tbuckley/cabot-search huggingface dataset:
Abstract 1678: Bioavailability and anti-tumor activity of capsaicin in human small cell lung cancer
Authors: John D. Hurley, William D. Rollyson, Cody A. Stover, Kathleen C. Brown, Haley E. Perry, Cathryn D. Stevenson, Clayton M. Crabtree, Aaron M. Dom, Jamie K. Lau, Theodore R. Witte, W E. Hardman, Piyali Dasgupta
Journal: Cancer Research (2015)

Abstract The nutritional compound capsaicin has been shown to display anti-neoplastic activity in breast, prostate and colon tumors xenografted in nude mice. Based on these data from other research laboratories, we wanted to determine the bioavailability of capsaicin in nude mice in vivo. We found that capsaicin was rapidly metabolized primarily in the liver. The bioavailability of intact capsaicin was highest in the lung. Therefore, we hypothesized that capsaicin should suppress the growth of lung tumors. We found that capsaicin induced robust apoptosis in human SCLC cell lines. Capsaicin decreased the growth rates of human SCLC tumors in two in vivo models, namely the CAM model and the nude mouse model. HPLC studies showed intact capsaicin in the tumors excised from nude mice. The heat-sensation activity of capsaicin is mediated by the transient receptor potential vanilloid (TRPV) family of proteins. Capsaicin functions as an agonist of the TRPV1 receptor. The apoptotic activity of capsaicin was found to be mediated by TRPV6 and not TRPV1. Preliminary data shows that capsaicin increases the expression of the TRPV6 receptor, causing apoptosis in human SCLCs. Citation Format: John D. Hurley, William D. Rollyson, Cody A. Stover, Kathleen C. Brown, Haley E. Perry, Cathryn D. Stevenson, Clayton M. Crabtree, Aaron M. Dom, Jamie K. Lau, Theodore R. Witte, W E. Hardman, Piyali Dasgupta. Bioavailability and anti-tumor activity of capsaicin in human small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1678. doi:10.1158/1538-7445.AM2015-1678
Mechanism of antitumor activity of E7080, a selective VEGFR and FGFR tyrosine kinase inhibitor (TKI), in combination with selective mutant BRAF inhibition.
Authors: J. Matsui, Y. Narita, T. Semba, Y. Adachi, T. Kadowaki, J. Oestreicher, M. Matijevic, M. Byrne, Y. Funahashi
Journal: Journal of Clinical Oncology (2011)

8567 Background: E7080 is a TKI targeting VEGFR1-3, FGFR1-4, KIT, RET and PDGFR. Anti-tumor activity has been observed in melanoma patients in phase I. The objective of this study was to examine the effect of E7080 alone and in combination with PLX-4032 on tumor response, gene expression and tumor microvasculature in BRAFmu melanoma. Methods: BRAF mutant (mu) cell lines were created by transfection of BRAF V600E constructs into BRAF wild type (wt) cell lines. Anti-tumor activity of E7080 alone or in combination with the selective BRAF inhibitor PLX-4032 was examined in xenografted models bearing mock and BRAFmu transfectants. Results: The ratio of ANGPT1/2 expression was significantly higher in BRAFmu/ PTENwt compared to BRAFwt/PTENwt and BRAFmu/PTENmu among 14 melanoma cell lines. ANGPT1 expression was up-regulated in BRAFmu by 330%, and ANGPT2 in PTENmu by 290% compared to wt. PLX-4032 decreased ANGPT1 expression and pericyte coverage of tumor vessels in BRAFmu/PTENwt A375 melanoma. Similarly, overexpression of BRAF V600E in BRAFwt SK-MEL-2 melanoma resulted in increased ANGPT1 expression along with increased pericyte coverage. E7080 at 3, 10, 30 to 100 mg/kg showed significant anti-tumor activity against mock transfectants, but only at 100 mg/kg against BRAF V600E transfectants. Combination of E7080 at 10 mg/kg with PLX-4032 at 100 mg/kg showed synergistic anti-tumor activity against A375 melanoma and caused tumor regression, not observed by either single agent E7080 or PLX-4032. E7080 alone increased pericyte coverage of tumor vessels, but in combination with PLX-4032 resulted in marked decreased in pericyte coverage and microvessel density. Conclusions: The BRAFmu/ PTENwt melanomas studied demonstrate high pericyte coverage and resistance to E7080. Combination of E7080 with PLX-4032 achieves synergistic antitumor effect with enhanced reduction of pericyte coverage. These data provide a mechanistic basis for clinical study of BRAF inhibitors in combination with VEGFR and FGFR targeted agents.
Update on the use of immunoglobulin in human disease: A review of evidence
Authors: Elena E. Perez, Jordan S. Orange, Francisco Bonilla, Javier Chinen, Ivan K. Chinn, Morna Dorsey, Yehia El-Gamal, Terry O. Harville, Elham Hossny, Bruce Mazer, Robert Nelson, Elizabeth Secord, Stanley C. Jordan, E. Richard Stiehm, Ashley A. Vo, Mark Ballow
Journal: Journal of Allergy and Clinical Immunology (2016)
Structural and Functional Evidence on the Role of Sulfated Tyrosine Residues In Glycoprotein Ib Binding to α-Thrombin Exosites
Authors: Alessandro Zarpellon, Reha Celikel, Richard McClintock, James R. Roberts, G. Loredana Mendolicchio, Hua Jing, Kottayil I Varughese, Zaverio M. Ruggeri
Journal: Blood (2010)
Abstract 760: On the evolution of erlotinib-resistant NSCLC subpopulations
Authors: Michael E. Ramirez, Robert J. Steininger, Lani F. Wu, Steven J. Altschuler
Journal: Cancer Research (2015)

