bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-401: The chemosensitizing properties of iniparib in combination with DNA-damaging agents in the MDA-MB-468(−) triple-negative breast cancer (TNBC) cell line
Authors: Ossovskaya Valeria , Lim Chang-Uk , Schools Gary , Kalurupalle Swathi , Roninson Igor B. , Broude Eugenia 
Published: August 2014

Abstract
BACKGROUND: Iniparib (BSI-201) has demonstrated promising efficacy and safety in the treatment of patients with metastatic triple-negative breast cancer (TNBC). The addition of iniparib to gemcitabine (G) and carboplatin (C) improved the clinical benefit rate from 34% to 56% (P = 0.01) and the overall response rate from 32% to 52% (P = 0.02) in a phase II clinical study (O'Shaughnessy et al. N Engl J Med. 2011).We investigated the chemosensitizing properties of iniparib with irinotecan (I) or ionizing radiation (IR).
METHODS: The chemosensitizing properties of a single dose of iniparib combined with I or IR were evaluated in TNBC MDA-MB-468 breast carcinoma cells. Cell proliferation was evaluated with FACS-based cell cycle analysis, including DNA staining and bromodeoxyuridine incorporation.
RESULTS: FACS analysis showed that in TNBC MDA-MB-468 breast carcinoma cells iniparib potentiated cell cycle arrest induced by I, with cells arrested in S and G2/M phases, or potentiated cell cycle arrest induced by IR, with cells arrested mostly in G2/M, at 72 hours after treatment (Table 1).
CONCLUSIONS: These data demonstrate the potentiation of the antiproliferative activity of I and IR by iniparib in TNBC MDA-MB-468 breast carcinoma cells. These data support investigation of iniparib in combination with these DNA-damaging agents in clinical studies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-401. doi:10.1158/1538-7445.AM2011-LB-401
Abstract 1172: Phase I study of histone deacetylase inhibitor belinostat in combination with warfarin in patients with solid tumors or hematological malignancies.
Authors: Agarwal Neeraj , Wade Mark L. , Batten Julia , Davidson Cynthia , Sun Show-Li , Sharma Sunil 
Published: August 2014

Abstract
Background: The family of Histone Deacetylase (HDAC) enzymes serves as important epigenetic regulators of gene expression through modulation of acetylation on important histone and non-histone proteins. Aberrant acetylation of histones can alter gene expression believed to be important in the tumorigenic process. Belinostat, a potent inhibitor of HDAC proteins has demonstrated anti tumor activity in animal models and in humans. The purpose of this study was to examine the pharmacokinetic and pharmacodynamic properties of warfarin in combination with belinostat and to evaluate the safety profile of belinostat with concomitant warfarin.
Methods: Eligible patients enrolled on the study received 5 mg PO warfarin 14 days prior to administration of belinostat. Belinostat was administered as an iv infusion, 1000mg/m2 over 30 minutes for 5 consecutive days every 21 days. On day 3, cycle 1 of belinostat treatment, a second dose of 5mg PO warfarin was administered 2 hours prior to belinostat. Pharmacokinetic blood samples were obtained during cycle 1 of the study to measure warfarin and belinostat metabolism. Toxicities were monitored regularly throughout treatment and response was monitored according to standard of care guidelines.
Results: 18 patients, with solid tumors or hematologic malignancies, treated with belinostat and warfarin were included in this analysis. Median age was 55 years (31-77). 11 (61%) patients were male and 7(39%) patients were female. The most common Grade 1 or 2, toxicities observed during the study were anemia (78%), fatigue (72%) and nausea (61%). The most frequent Grade 3 or 4 toxicities were nausea (11%) and hyperuricemia (11%). No Grade 3 or 4 thrombocytopenia or neutropenia were reported. No treatment related Grade 5 toxicities were reported. During cycle 1 no patient experienced treatment delays or discontinued study as result of treatment related toxicity.
Conclusion: Belinostat was generally well tolerated in patients with solid tumors or hematologic malignancies with the major toxicity being anemia, fatigue or nausea. Pharmacokinetic results will be presented at the conference.
Citation Format: Neeraj Agarwal, Mark L. Wade, Julia Batten, Cynthia Davidson, Show-Li Sun, Sunil Sharma. Phase I study of histone deacetylase inhibitor belinostat in combination with warfarin in patients with solid tumors or hematological malignancies. [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 1172. doi:10.1158/1538-7445.AM2013-1172
Abstract 1279: Serum biochemistry and microarray analysis of liver and colonic mucosa in LETO and diabetic OLETF rats treated with 20% caloric restriction and high-fat diet.
Authors: Izumi Keisuke , Takasu Chie , Takahashi Tetsuyuki , Uehara Hisanori 
Published: August 2014

