tbuckley/cabot-search huggingface dataset:
Abstract 737: Signficant DLX4 expression in inflammatory breast cancer tumors from African American patients
Authors: Jaehong Jeong, Tammey Naab, Martin Ongkeko, Kepher Makambi, Farhan A. Khan, Jan Blancato
Journal: Cancer Research (2017)

Abstract Purpose: To examine protein expression characteristics of Distal-less homeobox4 (DLX4) in inflammatory breast cancer (IBC) cases from an African-American population to determine if a) DLX4 over-expression occurs in IBC vs. normal mammary tissue and b) over-expression is associated with clinico-pathologic features such as ER, PR, HER2. Experimental Design: Twenty nine blocks of formalin-fixed paraffin-embedded (FFPE) tissues from well-characterized human IBC cases were used for immuno-histochemical staining (IHC). Tumor tissues were from African American subjects seen at Howard University Hospital. Normal breast tissues from 30 mammoplasties were controls. IHC results were assigned intensity and percentage scores based upon intensity of positive staining and % of stained cells. Percentage scores were assigned as 0, 1 (0%-25%), 2 (26%-50%), 3 (51%-75%) or 4 (76%-100%) and intensity scores were assigned 0, 1+, 2+ or 3+. For the analysis of the IHC, a percentage score of 3 or 4 was considered high and an intensity score of 2+ or 3+ was categorized as high. Chi-square and Fisher’s exact tests were used for analysis. Results: The staining pattern for the categorized cohort in which 82.8% (24 out of 29) of IBC cases showed high percentages of positive cells staining for DLX4 protein, while 40.0% (12 out of 30) normal breast tissues demonstrated DLX4 expression (P=0.001). In terms of staining intensity, 75.9% (22 out of 29) of IBC cases showed a high level of intensity, compared to 20.0% (6 out of 30) of normal breast tissues (P&amp;lt;0.001). In terms of the association between breast cancer characteristics and IHC staining, intensity of DLX4 was higher in HER2- (87.0%, 20 out of 23) than HER2+ (33.3%, 2 out of 6; P=0.018). Other associations were not statistically significant in this pilot study. Conclusions: DLX4 expression is significantly higher in this pilot study of IBC cases from AA patients than in normal breast tissue cases. In addition, HER2- is associated with high intensity of DLX4 expression in IBC. Associations DLX4 protein expression (IHC) In IBC and normal breast tissuesLowHighP-valuePercent positivityn (%)n (%)Controls (n=30)18 (60.0)12 (40.0)0.001IBCs (n=29)5 (17.2)24 (82.8)Staining intensityn (%)n (%)Controls (n=30)24 (80.0)6 (20.0)&amp;lt;0.001IBCs (n=29)7 (24.1)22 (75.9) Citation Format: Jaehong Jeong, Tammey Naab, Martin Ongkeko, Kepher Makambi, Farhan A. Khan, Jan Blancato. Signficant DLX4 expression in inflammatory breast cancer tumors from African American patients [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 737. doi:10.1158/1538-7445.AM2017-737
Abstract 2944: miR-130a and -145 reprogram myeloid derived suppressor cells and enhance anti-tumor immunity
Authors: Hiroki Ishii, Suman K. Vodnala, Bhagelu R. Achyut, Christine M. Hollander, Ashish Lal, Li Yang
Journal: Cancer Research (2017)

