tbuckley/cabot-search huggingface dataset:
Abstract 2178: Targeted delivery of chemotherapeutic agents employing nanovesicles effectively reduced intrahepatic tumors
Authors: Joseph George, Nobuhiko Hayashi, Takashi Saito, Mikihiro Tsutsumi, Mutsumi Tsuchishima
Journal: Cancer Research (2019)

Abstract Background and Aims: Currently there is no appropriate method for effective and targeted delivery of chemotherapeutic agents to tumor sites. The conventional chemotherapy is afflicted with lack of effective drug delivery to the tumor site, unwanted injury to actively dividing healthy cells, and numerous side effects due to toxicity. The present study was aimed to develop a biologically derived nanoparticle based drug delivery system for the effective treatment of primary hepatic tumors. Methods: Intrahepatic tumors were induced in immunosuppressed mice using PLC/PRF/5 hepatocellular carcinoma (HCC) cells stably transfected with a mammalian expression vector carrying luciferase gene for in-vivo imaging. Nanovesicles ranging from 80-150 nm were isolated from bovine skim milk using ultracentrifugation and characterized using nanoparticle tracking analysis (NTA) and electron microscopy. Purified nanovesicles were loaded with chemotherapeutic agents and antisense oligonucleotides for grossly deregulated microRNAs specific to HCC. Animals with uniform intrahepatic tumors were injected with nanovesicle loaded anticancer agents through tail vein. Tumor regression was monitored weekly using in-vivo imaging system and the animals were maintained up to 8 weeks. Results: Bioluminescence based in-vivo imaging demonstrated significant reduction of tumor size in treated animals compared to untreated controls. There was increased survival rate and complete absence of metastasis in all treated animals. Untreated mice developed large intrahepatic tumors, which also metastasized to other organs. There were no side effects or immunological reactions in animals injected with plain nanovesicles without loading of any anticancer agents. Conclusions: The present study demonstrated that milk derived nanovesicles can be effectively used for successful delivery of anticancer agents into intrahepatic tumors. Nanovesicle based targeted drug delivery system could be an effecient method for the treatment of primary hepatic tumors.* Presenting author E-mail: georgej@kanazawa-med.ac.jp Note: This abstract was not presented at the meeting. Citation Format: Joseph George, Nobuhiko Hayashi, Takashi Saito, Mikihiro Tsutsumi, Mutsumi Tsuchishima. Targeted delivery of chemotherapeutic agents employing nanovesicles effectively reduced intrahepatic tumors [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 2178.
Abstract 1993: Gluthathione peroxidase 2 downregulation in the PyMT mammary tumor model leads to an aggressive phenotype due to stimulation of angiogenesis and tumor stemness via HIF1 alpha signaling
Authors: Zuen Ren, Huizhi Liang, Outhiriaradjou Benard, Kimita Suyama, Joseph M. Albanese, Larry Norton, Wei Zheng, Rachel B. Hazan
Journal: Cancer Research (2019)

