tbuckley/cabot-search huggingface dataset:
Abstract 887: Silver nanoparticles and ionizing radiation induce mitochondrial protein oxidation and effects on cell cycle and proliferation in lung cancer cell lines
Authors: Reetta J. Holmila, Stephen A. Vance, Ravi Singh, S. Bruce King, Cristina M. Furdui
Journal: Cancer Research (2019)

Abstract Silver nanoparticles (AgNP) are widely applied nanomaterials for both commercial and clinical biomedical applications. AgNP have been shown to have cytotoxicity in various cancer cell lines, as well as radiosensitizing properties. The AgNPs may induce free radicals via Fenton-type reactions, but the cellular mechanisms related to reactive oxygen species (ROS) production remain largely unknown. Both ionizing radiation (IR) and AgNP exposure lead to apoptotic and necrotic cell death through mechanisms that involve DNA damage and induction of oxidative stress, possibly targeting mitochondria. Changes in the thiol redox state of mitochondrial proteins, such as protein sulfenylation, play an important role in a number of cellular processes, and mitochondrial damage and dysfunction along with increased mitochondrial ROS are implicated in a range of human diseases such as cancer. In this work we studied the molecular effects of AgNP exposure with and without IR in a panel of lung cell lines (three cancer cell lines: A549, Calu-1 and NCI-H358 and one immortalized lung epithelial cell line: BEAS-2B). Both AgNP and IR exposures increased mitochondrial protein oxidation detected by a recently developed mitochondria targeted probe for protein sulfenylation (DCP-NEt2C). This increase in DCP-NEt2C labeling was dose and time dependent and the exposures also showed a combined effect. Moreover, the exposures induced changes in cell cycle and decreased cellular proliferation. There were marked differences between different cell lines, likely reflecting differences in the cellular redox state and metabolism. In conclusion, the AgNP and IR exposures increase the mitochondrial ROS as demonstrated by increased protein oxidation and have effects on the cell cycle and cell proliferation. They also appear to have a combined effect which might have implications for clinical applications as well as environmental risk assessment. Citation Format: Reetta J. Holmila, Stephen A. Vance, Ravi Singh, S. Bruce King, Cristina M. Furdui. Silver nanoparticles and ionizing radiation induce mitochondrial protein oxidation and effects on cell cycle and proliferation in lung cancer cell lines [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 887.
Abstract 17175: Coronary Vascular Dysfunction in the Absence of Overt Coronary Atherosclerosis is Independently Associated with Left Ventricular Diastolic and Subclinical Systolic Dysfunction
Authors: Venkatesh L Murthy, Amil M Shah, John D Groarke, Masanao Naya, Akshay S Desai, Marcelo F Di Carli
Journal: Circulation (2012)

Background: The relationship between coronary vascular dysfunction and myocardial diastolic and systolic dysfunction has not been well described. We evaluated the hypothesis that myocardial blood f...
Abstract 2490: R2: Genomics analysis and visualization platform
Authors: Jan Koster, Richard Volckmann, Danny Zwijnenburg, Piet Molenaar, Rogier Versteeg
Journal: Cancer Research (2019)

Abstract Given the complexity, omics data like RNA-seq are often analyzed by bioinformaticians, and not the wetlab researchers that performed the experiments. With the biomedical researcher (with limited or no bioinformatics skills) in mind as the end-user, we developed the user-friendly, publicly accessible R2 platform (http://r2.amc.nl), enabling biomedical scientists to work with their own data from anywhere at any time. R2 (cited in &amp;gt;850 peer-reviewed scientific publications) consists of an omics database, coupled to an extensive set of interactive tools to analyze/visualize the datasets. Interactive analyses within the software are highly connected, allowing quick navigation between various aspects of the datamining process. Besides password protected private data, R2 also contains an extensive body of publicly available omics data, enabling users to relate their findings to other diseases / tissues, or as validation in integrative analyses. Next to gene expression (bulk as well as single cell), R2 is also being employed for the integration, analysis and visualization of copynumber, SNP, methylation, miRNA, drug response, ChIP-seq, and NGS exome/WGS DNA sequencing data. Analyses include correlation, differential expression, gene sets, gene ontology, transcription factor binding sites, tSNE, PCA, k-means, Kaplan Meier survival scans, signature creation etc. Visualizations include various gene oriented plots, heatmaps, Circos plots, embedded genome browser, Venn diagrams, etc. The real power of the platform lies in the chaining of results of analyses; e.g. the results of a differential expression analysis can be further trimmed down using a Kaplan Meier analysis that in turn can be used for a Gene Ontology over-representation analysis. Furthermore, the webserver allows for overviews across different datasets (such as MegaSampler and 2D distribution), where a user can harness the power of thousands of measurements. Recently, integrated analyses for personalized medicine, where copy number, mRNA expression, methylation and mutation data are combined into a comprehensive overview, occasionally supplemented with PDX/organoid drug response data. These serve clinical decision making for a patient, but as growing cohorts also form a treasure trove for scientific discovery. R2 provides a central starting point from where data mining and analysis paths can be followed within one environment. Data/analyses can be shared between R2-users via our community options, making R2 an outstanding environment for discovery, hypothesis testing and scientific collaboration. Citation Format: Jan Koster, Richard Volckmann, Danny Zwijnenburg, Piet Molenaar, Rogier Versteeg. R2: Genomics analysis and visualization platform [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 2490.
Abstract 3295: De-induction of the Maladaptive Fetal Gene Program During Chronic Monotherapy with Metoprolol Succinate is Retained Following Withdrawal of Therapy in Dogs with Chronic Heart Failure
Authors: Rasha Bazari, Sharad Rastogi, Valerio Zaca, Sidney Goldstein, Hani N Sabbah
Journal: Circulation (2007)

