bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 45: Dynamic biochemical tissue analysis of P-selectin ligands expressed on colon cancer.
Authors: Martin Eric W. , Shirure Venktesh S. , Malgor Ramiro , Resto Vicente A. , Goetz Douglas J. , Burdick Monica M. 
Published: August 2014

Abstract
Selectin ligands are known to be upregulated in metastatic tumor cell lines, and growing evidence suggests selectin/selectin-ligand interactions mediate the adhesion of circulating tumor cells to distant sites. Thus, novel methods of characterizing selectin ligands expressed on human tissue may serve as valuable assays with significant diagnostic and prognostic potential. Because the kinetic and tensile properties of selectin/selectin-ligand bonds are influenced by local physiological conditions, i.e., wall shear stress due to hydrodynamic force, traditional immunohistochemical approaches cannot adequately detect selectin ligands. That is, though immunohistochemistry is very successful in identifying high affinity interactions, selectin/selectin-ligand interactions exhibit high affinity only when the external force applied on the bond is at an optimal value. This affinity is considerably weaker when applied force on the bond is significantly larger than this optimal value, or else is low or zero, as in traditional immunohistochemistry. Therefore, we have developed a method for detecting selectin ligands expressed on human tissue using a dynamic approach that allows for precise control of the force applied to the bonds between probe and target molecules. More specifically, we conjugated recombinant P-selectin to polystyrene microspheres and perfused this probe over tissue sections of colon cancer - which is known to express P-selectin ligands. Selectin/selectin-ligand adhesive interaction in the form of microsphere rolling on tissue was observed, and specific interaction was confirmed using 10 mM EDTA as a negative control. Increased probe surface coverage (i.e., higher density of P-selectin molecules coated on the surface of the microspheres) resulted in increased interaction with colon cancer tissue. In addition, rolling velocities measured between physiological wall shear stresses 0.25-2.0 dyne/cm2 indicated adhesive interaction of the selectin-conjugated probe with ligands in colon cancer tissues was stabilized at 0.75 dyne/cm2. Analysis of distinct regions within colon cancer tissue sections subjected to this dynamic biochemical tissue analysis revealed different levels of microsphere adhesion in discrete areas, evidence of heterogeneous cellular expression of P-selectin ligands. Taken together, these results demonstrate that functional P-selectin ligands are detectable using dynamic biochemical tissue analysis.
Citation Format: Eric W. Martin, Venktesh S. Shirure, Ramiro Malgor, Vicente A. Resto, Douglas J. Goetz, Monica M. Burdick. Dynamic biochemical tissue analysis of P-selectin ligands expressed on colon 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 45. doi:10.1158/1538-7445.AM2013-45
Abstract 4503: Novel curcumin loaded magnetic nanoparticles for pancreatic cancer treatment.
Authors: Yallapu Murali M. , Ebleling Mara C. , Khan Sheema , Chauhan Neeraj , Gupta Brij K. , Sundram Vasudha , Jaggi Meena , Chauhan Subhash C. 
Published: August 2014

Abstract
Curcumin (CUR), a naturally occurring polyphenol derived from the root of Curcuma longa, has demonstrated potent anti-cancer and cancer prevention activity in a variety of cancers. However, the clinical translation of curcumin has been significantly hampered due its extensive degradation, suboptimal pharmacokinetics and poor bioavailability. To address these clinically relevant issues, we have developed a novel curcumin loaded magnetic nanoparticle (MNP-CUR) formulation. Herein, we have evaluated the in vitro and in vivo therapeutic efficacy of this novel MNP-CUR formulation in pancreatic cancer. Human pancreatic cancer cells (HPAFII and Panc-1) exhibited efficient internalization of the MNP-CUR formulation in a dose dependent manner. As a result, MNP-CUR formulation effectively inhibited growth of HPAFII and Panc-1 cells in cell proliferation and colony formation assays. Similarly, the MNP-CUR formulation suppressed pancreatic tumor growth in an HPAFII xenograft mice model and improved mice survival by delaying tumor growth. The growth inhibitory effect of MNP-CUR formulation was correlated with the suppression of PCNA, Bcl-xL, Mcl-1, MUC1, collagen I and enhanced membrane β-catenin expression. Interestingly, our MNP-CUR formulation did not show any sign of hemotoxicity and stable after incubation with human serum proteins. Additionally, our MNP-CUR formulation improved serum bioavailability of curcumin in mice up to 2.5 fold as compared to curcumin in Tween-20. Furthermore, biodistribution studies of our MNP-CUR formulation demonstrate a significant amount of formulation was able to reach the pancreatic xenograft tumor(s) which suggests its clinical translational potential. In conclusion, our study suggests that our novel MNP-CUR formulation can be valuable for the treatment of pancreatic cancer.
