tbuckley/cabot-search huggingface dataset:
Temozolomide Sensitizes MGMT-Deficient Tumor Cells to ATR Inhibitors
Authors: Christopher B. Jackson, Seth I. Noorbakhsh, Ranjini K. Sundaram, Aravind N. Kalathil, Sachita Ganesa, Lanqi Jia, Hank Breslin, Danielle M. Burgenske, Oren Gilad, Jann N. Sarkaria, Ranjit S. Bindra
Journal: Cancer Research (2019)

Abstract O6-methylguanine-DNA methyltransferase (MGMT) is an enzyme that removes alkyl groups at the O6-position of guanine in DNA. MGMT expression is reduced or absent in many tumor types derived from a diverse range of tissues, most notably in glioma. Low MGMT expression confers significant sensitivity to DNA alkylating agents such as temozolomide, providing a natural therapeutic index over normal tissue. In this study, we sought to identify novel approaches that could maximally exploit the therapeutic index between tumor cells and normal tissues based on MGMT expression, as a means to enhance selective tumor cell killing. Temozolomide, unlike other alkylators, activated the ataxia telangiectasia and Rad3–related (ATR)–checkpoint kinase 1 (Chk1) axis in a manner that was highly dependent on MGMT status. Temozolomide induced growth delay, DNA double-strand breaks, and G2–M cell-cycle arrest, which led to ATR-dependent phosphorylation of Chk1; this effect was dependent on reduced MGMT expression. Treatment of MGMT-deficient cells with temozolomide increased sensitivity to ATR inhibitors both in vitro and in vivo across numerous tumor cell types. Taken together, this study reveals a novel approach for selectively targeting MGMT-deficient cells with ATR inhibitors and temozolomide. As ATR inhibitors are currently being tested in clinical trials, and temozolomide is a commonly used chemotherapeutic, this approach is clinically actionable. Furthermore, this interaction potently exploits a DNA-repair defect found in many cancers. Significance: Monofunctional alkylating agents sensitize MGMT-deficient tumor cells to ATR inhibitors.
Abstract 4414: Inhibition of CDK2 overcomes primary and acquired resistance to CDK4/6 inhibitors
Authors: Claire R. Hall, John E. Bisi, Jay C. Strum
Journal: Cancer Research (2019)

Abstract The cyclin dependent kinase (CDK) family of proteins is associated with cell cycle progression and transcriptional regulation. Abnormalities in the cell cycle, including modifications to the function of CDKs, their regulators (cyclins), or their natural inhibitors, are frequently associated with the formation and growth of tumors. While recent advances in treatments using CDK inhibition have focused on targeting CDK4/6, with regulatory approvals of palbociclib, ribociclib, and abemaciclib, these compounds only target tumors sensitive to CDK4/6 inhibitors. We are focused on developing a novel, potent, and selective inhibitor of CDK2 to treat patients whose tumors are insensitive to CDK4/6 inhibition, either by primary resistance or acquired resistance by prior treatment with a CDK4/6 inhibitor. CDK2, a serine-threonine kinase, is a member of the CDK family that binds two regulatory cyclins, E and A. CDK2 when complexed to cyclin E is involved in the G1 to S-phase transition. However, when CDK2 is complexed with cyclin A, the cell will progress through the S to M-phase. Overexpression of cyclin E has been described in a subset of triple negative breast cancer (TNBC), tumors with acquired resistance to CDK4/6 inhibition such as ER+ Her2- breast cancer, as well as ovarian, lung, and other tumor types. We have utilized medicinal chemistry and structure activity relationship (SAR) modeling, starting from our proprietary scaffold, to generate a series of small molecule CDK2 inhibitors with drug-like properties. These compounds were initially screened for potency and selectivity using an array of biochemical and in-vitro assays. We identified multiple small molecule inhibitors with sub-nanomolar biochemical IC50s for CDK2 when complexed with either cyclin E or cyclin A and evaluated their activity in normal cell lines, a breast cancer cell line resistant to CDK4/6 inhibition, TNBC, and other tumor cell lines. We examined cell cycle analysis, EdU incorporation, cell proliferation, caspase activation, and western blot analysis of genes associated with the downstream targets of CDK2. These CDK2 inhibitors potently arrest cells in the G2/M-phase and inhibit proliferation in a manner dependent on time and dose, with a corresponding decrease in phosphorylated Rb. Our lead compound was also evaluated in mouse xenograft studies for efficacy, investigating tumor growth inhibition in a model with cyclin E overexpression and a model with an acquired resistance to CDK4/6 inhibition. These potent CDK2 inhibitors demonstrate a potentially promising method of treating tumors with primary or acquired resistance to CDK4/6 inhibitors. Citation Format: Claire R. Hall, John E. Bisi, Jay C. Strum. Inhibition of CDK2 overcomes primary and acquired resistance to CDK4/6 inhibitors [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 4414.
The Purinergic System as a Pharmacological Target for the Treatment of Immune-Mediated Inflammatory Diseases
Authors: Luca Antonioli, Corrado Blandizzi, Pál Pacher, György Haskó
Journal: Pharmacological Reviews (2019)

