tbuckley/cabot-search huggingface dataset:
Abstract 1817: Resistin induces angiogenesis and lymphangiogenesis in human chondrosarcoma
Authors: Meng-Ju Chi, Chih-Yang Lin, Chih-Hsin Tang
Journal: Cancer Research (2017)

Abstract Chondrosarcoma is a common kind of bone cancers, and it may develop distant metastasis, followed by a significant decline in overall survival. However, there are still no specific therapeutic methods for it today. For tumors to metastasis, angiogenesis and lymphangiogenesis are both important in the early processes. Therefore, inhibiting the development of angiogenesis and lymphangiogenesis could be a method to decline tumor metastasis. Resistin was discovered as an adipocyte-secreting adipokine, which may play a critical role in modulating cancer pathogenesis. In our lab, we previously found that resistin appears to increase MMP-2 expression and then promotes metastasis in human chondrosarcoma cells. Nevertheless, the role of resistin in angiogenesis and lymphangiogenesis of human chondrosarcoma is still unknown. To examine angiogenetic and lymphangiogenetic effects of resistin, we used human endothelial progenitor cells (EPCs) and lymphatic endothelial cells (LECs) to mimic capillary and lymphatic vessels formation. The results indicated that resistin-treated chondrosarcoma cell lines promoted EPCs VEGF-A-dependent as well as LECs VEGF-C-dependent tube formation and cell migration. Then we confirmed that treating cells with resistin increased VEGF-A and VEGF-C expression in human chondrosarcoma cell lines. Moreover, we found resistin-induced VEGF-A and VEGF-C expressions are mediated by PI3K/AKT signaling and by the activation of c-Src separately. In addition, resistin decreased the expression of miR-16-5p via PI3K/AKT pathway, and so of miR-186 via c-Src. We also demonstrated that miR-186 directly targeted on VEGF-C 3’ untranslated region, and regulated the VEGF-C production. Besides, we found the expressions of resistin, VEGF-A and VEGF-C was higher in human chondrosarcoma biopsy tissues than those in normal cartilage. Taken together, resistin not only promotes human chondrosarcoma angiogenesis through the activation of PI3K/AKT signaling pathway and down-regulating miR-16-5p expression, but also promotes human chondrosarcoma lymphangiogenesis through the activation of c-Src and down-regulating miR-186. Consequently, resistin may represent a potential novel molecular therapeutic target for human chondrosarcoma therapeutic treatment. Citation Format: Meng-Ju Chi, Chih-Yang Lin, Chih-Hsin Tang. Resistin induces angiogenesis and lymphangiogenesis in human chondrosarcoma [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 1817. doi:10.1158/1538-7445.AM2017-1817
Abstract 3813: MPF as a monitoring biomarker for a mesothelin-targeted therapy against malignant mesothelioma and other cancer
Authors: Yunkai Yu, Raffit Hassan, Jingli Zhang, Masanori Onda, Ira Pastan, Liang Cao
Journal: Cancer Research (2017)

Abstract Introduction: Tumor antigen mesothelin had been shown to be elevated in mesothelioma, ovarian, pancreatic, and lung cancer. The mesothelin gene encodes a precursor protein of 69 kDa, which is cleaved into a 31 kDa soluble megakaryocyte potential factor (MPF), and a cell membrane-bound 40 kDa mesothelin. There is a high degree of interest in targeting mesothelin for mesothelioma and other cancers with various antibody-based agents, and some successes in early stage clinical trials with some of the agents. For the development of these targeted therapeutics, specific biomarkers would be needed for monitoring treatment responses, and detecting and evaluating tumor progression. The current test that detects mesothelin is not suitable due to the antigen-binding from the therapeutic antibodies. There is an urgent need to develop and validate an alternative test to support these clinical trials and for disease management. Methods: Using ECLIA technology and proprietary antibody reagents, we developed a new test for the cleaved MPF polypeptide. We further conducted comprehensive analytical and clinical validation of the test according to the guidelines for tumor antigen tests. Using samples from a retrospective clinical trial with an anti-mesothelin immunotoxin and the standard 1st line chemotherapeutic agents for newly diagnosed malignant mesothelioma patients, we examined the effectiveness of the test for treatment monitoring of the investigational therapy. Results: Our data gives a strong validation for the analytical and clinical performances of MPF test. While no other current test has been proven to be able to monitor response of mesothelioma to systemic therapies, our data provides the proof of clinical effectiveness for MPF test. In the patients with the elevated tumor antigen, there is a specific and highly significant reduction of MPF at the end of each treatment cycle for a total of 6 cycles in the patients with objective response. Later, about half of these patients with objective response and MPF reduction regained the levels of MPF at the time of disease progression. Conclusion: The study indicates that MPF test is effective in monitoring the treatment response to systemic therapies for mesothelioma patients with elevated MPF. It may also provide pivotal information on the expression of target mesothelin protein when tumors progress. Citation Format: Yunkai Yu, Raffit Hassan, Jingli Zhang, Masanori Onda, Ira Pastan, Liang Cao. MPF as a monitoring biomarker for a mesothelin-targeted therapy against malignant mesothelioma and other 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 3813. doi:10.1158/1538-7445.AM2017-3813
Abstract 161: TRPC6 Activator Hyperforin Facilitates Arrhythmias Via Activating Store-operated Calcium Entry
Authors: Hairuo Wen, Richard Gordan, Nadezhda Fefelova, Lai-Hua Xie
Journal: Circulation Research (2013)

