tbuckley/cabot-search huggingface dataset:
B1a B Lymphocytes Are Atheroprotective by Secreting Natural IgM That Increases IgM Deposits and Reduces Necrotic Cores in Atherosclerotic Lesions
Authors: TinKyaw, ChristopherTay, SurendranKrishnamurthi, PeterKanellakis, AlexAgrotis, PeterTipping, AlexBobik, Ban-HockToh
Journal: Circulation Research (2011)

Rationale:Aggravated atherosclerosis in B lymphocyte-deficient chimeric mice and reduced atherosclerosis after transfer of unfractionated spleen B lymphocytes into splenectomized mice have led to the widely held notion that B lymphocytes are atheroprotective. However, B lymphocytes can be pathogenic, because their depletion by anti-CD20 antibody ameliorated atherosclerosis, and transfer of B2 lymphocytes aggravated atherosclerosis. These observations raise the question of the identity of the atheroprotective B-lymphocyte population. Objective:The purpose of the study was to identify an atheroprotective B-lymphocyte subset and mechanisms by which they confer atheroprotection. Methods and Results:Splenectomy of apolipoprotein E–deficient mice selectively reduced peritoneal B1a lymphocytes, plasma IgM, and oxidized low-density lipoprotein IgM levels and lesion IgM deposits. These reductions were accompanied by increased oil red O–stained atherosclerotic lesions and increased necrotic cores, oxidized low-dens...
Abstract 318: Inhibition of FASN induces apoptosis and senescence in breast cancer
Authors: Travis Vander Steen, Ruth Lupu
Journal: Cancer Research (2018)

Abstract Fatty Acid Synthase (FASN), the key multienzyme in de novo lipogenesis, is upregulated and activated in numerous carcinomas, including breast cancer. Fatty acids play a fundamental role in cellular structure, energy production and storage and are intermediates in the biosynthesis of hormones and other biologic molecules. Therefore, FASN is a novel therapeutic target for treatment in cancer cells that have upregulated FASN protein. BT474 breast cancer cells, which overexpress FASN, were treated with a pharmacologic FASN inhibitor and resulted in apoptosis in a dose-dependent manner. Inhibition of FASN simultaneously upregulates the pro-apoptotic BCL2 family members Bim, Puma, and Noxa; additionally, FASN inhibition alters the NDAPH/NADP+ balance and induces reactive oxygen species (ROS) production. Most significantly, FASN inhibition induces sensitization of breast cancer cells to the BH3 mimetic navitoclax, a potential opportunity to use BH3 mimetics for the treatment of breast carcinomas. These results support further preclinical and potentially clinical development of a dual FASN and Bcl-2 treatment for breast cancer tumors that express FASN. In addition to apoptosis, there is an increase in cellular senescence in breast cancer cells overexpressing FASN when treated with FASN inhibitors. The increase in ROS, a known effect of FASN inhibition, is known to induce cellular stress, resulting in both apoptosis and senescence. Increased senescence was initially observed by x-gal staining of BT474 cells treated with FASN inhibitors via microscopy and FLOW. We also observed an increased expression of several pro-senescent genes both at the protein and mRNA levels, including p16/INK4a, p14ARF/p19ARF, p15, and p21. A hallmark of age-induced cellular senescence is the shortening of telomeres. However, telomere shortening was not observed, suggesting that senescence was a result of FASN inhibition and activation of senescence-induced genes. Therefore, inhibition of FASN appears to be an ideal target for therapeutic treatment of breast cancers that overexpress FASN through both apoptosis and senescence. Citation Format: Travis Vander Steen, Ruth Lupu. Inhibition of FASN induces apoptosis and senescence in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 318.
Abstract 5464: Pharmacologic activation of REV-ERBs is lethal in cancer and oncogene-induced senescence
Authors: Gabriele Sulli, Amy Rommel, Xiaojie Wang, Matthew J. Kolar, Francesca Puca, Alan Saghatelian, Maksim V. Plikus, Inder M. Verma, Satchidananda Panda
Journal: Cancer Research (2018)