Citation Format: Murali M. Yallapu, Mara C. Ebleling, Sheema Khan, Neeraj Chauhan, Brij K. Gupta, Vasudha Sundram, Meena Jaggi, Subhash C. Chauhan. Novel curcumin loaded magnetic nanoparticles for pancreatic cancer treatment. [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 4503. doi:10.1158/1538-7445.AM2013-4503
Abstract 4520: Nanotechnology based drug delivery in childhood leukemia therapy: A novel approach to reduce side-effects.
Authors: Krishnan Vinu , Xu Xian , Barwe Sonali , Yang Xiaowei , Waldman Scott A. , Mason Robert W. , Jia Xinqiao , Rajasekaran Ayyappan K. 
Published: August 2014

Abstract
Despite attaining 5-year survival rates of 90%; more than 60% of pediatric cancer survivors are affected by at-least one life threatening event in their lifetime. Childhood leukemia is currently treated with a combination of chemotherapeutics that are effective in combating the disease. However, these drugs also affect the normal growing cells in children causing devastating side-effects. The goal of this study is to develop nanosized drug delivery formulations that deliver drugs specifically to leukemic cells and ultimately reduce treatment related side-effects in children. Multi-step chemical transformations were employed to construct amphiphilic block copolymers consisting of hydrophilic polyether (PEG) and hydrophobic polyester (PCL) bearing pendent cyclic ketals. The functional block copolymers self-assemble into micelles with a core-shell architecture comprising a segregated PCL core that encapsulates the steroid drug (Dexamethasone) and a sterically stabilized PEG shell that provides a platform to conjugate targeting moieties. Dexamethasone (Dex) and fluorescent-dye encapsulated nanoparticles (NPs) were formulated by a nanoprecipitation method. The size and morphology of all formulations were analyzed by dynamic light scattering (DLS) and transmission electron microscopy (TEM) methods. The non-toxic nature of the blank-NPs was confirmed both in vitro and in vivo. The drug encapsulated NPs (Dex-NPs) are endocytosed into leukemic cells and induced cytotoxicity similar to that of free Dex, but at reduced doses. The Dex-NPs significantly improved survival in preclinical mouse models of leukemia. A second generation drug encapsulated targeted NPs with transferrin as the targeting moiety improved NP uptake in leukemic cells by comparison to non-targeted NPs. The demonstrated efficacy of such novel nanotherapeutic systems in vitro and in pre-clinical mouse models of acute leukemia have provided the foundation to successfully create novel therapeutic delivery systems that target and treat pediatric hematological malignancies with enhanced efficacy and reduced toxicity.
Citation Format: Vinu Krishnan, Xian Xu, Sonali Barwe, Xiaowei Yang, Scott A. Waldman, Robert W. Mason, Xinqiao Jia, Ayyappan K. Rajasekaran. Nanotechnology based drug delivery in childhood leukemia therapy: A novel approach to reduce side-effects. [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 4520. doi:10.1158/1538-7445.AM2013-4520
Abstract 4536: Combination external beam and internal radiation via 131I-CLR1404 in the treatment of head and neck squamous cell carcinoma xenografts.
Authors: Saker Jarob , Armstrong Eric , Bednarz Bryan , Farhoud Mohammed , Besemer Abigail , Weichert Jamey , Harari Paul 
Published: August 2014

Abstract
Radiotherapy (RT) is a central treatment modality for head and neck cancer (HNC). However, optimal outcome is commonly limited by the radiation tolerance of adjacent normal tissue structures. Radiation is sometimes valuable in the setting of locoregional tumor recurrence, however the risk of significant normal tissue toxicity is substantial with repeat irradiation and can have a profound adverse impact on patient quality of life. Although technical advances including intensity modulated radiotherapy (IMRT) can reduce normal tissue effects, the problem of repeat exposure of normal tissues to radiation is frequently limiting. The radiolabeled drug 124/131I-CLR1404 is a phospholipid ether analogue (PLE) that accumulates preferentially within malignant tumors and enables internal delivery of radiation. This allows a combination of external and internal radiotherapy delivery with a goal of improving treatment outcome without enhanced normal tissue toxicities.
