tbuckley/cabot-search huggingface dataset:
Abstract 2608: Dietary polyunsaturated fatty acids modulate adipose inflammation and the adipokine secretome to influence mammary stem cell self-renewal
Authors: Raymond M. Esper, Evan Hill, Yan Jiang, Nadeem Aslam, Becky Simon, Max Wicha, William Smith, Dean E. Brenner
Journal: Cancer Research (2016)

Abstract Obesity strongly increases risk for multiple malignancies. One potential contributor may be the chronic low-grade inflammation that is likely driven by dysfunctional adipose characterized by aberrant adipokine production and macrophage activation/polarization. In adipose tissue, free fatty acids and their lipid mediators serve as important regulators of adipokine gene transcription. The adipocyte fatty acid composition is influenced by dietary availability. Here we present data demonstrating that dietary fish oil supplementation in obese rats (achieving a 2.5:1 ω6:ω3 PUFA ratio, comparable to a Mediterranean diet) attenuates adipose inflammation characterized reduction in the M1/M2 macrophage polarization ratio compared to a typical Western diet with a 20:1 ω6:ω3 PUFA ratio. We developed a novel adipose explant culture system to directly assay the secretome, and demonstrate that quenching adipose inflammation in obese animals is associated with a favorably rebalanced adipokine milieu, most notably increased adiponectin concentration and decreased leptin secretion. We previously showed that these two adipokines differentially modulate mammary stem cell self-renewal; here, we studied the effect of adipose conditioned media from obese rats on mammary stem cells using the mammosphere formation assay. Adipokines from obese rats fed the high-ω6 diet increased mammary stem cell symmetric self-renewal by 86.7 ± 7.5% (± SEM), whereas adipose-derived factors from the obese animals fed a low-ω6 diet supplemented with fish oil reduced the number of secondary mammospheres by 30.3 ± 10.1% by promoting either apoptosis, quiescence, or symmetric division-differentiation of the primary stem cells. Using a neutralizing antibody and a soluble receptor, we demonstrate that leptin contributes only 19% of the adipose-derived effect on mammary stem cell self-renewal. Taken together, our data suggests that a simple dietary intervention to modify the dietary PUFA ratio is an effective method to quench adipose inflammation and rebalance the adipokine milieu, which may modulate the mammary stem cell pool. If normal stem cells can give rise to breast cancer as has been theorized, then dietary interventions to quench adipose inflammation and reduce the rate of symmetric stem cell self-renewal might protect against the increased incidence of breast cancer seen in obese post-menopausal women. Citation Format: Raymond M. Esper, Evan Hill, Yan Jiang, Nadeem Aslam, Becky Simon, Max Wicha, William Smith, Dean E. Brenner. Dietary polyunsaturated fatty acids modulate adipose inflammation and the adipokine secretome to influence mammary stem cell self-renewal. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2608.