Abstract The circadian clock drives daily rhythms in cell proliferation, metabolism, inflammation and DNA damage response. Perturbations of these processes are hallmarks of cancer, and circadian rhythm disruption predisposes to tumor development in animal models and humans. This raises the hypothesis that pharmacologic modulation of the circadian machinery may be an effective therapeutic strategy for combating cancer. The nuclear hormone receptors REV-ERBα and REV-ERBβ (REV-ERBs) are essential components of the circadian clock. Here we show that SR9009 and SR9011, two different agonists of REV-ERBs, are specifically lethal to cancer cells and oncogene-induced senescent (OIS) cells, including melanocytic naevi, while having no effect on viability of normal cells or tissues. Anticancer activity of SR9009 and SR9011 affects several oncogenic drivers (such as H-RAS, BRAF, PIK3CA, and others), and persists in the absence of p53 and under hypoxic conditions. The regulation of autophagy and de novo lipogenesis by SR9009 and SR9011 plays a critical role in evoking an apoptotic response in malignant cells. Importantly, the selective anticancer properties of these REV-ERB agonists impair glioblastoma growth in vivo and improve survival without causing any overt toxicity in mice. These results indicate that pharmacologic modulation of circadian regulators is an effective novel antitumor strategy, identifying the existence of a previously unknown class of anticancer agents with a wide therapeutic window. We propose that REV-ERB agonists are novel autophagy and de novo lipogenesis inhibitors with selective activity towards malignant and benign neoplasms. Citation Format: Gabriele Sulli, Amy Rommel, Xiaojie Wang, Matthew J. Kolar, Francesca Puca, Alan Saghatelian, Maksim V. Plikus, Inder M. Verma, Satchidananda Panda. Pharmacologic activation of REV-ERBs is lethal in cancer and oncogene-induced senescence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5464.
Abstract 5518: Bi-allelic loss of CDKN2A initiates melanoma invasion and metastasis via E2F1-BRN2 axis
Authors: Hanlin Zeng, Aparna Jorapur, A. Hunter Shain, Ursula E. Lang, Rodrigo Torres, Yuntian Zhang, Thomas Botton, Jue Lin, Andrew S. Mcneal, Matthew Donne, Ingmar N. Bastian, Jeffrey North, Laura Pincus, Richard Yu, Beth S. Ruben, Nancy Joseph, Iwei Ye, Boris C. Bastian, Robert L. Judson
Journal: Cancer Research (2018)

Abstract CDKN2A acts as a critical tumor suppressor in melanoma, as evidenced by frequent loss of function mutations and deletion. Loss of CDKN2A is believed to permit escape from senescent pre-neoplastic cell populations through relieve of a cell cycle block mediated by its two gene products. We performed a comprehensive analysis of CDKN2A gene status, mRNA and protein expression levels of p16 and p14 in a cohort of melanomas and their adjacent pre-neoplastic lesions and observed that bi-allelic CDKN2A loss coincides with the progression stage when primary melanomas become invasive. In melanoma lines, p16INK4A, one of the protein products of the CDKN2A locus, is a potent barrier to metastasis, independent of its known role inhibiting cell proliferation. We genetically engineered primary human melanocytes to harbor CDKN2A deletions and/or BRAF V600E mutation at their endogenous BRAF locus. Using this physiologic model for the early phases of neoplastic transformation, we found no evidence for BRAF-induced senescence, rather observing that p16INK4A loss activates a master regulator of melanoma invasion, BRN2, through Rb-E2F1 pathway. These results demonstrate that one of the most frequently altered genes across human cancers, CDKN2A, has an unexpected novel role in inhibiting cellular invasion through lineage specific transcription factors and acts as an essential gatekeeper of early metastatic dissemination. Citation Format: Hanlin Zeng, Aparna Jorapur, A. Hunter Shain, Ursula E. Lang, Rodrigo Torres, Yuntian Zhang, Thomas Botton, Jue Lin, Andrew S. Mcneal, Matthew Donne, Ingmar N. Bastian, Jeffrey North, Laura Pincus, Richard Yu, Beth S. Ruben, Nancy Joseph, Iwei Ye, Boris C. Bastian, Robert L. Judson. Bi-allelic loss of CDKN2A initiates melanoma invasion and metastasis via E2F1-BRN2 axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5518.
Abstract 3062: Ablation of parathyroid hormone-related protein in the triple negative human breast cancer line MDA-MB-231 inhibits its cancer stem cell phenotype
Authors: Jiarong Li, Louis Doré-Savard, Karine Sellin, Anne Camirand, Richard Kremer
Journal: Cancer Research (2018)

