tbuckley/cabot-search huggingface dataset:
Abstract 5655: Inhibition of CCR2 potentiates checkpoint inhibitor immunotherapy in murine model of pancreatic cancer
Authors: Christine Janson, Heiyoun Jung, Linda Ertl, Shirley Liu, Ton Dang, Yibin Zeng, Antoni Krasinski, Jeff McMahon, Penglie Zhang, Israel Charo, Rajinder Singh, Thomas J. Schall
Journal: Cancer Research (2017)

Abstract Pancreatic cancer is an aggressive malignancy with a 5 year survival rate of less than five percent. The predominant immune cells infiltrating the tumor microenvironment are monocytes/macrophages, which are reported to support tumor growth by suppressing host immune responses to the tumor. Recruitment of monocytes to various tissues, including tumors, is dependent upon activation of the chemokine receptor CCR2 by one or more of the chemokines CCL2, CCL8 and CCL13. In preclinical and clinical studies, inhibition of CCR2 in pancreatic cancer has shown to decrease tumor progression by blocking recruitment and accumulation of monocytes/macrophages in the tumor microenvironment. Analysis of human pancreatic tumors revealed elevation of both CCL2 and CSF1, which recruit monocytes, as well as the monocyte marker CD14, in advanced pancreatic cancers. Current immunotherapy using checkpoint inhibitors are effective in some tumors, but lack efficacy in immune insensitive cancers, including pancreatic cancer. Here, we report that the inhibition of CCR2 using a small molecule antagonist potentiates anti-PD-1 immunotherapy in a syngeneic, orthotropic mouse model of pancreatic cancer. Our data reveal that blocking CCR2 decreases tumor burden by blocking monocyte infiltration and creating a microenvironment more favorable for CD8 T cells activity, and provide a mechanistic rationale for investigating the combination of a CCR2 antagonist and an immune checkpoint inhibitor in pancreatic cancer. Citation Format: Christine Janson, Heiyoun Jung, Linda Ertl, Shirley Liu, Ton Dang, Yibin Zeng, Antoni Krasinski, Jeff McMahon, Penglie Zhang, Israel Charo, Rajinder Singh, Thomas J. Schall. Inhibition of CCR2 potentiates checkpoint inhibitor immunotherapy in murine model of pancreatic 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 5655. doi:10.1158/1538-7445.AM2017-5655
Abstract 4441: Unveil the role of cell-free circulating microRNA in lung cancer
Authors: Fabrizio Bianchi, Valentina Melocchi, Tommaso Colangelo, Roberto Cuttano, Lucia Anna Muscarella, Elisa Dama
Journal: Cancer Research (2017)

Abstract We previously reported the identification of a signature composed by 34 serum circulating cell-free microRNAs (cf-miRNA) diagnostic for lung cancer. Using this signature, we developed a blood test (miR-test) which was capable of detecting asymptomatic lung cancer in a large cohort (N&amp;gt;1000) of high-risk individuals (&amp;gt;50years and smokers). Interestingly, we now found that a fraction (~30%) of these cf-miRNAs were preferentially expressed in cells of epithelial origin, while another ~30% were more expressed in hematopoietic cells. We reasoned that this cf-miRNA signature could result from the extracellular release of miRNAs from cancer epithelial cells as well as from immune/stromal cells composing the tumor microenvironment. We developed an integrated strategy for the identification of the origin of cf-miRNAs through combined analysis of published circulating and intracellular miRNAs expression datasets (microarray and qRT-PCR based) and of NGS analysis of cf-miRNAs in lung tumors. Our approach will contribute elucidating the biological role of cf-miRNAs in lung cancer and explore eventual therapeutic implications. Citation Format: Fabrizio Bianchi, Valentina Melocchi, Tommaso Colangelo, Roberto Cuttano, Lucia Anna Muscarella, Elisa Dama. Unveil the role of cell-free circulating microRNA in 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 4441. doi:10.1158/1538-7445.AM2017-4441
What is a number? The interplay between number and continuous magnitudes
Authors: Rosa Rugani, Umberto Castiello, Konstantinos Priftis, Andrea Spoto, Luisa Sartori
Journal: Behavioral and Brain Sciences (2017)

