bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4630: Feedback dependent suppression of mitogenic signaling and its effect on RAF inhibition in BRAFV600E melanomas.
Authors: Lito Piro , Pratilas Christine , Joseph Eric , Tadi Madhavi , Halilovic Ensar , Zubrowski Matthew , Huang Alan , de Stanchina Elisa , Chandarlapaty Sarat , Poulikakos Poulikos , Rosen Neal 
Published: August 2014

Abstract
RAF inhibitors have remarkable activity in melanomas harboring BRAFV600E mutations. We previously found that active Ras induces RAF dimers in tumors with wild-type RAF, and, that RAF inhibitors transactivate these dimers. Because BRAFV600E melanomas have enhanced ERK signaling, they are hypothesized to have feedback-mediated suppression of Ras in order to maintain monomeric and inhibitor-sensitive BRAFV600E. To test this hypothesis we evaluated the response of these tumors to RAF inhibitors over time. We found that in the treatment-naive state, BRAFV600E melanomas had suppressed RTK signaling and maintained a low level of Ras-GTP. This occurred through a multifactorial negative feedback process driven by active ERK. In this baseline state, BRAFV600E was sensitive to RAF inhibitors. After treatment with RAF inhibitors, however, inhibition of ERK signaling lead to loss of feedback, a process that restored signaling from RTKs and resulted in Ras activation. In turn, this diminished the effect of RAF inhibitors and lead to a partial, but sustained, reactivation of ERK signaling. In this post-treatment state, ERK signaling was insensitive to RAF inhibitors but sensitive to MEK inhibitors. Targeting the regulatory components of this new steady state, either through co-administration of a MEK inhibitor or a RTK inhibitor along with a RAF inhibitor resulted in improved antitumor activity. These results highlight the need to understand the adaptive response to ERK pathway inhibition in order to design better combinatorial therapies and achieve maximal antitumor effects.
Citation Format: Piro Lito, Christine Pratilas, Eric Joseph, Madhavi Tadi, Ensar Halilovic, Matthew Zubrowski, Alan Huang, Elisa de Stanchina, Sarat Chandarlapaty, Poulikos Poulikakos, Neal Rosen. Feedback dependent suppression of mitogenic signaling and its effect on RAF inhibition in BRAFV600E melanomas. [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 4630. doi:10.1158/1538-7445.AM2013-4630
Abstract 4668: Antitumor efficacy of AZD1480 in head and neck squamous cell carcinoma.
Authors: Sen Malabika , Black John , Wheeler Sarah , Freilino Maria L. , Joyce Sonali , Lui Vivian , Zeng Yan , Marshall Korey , Grandis Jennifer R. 
Published: August 2014

Abstract
Aberrant activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway has been implicated in cancer cell proliferation and survival. AZD1480, a pharmacologic inhibitor of JAK2, has been tested in several cancer models including glioblastoma, lung, renal, prostate, breast, and ovarian cancer. However JAK inhibitors, including AZD1480 has not been evaluated in head and neck squamous cell cancer (HNSCC). In the present study, the in vitro and in vivo efficacy of AZD1480 was evaluated in HNSCC preclinical models. AZD1480 decreased HNSCC proliferation in cell lines with varying levels of pJAK2 and pSTAT3 with an IC50 ranging from 0.9μM - 4μM. Further evaluation demonstrated downmodulation of pJAK2 and pSTAT3 in HNSCC cell lines by AZD1480. Furthermore, in vivo antitumor efficacy of AZD1480 was tested in heterotopic xenograft tumor models derived from 2 HNSCC patient tumors. AZD1480 at a dose of 30mg/kg, was given twice daily via oral gavage and compared with vehicle (0.5% Hypromellose) control. Tumors treated with AZD1480 exhibited significant growth inhibition relative to the tumors treated with vehicle (p=0.0037). In addition, significant decrease in pSTAT3Tyr705 expression was observed in both the patient tumors treated with AZD1480 compared to vehicle alone indicating that AZD1480 targets pSTAT3 and may be considered for study in the treatment of HNSCC patients.
Citation Format: Malabika Sen, John Black, Sarah Wheeler, Maria L. Freilino, Sonali Joyce, Vivian Lui, Yan Zeng, Korey Marshall, Jennifer R. Grandis. Antitumor efficacy of AZD1480 in head and neck squamous cell carcinoma. [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 4668. doi:10.1158/1538-7445.AM2013-4668
Abstract 468: Phenotyping TILs in situ: Automated enumeration of intra- and extra-follicular Foxp3+ regulatory T cells in follicular lymphoma.
Authors: Mansfield James , Nelson Lilli , van der Loos Chris , Byers Richard 
Published: August 2014