Abstract 1657: Mapping mechanisms of radiotherapy resistance in prostate cancer
Authors: Serena T. Bruens, Chiara Milanese, Nicole Verkaik, Pier Mastroberardino, Akos Gyenis, Jiang Chang, Kasper Derks, Erik Wiemer, Dik van Gent, Wytske van Weerden, Guido Jenster, Jan Hoeijmakers, Joris Pothof
Journal: Cancer Research (2016)

Abstract Cancer cells that acquire radio-resistance are major problem for treatment outcome. We aimed at identifying mechanisms and networks that control ionizing radiation (IR)-resistance in prostate cancer cells. To this end, we applied to cancer cell lines an identical radiotherapy regiment as performed in the clinic, i.e. a total dose of 78 Gy in steps of 2 Gy per day for 5 consecutive days followed by 2 days rest. We observed that radio-resistance occurs early during treatment as seen in colony survival assays in which 100% of cells that can form colonies are resistant up to 8 Gy. Remarkably, a two-week period of culturing without radiotherapy completely sensitized these resistant cancer cell lines, indicating that resistance is not acquired by permanent mutations or chromosomal rearrangements. Currently, we are characterizing these extreme resistant cancer cell cultures by comparing these to their sensitive parental cancer cell lines and the two-week re-sensitized cancer cell lines. We observe changes in DNA repair pathway utilization, DNA damage checkpoint activation and energy metabolism parameters, but not in PI3-kinase signalling and cancer stem cell markers. We also performed genome-wide gene expression analysis by next generation sequencing and isolated gene signatures that correlate with resistance. Based on our results we applied inhibitors to sensitize these IR-resistant cells. Notably, application of single inhibitors did not lead to sensitivity. Combinations of small molecule inhibitors however, were able to sensitize these cancer cell lines, indicating that IR-resistance is a multi-factorial process. In summary, mapping gene networks and mechanisms will uncover new pathways associated with IR-resistance. Citation Format: Serena T. Bruens, Chiara Milanese, Nicole Verkaik, Pier Mastroberardino, Akos Gyenis, Jiang Chang, Kasper Derks, Erik Wiemer, Dik van Gent, Wytske van Weerden, Guido Jenster, Jan Hoeijmakers, Joris Pothof. Mapping mechanisms of radiotherapy resistance in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1657.
Histologic subtyping and clinical efficacy of platinum-based first-line chemotherapy (CT) in advanced-stage non-small cell lung cancer (NSCLC): A retrospective analysis.
Authors: F. Valentino, M. Torchio, F. Corbella, P. Massaro, P. Morbini, E. Pozzi, M. Danova
Journal: Journal of Clinical Oncology (2010)

e18084 Background: Until few years ago, the standard first-line CT for NSCLC was based on a platinum-containing doublets, despite of the histological subtyping. This aspect is now becoming relevant in view of a treatment decision process based on the differential activity of new drugs. In this study, we have focused on the impact of histology in pts with advanced-stage NSCLC treated since 2005, at our Institution, outside clinical trials, by a multidisciplinary team, with first-line, standard platinum-based regimens. Methods: We retrospectively evaluated 261 pts, with stage IIIB-IV NSCLC: 164 non-squamous subtype (104 males/60 females; median age 65.4 yrs; 36-82) and 97 with squamous differentiation (88 males/9 females; median age 68.5 yrs; 44-82). All pts have completed four courses of a platinum compound + gemcitabine (47%) or vinorelbine (53%) at standard doses. The clinical impact of the drug combination administered was evaluated, as % objective response (OR) at the end of the four courses, and as progression-free survival (PFS). Results: In the non-squamous group, the OR: were 62% when the platinum compound was associated with gemcitabine and 65% when the association was with vinorelbine (p = n.s.). In the squamous group, these % were 54 and 57, respectively (p = n.s.). The median PFS for the non-squamous group were: 4.7 months with gemcitabine-, and 4.8 months with vinorelbine-containing doublets, respectively (p = n.s.). In the squamous group the median PFS were 3.8 months with gemcitabine- and 3.5 months with Vinorelbine-containing doublets, respectively (p = n.s.). The difference between the median PFS for the two histological subgroups was statistically significant (p = 0.05), irrespectively from the employed regimen. Conclusions: Our analysis showed that platinum-based doublets with gemcitabine or vinorelbine produced the same OR in all subgroups, without correlation with the histological subtype. However, the median PFS was significantly lower in pts with squamous NSCLC. This confirms the importance of conducting prospective studies aimed to select new therapeutic agents and/or drug combinations for this group of pts. No significant financial relationships to disclose.