Abstract
We showed recently that diabetic and mildly obese Otsuka Long-Evans Tokushima Fatty (OLETF) rats were more susceptible to azoxymethane-induced carcinogenesis than control Long-Evans Tokushima Otsuka (LETO) rats, and carcinogenesis was inhibited by 20% caloric restriction (CR) and enhanced by high-fat diet (HFD, control diet with 10% safflower oil). To elucidate the mechanism of cancer susceptibility, we performed serum biochemical analysis and microarray analysis of the liver and colonic mucosa. Male LETO and OLETF rats were given control diet, 20% CR diet or HFD for 5 weeks, and euthanized at 24 weeks of age (n=5, respectively). In both strains, blood glucose, serum triglyceride, total cholesterol, insulin and leptin levels decreased by 20% CR, and increased by HFD. Steatosis of hepatocytes in OLETF rats was ameliorated by 20% CR and enhanced by HFD. Microarray analysis of the liver showed that 20% CR up-regulated metallothionein 1A gene, and down-regulated heat shock 105kDa/110kDa protein 1 (Hsph1) and heat shock 70kDa protein 1B (Hspa1b) genes in both strains. There were no histological differences in the colonic mucosa in both strains and the effect of the dietary difference was not found. Microarray analysis of the colonic mucosa showed that 20% CR down-regulated Hsph1 and Hspa1b genes, and HFD up-regulated fatty acid binding protein 2 in both strains. These data suggest that hyperinsulinemia, hyperlipidemia and oxidative stress by overnutrition exert significant role in cancer susceptibility in OLETF rats.
Citation Format: Keisuke Izumi, Chie Takasu, Tetsuyuki Takahashi, Hisanori Uehara. Serum biochemistry and microarray analysis of liver and colonic mucosa in LETO and diabetic OLETF rats treated with 20% caloric restriction and high-fat diet. [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 1279. doi:10.1158/1538-7445.AM2013-1279
Abstract 1429: Role of monocyte chemotactic protein-1 (MCP-1) in the tumor microenvironment.
Authors: Kucheryavykh Lilia Y. , Rivera-Pagán Aixa F. , Rolón-Reyes Kimberleve , Skatchkov Serguey N. , Eaton Misty J. 
Published: August 2014

