bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B82: Olanzapine for cachexia in patients with advanced cancer.
Authors: Abdelrahim Maen , Naing Aung , Dalal Shalini , Wheler Jennifer , Hess Kenneth , Fu Siqing , Hong David S. , Janku Filip , Falchook Gerald S. , Ilustre Alyson , Ouyang Fengying , Kurzrock Razelle 
Published: August 2014

Abstract
Background: This study assessed the safety, tolerability as well as effectiveness of olanzapine as a treatment for cachexia in patients with advanced cancer.
Methods: Patients with advanced cancers were recruited into this exploratory, open-label, study of olanzapine for cachexia starting at 2.5 milligram (mg) once-daily oral dosing. All patients received anti-neoplastic treatments for their cancers in addition to our study drug olanzapine. Serum samples from patients were collected at baseline, and after weeks 1, 2, 4, and 8 for analysis of levels of leptin, growth hormone, ghrelin, and interleukin-6 (IL-6).
Results: Thirty-nine patients received olanzapine. Of the 39 participants, 31 were evaluable for weight change. Six were excluded because they had developed ascites, and two were excluded because of incomplete body weight data. Toxicities related olanzapine are Grade II somnolence (n=1), grade II pancreatitis (n=1), grade II extrapyramidal symptoms (n=1) and grade II nausea/ vomiting (n=1). No dose-limiting toxicities were reported. The recommended dose was defined as 20 mg daily by mouth once daily. Samples from twenty-nine patient were eligible for analysis of serum cytokine levels. Mean values of leptin levels before treatment and on treatment were 3153 pg/ml vs 2488 pg/ml (p=0.085); for growth hormone the values were 2961 pg/ml vs 3758 pg/ml (p=0.33); for interleukin-6, the values were 27.5 pg/ml vs 40.9 pg/ml (p=0069) and for ghrelin they were 0.18 ng/ml vs 0.19 ng/ml p=0.52. The mean change in slope in weight from prior to and during the study is 0.24 with 95% CI = (-0.08, 0.56) and p = 0.13. Associations between changes in different cytokines and weight were inconclusive.
Conclusion: Though some patients’ serum cytokines levels increased or decreased, these changes did not correlate with change in body weight. Treatment with Olanzapine had a modest effect in changing the trajectory of weight loss.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B82.
Citation Format: Maen Abdelrahim, Aung Naing, Shalini Dalal, Jennifer Wheler, Kenneth Hess, Siqing Fu, David S. Hong, Filip Janku, Gerald S. Falchook, Alyson Ilustre, Fengying Ouyang, Razelle Kurzrock. Olanzapine for cachexia in patients with advanced cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B82.
Abstract 4067: Pegylated arginine deiminase (ADI-PEG20) as a potential novel therapy for argininosuccinate synthetase-deficient acute myeloid leukemia
Authors: Szlosarek Peter W. , Luong Fiona , Clear Andrew , Taussig David , Joel Simon , Calaminici Maria , Debernardi Silvana , Fitzgibbon Jude , Bomalaski John S. , Frankel Arthur E. , Bonnet Dominique 
Published: August 2014

Abstract
Acute myeloid leukemia (AML) is the most common leukemia in adults and the second most common leukemia in children, accounting for a significant share of health care costs with ten thousand cases diagnosed per annum in the US alone. Enzyme-based therapy in the form of asparaginase has revolutionized the treatment of acute lymphoblastic leukemia and there is increasing interest in exploiting analogous tractable metabolic defects in AML. Interestingly, arginine auxotrophic tumors due to deficiency of the rate-limiting enzyme for arginine production, argininosuccinate synthetase (ASS1) are susceptible to arginine-degrading enzymes. Here, we studied whether ASS1 negativity would predict for the efficacy of pegylated arginine deiminase (ADI-PEG20) using AML cell lines and primary AML samples. A lack of ASS1 protein was identified in three of seven leukemic cell lines (K562, Kasumi and KG-1) and in all nine samples from patients with cytogenetically normal and abnormal karotype AML. Methylation of the ASS1 promoter correlated with reduced levels of ASS1 mRNA and absence of ASS1 expression. Bone marrow trephines from patients with AML revealed absence of ASS1 protein in 87% (46/53) of samples by immunohistochemistry, indicating that ASS1 expression may be a biomarker of response to ADI-PEG20 in vivo. Increased levels of ASS1 mRNA and detectable ASS1 protein expression were noted in acute promyelocytic leukemia with the translocation t(15;17). Significantly, ADI-PEG20 reduced the viability of ASS1-negative AML lines whereas the ASS1-positive control lines, Fujioka and U937, were resistant to drug-induced arginine deprivation. Recently, we have identified primary ASS1-negative AML samples with good engraftment in NOD/SCID mice and are proceeding to test the efficacy of ADI-PEG20 using this primary AML xenograft model. Based on our preliminary data and the potential efficacy with low toxicity of arginine deprivation in humans, a phase II trial of ADI-PEG20 is planned in patients with relapsed AML.