<i>EGFR</i> polymorphism and <i>KRAS</i> mutational status as predictors of resistance to anti-EGFR therapy in advanced colorectal cancer (ACRC): A GEMCAD study
Authors: J. Maurel, V. Alonso-Espinaco, V. Alonso, P. Escudero, M. Jimeno, X. Garcia-Albeniz, J. Muñoz, C. Fernandez- Martos, E. Carcereny, S. Castellví-Bel
Journal: Journal of Clinical Oncology (2009)

4060 Background: Single nucleotide polymorphism (SNP) in codon R497K of EGFR by reducing EGFR activity has been associated to resistance to anti-EGFR monoclonal antibodies in ACRC (Carcereny, ASCO2008). Methods: We retrospectively investigated the role of EGFR R497K and KRAS mutational status in primary CRC or metastases, in predicting response rate (RR), progression free survival (PFS) and overall survival (OS) of cetuximab or panitumumab in second or third line therapy in patients (pts) with ACRC. EGFR R497K was detected by real-time PCR using the TaqMan technology and KRAS mutation status in codons 12/13 was determined by sequencing. CT scans were done every 6–8 weeks (w) until progressive disease. Results: A total of 117 pts with available tissue out of 168 pts treated with anti-EGFR therapy in 6 Spanish Institutions, were analysed for EGFR R497K and KRAS mutational status. There were no differences in RR (18.8 vs.16.8%), PFS (13.2 vs. 12 w) and OS (31 vs. 28 w) between the whole and the selected cohort. We found no significant differences on RR (9/59;15.2 vs. 9/52; 17.3%), PFS (13.5 vs. 13.2 w) and OS (33 vs. 26.8 w) according to EGFR R497K (GG vs. GA/AA). Pts with wild-type (WT) KRAS had better response (20.7% vs. 8.1%;p=0.07) and PFS (14.4 vs. 11.7 w; p=0.006) compared with mutant KRAS. Interestingly, a significant increment on RR (30 vs. 0%, p=0.003), PFS (14.4 vs. 7.4 w, p=0.002) and OS (34.1 vs. 20 w, p=0.03) was observed only in those patients with WT KRAS and &gt;1x upper limit of normal (ULN) lactate dehydrogenase (LDH) levels compared with mutant KRAS, but these differences were not found in pts with WT KRAS and &lt;1xULN levels of LDH: [RR (14 vs. 14%, p=NS), PFS (14.4 vs. 13.1 w, p=NS) and OS (31 vs. 31 w; p=NS)]. Conclusions: EGFR R497K is not a predictive marker of efficacy to EGFR-inhibitors. Our study suggest that pts with WT KRAS and &gt;1xULN levels of LDH, have major benefit to anti-EGFR therapy in second-third line therapy. No significant financial relationships to disclose.
127O Phase 1 study of safety and tolerability of selinexor in Asian patients with advanced solid cancers: updated results
Authors: V.Y.M. Heong, P. Koe, W.P. Yong, R. Soo, C.E. Chee, Y.L. Thian, A. Gopinathan, A. Wong, R. Sundar, J. Ho, S. Friedlander, D. McCauley, C. Choe-Juliak, S.C. Lee, B.C. Goh, D.S. Tan
Journal: Annals of Oncology (2015)
Abstract 899: Cancer protection associated with dietary methyl donor deficiency is characterized by persistent changes to epithelial proliferation and metabolism
Authors: Matthew P. Hanley, Daniel W. Rosenberg
Journal: Cancer Research (2016)

Abstract The role of folate one-carbon metabolism in colorectal cancer development is incompletely understood, and nutritional intervention studies have produced conflicting results. We previously demonstrated that a diet deficient in the methyl donors folic acid, methionine, choline and vitamin B12, and supplemented with homocysteine, reduces intestinal tumor incidence by greater than 95% in ApcMin/+ mice. Here we extend these findings to a second mouse tumor model, ApcÄ14, and further show that the cancer protection afforded by even short-term dietary methyl donor deficiency (MDD) is long-lasting. Eleven weeks of MDD followed by methyl donor repletion was sufficient to maintain tumor suppression for at least 7 additional weeks (22.2 ± 3.5 vs 70.2 ± 4.6 intestinal tumors; p &amp;lt; 0.001). Sustained tumor protection was associated with altered intestinal crypt homeostasis. MDD increased the proportion of intestinal epithelial cells undergoing apoptosis in normal crypts and in tumors (4.9- and 3.2-fold, respectively), while reducing cell proliferation (Ki-67) and mitosis (PHH3). In addition, metabolomic profiling and metabolite set enrichment analysis (MSEA) revealed that tumor protection is associated with persistent alterations to metabolic pathways related to cellular proliferation, including glutamine metabolism, biogenic amine synthesis, nucleotide salvage and glutathione synthesis. Taken together, these results indicate that even a temporary dietary methyl donor restriction in cancer-prone mice can induce persistent changes to the intestinal epithelium that provide long-lasting protection in adult mice. Citation Format: Matthew P. Hanley, Daniel W. Rosenberg. Cancer protection associated with dietary methyl donor deficiency is characterized by persistent changes to epithelial proliferation and metabolism. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 899.
