tbuckley/cabot-search huggingface dataset:
Toward an integrative approach to numerical cognition
Authors: Tali Leibovich, Naama Katzin, Moti Salti, Avishai Henik
Journal: Behavioral and Brain Sciences (2017)

Abstract In response to the commentaries, we have refined our suggested model and discussed ways in which the model could be further expanded. In this context, we have elaborated on the role of specific continuous magnitudes. We have also found it important to devote a section to evidence considered the “smoking gun” of the approximate number system theory, including cross-modal studies, animal studies, and so forth. Lastly, we suggested some ways in which the scientific community can promote more transparent and collaborative research by using an open science approach, sharing both raw data and stimuli. We thank the contributors for their enlightening comments and look forward to future developments in the field.
Abstract 3923: Oncogenic kinase-induced PKM2 Y105 phosphorylation promotes tumorigenesis and cancer stem cell-like property
Authors: Zhifen Zhou, Min Li, Lin Zhang, Dihua Yu
Journal: Cancer Research (2017)

Abstract The role of pyruvate kinase M2 isoform (PKM2) in tumor progression is controversial. Previously, it was reported that PKM2 has an oncogenic function in promoting tumor growth in xenograft models; however, PKM2 was indicated non-oncogenic or even anti-oncogenic because depletion of PKM2 accelerates mammary tumor growth in the Brca1 knockout mouse model of breast cancer. Since tumors frequently harbor various abnormally activated oncogenic kinases, we hypothesized that phosphorylation of PKM2 by oncogenic kinases in tumor cells enables PKM2 to promote tumor growth, while unphosphorylated PKM2 in non-transformed cells cannot promote tumor growth. Here, we report that PKM2 proteins were largely unphosphorylated and formed tetramers in normal mammary epithelial cells (MCF10A, MCF12A). On the other hand, PKM2 proteins were phosphorylated at Y105 and formed dimers in breast cancer cells (MDA-MB-231, MDA-MB-435). Knocking down PKM2 didn’t affect normal mammary epithelial cell (MCF10A) growth but significantly decreased breast cancer cell MDA-MB-231 proliferation. In addition, introducing the PKM2-Y105D phosphomimetic mutant into MCF10A cells induced epithelial to mesenchymal transition, increased CD44Hi/CD24Neg stem cell-like cell population, and induced colony formation in soft agar, promoted cell migration and invasion. Interestingly, PKM2-Y105D increased YAP1 protein nuclear localization in MCF10A cells, whereas inhibiting YAP1 by siRNA or a chemical inhibitor (Verteporfin) decreased PKM2-Y105D-induced cancer stem cell-like population and colony formation ability. The data indicate that YAP1 is a novel downstream target of pY105-PKM2 in promoting the stem-like property and triggering mammary tumor initiation. Next, we performed receptor tyrosine kinase array and identified several oncogenic tyrosine kinases (AXL, EPHA2, FAK, Src, JAK3 and so on) that effectively phosphorylates PKM2 at Y105. Currently, we are testing the efficacy of targeting these oncogenic tyrosine kinases in reversing the phosphorylation of PKM2 and blocking its tumor-promoting function. Together, our data indicate that oncogenic kinases-induced phospho-Y105-PKM2, but not the unphosphorylated PKM2, promotes mammary tumor initiation by increasing cancer stem cell populations. Citation Format: Zhifen Zhou, Min Li, Lin Zhang, Dihua Yu. Oncogenic kinase-induced PKM2 Y105 phosphorylation promotes tumorigenesis and cancer stem cell-like property [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 3923. doi:10.1158/1538-7445.AM2017-3923
Abstract 1048: Reactive oxygen species-mediated synergistic and preferential induction of cell death and reduction of drug resistance in oncogenic H-Ras-expressing bladder cancer cells by combined romidepsin and cisplatin with gemcitabine
Authors: Lenora A. Pluchino, Hwa-Chain R. Wang
Journal: Cancer Research (2017)

