bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3628: The forced interaction of α4 integrin and CD44 by the novel peptide HYD1 may be a determinant of HYD1-induced cell death in multiple myeloma
Authors: Gebhard Anthony W. , Emmons Michael F. , Argilagos Raul F. , McLaughlin Mark , Koomen John , Cress Anne E. , Hazlehurst Lori A. 
Published: June 2012

Abstract
Our laboratory has previously shown that treatment with the novel d-amino acid peptide HYD1 (kikmviswkg) induces necrotic cell death in multiple myeloma (MM) cell lines. Furthermore, we have implicated the adhesion receptor VLA-4 as being involved in this process via shRNA silencing strategies. However, reducing α4 integrin only demonstrated partial protection indicating that other components of the HYD1 binding complex may be required for cell death. Thus, in the present study, we investigated the possible role of other adhesion molecules and/or complexes that may contribute to HYD1-induced cell death. Using an unbiased approach, we performed a total membrane pull-down with biotin conjugated HYD1 and NeutrAvidin beads on NCI-H929 MM cells. Samples were then loaded on an SDS-PAGE gel and analyzed by Mass Spectrometry. Data were then mined with the Scaffold 3 proteome software to determine pertinent hits. The adhesion receptor CD44 was determined to have the most peptide match hits and was confirmed as a valid hit via Western Blot analysis. Preliminary data using ELISA based binding studies with biotin-HYD1 as bait shows that recombinant CD44 directly binds to biotin-HYD1 in a concentration dependent manner. In order to identify complexes involved in HYD1-induced cell death, membrane immunoprecipitation assays were performed using CD44 and α4 integrin mAbs in both the presence and absence of HYD1. While Western Blot analysis confirmed basal levels of complex interactions between α4 integrin and CD44, the complex was significantly enhanced in the presence of HYD1. These data not only indicate a possible role of CD44 in HYD1-induced cell death, but also the ability of HYD1 to induce interactions among adhesion molecules and complexes. Further studies, including CD44shRNA targeting strategies, as well as looking at other adhesion molecules will be needed in order to confirm the role of individual cell surface receptors identified in the biotin-HYD1 complex in mediating HYD1 induced cell death.
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 3628. doi:10.1158/1538-7445.AM2011-3628
Abstract 3638: MM-302, HER2-targeted liposomal doxorubicin, does not impair cardiomyocyte function in vitro
Authors: Reynolds Joseph , Klinz Stephan , Leonard Shannon , Geretti Elena , Lee Helen , Eckelhofer Isabelle , Gaddy Daniel , Hendriks Bart , Wickham Tom 
Published: June 2012

Abstract
In HER2+ (ErbB2+) breast cancer, the ability to combine anthracyclines, such as doxorubicin, with anti-HER2 targeted therapies is limited clinically due to potential synergistic cardiotoxicity: doxorubicin directly damages heart cells and HER2 is an important mediator of cardiac repair signaling. Herein we detail findings for MM-302, a novel HER2-targeted liposomal doxorubicin formulation. The liposomal encapsulation is designed to protect the heart from doxorubicin exposure and the HER2-targeting component mediates uptake in HER2-positive cells without blocking HER2 signaling. In order to study the potential effects of MM-302 on the heart, we performed studies using Embryonic Stem Cell (ESC)-derived cardiac cells. Total cell uptake of free doxorubicin and MM-302 into ESC-derived cardiac cells was measured using HPLC. We found that, despite expressing low levels of HER2, the ESC-derived cardiac cells do not take up MM-302, whereas doxorubicin freely enters the cells in a time and dose-dependent manner over a 3 hour time course. Subsequent to delivery, cell viability was assessed in response to free doxorubicin or MM-302 at 24 hours post 3-hour exposure. Doxorubicin resulted in cell death in a dose-dependent manner, whereas MM-302 had no effect on cardiac cell viability. To understand the mechanism underlying the cardiotoxicity associated with doxorubicin exposure, and to differentiate MM-302 from existing therapies, we measured cell functional responses in ESC-derived cardiac cells, including cell stress (phopsho-p53), DNA damage (gamma-H2AX) and apoptosis (cleaved-PARP) with high-content microscopy. We demonstrated that, while doxorubicin treatment results in DNA damage, cell stress, apoptosis, and ultimately cell death in a dose-dependent manner, MM-302 does not. Our findings demonstrate that MM-302 provides a means to deliver doxorubicin to high HER2-expressing cancer cells, while sparing exposure, accumulation, and toxicity in non-target (low HER2-expressing) cells, such as cardiomyocytes. This opens an exciting avenue for potentially introducing a novel anthracycline product for the treatment of HER2+ breast cancer.
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 3638. doi:10.1158/1538-7445.AM2011-3638
Abstract 3643: Phosphatidylserine-targeting antibody combined with Sorafenib has strong anti-tumor activity against human hepatocellular carcinomas in mice
Authors: Cheng Xiaoyun , Thorpe Philip E. 
Published: June 2012

