tbuckley/cabot-search huggingface dataset:
Abstract 2972: Urolithin A decreases cell proliferation of three genetically diverse glioblastoma multiforme cell lines
Authors: Alexandra Lynn Hearne, Dakota Brockway, Shiyong Wu, Yunsheng Li
Journal: Cancer Research (2020)

Abstract Glioblastoma multiforme is one of the most common and malignant tumors of the central nervous system, remaining incurable with a median survival time of only 15 months. Over the past 50 years there has been little change in this overall survival rate, due to the many challenges in treating glioblastoma, including molecular complexity, tumor location, and resistance towards standard therapies. Therefore, an improved method for treating glioblastoma is urgently needed. Urolithin A is a natural biometabolite from ellagitannins and ellagic acid, which can be found in pomegranates, berries, and nuts. Urolithin A exhibits anti-cancer activities in several cancer cell lines, including prostate, colon, and bladder cancer cells. However, the anti-cancer activities of urolithin A have yet to be characterized in glioblastoma multiforme. In this project, we investigated whether urolithin A could reduce human glioblastoma cell proliferation by conducting clonogenic assays and cell cycle analysis in three genetically diverse human glioblastoma cell lines: U87MG, T98G, and LN229. Clonogenic assay results showed that urolithin A significantly decreased cell proliferation in a dose-dependent manner in all three glioblastoma cell lines. Depending on the different cell lines, the cell proliferation was inhibited at concentrations of 10 to 60 µM urolithin A. In addition, cell cycle analysis via flow cytometry found that urolithin A was capable of arresting cell cycle progression in either the G2/M or S phase of the cell cycle in U87 and LN229 or T98G cells, respectively. In conclusion, we have found that urolithin A can reduce cell proliferation and alter cell cycle progression of three genetically diverse glioblastoma cell lines. Importantly, urolithin A can pass the blood-brain barrier and has previously shown to be non-toxic in humans, a prerequisite for a drug to treat glioblastoma. Therefore, urolithin A has the potential to be used as a novel drug which can be combined with current standard methods to improve the efficacy of glioblastoma treatment. In the future, we plan to investigate specific signaling pathways involved in apoptosis, cellular proliferation, and cell cycle arrest. Once we elucidate the specific mechanisms we will investigate the efficacy of urolithin A in vivo, using an animal model. If successful, urolithin A will have the potential to be used alongside radiation and chemotherapy to further reduce glioblastoma cell proliferation. Citation Format: Alexandra Lynn Hearne, Dakota Brockway, Shiyong Wu, Yunsheng Li. Urolithin A decreases cell proliferation of three genetically diverse glioblastoma multiforme cell lines [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2972.
Abstract 5956: New molecular mechanisms of small cell lung cancer growth
Authors: Sk. Kayum Alam, Li Wang, Yanan Ren, Christina E. Hernandez, Farhad Kosari, Anja C. Roden, Rendong Yang, Luke H. Hoeppner
Journal: Cancer Research (2020)

Abstract Lung cancer is the leading cause of cancer death among both men and women in the United States. Small cell lung cancer (SCLC) results in over 30,000 deaths of Americans annually and comprises 15-17% incidences of lung cancer. SCLC is the most aggressive form of lung cancer due to its rapid doubling time and early widespread metastasis. Most SCLC patients present with advanced disease, respond to initial systemic chemotherapy, and then treatment refractory progression usually occurs within one year due to acquired drug resistance. Consequently, the median survival time of SCLC patients is only 9 to 20 months and merely 7% of SCLC patients survive beyond five years. A better molecular understanding of SCLC is necessary to develop much needed new treatment strategies. For the first time, we demonstrate that dopamine and cAMP-regulated phosphoprotein, Mr 32000 (DARPP-32) and its splice variant t-DARPP stimulate tumors of neuroendocrine origin, and we show DARPP-32 proteins are aberrantly overexpressed in human SCLC. Upregulation of t-DARPP protein in a subset of SCLC patients positively correlates with overexpression of genes associated with Notch signaling, including achaete-scute homologue 1 (ASCL1). We reveal that DARPP-32 isoforms are transcriptionally activated by ASCL1 in human SCLC cells. To determine whether DARPP-32 drives SCLC growth in vivo, we utilized an orthotopic lung cancer xenograft mouse model. Mice challenged with DARPP-32-ablated DMS-53 cells show a substantial decrease in lung tumor growth relative to controls. Correspondingly, we demonstrate increased tumor growth in mice harboring lung tumors formed by administration of DMS-53 or H1048 cells overexpressing DARPP-32 and t-DARPP proteins. Mechanistically, we describe how DARPP-32 isoforms promote SCLC growth through increased proliferation, Akt/Erk-mediated survival, and anti-apoptotic signaling. Taken together, we define new regulatory mechanisms of SCLC oncogenesis that suggest DARPP-32 isoforms may represent a negative prognostic indicator for SCLC and serve as a potential target for the development of new therapies. Citation Format: Sk. Kayum Alam, Li Wang, Yanan Ren, Christina E. Hernandez, Farhad Kosari, Anja C. Roden, Rendong Yang, Luke H. Hoeppner. New molecular mechanisms of small cell lung cancer growth [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5956.
Does chemotherapy reactivate SARS-CoV-2 in cancer patients recovered from prior COVID-19 infection?
Authors: Jianping Bi, Hong Ma, Dongsheng Zhang, Jing Huang, Dongqin Yang, Yajie Wang, Vivek Verma, Tao Zhang, Desheng Hu, Qi Mei, Guang Han, Jian Li
Journal: European Respiratory Journal (2020)