Abstract Human urinary bladder cancer is the fifth most commonly diagnosed cancer in the United States and is often associated with induction of oncogenic H-Ras. Long-term survival of patients is suboptimal with the current chemotherapeutic regimen of combined cisplatin and gemcitabine and others due to acquired drug resistance and recurrence. Thus, it is urgent to develop new regimens effective in control of tumor growth, drug resistance, and recurrence to reduce the morbidity and mortality of this disease. We used our cellular system, consisting of human urinary bladder cancer J82 cells paired with its derived oncogenic H-Ras-expressing J82-Ras cells, to investigate the efficacy of a novel combination regimen in treating bladder cancer cells. Our studies revealed, for the first time, the ability of a combination of cisplatin and romidepsin with gemcitabine to synergistically and preferentially induced cell death and reduced drug resistance in J82-Ras versus J82 cells. The Ras-ERK-Nox pathway played an essential role in mediating signals to elevate reactive oxygen species (ROS), leading to enhanced caspase activation, DNA damage, and DNA oxidation, as well as reduced glutathione, to synergistically increased cell death and reduced drug resistance in cells treated with combined romidepsin, cisplatin, and gemcitabine. Preferentially induced Ras-ERK-Nox-ROS pathway, caspase activation, and DNA damage/oxidation, as well as reduced glutathione, contributed to the preferentially induced cell death and reduced drug resistance in J82-Ras versus J82 cells. Synergistically induced death and reduced drug resistance were also detected in human bladder cancer SW780 cells treated with combined romidepsin, cisplatin, and gemcitabine. Hence, our results lead us to suggest that a combination of romidepsin, cisplatin, and gemcitabine should be seriously considered as a new therapeutic regimen for controlling the development and recurrence of human urinary bladder cancer, especially Ras-ERK-activated cancers. Citation Format: Lenora A. Pluchino, Hwa-Chain R. Wang. Reactive oxygen species-mediated synergistic and preferential induction of cell death and reduction of drug resistance in oncogenic H-Ras-expressing bladder cancer cells by combined romidepsin and cisplatin with gemcitabine [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 1048. doi:10.1158/1538-7445.AM2017-1048
Abstract 5729: Loss of USP10 and p14ARF protein expression is associated with poor prognosis patients with small intestinal adenocarcinoma
Authors: Joon Seon Song, Hanbyoul Cho, Joon-Yong Chung, Ilseon Hwang, Hee Jin Lee, Seung-Mo Hong, Stephen M. Hewitt
Journal: Cancer Research (2017)

Abstract Ubiquitin Specific Peptidase 10 (USP10) is a member of the ubiquitin-specific protease family and its related pathways are apoptosis, autophagy and DNA damage. P14ARF is encoded by an alternative reading frame within the INK4a/ARF locus at chromosome 9p21, which is related with cell cycle arrest and apoptosis. Recently, ablation of USP10 prevented c-myc induced cellular senescence by destabilization of p14ARF and p53, and accelerated hyper-proliferation and transformation of normal cells, suggesting USP10 have a crucial role in oncogenes induced senescence by keeping the stability of p14ARF and p53, key regulator of cellular senescence. However, knowledge on the clinical and prognostic significance of USP10 and p14ARF expression in patients with small intestine adenocarcinoma is limited. In the present study, we investigated the prognostic significance of USP10 and p14ARF by immunohistochemistry. 195 of resected small intestine adenocarcinomas were retrieved from 22 South Korean institutions by Korean Small Intestinal Cancer Study Group. Tissue microarrays were constructed using formalin-fixed paraffin-embedded specimen. 70 (35.9 %) out of 195 patients showed immunoreactivity for USP10 and 124 (63.6 %) showed loss of immunoreactivity for USP10. 120 (61.5 %) of 195 patients were immunopositive for p14ARF and 75 (38.5 %) patients showed loss of immunoreactivity for p14ARF. Loss of USP 10 was correlated with male predominancy (p=0.014), higher pT stage (p=0.044), presence of lymphatic invasion (p=0.033), absences of sporadic adenoma (p=0.024) and absences of peritumoral dyplasia (p=0.019). On multivariate survival analysis, loss of USP10 expression was independent poor prognostic factor ( HR=3.04, 95% CI= 1.79-5.18, p &amp;lt; 0.001) and also both loss of USP10 and p14ARF expressions showed similar result ( HR=3.76, 95% CI= 1.93-7.23, p &amp;lt; 0.001) while loss of p14ARF was not an independent prognostic factor ( p= 0.587). Our findings indicate that loss of USP10, associated with loss of p14ARF protein expression, could be poor prognostic factors in small intestine adenocarcinoma. Citation Format: Joon Seon Song, Hanbyoul Cho, Joon-Yong Chung, Ilseon Hwang, Hee Jin Lee, Seung-Mo Hong, Stephen M. Hewitt. Loss of USP10 and p14ARF protein expression is associated with poor prognosis patients with small intestinal adenocarcinoma [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 5729. doi:10.1158/1538-7445.AM2017-5729
Mutually exclusive expression of CD73 and PDL1 in tumors from patients (pt) with NSCLC, gastroesophageal (GE) and urothelial bladder carcinoma (UBC).
Authors: Philip Martin, Andreas Spitzmueller, Song Wu, Moritz Widmaier, RENE KORN, Sonja Althammer, Jiping Zha, Brandon W. Higgs, Zachary Cooper, Keith Steele
Journal: Journal of Clinical Oncology (2017)

