tbuckley/cabot-search huggingface dataset:
Abstract 495: Leptin facilitates ovarian cancer metastasis through miR-28-3p and matrix metalloproteinase-1 in the omental tumor microenvironment
Authors: Chi Lam Au Yeung, Ngai Na Co, Tsz-Lun Yeung, Samuel C. Mok
Journal: Cancer Research (2018)

Abstract Advanced stage serous ovarian cancers spread beyond the pelvis and preferentially metastasize to the omentum, which is mainly composed of adipose tissue, suggesting that the omental microenvironment is a favorable niche for ovarian cancer cells. By comparing the transcriptome profiles of microdissected ovarian cancer tissues from the primary ovarian site and from the omental site, we identified matrix metalloproteinase-1 (MMP-1) as one of the most significant genes that was up-regulated in the omental site compared with that in the primary site. To identify mediators secreted by the omental microenvironment that up-regulated MMP-1 in the omental site tumors, transcriptome profiling was performed on microdissected ovarian tumor associated adipose tissue in the omental site and the ovarian stromal tissue in the primary ovarian tumor site. We identified leptin as one of the top differentially expressed genes in ovarian tumor associated adipose tissue in the omental site, suggesting that it might up-regulate MMP-1 in the omental ovarian cancer. To further delineate the role of MMP-1 in mediating the effect of leptin on ovarian cancer cell metastasis, ovarian cancer SKOV3 and OVCA433 cells were treated with leptin. The results showed that leptin increased MMP-1 mRNA and protein expression as assessed by quantitative RT-PCR and Western blot analyses, respectively. Furthermore, we demonstrated that leptin induced both the cell migration and invasion potential of SKOV3 and OVCA433 cells, and the effects were abrogated by transfecting cells with MMP-1 siRNAs. In addition, using Ion Torrent next generation sequencing, we found that miR-28-3p is down-regulated in leptin-treated SKOV3 and OVCA433 cells compared to the untreated cells, suggesting that it may play a role in mediating the effect of leptin on MMP-1 expression and the subsequent ovarian cancer cell motility and invasion potential. In conclusion, leptin secreted by the adipocytes in ovarian cancer associated omental microenvironment may be important in facilitating the ovarian cancer cell metastasis through the miR-28-3p/MMP-1 pathway. Citation Format: Chi Lam Au Yeung, Ngai Na Co, Tsz-Lun Yeung, Samuel C. Mok. Leptin facilitates ovarian cancer metastasis through miR-28-3p and matrix metalloproteinase-1 in the omental tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 495.
Abstract 5498: Natural product-derived carbon nanodots overcome drug resistance through regulation of Hippo pathway effectors
Authors: Ayan A. Nurkesh, Mannix P. Balanay, Tleubek Yeleusizov, Darkhan Tursynkhan, Qing Yang, Xiaoling Wan, Limara Manarbek, Aisulu Maipas, Bakhyt Matkarimov, Yan Zhang, Haiyan Fan, Li-Xia Miao, Si-Pian Li, Zhenbang Chen, Yingqiu Xie
Journal: Cancer Research (2018)

Abstract The yes-associated protein 1 (YAP) is a nuclear downstream effector of Hippo pathway that plays a critical role in various cancers. Literature shows that, in addition to nucleus, YAP also localizes in cytosol and membrane of cells. We and our collaborators previously reported that elevation of YAP associates with Arf in the genetically-engineered mouse (GEM) model of Pten/Trp53, implicating the possible correlation between Hippo/YAP and ARF in human cancers. We recently found ARF is indeed involved in dysregulation of Hippo pathway in prostate cancer. In details, ARF inhibited nuclear YAP translocation in cancer cells, and ARF knockdown suppressed the stability of YAP protein with upregulated active AKT and dysregulated phosphorylation of YAP through ARF/AKT/mTOR/YAP pathway. Here we further report that carbon nanodots (c-dots) can induce DNA damage through an increase of ROS by upregulation of γH2AX and DNA tails in PC3 and DU145 prostate cancer cells. We found that c-dots derived from natural products such as tea or beet can enter into cancer cell