Abstract Leibovich et al. argue that it is impossible to control for all continuous magnitudes in a numerical task. We contend that continuous magnitudes (i.e., perimeter, area, density) can be simultaneously controlled. Furthermore, we argue that shedding light on the interplay between number and continuous magnitudes – rather than considering them independently – will provide a much more fruitful approach to understanding mathematical abilities.
Abstract 887: Magnetic relaxometry detection of stealth, antibody-targeted micellar iron oxide nanoparticles in-vivo
Authors: Rebeca Romero Aburto, Konstantin Sokolov, Adam M. Kulp, Erika C. Vreeland, Zhen Lu, Robert C. Bast, John D. Hazle, Kelsey B. Mathieu
Journal: Cancer Research (2017)

Abstract Magnetic relaxometry (MRX) has the potential to provide unprecedented sensitivity in early detection of cancer by sensing changes in magnetic relaxation of iron oxide (Fe3O4) nanoparticles targeted to cancer biomarkers and is expected to exceed the detection limits of established clinical modalities. MRX uses superconducting quantum interference device (SQUID) sensors to measure Neél relaxation of bound particles. Our strategy was to develop molecular specific Fe3O4 nanoparticles using amphiphilic functionalized phospholipids that allow for clinical translation of the MRX technology. To accomplish this, we used automated, controlled rate, direct infusion of an organic phase mixture of phospholipids and nanoparticles into water to produce monodisperse micellar nanoparticles with a mean diameter of 75±12 nm and surface charge of -10mV. The particles were determined to be stable in various biological media, including human plasma, for more than 24 hours with no detectable formation of a protein corona. Furthermore, in-vivo studies in healthy mice showed blood circulation times of more than 2 hours, as well as minimal MRX signals during this time. Additionally, we developed maleimide conjugation chemistry for epidermal growth factor receptor (EGFR) antibody attachment to micellar nanoparticles. We have achieved molecular specific labeling of cancer cells over-expressing EGFR. In the future, we will evaluate the MRX signal impact from injecting EGFR-conjugated nanoparticles into tumor-bearing mice. Citation Format: Rebeca Romero Aburto, Konstantin Sokolov, Adam M. Kulp, Erika C. Vreeland, Zhen Lu, Robert C. Bast, John D. Hazle, Kelsey B. Mathieu. Magnetic relaxometry detection of stealth, antibody-targeted micellar iron oxide nanoparticles in-vivo [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 887. doi:10.1158/1538-7445.AM2017-887
The HLF/IL-6/STAT3 feedforward circuit drives hepatic stellate cell activation to promote liver fibrosis
Authors: Dai-Min Xiang, Wen Sun, Bei-Fang Ning, Teng-Fei Zhou, Xiao-Feng Li, Wei Zhong, Zhuo Cheng, Ming-Yang Xia, Xue Wang, Xing Deng, Wei Wang, Heng-Yu Li, Xiu-Liang Cui, Shi-Chao Li, Bin Wu, Wei-Fen Xie, Hong-Yang Wang, Jin Ding
Journal: Gut (2017)

Background and aims Liver fibrosis is a wound-healing response that disrupts the liver architecture and function by replacing functional parenchyma with scar tissue. Recent progress has advanced our knowledge of this scarring process, but the detailed mechanism of liver fibrosis is far from clear. Methods The fibrotic specimens of patients and HLF (hepatic leukemia factor) PB/PB mice were used to assess the expression and role of HLF in liver fibrosis. Primary murine hepatic stellate cells (HSCs) and human HSC line Lx2 were used to investigate the impact of HLF on HSC activation and the underlying mechanism. Results Expression of HLF was detected in fibrotic livers of patients, but it was absent in the livers of healthy individuals. Intriguingly, HLF expression was confined to activated HSCs rather than other cell types in the liver. The loss of HLF impaired primary HSC activation and attenuated liver fibrosis in HLF PB/PB mice. Consistently, ectopic HLF expression significantly facilitated the activation of human HSCs. Mechanistic studies revealed that upregulated HLF transcriptionally enhanced interleukin 6 (IL-6) expression and intensified signal transducer and activator of transcription 3 (STAT3) phosphorylation, thus promoting HSC activation. Coincidentally, IL-6/STAT3 signalling in turn activated HLF expression in HSCs, thus completing a feedforward regulatory circuit in HSC activation. Moreover, correlation between HLF expression and alpha-smooth muscle actin, IL-6 and p-STAT3 levels was observed in patient fibrotic livers, supporting the role of HLF/IL-6/STAT3 cascade in liver fibrosis. Conclusions In aggregate, we delineate a paradigm of HLF/IL-6/STAT3 regulatory circuit in liver fibrosis and propose that HLF is a novel biomarker for activated HSCs and a potential target for antifibrotic therapy.
Abstract 4368: The clinicopathological significance of glutathione S-transferase P1 hypermethylation in breast cancer, a meta-analysis and literature review
Authors: Mingli Liu
Journal: Cancer Research (2017)

