tbuckley/cabot-search huggingface dataset:
Abstract 3185: Adipocyte-derived hydrogen peroxide promotes chemoresistance to daunorubicin in leukemia cells
Authors: Jean-Hugues Parmentier, Christina M. Dieli-Conwright, Steven D. Mittelman
Journal: Cancer Research (2017)

Abstract Background: Adipocytes protect acute lymphoblastic leukemia (ALL) cells from several chemotherapeutic drugs. This protection is associated with an oxidative stress response in adipocytes. Since adipocytes are known to release reactive oxygen species, and anthracyclines are sensitive to inactivation mediated by hydrogen peroxide (H2O2), we investigated whether adipocyte release of H2O2 into the micro-environment might contribute to drug resistance of ALL cells. Methods: Pre-B lymphoblast/myeloblast BV173 cells in complete media (CM) were co-cultured for 3 days in transwells over 3T3-L1 fibroblasts or adipocytes. Viable cells were determined by Trypan blue exclusion for BV173 cells. Leukemia Conditioned Media (LCM) was prepared from BV173 cultured for 48 hrs. Total antioxidant capacity was measured by ABTS-based assay. H2O2 released in the extracellular compartment of adipocytes was monitored with Amplex Red and ROS-Glo. Results: BV173 cells were protected from DNR in presence of 1 mM H2O2 (9.34±2.15x104 vs. 3.33±1.01x104 viable cells with and without H2O2, p=0.03). Interestingly, this protection was only observed when pyruvate was present in the culture media at equimolar concentrations with H2O2 (DNR: 4.14±2.14x104; DNR+pyruvate: 4.17±1.53x104; DNR+H2O2: 3.77±2.74x103; DNR+pyruvate+H2O2: 3.21±0.59x105, p=0.02). Adipocytes released H2O2 into the media measured with Amplex Red fluorescence in a time-dependent manner significantly more than fibroblasts (1.96-fold, p=0.001). LCM potentiated adipocyte H2O2 released (1.5-fold over CM, p=0.05). Human adipose tissue biopsies from breast cancer survivors also released H2O2 (4.37x103 RFU for biopsies vs. 0.65x103 RFU for HBSS, 90 min, n=5). Co-culture of adipocytes and BV173 cells increases the survival of BV173 to DNR treatment (1.55±0.34x105 vs. 6.88±2.91x103 viable cells with and without adipocytes, p=0.006). Adipocyte-mediated protection of BV173 cells was reversed in a dose-dependent manner by adding the H2O2-inactivating enzyme catalase to the extracellular media (7.28±1.44x104 vs. 15.58±3.48x104 viable cells with and without 500 U/ml catalase, p=0.01). Conclusion: These data show that adipocytes release H2O2, which in the presence of pyruvate, protects ALL cells from DNR. Further work is needed to determine whether adipocytes secrete significant amounts of H2O2 in the bone marrow micro-environment to contribute to anthracycline resistance. Citation Format: Jean-Hugues Parmentier, Christina M. Dieli-Conwright, Steven D. Mittelman. Adipocyte-derived hydrogen peroxide promotes chemoresistance to daunorubicin in leukemia cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3185. doi:10.1158/1538-7445.AM2017-3185
Abstract 3558: Src regulation of peroxisome proliferator-activated receptor gamma (PPARγ) in lipid metabolism of lung cancer
Authors: Tuyen N. M. Hua, Ai N. H. Phan, Yangsik Jeong
Journal: Cancer Research (2017)