Abstract Myeloid derived suppressor cells (MDSCs) are increased in tumor bearing condition, and elicit immunosuppression via type 2 polarization. We have previously reported that TGF-β signaling in MDSCs is essential for tumor metastasis. TGFβR2, a receptor essential for TGF-β signaling, is elevated in MDSCs. Deletion of Tgfbr2 in MDSCs, the gene encoding TGFβR2, significantly decreased tumor metastasis. However, it is unclear how TGFβR2 is regulated in MDSCs. We identify microRNA-130a and -145, which directly target Tgfbr2 in MDSCs and inhibit the expression of TGF-β receptor II (TβRII). Both miRs levels were lower in MDSCs from advanced tumor bearing mice correlating to increased TβRII level. Overexpression of miR-130a or -145 in MDSCs shift their immunological phenotype from type 2 to type 1 polarization. Moreover, tumor metastasis was significantly suppressed in myeloid specific miR-130 transgenic mice. In pre-clinical mouse models, the number of lung metastasis was significantly decreased when mice were treated with combination therapy of miR-130a or -145 with paclitaxel when compared with miR-130a, -145, or paclitaxel alone. We proposed that reprogramming of MDSCs by miR-130a and -145 could be a novel strategy in therapeutic treatment for breast cancer metastasis. Citation Format: Hiroki Ishii, Suman K. Vodnala, Bhagelu R. Achyut, Christine M. Hollander, Ashish Lal, Li Yang. miR-130a and -145 reprogram myeloid derived suppressor cells and enhance anti-tumor immunity [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 2944. doi:10.1158/1538-7445.AM2017-2944
Abstract 3021: CCR5 inhibition: macrophage repolarization therapy for colorectal cancer
Authors: Niels Halama, Inka Zoernig, Anna Berthel, Christoph Kahlert, Fee Klupp, Meggy Suarez-Carmona, Karsten Brand, Juergen Krauss, Felix Lasitschka, Alexis Ulrich, Juergen Weitz, Martin Schneider, Markus Buechler, Laurence Zitvogel, Thomas Herrmann, Axel Benner, Christina Kunz, Stephan Luecke, Christoph Springfeld, Christine S. Falk, Dirk Jaeger
Journal: Cancer Research (2017)

Abstract In patients with metastatic colorectal cancer (CRC), the local immune response influences the clinical course. An in-depth analysis of the invasive margin of human CRC liver metastases revealed a distinct immunological microenvironment. Within this microenvironment, two distinct subsets of myeloid cells induce an influx of T cells into the invasive margin via CXCL9/CXCL10. CCL5 is produced by these T cells and stimulates pro-tumoral effects via CCR5, creating an exploitive loop. CCR5 was found on macrophages, lymphocytes and on the vast majority of tumor cells. Inhibition of CCR5 in patient-derived functional in vitro organotypic culture models showed a promising macrophage repolarization with anti-tumoral effects. These effects are mediated by activation of an antiviral program in macrophages, leading to interferon and reactive oxygen species production and subsequent selective tumor cell death. These anti-tumoral effects were confirmed in a phase I trial with a CCR5 antagonist in 14 patients with liver metastases of advanced refractory CRC. Treatment with the oral CCR5 Inhibitor was very well tolerated and objective responses were seen, especially in combination with previously ineffective chemotherapy. Biopsies revealed mitigation of tumor-promoting inflammation within the tumor tissue, confirming the validity of the explant model and highlighting the feasbility of this approach. It furthermore shows the proof-of-concept for macrophage repolarization in cancer patients. Citation Format: Niels Halama, Inka Zoernig, Anna Berthel, Christoph Kahlert, Fee Klupp, Meggy Suarez-Carmona, Karsten Brand, Juergen Krauss, Felix Lasitschka, Alexis Ulrich, Juergen Weitz, Martin Schneider, Markus Buechler, Laurence Zitvogel, Thomas Herrmann, Axel Benner, Christina Kunz, Stephan Luecke, Christoph Springfeld, Christine S. Falk, Dirk Jaeger. CCR5 inhibition: macrophage repolarization therapy for colorectal 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 3021. doi:10.1158/1538-7445.AM2017-3021
Abstract 4041: SUV39H2 inhibition enhances sensitivity of breast cancer cells to doxorubicin through downregulation of γ-H2AX production
Authors: Theodore Vougiouklakis, Vassiliki Saloura, Yo Matsuo, Yusuke Nakamura
Journal: Cancer Research (2017)

