bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-340: Mechanism of bevacizumab internalization and fate by brain endothelial cells .
Authors: Muller-Greven Gaelle M. , Carlin Cathleen , Gladson Candece L. 
Published: August 2014

Abstract
Antiangiogenic immunotherapy shows great promise for treatment of malignancies, including cancer. Bevacizumab is a humanized monoclonal antibody that inactivates vascular endothelial growth factor-A (VEGF-A), thereby inhibiting angiogenesis. It has received FDA approval for patients with recurrent glioblastoma (GBM); however, more than 30% of patients are non-responsive. The internalization and fate of bevacizumab in endothelial cells (ECs) may play a critical role in the response to therapy, i.e., bevacizumab may be degraded, recycled to the vessel lumen, or transcytosed to the sub-basal EC where tumor cell VEGF-A is found. We examined the internalization of bevacizumab by normal brain ECs in different conditions and found that internalization increased in a time-dependent manner (30 min - 24 hrs). Epidermal growth factor (EGF) stimulated internalization, suggesting bevacizumab enters the cells by an endocytic pathway that is induced by growth factors, such as macropinocytosis. Also, internalized bevacizumab was compartmentalized into vesicles that in part co-localized with the EGF receptor. Treatment with Amiloride (inhibitor of macropinocytosis) decreased the number of bevacizumab-containing vesicles per cell, suggesting macropinocytosis may be one mechanism of internalization. Treatment with Bafilomycin A1 (inhibitor of lysosomal acidification) caused accumulation of bevacizumab, suggesting one fate is lysosomal degradation. Ongoing experiments will determine the endocytic compartment(s) containing bevacizumab, its trafficking, and whether it is transcytosed across normal brain and tumor-associated ECs. Understanding the mechanism of internalization and trafficking of bevacizumab in brain ECs will positively impact the design and modification of monoclonal antibody therapy for GBM patients and for other cancers.
Citation Format: Gaelle M. Muller-Greven, Cathleen Carlin, Candece L. Gladson. Mechanism of bevacizumab internalization and fate by brain endothelial 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 LB-340. doi:10.1158/1538-7445.AM2013-LB-340
Abstract LB-342: Macrophage-secreted cytokines drive acinar-to-ductal metaplasia of the pancreas.
Authors: Liou Geou-yarh , Doeppler Heike , Storz Peter 
Published: August 2014

Abstract
In response to inflammation, pancreatic acinar cells can undergo acinar-to-ductal metaplasia (ADM), a reprogramming event that induces transdifferentiation to a duct-like phenotype and in the context of additional oncogenic stimulation, contributes to development of pancreatic cancer. The signalling mechanisms underlying pancreatitis-inducing ADM are largely undefined. Our results provide evidence that macrophages infiltrating the pancreas drive this transdifferentiation process. We identify the macrophage-secreted inflammatory cytokines RANTES and TNFα as mediators of such signaling. Both RANTES and TNFα induce ADM through activation of nuclear factor κ-B and its target genes involved in regulating survival, proliferation and degradation of extracellular matrix. In particular we identify matrix metalloproteinases (MMPs) as targets that drive ADM, and provide in vivo data suggesting that MMP inhibitors may be efficiently applied to block pancreatitis-induced ADM in therapy.
Citation Format: Geou-yarh Liou, Heike Doeppler, Peter Storz. Macrophage-secreted cytokines drive acinar-to-ductal metaplasia of the pancreas. [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 LB-342. doi:10.1158/1538-7445.AM2013-LB-342
Abstract LB-343: Host response to paclitaxel chemotherapy promotes metastasis via the secretion of VEGF-C by macrophages.
Authors: Gingis-Velitski Svetlana , Kaidar-Person Orit , Alishekevitz Dror , Bril Rotem , Fremder Ella , Shaked Yuval 
Published: August 2014