Abstract Metabolic reprogramming, recently becoming one of the cancer hallmarks, is linked to oncogenic signal transduction to find a better solution for cancer therapy. As one of key mediators in oncogenic signal transduction, non-receptor tyrosine kinase Src is known to drive cancer progression by promoting cell proliferation, metastasis, and drug resistance. Although previous studies reported that Src promotes fat accumulation and suppresses browning of white adipocytes, little is known about the mechanistic role of Src in cancer metabolism. Here we report that Src mediates lipid mobilization by suppressing transcriptional activity of PPARγ, a key regulator of lipid metabolism. Firstly, we found Src suppression of PPARγ activity which, interestingly, turned out to be independent of Src kinase domain or a known Src phosphorylation site of PPARγ at tyrosine 78. Since the treatment of Src inhibitor (e.g., SU6656, PP2) could rescue Src-driven PPARγ suppression by possibly changing Src conformation, we might suggest the involvement of Src-PPARγ interaction in the regulatory mechanism. Mechanistically, further in vitro experiment showed Src inhibitor treatment recovered expression of PPARγ target genes such as fatty acid binding protein 4 (FABP4) and cluster of differentiation 36 (CD36) in a subset of non-small cell lung cancer cell lines. The increase of FABP4 and CD36 expression was associated with the reduction of lipid droplets, suggesting the role of Src regulation of PPARγ in lipid mobilization. Collectively, this finding provides better understandings about the role of Src in cancer lipid metabolism, and an insight into therapeutic combination of targeting oncogenic signal transduction and lipid metabolism to treat cancer. Note: This abstract was not presented at the meeting. Citation Format: Tuyen N. M. Hua, Ai N. H. Phan, Yangsik Jeong. Src regulation of peroxisome proliferator-activated receptor gamma (PPARγ) in lipid metabolism of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3558. doi:10.1158/1538-7445.AM2017-3558
Abstract 3655: Biomarker strategy to guide the clinical development of ImmTACTM molecules, a novel class of bispecific T cell engaging biologic drugs
Authors: Cheryl McAlpine, David Krige, Sandra Herrero-Gonzalez, Sarah Franklin, Jacob Hurst, William Shingler, Sanjay Patel, Andy Johnson, Debbie Parker, Christina M. Coughlin, Namir J. Hassan, Bent K. Jakobsen
Journal: Cancer Research (2017)

Abstract IMCgp100, a first in class immunotherapy, is a T cell redirecting bispecific biologic comprising an affinity enhanced T-cell receptor specific for gp100 and an anti-CD3 scFV. Phase I/IIa data has provided evidence of a favourable safety profile, and durable responses in both cutaneous and uveal melanoma have been observed. To complement the clinical studies we have developed a comprehensive biomarker strategy to aid our understanding of pharmacodynamics, patient response and potential mechanisms of resistance which includes analysis of markers in both the tumour and periphery. The data obtained to date provide evidence of the pharmacodynamic effects of the molecule including chemokine/cytokine release, in both the tumor and periphery, and lymphocyte infiltration into tumors. In addition, changes in the levels of certain chemokines following the first dose of IMCgp100 were associated with tumor shrinkage. The biomarker strategy we have developed forms the basis for the support of the on-going Ph II development of IMCgp100 in both cutaneous and uveal melanoma and for other ImmTAC molecules, as single agents and in combination, for the treatment of solid tumours. Citation Format: Cheryl McAlpine, David Krige, Sandra Herrero-Gonzalez, Sarah Franklin, Jacob Hurst, William Shingler, Sanjay Patel, Andy Johnson, Debbie Parker, Christina M. Coughlin, Namir J. Hassan, Bent K. Jakobsen. Biomarker strategy to guide the clinical development of ImmTACTM molecules, a novel class of bispecific T cell engaging biologic drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3655. doi:10.1158/1538-7445.AM2017-3655
OP0263 Trans-ancestral meta-analysis identifies 13 new loci associated with serum urate levels
Authors: TR Merriman, M Cadzow, R Topless, D Mount, H Choi, Y Okada, J Boocock, E Stahl
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Serum urate is an important biomarker for gout disease and kidney function. Genome-wide association study (GWAS) meta-analyses have identified 28 loci in European and East Asian population samples. Combined analysis of these summary data across populations offers the opportunity to discover new serum urate associations through greater sample size and power, and trans-ancestral analyses provide the opportunity for fine-mapping associations with greater resolution given differing linkage disequilibrium patterns between populations. <h3>Objectives</h3> To conduct a meta-analysis of European and East Asian serum urate GWAS. <h3>Methods</h3> Summary statistics from European (N=110,238) (Kottgen et al. 2013) and east Asian (N=21,268) (Okada et al. 2012) meta-analyses were obtained. We used ImpG v1.0 to impute the results into 1000 Genomes phase 3 variants, and performed sample-size weighted z-score meta-analysis. Linkage-disequilibrium (LD)-independent variants with P<sub>META</sub>&lt; 5x10–8, not in LD (r2&lt;0.1) with previously identified regions, were considered novel serum urate loci. We used functional partitioned LD score regression on all associated loci in the European GWAS to identify SNP-heritability enriched tissue-specific regulatory regions, for use as functional priors in PAINTOR fine mapping analyses to identify putative causal variants. <h3>Results</h3> The trans-ancestral meta-analysis of European and East Asian GWAS revealed nine new serum urate-associated loci (P<sub>META</sub>&lt;5x10<sup>-8</sup>). Three of the new loci are located in the 11q12.3–13.2 region near the established SLC22A11/12 locus. Additional novel loci are located near the FGF5, LNC00603, HLA-DQB1, B4GALT1, BICC1 and USP2 genes. Tissue-focused functional partitioning of SNP-heritability indicated the strongest enrichments of kidney, GI and liver tissues (P&lt;10<sup>-7</sup>), among other significant tissues. Trans-ancestral meta-analysis and functional fine-mapping decreases the numbers of SNPs in causal variant credible sets, and for example pinpoints the rs17632159 SNP as likely causal (posterior P&gt;0.9) at the TMEM171/174 locus. <h3>Conclusions</h3> Meta-analysis of existing GWAS increases power and leads to the identification of nine new loci associated with serum uric acid levels. Increased resolution in trans-ancestral GWAS, with functional annotation enrichments, improves fine-mapping of serum urate GWAS loci. <h3>References</h3> Köttgen A, et al. Genome-wide association analyses identify 18 new locis associated with serum urate concentrations. Nature Genet. 2013;45:145–54. Okada Y, et al. Meta-analysis identifies multiple loci associated with kidney function-related traits in east Asian populations. Nature Genet. 2012;44:904–9. <h3>Disclosure of Interest</h3> None declared
Abstract 2063: The farnesyltransferase inhibitor tipifarnib causes dramatic tumor regression and increases survival in murine HrasG12V driven aggressive thyroid cancers: Consequent adaptive and acquired resistance mechanisms inform combination treatments with improved responses
Authors: Brian R. Untch, Vanessa Dos Anjos, Maria ER Garcia-Rendueles, Jeff A. Knauf, Alan L. Ho, James A. Fagin
Journal: Cancer Research (2017)

