tbuckley/cabot-search huggingface dataset:
Adventitial fibroblast-derived vascular endothelial growth factor promotes vasa vasorum-associated neointima formation and macrophage recruitment
Authors: Xiao-Dong Li, Mo-Na Hong, Jing Chen, Yuan-Yuan Lu, Mao-Qing Ye, Yu Ma, Ding-Liang Zhu, Ping-Jin Gao
Journal: Cardiovascular Research (2019)

Abstract Aims Adventitial vasa vasorum provides oxygen and nourishment to the vascular wall, but whether it regulates vascular disease remains unclear. We have previously shown that an increased expression of VEGF (vascular endothelial growth factor) is associated with macrophage infiltration. This study aims to determine whether adventitial fibroblast (AF)-derived VEGF increases the number of vasa vasorum contributing to neointima formation through macrophage recruitment. Methods and results In rat balloon injury model, vasa vasorum count was increased particularly in the adventitia accompanied by cell proliferation and VEGF expression. Both endogenous and PKH26-labelled exogenous macrophages were mainly distributed in adventitia around vasa vasorum. Interestingly, perivascular delivery of Ranibizumab preferentially concentrated in adventitia resulted in a decrease of neointima formation with concurrent reduction of vasa vasorum count and macrophage infiltration. AFs with adenovirus-mediated VEGF over-expression delivered to the adventitia significantly enhanced these pathological changes after injury. In Tie2-cre/Rosa-LoxP-RFP mice, endothelial cells were increased in the adventitia after wire injury. By using multiphoton laser scanning microscopy, macrophage rolling, adhesion and transmigration were observed in vasa vasorum. Moreover, adoptive transfer of macrophages accelerated injury-induced neointima formation. VEGF-neutralizing antibody administration also attenuated wire injury-induced neointima formation and macrophage infiltration. In primary cultured AFs, exogenous VEGF increased VEGF expression and secretion in a time- and dose-dependent manner. AF-conditioned medium promoted endothelial cell angiogenesis, vascular cell adhesion molecule-1 expression and macrophage adhesion was blocked by VEGF-neutralizing antibody and VEGFR2 inhibitor ZM323881, which also inhibited activation of VEGFR2/ERK1/2 pathway. Conclusion These results demonstrate that AF-derived VEGF plays a significant role in the increase of vasa vasorum count which is involved in macrophage recruitment and neointima formation.
Abstract 188: The oncometabolite d-2-hydroxyglutarate induces angiogenic activity through the vascular endothelial growth factor receptor 2 signaling pathway
Authors: You Mie Lee, Jiyoon Seok, Soo-Hyun Yoon, Sun-Hee Lee, Jong Hwa Jung
Journal: Cancer Research (2019)

Abstract Mutation of isocitrate dehydrogenase (IDH) 1 (R132H) and IDH2 (R172K) and induction of hypoxia in various solid tumors results in changes to metabolic profiles, including production of the d- or l-forms of 2-hydroxyglutarate (2HG) from α-ketoglutarate in aerobic metabolism in the TCA cycle. However, it is unclear whether the oncometabolite d-2HG increases angiogenesis in endothelial cells. Therefore, in this study, we analyzed the levels of various metabolites, including d-2HG, under hypoxic conditions and in IDH2R172K mutant breast cancer cells by mass spectrometry. We then further evaluated the effects of this metabolite on angiogenesis in breast cancer cells. Our results showed that treatment with d-2HG increased the levels of secreted vascular endothelial growth factor (VEGF) in cancer cells and enhanced endothelial cell proliferation in a concentration-dependent manner. Wound healing and transwell migration were significantly increased by d-2HG to a level similar to that induced by VEGF. Tube formation was significantly stimulated by d-2HG, and chick chorioallantoic membrane angiogenesis was also enhanced by d-2HG. d-2HG activated VEGF receptor (VEGFR) 2 and VEGFR2 downstream signaling, extracellular signal-regulated kinase 1/2, focal adhesion kinase, AKT, and matrix metalloproteinase (MMP) 2. Taken together, our results suggested that d-2HG induced angiogenic activity via VEGFR2 signaling and increased MMP2 activity. Citation Format: You Mie Lee, Jiyoon Seok, Soo-Hyun Yoon, Sun-Hee Lee, Jong Hwa Jung. The oncometabolite d-2-hydroxyglutarate induces angiogenic activity through the vascular endothelial growth factor receptor 2 signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 188.
Abstract 2037: Macrophage Inflammatory Protein-3 beta (MIP-3β) from cancer-associated fibroblasts promote the proliferation of melanoma cells
Authors: Heishiro Fujikawa, Masakazu Yashiro, Takaharu Hatano, Shusaku Maeda, Hisashi Motomura
Journal: Cancer Research (2019)