Abstract Breast tumors are known to undergo high levels of mitochondrial oxidative phosphorylation leading to accumulation of reactive oxygen species (ROS), which in turn potentiate cancer stem cells and chemoresistance. This was shown to be due to HIF1α stabilization by ROS; however, the signaling events downstream of HIF1α regulating the cancer stem cell (CSC) phenotype remain unknown. Kaplan Meier survival curves upon the gene profiling database of breast cancer patients showed that reduced levels of the ROS scavenging enzyme, glutathione peroxidase 2 (GPx2) in breast cancers was associated with shorter patient survival duration. Consistent with this idea, we found that GPx2 was downregulated in metastatic mammary tumor cells, suggesting GPx2 loss enhances metastasis. Indeed, GPx2 knockdown in poorly metastatic cells increased ROS production, shortened tumor latency, and stimulated dramatic mammary tumor growth and metastasis. These effects were associated with marked increases in angiogenesis, CSC-like properties, and chemoresistance. Here, we show that GPx2 downregulation in mammary epithelial cells increases ROS production and HIF1α stabilization which were accompanied by VEGF upregulation and enhanced angiogenesis. On the other hand, GPx2 loss caused dramatic mammosphere formation and resistance to doxorubicin, implying effects on stemness leading to chemoresistance. These data suggest that GPx2 loss is a critical event that drives mammary tumorigenesis and metastasis via HIF1α signaling leading to stimulation of angiogenesis and stemness properties. Understanding the ramifications of GPx2 loss in breast cancer will allow us to identify key regulators of stemness and chemoresistance, with the goal of identifying novel drug targets in metastasis. Citation Format: Zuen Ren, Huizhi Liang, Outhiriaradjou Benard, Kimita Suyama, Joseph M. Albanese, Larry Norton, Wei Zheng, Rachel B. Hazan. Gluthathione peroxidase 2 downregulation in the PyMT mammary tumor model leads to an aggressive phenotype due to stimulation of angiogenesis and tumor stemness via HIF1 alpha signaling [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 1993.
Abstract 5136: Reduction in Myocardial Ischemia-reperfusion Injury in Group IV Cytosolic Phospholipase A2-deficient Mice Partly Due to Inhibition of TNFα-mediated Pathway to Cell Injury
Authors: Yukio Saito, Yousuke Watanabe, Hideto Mishina, Kazuhiro Watanabe, Toshiaki Yano, Tsuyoshi Kobayashi, Jun-ei Obata, Ken-ichi Kawabata, Takao Shimizu, Kiyotaka Kugiyama
Journal: Circulation (2009)

Type IV cytosolic phospholipase A2 (cPLA2), which preferentially cleaves arachidonic acid from phospholipids, plays an important role in tissue injury. The downstream signal in response to TNFα, a ...
Multiplex profiling of peritoneal metastases from gastric adenocarcinoma identified novel targets and molecular subtypes that predict treatment response
Authors: Ruiping Wang, Shumei Song, Kazuto Harada, Fatemeh Ghazanfari Amlashi, Brian Badgwell, Melissa Pool Pizzi, Yan Xu, Wei Zhao, Xiaochuan Dong, Jiangkang Jin, Ying Wang, Ailing Scott, Lang Ma, Longfei Huo, Diego Vicente, Mariela Blum Murphy, Namita Shanbhag, Ghia Tatlonghari, Irene Thomas, Jane Rogers, Makoto Kobayashi, Jody Vykoukal, Jeannelyn Santiano Estrella, Sinchita Roy-Chowdhuri, Guangchun Han, Shaojun Zhang, Xizeng Mao, Xingzhi Song, Jianhua Zhang, Jian Gu, Randy L Johnson, George Adrian Calin, Guang Peng, Ju-Seog Lee, Samir M Hanash, Andrew Futreal, Zhenning Wang, Linghua Wang, Jaffer A Ajani
Journal: Gut (2019)

Peritoneal carcinomatosis (PC) occurs frequently in patients with gastric adenocarcinoma (GAC) and confers a poor prognosis. Multiplex profiling of primary GACs has been insightful but the underpinnings of PC's development/progression remain largely unknown. We characterised exome/transcriptome/immune landscapes of PC cells from patients with GAC aiming to identify novel therapeutic targets.We performed whole-exome sequencing (WES) and whole transcriptome sequencing (RNA-seq) on 44 PC specimens (43 patients with PC) including an integrative analysis of WES, RNA-seq, immune profile, clinical and pathological phenotypes to dissect the molecular pathogenesis, identifying actionable targets and/or biomarkers and comparison with TCGA primary GACs.We identified distinct alterations in PC versus primary GACs, such as more frequent CDH1 and TAF1 mutations, 6q loss and chr19 gain. Alterations associated with aggressive PC phenotypes emerged with increased mutations in TP53, CDH1, TAF1 and KMT2C, higher level of 'clock-like' mutational signature, increase in whole-genome doublings, chromosomal instability (particularly, copy number losses), reprogrammed microenvironment, enriched cell cycle pathways, MYC activation and impaired immune response. Integrated analysis identified two main molecular subtypes: 'mesenchymal-like' and 'epithelial-like' with discriminating response to chemotherapy (31% vs 71%). Patients with the less responsive 'mesenchymal-like' subtype had high expression of immune checkpoint T-Cell Immunoglobulin And Mucin Domain-Containing Protein 3 (TIM-3), its ligand galectin-9, V-domain Ig suppressor of T cell activation (VISTA) and transforming growth factor-β as potential therapeutic immune targets.We have uncovered the unique mutational landscape, copy number alteration and gene expression profile of PC cells and defined PC molecular subtypes, which correlated with PC therapy resistance/response. Novel targets and immune checkpoint proteins have been identified with a potential to be translated into clinics.
Abstract 4138: Understanding the effects of NF-kappaB signaling on macrophage phenotype to inform therapeutic approaches
Authors: Evan B. Glass, Alyssa Hoover, Whitney Harris, Zahra Mirafzali, Todd D. Giorgio, Andrew Wilson, Fiona Yull
Journal: Cancer Research (2019)

