tbuckley/cabot-search huggingface dataset:
COVID-19 prevention and treatment: A critical analysis of chloroquine and hydroxychloroquine clinical pharmacology
Authors: Nicholas J. White, James A. Watson, Richard M. Hoglund, Xin Hui S. Chan, Phaik Yeong Cheah, Joel Tarning
Journal: PLoS Medicine (2020)

points• Chloroquine and hydroxychloroquine have been used for over 60 years in the treatment of malaria, amoebic liver abscess, and several rheumatological conditions, but their clinical pharmacology is not well understood.COVID-19 is a new potential indication, although these drugs have only moderate in vitro activity against the SARS-CoV-2 virus and there is no convincing evidence at this time of significant clinical efficacy.• Chloroquine and hydroxychloroquine both have unusual pharmacokinetic properties with enormous apparent volumes of distribution (chloroquine > hydroxychloroquine) and very slow elimination from the body (terminal elimination half-lives > 1 month).• The free plasma concentrations that drive potentially serious adverse reactions (hypotension, cardiac conduction disturbances, delayed ventricular repolarization, and neurotoxicity) are determined largely by distribution processes.• Hydroxychloroquine was slightly safer than chloroquine in preclinical testing and is considered better tolerated over the long term.Both drugs are dangerous when overdosed, and parenteral administration needs careful control.• There are different salts, each with a different base equivalent.This has led to confusion and sometimes mistakes in dosing.As different salts are available in different places, malaria treatment is usually recommended in terms of base equivalent.Tablets of the two most widely available forms, chloroquine diphosphate 250 mg salt and hydroxychloroquine sulphate 200 mg salt, both contain 155 mg base.• The pro-arrhythmic and anti-arrhythmic effects of chloroquine and hydroxychloroquine have been poorly characterised, although the majority of evidence for current regimens is very reassuring.Arrhythmia risks have been inferred from QT prolongation rather than observed.• We used available pharmacokinetic information from healthy volunteers, the treatment of malaria, the chronic treatment of rheumatological conditions, and the toxicokinetics
Abstract 4783: Suppression of IL-6-induced metastatic potential by inhibition of mitochondrial fission in ovarian cancer cells
Authors: Juwon Lee, Youngjin Han, Yong Sang Song
Journal: Cancer Research (2020)