3079 Background: Tumors use multiple means of immune evasion, notably the programmed death-1 (PD1)/PDL1 pathway. Anti-PD1/PDL1 therapy induces anti-tumor activity and has improved pt outcomes. Activation of the immunosuppressive CD39/CD73/adenosine pathway might play a role in pts who do not benefit from anti-PD1/PDL1 therapies. We evaluated expression of CD73 and PDL1 and explored the association between CD73 and intraepithelial (IE) CD8+ cells (TILs) to begin to understand their potential interplay in cancer. Methods: Immunohistochemistry for PDL1, CD73 and CD8 was conducted on tumors of non-squamous NSCLC (NSq) (n=42), GE (n=50), and UBC (n=50). PDL1 and CD73 were scored by image analysis with Definiens software. IE CD8+ TILs were scored semi-quantitatively by a pathologist (0-2 = low; 3-4 = high). Using the top tertile of PDL1 and CD73 for high expression levels, a Fisher’s meta-analysis was calculated across the three indications. Results: Across all tumors, 25% (35/142) were PDL1 high (+), but CD73 low (-) and another 25% (35/142) were CD73+ but PDL1- (p=0.06, see table). This trend for mutually exclusive high expression of PDL1/CD73 was strongest in GE (p&lt;0.01). In the PDL1+ group 76% (35/46) had high IE CD8+ TILs whereas in the CD73+ group only 35% (16/46) had high TILs (p&lt;0.0001 using a proportions test). In the PDL1+/CD73- pt subset 77% (27/35) were CD8+ high vs only 23% (8/35) in the PDL1-/CD73+ subset. Conclusions: The identification of distinct pt subsets based on high PDL1 and/or CD73 expression suggests that tumors have multiple mechanisms of immune evasion. Increased IE CD8+ TILs were associated with PDL1 expression. The finding that PDL1-/ CD73+ tumors have lower IE CD8+ TILs compared to PDL1+/CD73- tumors suggests a role for CD73 in excluding IE TILs. Larger sample sets are needed to confirm these findings and to further explore any relationship with the tumor microenvironment. Our data suggests potential approaches to identify subsets of pts likely to benefit from immunotherapy targeting PDL1 and CD73. [Table: see text]
Abstract SY28-01: Stromal contributions of adipocytes to cancer
Authors: Philipp E. Scherer
Journal: Cancer Research (2017)

Abstract The past few years have provided substantial evidence for the vital role of the local tumor microenvironment in various aspects of tumorigenesis. With obesity and its pathophysiologic sequelae still on the rise, the adipocyte is increasingly moving to center stage in the context of tumor stroma-related studies. To date, we have limited insights into how systemic changes associated with obesity and altered adipokine secretion influence the incidence and progression of obesity-associated cancers. Adipocytes are the major constituents of adipose tissue and play a key role in whole body metabolism. They not only fulfill an important role as a buffer for excess triglycerides, but they also secrete many lipid and protein factors and are therefore considered major endocrine cells that influence metabolism of other tissues, including liver, muscle, brain, and pancreatic β-cells. With chronic excess of energy intake, adipocytes develop hypertrophy and face various physiologic insults, such as hypoxia, oxidative stress, and disruptions in the protein secretory pathway due to ER stress. As a result, adipocytes become dysfunctional and less efficient at fulfilling their primary function of storing and neutralizing potentially toxic free fatty acids. Adipocyte dysfunction has been widely appreciated as a major cause underlying obesity-related metabolic disorders, including insulin resistance, type 2 diabetes, cardiovascular disease, chronic inflammation, and cancers due to inappropriate release of mitogenic and inflammatory factors. As a result, these dysfunctional adipocytes also support the growth of infiltrating transformed ductal epithelial cells in the mammary gland, at the level of secretion of critical growth factors, proinflammatory cytokines, increased ECM production, and support of tumor lesion growth through release of critical metabolites. Therefore, the adipocyte with its paracrine influence on the microenvironment as well as its endocrine functions is an important area of research for both primary and metastatic tumor growth. Citation Format: Philipp E. Scherer. Stromal contributions of adipocytes to 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 SY28-01. doi:10.1158/1538-7445.AM2017-SY28-01
Abstract 4115: Combination of FTY720 and tamoxifen inhibits drug-resistant ovarian cancer cell proliferation
Authors: Kelly Marie Kreitzburg, Charles N. Landen, Tracy Gamblin, Rebecca Arend, Ronald Alvarez, Karina Yoon
Journal: Cancer Research (2017)