nucleus to interact with ARF for the regulation of the ARF-mediated signaling such as the nuclear translocation of YAP. Mechanistically, c-dots bind ARF to induce cell cycle arrest, apoptosis, and PARP cleavage in prostate cancer cells. Most importantly, addition of c-dots into cultured PC3 cells leads to the reversal of drug resistance to mTOR inhibitor Rapamycin and MET inhibitor Crizotinib by enhancing DNA damage. Moreover, c-dots suppress the tumor size and growth of PC3 cells in xenograft mouse model in vivo. Our data suggest that the nano-scale of c-dots derived from natural food may be efficient in overcoming drug resistance via augmentation of DNA damage linked cell death. Thus we reported a new approach of abolishing drug resistance of aggressive malignancy using nanoparticles, implicating an innovative avenue for precision cancer treatment. Citation Format: Ayan A. Nurkesh, Mannix P. Balanay, Tleubek Yeleusizov, Darkhan Tursynkhan, Qing Yang, Xiaoling Wan, Limara Manarbek, Aisulu Maipas, Bakhyt Matkarimov, Yan Zhang, Haiyan Fan, Li-Xia Miao, Si-Pian Li, Zhenbang Chen, Yingqiu Xie. Natural product-derived carbon nanodots overcome drug resistance through regulation of Hippo pathway effectors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5498.
Abstract 332: The BET bromodomain inhibitor JQ1 synergizes with WEE1 inhibitor AZD1775 by impairing non-homologous end joining and enhancing DNA damages in non-small cell lung cancer
Authors: Yuta Takashima, Eiki Kikuchi, Junko Kikuchi, Tetsuaki Shoji, Megumi Furuta, Hajime Kikuchi, Jun Sakakibara-Konishi, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Masaharu Nishimura
Journal: Cancer Research (2018)

Abstract Background: The bromodomain and extraterminal domain (BET) inhibitors are broadly active in different cancer types, including non-small cell lung cancer (NSCLC). Although their activity on oncogene expression such as c-Myc has been addressed in many studies, the mechanism of BET inhibition on the cytotoxicity remain unknown. BET proteins have been also reported to interact with some DNA damage repair-related genes. AZD1775, a selective WEE1 G2 checkpoint kinase inhibitor, induces DNA damage and consequent apoptosis by abrogating G2 cell cycle arrest and inducing premature mitotic entry. We hypothesized that repression of BET activity would increase WEE1 inhibitor-induced cytotoxicity by impairing DNA damage repair. Here, we evaluate the efficacy and mechanistic rationale for combining AZD1775 and JQ1 as a potential therapy for NSCLC. Methods: NSCLC cell lines (A549, H1299, H1975) and human embryonic kidney cells line (293T) were used in the present study. Anti-tumor activities of JQ1, AZD1775, or the combination were analyzed using MTT survival assay. Changes in protein expression were analyzed by Western Blot analysis. mRNA expressions were evaluated by quantitative rt-PCR. Cell cycle was analyzed by flow cytometry using PI staining. Activity of non-homologous end joining (NHEJ) was evaluated using NHEJ reporter plasmid. Results: The combination of AZD1775 and JQ1 showed synergistic effects for NSCLC cell lines in vitro with combination indices of 0.1-0.5. The JQ1 monotherapy did not induce gamma-H2AX expression, but JQ1 increased and prolonged AZD1775-induced gamma-H2AX expression. The mRNA analysis showed that JQ1 significantly repressed NHEJ-related genes, such as XRCC4 and LIG4. Moreover, NHEJ reporter assay revealed JQ1 diminished NHEJ activity. Conclusions: Our data demonstrate that the combination of JQ1 and AZD1775 has a synergistic effect against NSCLC cell lines via a mechanism of compromised DNA damage repair by JQ1. This combination therapy can be a novel therapeutic strategy for NSCLC. Citation Format: Yuta Takashima, Eiki Kikuchi, Junko Kikuchi, Tetsuaki Shoji, Megumi Furuta, Hajime Kikuchi, Jun Sakakibara-Konishi, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Masaharu Nishimura. The BET bromodomain inhibitor JQ1 synergizes with WEE1 inhibitor AZD1775 by impairing non-homologous end joining and enhancing DNA damages in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 332.