Hyperforin, a major antidepressant constituent of St. John’s wort ( Hypericum perforatum ), exhibits high selectivity in activating the canonical transient potential channel 6 (TRPC6). Our previous studies have shown that TRPC6 may modulate Ca 2+ handling via store-operated Ca 2+ entry (SOCE) in adult ventricular myocytes. In the present study, we aim to test whether hyperforin is arrhythmogenic by facilitating Ca 2+ waves. Intracellular Ca 2+ fluorescence (F/F 0 ) was imaged in Fluo-4-AM loaded ventricular myocytes isolated from adult mice (2-4 month old). SOCE was evaluated by increasing the external Ca 2+ concentration ([Ca 2+ ] o ) from 0 to 1 mM after caffeine (10 mM) and thapsigargin (10 µM) were used to completely deplete SR Ca 2+ . Hyperforin (0.1-10 µM) perfusion increased SOCE up to 3.7 folds (F/F 0 = 3.73 ± 0.42, n = 7, compared to the control F/F 0 = 1.69 ± 0.37, n = 9, p &lt; 0.05), in a concentration dependent fashion. Whole-cell currents were recorded using ramp pulses from -110 mV to +50 mV, while K + , Na + , L-type Ca 2+ , and Na + -Ca 2+ exchange currents were pre-blocked. Hyperforin at a lower concentration (0.1 µM) induced a significant increase of inward current (from -1.44 ± 0.23 pA/pF to -2.56 ± 0.36 pA/pF, n = 8, p &lt; 0.05), which was then inhibited by the SOCE blocker Gd 3+ (1 mM) (-0.43 ± 0.22 pA/pF, n = 8, p &lt; 0.05). Hyperforin promotes spontaneous CaWs ([Ca 2+ ] o 4 mM) by increasing the frequency to 180± 14 % (n = 11. p &lt; 0.05), which can be attenuated by Gd 3+ (1 mM), or SKF-96265 (10 μM). In addition, both the amplitudes of Ca 2+ transients (F/F 0 =1.92 ± 0.09 to 2.09 ± 0.10, n = 12, p &lt; 0.05) and calcium content (control: F/F 0 = 2.03 ± 0.11, n=16 to 2.12 ± 0.13, n = 11, p &lt; 0.05) were enhanced by acute hyperforin perfusion (0.1 µM), when the cells were paced at a pacing cycle length of 2 seconds. The proarrhythmic effect of hyperforin was also confirmed in Langendorff-perfused hearts, from which optical membrane voltage mapping and EKG were simultaneously recorded. In conclusion, the TRPC6 activator hyperforin exhibits an arrhythmogenic effect in the heart. Its action is likely to be mediated by generating an inward current and increasing the calcium load in cardiac myocytes through the SOCE pathway. Caution should be taken when prescribing this drug to patients with heart disease.
Abstract 2696: PD-1 antibody treatment induces gut microbiota changes in CT-26 colon cancer syngeneic model
Authors: Jian Ding, Binchen Mao, Qian Shi
Journal: Cancer Research (2017)