In this study, we characterized the ability of 131I-CLR1404 to augment RT response using xenografted mice harboring human squamous cell carcinomas (SCC). We determined tumor growth delay as well as tumor and normal tissue dose distribution of 131I-CLR-1404 via Monte Carlo simulation using PET data generated with 124I-CLR1404 imaging. Tumor growth delay was extended by 15.5 days using combined 3.7MBq 131I-CLR1404 and RT compared to RT or 131I-CLR1404 alone. In combination therapy, single dose administration of 7.4 MBq 131I-CLR1404 as well as split dosing with 2 x 3.7 MBq separated by one week showed the same additional growth delay of 27 days compared to single dose of 3.7 MBq. Monitoring drug distribution via PET/CT showed high tumor selectivity with a tumor-to-liver ratio of 6.2±0.65 and a tumor-to-muscle ratio of 6.7±0.21.
These data illustrate the tumor selectivity of the CLR1404 PLE delivery platform as well as augmentation of tumor response with combined RT and 131I-CLR1404 treatment. De-intensification of external beam radiation dose, with attendant reduction in normal tissue toxicities so common in HNC patients represents a central objective to be tested in controlled clinical trials with the ultimate goal of improving treatment outcome and quality of life for HNC patients.
Citation Format: Jarob Saker, Eric Armstrong, Bryan Bednarz, Mohammed Farhoud, Abigail Besemer, Jamey Weichert, Paul Harari. Combination external beam and internal radiation via 131I-CLR1404 in the treatment of head and neck squamous cell carcinoma xenografts. [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 4536. doi:10.1158/1538-7445.AM2013-4536
Abstract 4555: Design and discovery of novel small molecule redox modulators as therapies for pancreatic cancer.
Authors: Pathania Divya , Sechi Mario , Palomba Michele , Sanna Vanna , Berrettini Francesco , Sias Angela , Taheri Laleh , Neamati Nouri 
Published: August 2014

Abstract
Pancreatic cancer is a complex disease. Late stage detection, poor prognosis, and resistance to available chemotherapeutics highlight the need to discover new and potent anticancer agents for its effective treatment. Altered cellular bioenergetics and oxidative stress are emerging hallmarks of most forms of cancer including pancreatic cancer. Cancer cells are more prone to reactive oxygen species (ROS)-mediated cell death due to their inherent elevated basal oxidative stress as compared to normal cells. Increased basal ROS levels could represent the Achilles’ heel of cancer cells. Even though cancer cells have adapted to survive in an oxidative stress environment, exogenous oxidative insults can overwhelm the adaptive antioxidant capacity of cancer cells and trigger ROS-mediated cell death
We have identified a novel class of compounds that act as redox modulators and specifically induce cell death in cancer cells. Compound 3a was identified through a medium throughput screen of ∼1000 highly diverse in-house compounds and chemotherapeutic agents for their ability to alter cellular bioenergetics using XF 24 extracellular flux analyzer (Seahorse Bioscience, Billerica, MA). Further structural optimizations led to the discovery of a more potent analog, 3b that displayed anti-proliferative activities at low micromolar levels in both drug-sensitive and drug-resistant cancer cell lines. Treatment with compound 3b causes Akt activation resulting in increased cellular oxygen consumption, oxidative stress and depletion of cellular antioxidant pool in pancreatic cancer cells. Akt is a pro-survival kinase that is upregulated in several forms of human cancers. Hyperactive Akt inhibits apoptosis induced by numerous stimuli. However, Akt is unable to inhibit ROS-mediated cell death, and in fact, Akt aids in ROS-directed cell death by inducing cellular oxygen consumption, promoting ROS generation, and impairing ROS degeneration.