Abstract Ovarian cancer is the fifth most common cause of cancer death among females in the United States. In tumor microenvironment, inflammation has been shown to play a key role, governing malignant properties of cancer cells such as angiogenesis, chemoresistance and metastasis. Interleukin-6 (IL-6) is a pro-inflammatory cytokine, produced in response to injury, infection, and inflammation. IL-6 can regulate growth, differentiation and gene expression of cells. In our previous study, we have shown that IL-6 was found to be present at a high level in malignant ascites when compared to those in benign ascites. Similar to many other oncogenic cytokines, IL-6 has been reported to increase malignant properties of cancer such as metastasis. Mitochondria, energy plants of cells regulating metabolic homeostasis, are structurally dynamic organelles undergoing continuous fission and fusion. In metastatic cancer cells, mitochondrial fission has been shown to be more frequent, than in the primary cancer cells. A key facilitator of mitochondrial fission is a molecule called dynamin-1-related protein 1 (Drp1) and its phosphorylation status can determine the activity of the molecule. Herein, we investigated the effect of the inflammatory cytokine IL-6 on the mitochondrial dynamics and the relationship between the changes in mitochondrial dynamics and metastatic potential of ovarian cancer cells. Treatment of IL-6 on epithelial ovarian cancer (EOC) cell lines (PA-1 and SKOV3) increased the metastatic potential, such as invasion and migration, verified by trans-well invasion and wound healing assays. IL-6 did not change the Drp1 expression at the protein level but modulated the ratio of phospho-Drp1s616 (active form) and phospho-Drp1s637 (inactive form), together with increased fission of mitochondria in the EOC cells. An increase of mitochondrial fission by IL-6 was confirmed through MitoSpy staining. Inhibition of mitochondrial fission by RNAi and a pharmacologic inhibitor attenuated metastatic potential of the EOC cells. Altogether, our study strongly suggests the role of mitochondrial fission in the metastatic potential of EOC cells induced by IL-6. The inhibition of mitochondrial fission could be a potential therapeutic approach suppressing the metastasis of EOC. Citation Format: Juwon Lee, Youngjin Han, Yong Sang Song. Suppression of IL-6-induced metastatic potential by inhibition of mitochondrial fission in ovarian cancer cells [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 4783.
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Siltuximab (Anti IL-6 Monoclonal Antibody) in Patients with High-Risk Smoldering Multiple Myeloma
Authors: Timothy Brighton, Simon J. Harrison, David Ghez, Brendan M. Weiss, Andreas Kirsch, Hila Magen, Mercedes Gironella, Albert Oriol, Matthew Streetly, Xiang Qin, Rajesh Bandekar, Peter Hu, Ming Qi, Sepideh Nemat, Hartmut Goldschmidt
Journal: Blood (2017)
Abstract 4123: ORIC-101 overcomes glucocorticoid receptor-mediated chemoresistance in pancreatic cancer models
Authors: Jessica D. Sun, Haiying Zhou, Wayne Kong, Natalie Yuen, Frank L. Duong, Shravani Barkund, Aleksandr Pankov, Dan McWeeney, Qiuping Ye, Omar Kabbarah, Lori S. Friedman, Anneleen Daemen, Melissa Junttila
Journal: Cancer Research (2020)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and one of the most lethal cancers, with a 5-year survival rate of 8%. Chemotherapy remains the main treatment option for patients with advanced and metastatic tumors. However, intrinsic resistance to chemotherapeutics and lack of effective targeted therapies are major factors contributing to the dismal prognosis. Activation of glucocorticoid receptor (GR) signaling confers resistance to chemotherapy in solid tumors, making GR antagonism an attractive combination treatment strategy to overcome chemotherapeutic resistance. ORIC-101 is a novel selective GR antagonist under clinical evaluation in combination with anticancer therapies. We previously reported that ORIC-101 can sensitize triple-negative breast cancer cells to chemotherapy by reversing multiple GR-modulated pathways. Here, we investigate the effects of ORIC-101 in preclinical models of PDAC. Employing in vitro functional assays and gene expression analysis, ORIC-101 exhibited chemo-potentiation in a panel of PDAC cell lines. Biomarker analysis of transcription activity following ORIC-101 treatment in vitro confirmed pharmacodynamic (PD) modulation of core GR target genes, indicative of suppressed GR signaling. Extending these findings in vivo across several PDAC xenograft models (SW1990, BxPC3, and HPAC) revealed that ORIC-101 blocks GR transcriptional activity induced by dexamethasone in a dose-dependent manner. The PD modulation observed in vivo correlated with ORIC-101 plasma exposure. Consistent with ORIC-101's ability to suppress GR activity, in vivo efficacy studies in combination with paclitaxel significantly inhibited PDAC tumor growth compared to the paclitaxel control group. These results in PDAC preclinical models support the clinical development of ORIC-101 in overcoming GR-driven chemoresistance. A phase 1b study of ORIC-101 in combination with nab-paclitaxel in patients with advanced or metastatic solid tumors is ongoing (NCT03928314). Citation Format: Jessica D. Sun, Haiying Zhou, Wayne Kong, Natalie Yuen, Frank L. Duong, Shravani Barkund, Aleksandr Pankov, Dan McWeeney, Qiuping Ye, Omar Kabbarah, Lori S. Friedman, Anneleen Daemen, Melissa Junttila. ORIC-101 overcomes glucocorticoid receptor-mediated chemoresistance in pancreatic cancer models [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 4123.
Abstract 4436: Combination therapy with an antibody specific for transferrin receptor 1 (ch128.1/IgG1) and bortezomib or lenalidomide results in increased survival in an <i>in vivo</i> model of human multiple myeloma
Authors: Pierre V. Candelaria, Miguel Nava, Otoniel Martinez-Maza, Tracy R. Daniels-Wells, Manuel L. Penichet
Journal: Cancer Research (2020)