Abstract
Recent studies indicate that while chemotherapy can strongly restrict or reverse tumor growth, the response of the normal host tissue to the therapy can counteract tumor growth control by promoting the re-growth of residual tumor cells and the outgrowth of metastases. We sought for host factors promoting metastasis following paclitaxel (PTX) chemotherapy. The prolymphangiogenic growth factor, VEGF-C, was highly expressed in plasma of PTX-treated mice, and could induce migration, invasion, and tube formation of lymphatic vessels when compared to plasma from control mice. In both 4T1 breast and Lewis lung carcinomas we found an increased number of lymphatic vessels positioned at the center of the tumors from PTX-treated mice, in contrast to tumors from control mice, in which lymphatic vessels were positioned at the tumor periphery. Since VEGFR3 is the major receptor for VEGF-C-induced lymphangiogenesis, we evaluated the therapeutic effect of anti-VEGFR3 blocking antibody in combination with PTX. 4T1 bearing mice treated with PTX+anti-VEGFR3 exhibited a significant reduction in tumor re-growth and inhibition of metastasis which enhanced their overall survival, when compared to mice treated with PTX alone. However, no significant difference in survival of mice bearing 4T1 experimental metastasis in the lungs, was observed in any of the treatment groups, suggesting that VEGFR3 and VEGF-C promote tumor cell dissemination from treated tumors, but may not affect their seeding at metastatic sites. In addition, an abundant number of macrophages highly secreting VEGF-C were found to colonize 4T1 tumors from PTX-treated mice when compared to tumors from untreated mice. Similarly, breast carcinomas from cancer patients after neoadjuvant chemotherapy exhibited high expression of VEGF-C when compared to their pre-treated biopsies. Overall, our results suggest an additional role for macrophages in the tumor microenvironment, which in response to chemotherapy promote tumor re-growth and metastasis spread, a process which can be blocked by the disruption of VEGF-C/VEGF-R3 pathway.
Citation Format: Svetlana Gingis-Velitski, Orit Kaidar-Person, Dror Alishekevitz, Rotem Bril, Ella Fremder, Yuval Shaked. Host response to paclitaxel chemotherapy promotes metastasis via the secretion of VEGF-C by macrophages. [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 LB-343. doi:10.1158/1538-7445.AM2013-LB-343
Abstract LB-344: Vascular normalization as an emerging strategy to enhance cancer immunotherapy.
Authors: Huang Yuhui , Yuan Jianping , Righi Elda , Duda Dan G. , Fukumura Dai , Poznanasky Mark C. , Jain Rakesh K. 
Published: August 2014

Abstract
The recent approval of a prostate cancer vaccine has renewed hope for anti-cancer immunotherapies. However, the immunosuppressive tumor microenvironment may limit the effectiveness of current immunotherapies. Antiangiogenic agents have the potential to modulate the tumor microenvironment and improve immunotherapy, but they are often used at high doses in the clinic to prune tumor vessels and may paradoxically compromise various therapies. Here, we demonstrate that targeting tumor vasculature with lower “vascular normalizing” doses, but not high “anti-vascular/anti-angiogenic” doses of an anti-vascular endothelial growth factor receptor 2 (VEGFR2) antibody results in a more homogeneous distribution of functional tumor vessels. Furthermore, lower doses are superior to the high doses at polarizing tumor-associated macrophages from immune inhibitory M2-like towards immune stimulatory M1-like phenotype, and in facilitating CD4+ and CD8+ T cell tumor infiltration. Based on this mechanism, scheduling lower dose anti-VEGFR2 therapy with T cell activation induced by a whole cancer cell vaccine therapy enhanced anti-cancer efficacy in a CD8+ T cell-dependent manner in both immune tolerant and immunogenic murine breast cancer models. These findings indicate that vascular normalizing lower doses of anti-VEGFR2 antibody can reprogram the tumor microenvironment away from immunosuppression toward potentiation of cancer vaccine therapies. Given that the combinations of high doses of bevacizumab with chemotherapy have not improved overall survival of breast cancer patients, our study suggests a new strategy to more effectively use antiangiogenic agents in breast cancer with active immunotherapy and potentially other anti-cancer therapies.
Citation Format: Yuhui Huang, Jianping Yuan, Elda Righi, Dan G. Duda, Dai Fukumura, Mark C. Poznanasky, Rakesh K. Jain. Vascular normalization as an emerging strategy to enhance cancer immunotherapy. [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 LB-344. doi:10.1158/1538-7445.AM2013-LB-344
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract LB-36: JAK2/STAT5 inhibition circumvents resistance to PI3K/mTOR blockade: A rationale for co-targeting these pathways in metastatic breast cancer.
Authors: Britschgi Adrian , Andraos Rita , Brinkhaus Heike , Klebba Inna , Murakami Masato , Romanet Vincent , Müller Urs , Radimerski Thomas , Bentires-Alj Mohamed 
Published: August 2014