Abstract The gut microbiota plays an important role in shaping systemic immune response. One novel frontier in cancer research is investigating how the gut microbiota change immune response and influence the efficacy of anticancer immunotherapy drugs; this has been reported in CTLA4 and PD-L1 antibody treatment, both in laboratory and clinical settings. One recent study reported that composition of patient`s gut microbes appears to be a determining factor for immunotherapy, at least in melanoma patients. These findings shed light on the potential use of gut microbial as a biomarker for responders in cancer immunotherapy and even as a novel treatment. Here, we evaluated the gut microbiota profiling upon PD-1 antibody (RMP1-14) treatment in CT-26 colon cancer syngeneic mouse model. Fresh feces were collected at different time points before and after treatment, snap frozen and sent for 16s RNA sequencing for microbiome profiling. Our results identified top 25 abundant taxa in genus level in CT-26 feces. Significant abundance changes were observed in several genera after PD-1 antibody treatment, especially in Akkermansia. These findings indicate that immunotherapy like PD-1 antibody can induce the profile changes of gut microbiota in CT-26 model. Furthermore, we also investigated the correlation of gut microbiome with immune- microenvironment and the efficacy upon IO therapy, as well as the possibility to utilize microbiota profiling as a quality control step that may help to explain the variability observed in many syngeneic studies. Citation Format: Jian Ding, Binchen Mao, Qian Shi. PD-1 antibody treatment induces gut microbiota changes in CT-26 colon cancer syngeneic model [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 2696. doi:10.1158/1538-7445.AM2017-2696
Perceiving numerosity from birth
Authors: Maria Dolores de Hevia, Elisa Castaldi, Arlette Streri, Evelyn Eger, Véronique Izard
Journal: Behavioral and Brain Sciences (2017)

Abstract Leibovich et al. opened up an important discussion on the nature and origins of numerosity perception. The authors rightly point out that non-numerical features of stimuli influence this ability. Despite these biases, there is evidence that from birth, humans perceive and represent numerosities, and not just non-numerical quantitative features such as item size, density, and convex hull.
Abstract 3101: Hyperthermia at the single-cell level for disseminated cancer disease with immuno-magnetic nanoparticles
Authors: Tetsuya Kagawa, Hiroyuki Kishimoto, Toshiaki Ohara, Hiroshi Tazawa, Shunsuke Kagawa, Takeshi Nagasaka, Satoshi Nohara, Ichiro Kato, Adarsh Sandhu, Hiromichi Aono, Toshiyoshi Fujiwara
Journal: Cancer Research (2017)

Abstract Hyperthermia using magnetic nanoparticles and alternating magnetic field is promising for cancer therapy. In most cases, the usefulness of this magnetic nanoparticle-based hyperthermia has been shown by applying magnetic nanoparticles to tumor tissue such as a subcutaneous tumor with direct injection technique; however, if the magnetic nanoparticles can be cancer cell-specifically delivered at the cellular level, the magnetic field hyperthermia would have the potential to treat various sorts of disseminated cancer diseases. The aim of this study is to prove this concept. Maghemite nanoparticles (MNPs) were conjugated with the anti-HER2 antibody (Tmab) for cancer targeting, and the Tmab-MNPs were applied to the co-culture flask containing both HER2-expressing breast cancer AU565 cells and normal fibroblast FEF3 cells. Thirty minutes later from the Tmab-MNPs administration, the medium was removed and the cells were washed to remove excess Tmab-MNPs. Prussian blue iron staining and immunostaining for Tmab showed co-localization of the maghemite nanoparticles and Tmab only on the cancer cells, which suggested that MNPs conjugation with Tmab was successful and that cancer specific delivery of MNPs at the cellular level was achieved in vitro. Moreover, application of alternating current magnetic field at 280 kHz for 1 hour caused apoptotic-like cell death only to cancer cells without any cell damage to normal fibroblast FEF3 cells. Intracellular hyperthermia using cancer-specific antibody-modified magnetic nanoparticles have the potential to be applied to the treatment of disseminated cancer diseases. Citation Format: Tetsuya Kagawa, Hiroyuki Kishimoto, Toshiaki Ohara, Hiroshi Tazawa, Shunsuke Kagawa, Takeshi Nagasaka, Satoshi Nohara, Ichiro Kato, Adarsh Sandhu, Hiromichi Aono, Toshiyoshi Fujiwara. Hyperthermia at the single-cell level for disseminated cancer disease with immuno-magnetic nanoparticles [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 3101. doi:10.1158/1538-7445.AM2017-3101
Abstract 2628: BGB-A425: a humanized anti-human Tim-3 antibody that exhibits strong immune cell activation
Authors: Tong Zhang, Liu Xue, Jing Zhang, Qi Liu, Jie Ma, Yi Zhang, Yingdi Shi, Hongjia Hou, Hao Peng, Ning Liu, Yilu Zhang, Xiaomin Song, Yucheng Li, Jing Song, Lai Wang, Min Wei, Kang Li
Journal: Cancer Research (2017)