Functional Evidence for an Inward Rectifier Potassium Current in Rat Renal Afferent Arterioles
Authors: LisaChilton, RodgerLoutzenhiser
Journal: Circulation Research (2001)

Abstract—An inward rectifier potassium current, Kir, has been identified in cerebral and coronary resistance vessels, where it is considered to be an important determinant of resting membrane potential (RMP) and to play a role in blood flow regulation. We investigated the functional role of Kir in the renal afferent arteriole using the in vitro–perfused hydronephrotic rat kidney. Increasing external KCl from 5 to 15 mmol/L induced afferent arteriolar vasodilation. This response was inhibited by 10 to 100 μmol/L Ba2+, concentrations selective for blockade of Kir, and by chloroethylclonidine (100 μmol/L) but was not blocked by glibenclamide (10 μmol/L) or ouabain (3 mmol/L). Reducing external KCl from 5 to 1.5 mmol/L to enhance rectification of Kir caused vasoconstriction at low renal arterial pressure (40 mm Hg) and vasodilation during myogenic vasoconstriction (120 mm Hg), suggesting that this current dominates RMP at low perfusion pressures. When administered to kidneys perfused at 40 mm Hg renal arteria...
Abstract 3847: Inhibition of GCN2 sensitizes ASNS-downregulated cancer cells to asparaginase by disrupting amino acid response
Authors: Akito Nakamura, Tadahiro Nambu, Shunsuke Ebara, Yuka Hasegawa, Kosei Toyoshima, Yasuko Tsuchiya, Daisuke Tomita, Jun Fujimoto, Osamu Kurasawa, Chisato Takahara, Ayumi Kawamura, Ryuichi Nishigaki, Yoshinori Satomi, Akito Hata, Takahito Hara
Journal: Cancer Research (2018)

Abstract General control nonderepressible 2 (GCN2) plays a major role in cellular response to amino acid limitation. Although maintenance of amino acid homeostasis is critical for tumor growth, little is known concerning the contribution of GCN2 to cancer cell proliferation and its potential as a therapeutic target. In this study, we demonstrate that inhibition of GCN2 with small-molecule compounds sensitizes cancer cells to anti-leukemic agent asparaginase (ASNase). We first tested acute lymphoblastic leukemia (ALL) cells and showed that treatment with GCN2 inhibitors rendered ALL cells sensitive to ASNase by preventing the induction of asparagine synthetase (ASNS). The prevention of ASNS expression suppresses asparagine synthesis and thus inhibits protein translation. In addition, comprehensive gene expression profiling revealed that the combined treatment induced stress-activated MAPK pathway and thereby triggering apoptosis. Using cell-panel analyses, we also identified a clear synergy between GCN2 inhibitors and ASNase in acute myelogenous leukaemia (AML) and pancreatic cancer cells besides ALL. Notably, basal ASNS expression levels were significantly correlated with sensitivity to combinatorial treatment. Furthermore, the combination displayed robust antitumor activity in mouse xenograft models of ALL, AML, and pancreatic cancer. These results demonstrate a novel mechanistic insight into a role of GCN2 in amino acid response and provide a rationale for further investigating GCN2 inhibitors for the treatment of cancer. Citation Format: Akito Nakamura, Tadahiro Nambu, Shunsuke Ebara, Yuka Hasegawa, Kosei Toyoshima, Yasuko Tsuchiya, Daisuke Tomita, Jun Fujimoto, Osamu Kurasawa, Chisato Takahara, Ayumi Kawamura, Ryuichi Nishigaki, Yoshinori Satomi, Akito Hata, Takahito Hara. Inhibition of GCN2 sensitizes ASNS-downregulated cancer cells to asparaginase by disrupting amino acid response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3847.