Immune-mediated inflammatory diseases (IMIDs) encompass a wide range of seemingly unrelated conditions, such as multiple sclerosis, rheumatoid arthritis, psoriasis, inflammatory bowel diseases, asthma, chronic obstructive pulmonary disease, and systemic lupus erythematosus. Despite differing etiologies, these diseases share common inflammatory pathways, which lead to damage in primary target organs and frequently to a plethora of systemic effects as well. The purinergic signaling complex comprising extracellular nucleotides and nucleosides and their receptors, the P2 and P1 purinergic receptors, respectively, as well as catabolic enzymes and nucleoside transporters is a major regulatory system in the body. The purinergic signaling complex can regulate the development and course of IMIDs. Here we provide a comprehensive review on the role of purinergic signaling in controlling immunity, inflammation, and organ function in IMIDs. In addition, we discuss the possible therapeutic applications of drugs acting on purinergic pathways, which have been entering clinical development, to manage patients suffering from IMIDs.
Abstract 10290: αB-crystallin Knockout Alleviate Tsc1 Deletion Induced Cardiomyopathy
Authors: Kemei Liu, Lianmei Wang, Yi Chen, Hongbing Zhang, Hongbing Yan
Journal: Circulation (2015)

Introduction: Mechanistic target of rapamycin (mTOR) signaling is important in many diseases, such as cancer, metabolic diseases and cardiac diseases. Inactive mutation of either TSC1 or TSC2 leads to activation of mTOR. We recently reported that cardiomyocyte-specific TSC1 deficiency induced cardiomyopathy and impaired cardiac function in mice. A ubiquitous small heat-shock protein (sHSP), αB-crystallin as a downstream target protein of mTOR signaling pathway is one of the central controllers of cell growth, proliferation and cancer development. Hypothesis: Hyper-activation of mTOR induces cardiac hypertrophy through upregulation of αB-crystallin and inhibition of αB-crystallin may abolish mTOR activation-induced cardiomyopathy. Methods: Cardiomyocyte-specific Tsc1 knockout ( Tsc1 -cKO) mice were mated with αB-crystallin knockout ( αB -KO) mice to create Tsc1 and αB-crystallin double knockout (dKO) mice. Tamoxifen(TMX) was used to induce cardiomyocyte-specific Tsc1 knockout. Analysis of morphology, cardiac function and fetal gene expression were performed in different genotypes of mice. Results: Tsc1 -cKO mice showed higher heart weight/body weight (HW/BW) ratio, thinner ventricular walls and larger cardiac chambers, nevertheless all of these changes significantly alleviated in the dKO mice(Figure A and B). Cardiac function detected by echocardiography impaired in the Tsc1 -cKO mice, while dKO mice showed no different with the control littermates (Figure C). The mRNA expression of fetal genes including α-skeletal actin (α-SKA), atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and β-myosin heavy chain (β-MHC) elevated significantly in the Tsc1 -cKO mice, however, the expression of these genes in the dKO mice was the same as the control mice(Figure D). Conclusions: The present study indicates that αB-crystallin plays a critical role in TSC1 deficiency induced cardiomyopathy.
Abstract 2167: Antibody glycoengineering for drug delivery applications
Authors: Drishti Navin Sehgal, Stephen Kalscheuer, Jayanth Panyam
Journal: Cancer Research (2019)