Moreover, oxidative stress induced by 3b promoted activation of stress kinases (p38/JNK) and resulted in cancer cell apoptosis. Treatment with antioxidants was able to reduce cell death confirming ROS-mediated cytotoxicity. In conclusion, our novel class of compounds are promising leads that by exacerbating oxygen consumption, ROS production, and reducing the antioxidant capacity of cancer cells tip the balance towards activation of stress kinases that ultimately leads to cell death.
Citation Format: Divya Pathania, Mario Sechi, Michele Palomba, Vanna Sanna, Francesco Berrettini, Angela Sias, Laleh Taheri, Nouri Neamati. Design and discovery of novel small molecule redox modulators as therapies for pancreatic 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 4555. doi:10.1158/1538-7445.AM2013-4555
Abstract 4596: LIN28B drives neuroblastoma oncogenesis through let7-MYCN signaling.
Authors: Schulte Johannes H. , Molenaar Jan , Lindner Sven , Schramm Alexander , Mestdagh Pieter , Speleman Frank , Versteeg Rogier , Eggert Angelika 
Published: August 2014

Abstract
LIN28B regulates developmental processes by modulating miRNAs of the let-7 family. A role for LIN28B in cancer has been proposed, but has not been established in vivo. We report LIN28B amplification or overexpression in high risk neuroblastoma. LIN28B repressed let-7 family miRNAs and induced MYCN expression in neuroblastoma cells in vitro. LIN28B-let-7-MYCN signaling induced proliferation and blocked differentiation of normal neuroblasts and neuroblastoma cells. The effect of LIN28B knock-down was rescued by overexpression of let-7-resistant MYCN. To analyse the tumor-initiating capacity and oncogenicity of Lin28b in vivo, mice were generated by knock-in of the CAG-LSL-Lin28b-IRES-Luciferse vector (LSL-Lin28b) into the ROSA26 locus. Crossbreeding these mice with DBH-iCre mice targeted Lin28b expression to the neural crest. Abdominal tumors developed in 7 of 18 DBHiCre;LSL-Lin28b mice at 36-62 days of age. Autopsy revealed uni- or bilateral adrenal tumors in all mice, reflecting the most frequent localization of human NB. Tumors consisted of small round blue cells and expressed the NB markers, DBH, TH and Phox2b. The macroscopic tumor appearance, primary tumor sites, tumor histology and marker gene expression confirmed these tumors as NB. Successful serial transplantation supported that the primary tumors from this model system were fully transformed malignant tumors. Both the Lin28b and MYCN proteins were strongly expressed in all tumors and members of the let-7 miRNA family were significantly downregulated. We demonstrate that overexpressing Lin28b in the neural crest can drive NB tumor formation in mice, supporting LIN28B as an important oncogene for NB and potentially for other malignancies. Therapeutic approaches aimed at inhibiting Lin28b or let-7 family re-expression may be useful therapeutic approaches to circumvent MYCN addiction in NB.
Citation Format: Johannes H. Schulte, Jan Molenaar, Sven Lindner, Alexander Schramm, Pieter Mestdagh, Frank Speleman, Rogier Versteeg, Angelika Eggert. LIN28B drives neuroblastoma oncogenesis through let7-MYCN signaling. [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 4596. doi:10.1158/1538-7445.AM2013-4596
Abstract 4599: Sequential monitoring of single-cell copy number variation in metastatic prostate cancer.
Authors: Kuhn Peter , Dago Angel E. , Stepansky Asya , Carlsson Anders , Felch Natalie , Luttgen Madelyn , Kolatkar Anand , Hicks James , Gross Mitchell E. 