Abstract
Hepatocellular Carcinoma (HCC) is the third leading cause of cancer-related deaths in the world. The incidence of the HCC is increasing in the United States. HCC is refractory to most forms of therapy. Sorafenib is the only chemotherapeutic agent approved for the treatment of advanced HCC. Therefore, there is a huge unmet need for a new systemic therapy for HCC patients. A promising approach would be to combine sorafenib with bavituximab to treat HCC. Bavituximab is a vascular targeting antibody that is in Phase IIb clinical trials in patients with non-small cell lung cancer (NSCLC). Bavituximab targets phosphatidylserine (PS), which is normally intracellular but becomes exposed on the external surface of vascular endothelium in tumors. Bavituximab binds to PS-expressing tumor vascular endothelial cells and causes monocytes and macrophages to attack the vessels by antibody-dependent cellular cytotoxicity (ADCC). This results in death of tumor cells through deprivation of oxygen and nutrients. Chemotherapy and irradiation increase the exposure of PS on tumor vessels and enhance the anti-tumor activity of bavituximab-related antibodies in multiple rodent tumor models. We hypothesized that sorafenib would also induce exposure of PS on HCC vasculature because it interferes with anti-apoptotic signaling by VEGF and other angiogenic growth factors. We found that sorafenib induced PS exposure on human microvascular endothelial cells in vitro and in vivo. Treatment of mice bearing subcutaneous C3A, Huh7 or PLC/PRF/5 HCC tumors with sorafenib increased PS exposure on tumor vessels from 21% to 51% in PLC/PRF/5 tumors, from 22% to 67% in C3A tumors, and from 32% to 52% in Huh7 tumors. Combining a murine version of bavituximab with sorafenib significantly improved the anti-tumor effect in the PLC/PRF/5 xenograft model. The combination inhibited tumor growth by 95%, as compared with 80% for sorafenib alone (p&lt;0.05). Bavituximab in combination with sorafenib has promise as a new systemic therapy for the treatment of advanced HCC patients.
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 3643. doi:10.1158/1538-7445.AM2011-3643
Abstract 3651: Phosphatidylserine-targeting antibody induces differentiation of myeloid-derived suppressor cells into M1-like macrophages
Authors: Huang Xianming , Ye Dan , Thorpe Philip E. 
Published: June 2012

Abstract
Introduction: The phosphatidylserine (PS)-targeting antibody, bavituximab, is currently in Phase IIb clinical trials in patients with lung cancer. Bavituximab, and its murine counterpart, 2aG4, induce the attack of monocytes and macrophages on PS-expressing tumor vascular endothelium and tumor cells and inhibit the immunosuppressive effects of PS in the tumor microenvironment. Myeloid-derived suppressor cells (MDSC) are one of the major cells responsible for the immunosuppressed state in tumors. In this study, we tested the influence of 2aG4 on the differentiation of MDSC into M1-like tumor associated macrophages (TAMs). Methods: MDSC were isolated from 4T1 tumor bearing mice with anti-Gr1-coated magnetic beads. The purified MDSC were then cultured for 5 days in the presence of 2aG4 or control C44 antibody. For in vivo studies, PC3 tumor-bearing mice were treated with 2aG4 for 30 days and MDSC and TAMs in tumors and spleens were analyzed by FACS and immunohistochemistry. Results: 2aG4 treatment of purified MDSC switched their cytokine production from an immunosuppressive IL-10-dominated response to a pro-inflammatory IL-12- and TNFα -dominated response. The percentage of Gr1+ cells decreased to 8% in the 2aG4-treated cultures (P&lt;0.0001) but only to 50 – 57% in the PBS and C44-treated cultures. Treatment with 2aG4 induced the differentiation of MDSC into M1-like macrophages that expressed lower CD206 and produced more NO than control cultures. Treatment of mice bearing PC3 prostate tumors with 2aG4 decreased the percentage of MDSC from 7% to 4% (P&lt;0.001) in the tumors and from 28% to 20% (P&lt;0.001) in the spleens. The antibody treatment also increased the ratio of M1 to M2 TAMs in PC3 tumors from 0.7% to 1.4% (P&lt;0.001). Conclusion: Taken together, our results suggest that 2aG4 causes the differentiation of MDSCs into macrophages having an M1-like phenotype. 2aG4 treatment decreased IL-10 production and increased IL-12 and TNFα-production. These results suggest that 2aG4 treatment reactivates innate immunity in tumors.
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 3651. doi:10.1158/1538-7445.AM2011-3651
Abstract 3659: Mast cell interactions with T-regulatory cells determine the outcome of colon cancer
Authors: Khazaie Khashayarsha 
Published: June 2012