Abstract
Background. In many cancers, tumor-infiltrating lymphocytes (TILs) indicate levels of tumor immunogenicity and are a strong predictor of survival. In particular, increased levels of regulatory T cells (Tregs) are associated with poorer prognosis in some cancers. An understanding of the phenotype and spatial distribution of TILs in situ within tumor regions would be advantageous. However, visual TIL assessment cannot easily determine the type of lymphocyte in situ and multimarker quantitation is difficult with standard methods. Here we present a multi-marker, computer-aided event-counting method for determining the phenotypes of lymphocytes in follicular lymphoma sections using a multispectral imaging (MSI) and automated tissue segmentation and counting approach.
Design. A single section of a tissue microarray containing 70 follicular lymphoma cores from [42 male, 28 female, 17 alive and 53 dead at the end of followup, survival range 2-171 months (median 55 months)] was stained for CD3, Foxp3 and hematoxylin. Each core was imaged using MSI and the individual staining of each marker separated from each other using spectral unmixing. The images were analyzed using software which had been trained to recognize the follicular areas based on the tissue morphology. Then the Foxp3 status of each CD3+ TIL was then determined and the number of each Treg (Foxp3+ T cell) counted for both the intra- and extra-follicular tissue compartments.
Results. Results indicate that machine-learning software can be trained to accurately recognize follicular and non-follicular regions within each core. MSI enabled the accurate quantitation of two immunostains in the sample without crosstalk. The number of Tregs were determined for each core and ranged from 0 to 453 per core (median 58, stddev 97.5).
Conclusion. Understanding the number and location (intra- and extra-follicular) of Tregs is an assay with potentially important clinical prognostic implications. Thus study shows that an automated method for counting Tregs can be developed for follicular lymphoma. This multimarker phenotyping and counting approach shows the potential for broad applicability in the enumeration of a wide range of specifically phenotyped TILs in situ in many solid tumors.
Citation Format: James Mansfield, Lilli Nelson, Chris van der Loos, Richard Byers. Phenotyping TILs in situ: Automated enumeration of intra- and extra-follicular Foxp3+ regulatory T cells in follicular lymphoma. [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 468. doi:10.1158/1538-7445.AM2013-468
Abstract 4714: Vemurafenib reverses immunosuppression by myeloid derived suppressor cells.
Authors: Schilling Bastian , Sucker Antje , Griewank Klaus , Zhao Fang , Weide Benjamin , Görgens Andre , Giebel Bernd , Schadendorf Dirk , Paschen Annette 
Published: August 2014

Abstract
Purpose: To evaluate the impact of Vemurafenib on myeloid derived suppressor cell (MDSC) populations in patients with advanced melanoma.
Experimental Design: Ex vivo MDSCs were obtained from PBMCs of late stage melanoma patients treated with Vemurafenib as well as healthy controls. The frequency and phenotype of MDSCs was determined by flow cytometry. MDSC populations were characterized for their suppressive function on autologous T cells in CFSE proliferation assays. Additionally, conditioned medium of a melanoma cell line treated with Vemurafenib or not was studied for its effect on MDSCs in vitro.
Results: In comparison to healthy donors, patient PBMCs showed an increased frequency of CD14+HLA-DR−/low monocytic MDSCs (moMDSCs) and of a previously unrecognized population of CD14−CD66b+Arginase1+ granulocytic MDSCs (grMDSCs). In vitro, both populations suppressed autologous T-cell proliferation. Vemurafenib treatment of melanoma patients reduced the frequency of both moMDSCs and grMDSCs. Accordingly, conditioned medium from Vemurafenib treated melanoma cells was less active in inducing moMDSCs in vitro.
Conclusion: Patients with advanced melanoma show increased levels of moMDSCs, as well as a population of CD14−CD66b+Arginase1+ grMDSCs. Both MDSCs are distinct populations capable of suppressing autologous T-cell responses independently of each other. In vitro as well as in vivo, Vemurafenib inhibits the generation of human moMDSCs. Thus, Vemurafenib decreases immunosuppression in patients with advanced melanoma, indicating its potential as a part of future immunotherapies.
Citation Format: Bastian Schilling, Antje Sucker, Klaus Griewank, Fang Zhao, Benjamin Weide, Andre Görgens, Bernd Giebel, Dirk Schadendorf, Annette Paschen. Vemurafenib reverses immunosuppression by myeloid derived suppressor 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 4714. doi:10.1158/1538-7445.AM2013-4714
Abstract 4730: The double bromodomain protein Brd2 controls B cell expansion and mitogenesis.
Authors: Belkina Anna C. , Blanton Wanda P. , Lombardi Frank L. , Denis Gerald V. 
Published: August 2014

