bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4408: Molecular mechanisms underlying cancer pain: Application of cellular models
Authors: He Ying , Jhun Ellie , Wang Zaijie Jim 
Published: June 2012

Abstract
Pain is a major complaint in cancer patients. Little is known about the mechanisms leading to or maintaining cancer pain. This study is aimed to develop novel cellular models to study cancer pain. Isolated primary afferent sensory neurons were employed as a model system in order to produce cancer pain microenvironment in the presence of chemotherapeutic agents and cancer cells. Ca2+ imaging in sensory neurons showed increased [Ca2+]i within cancer pain microenvironment, suggesting a direct activation of sensory neurons. As a critical step in the initiation and transmission of pain cascades, release of pain neurotransmitters such as substance P and calcitonin-gene related peptide from primary afferent sensory neurons was studied and found to be significantly enhanced. As a result of sensory neuron activation, intracellular signaling transduction involving several major protein kinases was activated. For example, sub-apoptotic concentrations of paclitaxel (≤ 10 nM) potently elicit [Ca2+]i spikes, leading to PKA and PKC activation, and substance P release from primary afferent neurons. Moreover, AKAP150 was identified as a molecular mechanism synchronizing and transducing the activation of PKA to PKC. Our results reveal the presence of a specific cellular signaling pathway involving Ca2+/PKA/AKAP150/PKC(ε, βII, & Δ), independent of apoptosis, mediating pain neurotransmitter release and, ultimately, neuropathic pain induced by paclitaxel. Developing cellular models of cancer pain and identifying biomarkers/pathways may lead to novel diagnostic and therapeutic strategies for cancer pain.
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 4408. doi:10.1158/1538-7445.AM2011-4408
Abstract 4411: γH2AX as a marker of genomic instability predicts cisplatin sensitivity in triple negative breast cancer cells
Authors: Lehmann Brian D. , Bauer Josh A. , Sanders Melinda E. , Chakravarthy Bapsi A. , Pietenpol Jennifer A. 
Published: June 2012

Abstract
Triple negative breast cancers (TNBCs), that are hormone receptor negative (estrogen and progesterone) and lack HER2 amplification have limited treatment options. There is increasing evidence that TNBC is a heterogeneous disease and that patients with TNBC differentially respond to standard chemotherapies, which in many cases predicts for outcome. A portion of TNBC is considered genomically unstable as evidenced by array CGH analysis and the high frequency of BRCA1/2-mutations in TNBC patients. The identification of tumors displaying significant genomic instability may allow pre-selection of patients for select therapies (e.g. cisplatin, PARP inhibitors) that are more effective in the setting of deficient DNA damage response signaling. To determine if inherent genomic instability exists in TNBC, cell lines were analyzed for the phosphorylated histone variant 2AX (γ-H2AX) by immunohistochemistry and immunofluorescence as a marker of endogenous DNA damage. Tissue microarray blocks were created from 28 TNBC cell lines as well as appropriate controls to develop experimental conditions for γ-H2AX detection. TNBC cell lines significantly varied in the levels of baseline γ-H2AX foci, with BRCA1/2-mutant cell lines (HCC1937, HCC1599 and SUM149PT) having some of the highest levels. The presence of γ-H2AX foci in the absence of stress correlated with sensitivity (IC50) to cisplatin (R2 = 0.620), but not PARP inhibitors (R2 = 0.006). In addition to cell lines, we demonstrate that γ-H2AX staining can be detected in archived formalin-fixed, paraffin-embedded breast cancer tissue with approximately 25% of the tumors displaying high levels of nuclear γ-H2AX staining. Therefore endogenous levels of γ- H2AX may have potential use as a clinical biomarker to identify patients that will benefit from treatment with DNA-damaging agents.
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 4411. doi:10.1158/1538-7445.AM2011-4411
Abstract 4412: Prognostic significance of NF-κB in Middle Eastern diffuse large B cell lymphoma and efficacy of NF-κB inhibition as a viable therapeutic target
Authors: Bavi Prashant , Uddin Shahab , Bu Rong , Ahmed Maqbool , Abubaker Jehad , Al-Dayel Fouad , Balde Valorie , Naidu Padmanabhan , Al-Dossari Hassan , Qadri Zeeshan , Prabhakaran Sarita E. , Hussain Azhar R. , Al-Kuraya Khawla S. 
Published: June 2012