Abstract
Glioblastomas, the most malignant form of gliomas, harbor multiple cell types. In particular, microglial cells can contribute up to 30% of a brain tumor mass, and can promote glioma cell growth and dispersal. The purpose of the present study was to test the hypothesis that glioma cells recruit nearby microglia through an MCP-1-mediated mechanism and enhance their production of MCP-1 in the tumor microenvironment. We evaluated the role of MCP-1 on glioma cell proliferation and invasion. Consistent with previous studies in rat models (Platten et al., 2003), we found that U-87 and A-172 human glioma cells promote microglial migration towards the glioma environment using a modified Boyden chamber migration assay. Furthermore, this effect was decreased after immunoneutralization of MCP-1 released from glioma cells. Additionally, using an antibody array we found that U-87 or A-172 glioma cell conditioned medium stimulates a 7-10 fold increase of MCP-1 release by microglia by 24 hours. We next analyzed the consequences of elevated MCP-1 on the invasiveness and proliferation of glioma cells. Using standard invasion assays with or without microglia in a lower compartment, we demonstrated that microglia significantly increased invasion of glioma cells, but this effect was not blocked by MCP-1 immunoneutralization. This suggests that the stimulatory effect of microglia on glioma invasion was due to some other factor such as release of matrix metalloproteinases (MMPs). In contrast, microglia increased U-87 and A-172 glioma cell proliferation within 72 hours and MCP-1 immunoneutralization reversed this proliferative effect of microglia in both cell lines.
Based on these results, we propose that glioma cells release low levels of MCP-1 to recruit nearby microglia and enhance the production of MCP-1. This increased secretion of MCP-1 from microglial cells recruits more microglial cells into the tumor and stimulate glioma progression. A variety of substances released by microglia in tumor microenvironment, including cytokines, growth factors, proteases and extracellular matrix components could lead to increased proliferation and invasiveness of glioma cells.
Supported by G11 HD052352, G12 RR03035, 8G12MD007583-27, U54 NS039408 and by the UCC Pilot Project Program
Citation Format: Lilia Y. Kucheryavykh, Aixa F. Rivera-Pagán, Kimberleve Rolón-Reyes, Serguey N. Skatchkov, Misty J. Eaton. Role of monocyte chemotactic protein-1 (MCP-1) in the 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 1429. doi:10.1158/1538-7445.AM2013-1429
Abstract 1459: Detection of EpCAM negative circulating tumor cells in CellSearch waste.
Authors: van Dalum Guus , Lenferink Aufried T.M. , Terstappen Leon W.M.M. 
Published: August 2014

Abstract
Introduction: Circulating tumor cells (CTC) measured with the CellSearch system in patients with metastatic carcinomas are associated with poor survival. The CellSearch system uses immunomagnetic enrichment targeting the EpCAM antigen. A frequently raised question is what the frequency and significance is of CTC that do not express EpCAM within the CTC of the individual patient and between different patients. To investigate this, a device was constructed that collects the blood discarded by the CellSearch system and passes the blood through micro sieves with 5um pores to enrich for the larger CTC.
Methods: A sample collection device was attached to the waste line of the CellTracks Autoprep (AP). The blood discarded after immunomagnetic separation was detected in the waste line and collected into a separate 50ml conical tube for each patient sample. After collection, the blood was filtered through microfabricated silicon nitride filters with pore diameters of 5 micrometer (Aquamarijn, Zutphen, The Netherlands) with a pressure below 40mbar. To evaluate recovery on the filter the COLO320(median size 11μm), SKBR3(16μm) and T24(16μm) cell lines where used. To evaluate recovery from the AP waste the SKBR3(445000 EpCAM antigens) and T24(2167 EpCAM antigens) cell lines where used. 300 cells where spiked in 7.5ml of blood collected in CellSave tubes from healthy volunteers. All samples were processed the day after collection.
Results: The average recovery on filter from whole blood is 29% for COLO320 and ≥80% for SKBR3 and T24. The average recovery of the SKBR3 cell line with the CellSearch system is 91% and 5% are recovered from the AP waste using filtration. In contrast, the average recovery of T24 cell line with the CellSearch system is only 30% but 51% are recovered from the AP waste after filtration. The carryover between spiked and unspiked samples collected from the AP waste was &lt;1.3% of the spiked cells for unspiked samples with a mean of 0.9%.
Conclusions: We present a method and device that enables the identification and characterization of CTC not detected by the CellSearch system which allows a systematic evaluation of the clinical relevance of these CTC.
Citation Format: Guus van Dalum, Aufried T.M. Lenferink, Leon W.M.M. Terstappen. Detection of EpCAM negative circulating tumor cells in CellSearch waste. [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 1459. doi:10.1158/1538-7445.AM2013-1459
Abstract 1599: Radiosensitization of GBM by a novel peptidomimetic of the Second Mitochondria-derived Activator of Caspases (SMAC).
Authors: Cerna David , Carter Donna , Takebe Naoko , Coleman C. Norman , Ahmed Mansoor M. , Yoo Stephen 
Published: August 2014