Abstract Background: Tim-3 (T-cell immunoglobin and mucin-domian containing-3) is a “checkpoint” inhibitory receptor, which is primarily expressed in activated or “exhausted” T cells, NK cells, macrophages and DCs. Engagement of Tim-3 receptor by its ligand phosphatidylserine (PtdSer) or galectin-9 leads to activation of negative regulatory signaling in T-cells, promoting functional exhaustion of tumor-infiltrating T-lymphocytes. BGB-A425 is a novel humanized IgG1 (variant) anti-Tim-3 antibody under preclinical development. The immunomodulatory activity of BGB-A425 was evaluated both in vitro and in vivo. Materials and methods: BGB-A425 was generated through hybridoma fusion, humanized by CDR grafting and structural simulation. The Fc region (IgG1) of BGB-A425 was engineered to remove Fc gamma receptor (FcγR) binding. The binding affinity and specificity were studied by ELISA, FACS and SPR (Biacore). The immunomodulatory functions of BGB-A425 were evaluated using primary immune cells as well as cell lines. Results: BGB-A425 binds to the extracellular domain of human Tim-3 with high affinity (KD = 0.36 nM) and specificity. In a competition assay, BGB-A425 efficiently blocks the interactions between Tim-3 and PtdSer. In vitro, BGB-A425 significantly enhances IFN-γ production of primary T cells and NK-mediated cytotoxicity against tumor cells. In a MLR assay, BGB-A425 augments T-cell response to allogeneic antigens either alone or in combination with an anti-PD-1 antibody BGB-A317. Besides blocking Tim-3, BGB-A425 can also induce the internalization of Tim-3 receptor on cell surface. In vivo, BGB-A425 in combination with BGB-A317 inhibits tumor growth in a mouse xenograft cancer model. Conclusions: BGB-A425 demonstrates potent activity to stimulate immune cell function both in vitro and in vivo, supporting its clinical development for the treatment of human cancers. Citation Format: Tong Zhang, Liu Xue, Jing Zhang, Qi Liu, Jie Ma, Yi Zhang, Yingdi Shi, Hongjia Hou, Hao Peng, Ning Liu, Yilu Zhang, Xiaomin Song, Yucheng Li, Jing Song, Lai Wang, Min Wei, Kang Li. BGB-A425: a humanized anti-human Tim-3 antibody that exhibits strong immune cell activation [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 2628. doi:10.1158/1538-7445.AM2017-2628
Hepatitis B cure: From discovery to regulatory approval
Authors: Anna S. Lok, Fabien Zoulim, Geoffrey Dusheiko, Marc G. Ghany
Journal: Hepatology (2017)

The majority of persons currently treated for chronic hepatitis B require long-term or lifelong therapy. New inhibitors of hepatitis B virus entry, replication, assembly, or secretion and immune modulatory therapies are in development. The introduction of these novel compounds for chronic hepatitis B necessitates a standardized appraisal of the efficacy and safety of these treatments and definitions of new or additional endpoints to inform clinical trials. To move the field forward and to expedite the pathway from discovery to regulatory approval, a workshop with key stakeholders was held in September 2016 to develop a consensus on treatment endpoints to guide the design of clinical trials aimed at hepatitis B cure. The consensus reached was that a complete sterilizing cure, i.e., viral eradication from the host, is unlikely to be feasible. Instead, a functional cure characterized by sustained loss of hepatitis B surface antigen with or without hepatitis B surface antibody seroconversion, which is associated with improved clinical outcomes, in a higher proportion of patients than is currently achieved with existing treatments is a feasible goal. Development of standardized assays for novel biomarkers toward better defining hepatitis B virus cure should occur in parallel with development of novel antiviral and immune modulatory therapies such that approval of new treatments can be linked to the approval of new diagnostic assays used to measure efficacy or to predict response. Combination of antiviral and immune modulatory therapies will likely be needed to achieve functional hepatitis B virus cure. Limited proof-of-concept monotherapy studies to evaluate safety and antiviral activity should be conducted prior to proceeding to combination therapies. The safety of any new curative therapies will be paramount given the excellent safety of currently approved nucleos(t)ide analogues. (Hepatology 2017).
Abstract LB-019: Hakai, an E3-ligase for E-cadherin, stabilizes δ-catenin through Src kinase
Authors: Hridaya Shrestha, Taeyong Ryu, Young-woo Seo, So-yeon Park, Yongfeng He, Weiye Dai, Eunsook Park, Shishli Simkhada, Hangun Kim, Keesook Lee, Kwonseop Kim
Journal: Cancer Research (2017)