Abstract Background: Glutathione S-transferase P1 (GSTP1) has been reported to function as a tumor suppressor gene in various types of human cancers including breast cancer (BC). However, the association and clinicopathological significance between GSTP1 hypermethylation and BC remains unclear. The purpose of this study is to conduct a meta-analysis and literature review to investigate clinicopathological significance of GSTP1 methylation in BC. Method: A detailed literature search was made in PubMed, EMBASE, Web of Science and Google Scholar databases. The data were extracted and assessed by two reviewers independently. Odds Ratios (OR) with 95% corresponding confidence intervals (CIs) were calculated. A total of twenty four relevant articles were available for meta-analysis. Results: The frequency of GSTP1 hypermethylation was significantly increased in BC than in benign breast disease, the pooled OR was 7.09, p&amp;lt;0.00001. The rate of GSTP1 hypermethylation was significantly different between early stage I/II and later stage III/IV, OR was 2.05, p&amp;lt;0.0001. In addition, the rate of GSTP1 hypermethylation was also significantly different regarding the node involvement status. The rate of GSTP1 hypermethylation in node positive BC was higher than that in node negative BC, OR was 1.77, p=0.006. However, GSTP1 hypermethylation was not significantly associated with ER, PR and HER2 status. Conclusion: In summary, our meta-analysis indicated that the frequency of GSTP1 hypermethylation was significantly increased in BC than in benign breast disease. The rate of GSTP1 hypermethylation in late stages of BC was higher than that in early stages. Our data suggested that GSTP1 hypermethylation could be a risk factor and a diagnostic biomarker of BC carcinogenesis. GSTP1 hypermethylation may have a role in the progression of BC. GSTP1 is a potential drug target for development of demethylation treatment for patients with BC. Note: This abstract was not presented at the meeting. Citation Format: Mingli Liu. The clinicopathological significance of glutathione S-transferase P1 hypermethylation in breast cancer, a meta-analysis and literature review [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 4368. doi:10.1158/1538-7445.AM2017-4368
Abstract 2684: Multiplex immunofluorescence profiling of tumor infiltrating immune subsets in HNSCC biopsies provides a powerful tool when combined with patient outcome data
Authors: Matt Levin, Mark Lingen, David Schwartz, Helen Snyder
Journal: Cancer Research (2017)