Abstract It is recognized that modulation of macrophage phenotypes within the tumor microenvironment has the potential to achieve anti-tumor outcomes. However, formulating a strategy to achieve the benefits of such an approach in a cell-specific manner while minimizing off-target or uncontrolled deleterious side effects remains a challenge. We hypothesize that modulation of Nuclear Factor Kappa-B (NF-kappaB) signaling within macrophages in the proximal tumor microenvironment represents an effective approach. However, there remains controversy whether NF-kappaB signaling in macrophages induces pro- or anti-tumor outcomes. Understanding the mechanisms by which this signaling pathway defines predominant macrophage characteristics is therefore critical in order to use strategic interventions to obtain therapeutic benefits. Our goal is to gain insight into how to modulate NF-kappaB signaling in macrophages to generate anti-tumor phenotypes and to use this information to develop new treatments. We use immortalized bone marrow-derived macrophages or ex vivo macrophages in cell culture approaches to investigate impacts of modulation of NF-kappaB signaling on macrophage phenotypes. We have three methods to modulate signaling: doxycycline inducible transgenic mice, liposomal delivery of the bacterial cell mimic MTP-PE, and optimized polymeric nanoparticle-mediated delivery of siRNA targeting the NF-kappaB inhibitor. In addition to our in vitro assays, we also employ in vivo murine models of ovarian and breast tumor progression. This multi-faceted approach is providing insights into how altering NF-kappaB signaling in macrophages impacts their interactions with tumor cells and other cells in the tumor microenvironment. Our data suggests that high levels of NF-kappaB signaling in macrophages induce both direct tumor cell-killing and immune-stimulating responses. These studies are designed to better understand the mechanisms by which NF-kappaB regulates macrophage functions to inform development of a novel macrophage-based immunotherapy that will be effective across a wide spectrum of solid tumors and metastatic disease. Citation Format: Evan B. Glass, Alyssa Hoover, Whitney Harris, Zahra Mirafzali, Todd D. Giorgio, Andrew Wilson, Fiona Yull. Understanding the effects of NF-kappaB signaling on macrophage phenotype to inform therapeutic approaches [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 4138.
Abstract LB-277: Characterization of the anti-cancer and immunologic activity of RGX-019, a novel pre-clinical stage humanized monoclonal antibody targeting the MERTK receptor
Authors: Shugaku Takeda, Celia Andreu-Agullo, Subhasree Sridhar, Nils Halberg, Ivo C. Lorenz, Sohail Tavazoie, Isabel Kurth, Masoud Tavazoie
Journal: Cancer Research (2019)