Published: August 2014

Abstract
The high-definition circulating tumor cell (HD-CTC) assay provides for an enrichment-free approach to CTC identification. Here, we utilized the HD-CTC approach to study androgen receptor (AR) expression combined with single-nucleus sequencing for genome-wide analysis of copy number variation (CNV) in sequential CTCs samples obtained from a patient with metastatic prostate cancer treated with abiraterone acetate (an androgen synthesis inhibitor). At baseline, before initiation of abiraterone treatment, we observed a balanced proportion of AR-negative and AR-positive CTCs. During a brief period of clinical response (marked with a decreased serum PSA and decreased pain) the proportion of AR-positive CTCs declined followed by a rapid increase associated with clinical progression (increased PSA and pain). CNV analysis of single CTCs revealed multiple genomic rearrangements, such as AR amplification along with the chromosomal gains and losses typical of prostate cancer, in multiple cells at baseline. During treatment response, the frequency of CNV alterations significantly declined, followed by a reemergence to a pattern of multiple, complex alterations associated with clinical progression. Detailed analysis of the CNV profiles revealed that many abnormalities were commonly shared between the CTC populations, but a number were unique to the AR+ resistant/hormone refractory CTC population including increased MYC amplification alteration and the AR amplicon that include additional adjacent genes. Remarkably, the reconstruction of tumor lineage history based on the CTC genomic profiles enables us to trace and identify the precise treatment time point where the putative therapy-resistant CTC clone emerges, under therapeutic pressure, until it eventually expanded to become the AR+ resistant CTC population at the point of therapeutic relapse. Overall, our results demonstrated that the integration of the HD-CTC enumeration technology with protein expression and single cell genomic analyses could successfully be applied to real time monitoring of ADT therapy emergent change in a prostate cancer patient, and may provide a direct roadmap for personalized cancer medicine in the near future.
Citation Format: Peter Kuhn, Angel E. Dago, Asya Stepansky, Anders Carlsson, Natalie Felch, Madelyn Luttgen, Anand Kolatkar, James Hicks, Mitchell E. Gross. Sequential monitoring of single-cell copy number variation in metastatic prostate 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 4599. doi:10.1158/1538-7445.AM2013-4599
Abstract 461: Inhibition of HMGB1 delays tumor progression, reduces MDSC-mediated immune suppression, and diminishes MDSC-macrophage cross-talk interaction.
Authors: Parker Katherine , Rosenberg Suzanne , Sinha Pratima , Yang Huan , Tracey Kevin , Li Jianhua 
Published: August 2014

Abstract
Cancer immunotherapy aims to harness the power of the immune system to fight advanced stages of cancer. A main hindrance to cancer immunotherapy is tumor-induced immune suppression. Within the tumor microenvironment are a plethora of immune suppressive cells including Myeloid-Derived Suppressor Cells (MDSC). MDSC are present in nearly all types of cancer blocking T cell activation and shifting immunity towards a type 2 tumor-promoting phenotype through cross-talk with macrophages that enhances the secretion of pro-tumor molecules such as IL-10, and simultaneously drops IL-12 production by macrophages. MDSC accumulation is induced by pro-inflammatory cytokines including IL-1β, IL-6 and VEGF as well as alarmins such as S100A8/9. Because the alarmin HMGB1 is increased in many cancers, we are determining if HMGB1 drives MDSC. Inhibition of HMGB1 in vitro by chemical inhibitors Glycyrrhizin and Ethyl Pyruvate decreased cross-talk-induced IL-10 production by MDSC and IL-6 production by macrophages. Ethyl Pyruvate also reduced MDSC suppressive capacity in transgenic T cell suppression assays, suggesting that HMGB1 regulates multiple aspects of MDSC function. Treatment of BALB/c mice with 4T1 mammary carcinoma with HMGB1 inhibitors Glycyrrhizin and Ethyl Pyruvate reduced lung metastases and did not impact primary tumor progression. Treatment of C57BL/6 mice with MC38 colon carcinoma with an HMGB1 neutralizing antibody (2G7) reduced MDSC levels in the blood, spleen, and tumor. HMGB1 consists of two domains, the pro-inflammatory B box domain and an anti-inflammatory A box domain. Treatment of C57BL/6 mice with MC38 tumor with A box significantly reduced primary tumor growth and decreased MDSC levels in the blood. These findings indicate that full-length HMGB1 drives inflammation and tumor progression, while the anti-inflammatory A box domain counteracts full-length HMGB1 and reduces tumor growth and MDSC. These results suggest that HMGB1 drives MDSC accumulation and tumor progression and that A box can be used to target MDSC-mediated tumor-induced immune suppression.
(Research supported by NIH RO1CA115880 and RO1CA84232)
Citation Format: Katherine Parker, Suzanne Rosenberg, Pratima Sinha, Huan Yang, Kevin Tracey, Jianhua Li. Inhibition of HMGB1 delays tumor progression, reduces MDSC-mediated immune suppression, and diminishes MDSC-macrophage cross-talk interaction. [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 461. doi:10.1158/1538-7445.AM2013-461