Abstract Introduction: Malignant tumors are composed of cancer cells and various types of stromal cells, including fibroblasts, vascular endothelial cells, and immune cells. It has been reported that fibroblasts in the tumor stroma termed as cancer-associated fibroblasts (CAFs) may affect cancer progression. However, the currently available evidence regarding the function of CAFs remains controversial, with some studies reporting stimulatory activity and some studies reporting inhibitory activity in malignant melanoma cells. Previously, we reported that CAFs possibly exert a stimulatory effect on the proliferation of melanoma cells. In this study, we identified a factor from CAFs that are involved in melanoma progression. Materials and Methods: We used three malignant melanoma cell lines, namely MMAc, COLO679, and A375. Three CAFs and one type of non-affected fibroblasts (NAFs) were established from sebaceous carcinoma/skin malignant melanoma and normal skin, respectively. Serum-free conditioned medium from CAFs (CAF-CM) was prepared as follows: CAFs were seeded into 100-mm plastic dishes with 10 ml of Dulbecco's modification of Eagle medium (DMEM) containing 5% fetal calf serum. To obtain CAF-CM, CAFs were washed using phosphate-buffered saline and subsequently incubated for 3 days with serum-free DMEM, and the conditioned medium was collected as CAF-CM. Additionally, we obtained NAF-CM from NAFs using the same procedure. These fibroblasts were cultured and used before the 15th passage. The cytokines included in each conditioned medium were determined using cytokine assay. Subsequently, we selected some cytokines, which were released more abundantly in CAFs than in NAFs, as potential factors affecting the proliferation of melanoma cells. The effects of these cytokines on the proliferation of melanoma cells were determined using MTT assay and cytometry assay using a Coulter Counter. Results: CAF-CM contained significantly high concentration of MIP-3β, in compared with that in NAF-CM. In addition, MIP-3β significantly increases in the proliferation of melanoma cells, A375 and COLO679, at 48 h and 72 h culture. Conclusion: CAFs from skin cancer might promote the proliferation of malignant melanoma cells via MIP-3β signaling. Citation Format: Heishiro Fujikawa, Masakazu Yashiro, Takaharu Hatano, Shusaku Maeda, Hisashi Motomura. Macrophage Inflammatory Protein-3 beta (MIP-3β) from cancer-associated fibroblasts promote the proliferation of melanoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2037.
Glutaminase 1 Inhibition Reduces Glycolysis and Ameliorates Lupus‐like Disease in <scp>MRL</scp>/<i>lpr</i> Mice and Experimental Autoimmune Encephalomyelitis
Authors: Michihito Kono, Nobuya Yoshida, Kayaho Maeda, Abel Suárez‐Fueyo, Vasileios C. Kyttaris, George C. Tsokos
Journal: Arthritis & Rheumatology (2019)

Glutaminase 1 (Gls1) is the first enzyme in glutaminolysis. The selective Gls1 inhibitor bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) suppresses Th17 development and ameliorates experimental autoimmune encephalomyelitis (EAE). The present study was undertaken to investigate whether inhibition of glutaminolysis is beneficial for the treatment of systemic lupus erythematosus (SLE), and the involved mechanisms.MRL/lpr mice were treated with BPTES or vehicle control, and disease activity was examined. Then naive CD4+ T cells from patients with SLE were cultured under Th17-polarizing conditions with BPTES or vehicle. Furthermore, using newly generated Gls1 conditional-knockout mice, in vitro Th17 differentiation was examined, and EAE was induced in the mice. Glutaminolysis and glycolysis were measured with an extracellular flux analyzer. The expression of hypoxia-inducible factor 1α (HIF-1α) was examined by Western blotting.Treatment of MRL/lpr mice with BPTES improved autoimmune pathology in a Th17-dependent manner. T cells from patients with SLE treated with BPTES displayed decreased Th17 differentiation (P < 0.05). Using the conditional-knockout mice, we demonstrated that both in vitro Th17 differentiation (P < 0.05) and the development of EAE were dependent on Gls1. Gls1 inhibition reduced glycolysis and the expression of HIF-1α protein, which induces glycolysis.We demonstrated that inhibition of glutaminolysis represents a potential new treatment strategy for patients with SLE and Th17-related autoimmune diseases. Mechanistically, we have shown that inhibition of glutaminolysis affects the glycolysis pathway by reducing HIF-1α protein in Th17 cells.
Abstract 4923: Analysis of companion diagnostic potentials for multifaceted PD-L1 assays
Authors: Jeni Caldara, Joseph S. Krueger, Elliott Ergon, Staci Kearney, Bharathi Vennapusa
Journal: Cancer Research (2019)