Cancer patients are particularly vulnerable to coronavirus disease 2019 (COVID-19) [1–3]. These individuals are not only more susceptible to this infection, but also more frequently develop severe pneumonia during the disease course [1–3]. One factor associated with an increasing risk for developing severe events in this population is oncologic therapy, especially cytotoxic chemotherapy. Therefore, some oncologists and societies recommend that chemotherapy should generally not be started until COVID-19 symptoms have completely resolved and viral testing becomes negative [3, 4]. Additionally, some cancer patients who have recovered from infection are recommended to withhold, postpone, or switch to alternative routes of chemotherapy ( e.g. oral instead of intravenous infusion) until the end of the COVID-19 pandemic [3, 4]. Recovered COVID-19 cancer patients remain negative for SARS-CoV-2 after delivery of chemotherapy <https://bit.ly/2QNTqO0> We thank Tian Tang (Renmin Hospital of Wuhan University, Wuhan, China) for her assistance in the study and we thank all patients involved in the study.
Placental thromboinflammation impairs embryonic survival by reducing placental thrombomodulin expression
Authors: Shrey Kohli, Kunal Kumar Singh, Anubhuti Gupta, Paulina Markmeyer, Franziska Lochmann, Dheerendra Gupta, Rajiv Rana, Ahmed Elwakiel, Hanna Huebner, Matthias Ruebner, Berend Isermann
Journal: Blood (2020)
Size, shape, charge and “stealthy” surface: Carrier properties affect the drug circulation time in vivo
Authors: Jinwei Di, Xiang Gao, Yimeng Du, Hui Zhang, Jing Gao, Aiping Zheng
Journal: Asian Journal of Pharmaceutical Sciences (2020)

The present review sets out to discuss recent developments of the effects and mechanisms of carrier properties on their circulation time. For most drugs, sufficient in vivo circulation time is the basis of high bioavailability. Drug carrier plays an irreplaceable role in helping drug avoid being quickly recognized and cleared by mononuclear phagocyte system, to give drug enough time to arrive at targeted organ and tissue to play its therapeutic effect. The physical and chemical properties of drug carriers, such as size, shape, surface charge and surface modification, would affect their in vivo circulation time, metabolic behavior and biodistribution. The final circulation time of carriers is determined by the balance between macrophage recognitions, blood vessel penetration and urine excretion. Therefore, when designing the drug delivery system, we should pay much attention to the properties of drug carriers to get enough in vivo circulation time to arrive at target site eventually. This article mainly reviews the effect of carrier size, size, surface charge and surface properties on its circulation time in vivo, and discusses the mechanism of these properties affecting circulation time. This review has reference significance for the research of long-circulation drug delivery system.
Abstract 4144: A tissue-microfluidic derived aptamer displays prognostic and therapeutic characteristics in serous ovarian carcinoma through heat shock protein 70(HSP70)
Authors: Chang-Ni Lin, Yu-Ling Liang, Pei-Ying Wu, Gwo-Bin Vincent Lee, Keng-Fu Hsu
Journal: Cancer Research (2020)