Abstract 4548: Host immunogenetics and hyperprogression under PD1/PD-L1 checkpoint inhibitors
Authors: Sadal Refae, Nathalie Ebran, Jocelyn Gal, Josiane Otto, Damien Giacchero, Delphine Borchiellini, Joel Guigay, Frederique Peyrade, Gerard Milano, Esma Saada
Journal: Cancer Research (2018)

Abstract Background: Hyperprogressive disease (HPD) has been described in advanced solid tumors patients treated with anti PD1 anti PDL1 monotherapy (Champiat, Clin Can Res 2016; Saada-Bouzid, Ann Oncol, 2017). Our aim was to explore whether host constitutional variations in the nucleotide sequence of genes involved in immune response might be associated with the occurrence of HPD in patients treated with anti PD-(L)1. Methods : From April to August 2017, 98 patients were treated in the Centre Antoine Lacassagne (Nice, France) with anti PD-(L)1. Potential SNPs for four candidate genes with a minor allele frequency≥ 5% in caucasians were selected according to genome browser data-base: PD1 (rs10204525, rs11568821, rs2227981), PD-L1 (rs2282055, rs2297136, rs2297137, rs4143815, rs10815225), IDO1 (rs3739319, rs3808606, rs373931, rs9657182) and VEGR2 (rs2305948, rs1870377, rs2071559). High through-output genotyping was done by MassARRAY (AGENA). HPD was defined as a TGKR (ratio of the slope of tumor growth before treatment and the slope of tumor growth on treatment) ≥ 2. Results: Patients were treated for head and neck squamous cell carcinoma (16/98), non-small cell lung cancer (48/98), melanoma (13/98), renal cell carcinoma (14/98) and 7 others. Median age was 66 years old, 33 were male. All tested SNPs were in Hardy-Weinberg equilibrium. Responses were associated with G3-G4 toxicities (10% vs 42%, p=0.001). TGKR was assessable in 80 patients. HPD was observed in 11/80 (14 %) patients. HPD was significantly associated with age≥70y (6% vs 25%, p=0.02) and genotype for PD1 rs 2227981 (8/32=35% G/G vs 2/43=5% A/G or A/A, p=0.02), PDL1 rs 2282055 (1/37=3% T/T vs 10/43=23% T/G or G/G,p=0.02) and VEGFR2 rs1870377 (2/48=5% T/T vs 9/32=28% T/A or A/A, p=0.005). Multivariate analysis confirmed the association between HPD and VEGFR2 rs1870377 T/A or A/A (OR=15.3, p=0.007), PDL1 rs 2282055 T/G or G/G (OR=18.7, p=0.01) and age≥70y (OR=14.4, p=0.006).). Combining the three alleles at risk for HPD gave an OR =12.4 (p=0.001). Conclusion: In patients treated with anti PD-(L)1, HPD was independently associated with older age and host related gene variations. Host related immunogenetics could become an integrative part of predictive factor for immunotherapy outcome. Citation Format: Sadal Refae, Nathalie Ebran, Jocelyn Gal, Josiane Otto, Damien Giacchero, Delphine Borchiellini, Joel Guigay, Frederique Peyrade, Gerard Milano, Esma Saada. Host immunogenetics and hyperprogression under PD1/PD-L1 checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4548.