Background: Chronic therapy with extended release metoprolol succinate (MET), a selective β1 adrenergic receptor blocker, improves left ventricular (LV) function and attenuates global LV remodeling in dogs with chronic heart failure (HF). We previously showed that chronic therapy with β-blockade results in de-induction of the fetal gene program (FGP) in LV myocardium of dogs with HF. In this study, we tested the hypothesis that in dogs with HF withdrawal of chronic MET does not lead to re-induction of FGP. Methods: Studies were performed in 17 intracoronary microembolization-induced HF dogs randomized to 3 months oral therapy with MET (100 mg, once daily, n=11) or no therapy at all (Controls, n=6). In dogs randomized to MET, 6 were sacrificed after 3 months of therapy and in the remaining 5, MET was withdrawn after 3 months of therapy and dogs were observed for 6 weeks after withdrawal of MET (MET-W) and then sacrificed. LV tissue was also obtained from 6 normal (NL) dogs for comparison. mRNA expression of the FGP genes namely, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), sarcoplasmic reticulum calcium ATPase (CAA), cardiac β-1 adren-ergic receptor (AR) and α-myosin heavy chain isoform (α-MHC) was measured using reverse transcriptase polymerase chain reaction (RT-PCR) and bands were quantified in densitometric units (du). Results: In Controls, mRNA expression of ANP and BNP increased and expression of CAA, β 1-AR and α-MHC decreased. Treatment with MET decreased expression of ANP and BNP and increased expression of CAA, β 1-AR and α-MHC. Except for α-MHC, the improvement in FGP seen during MET treatment was preserved in MET-W dogs. Conclusions: Withdrawal of MET is associated with sustained de-induction of the FGP in LV myocardium of dogs with HF. This observation supports the concept that chronic β-blockade therapy in HF confers lasting reversal of LV remodeling and molecular recovery of the failing myocardium.
Trifluridine/tipiracil safety and efficacy in Russian patients with metastatic colorectal cancer and refractory or intolerant to standard chemotherapies: Results of the primary analysis
Authors: M. Fedyanin, D. Chekini, V. Chubenko, S. Tjulandin, A. Zhabina, N. Amellal, P. Aubel, E. Gandossi, V. Moiseenko
Journal: Annals of Oncology (2019)
Population-level impact and herd effects following the introduction of human papillomavirus vaccination programmes: updated systematic review and meta-analysis
Authors: Mélanie Drolet, Élodie Bénard, Norma Pérez, Marc Brisson, Hammad Ali, Marie-Claude Boily, Vincenzo Baldo, Paul Brassard, Julia M L Brotherton, Denton Callander, Marta Checchi, Eric P F Chow, Silvia Cocchio, Tina Dalianis, Shelley L Deeks, Christian Dehlendorff, Basil Donovan, Christopher K Fairley, Elaine W Flagg, Julia W Gargano, Suzanne M Garland, Nathalie Grün, Bo T Hansen, Christopher Harrison, Eva Herweijer, Teresa M Imburgia, Anne M Johnson, Jessica A Kahn, Kimberley Kavanagh, Susanne K Kjaer, Erich V Kliewer, Bette Liu, Dorothy A Machalek, Lauri Markowitz, David Mesher, Christian Munk, Linda Niccolai, Mari Nygård, Gina Ogilvie, Jeannie Oliphant, Kevin G Pollock, Maria Jesús Purriños-Hermida, Megan A Smith, Marc Steben, Anna Söderlund-Strand, Pam Sonnenberg, Pär Sparen, Clare Tanton, Cosette M Wheeler, Petra J Woestenberg, Bo Nancy Yu
Journal: The Lancet (2019)
NOTCH Signaling via WNT Regulates the Proliferation of Alternative, CCR2-Independent Tumor-Associated Macrophages in Hepatocellular Carcinoma
Authors: Yu-Chen Ye, Jun-Long Zhao, Yi-Tong Lu, Chun-Chen Gao, Yang Yang, Shi-Qian Liang, Ying-Ying Lu, Lin Wang, Shu-Qiang Yue, Ke-Feng Dou, Hong-Yan Qin, Hua Han
Journal: Cancer Research (2019)