Abstract Background: Previously, we have identified aptamers through ovarian cancer (OC) tissue microfluidic platform which show high specificity to ovarian cancer tissue and cells. However, the clinical diagnostic and therapeutic roles of these aptamers are still largely unknown. Materials and Methods: Liquid chromatography-mass spectrometry (LC-MS) was used to find binding candidates of aptamer, Tx-01, from serous type ovarian cancer cells. Immunohistochemistry (IHC), clinical survival analysis, western blotting and confocal microscopic images were performed to detect the expression of Tx-01 and HSP70/ Notch1 intracellular domain (NICD) in OC tissues. The functions of Tx-01 were studied in vitro and in vivo experiments. Inhibitors treatment, nuclear protein extraction and western blotting were carried out to demonstrate the possible mechanisms of Tx-01 function. Results: High expression Tx-01 in OC tissues was correlated to poor patients' survival in serous ovarian carcinoma. In vitro experiments showed that Tx-01 has a feature of recognizing membrane-bound HSP70. In the meantime, Tx-01 inhibit HSP70 signal activation via interrupting intracellular HSP70/NICD interaction to reduce cell migration and invasion. Furthermore, Tx-01 inhibited the tumor growth in the mice experiment. Conclusion: Our data showed that Tx-01 acted as a prognostic predictor in serous OC through recognizing the membrane-bound HSP70. Also, Tx-01 reduced the tumor cell migration, invasion through blocking HSP70 signal activation. Thus, our work demonstrated that Tx-01 might be a prognostic biomarker and potential inhibitor in serous OC therapy. Citation Format: Chang-Ni Lin, Yu-Ling Liang, Pei-Ying Wu, Gwo-Bin Vincent Lee, Keng-Fu Hsu. A tissue-microfluidic derived aptamer displays prognostic and therapeutic characteristics in serous ovarian carcinoma through heat shock protein 70(HSP70) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4144.
Abstract 4973: Comparison of tumor immune microenvironment in triple negative breast cancer (TNBC) of African American versus that of white patients
Authors: Vesal Yaghoobi, Vasiliki Pelekanou, Tess O'Meara, Andrea Silber, Lajos Pusztai, David Rimm, Kim Blenman
Journal: Cancer Research (2020)

Abstract Introduction: Although there are many possible causes, it has been observed that Triple Negative Breast Cancer (TNBC) has a worse overall outcome in African American (AA) than white patients. Recently, there is also evidence that the patients response to the tumor, or the biological response expressed as the tumor immune microenvironment, impacts outcome. The goal of this study was to compare the Tumor Microenvironment (TME) of TNBC in the two mentioned groups in order to seek molecular parameters that are different in TNBC in AA patients as compared to whites. Methods: We selected N=50 AA and N=50 white TNBC samples from the Yale Pathology archives that were matched by diagnosis date. We measured CD45, CD3, CD8, CD20, CD14, CD68, PD-L1, THY1, aSMA and Fibroblast Activation Protein (FAP) expression in both the tumor and stromal compartments in whole slides from formalin fixed paraffin embedded (FFPE) tissues using multiplexed quantitative immunofluorescence (QIF). We also assessed the activation status of CD3-positive cells using Ki67 and Granzyme B markers. Median of each marker expression was calculated for each case by using quantitation from all Fields of View (FOV) that contained at least 10% tumor area. Results: AA tumors contained a significantly higher CD45-positive cells in overall, within tumor and stromal compartments (p = 0.0102, 0.0007 and 0.0280 respectively). Being more specific about CD45 marker, AA also showed to have a significantly higher level of overall lymphocyte population, measured by quantitating CD45+ CD14- cells (p =0.0081). AA tumors also had a significantly higher level of CD8 expression (p &amp;lt;0.0001). Even though we could not find any differences in CD3 expressions between the two groups, AA tumors contained a significantly higher level of activated T-cells (p =0.0432), where activation is defined as CD3 cells with high Ki67 or Granzyme B. AA tumors contained a significantly higher level of CD68 positive cells (p &amp;lt; 0.0001) and PD-L1 expression in CD68+ cells (p =0.0101). All other markers showed no difference between the two groups. Conclusion: Significant differences are seen in the TME of AA vs. white TNBCs. Further characterization of macrophages, fibroblasts, regulatory T-cells and Extracellular Matrix are underway to more specifically define TME and determine the relationship between TME features and outcome. Citation Format: Vesal Yaghoobi, Vasiliki Pelekanou, Tess O'Meara, Andrea Silber, Lajos Pusztai, David Rimm, Kim Blenman. Comparison of tumor immune microenvironment in triple negative breast cancer (TNBC) of African American versus that of white patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4973.
Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice
Authors: Azar Asadi Shahmirzadi, Daniel Edgar, Chen-Yu Liao, Yueh-Mei Hsu, Mark Lucanic, Arash Asadi Shahmirzadi, Christopher D. Wiley, Garbo Gan, Dong Eun Kim, Herbert G. Kasler, Chisaka Kuehnemann, Brian Kaplowitz, Dipa Bhaumik, Rebeccah R. Riley, Brian K. Kennedy, Gordon J. Lithgow
Journal: Cell Metabolism (2020)
Enhanced tuberculosis clearance through the combination treatment with recombinant adenovirus-mediated granulysin delivery
Authors: Ling Hao, Jilei Ma, Chunwei Shi, Xiaosong Lin, Yandi Zhang, Banga Ndzouboukou Jo-Lewis, Qing Lei, Nadeem Ullah, Zhongjie Yao, Xionglin Fan
Journal: Theranostics (2020)