Abstract Multiple myeloma (MM) is a B-cell proliferative disorder of monoclonal malignant plasma cells. It is the second most common hematologic malignancy in the United States, after non-Hodgkin lymphoma (NHL). Clinical manifestations of MM include osteolytic bone lesions, hypercalcemia, renal failure, anemia, recurrent infections, and neuropathy. Standard treatments for MM include the proteasome inhibitor bortezomib, as well as lenalidomide, a thalidomide analog with immunomodulatory and antiangiogenic properties. Although the use of these two agents in combination with other therapies have significantly improved MM survival, the disease remains incurable. We previously developed a mouse/human chimeric antibody (ch128.1/IgG1) specific for human transferrin receptor 1 (TfR1). TfR1, also known as CD71, is a meaningful target for antibody-based cancer therapy, given its high expression on malignant cells and relevant role in cancer cell pathology. We have reported that treatment of SCID-Beige mice bearing disseminated human KMS-11, MM.1S, or MM.1R myeloma tumors with ch128.1/IgG1 results in significant antitumor activity in early and late disease stages. The mechanism of antitumor activity is Fc-mediated in which macrophages are considered to play a relevant role. Since combining multiple treatments with differing mechanisms of action is an effective antitumor strategy, and given the relevance of bortezomib and lenalidomide in MM therapy, we decided to explore, for the first time, the combination of these two agents with ch128.1/IgG1. We found that treatment with a single dose of ch128.1/IgG1, or multiple doses of bortezomib or lenalidomide used as single agents, results in significant antitumor activity in SCID-Beige mice bearing late stage disseminated human MM.1S tumors. However, this antitumor activity is superior when ch128.1/IgG1 was combined with bortezomib or lenalidomide, showing significantly longer survival compared to each therapy used alone. These results suggest that the addition of a ch128.1/IgG1 therapy arm in a combinatorial treatment regimen involving bortezomib and/or lenalidomide is a promising strategy against human B-cell malignancies such as MM. Citation Format: Pierre V. Candelaria, Miguel Nava, Otoniel Martinez-Maza, Tracy R. Daniels-Wells, Manuel L. Penichet. Combination therapy with an antibody specific for transferrin receptor 1 (ch128.1/IgG1) and bortezomib or lenalidomide results in increased survival in an in vivo model of human multiple myeloma [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 4436.
Tailored elasticity combined with biomimetic surface promotes nanoparticle transcytosis to overcome mucosal epithelial barrier
Authors: Yaxian Zheng, Liyun Xing, Liqiang Chen, Rui Zhou, Jiawei Wu, Xi Zhu, Lian Li, Yucheng Xiang, Ruinan Wu, Ling Zhang, Yuan Huang
Journal: Biomaterials (2020)
Flags of hope and gratitude
Authors: Alison Shepherd
Journal: BMJ (2020)

To pay tribute to people who have died from covid-19 and to honour the sacrifice of health workers in the NHS and across Europe, British artist Luke Jerram created the temporary installation In Memoriam.Shown here in Antwerp, the display has also been seen in London and will tour the UK and Europe in the coming months.In Memoriam, which is created from bed sheets, is intended to be an evocative symbol of local, national, and international solidarity and to offer a space for peace and contemplation.At the unveiling of his creation Jerram said, "With so much tragic loss over recent months I'm hoping the artwork may be of value to those experiencing trauma or bereavement.
Abstract IA26: Combined PARP and immune checkpoint inhibition in ovarian cancer
Authors: Panagiotis A. Konstantinopoulos
Journal: Clinical Cancer Research (2020)

Abstract Ovarian cancer (OC) is one of the few malignancies in which immunotherapy with immune checkpoint inhibitors exhibits only modest activity and currently has no FDA-approved indication. Therefore, the development of strategies to improve the efficacy of immune checkpoint blockade is a high priority in this disease. Recent studies in OC models have demonstrated that PARP inhibitors (PARPi), besides their direct cytotoxic effects, exhibit antitumor immunity that occurs in a STING-dependent manner and is augmented by immune checkpoint blockade. Based on these studies, combined PARP and immune checkpoint inhibition represents an active area of clinical investigation in OC. The goal of this presentation is to outline the preclinical data behind combined PARP and immune checkpoint inhibition in OC, highlight preliminary results as well as ongoing clinical trials of PARPi/immune checkpoint inhibitor combinations in both first-line and recurrent disease, and discuss emerging biomarkers of response. Citation Format: Panagiotis A. Konstantinopoulos. Combined PARP and immune checkpoint inhibition in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr IA26.
Prospective of extracellular matrix and drug correlations in disease management
Authors: Varish Ahmad
Journal: Asian Journal of Pharmaceutical Sciences (2020)