Abstract
Mast cells (MCs) are a bone marrow-derived, long-lived, heterogeneous cellular population that act both as positive and negative regulators of immune responses. They are arguably the biggest chemical factory in the body, and influence other cells through both soluble mediators and cell to cell interaction. MCs are commonly seen in various tumors and have been attributed alternatively with tumor rejection or promotion properties. Tumor infiltrating MCs are derived both from sentinel resident MC progenitors as well as from recruited progenitor cells (1). MC directly influence tumor cell proliferation and invasion (2, 3), but also help shape the tumor microenvironment (1) and modulate immune responses to tumors. Best known for orchestrating inflammation and angiogenesis, the role of MCs in modulating adaptive immune responses has only recently attracted attention. MCs are responsible for expansion of lymph nodes, and recruitment of dendritic cells. MC mediate immune suppression by Treg but can also reverse suppressive properties of Treg (4) or convert Treg into TH17 pro-inflammatory cells The central role of MC in the control of innate and adaptive immunity endows them with the ability to tune the nature of host responses to cancer and ultimately determine the outcome of disease and fate of the cancer patient (5) (6).
1. Maltby S, Khazaie K, McNagny KM. Mast cells in tumor growth: Angiogenesis, tissue remodelling and immune-modulation. Biochim Biophys Acta. 2009;1796(1):19-26. PMCID: 2731828.
2. Strouch MJ, Cheon EC, Salabat MR, Krantz SB, Gounaris E, Melstrom LG, et al. Crosstalk between mast cells and pancreatic cancer cells contributes to pancreatic tumor progression. Clin Cancer Res. 2010;16(8):2257-65.
3. Cheon EC, Khazaie K, Khan MW, Strouch MJ, Krantz SB, Phillips J, et al. Mast cell 5-Lipoxygenase activity promotes intestinal polyposis in APCΔ468 mice. Cancer Research. 2010;(in press).
4. Gounaris E, Blatner NR, Dennis K, Magnusson F, Gurish MF, Strom TB, et al. T-regulatory cells shift from a protective anti-inflammatory to a cancer-promoting proinflammatory phenotype in polyposis. Cancer Res. 2009;69(13):5490-7.
5. Blatner NR, Bonertz A, Beckhove P, Cheon EC, Krantz SB, Strouch M, et al. In colorectal cancer mast cells contribute to systemic regulatory T-cell dysfunction. Proc Natl Acad Sci U S A. 2010;107(14):6430-5. PMCID: 2851977.
6. Colombo MP, Piconese S. Polyps Wrap Mast Cells and Treg within Tumorigenic Tentacles. Cancer Res. 2009.
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 3659. doi:10.1158/1538-7445.AM2011-3659
Abstract 366: Novel self-folding tricyclic cholic acid-peptide hybrids as nanotherapeutic ligands targeting prostate and breast cancers and human embryonic stem cells
Authors: Olivos David J. , Saunders Mary R. , Maeda Yoshiko , Lam Kit S. 
Published: June 2012