Abstract Accumulating evidence has demonstrated the biological importance of protein methyltransferases in human tumorigenesis, and several small molecular inhibitors targeting these enzymes have been developed. Moreover, inhibiting pathways involved in DNA repair has been shown to enhance the cytotoxicity of DNA-damaging agents. Herein, we report the development of a potent SUV39H2 inhibitor (OTS193320) that decreases global histone H3 lysine 9 tri-methylation (H3K9me3) levels in cancer cells and attenuates cancer cell proliferation, and suppresses the tumor growth in mouse xenograft models. SUV39H2 (Suppressor of variegation 3-9 homolog 2), is a protein methyltransferase known to methylate histone H3 at lysine 9 (H3K9), and recently reported to methylate histone H2AX at lysine 134, which enhances the accumulation of phosphorylated H2AX (γ-H2AX) and regulates the DNA repair pathway in human cancer. SUV39H2 is highly expressed in many cancer types, including lung and breast cancers, while its expression levels are restricted to testis in normal adult tissues. Exposure of OTS193320 to two triple negative breast cancer cell lines attenuated H3K9me3 levels in a dose-dependent manner and triggered apoptotic cell death. Combination of OTS193320 and doxorubicin (DOX) resulted in reduction of γ-H2AX levels compared to single agent DOX, as visualized on western blot and immunocytochemical analysis. Furthermore, combination therapy attenuated the levels of p53-binding protein 1, which is reported to co-localize with γ-H2AX foci, compared to single agent DOX. Cell viability assays demonstrated a significant growth suppressive effect when OTS193320 was combined with DOX, compared to single agent treatment of either drug, suggesting chemosensitization to DOX. Importantly, in a mouse xenograft model of A549 lung cancer cells, we observed a tumor growth inhibition of 60.8% at day 14 with 25mg/kg intravenous administration of the inhibitor, without significant body weight loss or toxicity. Immunohistochemical staining of tumors treated with the inhibitor demonstrated a significantly lower number of Ki-67 positive cells and attenuated distribution patterns of H3K9me3 compared to the control tumors. Collectively, our results demonstrate that SUV39H2 inhibition may be a promising approach to develop a novel class of anti-cancer treatment. Citation Format: Theodore Vougiouklakis, Vassiliki Saloura, Yo Matsuo, Yusuke Nakamura. SUV39H2 inhibition enhances sensitivity of breast cancer cells to doxorubicin through downregulation of γ-H2AX production [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 4041. doi:10.1158/1538-7445.AM2017-4041
Circulating neutrophil adhesion molecules in patients with chronic liver cirrhosis
Authors: Samia H. Rizk, Nora E. El Bassiouni, Azza E. El Bassiouni, Faiza M. Essawy, Moushira M. Halouda, Hisham R. El Khiat, Maged I. El Ganam, Sahar K. Hussein, Hoda A. Taleb, Hoda A. Tabeq, Ola M. Mahmoud
Journal: Blood (2003)
Abstract 2925: Distribution of copy number alterations defines clonal populations involved in colorectal cancer evolution
Authors: Isabel Quintanilla, Elena Asensio, Maria Pellisé, Antoni Castells, Miriam Cuatrecasas, Jordi Camps
Journal: Cancer Research (2017)

Abstract Colorectal cancer progresses in a multi-step manner with adenoma being the most well-known precursor lesion. Malignant polyp, an adenoma that contains a focus of adenocarcinoma, is a suitable model to study the colorectal tumor evolution. Although the mutations that lead adenoma to evolve into carcinoma have been previously described, the copy number changes involved in this malignant transformation have not been fully explored. To understand how these genomic alterations contribute to carcinogenesis, we used sequential fluorescence in situ hybridization using probes for the oncogenes EGFR, MYC, CDX2, and ZNF217 and the tumor suppressor genes SMAD7 and APC in order to analyze the copy number changes in 23 cases of malignant polyps and 10 cases of low grade dysplasia (LGD) adenomas based on single cell analyses. We found the levels of genomic heterogeneity increased from LGD adenomas to malignant polyps, with the adenoma component having a lower degree of chromosomal instability than the adenocarcinoma component. Despite the intercellular heterogeneity, we observed different patterns of evolution. The gain of ZNF217 was the earliest event as it was found to be in some cases of the LGD adenoma, and was also important in the neoplastic transformation of malignant polyps. Other notable genomic imbalances we observed during the malignant transformation were the gain of CDX2 and the loss of SMAD7. Interestingly, in a significant proportion of cases we observed the gain of all loci analyzed to be the decisive step in the transition from adenoma to carcinoma, suggesting a whole genome duplication event. Lastly, in half of the malignant polyps studied the main clone in the carcinoma component was already present in the adjacent adenoma component, although in some cases at a low frequency only detected by single cell analysis. Our data suggest that copy number changes are early events in colorectal carcinogenesis that can determine the evolution from adenoma to carcinoma. Citation Format: Isabel Quintanilla, Elena Asensio, Maria Pellisé, Antoni Castells, Miriam Cuatrecasas, Jordi Camps. Distribution of copy number alterations defines clonal populations involved in colorectal cancer evolution [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 2925. doi:10.1158/1538-7445.AM2017-2925
Abstract 2711: Whole exome sequencing analyses of colorectal cancers associated with liver metastasis
Authors: Yanlei Ma, Wenhao Weng, Yongzhi Yang, Qing Wei, Sanjun Cai
Journal: Cancer Research (2017)