The extracellular matrix (ECM) comprises of many structural molecules that constitute the extracellular environment. ECM molecules are characterized by specific features like diversity, complexity and signaling, which are also results of improvement or development of disease mediated by some physiological changes. Several drugs have also been used to manage diseases and they have been reported to modulate ECM assembly, including physiological changes, beyond their primary targets and ECM metabolism. This review highlights the alteration of ECM environment for diseases and effect of different classes of drugs like nonsteroidal anti-inflammatory drugs, immune suppressant drug, steroids on ECM or its components. Thus, it is summarized from previously conducted researches that diseases can be managed by targeting specific components of ECM which are involved in the pathophysiology of diseases. Moreover, the drug delivery focused on targeting the ECM components also has the potential for the discovery of targeted and site specific release of drugs. Therefore, ECM or its components could be future targets for the development of new drugs for controlling various disease conditions including neurodegenerative diseases and cancers.
Abstract 3125: Disturbance of <i>CALR</i> mutation profile in MPNs by NGS and Real-Time PCR
Authors: Cagla Rencuzogullari, Sevcan Tug Bozdogan, Birol Guvenc, Atil Bisgin
Journal: Cancer Research (2020)

Abstract Myeloproliferative neoplasms (MPNs) are clonal disorders which are driven by one of three driver mutations that cause activation of JAK/STAT signaling. MPNs have classically been divided into three main conditions; essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). CALR mutations act as a driver mutation early in the pathogenesis of these disorders and the mutations in exon 9 of CALR gene occur in approximately 30% of patients with MPNs. Thus, in this study CALR mutation profiling had been performed by real time PCR then the next generation sequencing (NGS) to identify the differential genetic profile of Turkish population in MPNs. Genomic DNA was isolated from peripheral blood samples. A real time PCR test was used to detect c.1092_1143del variant, c.1154_1155insTTGTC variant and other 34 minor variants (Ipsogen CALR RGQ PCR Kit). Then the minor variants and possible other variants were identified via NGS (GeneReader NGS System). CALR mutations were detected in 34/128 of the patients. Among the 34 patients with CALR mutations, 15 of them had at least one mutation and 19 had at two mutations. 22 of 34 patients who were classified as in minor variants by real time PCR, were then studied via NGS to specify the mutations. The detected sub-variants are shown at Table 1. Interestingly, five mutations that are unique and not included in the real time PCR were identified by sequencing. Identification of the driver mutations are important for disease diagnosis and progress. Though, our study shows the disturbance of the mutations in Turkey together with the redundance of real time PCR and NGS data. Identified CALR mutations by NGSVariant DetectedTotal Number of Patientsc.1099_1150delCTTAAGG10c.1142_1144delAGG7c.1100_1101delTTinsAC1c.1154_1155insTTGTC6c.1124A&amp;gt;G1c.1103_1136del AGGAGGA1 Citation Format: Cagla Rencuzogullari, Sevcan Tug Bozdogan, Birol Guvenc, Atil Bisgin. Disturbance of CALR mutation profile in MPNs by NGS and Real-Time PCR [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 3125.
Early Rhythm-Control Therapy in Patients with Atrial Fibrillation
Authors: Paulus Kirchhof, A. John Camm, Andreas Goette, Axel Brandes, Lars Eckardt, Arif Elvan, Thomas Fetsch, Isabelle C. van Gelder, Doreen Haase, Laurent M. Haegeli, Frank Hamann, Hein Heidbüchel, Gerhard Hindricks, Josef Kautzner, Karl-Heinz Kuck, Lluis Mont, G. Andre Ng, Jerzy Rekosz, Norbert Schoen, Ulrich Schotten, Anna Suling, Jens Taggeselle, Sakis Themistoclakis, Eik Vettorazzi, Panos Vardas, Karl Wegscheider, Stephan Willems, Harry J.G.M. Crijns, Günter Breithardt
Journal: New England Journal of Medicine (2020)

Despite improvements in the management of atrial fibrillation, patients with this condition remain at increased risk for cardiovascular complications. It is unclear whether early rhythm-control therapy can reduce this risk.
Abstract 11441: Inhibition of Prolyl Hydroxylase Domain-Containing Protein Promoted Neovascularization and Ameliorated Cardiac Dysfunction in Experimental Autoimmune Myocarditis in Mice
Authors: Yuko Tada, Masahito Ogawa, Jun-ichi Suzuki, Takashi Dan, Toshio Miyata, Mitsuaki Isobe, Issei Komuro
Journal: Circulation (2013)

Introduction: Mechanisms of cardiac dysfunction in myocarditis have not been fully elucidated.Though it remains controversial whether angiogenesis is beneficial or harmful in inflammatory disease, ...
Abstract 2730: BCL6 promotes ovarian cancer metastasis
Authors: Duc Ngoc Hong Nguyen, David F. Walker, David A. Frank, Sarah R. Walker
Journal: Cancer Research (2020)