Abstract Antibody-drug conjugates (ADC) hold considerable promise as anticancer agents. A critical determinant of the effectiveness of ADCs is the chemistry that is used to conjugate the payload. Currently used approaches include primarily conjugation to either side-chain amine or carboxylic acid groups or conjugation to thiols. Because these reactions are not site specific and not easily controlled, these chemistries can result in reduced affinity for the target antigen. Further, these conjugation reactions lack selectivity and can result in heterogeneous mixtures of products that differ in the sites and stoichiometry of modification. We investigated a glycoengineering strategy that enables the introduction of artificial azide groups in the antibody without affecting their antigen affinity. This is based on the observation that glycosyltransferases can incorporate non-natural sugars (e.g., azido mannose) at different sites on an IgG molecule. The azide groups in these artificial sugars are then available to react with alkynes through copper-catalyzed ‘click’ chemistry or with strained alkynes such as dibenzyl cyclooctyne (DBCO) allowing for biorthogonal, copper-free ‘click’ chemistry. Because the sugars are added reproducibly and at a site that does not affect antigen binding, the glycoengineering technology would overcome problems associated with traditional conjugation strategies. Using this approach, azide groups were introduced in anti-CD133 and anti-perlecan antibodies. Further, the azide groups were available to react with various DBCO conjugates including fluorophores, drug molecules and nanoparticles. Importantly, the addition of artificial sugar and subsequent azide-alkyne reaction did not affect the affinity of the antibody for the target antigen. Conjugation of a cytotoxin to the antibody resulted in enhanced cell kill in vitro and efficacy in vivo. We plan on further improving the effectiveness of this approach by investigating cleavable linker technology in combination with the glycoengineering strategy. We expect that this strategy will prove to be a unique platform technology that will have a significant impact on antibody-based therapeutics. Citation Format: Drishti Navin Sehgal, Stephen Kalscheuer, Jayanth Panyam. Antibody glycoengineering for drug delivery applications [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 2167.
Abstract 17837: Fibronectin is Sufficient for Robust Matrix Sandwich-based Cardiac Differentiation of Human Pluripotent Stem Cells in Fully Defined Conditions
Authors: Jianhua Zhang, Amanda M Herman, Gisela F Wilson, Matthew R Barron, Timothy J Kamp
Journal: Circulation (2012)

Cardiomyocytes (CMs) differentiated from human pluripotent stem cells (PSCs) are increasingly being used for cardiovascular research including disease modeling and hold promise for clinical applica...
Abstract 16145: PDGF Signaling in Cardiac-Resident Mesenchymal Stem Cells Promotes Their Myofibroblastic Differentiation and Worsens Post-Infarction Cardiac Remodeling in Chronic Heart Failure
Authors: Tariq Hamid, Yuanyuan Xu, Mohamed Ameen Ismahil, Shyam S Bansal, Sumanth D Prabhu
Journal: Circulation (2018)

Failing hearts exhibit chronic inflammation, progressive fibrosis, and persistent activation of pro-fibrotic myofibroblasts. Along with fibroblasts, tissue mesenchymal stem cells (MSCs) also differ...
Abstract 5052: Immune profiles in the San Francisco Adult Glioma Study using Immunomethylomics
Authors: John K. Wiencke, Annette Molinaro, Warrier Gayathri, Jennifer Clarke, Jennie Taylor, Devin Koestler, Joe Wiemels, Helen Hanson, Lee Sean, Terri Rice, Lucie McCoy, Lucas Salas, Wrensch Margaret, Brock Christensen, Karl T. Kelsey
Journal: Cancer Research (2019)

Abstract Glioma patients demonstrate abnormalities in peripheral blood leukocytes that have been associated with survival time. Here we assessed immune cell profiles in archival blood samples obtained 5-25 years ago using a novel epigenetic approach called immunomethylomics. We first validated the approach to measure the proportions of CD4 T, CD8 T cells, B cells, NK cells, neutrophils, and monocytes in archival blood using the new 850,000 feature EPIC Illumina methylation bead array. The immunomethylomic assay was shown to match the performance of multiparametric flow cytometry and thus is a highly accurate method for immune profiling. We next measured cell profiles in blood from 312 molecularly defined AGS subjects. In this cohort we enriched for patients with triple negative tumor subtypes (IDH wildtype, 1p19q negative, TERT non-mutant). Elevations in the neutrophil lymphocyte ratio (NLR) significantly increased with grade, whereas the proportions of T and B cells decreased with increasing grade. Using an established cut point of &amp;gt; 4.0 for the NLR revealed that this immune parameter was associated with shorter survival times in glioblastoma (median overall survival (mOS) 12.6 vs. 16.9 months) and non-glioblastoma (mOS 16.7 vs. 36 months) patients. Ongoing analyses of the cohort will be presented to evaluate the effects of age, gender, surgery, chemoradiation and tumor grade on the survival results. Because DNA based immune cell profiles do not require intact cells nor preserved proteins, they provide a powerful tool to glean potentially important immunologic information from historic stored samples that would otherwise be useless using current cytometry-based approaches. Citation Format: John K. Wiencke, Annette Molinaro, Warrier Gayathri, Jennifer Clarke, Jennie Taylor, Devin Koestler, Joe Wiemels, Helen Hanson, Lee Sean, Terri Rice, Lucie McCoy, Lucas Salas, Wrensch Margaret, Brock Christensen, Karl T. Kelsey. Immune profiles in the San Francisco Adult Glioma Study using Immunomethylomics [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 5052.
Abstract 75: Anti-tumor activity of a novel selenonucleoside via targeting Skp2 degradation in paclitaxel-resistant prostate cancer
Authors: Woong Sub Byun, Minkyung Jin, Jinha Yu, Won Kyung Kim, Lak Shin Jeong, Sang Kook Lee
Journal: Cancer Research (2019)