Use of the GUARDANT360 noninvasive tumor sequencing assay on 300 patients across colorectal, melanoma, lung, breast, and prostate cancers and its clinical utility.
Authors: AmirAli Talasaz, Stefanie Mortimer, Dragan Sebisanovic, LaiMun Siew, Aubrey Zapanta, Gangwu Mei, Ben Schiller, Helmy Eltoukhy
Journal: Journal of Clinical Oncology (2014)

e22041 Background: Analysis of genomic alterations in advanced malignant disease is quickly becoming the standard of care in oncology. Biopsies are risky, often costly and may not capture genetic changes that can emerge over time or in response to therapy. In contrast, GUARDANT360, a blood-based liquid biopsy approach that analyzes circulating tumor DNA (ctDNA), offers a simple and comprehensive tool for real-time tumor genetic profiling in advanced refractory cancer patients. Methods: We studied the performance of GUARDANT360 in five prevalent cancers: colorectal, melanoma, lung, breast, and prostate. Over 500 plasma samples and 100 matched tumors from a total of 300 unique patients were analyzed using GUARDANT360, a single-molecule next-generation digital sequencing assay with ability to detect somatic mutations and copy number variations with exquisite sensitivity. The assay covers sequences across a total of 54 actionable genes covering approximately 80 kbps. Select patients were treated on the basis of ctDNA alterations detected by GUARDANT360. Results: The overall detection rate of somatic alterations in ctDNA approached 85% for all indications (the range of detectable ctDNA mutations was 0.03%-87%). The concordance of tumor mutations to GUARDANT360 ranged from 67% (blood draw > 6 months post biopsy) to 93% (concurrent blood draw at time of biopsy). The dominant genetic mutations observed were similar to those previously reported for solid tumors. About 60% of cases with colorectal, breast and lung cancers had actionable mutations. The select patients treated on the basis of observed ctDNA alterations exhibited significant positive clinical outcomes (PR) suggesting strong potential for clinical utility of ctDNA sequencing. Conclusions: Advances in single-molecule sequencing and bioinformatics make possible the ultra-sensitive detection of somatic mutation and amplifications. Comprehensive profiling of ctDNA shows reasonable concordance to tumor profiles and illustrates the potential to improve the care of advanced refractory cancer patients.