Rationale: Tuberculosis (TB) remains the leading cause of death among infectious diseases worldwide. Poor compliance of TB patients to the lengthy treatment increases the risk of relapse and leads to the emergence of multidrug-resistant and extensively drug-resistant TB (MDR-TB and XDR-TB). More effective therapies for TB are urgently needed. We hypothesized that granulysin-mediated clearance of M. tuberculosis parasited inside and outside of alveolar macrophages in presumptive infected hosts might enhance the chemotherapeutic efficacy on TB. Methods: Recombinant adenovirus type 5 (rAd5) based therapeutic vaccines rAdhGLi and rAdhGLs (rAds) were respectively developed to express intracellular and extracellular granulysin. The ex vivo bactericidal effects of rAdhGLi and rAdhGLs were evaluated on U937 and RAW264.7 cells. The efficacy of immunotherapy with both rAdhGLi and rAdhGLs on TB SCID mice, or immunotherapy combined with chemotherapy on drug-susceptible TB or MDR-TB mouse models were further evaluated. Results: rAdhGLs, as well as rAdhGLi, showed a direct bactericidal effect on extracellular or intracellular M. tuberculosis H37Rv and MDR-TB clinical strains, respectively. Immunotherapy with a dose of 109 PFU of rAdhGLi and 109 PFU of rAdhGLs demonstrated a more significant bactericidal effect on M. tuberculosis H37Rv infected SCID mice and prolonged their survival periods than rAdhGLi or rAdhGLs alone. More importantly, chemotherapy combined with rAds immunotherapy shortened the chemotherapeutic duration to 4 months on M. tuberculosis H37Rv infected mice and prevented the relapse. Combination of rAds with chemotherapy on MDR-TB mice also more significantly decreased organ bacterial load than their single use. Conclusions: Delivery of granulysin by recombinant adenovirus to the infected lung could enhance the clearance of TB in vivo and might be a promising adjunct therapeutic vaccine for TB and MDR-TB.
Erratum: New developments in the molecular pharmacology of the myo-inositol 1,4,5-trisphosphate receptor, Trends Pharmacol. Sci. 19, 467-475
Authors: R. A. Wilcox, W. U. Primrose, S. R. Nahorski, R. A.J. Challiss
Journal: Trends in Pharmacological Sciences (1998)
The peptide PROTAC modality: a novel strategy for targeted protein ubiquitination
Authors: Jinmei Jin, Ye Wu, Jinjiao Chen, Yiwen Shen, Lijun Zhang, Hong Zhang, Lili Chen, Hebao Yuan, Hongzhuan Chen, Weidong Zhang, Xin Luan
Journal: Theranostics (2020)

Despite dramatic advances in drug discovery over the decades, effective therapeutic strategies for cancers treatment are still in urgent demands. PROteolysis TArgeting Chimera (PROTAC), a novel therapeutic modality, has been vigorously promoted in preclinical and clinical applications. Unlike small molecule PROTAC, peptide PROTAC (p-PROTAC) with advantages of high specificity and low toxicity, while avoiding the limitations of shallow binding pockets through large interacting surfaces, provides promising substitutions for E3 ubiquitin ligase complex-mediated ubiquitination of "undruggable proteins". It is worth noting that successful applications of p-PROTAC still have some obstacles, including low stability and poor membrane permeability. Hence, we highlight that p-PROTAC combined with cell-penetrating peptides, constrained conformation technique, and targeted delivery systems could be the future efforts for potential translational research.
<i>QuickStats:</i> Rates* of Deaths Attributed to Unintentional Injury from Fire or Flames,† by Age Group and Urbanization Level§ — National Vital Statistics System, United States, 2018
Authors: Merianne Spencer, Holly Hedegaard, Matthew Garnett
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