Abstract
TL32711 is a novel small molecule peptidomimetic of the SMAC (Second Mitochondria-derived Activator of Caspases) that promotes caspase activation in the cytochrome c/Apaf-1/caspase-9 pathway. Normally SMAC is located in the mitochondria; however it is released into the cytosol when cells undergo apoptosis. Release into the cytosol and cleavage of SMAC promotes caspase-9 activation by binding to inhibitors of apoptosis proteins, IAPs. Removing the inhibitory activity of IAPs increases cells’ sensitivity to apoptotic stimuli and abrogates NF-κB survival signaling. Thus, by targeting and eliminating IAPs, SMAC mimetics re-activate death signals in cancer cells, inhibit resistance mechanisms and induce tumor death by apoptosis.
This study was undertaken to determine radiation sensitization potential of TL32711 in GBM using in vitro and in vivo approaches. TL32711 alone did not cause any killing effects in GBM cells. However, in vitro apoptosis was increased when TL32711 was combined with radiation in GBM cell lines. In vivo data demonstrated that TL32711 alone delayed the growth of implanted xenograft tumors that were further delayed when combined with radiation. The survival of mice was greatly increased in TL32711 plus radiation treated GBM intracranial orthotopic model when compared to TL32711 or radiation treatment alone. Mechanistically, TL32711 confers radiation sensitization by abrogating NFκB activity that is elevated by radiation-induced TNF-α. Taken together, this is the first report that provides strong evidence that TL32711 in combination with ionizing radiation has potential to increase the effectiveness of radiotherapy.
Funded by NCI Contract No. HHSN261200800001E.
Citation Format: David Cerna, Donna Carter, Naoko Takebe, C. Norman Coleman, Mansoor M. Ahmed, Stephen Yoo. Radiosensitization of GBM by a novel peptidomimetic of the Second Mitochondria-derived Activator of Caspases (SMAC). [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 1599. doi:10.1158/1538-7445.AM2013-1599
Abstract 1626: The impact on tumor-stromal interactions of loss of collagen XV from the basement membrane zone.
Authors: Clementz Anthony G. , Mutolo Michael , Harris Ann 
Published: August 2014

Abstract
Most clinical therapeutics used to date depend on specific targeting of cellular components to treat cancers. However, the environment outside the tumor cell is also critical since it may provide new targets to treat malignant and resistant cancers, independent of the tumor.
We aim to target the early stages of cancer, prior to metastasis by determining the role of a non-fibrillar collagen (Type XV) and its interactions with the tumor stroma and extracellular environment.
Type XV collagen (COLXV) is found in basement membrane zones where it assumes
a pretzel-like structure but unlike the majority of fibrillar collagens does not form tight lattice networks surrounding the cell. In aggressive cancers, including breast, pancreas, ovarian and melanomas, Loss of COLXV precedes basement membrane invasion and metastasis.
Moreover, the loss of COLXV from the distal side of basement membrane zones and the resulting deficit in its interactions with other proteins may determine its specific function in tumor progression and eventual metastasis. In this context we have identified critical collagen-binding cell surface receptors on the tumor cell, which interact with COLXV and appear to mediate its functions. A number of these interacting proteins show altered signaling in cancer. We previously showed that over-expression of COLXV in cervical cancer cells alters the growth properties of these cells in vitro and that type XV collagen is a dose-dependent suppressor of tumorigenicity in vivo. We now show that over-expression of COLXV inhibits epithelial to mesenchymal transition (EMT) in vitro through interactions with cell surface receptors and has a dramatic effect on the associated signaling events and alterations on the tumor cell periphery.
Alterations in the balance of downstream signaling events may be responsible for tumor progression after the loss of COLXV. We are now further investigating the mechanisms of tumor/stroma crosstalk that are impacted by COLXV and subsequently by its depletion.
Citation Format: Anthony G. Clementz, Michael Mutolo, Ann Harris. The impact on tumor-stromal interactions of loss of collagen XV from the basement membrane zone. [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 1626. doi:10.1158/1538-7445.AM2013-1626
Abstract 1631: Cav1 is a key mediator of tumor-stromal interactions in melanoma.
Authors: Trimmer Casey , Capozza Franco 
Published: August 2014