Abstract
Prostate cancer is the second leading cause of death in American men accounting for 10% of all cancer-related mortalities. According to NCI statistics from 2005-2007, 1 in 6 men will be diagnosed with prostate cancer during their lifetime. Despite the use of chemotherapy for the treatment of advanced or metastatic disease, cellular resistance to anticancer drugs and adverse side effects to healthy organs limit therapeutic efficacy. A targeted pro-apoptotic drug delivery system has been developed for the selective destruction of malignant tumors and tumorigenic stem cells. A novel self-folding tricyclic branched library was synthesized. Fixed hydrophobic amino acids near the N-terminus (position 5) of twin branched peptide arms fold back onto the hydrophobic face of the planar cholic acid molecule to form a compact tricyclic molecule. The novel bracelet library was screened using a One Bead Two Compounds (OB2C) combinatorial chemistry approach. Receptors expressed on cancerous cells serve as the targets for the tricyclic molecules to induce apoptotic signaling. Receptors for LDO 18, found on prostate cancer and stem cells, serve as the carrier vector, enabling the targeted delivery of the anticancer drug to the tumor mass. This approach spares normal tissues from toxic side effects of the peptidomimetic compounds. Preliminary studies suggest that tumors of ovarian and breast origin can also be targeted using LDO18. Lead therapeutic compounds will be conjugated to LDO18 nanocarriers along with LHRH analogues to evaluate the efficacy and combined potency to prostate, ovarian, and breast cancer xenografts in nude mice and orthotropic models.
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 366. doi:10.1158/1538-7445.AM2011-366
Abstract 3668: Single-dose activity of PSMA ADC against prostate cancer xenograft and explant tumors
Authors: Magargal Wells W. , Olson William C. 
Published: June 2012

Abstract
Introduction: Prostate-specific membrane antigen (PSMA) is an attractive target for antibody-targeted therapy of prostate cancer due to its abundant and selective expression on the surface of prostate cancer cells. We have generated a novel antibody-drug conjugate (ADC) by linking a fully human PSMA monoclonal antibody to monomethylauristatin-E (MMAE), a potent tubulin inhibitor. Here, we describe the use of PSMA ADC to treat SCID mice bearing LNCaP xenografts or LuCaP explants derived from surgical resections of prostate cancer patients.
Methods: PSMA expression in LNCaP and LuCaP tumor cells was evaluated by flow cytometry. Activity of PSMA ADC, assessed by decrease in tumor volume, was evaluated in LNCaP xenograft and LuCaP explant models. SCID mice were implanted subcutaneously with cultured LNCaP tumor cells or disaggregated human LuCaP 70 or LuCaP 77 prostate tumor tissue obtained from tumor-bearing mice. When average tumor size reached ∼300mm3, animals were randomized into groups of 9-10 mice and each animal was treated with a single intravenous dose of vehicle control, a control ADC of irrelevant specificity, or PSMA ADC. Treatment effects were assessed by measuring tumor volume and overall survival for up to 41 days post-treatment.
Results: Surface expression of PSMA was assessed by flow cytometry, with a rank order of expression as follows: LNCaP &gt; LuCaP 70, LuCaP 77, LuCaP 105 &gt; LuCaP 96.1 &gt; LuCaP 35V, LuCaP 141. Single-dose PSMA ADC demonstrated significant activity against LNCaP xenografts at a dose of 5 mg/kg (p&lt;0.0001 relative to either vehicle or control ADC) and against LuCaP 77 explants at a dose of 10 mg/kg (p=0.0003 relative to either vehicle or control ADC). A trend toward delayed tumor growth was observed in the LuCaP 70 tumor model.
Conclusion: Single-dose PSMA ADC showed activity against LNCaP xenografts and LuCaP explants derived from surgical resections of prostate cancer patients.
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 3668. doi:10.1158/1538-7445.AM2011-3668
Abstract 367: Engineering of targeted nanoparticles for cancer therapy using internalizing aptamers isolated by cell-uptake selection
Authors: Xiao Zeyu , Levy-Nissenbaum Etgar , Aizu Wataru , Langer Robert , Farokhzad Omid 
Published: June 2012