Abstract One of the foremost challenges to cancer treatment is the emergence of drug resistance. Adding complexity to this problem is the recent realization that drug resistance can stem from selection for both intrinsically resistant subpopulations as well as subpopulations that adapt to the drug challenge through epigenetic and/or signaling state changes. Because of this complexity, cells have many ways to survive in response to targeted inhibitors, resulting in a diversity of resistance states between and even within patient tumors. Ongoing strategies are aimed at finding the best second-line therapies for resistant tumors. However, the extent to which drug-resistant subpopulations exhibit similar or divergent sensitivities to second-line treatments is unknown. How different are drug-resistant subpopulations from one another? Do these differences affect the types of inhibitors that will be effective in killing these drug-resistant colonies, resulting in a variety of strategies for managing drug-resistant populations? What are the molecular changes that correspond to differences in secondary drug response? Here, we aim to determine the degree of heterogeneity between drug-resistant clonal populations by profiling their response to a panel of second-line therapies and examining mutational states to secondary drug response. This study will provide insight into whether or not drug-resistant subpopulations adopt similar or disparate drug-resistant states. Citation Format: Michael E. Ramirez, Robert J. Steininger, Lani F. Wu, Steven J. Altschuler. On the evolution of erlotinib-resistant NSCLC subpopulations. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 760. doi:10.1158/1538-7445.AM2015-760
Abstract 2468: Antibody targeting soluble NKG2D ligand sMIC induces regression of primary tumors and eliminates metastasis in multiple pre-clinical cancer models
Authors: Jennifer D. Wu, Fahmin Basher, Mark Rubinstein
Journal: Cancer Research (2015)

Abstract Expression of the MHC I-chain related molecules A and B (MICA/B) on epithelial cell surface in response to transformation or DNA damage can signal the immune system of the abnormality and thus initiate active immune surveillance by Natural Killer (NK) cells and cytotoxicity T cells. We and others have shown that malignant tumor cells can shed MICA/B to down regulate NKG2D expression and negatively impact NK and CD8 T cell function in cancer patients. Increased tumor-specific shedding of cell surface NKG2D ligand, MHC I chain related molecule (MIC), is associated with advanced stage and metastasis in many types of epithelial cancer. High serum levels of soluble MIC (sMIC) insults the immune system not only by down-regulating NKG2D expression on natural killer (NK) cells and effector T cells but also perturbing NK cell peripheral maintenance. Whether sMIC is an effective cancer therapeutic target has not been addressed due to the lack of specific sMIC-blocking reagent and clinically relevant pre-clinical animal models. Using a “humanized” clinically relevant spontaneous prostate carcinoma TRAMP/MIC bi-transgenic mouse model and multiple engineered syngeneic transplantable tumor models, we unprecedentedly show that therapy with a sMIC-specific monoclonal antibody induced rapid regression of primary tumors and metastasis without systemic toxicity. The therapy revamped a myriad of anti-tumor immune responses including NK cell homeostatic renewal and function, CD4 T cells to Th1 and Th17 responses. Using the well-defined melanoma model, we further show that anti-sMIC therapy augments Pmel-1 antigen-specific CD8 T cell responses. Notably, depletion of NK cells mitigated the therapeutic effect of anti-sMIC antibody and the effector function of both CD4 and CD8 T cells. We conclude that sMIC is an effective therapeutic target to potentiate innate and adoptive immune responses against MIC+ malignancies. Citation Format: Jennifer D. Wu, Fahmin Basher, Mark Rubinstein. Antibody targeting soluble NKG2D ligand sMIC induces regression of primary tumors and eliminates metastasis in multiple pre-clinical cancer models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2468. doi:10.1158/1538-7445.AM2015-2468
The core domain of hepatitis C virus glycoprotein E2 generates potent cross‐neutralizing antibodies in guinea pigs
Authors: Patricia T. Vietheer, Irene Boo, Jun Gu, Kathleen McCaffrey, Stirling Edwards, Catherine Owczarek, Matthew P. Hardy, Louis Fabri, Rob J. Center, Pantelis Poumbourios, Heidi E. Drummer
Journal: Hepatology (2016)