New path to treating pancreatic cancer: TRAIL gene delivery targeting the fibroblast-enriched tumor microenvironment
Authors: Haiping Jiang, Sujuan Wang, Xuefei Zhou, Liying Wang, Lidan Ye, Zhuxian Zhou, Jianbin Tang, Xiangrui Liu, Lisong Teng, Youqing Shen
Journal: Journal of Controlled Release (2018)
Abstract P048: Segment-Specific Pulse Wave Velocity and Subclinical Cardiac Overload and Damage in Older Adults: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Shuiqing Liu, Esther Kim, Aozhou Wu, Michelle L Meyer, Susan Cheng, Ron C Hoogeveen, Christie M Ballantyne, Hirofumi Tanaka, Gerardo Heiss, Elizabeth Selvin, Kunihiro Matsushita
Journal: Circulation (2018)

Background: Pulse wave velocity (PWV) independently predicts cardiovascular disease. However, few studies simultaneously explored the associations of segment-specific PWV measures with markers of both cardiac overload (natriuretic peptide [NT-proBNP]) and damage (high-sensitivity cardiac troponin T [hs-cTnT]) among adults without cardiac disease. Methods: We examined 2,845 whites and blacks (67-90 years) without clinical history of cardiac disease during ARIC visit 5 (2011-13). The association of PWV quartiles (cf [carotid-femoral], hc [heart-carotid], hf [heart-femoral], ha [heart-ankle], ba [brachial-ankle], and fa [femoral-ankle]) with log-transformed NT-proBNP and hs-cTnT was evaluated using linear and logistic regression models to adjust for potential confounders. Results: Most PWV measures demonstrated J- or U-shaped associations with NTpro-BNP and hs-cTnT [Figure]. The highest vs. the second lowest quartile of central PWV measures (cfPWV, hfPWV, and hcPWV) was associated with higher levels of NT-proBNP independently of demographic characteristics. The associations were weaker for hs-cTnT. These associations were attenuated after further adjustment, but hcPWV and NT-proBNP remained borderline significant (p=0.069). haPWV, baPWV, and faPWV including peripheral elements had less evident positive associations after adjusting for traditional risk. Conclusion: The positive associations between PWV and cardiac biomarkers were stronger for central vs. peripheral arterial stiffness and for NT-proBNP vs. hs-cTnT among older adults without prevalent cardiac disease. Our findings indicate the relative importance of central arterial stiffness behind subclinical cardiac overload.
Abstract 141: Class I Histone Deacetylases Localize to Cardiac Myocyte Mitochondria and Contribute to Ischemia Reperfusion Injury
Authors: Daniel J Herr, Mauhamad Baarine, Sverre Aune, Craig C Beeson, Lauren E Ball, Donald R Menick
Journal: Circulation Research (2017)

Approximately half of the damage done to the heart by a myocardial infarction occurs during reperfusion of the ischemic region while the patient is in the care of the treatment team. While many different adjuvant treatments have been explored in an attempt to attenuate this ischemia-reperfusion (I/R) injury, little progress has been made in translating novel therapies to the clinic. Recently, it was discovered that epigenetic enzymes contribute to reperfusion-induced damage, but little is known about the exact mechanism by which they exacerbate I/R injury. Previously, we have shown that class I histone deacetylase (HDACs) activity acutely exacerbates I/R injury, and that inhibition of class I HDACs with MS-275 (entinostat) preserves left-ventricular (LV) function and substantially reduces the area of infarcted tissue in isolated rat hearts subjected to ischemia-reperfusion (IR) injury. Notably, this protective effect occurs whether MS-275 is given as a pretreatment or during the reperfusion phase alone. Given the acute nature of this protective effect, we hypothesized that class I HDACs mediate reperfusion injury by modulating the acetylation state of non-histone proteins in signaling cascades that are essential to cell survival. To examine this, hearts from male Sprague-Dawley rats were subjected to ex vivo I/R injury +/- class I HDAC inhibition during reperfusion. We then performed mass spectrometry to analyze the changes in the acetylome between sham and I/R groups with and without class I HDAC inhibition. Unexpectedly, mass spectrometry analysis revealed significant changes in the acetylation state of multiple mitochondrial enzymes. Further biochemical studies show that class I HDACs localize to cardiac mitochondria and may directly modulate mitochondrial acetylation. Interestingly, these effects are correlated with a reduction in the mitochondrial respiratory capacity and mitochondrial oxidative stress during reperfusion. This study is the first to identify a class I HDAC that localizes to the mitochondria and emphasizes the importance of exploring class I HDAC inhibitors for protection against ischemia-reperfusion injury.