Abstract
Background: Bromodomain-containing coregulators of transcription have been identified recently as new epigenetic targets to treat a variety of hematologic malignancies, including acute myeloid leukemias. However, the bromodomain mechanisms that couple histone acetylation to transcription in lymphopoiesis, and that govern mature lymphocyte responsiveness to growth signals, are only partly understood. Brd2 is a transcriptional co-regulator that contains dual Bromodomains and an ExtraTerminal domain (defining the BET family) that couples chromatin modification to cell cycle progression. We previously reported the first functional characterization of a BET protein as an effector of mammalian mitogenic signal transduction: Eμ-Brd2 transgenic mice develop an ‘activated B cell’ type of diffuse large B cell lymphoma. There have been no other animal models reported for genetic or lentiviral expression of BET proteins, which hampers testing of novel anticancer drugs such as JQ1 and its derivatives.
Methods: Here we use Brd2 lentivirus transduction of hematopoietic stem cells and reconstitution of lethally irradiated recipient mice to examine the function of Brd2 in hematopoiesis in the bone marrow and mitogenesis in the periphery.
Results: Three-fold over-expression of Brd2 in hematopoietic stem cells selectively leads to a doubling of the B cell compartment and increases mature B cell mitogenic responsiveness ex vivo. Knockdown of Brd2 by shRNA totally ablates hematopoietic lineages, likely by inhibiting the lineage-committed progenitor expansion through down-regulation of cyclin A, which reinforces results from Eμ-Brd2 transgenic mice. The novel small molecule BET inhibitor JQ1 reduces B cell mitogenesis by about 60% in parallel experiments, but this effect likely extends to other related BET family members and lacks Brd2 specificity.
Conclusion/Significance: The Brd2 pathway integrates lymphopoiesis, leukemogenesis and normal mitogenesis. Targeting this pathway with therapeutic drugs may therefore confer multiple, diverse benefits in the treatment of hematologic malignancy, B cell mediated disease and likely inflammation.
Citation Format: Anna C. Belkina, Wanda P. Blanton, Frank L. Lombardi, Gerald V. Denis. The double bromodomain protein Brd2 controls B cell expansion and mitogenesis. [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 4730. doi:10.1158/1538-7445.AM2013-4730
Abstract 4733: Novel therapeutic and diagnostic antibodies against KIR3DL2, a unique tumor antigen overexpressed on subtypes of T Cell Lymphomas .
Authors: Viaud Nicolas , Granier Nathalie , Zerbib Stephanie , Dujardin Arnaud , Bonnafous Cecile , Blery Mathieu , Paturel Carine , Rossi Benjamin , Marie-Cardine Anne , Bensussan Armand , Bagot Martine , Sicard Helene 
Published: August 2014