Abstract Hakai ubiquitinates and induces endocytosis of the E-cadherin complex; thus, modulating cell adhesion and regulating the epithelial-mesenchymal transition in development of metastasis. Our previous published data show that δ-catenin promotes E-cadherin processing and thereby activates β-catenin-mediated oncogenic signals in prostate cancer. Although several published data show the interactions between δ-catenin and E-cadherin; and Hakai and E-cadherin separately, we found no published report on the relationship between δ-catenin and Hakai. In this study, we show Hakai stabilizes δ-catenin regardless of its E3-ligase activity. We found that Hakai and Src increase the stability of δ-catenin synergistically. Furthermore, we show that Hakai stabilizes Src, which in turn inhibits binding between glycogen synthase kinase-3β and δ-catenin, resulting in less glycogen synthase kinase-3β mediated phosphorylation and proteosomal degradation of δ-catenin. Taken together, these results suggest that stabilization of δ-catenin by Hakai is dependent on Src. Our novel findings on the Hakai mediated δ-catenin stabilization in an ubiquitination independent manner will add a new perspective to provide further insight into E3-ligase activity independent role of Hakai in cancer pathogenesis. Citation Format: Hridaya Shrestha, Taeyong Ryu, Young-woo Seo, So-yeon Park, Yongfeng He, Weiye Dai, Eunsook Park, Shishli Simkhada, Hangun Kim, Keesook Lee, Kwonseop Kim. Hakai, an E3-ligase for E-cadherin, stabilizes δ-catenin through Src kinase [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-019. doi:10.1158/1538-7445.AM2017-LB-019
Abstract 1916: Peptidylarginine deiminase IV (PADI4) is a novel tumor suppressor that may contribute to regulation of breast cancer stem cell dynamics
Authors: Nellie Moshkovich
Journal: Cancer Research (2017)

Abstract Breast cancer is a global problem that accounts for almost a fourth of all cancers in women. Despite the many therapeutic strategies currently in use, treated patients often suffer from cancer relapse and metastasis due to the presence of a subpopulation of tumorigenic cells capable of self-renewal and termed cancer stem cells (CSCs). To address the properties of this critical sub-population, we utilized our recently-developed lentiviral CSC reporter carrying an Oct4/Sox2 response element coupled to a green fluorescent protein (SORE6-GFP) to detect and isolate the CSC population in a low-grade ER+ human breast cancer model, MCF10Ca1h, by FACS. Whole transcriptome sequencing analysis (RNA-seq) on the sorted cells identified Peptidylarginine deiminase IV (PADI4) as differentially expressed between CSCs and non-CSCs. PADI4 was recently shown to regulate citrullination of histone H1, displacing it from chromatin and resulting in global chromatin decondensation and pluripotency induction in embryonic stem cells (Christophorou, et al., 2014, Nature 507:104). Thus, we hypothesized that PADI4 may also regulate the stemness phenotype in breast cancer CSCs, likely through effects on chromatin structure. We showed that PADI4 protein expression is higher in luminal breast cancer cell lines than other subtypes, and we did shRNA knockdown (KD) of PADI4 in the luminal MCF10Ca1h model. PADI4 KD increased tumorosphere formation and clonogenicity indicating increased CSC population/activity. Additionally, MCF10Ca1h cells treated with a PADI4 selective inhibitor showed an increase in CSCs as assessed using the SORE6-GFP stem cell reporter. In vivo limiting dilution studies demonstrate that PADI4 KD increased tumor incidence at low cell inoculum, reflecting a statistically significant 2-4 fold increase in CSCs upon PADI4 KD. Our findings suggest that PADI4 may function as a tumor suppressor in luminal breast cancer. In support of this conclusion, deep deletions of PADI4 locus are found in 1% of human breast cancers in the TCGA datasets. Analysis of the effect of PADI4 KD on chromatin organization in the CSC and non-CSC compartments is ongoing. Citation Format: Nellie Moshkovich. Peptidylarginine deiminase IV (PADI4) is a novel tumor suppressor that may contribute to regulation of breast cancer stem cell dynamics [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 1916. doi:10.1158/1538-7445.AM2017-1916