Abstract Head and neck squamous cell carcinoma (HNSCC) is one of the growing number of tumors for which an anti-tumor immune response is implicated to play a role in the course of the disease. Profiling of the tumor microenvironment including specific infiltrating lymphocyte subsets, antigen presenting cells, expression of regulatory molecules on both tumor and immune cells and spatial relationships between cells could lead to predictive signatures for responsiveness to both conventional and immune modulatory therapies. While flow cytometry results in multi-parametric analysis of immune populations within the tumor, their context i.e. the spatial relationship of these cells to tumor and to other immune cells, is lost. In this current study we use Cell IDx’s novel UltraPlex technology, which is based on a simple two-step, autostainer compatible protocol using hapten labeled primary antibody cocktails followed by fluor labeled anti-hapten secondary cocktails to simultaneously detect 4 cellular markers on the same cell in tumor biopsies. Image registration of serial sections increases multiplexing to 12-16 markers. This technology, which allows generation of full immune subset profiling, quantitative marker expression and relative cellular localization, was applied to a HNSCC tumor microarray as a test system. Data are presented showing the potential of this technology for correlation of tumor “immune signature” with patient outcome. Citation Format: Matt Levin, Mark Lingen, David Schwartz, Helen Snyder. Multiplex immunofluorescence profiling of tumor infiltrating immune subsets in HNSCC biopsies provides a powerful tool when combined with patient outcome data [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 2684. doi:10.1158/1538-7445.AM2017-2684
Human myiasis caused by the reindeer warble fly, Hypoderma tarandi, case series from Norway, 2011 to 2016
Authors: Jörgen Landehag, Andreas Skogen, Kjetil Åsbakk, Boris Kan
Journal: Eurosurveillance (2017)

Hypoderma tarandi causes myiasis in reindeer and caribou (Rangifer tarandus spp.) in most northern hemisphere regions where these animals live. We report a series of 39 human myiasis cases caused by H. tarandi in Norway from 2011 to 2016. Thirty-two were residents of Finnmark, the northernmost county of Norway, one a visitor to Finnmark, and six lived in other counties of Norway where reindeer live. Clinical manifestations involved migratory dermal swellings of the face and head, enlargement of regional lymph nodes, and periorbital oedema, with or without eosinophilia. Most cases of human myiasis are seen in tropical and subtropical countries, and in tourists returning from such areas. Our findings demonstrate that myiasis caused by H. tarandi is more common than previously thought. Healthcare professionals in regions where there is a likelihood of human infestation with H. tarandi (regions populated by reindeer), or treating returning travellers, should be aware of the condition. All clinicians are advised to obtain a detailed travel history when assessing patients with migratory dermal swellings. On clinical suspicion, ivermectin should be given to prevent larval invasion of the eye (ophthalmomyiasis). Since H. tarandi oviposits on hair, we suggest wearing a hat as a prevention measure.
Abstract 390: Identification and characterization of survival-associated genomic features across tumor types
Authors: Joan Smith, Ann Lin, Chris Giuliano, Jason M. Sheltzer
Journal: Cancer Research (2017)

Abstract The basic biology that differentiates a primary cell from a transformed cell has been elucidated over the past several decades. Mutations in a limited number of oncogenes and tumor suppressors free the cell from growth-inhibitory checkpoints and allow proliferation in the absence of external stimuli, leading to tumor formation. Yet, primary tumors themselves are rarely deadly: greater than 90% of cancer mortality results from metastasis. What drives metastasis, and, more broadly, what distinguishes a lethal cancer from one with a favorable prognosis, is poorly understood. To address this question, we have performed a comprehensive meta-analysis on genomic data from primary tumors that are linked to patients’ clinical outcomes. Utiliizing data from &amp;gt;20,000 patients, we have identified protein-coding genes, lncRNAs, miRNAs, methylation sites, and CNVs in primary tumors that are significantly associated with patient prognosis across cancer types. Multivariate analysis reveals a hierarchy of survival determinants: the strongest mortality-associated factors are enriched for components of the mitotic cell cycle, while secondary clusters of genes are involved in extracellular matrix remodeling, cell motility, and angiogenesis. Survival-associated genomic features are indicative of immune infiltration into primary tumors and oxidative phosphorylation activity. In vitro and in vivo analyses reveal that mortality-associated genes rarely promote the direct transformation of primary cells. Instead, CRISPR mutagenesis reveals that these genes largely represent tumor dependencies, and in their absence cancer cells fail to proliferate. Through this analysis, we have identified new genetic dependencies common across cancer cells, including C16ORF59 and C5ORF46. In total, our results represent the largest assessment of genomic features linked to cancer prognosis completed to date, and offer several lines of insight into the biological differences between fatal and benign cancers. Note: This abstract was not presented at the meeting. Citation Format: Joan Smith, Ann Lin, Chris Giuliano, Jason M. Sheltzer. Identification and characterization of survival-associated genomic features across tumor types [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 390. doi:10.1158/1538-7445.AM2017-390
Abstract 1517: AKT inhibition induces neuroendocrine phenotype in prostate cancer cells
Authors: RuiQi Chen, Yinan Li, Xuesen Dong
Journal: Cancer Research (2017)