Abstract Tumor-associated macrophages (TAM) play pivotal roles in tumor progression and metastasis, but the contribution and regulation of different macrophage populations remain unclear. Here we show that Notch signaling plays distinct roles in regulating different TAM subsets in hepatocellular carcinoma (HCC). Myeloid-specific NOTCH blockade by conditional disruption of recombination signal binding protein Jκ (RBPj cKO) significantly delayed the growth of subcutaneously inoculated Lewis lung carcinoma (LLC), but accelerated orthotopically inoculated hepatic Hepa1-6 tumors in mice. In contrast to subcutaneous LLC, RBPj cKO significantly increased the number of TAMs in hepatic Hepa1-6 tumors despite impeded differentiation of monocyte-derived TAMs (moTAM). The dominating TAMs in orthotopic HCC manifested properties of Kupffer cells (KC) and hence are tentatively named KC-like TAMs (kclTAM). The increased proliferation of RBPj cKO kclTAMs was maintained even in Ccr2−/− mice, in which moTAMs were genetically blocked. NOTCH signaling blockade accelerated proliferation of kclTAMs via enhanced β-catenin–dependent WNT signaling, which also downregulated IL12 and upregulated IL10 expression by kclTAMs likely through c-MYC. In addition, myeloid-specific RBPj cKO facilitated hepatic metastasis of colorectal cancer but suppressed lung metastasis in mice, suggesting that the phenotype of RBPj cKO in promoting tumor growth was liver-specific. In patient-derived HCC biopsies, NOTCH signaling negatively correlated with WNT activation in CD68+ macrophages, which positively correlated with advanced HCC stages. Therefore, NOTCH blockade impedes the differentiation of moTAMs, but upregulates Wnt/β-catenin signaling to promote the proliferation and protumor cytokine production of kclTAMs, facilitating HCC progression and hepatic metastasis of colorectal cancer. Significance: These findings highlight the role of NOTCH and WNT signaling in regulating TAMs in hepatocellular carcinoma.
Doctors spurn NHS long term plan
Authors: Richard Hurley
Journal: BMJ (2019)

Doctors at the BMA’s annual representative meeting have expressed strong doubts about NHS England’s strategy for the next decade, published in January.1

Representatives voted overwhelmingly against a part of a motion proposed by the Wigan division that the meeting, being held in Belfast this week, “welcomes and supports the aims and initiatives of the plan.”

Tom Dolphin, a consultant anaesthetist and member of the BMA Council, proposing the motion, compared the NHS Long Term Plan to a “sketchy unfunded wish list for the NHS.”

He said, “The plan has two major problems: …
Abstract 5239: Cisplatin disrupts MDM2-DAXX-HAUSP complex, p53 accumulation, cell cycle regulation, and apoptosis in acute leukemia cells
Authors: Sanjay Kumar, Paul Tchounwou
Journal: Cancer Research (2019)