Abstract Ovarian cancer remains a deadly disease with the five-year survival rate for ovarian cancer patients at about 50%. Ovarian spheroids, clusters of 3D growing cells, are thought to promote ovarian cancer metastasis and serve as a reserve of cancer cells that are not responsive to chemotherapy. Understanding genes associated with spheroid growth and metastasis may identify pathways to target for ovarian cancer therapy. We have found that the transcriptional modulator BCL6 is active in ovarian spheroids. BCL6 is a highly-conserved oncogene originally found to drive malignant transformation in B-cell lymphoma. Although BCL6 is thought to be a transcriptional repressor, we and others have found that it also upregulates genes. Little is known about the role of BCL6 in ovarian cancer. Using the Cancer Genome Atlas (TCGA) data and CBioPortal, we found that BCL6 is amplified in about 20% of high-grade serous ovarian cancer patients. In addition, analysis of nuclear extracts from a number of ovarian cancer cell lines demonstrated that BCL6 is overexpressed in many ovarian cancer cell lines. To assess transcriptional activity, we used a BCL6-responsive reporter and we found that BCL6 was active in most of these cell lines. Having demonstrated that BCL6 is active in ovarian cancer cells, we wanted to determine if BCL6 affected the viability of these cells. Therefore, we transfected ovarian cancer cells with siRNA to BCL6, measured their viability, and found that BCL6 is important for ovarian cancer cell survival. Recognizing that spheroids occur in advanced ovarian cancer, we analyzed the effects of BCL6 in 3D formation using micropatterned plates and discovered that BCL6 is also important for 3D spheroid formation. A major problem in advanced ovarian cancer is metastasis; therefore, we wanted to determine if BCL6 plays a role in promoting metastasis. We overexpressed BCL6 or downregulated BCL6 with siRNA and performed a mesothelial clearance assay to assess the early steps in ovarian cancer metastasis. While overexpressing BCL6 enhanced mesothelial clearance by the ovarian spheroids, reducing BCL6 expression also reduced mesothelial clearance. This suggested that BCL6 promotes ovarian cancer metastasis. We are currently in the process of identifying BCL6 target genes that are involved in metastasis. Taken together, our data suggests that BCL6 is an important transcriptional modulator in ovarian cancer and that targeting BCL6 in the future may be a useful strategy to treat metastatic ovarian cancer. Citation Format: Duc Ngoc Hong Nguyen, David F. Walker, David A. Frank, Sarah R. Walker. BCL6 promotes ovarian cancer metastasis [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 2730.
Antigen processing and presentation in cancer immunotherapy
Authors: Maxwell Y Lee, Jun W Jeon, Cem Sievers, Clint T Allen
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Knowledge about and identification of T cell tumor antigens may inform the development of T cell receptor-engineered adoptive cell transfer or personalized cancer vaccine immunotherapy. Here, we review antigen processing and presentation and discuss limitations in tumor antigen prediction approaches. Methods Original articles covering antigen processing and presentation, epitope discovery, and in silico T cell epitope prediction were reviewed. Results Natural processing and presentation of antigens is a complex process that involves proteasomal proteolysis of parental proteins, transportation of digested peptides into the endoplasmic reticulum, loading of peptides onto major histocompatibility complex (MHC) class I molecules, and shuttling of peptide:MHC complexes to the cell surface. A number of T cell tumor antigens have been experimentally validated in patients with cancer. Assessment of predicted MHC class I binding and total score for these validated T cell antigens demonstrated a wide range of values, with nearly one-third of validated antigens carrying an IC 50 of greater than 500 nM. Conclusions Antigen processing and presentation is a complex, multistep process. In silico epitope prediction techniques can be a useful tool, but comprehensive experimental testing and validation on a patient-by-patient basis may be required to reliably identify T cell tumor antigens.
Abstract 12925: The Role of HDL Cholesterol in Patients With Atherosclerotic Cardiovascular Disease Under Statin Treatment
Authors: Li Yi-Heng, Wei-Hsian Yin, Wei-Kung Tseng, Fang-Ju Lin, Yen-Wen Wu, I-Chang Hsieh, Tsung-Hsien Lin, Huey-Herng Sheu, Hung-I Yeh, Jaw-Wen Chen, Chau-Chung Wu
Journal: Circulation (2018)

Background: Low HDL-C is a common lipid phenotype in Asia. Although low HDL-C is a risk factor of atherosclerotic cardiovascular disease (ASCVD) in general population, it is controversial whether t...