Abstract In vitro diagnostic (IVD) approvals of qualitative immunohistochemical (IHC) assays offer unique patient selection strategies by equipping pathologists with new tools to assess tumor status including tumor immune landscape. PD-L1/PD-1 checkpoint therapies require accurate diagnostic tools for optimal patient selections, however the interpretation of these tests may be very complicated upon manual assessment. As assessment criteria have increased in complexity, an accurate quantitative approach is needed to objectively and consistently interpret challenging paradigms. Recent IVD tests have multifaceted paradigms which assess both tumor and immune positivity. Although the Ventana PD-L1 SP263 and the Dako PD-L1 22C3 qualitative diagnostics are guiding immunotherapy decisions, interpretation of the results may be subjective and challenging in many cases. This creates a further level of complexity as tumor cell positivity, and immune cell presence and positivity must be assessed in combination. In this study, we have used Flagship Biosciences’ image analysis platform (cTA®) to explore the use of artificial intelligence (AI) and machine learning in the context of complex PD-L1 assays to provide accurate and precise quantification that allows for objective interpretation of the IVD. Non-small cell lung cancer (NSCLC) and urothelial carcinoma (UC) samples were stained with the SP263 and 22C3 PD-L1 assays and image analysis was used to provide an interpretation status based upon the IVD scoring paradigms. A comparison of the cTA results across both tests and tissue indications was also performed to explore how we may further support cross-platform PD-L1 solutions that provide adaptable and objective quantification. The use of Flagship’s cTA platform to identify per-cell biofeatures, using machine learning, may successfully quantify PD-L1 staining in various cell populations. The ability to independently assess these populations allows for a consistent and unbiased method for the assessment tumor status for PD-L1 immunotherapy treatment decisions. Citation Format: Jeni Caldara, Joseph S. Krueger, Elliott Ergon, Staci Kearney, Bharathi Vennapusa. Analysis of companion diagnostic potentials for multifaceted PD-L1 assays [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4923.
Risk of stillbirth increases after 41 weeks, study finds
Authors: Jacqui Wise
Journal: BMJ (2019)

The risk of stillbirth increases with every week that a pregnancy continues past 37 weeks, according to an analysis of more than 15 million pregnancies.1

Pregnancies that continued to 41 weeks—currently still considered normal term gestation —had a small but significant increase in the risk of stillbirth compared with those delivered at 40 weeks, with no difference in neonatal mortality.

More than 3000 babies are stillborn every year in the UK and a third of these are term babies—born at 37 weeks or beyond—who were considered to be healthy before …
Abstract 1990: Cjc-1134-pc, a long-acting glp-1r agonist, effects in modulating pro-inflammatory cytokines in the tumor environment
Authors: Xiping Liu, Sean Hong, Shijuan Wu, Zhiwen Yao, Qiang Xie
Journal: Cancer Research (2019)

Abstract The incidence rates of The incidence rates of diabetes and cancer are growing globally. It is reported that type 2 diabetes (T2D) is associated with increased risk of cancers, which suggests a synergy. There is a strong association among inflammation and cancer on diabetes, which is reflected by the high cytokine prevalence in the microenvironment. Previously our studies showed that IL-2 and IFN-γ were downregulated but IL-6 and TNFα were upregulated in diabetic mice. The levels of IL-2, IFN-γ, IL-6 and TNFα returned to baseline levels similar to that of non-diabetic mice after the treatment of CJC-1134-PC. In order to explore the benefits of CJC-1134-PC beside its glucose lowering effects, the level of pro-inflammatory cytokines has been measured and compared between vehicle and CJC-1134-PC treated BALB/c mice bearing CT26 colon tumors. All mice bearing tumors showed high IL-6 and TNF-r compared with the normal mice. Interestingly, after CJC-1134-PC treatment, IL-6 and TNFα levels decreased significantly (P &amp;lt; 0.05), which makes the cytokine profile close to the reported levels in normal mice. Overall, the data suggests that CJC-1134-PC plays a role in modulating inflammation, which could benefit cancer treatment in addition to achieving glycemic control. Citation Format: Xiping Liu, Sean Hong, Shijuan Wu, Zhiwen Yao, Qiang Xie. Cjc-1134-pc, a long-acting glp-1r agonist, effects in modulating pro-inflammatory cytokines in the tumor environment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1990.
The <i>AURORA</i> of a New Way to Value Myeloid Immunosuppression in Cancer
Authors: Licia Rivoltini, Claudio Vernieri, Veronica Huber
Journal: Cancer Research (2019)