Abstract MERTK, a receptor tyrosine kinase of the TYRO3/AXL/MERTK (TAM) family, is expressed in innate immune cells including macrophages, dendritic cells and NK cells and is overexpressed in a wide variety of cancers, including leukemia and many solid cancers. Activation of MERTK on cancer cells via ligand binding results in activation of several tumor-promoting signaling pathways, which stimulate proliferation, migration and angiogenesis, and decrease apoptosis and chemosensitivity. Furthermore, activation of MERTK on macrophages drives immune evasion through the promotion of an immune-suppressive M2 phenotype. Pre-clinical and clinical studies have shown promising emerging evidence of anti-tumor efficacy upon modulation of TAM receptor signaling. Herein, we report the pre-clinical characterization of RGX-019, a humanized IgG1 antibody with high affinity and specificity for human MERTK. Surface Plasmon Resonance, cell-based binding assays and competition ELISA demonstrate high affinity/avidity binding for RGX-019 to human MERTK. In contrast, binding to human AXL, human TYRO3, or murine MERTK was not detected. Binding of RGX-019 to the MERTK receptor triggered its rapid internalization and degradation from the surface of human cancer cells within 4 hours and prevented Gas6 induced phosphorylation of AKT, a downstream signal transduction pathway that promotes cell growth and survival. RGX-019 treatment of SKMel5 melanoma cells effectively inhibited colony formation. RGX-019-induced degradation of MERTK in in vitro differentiated human M2 macrophages reduced AKT activation and promoted a pro-inflammatory cytokine signature. Furthermore, a related surrogate murine MERTK antibody significantly inhibited growth of MDA-MB-231 breast cancer tumors, demonstrating single agent anti-tumor efficacy in vivo. These findings demonstrate that RGX-019 is a potent and selective inhibitor of MERTK signaling with a unique mechanism-of-action that potently disrupts MERTK signaling in both cancer cells and immune-suppressive macrophages via MERTK receptor degradation. This activity results in robust repression of cancer cell growth both in vitro and in vivo. Overall, these data support further development of RGX-019 as a cancer therapeutic. Citation Format: Shugaku Takeda, Celia Andreu-Agullo, Subhasree Sridhar, Nils Halberg, Ivo C. Lorenz, Sohail Tavazoie, Isabel Kurth, Masoud Tavazoie. Characterization of the anti-cancer and immunologic activity of RGX-019, a novel pre-clinical stage humanized monoclonal antibody targeting the MERTK receptor [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 LB-277.
Reimagining Specialty Consultation in the Digital Age
Authors: Robert M. Wachter, Timothy J. Judson, Michelle Mourad
Journal: JAMA (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Abstract 18604: Prospective Validation of the EHMRG Risk Model for Patients Presenting With Acute Heart Failure in the Emergency Department
Authors: Douglas S Lee, Jacques S Lee, Michael J Schull, Bjug Borgundvaag, Marcia Edmonds, Maria Ivankovic, Shelley McLeod, Jonathan Dreyer, Sam Sabbah, Phillip D Levy, Tara O'Neill, Cindy H Fong, Alice Chong, Therese A Stukel, Jeremy M Grimshaw, Peter C Austin, Jack V Tu
Journal: Circulation (2017)

Background: Risk prediction models may potentially improve disposition decision-making for patients with heart failure (HF). However, few acute HF models have been prospectively validated or compar...
The evolution of COPD species; or, something is changing for good in COPD
Authors: Joan B. Soriano
Journal: European Respiratory Journal (2019)

At age 50 years, Charles Darwin (figure 1) published his theory of evolution, On the Origin of Specie s, in full, for his fellow scientists and for the public at large [1]. It was exactly 160 years ago, on a Thursday, 24 November 1859, priced at fifteen shillings. Three recent reports in the European Respiratory Journal on chronic obstructive pulmonary disease (COPD) have reminded us that not only species, but also diseases, experience evolution. At first glance, the three papers appear unconnected. COPD, both clinically and epidemiologically, is in constant evolution <http://bit.ly/2X04qcn>
Основні показники хірургічної допомоги пацієнтам із біліарною патологією на вторинному рівні
Authors: Yu.M. Stepanov, I.Yu. Skyrda
Journal: GASTROENTEROLOGY (2013)