Abstract
Several lines of experimental evidence have demonstrated the importance of the tumor microenvironment in controlling melanoma tumor growth and melanoma metastasis. Caveolin1 (Cav1), the main structural component of the plasma membrane microdomains termed Caveolae, is emerging as an important signaling molecule in the stroma of several tumor types. However, Cav1’s function in the melanoma microenvironment of primary tumors and of metastasis remains largely unexplored. Here, we devise various experimental approaches to elucidate the function of stromal Cav1 in the development of melanoma in mice. We show that loss of Cav1 (but not Cav2) in mice promotes the growth of orthotopically implanted melanoma cells. We use cocultures of fibroblasts and melanoma cells coupled with cytokine analysis to identify various Cav1 regulated factors that function in a paracrine fashion in melanoma. Cav1KO fibroblasts secrete increased amount of ShhN, bFGF, and MMP2/3, cytokines known to promote proliferation of melanoma cells and remodeling of the tumor stroma during melanomagenesis. Intradermal xenografts of fibroblasts and melanoma cells (5:1 ratios) confirmed the tumor promoting role of fibroblasts lacking Cav1. Interestingly, constitutive inhibition of the Shh pathway in melanoma cells reverses the growth and tumor-promoting effects of Cav1KO fibroblasts in co-culture or co-injection experiments suggesting a Cav1 mediated Shh heterotypic interaction between fibroblasts and melanoma cells. In summary, these studies reveal previously undefined functions for Cav1 in the melanoma microenvironment that could potentially be targeted for therapy.
Citation Format: Casey Trimmer, Franco Capozza. Cav1 is a key mediator of tumor-stromal interactions in melanoma. [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 1631. doi:10.1158/1538-7445.AM2013-1631
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 1639: Chondroitin sulfate proteoglycans potently inhibit invasion and serve as a central organizer of the brain tumor microenvironment.
Authors: Silver Daniel J. , Siebzehnrubl Florian A. , Schildts Michela J. , Yachnis Anthony T. , Smith George M. , Smith Amy A. , Scheffler Bjorn , Reynolds Brent A. , Silver Jerry , Steindler Dennis A. 
Published: August 2014

Abstract
Despite tremendous effort, glioblastoma (GBM) remains the most pervasive and lethal of all brain malignancies. One factor that contributes to this exceedingly poor prognosis is the highly invasive character of the tumor. GBM is characterized by microscopic infiltration of tumor cells throughout the otherwise healthy brain, whereas non-neural metastases, as well as select lower-grade gliomas develop as self-contained and clearly delineated lesions. Illustrated by rodent xenograft tumor models as well as pathological human patient specimens, we present evidence that one fundamental switch between these two distinct pathologies - invasion and non-invasion - is mediated through the tumor extracellular matrix (ECM). Specifically, non-invasive lesions are associated with a rich matrix containing substantial amounts of glycosylated chondroitin sulfate proteoglycans (CSPGs), whereas glycosylated CSPGs are essentially absent from diffusely infiltrative tumors. CSPGs, acting as a central organizer of the tumor microenvironment, dramatically influence resident reactive astrocytes, inducing their exodus from the tumor mass and the resultant encapsulation of non-invasive lesions. Additionally, CSPGs induce activation of tumor-associated microglia. We demonstrate that the astrogliotic barrier can directly inhibit tumor invasion, and its absence from GBM presents an environment favorable to diffuse infiltration. We also identify the LAR phosphatase receptor as a putative intermediary between extracellular CSPGs and the tumor cells themselves. In all, we present CSPGs as critical regulators of brain tumor histopathology and help to clarify the role of the tumor microenvironment in brain tumor invasion.
Citation Format: Daniel J. Silver, Florian A. Siebzehnrubl, Michela J. Schildts, Anthony T. Yachnis, George M. Smith, Amy A. Smith, Bjorn Scheffler, Brent A. Reynolds, Jerry Silver, Dennis A. Steindler. Chondroitin sulfate proteoglycans potently inhibit invasion and serve as a central organizer of the brain 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 1639. doi:10.1158/1538-7445.AM2013-1639