Abstract Cisplatin (CDDP) is an antitumor drug successfully used in the treatment of various types of human malignancies. It enhances toxicity of arsenic trioxide (ATO) in head and neck squamous cell carcinoma cell, small cell lung cancer, ovarian cancer cells, and oral squamous cell carcinoma cells (, and chronic myelogenous leukemia cells. CDDP induces cytotoxicity, DNA damage, oxidative stress, and apoptosis in acute promyelocytes leukemia (APL) cells. However, the molecular mechanisms of CDDP-induced P53 activation, cell cycle arrest, and apoptosis in APL cells remain poorly understood. We hypothesized that CDDP inhibits proliferation of APL cells through MDM2-DAXX-HAUSP complex disruption, p53 activation leading to cell cycle arrest and apoptosis. To test hypothesis, we used three APL cell lines and mice model of APL and investigated CDDP effects on cells growth, complex disruption, cell cycle progression, and apoptosis by applying western blotting, IP, gene knockdown techniques, immune/histochemistry, and confocal imaging. We found that CDDP - induced stress signal transmitted by protein kinase (ATM, ATR) and its downstream targets (CHK1 &amp; CHK2) phosphorylation leading to down-regulation of complex molecules expression and accumulation of p53. CDDP-induced p53 expression modulated cell cycle progression and apoptosis in APL cells, and stimulated the formation of more promyelocytes with dense granules through reduction of MDM2 expression in bone marrow cells. CDDP also activated p53 in APL mice liver tissues. This novel mechanism of action of CDDP in APL cells may help in the design of new anti-leukemic drugs for treatment of APL patients. Acknowledgements: This research was supported by National Institutes of Health NIMHD [grant # G12MD007581], through the RCMI-Center for Environmental Health at Jackson State University. Citation Format: Sanjay Kumar, Paul Tchounwou. Cisplatin disrupts MDM2-DAXX-HAUSP complex, p53 accumulation, cell cycle regulation, and apoptosis in acute leukemia 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 5239.
Abstract 4365: Induction of distinct p53 mutation types differentially influences the control of cellular iron metabolism
Authors: Eshan Dandekar, Aishwarya Srinivasan, Stephen Clarke, Mckale Montgomery
Journal: Cancer Research (2019)

Abstract The most commonly mutated gene in all human cancers is the tumor suppressor gene p53, but in addition to loss of tumor suppressor functions, mutations in p53 can also promote cancer progression by altering cellular iron acquisition and metabolism. The primary objective of this work was to determine how p53 mutation status influences the molecular control of iron homeostasis. Though hundreds of p53 mutations have been identified, the majority occur within the DNA binding domain and can be subdivided into two broad classes: contact (e.g., R273H) or conformational (e.g., R175H). By generating cell lines with inducible versions of some of the most common conformational and contact-type p53 mutations we have established that introduction of specific p53 mutation types alone is sufficient to disrupt cellular iron metabolism. We also demonstrate these effects are mediated at least in part due to differences in the responsiveness of Iron Regulatory Proteins (IRP) to cellular iron availability. IRP are considered the master regulators of intracellular iron homeostasis because they coordinate the expression of iron storage (ferritin) and iron uptake (transferrin receptor) genes. In response to changes in iron availability cells harboring either a wild-type p53 or contact (R273H) p53 mutation display canonical IRP-mediated responses, but neither IRP1 RNA binding activity nor IRP2 protein levels are affected by changes in iron status in cells harboring the conformational type mutant (R175H). Yet, both contact and conformational mutants exhibit robust changes in ferritin and transferrin receptor protein expression in response to iron loading and iron chelation, respectively. These findings suggest a novel, IRP-independent mode of iron regulation in cells expressing conformational type p53 mutants. Preliminary proteomics data suggests that lack of IRP responsiveness in cells expressing conformational p53 mutations may result from impaired iron-sulfur cluster biogenesis. These findings are currently being explored as a means of exploiting distinct p53 mutation types to more favorably induce iron-mediated cell death via the activation of ferroptosis. As p53 is mutated in nearly half of all human cancers, and iron is necessary for cancer cell growth and proliferation, the studies have implications for a wide range of clinically important cancers. Citation Format: Eshan Dandekar, Aishwarya Srinivasan, Stephen Clarke, Mckale Montgomery. Induction of distinct p53 mutation types differentially influences the control of cellular iron metabolism [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 4365.
Abstract 19487: Simvastatin Loaded High-Density Lipoprotein Nanoparticles Reduce Inflammation in Atherosclerotic Plaques by Directly Acting on Plaque Macrophages and Inflammatory Monocytes
Authors: Jun Tang, Raphael Duivenvoorden, Bernd Hewing, David Izquierdo-Garcia, Aneta J Mieszawska, Sarian M van Rijs, David P Cormode, Canturk Ozcan, Emma L Kuan, Catherine Martel, Mark E Lobatto, Erik S Stroes, Gwendalyn J Randolph, Valentin Fuster, Edward A Fisher, Zahi A Fayad, Willem J Mulder
Journal: Circulation (2012)