Abstract
NF-kB is frequently over expressed in variety of NHL and has been implicated in lymphomagenesis; however, its role in diffuse large B-cell lymphoma (DLBCL) as a prognostic biomarker has not been fully elucidated. Therefore, we investigated the role of NF-kB and its association with clinico-pathological features in a tissue microarray cohort of 230 DLBCL patient samples. We then elucidated the role of NF-kB inhibition on cell viability and apoptosis in-vitro using DLBCL cell lines. Using immunohistochemistry, NF-kB was detected in 25.6% (52/203) DLBCL tumors, was associated with activated B cell (ABC) phenotype (p=0.0054) and overexpression of anti apoptotic marker, XIAP (p=0.0013). DLBCL with nuclear expression of NF-kB showed a significantly poor overall survival as compared to those with no NF-kB expression (p=0.0236). In the multivariate analysis using Cox Proportional Hazard model for IPI and NF-kB expression, the relative risk was 2.97 for high NF-kB expression (95% CI 1.27-6.94; p=0.0113) and 7.55 for high IPI group (95% CI 3.34-18.35; p&lt;0.0001). In-vitro, Bay11-7085 inhibited constitutively active NF-kB expression in a dose dependent manner. Inhibition of NF-kB also down-regulated expression of down-stream target gene products, such as Bcl-2, Bcl-Xl, XIAP and Survivin leading to apoptosis via the mitochondrial apoptotic pathway. NF-kB overexpression was found to be an independent prognostic marker for poor survival in DLBCL. Inhibition of NF-kB caused apoptosis via activation of the mitochondrial apoptotic pathway. Altogether, these results suggest that NF-kB may be a useful prognostic biomarker and a potential target for therapeutic intervention in DLBCL.
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 4412. doi:10.1158/1538-7445.AM2011-4412
Abstract 4413: A 5-gene model predicts clinical outcome in ER+/PR+, early stage breast cancers treated with adjuvant tamoxifen
Authors: Kerr Daniel Alan , Wittliff James L. 
Published: June 2012

Abstract
Purpose: Patients with primary breast carcinomas expressing of both estrogen (ERα) and progesterone receptors (PR) are more likely to respond to Tamoxifen therapy than those with ERα and PR negative cancers, especially in women with early stage lesions. However, a significant number of these patients exhibiting clinicopathologic features suggesting good response and prognosis will relapse within 10 years. Additional markers are needed to identify patients at risk for breast cancer recurrence after administrative hormone therapy.
Procedures: Ten candidate genes associated with estrogen signaling were selected from a group of 200 genes identified from microarray studies of laser capture microdissected breast carcinoma cells of ER positive breast cancers and combined with those for conventional biomarkers (ESR1, PGR, ERBB2). Carcinoma cell content and pathology of each biopsy was confirmed. Expression of this 13-gene subset was analyzed by RT-qPCR in de-identified frozen tissue specimens from early stage, ER+/PR+ breast cancers treated with adjuvant Tamoxifen. A multivariate model was created by Cox regression using a training set of tissue sections from 36 biopsy specimens, and then applied to an independent validation set of sections from 24 specimens.
Results: A 5-gene model was derived from the training set that exhibited significant correlations with both relapse-free and overall survival. Applying this model to Kaplan-Meier regression, patients were separated into low risk (100% relapse-free at 150 months) and high risk (60% relapse-free at 150 months) groups (P = 0.03). When this model was applied to the validation set, similar risk stratification was achieved for both relapse-free and overall survival (P = 0.01 and 0.04, respectively). No significant difference in clinical features (e.g., tumor grade, tumor size and nodal status) was observed between the high and low risk groups.
Conclusions: We developed a 5-gene model composed of PgR, BCL2, ERBB4 JM-a, RERG and CD34 that identified a subset of early stage, ER+/PR+ breast cancers patients treated with Tamoxifen that exhibited high recurrence rates, although their clinicopathologic features suggested good prognosis and response. Furthermore, absence of association of the 5-gene model with tumor grade suggests the gene expression profile provides clinically relevant predictive information independent of proliferation. Supported in part by grants from the Phi Beta Psi Sorority Charity Trust and a CTSP award from the Commonwealth of Kentucky. DAK was a recipient of a Graduate Fellowship from the Integrated Programs in Biomedical Sciences, University of Louisville, and the Spatola Graduate Fellowship from IMD3.
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 4413. doi:10.1158/1538-7445.AM2011-4413
Abstract 4426: Preclinical development of a rare tumor model: Establishment and characterization of a patient-derived collecting duct carcinoma
Authors: Thangasamy Amalraj , Nieves Francis , Papadopoulos Kyriakos , Patnaik Amita , Tolcher Anthony , Wick Michael J. 
Published: June 2012