Abstract 2186: Drug treatment induces phenotypic switch and stemness during acquisition of drug resistance
Authors: Santhalakshmi Ranganathan, Annapoorni Rangarajan
Journal: Cancer Research (2018)

Abstract The breast tumor heterogeneity and development of drug resistance has become a challenge for anti-cancer therapy. Tumor cells acquire resistance due to intra-tumor heterogeneity imposed by epithelial to mesenchymal transition. The drugs which target epithelial cells may fail to target mesenchymal and the intermediate phenotypes due to which the cancer cells acquire drug resistance. This concept provoked us to understand the phenotypic diversity among the tumor heterogeneity which might lead to drug resistance. Hence the aim of our study is to identify the mechanisms of anti-cancer drug resistance which would ultimately help in identification of new clinical targets. Treatment of breast cancer cell lines MCF7 and MDA MB 231 with Doxorubicin showed a loss of epithelial markers and gain of mesenchymal markers in MCF7 cells, and vice versa in MDA MB 231 cells, thereby shifting them into an intermediate phenotype. Moreover, Doxorubicin treatment of MDA MB 231-Nanog stable cells led to an increase in Nanog positive cells confirming that the treatment-induced increase in stemness property of cancer cells. We predict that phosphoproteomic dataset of the anti-cancer drug-resistant cells let us analyze the possible molecular players involved in the phenotypic switch and hence drug resistance (work in progress). Thus, our current data suggest that the anti-cancer therapy induces cancer cells to undergo a phenotypic switch and increases the stemness property which might be responsible to gain resistance. Identification of the critical regulators of the phenotypic switch by phosphoproteomics analysis is likely to help us investigate the possible mechanisms underlying anti-cancer drug resistance. Previous reports also suggest that conventional therapies fail to eliminate cancer stem cells thereby allowing tumor relapse. These results suggest that understanding the protein abundance and phosphorylation state of key signaling molecules would elucidate specific signaling interactions or/and pathways differentially active in drug-resistant tumors would help us predict novel kinases, and hence identify drug targets. Citation Format: Santhalakshmi Ranganathan, Annapoorni Rangarajan. Drug treatment induces phenotypic switch and stemness during acquisition of drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2186.
Ca2+ Channel Subtypes and Pharmacology in the Kidney
Authors: KoichiHayashi, ShuWakino, NaokiSugano, YuriOzawa, KoichiroHomma, TakaoSaruta
Journal: Circulation Research (2007)

A large body of evidence has accrued indicating that voltage-gated Ca2+ channel subtypes, including L-, T-, N-, and P/Q-type, are present within renal vascular and tubular tissues, and the blockade of these Ca2+ channels produces diverse actions on renal microcirculation. Because nifedipine acts exclusively on L-type Ca2+ channels, the observation that nifedipine predominantly dilates afferent arterioles implicates intrarenal heterogeneity in the distribution of L-type Ca2+ channels and suggests that it potentially causes glomerular hypertension. In contrast, recently developed Ca2+ channel blockers (CCBs), including mibefradil and efonidipine, exert blocking action on L-type and T-type Ca2+ channels and elicit vasodilation of afferent and efferent arterioles, which suggests the presence of T-type Ca2+ channels in both arterioles and the distinct impact on intraglomerular pressure. Recently, aldosterone has been established as an aggravating factor in kidney disease, and T-type Ca2+ channels mediate aldos...