of cachexia it has caused in smooth muscle. And these change of cachexia is induced by not only one cytokine but several cytokines. Other important result is that cachexia is induced different degree by tumor origin.
Citation Format: Tatsuzo Matsuyama. Cachexia induced different tumor microenvironment. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5001. doi:10.1158/1538-7445.AM2013-5001
Abstract 5005: Deletion of bone morphogenetic protein receptor 1A impairs mammary gland development and tumor formation.
Authors: Owens Philip , Bobbitt Charli R. , Pickup Michael W. , Gorska Agnieszka E. , Novitskiy Sergey V. , Moses Harold L. 
Published: August 2014

Abstract
Bone Morphogenetic Proteins (BMPs) are secreted cytokines/growth factors belonging to the Transforming Growth Factor β (TGFβ) superfamily. BMP ligands have recently been shown to be overexpressed in human breast cancers. Normal breast and cancers display active BMP signaling as indicated by phosphorylated Smads 1, 5 and 8. BMP signaling is a known morphogen, responsible for differentiation of many cell types. This led us to hypothesize that BMP signaling may be required for development of the mammary gland and tumors. We first utilized the mammary epithelial specific Cre recombinase driven by the MMTV promoter to remove conditionally floxed BMPR1a alleles. We found that mice lacking BMPR1a (cKO) had significant reduction in epithelial branching morphogenesis within the mammary gland. We further analyzed BMPR1a loss in lactating mice using WAP promoter driven Cre, which demonstrated a loss of milk production. We next combined the MMTV.PyVmT oncogene with mice lacking BMPR1a and found this deletion resulted in delayed tumor onset and extended survival significantly (p-value &lt;.001). Furthering these studies, we investigated the morphology of BMPR1a deleted tumors and found a striking loss of luminal characteristics combined with a stromal desmoplasia. Immunofluorescence staining revealed that cKO tumors co-expressed cytokeratins and mesenchymal cell markers such as Vimentin. This indicated that epithelial-to-mesenchymal (EMT) like changes were occurring upon BMPR1a deletion. We performed a DNA microarray on these tumors and found unique changes, which supported a loss of mammary gland differentiation and resulted in EMT-like activation. We next examined human breast tumor cell lines that previously reported the molecular signature response to BMP stimulation and compared them to primary human mammary epithelial cells (HMEC). Comparing signatures, we found that BMP4 stimulation induced unique genes in HMECs compared to tumor cells. Interestingly, transcriptional targets that were absent from tumors and found in normal HMECs included differentiation related genes. These results suggest that BMP signaling is critically deregulated in tumors. In conclusion, we found that loss of the BMP pathway restricts mammary gland development and impairs tumor formation and progression.
Citation Format: Philip Owens, Charli R. Bobbitt, Michael W. Pickup, Agnieszka E. Gorska, Sergey V. Novitskiy, Harold L. Moses. Deletion of bone morphogenetic protein receptor 1A impairs mammary gland development and tumor formation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5005. doi:10.1158/1538-7445.AM2013-5005
Abstract 5010: Characterization of a novel cell type in human renal proximal tubules with connection to renal cell carcinoma development.
Authors: Hansson Jennifer , Hultenby Kjell , Cramnert Catharina , Lindgren David , Axelson Håkan , Johansson Martin E. 
Published: August 2014

Abstract
The proximal tubular segments of the kidney are extremely energy demanding, rendering this epithelium exceptionally sensitive to ischemic insults. Acute renal injury is a potentially life threatening condition, where the tubular cells detach and die. However, the tubules of injured kidneys have a substantial regenerative ability, and epithelial continuity, can with proper supportive care be restored. The cellular source of regeneration has been debated and until now the proximal tubules has been considered a completely homogenous cellular epithelium.
Using an assay based on aldehyde dehydrogenase (ALDH) activity followed by FACS, we have recently discovered a cell with progenitor cell characteristics scattered within the proximal tubules of the kidney. These novel proximal tubule rare cells (PTRCs) expressed stem cell markers CD133 and CD24, as well as intermediate filaments not normally seen in PTs. The gene expression profile of these cells shows a striking resemblance to that of papillary renal cell carcinoma (pRCC) and the gene signatures are also associated with a worse prognosis in clear cell renal carcinoma. Additionally, cells positive for PTRC-markers were seen in regenerating tubules after acute kidney injury. We have characterized these cells further at an ultra structural level, using electron microscopy. The cells were small, flask shaped and had a more densely packed chromatin pattern and drastically fewer mitochondria than the surrounding proximal tubular cells, indicating a different metabolic state. We suggest that these cells, in contrast to the surrounding highly oxygen dependent proximal tubular cells, constitute renal reserve cell pool capable of surviving ischemic renal injury with a capacity to spearhead subsequent tubular repopulation. We suggest that the increased probability for survival of these cells is due to their low mitochondrial content, structural robustness and anti-apoptotic signaling. Also, due to the considerable transcriptional similarities between pRCC, renal adenomas and the PTRCs we hypothesize that pRCC may arise through multistep oncogenic transformation of PTRCs.
Citation Format: Jennifer Hansson, Kjell Hultenby, Catharina Cramnert, David Lindgren, Håkan Axelson, Martin E. Johansson. Characterization of a novel cell type in human renal proximal tubules with connection to renal cell carcinoma development. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5010. doi:10.1158/1538-7445.AM2013-5010
Abstract 5016: The human sub-ependymal zone harbors glioblastoma precursors and represents a distinct therapeutic target.
Authors: Piccirillo Sara Grazia Maria , Spiteri Inma , Sottoriva Andrea , Touloumis Anestis , Ber Suzan , Price Stephen J. , Heywood Richard , Francis Nicola-Jane , Collins Vincent P. , Venkitaraman Ashok R. , Curtis Christina , Marioni John C. , Tavare’ Simon , Watts Colin 
Published: August 2014

Abstract
Glioblastoma (GB), the most common and aggressive adult brain tumor, is characterized by phenotypic diversity and ultimately treatment failure. Using fluorescence-guided sampling we integrated copy number aberration, gene expression and molecular clock data to show that the sub-ependymal zone (SEZ) contains precursor cells of the corresponding mass. The genetically distinct tumor margin contains non self-renewing cells that retain the potential to regenerate the tumor. Functional assays confirmed that SEZ and marginal disease were less clinically aggressive compared to the mass compartment in the same tumor. However, resistance to supra-maximal chemotherapy doses and differential patterns of drug response were observed between compartments. These data provide novel insights into the basis of clinical diversity, poor treatment response and emergence of resistant disease in GB patients.
Citation Format: Sara Grazia Maria Piccirillo, Inma Spiteri, Andrea Sottoriva, Anestis Touloumis, Suzan Ber, Stephen J. Price, Richard Heywood, Nicola-Jane Francis, Vincent P. Collins, Ashok R. Venkitaraman, Christina Curtis, John C. Marioni, Simon Tavare’, Colin Watts. The human sub-ependymal zone harbors glioblastoma precursors and represents a distinct therapeutic target. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5016. doi:10.1158/1538-7445.AM2013-5016