The Aggressive Molecular Signature of Peripheral Blood Chronic Lymphocytic Leukemia (CLL) Cells From Patients with Bulky Lymphadenopathy Closely Resembles That of CLL Cells From Lymph Nodes,
Authors: Amit K. Mittal, Javeed Iqbal, Christine E Gilling, Margaret Moragues, R. Gregory Bociek, Patricia Aoun, Dennis D Weisenburger, Shantaram S Joshi
Journal: Blood (2011)
Abstract 33: NSCLC cells internalize ATP <i>in vitro</i> and <i>in vivo</i> using multiple endocytotic pathways
Authors: Yanrong Qian, Xuan Wang, Yunsheng Li, Yanyang Cao, Xiaozhuo Chen
Journal: Cancer Research (2016)

Abstract Upregulated glycolysis in cancer, the Warburg effect, has been studied for almost one century. However, the biological reasons for the upregulation are still debated and the effect is far from fully understood. One of the major controversies related to the effect is the role of ATP synthesis. Intratumoral ATP concentrations are found to be 10⁁3-10⁁4 times higher than those in normal tissues of the same cell origin. However, whether and how cancer cells use the abundant extracellular ATP was unknown until we recently reported that cancer cells internalize ATP by macropinocytosis (1). Extracellular ATP was found to increase intracellular ATP concentration and promote cell proliferation and drug resistance in cancer cells (1). Here we report that, using a nonhydrolyzable fluorescent ATP (NHF-ATP) as an ATP surrogate, high and low molecular weight dextrans as endocytosis tracers and fluorescence microscopy detection, cultured human NSCLC A549 and H1299 cells as well as xenografted A549 tumors were found to internalize ATP at concentrations within the reported intratumoral ATP concentrations. Endocytosis inhibitor studies show that in addition to macropinocytosis, clathrin- and caveolae-mediated endocytoses contribute to the ATP internalization, which led to a ∼30% increase in intracellular ATP level after 45 min of ATP incubation. This increase cannot be accounted for by purinergic receptor signaling or increased intracellular ATP synthesis rates. Internalization of NHF-ATP and dextran exhibits time-dependent profiles parallel to the extracellular ATP-induced intracellular ATP level elevation. All these demonstrate the observed ATP increase is a result of internalization of extracellular ATP and NHF-ATP is a powerful tool for studying ATP internalization. These findings significantly deepen our understanding of the Warburg effect by showing how cancer cells in tumors take up intratumoral ATP and perform previously unrecognized biological functions. It strongly suggests ATP-sharing among cancer and stromal cells and identifies multiple novel anticancer targets (2). 1. Qian Y, Wang X, et al., Cancer Lett. 351(2014): 242-5. 2. Chen X, Qian Y, Wu S. Free. Radic. Biol. Med. 79(2015): 253-263. Citation Format: Yanrong Qian, Xuan Wang, Yunsheng Li, Yanyang Cao, Xiaozhuo Chen. NSCLC cells internalize ATP in vitro and in vivo using multiple endocytotic pathways. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 33.
Abstract 5150: Identification of higher mRNA expression of both Kitenin and ErbB4 CYT-2 isoform as a molecular marker for the prediction of transition from colon adenoma to carcinoma
Authors: Jeong A Bae, Eun Gene Sun, Yoo-Seung Ko, Hui Jeong Choi, Woo-Kyun Bae, Sang-Hee Cho, Ik Joo Chung, Kyung-Sub Moon, Young-Hyun Yu, Hyung-Ho Ha, Hangun Kim, Kyung Keun Kim
Journal: Cancer Research (2016)

Abstract Purpose: The molecular events in the malignant progression of colon adenoma after loss of adenomatous polyposis coli (APC) are not fully understood. KITENIN (KAI1 C-terminal interacting tetraspanin) increases the invasiveness of colorectal cancer (CRC) cells and we recently identified a novel EGFR-independent oncogenic signal of EGF that works under co-expressed KITENIN and ErbB4. Here we tested whether elevated KITENIN and ErbB4 contributes to further progression of intestinal adenoma following APC loss. Results &amp; Discussion: The intestinal tissues of villin-KITENIN transgenic mice in which villin-driven elevated KITENIN