Rationale: Although statins have been shown to have anti-inflammatory pleiotropic effects in experimental studies, the poor plaque targeting of orally administered statins limits their direct anti-inflammatory therapeutic effect. To that end, we have developed a simvastatin loaded high-density lipoprotein nanoparticle ([S]-rHDL), which has an improved plaque bioavailability and therefore exerts a higher therapeutic effect in apolipoprotein E knockout (ApoE KO) mice than orally administered simvastatin. The purpose of the current study is to understand the mechanism of this potent anti-inflammatory effect. Methods and Results: [S]-rHDL was found to specifically target plaque macrophages by fluorescence microscopy (a). To investigate the targeting efficiency of [S]-rHDL to monocytes/macrophages, we intravenously injected [S]-rHDL in ApoE KO mice (n=3/time point) and analyzed the cells from aortas and blood by flow cytometry. [S]-rHDL was found to target macrophages and monocytes in aortas (b), and to target inflammatory Gr-1hi monocytes more efficiently than anti-inflammatory Gr-1lo monocytes in blood (c). Last, laser capture microdissection was used to isolate plaque macrophages (n=7), and quantitative RT-PCR was used to measure their mRNA level of TNF-α, the hallmark of macrophage inflammation, which was significantly reduced (d). All the above data support our hypothesis that [S]-rHDL acts on inflammatory monocytes and plaque macrophages and thereby exerts a strong anti-inflammatory effect on atherosclerotic plaque. Conclusion: In ApoE KO mice, [S]-rHDL specifically targets plaque macrophages. [S]-rHDL also locally acts on macrophages in plaque and preferentially targets pro-inflammatory monocytes in blood, which results in a strong anti-inflammatory effect. This nanotherapy may represent a potent addition to the current standard of care for atherosclerosis patients.
Long-Term Follow-up of Patients with Chronic Granulomatous Disease Receiving Bone Marrow Transplantation Using Immunosuppressive Conditioning Regimen
Authors: Masao Kobayashi, Yoko Mizoguchi, Shuhei Karakawa, Mizuka Miki, Shiho Nishimura, Satoshi Okada, Hiroshi Kawaguchi
Journal: Blood (2017)
Abstract 3267: Cancer immunotherapy by use of FANA ASO therapy to silence Foxp3, impair Treg function and promote anti-tumor immunity
Authors: Wayne W. Hancock, Liqing Wang, Veenu Aishwarya
Journal: Cancer Research (2019)

Abstract There is an inverse correlation between tumor and draining lymph node infiltration by Foxp3+CD4+CD25+ Treg cells and clinical outcomes in carcinomas of the breast, liver, stomach, ovary, pancreas, and lung, as well as melanomas and glioblastomas. Tregs suppress tumor responses by host CD8 and CD4 T cells, B cells, NK cells, macrophages and dendritic cells. There are currently no effective ways to target Tregs, since toxins (e.g. IL-2-diptheria toxin) and cyclophosphamide have only transient effects with rebound and may also affect conventional T cells, use of CD25 monoclonal antibodies have confounding effects given IL-2 receptor (CD25) expression by activated T cells, and given the phenomenon of “peripheral” conversion (iTreg development) at the tumor site that can allow Tregs to evade therapy. These problems led us explore use of FANA antisense oligonucleotides (ASO) to suppress expression of Foxp3 mRNA. FANA ASO are highly specific and are taken up by cells without use of any delivery agents, conjugates or formulations, making them attractive compounds for cancer drug development. Various Foxp3 sequence-specific or scrambled FANAs were designed, and fluorescently-labeled FANA tested by addition to Foxp3+ Tregs in vitro; these studies showed successful uptake and both cytoplasmic and nuclear localization. FANAs were further screened by assessing effects on Treg suppressive function, and those resulting in 40-50% reductions were assessed for effects on expression of Foxp3 mRNA (qPCR) and protein (Western blots). We next tested the in vivo efficacy of Foxp3 FANA by intravenous or intraperitoneal injection, either daily or twice/week, of Foxp3 FANA, followed by isolation of Tregs from lymphoid tissues. Selected fluorescently-labeled FANA showed Treg uptake, and unlabeled FANA led to &amp;gt;75% reduction in Foxp3 protein expression (flow cytometry, Western blots), and marked reductions in Treg suppressive function. Lastly, we compared the effects of scrambled vs. specific Foxp3 FANA ASO on TC1 lung tumor growth in syngeneic C57BL/6 mice. Compared with mice receiving scrambled FANA ASO, mice receiving specific Foxp3 FANA ASO showed impaired tumor growth, with 50% showing complete tumor elimination (p&amp;lt;0.0001), and markedly reduced Foxp3+CD4+ Treg infiltration (p&amp;lt;0.01). Our data indicate that FANA oligos can modulate Foxp3 expression and Treg function in vitro and in vivo, such that their use may provide an important new approach to cancer immunotherapy. Citation Format: Wayne W. Hancock, Liqing Wang, Veenu Aishwarya. Cancer immunotherapy by use of FANA ASO therapy to silence Foxp3, impair Treg function and promote anti-tumor immunity [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 3267.