Abstract Inhibiting myeloid-derived suppressor cells (MDSC) might be the ultimate barrier to break down tumor defenses and recover the preexisting T-cell immunity required to respond to immunotherapy. However, selectively intercepting MDSCs to prove their etiologic role in cancer progression is not an easy task. In this issue of Cancer Research, Yin and colleagues demonstrate unequivocally that the Aurora A kinase inhibitor, alisertib, specifically neutralizes MDSCs and triggers the rapid accrual of cytotoxic T cells, with consequent tumor clearance potentiated by PD-L1 blockade. Translating this approach into the clinic might rescue tumor immunity in immune-desert landscapes. See related article by Yin et al., p. 3431
Abstract 2247: Platinoid-induced MHCI antigen presentation enables checkpoint inhibitor responsiveness
Authors: Ingmar Niels Bastian, Weihua Li, Qui Phung, Kathleen Fisch, Jennie Lill, Michael Karin, Shabnam Shalapour
Journal: Cancer Research (2019)

Abstract Many cancers are refractory to immune checkpoint therapy (ICT), but the causes of ICT resistance remain unknown. Despite low mutational burden, hepatocellular carcinoma (HCC) responds to PD-1 blockade, but prostate cancer (PCa) does not. RNA-seq analysis revealed that, unlike HCC, PCa cells poorly express MHC-I molecules and components of the MHC-I antigen processing and presentation machinery. We found that treatment of PCa cells and other tumor types with platin-based drugs, especially low dose Oxaliplatin, led to a pronounced upregulation of MHC-I molecules and their antigen generating and loading machinery. Most importantly, Oxaliplatin synergistically potentiated the effect of exogenous IFNγ; a conclusion based on two cumulative observations. First, ATAC-seq analyses revealed that Oxaliplatin activates MHC machinery through different pathways compared to well-known IFNγ signaling. Second, Oxaliplatin upregulates IFNγR2 expression in cancer cells. Induction of IFNγR2, which was needed for Oxaliplatin-potentiation of ICT-induced tumor rejection in vivo, depended on NF-κB signaling. Induction of IFNγR2, which was needed for Oxaliplatin-potentiation of ICT-induced tumor rejection in vivo, depended on NF-κB signaling. Moreover, we found that Oxaliplatin activates histone acetyltransferases (HATs) which alter chromatin structure of genes encoding MHC-I complex components, thereby enabling recruitment of a diverse array of activating transcription factors. Our data indicates that combining ICT with an appropriate low dose platinoid chemotherapeutic agent is useful in reinvigorating the immune response to tumors that have escaped immune destruction due to MHC-I downregulation and do not respond to single agent therapy. Citation Format: Ingmar Niels Bastian, Weihua Li, Qui Phung, Kathleen Fisch, Jennie Lill, Michael Karin, Shabnam Shalapour. Platinoid-induced MHCI antigen presentation enables checkpoint inhibitor responsiveness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2247.
Abstract 769: Mechanistic role of miR-29 in pancreatic ductal adenocarcinoma progression
Authors: Shatovisha Dey, Jason J. Kwon, Sheng Liu, Tricia Factoria, Gabriel A. Hodge, Jun Wan, Janaiah Kota
Journal: Cancer Research (2019)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with a 5-year survival rate of 8% (Kota et al., 2017, Cancer Lett.). Lack of curative treatment for PDAC warrants better understanding of its mechanisms. Our previous work demonstrated that miR-29 is commonly downregulated in PDAC, while its restoration exhibits tumor-suppressive effects (Kwon et al., 2016, Oncotarget; Kwon et al., 2015, Sci Rep.). To understand these mechanisms, first we performed siRNA mediated knockdown of several miR-29 promoter binding transcription factors, including MYC, which play a role in PDAC. Our results indicate MYC represses miR-29 expression, and MYC nuclear localization negatively correlates with miR-29 in pancreatic cancer cells (PCCs). Next, to identify global miR-29 targets associated with PDAC, we conducted RNAseq on two miR-29 overexpressing PCC lines. This identified 41 overlapping miR-29 targets downregulated in both datasets. Gene ontology and survival correlation analyses identified seven most prominent targets (LOXL2, MYBL2, TRIB2, HGK, NRAS, CD276 and CLDN1). Ectopic expression of miR-29 significantly altered protein levels of these genes, confirming a translational suppression mechanism mediated by miR-29. RNAi mediated silencing of these targets significantly reduced the migratory ability of the PCCs. Our top target LOXL2 is involved in regulation of EMT/migration and extracellular matrix (ECM) remodeling. Luciferase reporter assay verified LOXL2 as a direct miR-29 target in PDAC. Immunohistochemical analyses in clinical specimens from PDAC patients and KPC mice pancreatic tissues showed higher LOXL2 expression in regions of pancreatic intraepithelial neoplasia (PanIN) lesions as compared to non-cancerous areas. This increased LOXL2 level was accompanied by concomitant reduction in miR-29 expression. Thus, our current study provides insight into new miR-29 mediated regulatory pathways in PDAC and reveals the association of miR-29-LOXL2 axis in the disease progression. Together, our data suggest miR-29 to play a critical role in mechanisms of PDAC progression and could serve as a potential therapeutic target for the disease. Citation Format: Shatovisha Dey, Jason J. Kwon, Sheng Liu, Tricia Factoria, Gabriel A. Hodge, Jun Wan, Janaiah Kota. Mechanistic role of miR-29 in pancreatic ductal adenocarcinoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 769.
Abstract 11979: Noninvasive Evaluation of the Feature of Hypertensive Heart Failure using One-beat Real-time Three-dimensional Speckle Tracking Echocardiography With High Volume Rates
Authors: Masanori Kawasaki, Ryuhei Tanaka, Shingo Minatoguchi, Hidemaro Sato, Kijun Nagata, Shigeki Sawada, Maya Ishiguro, Takashi Yoshizane, Yoshiaki Goto, Makoto Iwama, Takeshi Hirose, Koji Ono, Masazumi Arai, Toshiyuki Noda, Sachiro Watanabe, Shinya Minatoguchi
Journal: Circulation (2015)