induced increased c-Jun expression exhibit mild epithelial cell proliferation but no epithelial lineage changes, compared with those of non-transgenic mice. Among the 4 ErbB4 isoforms, JM-a/CYT-2 and JM-b/CYT-2 exhibited the highest AP-1 activity when cells co-expressing KITENIN and each isoform were stimulated by EGF. Interestingly, predominant overexpression of ErbB4 CYT-2 isoform mRNA as well as increased EGFR expression were observed in intestinal adenoma of APCmin/+ mice making the microenvironment of activated EGF signaling. When we crossed villin-KITENIN mice with APCmin/+ mice, intestinal tumor tissues in the crossed mice showed the characteristics of early stage invading adenocarcinoma. In CRC patients, ErbB4-CYT-2 mRNA expression was significantly greater in tumor tissues than in normal adjacent tissues, but no differences in tumoral expression between the stages, and a positive correlation exists between KITENIN and ErbB4-CYT-2 mRNA expression. Thus, elevated expression of KITENIN and ErbB4-CYT-2 is newly identified as a factor that promotes the transition of colon adenoma to adenocarcinoma within an APC-loss-associated tumor microenvironment. Conclusion: Higher mRNA expression of both KITENIN and ErbB4-CYT-2 in colon adenoma tissues can be used as a molecular marker of the possible development of malignant transformation. Citation Format: Jeong A Bae, Eun Gene Sun, Yoo-Seung Ko, Hui Jeong Choi, Woo-Kyun Bae, Sang-Hee Cho, Ik Joo Chung, Kyung-Sub Moon, Young-Hyun Yu, Hyung-Ho Ha, Hangun Kim, Kyung Keun Kim. Identification of higher mRNA expression of both Kitenin and ErbB4 CYT-2 isoform as a molecular marker for the prediction of transition from colon adenoma to carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5150.
Novel Photodepletion Strategy to Preserve and Expand Tregs While Eliminating CD4+ Effector T Cells From Patients with Chronic Graft-Versus-Host Disease
Authors: Jean-Philippe Bastien, Gorazd Krosl, Cynthia Therien, Marissa Rashkovan, Christian Scotto, Sandra Cohen, David S. Allan, Donna E. Hogge, R. Maarten Egeler, Claude Perreault, Denis-Claude Roy
Journal: Blood (2010)
Synthesis, characterization and evaluation of in vitro toxicity in hepatocytes of linear polyesters with varied aromatic and aliphatic co-monomers
Authors: Deepak Kakde, Leagh G. Powell, Kuldeep K. Bansal, Steve Howdle, Derek Irvine, Giuseppe Mantovani, Gavin Millar, Lea Ann Dailey, Vicki Stone, Helinor J. Johnston, Cameron Alexander
Journal: Journal of Controlled Release (2016)
Similar biological activity in skin prick test for Oralair<sup>®</sup> (8200 <scp>BAU</scp>) and Grazax<sup>®</sup> (6200 <scp>BAU</scp>) reinforces effective SLIT dosing level
Authors: D. E. S. Larenas Linnemann, J. Singh, N. Rosario, R. Esch, J. J. Matta, J. Maspero, A. Michels, R. Mösges
Journal: Allergy (2016)

Abstract In Europe, allergen extracts are standardized based on skin prick wheal size in 20–30 allergic subjects. To understand the biological activity of clinically effective Sublingual immunotherapy , we used this method to determine the biological activity of solution and tablet Timothy grass pollen ( TIM ) extracts, compared to an FDA ‐approved extract (Reference) of 10 000 BAU/ml. Blinded, quadruplicate skin prick tests with concentrate and three serial half‐log dilutions allowed the construction of a semilogarithmic regression line per extract. Bioequivalent allergy units ( BAU ) values were obtained from the comparison with reference. Extracts and dilutions showed a neat linear dose response (all: R 2 &gt; 0.98) in 33 rhinitis patients. Relative potencies: Staloral ® 12 000 BAU/ml, Soluprick ® 10 300 BAU/ml, Oralair ® 8200 BAU, and Grazax ® 6200 BAU. Even though all extract concentrates differed in wheal size ( P = 0.01–0.001), Grazax ® producing a 25% smaller wheal size than Oralair ® , and the biological activity of these clinically effective TIM tablets led in the same range (6200–8200 BAU ; 0.92–1.23 cm 2 ). SLIT dose‐finding studies for other pollens might start with allergen extracts producing 1.1 cm 2 wheal surface.