Проаналізовані поширеність жовчнокам’яної хвороби (ЖКХ), хронічного холециститу (ХХ) і холангіту, захворюваність на цю патологію, а також хірургічна активність та післяопераційна летальність унаслідок оперативних втручань на органах біліарної системи серед населення України за останні 7 років (2006–2012 рр.). Відбулось зниження показників поширеності ЖКХ, ХХ і холангіту й захворюваності на цю патологію. Така динаміка показників більшою мірою пов’язана із зовнішніми факторами (умови життя, кризисні явища у суспільстві), ніж з тенденціями формування та розвитку патології біліарної системи. Водночас зі зменшенням кількості зареєстрованих пацієнтів із ЖКХ, ХХ і холангітом збільшилось число операцій при гострому холециститі, а також відзначене зростання питомої ваги термінових операцій від їх загальної кількості. На даний час смертність від операцій внаслідок гострого холециститу знизилась порівняно з рівнем 2006 р., відбулось зменшення післяопераційної летальності, у тому числі при пізній госпіталізації. Незважаючи на це, проблема хвороб біліарної системи далека від свого повного вирішення, оскільки вони посідають 1-ше місце в структурі гастроентерологічної патології, а гострий холецистит — 2-ге місце за кількістю операцій серед усіх хірургічних захворювань черевної порожнини. Тому потрібно загострити увагу хірургів, які оперують на органах біліарної системи, на аналізі ускладнень, при яких необхідно прийняти дуже важливе рішення про необхідність операції.
Abstract 17764: Multiple Gene Mutations Predicted Poor Prognosis in Patients with Hypertrophic Cardiomyopathy
Authors: Jizheng Wang, Yilu Wang, Yubao Zou, Kai Sun, Zhimin Wang, Jinqing Yuan, Wei Wei, Xuan Liu, Hongju Zhang, Shuo Gao, Channa Zhang, Yun Ji, Xianliang Zhou, Rutai Hui, Lei Song
Journal: Circulation (2012)

BACKGROUND The clinical outcomes of hypertrophic cardiomyopathy (HCM) are largely unpredictable. The presence of multiple mutations in HCM patients was revealed recently and suggested to be associa...
Abstract LB-303: Transposable element insertions impact the mutational landscape of breast cancer genomes and disease onset
Authors: Robin Paul, Milan Radovich, Jeffrey P. Solzak
Journal: Cancer Research (2019)

Abstract More than 50% of the human genome consists of transposable elements (TE), which mostly remain inactive and relatively stable in healthy individuals. These elements, commonly known as “jumping genes,” are sequences of DNA that are mobile and can change positions in the genome. However, only certain classes of retrotransposons (ALU, SVA, ERV and L1) are believed to be active in the human genome. Most TEs transpose by a “copy-and-paste” mechanism via transcription from DNA to an RNA intermediate followed by reverse transcription back to DNA and subsequent insertion of the copied DNA into the genome. In healthy individuals, this mechanism is silenced by various epigenetic pathways such as the piRNA pathway which helps silence the transcribed TE RNA intermediates. However during cancer, some retrotransposons are believed to become active due to loss of this epigenetic silencing and DNA damage repair mechanisms. In this study, we analyzed somatic and germline TE insertions in 77 TCGA breast cancer whole genomes and performed association analysis with corresponding somatic and germline variants. In our analysis, we identified a subset of patients who harbored a high number of germline TE insertions. Statistical burden testing of germline TE insertions with germline genetic variants (SNPs and Indels), revealed an enrichment of deleterious variants in the NRDE2 and TNKS1BP1 genes. NRDE2 gene involved in the piRNA pathway is known to regulate TEs using RNA silencing whereas, TNKS1BP1 gene is known to be involved in DNA damage repair mechanisms and also helps maintain genomic integrity. Further, patients with high germline TE insertions had a lower median age of diagnosis (top quartile vs bottom 75%, p-value=0.019), suggesting a potential novel role of germline TE insertions in cancer predisposition. Lastly, comparison of somatic TE insertion burdenpattern against somatic tumor mutation burden revealed an inverse correlation, indicating that analysis of TE insertions is critical to breast cancer diagnosis in the clinic. Our results definitively argue that characterization of TEs is essential for elucidating the complete mutational profile of a breast cancer genome. Citation Format: Robin Paul, Milan Radovich, Jeffrey P. Solzak. Transposable element insertions impact the mutational landscape of breast cancer genomes and disease onset [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 LB-303.