A vaccine that prevents hepatitis C virus (HCV) infection is urgently needed to support an emerging global elimination program. However, vaccine development has been confounded because of HCV's high degree of antigenic variability and the preferential induction of type-specific immune responses with limited potency against heterologous viral strains and genotypes. We showed previously that deletion of the three variable regions from the E2 receptor-binding domain (Δ123) increases the ability of human broadly neutralizing antibodies (bNAbs) to inhibit E2-CD81 receptor interactions, suggesting improved bNAb epitope exposure. In this study, the immunogenicity of Δ123 was examined. We show that high-molecular-weight forms of Δ123 elicit distinct antibody specificities with potent and broad neutralizing activity against all seven HCV genotypes. Antibody competition studies revealed that immune sera raised to high-molecular-weight Δ123 was poly specific, given that it inhibited the binding of human bNAbs directed to three major neutralization epitopes on E2. By contrast, the immune sera raised to monomeric Δ123 predominantly blocked the binding of a non-neutralizing antibody to Δ123, while having reduced ability to block bNAb binding to E2, and neutralization was largely toward the homologous genotype. This increased ability of oligomeric Δ123 to generate bNAbs correlates with occlusion of the non-neutralizing face of E2 in this glycoprotein form.The results from this study reveal new information on the antigenic and immunogenic potential of E2-based immunogens and provide a pathway for the development of a simple, recombinant protein-based prophylactic vaccine for HCV with potential for universal protection. (Hepatology 2017;65:1117-1131).
103. High-Capacity Adenoviral Vectors (HCAdV) Armed with a High Risk Human Papillomavirus (HPV) Oncogene Specific CRISPR/Cas9 Machinery Specifically Kill Cervical Cancer Cells
Authors: Eric Ehrke-Schulz, Anja Ehrhardt
Journal: Molecular Therapy (2016)