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 4067. doi:10.1158/1538-7445.AM2011-4067
Abstract 2377: MCT1 and MCT4 in NSCLC: Overexpression of MCT1 in tumor and stroma is an independent prognostic marker for NSCLC survival.
Authors: Eilertsen Marte , Andersen Sigve , Al-Saad Samer , Kiselev Yury , Donnem Tom , Stenvold Helge , Al-Shibli Khalid , Richardsen Elin , Busund Lill-Tove , Bremnes Roy Martin 
Published: August 2014

Abstract
Background: As non-small cell lung cancer (NSCLC) is a leading cause of cancer deaths, new prognostic and predictive markers are highly warranted. Monocarboxylate transporters (MCTs) 1 and 4 are transmembrane transporters of lactate and puruvate and are central in cancer cell metabolism. The biological and prognostic importance of MCT1 and MCT4 is not thoroughly studied in NSCLC. Herein, we aimed to explore the prognostic impact on disease specific survival (DSS) in both tumor and stromal cells from NSCLC-patients.
Methods: Tissue micro arrays (TMAs) were constructed, representing both epithelial tumor tissue and stromal tissue from 335 unselected patients diagnosed with NSCLC I-IIIA. Immunohistochemistry was used to evaluate the expression of MCT1 and MCT4.
Results: MCT1 and MCT4 expression was located to the cell membrane. In univariate analyses, patients with high MCT1 expression in tumors had a favorable disease-specific survival (DSS) (p=0.021). While high expression of MCT1 in stroma was associated with poor DSS (p=0.003). High expression of MCT4 in tumor was a negative prognostic factor (p=0.027), while high expression of MCT4 in stroma showed a trend toward being a positive prognostic factor (p=0.11). In the multivariate analysis, MCT1 in tumor was independently and significantly associated with a favorable DSS (HR = 1.80, CI 95% 1.23-2.64, p=0.003). MCT1 in stroma was independently and significantly associated with a poor DSS (HR = 1.7, CI 95% 1.1-2.7, p=0.016). MCT4 in tumor had no significant prognostic impact in the multivariate analysis.
Conclusions: High expression of MCT1 in tumor and stroma is an independent prognostic marker for NSCLC survival, and is therefore a candidate marker for prognostic stratification in NSCLC. These results also highlight the differential, but possible cooperative energy metabolism in tumor and stroma for NSCLC-patients.
Citation Format: Marte Eilertsen, Sigve Andersen, Samer Al-Saad, Yury Kiselev, Tom Donnem, Helge Stenvold, Khalid Al-Shibli, Elin Richardsen, Lill-Tove Busund, Roy Martin Bremnes. MCT1 and MCT4 in NSCLC: Overexpression of MCT1 in tumor and stroma is an independent prognostic marker for NSCLC survival. [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 2377. doi:10.1158/1538-7445.AM2013-2377
Abstract 299: Targeting epithelial-mesenchymal transition in breast cancer cells using Honokiol, a natural phenolic compound.
Authors: Avtanski Dimiter B. , Nagalingam Arumugam , Kupusamy Panjamurthi , Saxena Neeraj K. , Sharma Dipali 
Published: August 2014

Abstract
Introduction: The epithelial-mesenchymal transition (EMT) presents a critical step in the acquisition of metastatic state. Tumor cells undergoing EMT not only exhibit increased migration and invasion potential but also acquire increased resistance to chemotherapy and radiation therapy. Hence, EMT is an attractive target for therapeutic interventions directed against tumor metastasis. Honokiol (HNK) is a natural phenolic compound isolated from an extract of seed cones from Magnolia grandiflora. Recent studies from our lab show that honokiol inhibits breast carcinogenesis. The present study is designed to systematically elucidate if nontoxic lower doses of honokiol can be used to specifically inhibit EMT in breast cancer cells.