Abstract Prostate cancer (PC) is the most common disease in men over age 50, and its prevalence rate has been gradually increasing since 1980. Taxane-derived anticancer agents are the primary agents used to treat metastatic prostate cancer patients; however, the side effects and acquired drug resistance limit the success of these therapies. Because there is no specific treatment for paclitaxel-resistant prostate cancer, it is necessary to develop new targets and therapeutic strategies to overcome the acquired resistance. In this study, the antitumor activity of a novel selenonucleoside (4′-selenofuranosyl-2,6-dichloropurine, LJ-2618), a third-generation nucleoside, and its plausible mechanisms of action in paclitaxel-resistant prostate cancer (PC-3-Pa) cells were investigated. The established PC-3-Pa cells exhibited over 100-fold resistance against paclitaxel compared to the paclitaxel-sensitive PC-3 cells. LJ-2618, however, effectively inhibited the proliferation of both cell lines with similar IC50values in vitro. In PC-3-Pa cells, the activated PI3K/Akt signaling pathway was suppressed by LJ-2618 treatment. In addition, Skp2 was found to be over-expressed in paclitaxel-resistant cells, and the transfection of Skp2 siRNA recovered the sensitivity of paclitaxel in PC-3-Pa cells. Furthermore, LJ-2618 significantly down-regulated Skp2 expression in PC-3-Pa cells by promoting degradation and inducing destabilization of Skp2, which triggers G2/M cell cycle arrest. In a xenograft mouse model implanted with PC-3-Pa cells, LJ-2618 (3 or 10 mg/kg) effectively inhibited tumor growth with the enhancement of Skp2 degradation and induction of p27 expression in tumor tissues. These findings suggest that LJ-2618 may have a potential for overcoming paclitaxel resistance via promoting Skp2 degradation and stabilizing p27 expression in PC-3-Pa cells. Therefore, the novel selenonucleoside LJ-2618 may lead to the development of a new treatment strategy for patients with paclitaxel-resistant, castration-resistant prostate cancer. This study was supported by a National Research Foundation of Korea (NRF) Grant funded by the Korean Government (NRF-2016M3A9B6903499). Citation Format: Woong Sub Byun, Minkyung Jin, Jinha Yu, Won Kyung Kim, Lak Shin Jeong, Sang Kook Lee. Anti-tumor activity of a novel selenonucleoside via targeting Skp2 degradation in paclitaxel-resistant prostate cancer [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 75.
Plasma Thrombospondin 1 Is Increased and Associated with Markers of Vasculopathy In Sickle Cell Disease
Authors: Enrico M Novelli, Gregory J. Kato, Margaret V. Ragni, Mariana E Hildesheim, Suchitra Barge, Michael P Meyer, Andrea Cortese Hassett, Mark Gladwin, Jeffrey Isenberg
Journal: Blood (2010)
Focusing a lens on refugee families to address layers of avoidance
Authors: Mina Fazel
Journal: The Lancet Public Health (2019)

Post-traumatic stress disorder (PTSD) can affect individuals throughout their lifecourse. This condition also affects family membersw, with potential long-term effects on the health and psychosocial wellbeing of individuals in subsequent generations.1 Whether and how trauma is transmitted from one generation to the next and the effect it might have are important questions, which disciplines, including those exploring neural and biological processes, family systems, epidemiology, anthropology, sociology, and psychology, have tried to elucidate.
Abstract 9: Effect of C8-side chain on the cytotoxicity and NF-kB inhibitory capacity of pyrrolobenzodiazepines
Authors: David B. Corcoran, Thomas Lewis, Kazi S. Nahar, Christopher Fegan, Chris Pepper, David E. Thurston, Khondaker Miraz Rahman
Journal: Cancer Research (2019)