Abstract
Hyperactive PI3K/mTOR signaling is prevalent in the majority of human malignancies (1) and its inhibition exhibits potent antitumor activity in a wide spectrum of solid cancers. Unfortunately, single-agent targeted cancer therapy is usually short-lived and thwarted by different resistance mechanisms (2). Here, we report the discovery of a JAK2/STAT5-evoked positive feedback loop that causes adaptive resistance to dual PI3K/mTOR inhibition. Mechanistically, PI3K/mTOR inhibition increased IRS1-dependent activation of JAK2/STAT5 and secretion of IL-8 in several cell lines and primary triple-negative breast tumors. Genetic or pharmacological inhibition of JAK2 abrogated this vicious feedback loop. Combined PI3K/mTOR and JAK2 inhibition synergistically reduced cancer cell viability in vitro as well as tumor growth in vivo, and decreased tumor seeding and metastasis due to its impact on the IL-8 receptor CXCR1+ tumor-initiating subpopulation of cells. We further found that combined PI3K/mTOR and JAK2 inhibition increased event-free as a well as overall survival of tumor bearing animals. This study reveals a new link between growth factor signaling, JAK/STAT activation, cytokine secretion and metastasis. Our results provide a rationale for combined targeting of the PI3K/mTOR and JAK2/STAT5 pathways in triple-negative breast cancer, a particularly aggressive and currently incurable disease.
Citation Format: Adrian Britschgi, Rita Andraos, Heike Brinkhaus, Inna Klebba, Masato Murakami, Vincent Romanet, Urs Müller, Thomas Radimerski, Mohamed Bentires-Alj. JAK2/STAT5 inhibition circumvents resistance to PI3K/mTOR blockade: A rationale for co-targeting these pathways in metastatic 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 LB-36. doi:10.1158/1538-7445.AM2013-LB-36
Abstract LB-54: Identification of a RAF inhibitory auto-phosphorylation site.
Authors: Holderfield Matthew , Merritt Hanne , Lin Julie , Gao Zenhai , Stuart Darrin , McCormick Frank 
Published: August 2014

Abstract
Preclinical studies have demonstrated that BRAF wild-type cancer cells are not only refractory but paradoxically activate the MAPK pathway when treated with RAF inhibitors. Potentially through a related mechanism, multiple point mutations in the activation loop and Phosphate binding loop (P. loop) domains of BRAF have been characterized in human cancers, which often render BRAF catalytically impaired, yet stimulate phosphorylation of downstream targets in cells. However, the underlying biochemistry causing these phenomena has yet to be fully understood. In this study we investigate the biochemical mechanism of wild-type RAF activation in response to RAF inhibitor treatment and identify a novel auto-phosphorylation site within the well conserved BRAF/CRAF P. loop. Disruption of the auto-phosphorylation, either through pharmacologic or genetic alterations, results in activation of the MAPK pathway. This work offers new insight into RAF biochemistry by uncovering a previously unrecognized regulatory mechanism of RAF kinases that is bypassed by the BRAF oncoproteins.
Citation Format: Matthew Holderfield, Hanne Merritt, Julie Lin, Zenhai Gao, Darrin Stuart, Frank McCormick. Identification of a RAF inhibitory auto-phosphorylation site. [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 LB-54. doi:10.1158/1538-7445.AM2013-LB-54
Abstract LB-55: Comparing effects of individual Ras isoforms on cell signaling and growth.
Authors: Pitt Cameron L. , McCormick Frank 
Published: August 2014