Abstract
KIR3DL2 belongs to the killer immunoglobulin (Ig)-like receptors (KIRs) family and is composed of three extracellular Ig-like domains. KIR3DL2 is naturally expressed on some NK cells and minor subpopulations of CD8+ and CD4+ T cells. Physiologically, KIRD3L2 is an inhibitory receptor for human leukocyte antigen (HLA) class I molecules regulating NK cell activation. Remarkably, KIR3DL2 is also aberrantly overexpressed on several subtypes of T lymphomas/leukemias, such as Sezary Syndrome, transformed Mycosis Fungoides and HTLV1+ Adult T Cell Leukemia, making it a unique therapeutic target in cancer. We have generated a series of anti-KIR3DL2 monoclonal antibodies (mAbs) binding selectively to KIR3DL2, spanning epitopes on each of the three Ig domains. Their efficacy was evaluated in vitro and in vivo against KIR3DL2-expressing tumors and Sezary cell lines as disease model. Various modes of action, such as complement-dependent cytotoxicity (CDC) and antibody-dependent cell cytotoxicity (ADCC) were found involved in their anti-tumor activity. In parallel, anti-KIR3DL2 mAbs were also developed as unique and sensitive tools for the detection by immunohistochemistry of KIR3DL2 on tumor biopsies. Owing to the promising efficacy profile of our anti-KIR3DL2 mAb candidates and to the highly restricted expression pattern of the target on some T leukemia/lymphoma cells, an antibody-based therapy targeting KIR3DL2 stands as a potentially unequalled strategy in several orphan diseases with critical unmet medical need.
Citation Format: Nicolas Viaud, Nathalie Granier, Stephanie Zerbib, Arnaud Dujardin, Cecile Bonnafous, Mathieu Blery, Carine Paturel, Benjamin Rossi, Anne Marie-Cardine, Armand Bensussan, Martine Bagot, Helene Sicard. Novel therapeutic and diagnostic antibodies against KIR3DL2, a unique tumor antigen overexpressed on subtypes of T Cell Lymphomas . [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 4733. doi:10.1158/1538-7445.AM2013-4733
Abstract 474: Complete regression and long-term specific protective immune responses obtained in rodent tumor models after intratumoral treatment with LTX-315 .
Authors: Rekdal Øystein , Kvalheim Gunnar , Line Pål-Dag , Rolstad Bent , Camilio Ketil , Berge Gerd , Nestvold Janne , Wang Mengyu , Shi Jihua , Areffard Ali , Sveinbjørnsson Baldur 
Published: August 2014

Abstract
LTX-315 is a de novo designed peptide derived from a naturally occurring host defence peptide. LTX-315 has the potential to induce long-term specific protective immune responses by stimulating immune cells, inducing tumor cell lysis with subsequent release of danger signals (e.g. HMGB1) and tumor associated antigens (TAA`s). A complete tumor regression has been obtained in several syngenic rodent tumor models by intratumoral (i.t.) injection with LTX-315. The effect was T- cell- dependent since the intervention was inefficient in immune-deficient animals. Studies on treated tumor tissue confirmed infiltration of immune cells and a switch in the cytokine profile towards a Th1 response. Successfully treated animals were protected against re-challenge with the tumor cell type treated, but not against other types of tumor cells. Moreover, tumor resistance could be adoptively transferred by spleen cells from LTX-315-treated animals. The resistance was abrogated by depletion of T- lymphocytes. Additional studies also indicate that LTX-315`s potential to locally activate the innate immune system by the immunogenic stressing of cells, in addition to the subsequent release of endogenous adjuvants and natural danger signals, provides a strong rationale for using LTX-315 as an adjuvant for vaccines based on tumor-associated antigens (TAA) and for combination with other types of immune–modulatory therapies. LTX-315 is currently being tested in a Phase I dose escalation clinical study and may represents a novel strategy for personalized in situ vaccination against cancer.
Citation Format: Øystein Rekdal, Gunnar Kvalheim, Pål-Dag Line, Bent Rolstad, Ketil Camilio, Gerd Berge, Janne Nestvold, Mengyu Wang, Jihua Shi, Ali Areffard, Baldur Sveinbjørnsson. Complete regression and long-term specific protective immune responses obtained in rodent tumor models after intratumoral treatment with LTX-315 . [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 474. doi:10.1158/1538-7445.AM2013-474
Abstract 4754: A humanized, high affinity anti-CCR4 antibody for immunotherapy of cutaneous T cell lymphoma and characterization on T cell function.
Authors: Chang DeKuan , Han Thomas , Clark Rachael A. , Zhu Quan , Kupper Thomas S. , Marasco Wayne A. 
Published: August 2014