Abstract
Collecting duct carcinoma (CDC) is a rare type of renal tumor accounting for approximately 2% of all renal cell carcinomas (RCC). Unlike common RCC that arises from the convoluted tubules of the renal cortex, this aggressive tumor is derived from the renal medulla, possibly from the distal collecting duct of Bellini. Clinically this aggressive tumor is shown to have a poor response to therapy and the majority of patients when diagnosed are in the metastatic phase. While several agents have been recently approved for standard RCC, lack of useful preclinical models of CDC have limited drug screening for potential therapies.
To this end we have established a patient-derived model of CDC and characterized mutational status and target expression. In addition, we have evaluated in vivo drug sensitivity to agents approved for standard RCC including sorafenib and sunitinib as well as the chemotherapies irinotecan and gemcitabine and targeted therapy temsirolimus. For model establishment a core biopsy was collected and engrafted into an immune-deficient mouse; once take was confirmed tumor tissue was passaged until model stabilization at which point tissue was taken for characterization and in vivo drug sensitivity evaluated. For model characterization, mutation status and expression of target molecules in proliferation pathways were examined by PCR and immunohistochemistry. In the drug sensitivity study, targeted RCC therapies and gemcitabine reported modest tumor growth inhibition while irinotecan was active with significant inhibitory effects. Some activity was reported with the mTOR inhibitor temsirolimus but its effect was not found statistically significant.
Overall we have established and characterized a rare patient-derived tumor model of RCC and demonstrated its use as a tool for screening potentially useful agents for patients with collecting duct carcinoma.
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 4426. doi:10.1158/1538-7445.AM2011-4426
Abstract 4429: Toxicology and drug delivery by novel cucurbit[n]uril-type nanocontainers
Authors: Hettiarachchi Gaya , Ma Da , Nguyen Duc , Isaacs Lyle , Briken Volker 
Published: June 2012

Abstract
Many drug delivery systems are based on the ability of certain macrocyclic compounds – such as cyclodextrins – to act as molecular containers for pharmaceutical agents in water. Cucurbit[n]urils (CB[n]) are a class of molecular containers that bind to a variety of cationic and neutral species with high affinity and therefore show great promise as a drug delivery system. We hypothesized that these nanocontainers can be used to increase solubility of hydrophobic small chemical compound drugs. In this study we investigated the toxicology, uptake, and bioactivity of two cucurbit[n]urils CB[n]-type containers (named Motor1 and Motor2). Both containers induced no toxicity at concentrations of up to 1 mM in human cell lines originating from kidney, liver or blood tissue using assays for metabolic activity and cytotoxicity. Furthermore, the Motor1 container was tolerated in mice without any toxicity after intravenous dosing of up to 1.5g/kg bodyweight. Interestingly, Motor1 was able to bind the cancer drug paclitaxel and increase its solubility in water by a factor of 2000. Motor2 demonstrated an increase of water solubility of camptothecin by 500fold. Finally, bioactivity assays showed that the increase in solubility by paclitaxel via Motor1 led to a more efficient killing of the ovarian cancer cell line SKOV-3. In conclusion, our study reveals very low toxicity of two novel members of the cucurbit[n]uril family of nanocontainers. It demonstrates the increase in solubility of two important cancer drugs by the containers which led to increased killing of cancer cells in vitro. These results provide initial proof-of-concept towards the use of CB[n] molecular containers as an advanced drug delivery system.
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 4429. doi:10.1158/1538-7445.AM2011-4429
Abstract 4434: Thermally targeted delivery of a c-Myc inhibitory peptide to breast tumors in vivo using elastin-like polypeptide
Authors: Bidwell Gene L. , Perkins Eddie , Raucher Drazen 
Published: June 2012