Abstract Of the three RAS oncoproteins, only HRAS is delocalized and functionally inactivated by farnesyltransferase inhibition (FTI), an approach that has yet to be exploited clinically. We treated a murine model of poorly differentiated and anaplastic thyroid cancer (Tpo-cre/HrasG12V/p53flox/flox; Hras;p53) with the FTI tipifarnib, and observed sustained tumor regression and increased survival; however, tumors eventually recurred. Following HRAS delocalization by tipifarnib in vitro, ERK phosphorylation was only inhibited transiently in HRAS-mutant cell lines, which was associated with increased GTP loading of wild-type RAS proteins in the setting of RTK ligand stimulation. This adaptive reactivation of RAS-MAPK signaling was abrogated by selective RTK (i.e. EGFR, FGFR) inhibitors, or by MEK inhibitors. Importantly, tipifarnib combined with the MEK inhibitor AZD6244 led to improved responses in Hras;p53 mouse tumors, whereas combination with the EGFR/FGFR inhibitors erlotinib and ponatinib did not, suggesting heterogeneity of upstream inputs. In order to identify acquired resistance mechanisms, tumor-bearing Hras;p53 mice were treated with tipifarnib until resistance developed (6 months). Whole exome sequencing of resistant tumors identified a truncating NF1 mutation and an activating mutation in GNAS at high allelic frequency. Upon NF1 knockdown in the human HRAS- mutant cell line C643, tipifarnib failed to inhibit pERK in vitro and caused resistance to tipifarnib in xenografts. By contrast, activating GNAS mutations transduced into Hras;p53 mouse tumor cell lines produced tipifarnib-resistant xenografts that activated the GNAS-cAMP-CREB pathway and demonstrated signs of redifferentiation. These data show that pharmacological targeting of RAS in a genetically accurate, mouse model of a RAS-driven virulent cancer leads to objective major responses and improved survival. We identified adaptive and acquired resistance mechanisms, and show that combined treatment with selective MEK inhibitors are beneficial. These data should also inform a currently enrolling clinical trial of tipifarnib for HRAS-mutant malignancies. Citation Format: Brian R. Untch, Vanessa Dos Anjos, Maria ER Garcia-Rendueles, Jeff A. Knauf, Alan L. Ho, James A. Fagin. The farnesyltransferase inhibitor tipifarnib causes dramatic tumor regression and increases survival in murine HrasG12V driven aggressive thyroid cancers: Consequent adaptive and acquired resistance mechanisms inform combination treatments with improved responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2063. doi:10.1158/1538-7445.AM2017-2063
Abstract 2270: C-reactive protein and ovarian cancer risk: preliminary results from the Ovarian Cancer Cohort Consortium (OC3)
Authors: Elizabeth M. Poole, Britton Trabert, Renée T. Fortner, Nicolas Wentzensen, Shelley S. Tworoger
Journal: Cancer Research (2017)