Results: Our studies show that HNK inhibits EMT in human breast cancer cells. Exposure of estrogen-independent and estrogen-responsive breast cancer cells to nontoxic lower doses of HNK results in significant downregulation of mesenchymal marker proteins (Fibronectin, Vimentin) along with simultaneous upregulation of epithelial markers (E-cadherin, Cytokeratin-18). HNK also inhibits expression and nuclear translocation of transcriptional modulators of EMT-related genes (Snail, ZEB1/2 and Twist). Experimental EMT induced by exposure to TGFβ and TNFα in a spontaneously immortalized nontumorigenic human mammary epithelial cell line (MCF-10A) was also completely reversed by HNK treatment as evidenced by morphological changes (inhibition of fibroblast-like appearance, decreased pseudopodia and actin reorganization to membrane-bound location in TGFβ and TNFα treated MCF10A cells) as well as molecular changes (downregulation of Fibronectin, Vimentin, Snail, Zeb1/2 and upregulation of E-cadherin and Cytokeratin-18). Mechanistically, HNK inhibits MTA1-Wnt1 axis leading to stabilization and nuclear translocation of β-catenin to inhibit EMT. Analysis of breast tumors treated with honokiol show modulation of EMT markers and inhibition of key molecules of MTA1-Wnt1-β-catenin axis corroborating our in vitro findings.
Conclusions: Taken together, these data provide the first in vitro and in vivo evidence of the potential of HNK as a novel, non-toxic and non-endocrine therapeutic strategy for breast carcinoma. MTA1, Wnt1 and β-catenin appear to be novel biomarkers associated with HNK treatment.
Citation Format: Dimiter B. Avtanski, Arumugam Nagalingam, Panjamurthi Kupusamy, Neeraj K. Saxena, Dipali Sharma. Targeting epithelial-mesenchymal transition in breast cancer cells using Honokiol, a natural phenolic compound. [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 299. doi:10.1158/1538-7445.AM2013-299
Abstract 329: A mouse model of epithelial ovarian cancer with defined oncogenic drivers.
Authors: Agadjanian Hasmik , Cheon Dong-Joo , Diaz Elena , Laury Anna , Miller Carl , Karlan Beth , Orsulic Sandra , Walsh Christine 
Published: August 2014

Abstract
Epithelial ovarian cancers (EOC) represent the gynecologic malignancy with the highest mortality rate. The Cancer Genome Atlas demonstrated a high degree of genetic heterogeneity among the papillary serous (PS) tumors, the most lethal of the EOC subtypes. Aside from almost universal mutation in TP53, there was a low prevalence of recurrent mutations in other genes, presenting a challenge to the development of targeted therapeutics against this aggressive tumor type. We are developing a mouse model of EOC by introducing defined genetic alterations to mouse ovarian surface epithelial (MOSE) cells. We had a particular interest in developing a cyclin E amplified tumor model, as CCNE1 amplification is found in 20% of human EOC tumors, making this one of the most prevalent PS EOC subtypes. We infected MOSE cells from p53-/- mice with different combinations of oncogenes encoded in retroviral vectors including CCNE1, myc and H-RAS. MOSE cells were infected with one or two oncogenes, passaged and injected into the peritoneal cavity of nude mice. Myc-HRAS caused the rapid development of hemorrhagic ascites and intraperitoneal carcinomatosis in 5 of 5 mice by day 18. HRAS alone and HRAS-CCNE1 both caused intraperitoneal and omental tumors to develop with clear ascites by day 35 in 5 of 5 mice. Myc caused bloating due to the development of frank hemoperitoneum in all 5 mice between days 101 and 150. Only 4 of the 5 mice had small volume intraperitoneal tumors. Myc-CCNE1 similarly caused bloating due to ascites in 2 mice and hemoperitoneum in 2 mice. Three of these four mice had small volume intraperitoneal tumors. One mouse has not developed any phenotype by 150 days. CCNE1 alone has not caused tumor formation in any of 5 mice by day 150. Histology of the Myc-HRAS, HRAS, HRAS-CCNE1, and Myc tumors were all consistent with high-grade undifferentiated carcinoma. Tumor cells generated in the Myc-HRAS, HRAS and HRAS-CCNE1 experiments were capable of causing intraperitoneal tumor development in immunocompetent C57BL/6 mice by day 17, 29 and 54 respectively. Taken together, our data demonstrate a reproducible mouse model for the development of high-grade epithelial ovarian carcinomas with defined genetic alterations that are capable of study in both immunodeficient and immunocompetent mice. Tumor phenotypes varied based on the combination of activated oncogenes.