Persistent high risk human Papillomavirus (HPV) infections are the main cause of cervical cancer and partially also head and neck cancer. Recent studies showed that plasmid transfection of HPV oncogene specific designer nucleases effectively induced in/del mutations in the early promotors or oncogenes of HPV genomes integrated into the genome of cervical cancer cells by double-strand DNA break mediated non homologous end joining (NHEJ). Destruction or suppression of HPV oncogenes lead to decreased suppression of HPV oncogenes mediated by tumor suppressor protein p53 and retinoblastoma protein pRB inducing recovery from HPV oncogene mediated inhibition of apoptosis induction and cell cycle control. However, only few attempts have been made to improve delivery of respective designer nucleases by means of viral delivery allowing for translating these promising findings towards in vivo applications. Here we aimed at arming gene deleted high-capacity adenoviral vectors (HCAdVs) with HPV-specific CRISPR/cas9 machineries. By using a new toolbox that facilitates customization, cloning and production of CRISPR-HCAdVs we assembled HCAdV genomes containing the Streptococcus pyogenes Cas9 (spCas9) gene including either one gRNA expression unit specific for HPV18-E6 or two gRNA expression units specific for HPV18 and HPV16-E6 that have been shown efficiency to destroy respective genes. HPV specific CRISPR-HCAdVs were amplified in medium scale using a shortened protocol yielding high virus titers. Hela and Caski cervical cancer cells containing HPV18 or HPV16 genomes integrated into their cellular genome, as well as HPV negative A549 cells were infected with HPV specific CRISPR-HCAdVs. Adenoviral delivery of HPV specific CRISPR/Cas9 resulted in strong cell death in HPV positive cervical cancer cell lines whereas HPV negative A549 cells were unaffected. Moreover, HPV-specific CRISPR-HCAdVs infected Hela and Caski cells showed decreased proliferation compared to untreated cells and HPV negative control cells and cytotoxicity assays revealed strongly decreased cell viability of cervical cancer cells. In sharp contrast to control groups, increased apoptosis in HPV specific CRISPR-HCAdV treated cervical cancer cells was measured after performing apoptosis detection assays. Our results suggest that also HCAdVs can serve as oncolytic agents when armed with target specific designer nucleases such as CRISPR/Cas9. We believe that our approach will pave the way towards in vivo applications of CRISPR/Cas9 mediated oncolysis of HPV induced cervical cancer. As our CRISPR/Cas9-HCAdV production pipeline is adaptable to incorporate other or even more gRNA expression units specific for further HPV types, it provides a valuable platform to develop personalized antiviral or oncolytic vectors for any specific HPV target.
Recipient Dendritic Cells Are Regulated By MiR-146a during Acute GvHD
Authors: Natalie Stickel, Kathrin Hanke, Martin Köhler, Gabriele Prinz, Dietmar Pfeifer, Annette Schmitt-Graeff, Tilman Brummer, Juergen Finke, Justus Duyster, Ulrich Salzer, Robert Zeiser
Journal: Blood (2015)
Evaluation of safety and tolerance of escalating doses of RSR13 administered with a fixed dose of BCNU every six weeks in patients with recurrent malignant glioma: Results of the phase I NABTT 9806 clinical trial
Authors: P. Z. New, S. Grossman, T. Mikkelsen, T. Batchelor, S. Phuphanich, K. Carson, J. Fisher, M. Craig, P. Cagnoni
Journal: Journal of Clinical Oncology (2004)

1533 Background: RSR13 is an allosteric modifier of hemoglobin which has been shown to increase tumor oxygen delivery, with potential to improve cytotoxic therapy. Previous studies in glioblastoma have demonstrated that the agent is tolerable at 100 mg/kg when delivered daily prior to radiotherapy, and survival was reported in excess of one year. Preclinical studies have shown enhancement of the response to certain chemotherapeuticagents as well. This protocol is assessing the safety and tolerance of escalating doses of RSR13 when administered prior to BCNU in patients with recurrent high grade glioma, as well as maximum tolerated dose and pharmacokinetics of RSR13 when administered with BCNU. Methods: RSR13, in escalating doses of 25 mg/kg, to a maximum of 100 mg/ kg, in cohorts of six patients each, was administered over 30 minutes prior to infusion of BCNU 200 mg., every six weeks, for a maximum of six cycles. Only nonhematologic toxicities are assessed in determining the dose limiting toxicity (DLT) of the combination of agents. Results: A total of 33 patients have been accrued, 14 females, 19 males. Two grade 3/4 hematologic toxicities occurred in the first cohort of six patients at 25 mg/kg, therefore this cohort was expanded to 12. One non-hematologic DLT was observed in this cohort (generalized weakness) and in the 50 mg/kg cohort, a DLT of pulmonary edema was observed. There were no DLTs in the 75 mg/kg cohort. Symptomatic hypoxia was observed as a significant adverse event in two patients in the 100 mg/kg cohort which is still enrolling. Conclusions: Hematologic toxicity is manageable in this drug combination. The maximum tolerated dose of RSR13 with BCNU is projected to be 75 or 100 mg/kg. No significant financial relationships to disclose.
A Experimental Study and Clinical Result of Prophylaxis aGVHD with Humanized Anti-CD25 Monoclonal Antibody in Haploidentical BMT.
Authors: Shu-Quan Ji, Hui-Ren Chen, Heng-Xiang Wang, Hong-Min Yan, Mei Xue, Jing Liu, Chang-Q.(Micky) Xun
Journal: Blood (2004)
Endothelial Microparticles (EMP) and Their Interactions with Leukocytes in HIV Infected Patients with Optimal Response to Highly Active Antiretroviral Therapy (HAART).
Authors: Jacques Simkins, Vicente F. Corrales-Medina, Julio A. Chirinos, Stephen Symes, Dushyantha T. Jayaweera, Luis Espinoza, Joaquin J. Jimenez, Wenche Jy, Lawrence L. Horstman, Yeon-Soong Ahn
Journal: Blood (2006)
233. Designing Therapeutic Strategy By Studying Interactions and Effects of Hypoxia, HIF-1α, Surrounding Fibroblasts, and Ectopic p16 Expression on Breast Cancer Mobility and Invasion
Authors: Yi Lu, Jun Zhang
Journal: Molecular Therapy (2015)