Abstract
Although surgical resection with adjuvant chemotherapy and/or radiotherapy are used to treat breast tumors, normal tissue tolerance, development of metastases, and inherent tumor resistance to radiation or chemotherapy can hinder a successful outcome. Therefore, it is necessary to consider alternative targeted therapeutic approaches for adjuvant therapy that would significantly reduce undesired side effects in normal tissues. We have developed a thermally responsive polypeptide (CPP-ELP-H1) that inhibits breast cancer cell proliferation by blocking the activity of the oncogenic protein c-Myc. When administered IV into mice bearing orthotopic, syngeneic breast tumors, CPP-ELP-H1 exhibited a long plasma half life and accumulated in tumor tissue. The tumor levels of the CPP-ELP delivered H1 peptide were enhanced when hyperthermia was applied to the tumor site. Daily administration (7 days) of CPP-ELP-H1 followed by tumor heating induced over 70% reduction in tumor volume compared to unheated controls or controls lacking the H1 inhibitory peptide. This work provides a new modality for targeted delivery of a specific oncogene inhibitor. In addition to the peptide's intrinsic tumor targeting due to its oncogene inhibition, ELP can be physically targeted to the tumor site by application of external hyperthermia. Specific targeting of the proposed therapeutic polypeptides by local hyperthermia to breast tumors or to areas of potential metastasis following tumor resection would increase specificity and efficacy of treatment and reduce the cytotoxicity in normal tissues.
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 4434. doi:10.1158/1538-7445.AM2011-4434
Abstract 4435: Anti-multiple myeloma activity of NK012, a micelle-forming macromolecular prodrug of SN-38, in an orthotopic model
Authors: Miyazaki Osamu , Sekine Keiko , Nakajima Naoko , Ichimura Eiji , Ebara Keiko , Nagai Daichi , Matsumoto Shinichi , Onda Takeshi , Miyakawa Yoshitaka , Okamoto Kazuya , Morino Tomio 
Published: June 2012

Abstract
NK012 is a micelle-forming macromolecular prodrug of SN-38, an active metabolite of irinotecan (CPT-11). It accumulates in tumor tissue and gradually releases SN-38 in an enzyme-independent manner. We previously reported that NK012 showed stronger antitumor activity in a broad range of human solid tumor xenograft models than CPT-11 (2006 AACR Annual Meeting, #3062). Currently, phase II clinical trials of NK012 in patients with triple-negative breast cancer, small cell lung cancer, and colorectal cancer are ongoing in the United States and Japan. In this study, we evaluated the antitumor activity of NK012 in an orthotopic multiple myeloma model that shows typical infiltration of human myeloma cells into murine bone marrow tissue. A suspension of 2 × 106 cells of CD138 positive U266 human myeloma cells was injected into immunodeficient NOG (NOD/Shi-scid, IL-2Rγnull) mice via tail vein. The transplanted mice produced plasma M protein (human IgE) and developed lytic bone lesions. In addition, hind-leg paralysis caused by myeloma progression in spinal cord was observed. These symptoms were similar to complications observed in the patients with multiple myeloma. The intravenous administration of NK012 at 3.75, 7.5, and 15 mg/kg/day by q4d × 3 suppressed M protein concentration in plasma and proliferation of myeloma cells in bone marrow in a dose-dependent manner. Also observed were decrease in the area of osteolytic lesions and recovery of decreased total bone mineral density in the tibias. To examine the efficacy of NK012 in survival time, the myeloma-transplanted mice were treated with 9.4 mg/kg/day (28.2 mg/m2/day), q7d × 6, equivalent to the clinical recommended dose of 28 mg/m2/day as a single dose. NK012 significantly prolonged survival time of the mice compared with control group (78.5 days vs. 40 days, P&lt;0.001). We next examined the combination effect of NK012 with bortezomib, which is commonly used for multiple myeloma treatment. The combined treatment of NK012 (9.4 mg/kg/day, q7d × 3) with bortezomib (0.5 mg/kg/day, 2 times/week × 2, i.v.) exhibited increase in median survival time over bortezomib alone (83.5 days vs. 68 days). In conclusion, these results suggested NK012 is a promising candidate for human multiple myeloma treatment.
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 4435. doi:10.1158/1538-7445.AM2011-4435
Abstract 4438: A membrane modulating strategy improves doxorubicin therapy in spontaneous mouse breast carcinoma
Authors: van Hell Albert J. , Koning Gerben , Jonkers Jos , van Blitterswijk Wim , Verheij Marcel 
Published: June 2012