Abstract
Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of neoplastic disorders characterized by clonally derived and skin-homing malignant T cells that express high level of chemokine receptor CCR4, which is associated with their skin-homing capacity. CCR4 is also highly expressed on T-regulatory cells (Tregs) that can migrate to several different types of chemotactic ligand CCL17- and CCL22-secreting tumors to facilitate tumor cell evasion from immune surveillance. Thus, its high-level expression on CTCL cells and Tregs makes CCR4 a potential ideal target for antibody-based immunotherapy for CTCL and other types of solid tumors. Here, a humanized and affinity optimized anti-CCR4 monoclonal antibody (mAb), mAb2-3, was evaluated. In vitro mechanism studies demonstrated that the potent in vivo anti-tumor effects of this humanized anti-CCR4 mAb could be attributed to antibody dependent cellular cytotoxicity (ADCC), complement mediated cytotoxicity (CDC) and antibody dependent cellular phagocytosis (ADCP). In a mouse CTCL tumor model, anti-CCR4 mAb exhibited an antitumor effect by mediating cellular cytotoxicity through CDC and ADCC via FcγRIIIa expressed murine neutrophils and human nature killer (NK) cells. Moreover, this anti-CCR4 mAb also effectively inhibits chemotaxis of CD4+CD25high Tregs via CCL22 and abrogates Treg suppression activity in vitro by restoring the proliferation of CD4+CD25− effector T cells (Teffs). Taken together, this high-affinity humanized mAb2-3 with potent antitumor effect and a broad range of mechanisms of action on immunity may provide a novel immunotherapy for CTCL and other solid tumors.
Citation Format: DeKuan Chang, Thomas Han, Rachael A. Clark, Quan Zhu, Thomas S. Kupper, Wayne A. Marasco. A humanized, high affinity anti-CCR4 antibody for immunotherapy of cutaneous T cell lymphoma and characterization on T cell function. [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 4754. doi:10.1158/1538-7445.AM2013-4754
Abstract 4781: EBV infection of mammary epithelial cells promotes malignant transformation.
Authors: Hu Hai , Wulf Gerburg , Juvekar Ashish , Dittmer Dirk P , Fingeroth Joyce 
Published: August 2014

Abstract
Whether the human tumor virus, Epstein-Barr virus (EBV) promotes breast cancers remains controversial and a potential mechanism has remained elusive. Herein we show EBV binds mammary epithelial cells (MECs) via CD21 and upon establishing a persistent infection triggers expansion of MEC progenitor cells (CD24low/CD44high), increases mammosphere formation, blocks differentiation and in conjunction with activated Ras accelerates formation of breast cancers in NOD/SCID mice. Similar to nasopharyngeal carcinoma (NPC), breast cancers derived from EBV-infected and Ras-transduced MECs exhibited a latency II pattern infection (LMP1 high, LMP2A positive) with a significant number of lytic transcripts. A human gene expression signature for “EBVness” was derived from these tumors and application to publicly available data sets of breast cancer patients showed “EBVness” was - associated with high grade (40 vs 13.5%) estrogen-receptor (ER)-negative status (31.8 vs. 10.5%), p53 mutation (37.5 vs 14.5%) and poor survival.
Citation Format: Hai Hu, Gerburg Wulf, Ashish Juvekar, Dirk P Dittmer, Joyce Fingeroth. EBV infection of mammary epithelial cells promotes malignant transformation. [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 4781. doi:10.1158/1538-7445.AM2013-4781
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 4817: Dietary fiber intake reduces colorectal polyp risk in cigarette smokers.
Authors: Fu Zhenming , Shrubsole Martha J. , Zheng Wei 
Published: August 2014

Abstract
BACKGROUND
Results regarding the association of dietary fiber intake with colorectal tumor risk remain inconsistent. The association may differ between smokers and nonsmokers. We evaluated this hypothesis in a large colonoscopy-based case-control study.
METHODS
Dietary fiber intakes were estimated by a food frequency questionnaire designed to capture dietary intakes in the study population. Unconditional logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence limits (95% CLs) with adjustment for potential confounders. Analysis also was stratified by cigarette-smoking status and sex.
RESULTS
Overall, colorectal polyps (P-trend &lt; 0.001), including adenoma only (P-trend = 0.006), were associated inversely with high dietary fiber intake. When stratified by smoking status, this inverse association was only observed among tobacco smokers, but not among never smokers, (Pheterogeneity = 0.039) for either males or females and for all participants. The protective effect was observed only among smokers for high-risk adenomas (Pheterogeneity = 0.018) and low-risk adenomas, but not for never smokers. The protective effect was particularly strong for high-risk adenomas in smokers. Consuming more than 19.9 g/day of dietary fiber was associated with a 41-44% decreased risk for high-risk adenomas among smokers (P-trend &lt; 0.001).
CONCLUSIONS
Cigarette smoking may modify the association of dietary fiber intake and the risk of colorectal polyps, especially high-risk adenoma risk.
Citation Format: Zhenming Fu, Martha J. Shrubsole, Wei Zheng. Dietary fiber intake reduces colorectal polyp risk in cigarette smokers. [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 4817. doi:10.1158/1538-7445.AM2013-4817