Abstract Despite satisfactory initial responses to frontline therapies that combine surgical debulking with platinum based chemotherapy, virtually all women with advanced ovarian cancer relapse with drug resistant disease. There is a critical need to identify alternative, effective therapies. Previously, we used patient derived xenograft (PDX) models of ovarian cancer in mice to identify the sphingosine1 phosphate (S1P) pathway as one of the pathways most affected by two agents frequently used to treat ovarian cancer, carboplatin and paclitaxel. The S1P pathway contributes to multiple biological processes recognized as essential for tumor development, and aberrations in sphingolipid metabolism have been directly correlated with advanced disease and with resistance to chemotherapy and radiation. Further, recent studies indicate that tamoxifen may counteract drug resistance mechanisms through modulation of sphingolipid metabolism, specifically through inhibition of the ceramide converting enyzmes acid ceramidase and glucosylceramide synthase. Therefore, we evaluated the efficacy of modulating S1P metabolism using the sphingosine analog FTY720 and tamoxifen as an approach to inhibit the proliferation of drug-resistant ovarian tumor cells. We used alamarBlue cell proliferation assays to compare the anti-proliferative effect of FTY720 and tamoxifen with the effect of each drug as a single agent. FTY720 + tamoxifen synergistically decreased the cell viability of 3/3 ovarian cancer cell lines: estrogen receptor alpha (ERα) positive SKOV3.TR (taxane resistant), ERα negative A280.cp20 (platinum resistant) and HeyA8.MDR (taxane-platinum resistant). The combination also increased levels of apoptosis as reflected by Annexin V staining and cleaved caspase 3 levels. Further, administration of 5mg/kg i.p. FTY720 + 20mg/kg p.o. tamoxifen daily for 21 days to PDX-bearing mice demonstrated that FTY720 + tamoxifen suppressed tumor growth by ~60% compared to vehicle controls. Notably, immunohistochemical staining of tumors harvested from treated mice showed that the combination decreased expression of the proliferation marker Ki-67 and increased expression of apoptosis indicators ceramide and cleaved caspase 3 to a greater degree than in tumors exposed to either drug alone. We conclude that FTY720 + tamoxifen merit further investigation as potentially effective agents for the treatment of drug-resistant ovarian cancer. Citation Format: Kelly Marie Kreitzburg, Charles N. Landen, Tracy Gamblin, Rebecca Arend, Ronald Alvarez, Karina Yoon. Combination of FTY720 and tamoxifen inhibits drug-resistant ovarian cancer cell proliferation [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 4115. doi:10.1158/1538-7445.AM2017-4115
Abstract 2780: High nuclear FTH1 protein expression predicts early disease recurrence for BRCA1/2 mutation carriers
Authors: Antoinette Hollestelle, Mieke Timmermans, Renée Broeren-Foekens, Anita Trapman - Jansen, Carolien H. van Deurzen, Arzu Umar, John W. Martens, Maartje Hooning
Journal: Cancer Research (2017)