Citation Format: Hasmik Agadjanian, Dong-Joo Cheon, Elena Diaz, Anna Laury, Carl Miller, Beth Karlan, Sandra Orsulic, Christine Walsh. A mouse model of epithelial ovarian cancer with defined oncogenic drivers. [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 329. doi:10.1158/1538-7445.AM2013-329
Abstract 3504: Plasma growth differentiating factor-15 (GDF-15) and other inflammatory markers are associated with weight loss and poor prognosis in cancer patients.
Authors: Lorena Lerner , Hayes Teresa , Tao Nianjun , Krieger Brian , Feng Bin , Nicoletti Richard , Bai Ailin , Weng Zhigang , Liu Qing , Chiu Maria Isabel , Gyuris Jeno , Garcia Jose M. 
Published: August 2014

Abstract
Background: Cachexia is associated with increased inflammatory markers and decreased survival in cancer. Also, elevated GDF-15 has been associated with poor prognosis in several cancer types but its role in cachexia is not well-understood.
Methods: We measured body weight change, appetite, plasma GDF-15, and other inflammatory markers in 62 males with cancer-cachexia (CC), 72 non-cachectic cancer subjects (CNC) and 64 non-cancer controls (Co) matched by age, gender and pre-illness body weight. In a subset of patients we also measured grip strength (HGS), appendicular lean body mass (aLBM), ECOG and KPS.
Results: GDF-15, IL-6 and IL-8 were increased in CC vs. other groups. Activin and G-CSF were significantly upregulated in CC vs. Co. A subset analyses showed that GDF-15, Activin A and IL-8 were increased in CC vs. CNC in lung cancer patients and that GDF-15, IL-6 and IL-8 were increased in CC patients treated with platinum-based chemotherapy.
GDF15, IL-6 and IL-8 levels significantly correlated with 6-month weight loss and with IL-6, IL-1ra, IL-2, IL-4, IL-9, IL-10, IFN, MCP-10, MIP-1a, MIP-1b, TNF-a, VGEF and activin in cancer patients. Analysis in a subset of patients showed that CC had lower grip strength, aLBM, and fat mass; and that ECOG and KPS were lower in CC and CNC compared to controls. GDF-15 and IL-8 correlated negatively with aLBM, HGS and fat mass. Activin correlated negatively with aLBM.
Survival analysis showed that GDF-15 and IL-8 predicted survival adjusting for stage and weight change (Cox regression p&lt;0.01, HR 3).
Conclusion: GDF-15 and other inflammatory markers are associated with weight loss, decreased muscle mass and strength and poor survival in cancer patients. GDF-15 may serve as a prognostic indicator in cancer patients and be a novel therapeutic target for cancer cachexia.
Citation Format: Lerner Lorena, Teresa Hayes, Nianjun Tao, Brian Krieger, Bin Feng, Richard Nicoletti, Ailin Bai, Zhigang Weng, Qing Liu, Maria Isabel Chiu, Jeno Gyuris, Jose M. Garcia. Plasma growth differentiating factor-15 (GDF-15) and other inflammatory markers are associated with weight loss and poor prognosis in cancer patients. [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 3504. doi:10.1158/1538-7445.AM2013-3504
Abstract 366: Downregulation of THBS1 is a critical step in glioblastoma angiogenesis.
Authors: Brooks Michael D. , Jackson Erin , Piwnica-Worms David , Mitra Robi D. , Rubin Joshua B. 