Abstract
BACKGROUND: Frequently, clinical anti-cancer therapy is suboptimal because of the inability to deliver high levels of cytostatics into tumor cells. We identified a class of short-chain sphingolipids that facilitate the translocation of amphiphilic drugs over the plasma membrane, including various cytostatics.
RESULTS: The sphingolipid analogue N-octanoyl-GlucosylCeramide (GC) elevates intracellular doxorubicin levels four- to eight-fold, both in vitro and in xenografted B16 melanoma tumor tissue. In order to examine enhanced anti-tumor efficacy by GC preclinically, we used a spontaneous mouse breast cancer model that closely mimics human Invasive Lobular Carcinoma (ILC), and we applied a two-step experimental set-up with mouse cohorts of increasing tumor heterogeneity. In both populations, GC co-administration significantly increased tumor growth delay by doxorubicin, when compared to the conventional free or liposomal doxorubicin formulations. In contrast, the GC co-administration did not add upon bone marrow suppression, the main doxorubicin toxicity as revealed by pathological examination. Overall, mice treated with the GC-doxorubicin co-formulation better endured therapy and showed extended overall survival.
CONCLUSION: Concomitant in vivo membrane modulation by short-chain sphingolipids widens the therapeutic window of the anti-cancer agent doxorubicin in a preclinical model for human ILC.
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 4438. doi:10.1158/1538-7445.AM2011-4438
Abstract 4446: A novel nanoparticle drug delivery system: The anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes
Authors: Sun Dongmei , Zhuang Xiaoyin , Grizzle William , Miller Donald , Zhang Huang-Ge 
Published: June 2012

Abstract
Monocyte-derived myeloid cells play vital roles in inflammation related autoimmune/inflammatory diseases and cancers. Here, we report that exosomes can deliver anti-inflammatory agents, such as curcumin, to activated myeloid cells in vivo. This technology provides a means for anti-inflammatory drugs, such as curcumin, to target the inflammatory cells as well as to overcome unwanted off-target effects that limit their utility. Using exosomes as a delivery vehicle, we provide evidence that curcumin delivered by exosomes is more stable and more highly concentrated in the blood. We show that the target specificity is determined by exosomes and the improvement of curcumin bioavailability is achieved by directing curcumin to inflammatory cells associated with therapeutic, but not toxic, effects. Furthermore, we validate the therapeutic relevance of this technique in a LPS induced septic shock mouse model and mouse breast tumor model. We further show that exosomes, but not lipid alone, are required for the enhanced anti-inflammatory activity of curcumin. The specificity of using exosomes as a drug carrier creates opportunities for treatments of many inflammation related diseases without significant side effects due to innocent bystander or off target effects.
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 4446. doi:10.1158/1538-7445.AM2011-4446