Abstract Purpose: Liver metastasis is one of the major causes of death in colorectal cancer (CRC) patients. But the process is still unknown. Here, we analyzed genetic differences between primary tumors associated with liver metastasis and those without liver metastasis and predicted clinical significance. Experimental design: Eight primary tumors associated with liver metastasis and twelve without liver metastasis of CRC were analyzed by whole-exome sequencing. The functional characterisation for the role of metastatic-related genes was investigated through in vitro migration and invasion assays. For clinical relevance, TMAs were used for immunohistochemistry assay. Results: The mutation spectrum was similar to that of previous studies. TP53, APC and KRAS were the three most frequently mutated genes, with no significant difference of mutation frequency between primary tumors from patients with liver metastasis and those from other patients. Notably, four recurrently mutated genes (FBXW7, EDIL3, KCNK9 and PCDHGA7) were identified exclusively in the tumors associated with liver metastasis. Furthermore, in vitro analyses showed that EDIL3 and KCNK9 overexpression resulted in enhanced cell migration and invasion, while CRISPR-mediated deletion of FBXW7 and PCDHGA7 exhibited enhanced migratory and invasive properties as well. For clinical relevance, highly expressed EDIL3 and KCNK9 was significantly associated with liver metastasis, whereas the expression of FBXW7 and PCDHGA7 negatively correlated with it in our cohorts. Pathway enrichment analysis also indicated a role for cell adhesion signaling in liver metastasis of CRC patients. Conclusion: Our study identified candidate genes, which might response to the initiation of metastasis, exclusively mutated in tumors associated with liver metastasis. These findings also provided potential therapeutic targets for personalized treatment. Note: This abstract was not presented at the meeting. Citation Format: Yanlei Ma, Wenhao Weng, Yongzhi Yang, Qing Wei, Sanjun Cai. Whole exome sequencing analyses of colorectal cancers associated with liver metastasis [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 2711. doi:10.1158/1538-7445.AM2017-2711
Evidence for a number sense
Authors: David C. Burr
Journal: Behavioral and Brain Sciences (2017)

Abstract Numerosity is inherently confounded by related stimulus attributes such as density and area, and many studies have reported interactions of various strengths between area, density, and numerosity. However, direct measurements of sensitivity within the area-density-numerosity space show that numerosity emerges as the most spontaneous and sensitive dimension, strongly supporting the existence of a dedicated number sense.
Abstract 1647: Characterization of MiXenoTM humanized mouse model for immuno-oncological therapy evaluation
Authors: Juan Zhang, Qian Shi, Lan Zhang
Journal: Cancer Research (2017)

Abstract Backgrounds: Despite the unprecedented success of immune checkpoint antibody therapy in patients with various cancer types, lack of stable experimental immunotherapy models is still a big challenge in development of effective new immune-therapeutics. Different strategies of humanized mouse model system, including human hematopoietic stem cell (HSC) or human PBMC humanization in immune-deficient mice, or chimeric models harboring human immune checkpoint targets in immune-competent mice have been reported. CrownBio has successfully established a number of human PBMC-humanized xenograft models MiXenoTM for in vivo IO therapy evaluation, which has been shown to be a rapid and simple strategy of humanization. However, several outstanding questions, e.g. the optimal PBMC injection route and cell number, the donor dependence of the efficacy result and impact of donor HLA type on the efficacy, etc., need to be further addressed. Results: PBMC number was titrated in one of our MiXenoTM model HCC827, and PBMC injection via i.p. vs. i.v. was compared. Tumor growth curve, graft versus host disease (GVHD), and blood immunophenotyping were followed under different settings. Furthermore, the antitumor activity of PD-1 antibody pembrolizumab in a panel of PBMC donor context that bears diversified HLA types was precisely analyzed. We found that the efficacy was highly donor dependent, and there was lack of correlation between efficacy and donor/tumor HLA match. Conclusion: The MiXenoTM model provides an alternative to the full stem cell reconstitution approach. Better understanding on the characteristics of the model may allow a rational model selection and study design in the discovery IO therapeutics. Citation Format: Juan Zhang, Qian Shi, Lan Zhang. Characterization of MiXenoTM humanized mouse model for immuno-oncological therapy evaluation [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 1647. doi:10.1158/1538-7445.AM2017-1647
Abstract 2572: The novel long non-coding RNA PANCR is an intracellular p53 activator
Authors: Yu Cao
Journal: Cancer Research (2017)