Abstract FTH1 is a 21kD subunit of the ferritin complex, which is involved in intracellular iron storage. In a previous study we found that FTH1 proteins can be located either in the cytoplasm or nucleus and, depending on its cellular localization, is associated with good or poor prognosis in triple negative breast cancer (TNBC). Furthermore, cytoplasmic localization of cFTH1 was associated with an increased anti-tumor (CD8+) T-cell / tumor-promoting (CD4+) T-cell ratio suggesting an immune modulatory role for FTH1. In the current study we have assessed the prognostic value of FTH1 expression for BRCA1/2 mutation carriers. FTH1 proteins were visualized by immunohistochemistry on a tissue microarray containing primary breast cancer specimens from 222 BRCA1/2 mutation carriers that were diagnosed between 1982 and 2008. Primary breast cancers from BRCA1 carriers were predominantly of the TNBC subtype, whereas primary breast cancers from BRCA2 mutation carriers were mainly ER-positive. The association between FTH1 expression and clinical outcome was evaluated by a Cox proportional hazards regression model using left truncation to adjust for study inclusion bias. The median follow-up time of the study was 9.2 years. High nuclear FTH1 (nFTH1), but not cytoplasmic FTH1 (cFTH1), was associated with decreased metastasis-free and disease-free survival as compared with low nFTH1 (multivariable HR=3.54, 95% CI=1.45-8.66, P=0.0056 adjusted for tumor size and nodal status; multivariable HR=2.71, 95% CI=1.49-4.92, P=0.0011 adjusted for tumor size). Neither nFTH1 nor cFTH1 were associated with breast cancer-specific or overall survival. This suggests that high nFTH1 expression in primary breast cancer predicts earlier disease recurrence for BRCA1/2 mutation carriers. Since we had observed that CD4+:CD8+ T-cell ratios were increased among TNBCs with high nFTH1, we hypothesize that nFTH1 promotes recruitment of immune suppressive CD4+/FOXP3+ regulatory T-cells in TNBC and BRCA1/2-associated tumors, suppressing CD4+/FOXP3- and CD8+ T-cell anti-tumor immunity. Citation Format: Antoinette Hollestelle, Mieke Timmermans, Renée Broeren-Foekens, Anita Trapman - Jansen, Carolien H. van Deurzen, Arzu Umar, John W. Martens, Maartje Hooning. High nuclear FTH1 protein expression predicts early disease recurrence for BRCA1/2 mutation carriers [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 2780. doi:10.1158/1538-7445.AM2017-2780
Abstract 523: HGF mediated upregulation of PHLDA2 is associated with apoptosis in gastric cancer
Authors: Sung Ae Koh, Kyung Hee Lee, Jae Ryong Kim, Sang Woon Kim
Journal: Cancer Research (2017)

Abstract Pleckstrin homology-like domain family A member 2 (PHLDA2), a homolog of the mouse TDAG51 gene, was the first apoptosis-related gene shown to be imprinted and expressed from the maternal allele in normal development. It is located within the tumor suppressor region of 11p15, and its expression was reported to be suppressed in several cases of malignant tumors. But, the apoptotic regulatory mechanism and its role is not fully known in gastric cancer. The purpose of the this study is to identify of function of PHLDA2 associated with apoptosis in gastric cancer. We used cell culture, western blotting, RT-PCR, MTT assays, PHLDA2 knock-down with short hairpin RNA (shRNA). First, we confirmed that the expression level of PHLDA2 was up-regulated by HGF(hepatocyte growth factor). To identify associated pathway of HGF-induced LCN2, the cells were treated with PI3-kinase inhibitor (LY294002) or MEK inhibitor(PD098059) or p38 inhibitor(SB203580) and then analyzed by Western blotting. The HGF-mediated PHLDA2 protein level was only decreased with LY294002. The role for PHLDA2 with was determined by knock down cell of PHLDA2. PHLDA2-sh RNA cells showed a decreased level of P53 and a increased level of pAKT. We also examined to confirm the role of HGF-mediated PHLDA2. HGF-mediated cell proliferation and in vitro invasion was increased in PHLDA2 knock down cell. Also, HGF-mediated cell apoptosis decreased in PHLDA2 knock down cell. Our study showed that PHLDA2 upregulated HGF is regulated through PI3K/AKT pathway in gastric cancer, and PHLDA2 have a role in cell apoptosis in gastric cancer, which may be a possible target for developing gastric cancer therapy. Citation Format: Sung Ae Koh, Kyung Hee Lee, Jae Ryong Kim, Sang Woon Kim. HGF mediated upregulation of PHLDA2 is associated with apoptosis in gastric 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 523. doi:10.1158/1538-7445.AM2017-523