Abstract
Though proteins in the Ras family signal primarily through identical effectors, each isoform displays unique preferential coupling to cancer types. Membrane localization following modification at the C-terminus is required for Ras activation and downstream signaling. This step provides an avenue for signaling diversity, as the C-terminus is the only site of significant sequence variability between Ras proteins. Differential post-transcriptional modifications at the C-terminus produce different patterns of membrane binding and trafficking between isoforms. Broken up into varied membrane domains, each isoform has unique combinatorial access to activators and repressors of signaling as well as downstream molecules in pathways critical to cancer initiation and tumor maintenance. Introducing individual Ras isoforms around endogenous levels to cells originally devoid of expression of all of the major Ras isoforms has allowed us to separate their effects on cell signaling and interrogate key differences. Expression of any of the four major Ras isoforms is sufficient to restore growth of "Rasless" cells. Our findings display that Ras isoforms are differentially activated by growth factor stimulation and act primarily through different pathways. Expression of N-Ras or K-Ras 4A alone promotes more rapid growth than H-Ras or K-Ras 4B expression alone, likely due to increased pro-apoptotic signaling from H-Ras and K-Ras 4B. H-Ras is uniquely activated by IGF-1 and insulin to signal through PI3K to pAKT. While the kinetics of MAPK activation in response to growth factors vary depending on the Ras isoform expressed, the amplitude of the response through pERK is greatest in N-Ras and K-Ras expressing cells. We are currently performing comparative expression analysis of the downstream components of these two major Ras effector pathways to begin to mechanistically explain the differences observed in signaling. We are also using mutants of the Ras isoforms at the sites that differentiate their processing to determine whether differences in localization due to protein modifications cause a shift in the PI3K/MAPK signaling balance and account for isoform-dependent differences in cells relying on Ras signaling for growth.
Citation Format: Cameron L. Pitt, Frank McCormick. Comparing effects of individual Ras isoforms on cell signaling and growth. [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 LB-55. doi:10.1158/1538-7445.AM2013-LB-55
Abstract LB-7: The high-risk subject screening of ESCC by iTRAQ-coupled 2D LC-MS/MS.
Authors: Li Xiu-Min 
Published: August 2014

Abstract
Esophageal squamous cell carcinoma (ESCC) remains the leading cause of cancer-related deaths in China and the prognosis is very poor, the 5-year survival rate for ESCC at late stage is only about 15%. The molecular mechanism of poor prognosis is not clear. This study was to determine the changes of proteins associated with poor survival using protein profiling, Five ml of peripheral blood was taken from each ESCC patient. All the patients were followed up for more than 5 years. Based on the survival time, the patients were divided into three groups, i.e. ≤3 years (n=10), 3-5 years (n=10) and ≥5 years (n=10). Serum protein profiles for different groups were determined by the iTRAQ-coupled LC-MS/MS technique. We found that overall, 3987 different peptide spectra were identified, of which 556 were non-redundant proteins. Interestingly, 54 proteins showed over-expressed, and Carbonic anhydrase 1&2;Angiotensinogen; Collectin-10; 22kDa protein were associated with poor prognosis; 50 proteins were down-expressed in ESCC, and Alpha-2-macroglobulin; Apolipoprotein D; Isoform 14 of Fibronectin; V2-7 protein; Adiponectin; Transthyretin were associated with poor prognosis. Of the identified proteins, some (such as alpha-2-macroglobulin; apolipoprotein D; angiotensinogen; carbonic anhydrase 1 &2) have been reported to be related with metastasis and recurrence of the tumor. Further verification to these proteins may shed light on identifying novel candidate protein biomarkers for high-risk subject screening for ESCC and for prediction of poor prognosis.
Citation Format: Xiu-Min Li. The high-risk subject screening of ESCC by iTRAQ-coupled 2D LC-MS/MS. [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 LB-7. doi:10.1158/1538-7445.AM2013-LB-7
Abstract LB-78: Detection of circulating cell-free DNA is enhanced by targeting short fragments: high concordance of the KRAS and BRAF mutation status from plasma analysis, with tumor-tissue analysis in colorectal cancer..
Authors: Mouliere Florent , Pang Dalong , Messaoudi Safia El , Pezet Denis , Mathonnet Muriel , Ychou Marc , Dritschilo Anatoly , Thierry Alain R. 
Published: August 2014