Abstract Long non-coding RNAs (LncRNAs) function as oncogenes or tumor suppressors in development and progression of cancer. Chromosome 16q22.1 region is frequently deleted in breast cancer, which may contribute to breast carcinogenesis by inactivation of tumor suppressor genes. This study characterized a new LncRNA tumor suppressor, named p53 activating non-coding RNA (PANCR), located in this Chromosome 16q22.1 region. This PANCR LncRNA consists of 1.5kb in length.Our data showed that PANCR was downregulated in breast cancer cell lines and tissues. In the breast cancer cell lines, PANCR expression appeared reversely correlated with cell malignancy, and in breast cancer tissues, PANCR was downregulated over 2 times in 31(62.0%) of 50 cases when compared to adjacent normal breast tissues. In breast cancer cells MCF7 and immortalized human mammary epithelial cells MCF10A, ectopic expression of PANCR induced marked apoptosis, suppressing cell proliferation in culture and tumor growth in xenografts, but in contrast, shRNA-mediated silencing of PANCR promoted cell growth and proliferation. Mechanistic approaches revealed that in both MCF7 and MCF10A cell, PANCR activated p53 and upregulated pro-apoptotic proteins bid and bim and cell cycle inhibitors p21waf/cip1 and p27Kip1. We further explored the mechanism of action that PANCR activates p53, and our results from RNA immunoprecipitation (RIP), RNA pulldown and immunoprecipitation (Co-IP) demonstrated that the PANCR can bind to p53, dissociate p53-MDM2 complex and thus activate p53.Together our data suggest that the novel LncRNA PANCR located in the deleted Chromosome 16q22.1 region is an intracellular p53activator, functioning as a tumor suppressor by activating p53-mediated apoptosis. Citation Format: Yu Cao. The novel long non-coding RNA PANCR is an intracellular p53 activator [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 2572. doi:10.1158/1538-7445.AM2017-2572
Abstract 3960: Tumor cell drug resistance induced by the programmed death ligand 1 (PD-L1) immune checkpoint is associated with autophagy
Authors: Lori M. Minassian, Shannyn K. MacDonald-Goodfellow, Peter Truesdell, Daniel Sanwalka, Andrew W. Craig, Madhuri Koti, D Robert Siemens, Charles H. Graham
Journal: Cancer Research (2017)

Abstract The interaction between the Programmed Death Ligand 1 (PD-L1) immune checkpoint on the tumor cell surface with the Programmed Death-1 (PD-1) receptor on cytotoxic T lymphocytes (CTLs) leads to CTL inactivation, thereby promoting tumor cell escape from adaptive immunity. We previously demonstrated that signaling by PD-L1/PD-1 is bidirectional and leads to activation of oncogenic pathways as well as drug resistance in tumor cells. We also have preliminary evidence that Immunity Related GTPase M, an important mediator of autophagy, is up-regulated by PD-1/PD-L1 reverse signaling. Autophagy is a well-established mechanism of drug resistance in cancer cells. This led us to hypothesize that PD-1/PD-L1 signaling induces drug resistance in tumor cells by up-regulating autophagy. The MEK/ERK and the PI3K/Akt signaling pathways are known to increase and decrease autophagy, respectively. Breast cancer cells exposed to rPD-1 showed a time dependent increase in extracellular signal–regulated kinase (ERK) activation and a decrease in protein kinase B (Akt) activation. Conversion of microtubule-associated protein light chain 3 (LC3)-I to LC3-II is a requirement for autophagosome formation and is a robust marker of autophagy. Exposure of human breast cancer cells to recombinant PD-1 (rPD-1) showed a time-dependent increase in LC-3 II. We are currently conducting additional studies to confirm that the activation of PD-L1 signaling in tumor cells up-regulates autophagy. These results provide evidence that PD-1/PD-L1 reverse signaling activates autophagy as a potential mechanism of cancer cell chemoresistance. (Supported by a grant from the Canadian Institutes of Health Research.) Citation Format: Lori M. Minassian, Shannyn K. MacDonald-Goodfellow, Peter Truesdell, Daniel Sanwalka, Andrew W. Craig, Madhuri Koti, D Robert Siemens, Charles H. Graham. Tumor cell drug resistance induced by the programmed death ligand 1 (PD-L1) immune checkpoint is associated with autophagy [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 3960. doi:10.1158/1538-7445.AM2017-3960