Background: Left ventricular (LV) properties in hypertension (HTN) could be deteriorated by pressure overload that causes LV hypertrophy (LVH) resulting in hypertensive heart failure (HHF). However, transition from HTN to HHF and the feature of HHF have not been noninvasively examined. Methods: We examined 31 controls (age 69±9), 47 HTN without LVH: LVH (-) (age 70±9), 47 HTN with LVH: LVH (+) (age 69±6) and 37 HHF patients (age 71±11) by 3-dimensional speckle tracking echocardiography with volume rate of 70-80vps (3D-STE). LV contractility and relaxation were assessed by radial strain rate (SR) at systole (SR-S) and isovolumic relaxation (SR-IVR). LV torsion was measured by 3D-STE. Pulmonary capillary wedge pressure (PCWP) was calculated as 10.8 - 12.4 x log (left atrial active emptying function / left atrial minimum volume index) as we reported. Tau was estimated as isovolumic relaxation time / (ln 0.9 x systolic blood pressure - ln PCWP). LV stress was calculated as LV radius x pressure / thickness. LV stiffness was estimated as diastolic stress / strain. Results: LV SR-S and SR-IVR in HHF decreased (SR-S; control: 2.5±0.8, LVH (-): 2.6±0.6, LVH (+): 2.5±0.7, HHF: 1.9±0.4* s-1. SR-IVR; -0.8±0.5, -0.7±0.4, -0.7±0.4*, -0.5±0.4* s-1, *p&lt;0.05 vs control). LV ejection fraction (EF) in HHF decreased (66±9, 69±6, 67±11, 51±14* %) associated with reduced torsion (1.4±0.2, 1.4±0.3, 1.5±0.3, 1.2±0.2* °/cm) and increased systolic stress. Tau was prolonged even in LVH (-) (29±12, 41±14*, 47±14*, 65±19*, msec). LV stiffness increased in LVH (+) and HHF (0.5±0.2, 0.6±0.4, 0.6±0.3*, 1.5±1.2*) associated with elevated PCWP (7±2, 8±4, 9±4*, 15±5* mmHg) and diastolic stress (16±5, 19±12, 21±12, 32±13* dynes/cm2). On multivariate logistic analysis, ePCWP was the parameter that showed the strongest independent factor associated with HHF. Using 11mmHg as a cutoff value, sensitivity and specificity to predict HHF in the HTN group was 83 and 81%. Conclusion: Noninvasive 3D-STE examination revealed that LV contractility and relaxation were decreased in HHF and that HHF had more reduced EF, prolonged Tau and increased stiffness associated with reduced torsion, increased systolic and diastolic stress and PCWP. PCWP was an independent determinant of HHF in echo parameters.