Abstract Androgen receptor (AR) signaling pathway inhibition (ARPI) is the primary treatment for locally advanced, recurrent, or metastatic prostate cancer. While ARPI is effective in short term, a fatal relapse is inevitable. The AKT signaling pathway inhibition has been investigated under multiple ongoing clinical trials as a co-therapeutic target with ARPI. The AKT signaling pathway is targeted due to its role in tumorigenesis, prevalent over-activation, and reciprocal activation upon ARPI in prostate cancer. However, this novel combination therapy may in fact facilitate PCa to progress into one of the most lethal subtypes called neuroendocrine (NE) prostate cancer (NEPC). Specifically, evidence has shown that ARPI contributes to NEPC progression at least in part by down-regulating the expression of RE-1 Silencing Transcription Factor (REST). Loss of REST is a hallmark of NEPC progression because REST functions as a negative master regulator in neurogenesis by suppressing genes required for neural differentiation. Similar to ARPI, our studies found that AKT inhibition reduced REST protein expression and increased NEPC markers in multiple prostate cancer cell lines. We also showed that the loss of REST upon AKT inhibition was through protein degradation mediated by an E3-ubiquitin ligase TRCP, which recognizes a phosphorylated REST degron region to recruit ubiquitins. In vivo ubiquitination assays confirmed the elevated REST ubiquitination after the treatment of PI3K inhibitors. Furthermore, mutations within the REST degron region reversed the TRCP-mediated REST ubiquitination and degradation. Finally, co-treatment of AKT pathway inhibition and ARPI showed aggravated REST depletion and increased NE markers in the prostate cancer cell line LNCaP. Collectively, these findings indicate that AKT pathway inhibition can induce NE phenotype in prostate cancer cells via REST protein degradation. This study may provide a caution to the ARPI/AKT co-target strategy as this strategy can potentially facilitate NEPC development. Citation Format: RuiQi Chen, Yinan Li, Xuesen Dong. AKT inhibition induces neuroendocrine phenotype in prostate cancer 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 1517. doi:10.1158/1538-7445.AM2017-1517
Abstract LB-185: A PSMA-directed natural killer cell approach for prostate cancer immunotherapy
Authors: Lucas J. Brand, Alexander B. Zaslavsky, Ganesh S. Palapattu, Karen E. Knudsen
Journal: Cancer Research (2017)

Abstract Prostate Cancer (PCa) is the third leading cause of cancer mortality in men in the United States. Locally advanced or metastatic PCa is clinically managed with androgen deprivation therapy (ADT), androgen receptor antagonists, and/or taxane chemotherapy. While initially effective, patients eventually develop resistance, leading to onset of a lethal castration-resistant disease state for which no curative interventions currently exist. Cell-based immunotherapy—which is centered on infusion of modified, tumor-directed immune cells intended to drive a more potent anti-tumor response—could potentially provide a new approach to treating advanced PCa. In this study, we describe the modification of an allogeneic, immortalized human natural killer cell line, NK-92, with a chimeric antigen receptor (CAR) directed against prostate-specific membrane antigen (PSMA), a cell-surface antigen expressed by most prostate tumors. We observed that both unmodified and CAR-bearing NK-92 cells display potent cytolytic activity against the majority of PCa cell lines tested in vitro. Expression of PSMA on PCa cell lines affected the activity of CAR-modified, but not unmodified, NK-92. Combination of NK-92 immunotherapy with ADT and taxanes is also discussed, as well as ongoing in vivo preclinical modeling. Overall, CAR-modified NK-92 cells show promise as a novel immunotherapeutic agent for the treatment of PCa. Citation Format: Lucas J. Brand, Alexander B. Zaslavsky, Ganesh S. Palapattu, Karen E. Knudsen. A PSMA-directed natural killer cell approach for prostate cancer immunotherapy [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 LB-185. doi:10.1158/1538-7445.AM2017-LB-185