Abstract Background: C-reactive protein (CRP), a general marker of inflammation has been consistently associated with increased ovarian cancer risk. However, few studies have had the ability to evaluate differences in association by ovarian tumor subtype. Methods: We pooled existing data on CRP and ovarian cancer risk among nested case-control studies conducted within 6 studies participating in the Ovarian Cancer Cohort Consortium (OC3): CLUEII, EPIC, NHS, NHSII, NYUWHS, and PLCO. Cohort-specific tertiles and quartiles were analyzed using conditional logistic regression, as were common cutpoints at &amp;lt;1mg/L, 1-&amp;lt;10mg/L and ≥10mg/L and Odds Ratios (OR) and 95% confidence intervals (CI) were calculated using random-effects meta-analysis. We also evaluated differences in the association between serous and non-serous cancers. Results: There was no significant association between the top vs. bottom tertile (OR: 1.10; 95% CI: 0.91-1.32) or the top vs. bottom quartile (OR: 1.10; 95% CI: 0.89-1.36). However, there was a strong, positive association between very high CRP (≥10mg/L vs. &amp;lt;1 mg/L: OR: 1.96; 95% CI: 1.36-2.84). Associations of very high (≥10 mg/L vs. &amp;lt; 1 mg/L) did not differ by histologic type: serous OR: 1.63; 95% CI: 1.11-2.43; endometrioid OR: 1.78; 95% CI: 0.63-5.00; mucinous OR: 10.43; 95% CI: 1.27-85.86; clear cell OR: 2.30; 95% CI: 0.39-13.34). Conclusion: Our results confirm the consistent observation of a positive association between very high CRP levels and ovarian cancer risk. Pooled analyses accounting for potential confounders are ongoing. Note: This abstract was not presented at the meeting. Citation Format: Elizabeth M. Poole, Britton Trabert, Renée T. Fortner, Nicolas Wentzensen, Shelley S. Tworoger. C-reactive protein and ovarian cancer risk: preliminary results from the Ovarian Cancer Cohort Consortium (OC3) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2270. doi:10.1158/1538-7445.AM2017-2270
Taxanes-based neoadjuvant chemotherapy in advanced nonmetastatic breast cancer.
Authors: Tahir Mehmood, Muhammad Ali, Kamran Saeed, Atif Munawar, Sadaf Usman, Asma Rashid, Nabia Irfan, Abdul Ghaffar, Mazhar Ali Shah, Aamir Ali Syed, Arif Jamshed
Journal: Journal of Clinical Oncology (2013)

e12033 Background: Pakistan has the highest rate of breast cancer for any South Asian population and majority of the patients present with locally advanced or metastatic disease. We report on response and survival of primary locally advanced non-metastatic breast cancer in women treated with neoadjuvant Adriamycin/Taxanes (AT) based regimens at our institute. Methods: Between 1995 to 2009 the hospital information system identified 517 women with pathologically confirmed locally advanced breast cancer. All patients received neoadjuvant chemotherapy with AT based regimen followed by surgery. Median age was 43 years (range 17-71 years). AJCC stage; stage II 54% and stage III 46% of the patients. Axillary nodes were palpable in 72% of the patients at presentation. Histological sub-types; infiltrating ductal carcinoma 95%, infiltrating lobular carcinoma 3% and others 2% respectively. Pathological grade was I/II in 44% and grade III 56% of the patients. ER, PR, and Her2-neu receptors were positive in 44%, 40% and 24% of the patients respectively. Twenty one percent of the patients had triple negative breast cancer. Post operative radiotherapy was delivered to 94% of the patients. Patients with positive ER/PR receptors also received hormonal manipulation. Results: Following neo-adjuvant chemotherapy, pathological response was; complete response (CR) 13.5%, partial response 21%, stable disease 52% and progressive disease in 13% of the patients respectively. Breast conservation was possible in 36% of the patients. The 5 year disease free survival in patients with and without CR was 81% and 36% respectively. On multivariate analysis, T stage (p = 0.001) and response to neo-adjuvant chemotherapy (p = 0.001) were found to be independent predictors for disease free survival. Conclusions: Pathological response to neoadjuvant chemotherapy is a predictor of long term survival. Chemotherapy regimens with high response rates merit evaluation in randomized trials to improve outcome in locally advanced breast cancer.
Degradable Hollow Mesoporous Silicon/Carbon Nanoparticles for Photoacoustic Imaging-Guided Highly Effective Chemo-Thermal Tumor Therapy <i>in Vitro</i> and <i>in Vivo</i>
Authors: Jinfeng Zhang, Jun Zhang, Wenyue Li, Rui Chen, Zhenyu Zhang, Wenjun Zhang, Yongbing Tang, Xiaoyuan Chen, Gang Liu, Chun-Sing Lee
Journal: Theranostics (2017)