Abstract
There has been a substantial interest in the development of targeted nanoparticles (NPs) that provide increased efficacy and lower toxicity for cancer therapy. One of the major obstacles has been the paucity of optimal targeting ligands that can discriminate between the expression of antigens on cancer cells and normal cells, and subsequently deliver a therapeutic payload into the cancer cells. Using prostate cancer (PCa) as a model disease, we have addressed the difficulty by developing a “cell-uptake selection” strategy to isolate PCa-specific internalizing 2′-O-methyl RNA aptamers (Apts). Twelve cycles of selection and counter-selection were done to obtain a panel of PCa-specific internalizing Apts, with little or no internalization into non-prostate and normal prostate cells. After Apt characterization, size minimization, improvement of nuclease stabilization, and conjugation of the Apts with fluorescently-labeled polymeric NPs, the NP-Apt bioconjugates exhibit PCa specificity and enhancement in cellular uptake when compared to non-targeted NPs lacking the internalizing Apts. Furthermore, when docetaxel (Dtxl), a chemotherapeutic agent used for the treatment of PCa, was encapsulated within the NP-Apt, a significant improvement in cytotoxicity was achieved in targeted PCa cells. Further application of this Apt by conjugating with gold nanorods demostrated remarkable anti-tumor efficacy in vivo. To our knowledge, this is the first report of designing selection to enrich cancer cell-specific internalizing aptamers rather than highest affinity aptamers in previously reported selection process. A similar cell-uptake selection strategy may be used for developing specific internalizing ligands for a myriad of other diseases and can potentially facilitate delivering various molecules, including drugs and siRNAs, into cells.
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 367. doi:10.1158/1538-7445.AM2011-367
Abstract 3679: Preliminary results from a patient group, excluded from the National Lung Cancer Screening Trial, who are at high risk for lung cancer- heavy smokers with HIV
Authors: Hulbert Alicia , Hooker Craig , Brown Travis , Horton Karen , Wrangle John , Fishman Elliott , Pelosky Kristen , Lee Beverley , Shin James , Rutlege Marian , Sam Celis , Pridham Genevieve , Lee Sue , Luong Eli , Carter Yvonne , Brown Robert , Herman James , Brock Malcolm 
Published: June 2012

Abstract
Purpose: Within the HIV population, the incidence of lung cancer is estimated to be 2-4 times that of the general population. Of the non AIDS associated malignancies, lung cancer is the leading cause of death among HIV patients who develop malignancy because of its advanced stage of presentation. The National Lung Cancer Screening Trial recently reported a 20% reduction in mortality for patients undergoing low dose computed tomography (CT) screening, but individuals with HIV diagnosis were excluded. To report the results of an observational pilot study of lung cancer CT screening in a cohort of HIV heavy smokers.
Materials and Methods: A prospective cohort study was performed with 185 asymptomatic individuals with confirmed HIV diagnosis who had smoked 20 pack-years or more. All participants had baseline (prevalence) chest CT scanning and 107 patients (58.2%) also received at least one subsequent annual (incidence) examination of the chest and upper abdomen. All patients underwent hand held spirometry testing, cytologic analysis of sputa, and detailed health status questioning.
Results: Of the 185 individuals, there were 31.4% females, 68.6% males, 90.3% African-Americans, 8.7% Caucasian, and 1.1% Hispanic. The median age at enrolment was 48 years, and the median number of smoking pack-years was 34. Non-calcified nodules were detected in 4 participants (2.1%) by low-dose prevalent CT compared to no nodules on incident CT scans. Only one patient with malignancy was detected (0.54%) on prevalent scanning and none on incident scanning. Stage of malignancy was advanced. No biopsies were undertaken for benign disease. CT evidence of COPD and coronary artery disease were present in 24% and 27% of patients, respectively. Additional CT findings of clinical importance were noted in the chest in 132 (71.7%) patients and extrathoracically in 30 (16.3%) of patients, respectively.
Conclusion: The prevalence results of this pilot study are in line with other observational studies of greater sample size for HIV indeterminate patients. Although the sample size is small, it suggests no elevated incidence of lung cancer in HIV heavy smokers. Although the rate of incident scanning is low, CT screening of HIV patients is feasible. This justifies accruing a larger sample of HIV patients perhaps from an already well defined, large, prospective cohort of HIV heavy smokers.
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 3679. doi:10.1158/1538-7445.AM2011-3679