Abstract Pyrrolobenzodiazepines (PBDs) have long been of interest in chemotherapeutic research as potential clinical agents. Recently, the conjugation of non-covalently interactive moieties to the C8-position of the PBD structure via a linker of variable length has emerged as a strategy to enhance the DNA sequence specificity of PBDs. This has led to the development of highly cytotoxic agents, which also act as inhibitors of transcription factors such as NF-κB. For example, GWL-78, a C8-linked PBD-Py-Py (Py = pyrrole) conjugate, has been shown to block interaction of the transcription factor NF-Y, and KMR-28-39, a C8-linked PBD-MPB conjugate with an affinity for GC-rich sequences of DNA inhibits activity of the transcription factor NF-κB. As up-regulation of NF-κB has been implicated in the development and progression of several cancer types, this may contribute to the high potency observed for PBD monomers such as KMR-28-39 (i.e., femtomolar IC50 values in some cell lines). In this study, the relationship between the cytotoxicity and transcription factor inhibition of a series of C8-linked PBD hybrid structures was explored. The systematic shortening of the non-covalent element of a C8-linked PBD conjugate, DC-1-92 led to the synthesis of a 19-member library of novel C8-PBD monomers. The critical elements of DC-1-92, which were required to render the molecule cytotoxic, were elucidated by an annexin V assay. The effects of shortening the non-covalent element of the molecule on transcription factor inhibitory capacity were also explored through an ELISA-based measurement of nuclear NF-κB subunit DNA binding following exposure of JJN3 cells to the synthesised molecules. While shortening the non-covalently interactive component of DC-1-92 had less of an effect than expected upon cytotoxicity, the shortening notably reduced the NF-κB inhibitory activity of the shortened analogues. DC-1-92, containing the longest non-covalently interactive C8-element, displayed the most effective inhibition of NF-κB, and effects upon nuclear p65, and RelB levels appeared to diminish in tandem with the shortening of the length of the C8 side chain. These data suggest that the length of the C8 side chain of PBD hybrid structures impacts upon the DNA binding of both canonical and non-canonical NF-κB subunits but this is independent of their cytotoxic effects. Citation Format: David B. Corcoran, Thomas Lewis, Kazi S. Nahar, Christopher Fegan, Chris Pepper, David E. Thurston, Khondaker Miraz Rahman. Effect of C8-side chain on the cytotoxicity and NF-kB inhibitory capacity of pyrrolobenzodiazepines [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 9.
Abstract 9121: Intra-endoplasmic Reticulum Ca2+ Flow Recharges Preferentially to Subcompartments of ER at Caveolin-rich Cell Edges in Endothelial Cells
Authors: Masashi Isshiki, Toshiro Fujita
Journal: Circulation (2011)

Subcellular distribution of caveolin-1, a marker protein of caveolae, is polarized especially in migrating or subconfluent endothelial cells ( Fig. 1 ). In response to ATP, IP 3 production and Ca 2+ release originated at caveolin-1-rich cell edges (CRCE) and then propagated as spatiotemporally organized Ca 2+ waves ( Fig. 2 ). Here in this study, we investigated subcellular Ca 2+ dynamics in the endoplasmic reticulum (ER) Ca 2+ stores by using confocal microscopy and an ER-targeted version of cameleon (D1ER), a GFP-based Ca 2+ -sensing protein. As expected, FRET imaging using an ER-targeted Ca 2+ sensor revealed that the ATP-mediated decrease in local intra-ER Ca 2+ concentration ([Ca 2+ ] er ) at CRCE was more rapid and larger than in other subdomains ( Figs. 2, 3 ). Interestingly, the decreased [Ca 2+ ] er at such CRCE more rapidly returned to the baseline in the presence of normal extracellular Ca 2+ . Even in the absence of extracellular Ca 2+ , when maximal ATP stimulation continued to decrease global [Ca 2+ ] er , [Ca 2+ ] er at CRCE exhibited the opposite incremental recharging. Removal of extracellular Ca 2+ or thapsigargin treatment did not affect such local recharging of Ca 2+ , suggesting no major roles of store-operated Ca 2+ entry (SOCE) or reuptake of released Ca 2+ into the ER by a Ca 2+ -ATPase. Thus, we conclude that the local ER Ca 2+ store comprises functional subcompartments at CRCE and that an ATP-induced [Ca 2+ ] er decrease at the caveolin-1-rich region is preferentially recharged by intra-ER Ca 2+ flow from the other ER subcompartments ( Fig. 4 ).
Abstract 12565: Vitamin D Plus Calcium Supplementation and Risk of Atrial Fibrillation
Authors: Brian C Boursiquot, Joseph C Larson, Omaima A Shalash, Mara Z Vitolins, Elsayed Z Soliman, Marco V Perez
Journal: Circulation (2018)

Introduction: Atrial fibrillation (AF) is the most common arrhythmia in adults and significantly increases the risk of stroke. While vitamin D deficiency is associated with AF risk factors, retrosp...