Abstract
We investigated size distributions of circulating cell-free DNA (ccfDNA) to determine its value as a potential theranostic tool. CcfDNA quantification by Q-PCR was optimal when amplifying target lengths between 60 and 100 bp. CcfDNA sizes were previously believed to be greater than the length of the DNA per nucleosome (~180 bp). Q-PCR analyses of plasma samples from xenografted mice and from colorectal cancer (CRC) patients showed that tumor derived ccfDNA exhibited specific profiles of ccfDNA sizes with significantly higher ccfDNA fragmentation than was observed in samples from healthy individuals. Atomic Force Microscopy analysis confirmed these observations and, for the first time, enables visual representation of ccfDNA molecules. CcfDNA from plasma of CRC patients exhibited a median size of 135 bp and 88% of ccfDNAs are less than 180 bp in size. Based on these observations, we developed a refined single-step Allele Specific Q-PCR based method (Intplex) with improved specificity and sensitivity for enabling single-copy detection of variant alleles to a sensitivity of ≥ 0.005% mutant to WT ratio. We performed a blinded prospective study to compare KRAS and BRAF mutation status data by analysis of tumor tissue of CRC patients by standard methods and of plasma DNA (n=79). CcfDNA analysis showed 100% specificity and sensitivity for the BRAF V600E mutation. For the six tested KRAS point mutations, the method exhibited 100% specificity and 87% sensitivity with a concordance value of 96%. Mutation load expressed as the proportion of mutant alleles in ccfDNA, was highly variable (0.03% to 69%, median, 10.9%; n=128) and was determined in the plasma of every patient at stage I, II, III and IV (100% success rate). Tumor-derived ccfDNA did not correspond to "a tiny fraction" as it has been previously stated and it is likely not derived mainly from stroma cells. CcfDNA analysis could replace advantageously tumor-section analysis for determining KRAS and BRAF mutation status and expand the scope of personalized medicine for cancer patients.
Citation Format: Florent Mouliere, Dalong Pang, Safia El Messaoudi, Denis Pezet, Muriel Mathonnet, Marc Ychou, Anatoly Dritschilo, Alain R. Thierry. Detection of circulating cell-free DNA is enhanced by targeting short fragments: high concordance of the KRAS and BRAF mutation status from plasma analysis, with tumor-tissue analysis in colorectal 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 LB-78. doi:10.1158/1538-7445.AM2013-LB-78
Abstract LB-93: Calculating the statistical significance of synergy in cancer drug combinations.
Authors: Sult Erin , Zhao Wei , Yang Harry , Hollingsworth Robert , Sachsenmeier Kris F. 
Published: August 2014

Abstract
Single agent treatment in cancer often results in drug resistance and limited survival. Multi-drug treatment may overcome resistance to monotherapies given the heterogeneous nature of tumors. This may result in improved survival, increased efficacy and lower toxicity. Bliss Independence and Loewes Additivity are widely accepted methods for evaluating synergy with drug combinations, however these applications typically lack statistical significance. We have developed a novel Response-Surface (RS) method that enables us to identify statistically significant synergy at a 95% confidence level. In this presentation, the RS method will be described, compared to traditional methods, and applied to dual-drug combinations across various cancer cell models.
Citation Format: Erin Sult, Wei Zhao, Harry Yang, Robert Hollingsworth, Kris F. Sachsenmeier. Calculating the statistical significance of synergy in cancer drug combinations. [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 LB-93. doi:10.1158/1538-7445.AM2013-LB-93