Published: August 2014

Abstract
One of the hallmarks of Glioblastoma multiforme (GBM) is its abundant vasculature. These blood vessels support the tumor in a number of ways, including providing a niche for glioblastoma cancer stem cells. GBM tumors drive the formation of their vasculature and associated germinal niches through reciprocal inductive interactions between GBM cells and endothelial cells. Targeting the primary drivers of angiogenesis, VEGF and bFGF, in anti-angiogenic cancer treatments has value but is not curative. We hypothesize that identification of additional angiogenic molecules and pathways will provide new avenues for treatment. We used microarrays to perform global gene expression profiling to identify genes that are increased or decreased in expression as a consequence of functional interactions between GBM and brain microvascular endothelial cells. We identified several regulators of angiogenesis whose expression is modulated by this cell-cell interaction, but were particularly interested in the downregulation of Thrombospondin-1 (THBS1) and its associated receptors. THBS1 is a powerful anti-angiogenic protein and has previously been implicated in cancer, but its precise mechanism in glioblastoma angiogenesis is not yet known. A number of in-vitro experiments validated the importance of THBS1 in the interaction between GBM and endothelial cells. In-vivo mouse xenograft experiments showed that overexpression of THBS1 strongly inhibited tumor formation. We believe these results reveal the importance of factors other than VEGF in glioblastoma angiogenesis and provide a rationale to evaluate combinatorial targeted anti-angiogenic therapy for GBM.
Citation Format: Michael D. Brooks, Erin Jackson, David Piwnica-Worms, Robi D. Mitra, Joshua B. Rubin. Downregulation of THBS1 is a critical step in glioblastoma angiogenesis. [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 366. doi:10.1158/1538-7445.AM2013-366
Abstract 3806: Progressive biallelic loss of TP53 is associated with progression of pleuropulmonary blastoma initiated by germline loss and somatic mutation of DICER1.
Authors: Pugh Trevor J. , Yu Weiying , Yang Jiandong , Ambrogio Lauren , Carter Scott L. , Kiezun Adam , McKenna Aaron , Giannikopoulos Petros , Getz Gad , Messinger Yoav , Meyerson Matthew , Hill D. Ashley 
Published: August 2014

Abstract
Pleuropulmonary blastoma (PPB) is a rare, aggressive childhood cancer arising from lung mesenchymal cells. In early stages, these cells reside in the walls of epithelial-lined cysts and may remain dormant or progress to thickened cysts and then highly malignant masses over several years. Familial germline loss-of-function DICER1 variants have been described, although carriers may not be affected. Therefore, we sought to uncover additional genetic events underlying tumor development through whole exome sequencing of 15 tumor/normal pairs. In addition to known loss-of-function germline variants found throughout DICER1, this analysis identified somatic missense mutations clustered in the DICER1 RNase IIIb domain in nearly every case. While the somatic mutations impact novel amino acid residues, expression analysis demonstrated depletion of 5p-derived miRNAs similar to that described in other DICER1-mutant tumors. While mutation rates were relatively high compared to other pediatric solid tumors, most mutations, except those in DICER1 and TP53, appeared to be subclonal. Early stage tumors (PPB Type II) had predominantly single-copy deletion of TP53 whereas late stage tumors (PPB Type III) had secondary TP53 mutations. Several late stage tumors also had activating mutations in RAS pathway members, including NRAS and BRAF. Therefore, compound DICER1 loss appears to be initiating and synergistic with incremental loss of TP53 and acquisition of additional driver mutations. We subsequently characterized this molecular pattern using deep sequencing and immunohistochemistry in an extension cohort of 45 additional tumors. This step-wise series of germline and somatic alterations illustrates a genetic mechanism consistent with the progressive nature of pleuropulmonary blastoma.
Citation Format: Trevor J. Pugh, Weiying Yu, Jiandong Yang, Lauren Ambrogio, Scott L. Carter, Adam Kiezun, Aaron McKenna, Petros Giannikopoulos, Gad Getz, Yoav Messinger, Matthew Meyerson, D. Ashley Hill. Progressive biallelic loss of TP53 is associated with progression of pleuropulmonary blastoma initiated by germline loss and somatic mutation of DICER1. [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 3806. doi:10.1158/1538-7445.AM2013-3806