64 65 74 ≥75 Deaths per 100,000 population Urban Rural Age group (yrs)* Crude rates of deaths per 100,000 population, with 95% confidence intervals indicated with error bars.† Deaths attributed to unintentional injury from fire or flames were identified using International Classification of Diseases, Tenth Revision underlying cause-of-death codes X00-X09.§ Counties were classified using the 2013 National Center for Health Statistics urban-rural classification scheme for counties (https://www.cdc.gov/nchs/data/series/sr_02/sr02_166.pdf ).In 2018, the death rates attributed to unintentional injury from fire or flames were lowest among those aged 15-24 years and highest among those aged ≥75 years.In rural areas, death rates decreased with age from 2.0 per 100,000 for persons aged 0-4 years to 0.3 for those aged 15-24 years, and then increased with age to 5.6 for those aged ≥75 years.The pattern was similar for urban areas, where rates were 0.5 per 100,000 for persons aged 0-4 years, decreased to 0.1 for those aged 15-24 years, and then increased with age to 2.8 for those aged ≥75 years.Across all age groups, death rates were approximately two to four times higher in rural areas compared with urban areas.
THU0029 Effect of il-4 on il-1 induced intracellular ca2+ changs and inhibition of pg synthesis in articular chondrocytes
Authors: F Nishisaka, K Fukuda, S Soenn, M Saito, M Oh, T Matsushita, H Kikuchi
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Studies suggest that interleukin-1 (IL-1) is the key mediator of arthritis and we have investigated the effect of IL-1 on cartilage degradation. We demonstrated that IL-1 inhibited proteoglycan (PG) synthesis via enhanced nitric oxide (NO) synthesis by chondrocytes. We also demonstrated that IL-1 increased intracellular Ca<sup>2+</sup> ion concentration ([Ca<sup>2+</sup>]i) of chondrocytes. On the other hand, interleukin-4 (IL-4) is a T-cell derived 20 kDa glycoprotein and antagonise the cytokine mediated cartilage degradation. <h3>Objectives</h3> We examined the effect of IL-4 on IL-1-enhanced NO synthesis in parallel with intracellular Ca levels and PG synthesis. <h3>Methods</h3> Bovine articular chondrocytes were obtained. PG synthesis was measured with [35S] sulfate incorporation. NO levels were measured by use of an NO chemiluminescence analyzer. Ca<sup>2+</sup> imaging was carried out with Fura2-AM loaded chondrocyte using the digital fluorescence-imaging system. <h3>Results</h3> In the presence of IL-4, IL-1-enhanced NO release was completely abolished. IL-4 functions mainly as anti-inflammatory, as well as IL-10 and IL-13. To our knowledge, this is the first report demonstrating an inhibitory effect of IL-4 in NO release stimulated by IL-1. Alterations in [Ca<sup>2+</sup>]i provide a ubiquitous cell signalling system that mediates a variety of cellular process. IL-1 evoked an increase in the levels of [Ca<sup>2+</sup>]i, a response characterised by a steep onset and followed by a slower decline to preexisting values. IL-4 also abolished the IL-1-induced [Ca<sup>2+</sup>]i increase in the chondrocytes. We examined the effect of IL-4 on PG synthesis. Although IL-4 did not affect PG synthesis, IL-1-inhibited PG synthesis was reversed with the addition of IL-4. It is possible that IL-4 reversed the IL-1-inhibited PG synthesis through the inhibition of NO synthesis and [Ca<sup>2+</sup>]i increase. <h3>Conclusion</h3> IL-4 plays a chondroprotecting effect antagonising with IL-1-inhibited PG synthesis. <h3>References</h3> Yeh LA, Augustine AJ, Lee P, Riviere LR, Sheldon A. Interleukin-4, an inhibitor of cartilage breakdown in bovine articular cartilage explants. <i>J Rheumatol</i>. 1995;<b>22</b>(9):1740–6 Fukuda K, Kumano F, Takayama M, Saito M, Otani K, Tanaka S. Zonal differences in nitric oxide synthesis by bovine chondrocytes exposed to interleukin-1. <i>Inflamm Res</i>. 1995;<b>44</b>(10):434–7