Cancer cell migration and invasion play essential roles in the metastatic cascade that transforms the local, noninvasive confined tumor cells to the motile, metastatic cancer cells moving through the extracellular matrix and basement into the circulation. Accumulated evidences suggest that intratumoral hypoxia, a characteristic of fast-growing solid tumors, promotes cancer cell motility and invasive abilities. In this study, we investigated the effects of hypoxia and HIF-1α, surrounding fibroblasts, and p16 expression on the migration and invasion of breast cancer cells. We found that in general hypoxia promoted breast cancer cell migration and invasion, and cocultured fibroblasts stimulated invasiveness of breast cancer cells. Interestingly, HIF-1α from cancer cells and surrounding fibroblasts has respectively profound effects on the invasive ability of breast cancer cells. By applying both HIF-1α wild-type (WT) and knockout (KO) fibroblasts and breast cancer cells and using an in vitro invasion assay through commercially precoated invasion inserts, we found that fibroblasts, regardless their HIF-1α status, stimulated cell invasion of breast cancer cells that have intact HIF-1α. In contrast, only HIF-1α-expressing fibroblasts, not HIF-1α-nonexpressing ones, stimulated HIF-1α KO breast cancer cell invasion. These results suggest the complicated and respective HIF-1α contribution from breast cancer per se and surrounding fibroblasts to the tumor invasion and malignancy. Moreover, by using a Tet-on inducible system, we found that ectopic p16 gene transfer is capable of inhibiting hypoxia-induced cell migration and invasion of breast cancer cells, and suppressing cocultured fibroblast-stimulated invasiveness of breast cancer cells. These results suggest that p16, in addition to its well-known anti-tumor proliferation function, has novel anti-cancer properties capable of suppressing hypoxia/HIF-1α-mediated cancer cell migration and invasion. Furthermore, our current ongoing study implies an interaction between p16 and HIF-1α that may elucidate a novel p16-mediated tumor suppression pathway via HIF-1α-regulated signaling. These studies together may provide new information of the convergence of several important cell-growth regulation pathways on tumor invasion that would yield potential novel targets for effective cell- or gene-therapy strategy for treatment of breast cancer.
Abstract 807: Parental radiation elicits increased intestinal tumorigenesis in the F1 generation of APCMin/+ and APC1638N/+ mice
Authors: Shubhankar Suman, Santosh Kumar, Bo-Hyun Moon, Ziling Fan, Albert J. Fornace, Kamal Datta
Journal: Cancer Research (2015)

Abstract The risk of colorectal cancer (CRC) has been reported to increase with radiation exposures as well as with a positive family history. Radiation exposure has also been implicated in inducing heritable changes in parental germline cells and thus increasing risk of cancer in the offspring. However, effects of parental radiation exposure on trans-generational colorectal carcinogenesis in offspring have not been explored yet. We employed two well-characterized mouse models (APCMin/+ and APC1638N/+) of human CRC to determine trans-generational effects of low dose radiation on colorectal carcinogenesis. Male APCMin/+ and APC1638N/+, and female C57BL/6J mice were exposed to whole body 25 cGy of x rays. Mating was initiated two days after radiation exposure, F1 offspring were genotyped, and male and female APCMin/+ and APC1638N/+ were grouped and housed separately. APCMin/+ mice were euthanized 150 days after birth, APC1638N/+ mice after 210 days, and tumor frequency and size in intestine and colon were noted. Significantly increased intestinal tumor frequency and increased numbers of larger tumors were observed in F1 mice of irradiated parents relative to F1 mice of sham-irradiated parents. Greater trans-generational tumorigenic effects of radiation were observed in male offspring relative to female offspring. In conclusion, here we present an early report for the first time that low dose radiation exposure has a trans-generational effect on intestinal tumorigenesis with potential implications for radiation exposure-related human health consequences. Citation Format: Shubhankar Suman, Santosh Kumar, Bo-Hyun Moon, Ziling Fan, Albert J. Fornace, Kamal Datta. Parental radiation elicits increased intestinal tumorigenesis in the F1 generation of APCMin/+ and APC1638N/+ mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 807. doi:10.1158/1538-7445.AM2015-807