The development of nanoscaled theranostic agents for cancer combination therapies has received intensive attention in recent years.In this report, a degradable hollow mesoporous PEG-Si/C-DOX NP is designed and fabricated for pH-responsive, photoacoustic imaging-guided highly effective chemo-thermal combination therapy.The intrinsic hollow mesoporous structure endows the as-synthesized nanoparticles (NPs) with a high drug loading capacity (31.1%).Under NIR (808 nm) irradiation, the photothermal conversion efficiency of the Si/C NPs is as high as 40.7%.Preferential accumulation of the PEG-Si/C-DOX NPs around tumor tissue was demonstrated with photoacoustic images.Cellular internalization of the NPs and release of the DOX in nuclei are shown with fluorescent images.With efficient NIR photothermal conversion and high DOX loading capacity, the PEG-Si/C-DOX NPs are demonstrated to have remarkable cancer-cell-killing ability and to achieve complete in vivo tumor elimination via combinational chemo-thermal therapy.Last but not least, the NPs show good biodegradability and biosafety, making them a promising candidate for multifunctional drug delivery and cancer theranostic.
Abstract 894: Heparanase-induced shedding of syndecan-1 promotes cancer cell invasion : prevention by inhibitory synstatin peptide
Authors: Oisun Jung, Alan Rapraeger
Journal: Cancer Research (2017)

Abstract Syndecan-1 (Sdc1, CD138) is highly expressed in multiple myeloma (MM). Heparanase (HPSE), an enzyme that cleaves heparan sulfate (HS) chains on Sdc1, induces shedding of the Sdc1 ectodomain; this is associated with poor prognosis in this disease. However, the link between Sdc1 shedding and poor prognosis remains unclear. We now show that HPSE-induced shed Sdc1 (sSdc1) engages α4β1 integrin (VLA-4) and vascular endothelial cell growth factor receptor-2 (VEGFR2) to form a ternary receptor complex on the cell surface. This coupling of VEGFR2 to clusters of VLA-4 via sSdc1 leads to autoactivation of VEGFR2 and the subsequent activation of protein kinase A (PKA) bound to the VEGFR2 cytoplasmic domain. PKA activation proceeds via VEGFR2-mediated stimulation of the G-protein coupled cytokine receptor CXCR4 and the subsequent generation of cAMP by its activation of adenylate cyclase 7. This mechanism is prevented by SSTNVEGFR2, a peptide that competes for the VEGFR2 docking site in the Sdc1 ectodomain, thereby disrupting VEGFR2 binding to sSdc1. VLA-4 has been shown to mediate the polarized invasion of a variety of cells due to α4 integrin phosphorylation on Ser988 by PKA, followed by Rac GTPase activation, a process that is restricted to the leading edge of the cell. But how this is confined at the leading edge is wholly unknown. We find that HPSE-mediated shedding of Sdc1 promotes an invasive phenotype by re-localizing VLA-4 and VEGFR2 to the leading edge of migrating myeloma cells as well as human T-acute lymphoblastic leukemia, melanoma, and endothelial cells where VEGFR2-dependent PKA activation causes α4 integrin phosphorylation. These results reveal a novel mechanism in which the expression of HPSE, acting by causing Sdc1 shedding, potentially regulates angiogenesis and the extravasation and invasion of cancer cells and identifies SSTNVEGFR2 as a promising cancer therapeutic. Citation Format: Oisun Jung, Alan Rapraeger. Heparanase-induced shedding of syndecan-1 promotes cancer cell invasion : prevention by inhibitory synstatin peptide [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 894. doi:10.1158/1538-7445.AM2017-894
Computational foundations of the visual number sense
Authors: Ivilin Peev Stoianov, Marco Zorzi
Journal: Behavioral and Brain Sciences (2017)

Abstract We provide an emergentist perspective on the computational mechanism underlying numerosity perception, its development, and the role of inhibition, based on our deep neural network model. We argue that the influence of continuous visual properties does not challenge the notion of number sense, but reveals limit conditions for the computation that yields invariance in numerosity perception. Alternative accounts should be formalized in a computational model.