Abstract Parathyroid hormone-related protein (PTHrP) is a pleiotropic hormone involved in a wide range of developmental &amp; physiological processes. It is also dysregulated in advanced cancers where it causes malignancy-associated hypercalcemia &amp; plays a major role in the progression of bone metastases. We have shown previously that PTHrP ablation delays tumor initiation &amp; that it is preferentially expressed in triple negative breast cancer (TNBC).Here we investigated how PTHrP can influence the phenotype of the human TNBC cell line MDA-MB231 using CRISPR/cas 9 knockout technology. We used U6G RNA-Cas9-2A-red fluorescence protein (RFP) vector with a human PTHrP specific guide RNA directed to exon 4(knockout/KO) or an empty vector as control. PTHrP KO cells (RFP+) were isolated using AutoMacs Pro Separator &amp; single cells were exp&amp;ed in 96 well plates. Positive clones were confirmed by DNA sequencing. Real time PCR &amp; immunofluorescence staining confirmed that 5/96 KO clones had between 95-99% decrease in PTHrP expression compared to control cells. We then assessed cancer stem cell (CSC) characteristics of both KO &amp; control cell lines. Mammosphere formation was reduced by over 60% in KO cells. Stem cell phenotype assessed by ALDH1 &amp; CD44+/CD24 low using FACS analysis were significantly reduced by over 30% in KO cells. Cell morphology analysis showed a shift from a mesenchymal phenotype towards an epithelial phenotype. Overall our data show that PTHrP regulates TNBC towards a more aggressive phenotype &amp; suggest that it could be targeted therapeutically. Citation Format: Jiarong Li, Louis Doré-Savard, Karine Sellin, Anne Camirand, Richard Kremer. Ablation of parathyroid hormone-related protein in the triple negative human breast cancer line MDA-MB-231 inhibits its cancer stem cell phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3062.
Abstract IA27: Functional genetic architecture of serous ovarian cancer
Authors: Kyle Francis, Helen Burston, Daphna Mokady, Melany Wagner, Mauricio Medrano, Robert Rottapel
Journal: Clinical Cancer Research (2018)

Abstract The degree of genetic aberrations characteristic of high-grade serous ovarian cancer (HGSC) makes identification of the molecular features that drive tumor progression difficult. Here, we perform genome-wide RNAi screens and whole-kinome proteomics to identify genes that are critical to their survival. We report that the tetraspanin CD151 contributes to survival of a subset of HGSC cell lines associated with a ZEB transcriptional program and supports the growth of HGSC tumors. Moreover, we show that high CD151 expression is prognostic of poor clinical outcome. We have identified essential kinases that manage biosynthetic stress indicative of the ovarian cancer transformed state. These data suggest that targeting pathways that underlie adaptation to cellular stress states rather than driver oncogenes may provide new therapeutic avenues for treating HGSC. Citation Format: Kyle Francis, Helen Burston, Daphna Mokady, Melany Wagner, Mauricio Medrano, Robert Rottapel. Functional genetic architecture of serous ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA27.
Abstract 2791: Physiologically based pharmacokinetic modeling and simulations to estimate the efficacious dose of the CEACAM6 function-blocking antibody BAY 1834942
Authors: Sabine Wittemer-Rump, Christoph Niederalt, Joerg Willuda, Mark Trautwein, Merlin Luetke-Eversloh, Wolf-Dietrich Doecke, Clemens Guenther, Christian Scheerans
Journal: Cancer Research (2018)

Abstract BAY 1834942 is an immunostimulatory function-blocking (fb) antibody (Ab) against the target carcinoembryonic antigen related cell adhesion molecule 6 (CEACAM6) expressed on tumor cells in multiple cancer indications. The suggested mode of action of BAY 1834942 is the blockade of the immunosuppressive effect of CEACAM6 on activated T cells which restores the immune response against cancer cells. Available preclinical pharmacokinetic (PK) and in vitro pharmacodynamic (PD) data, target receptor density information and tumor (patho-)physiology were used to create a model framework taking into account the three most essential ‘pillars' (target exposure, target binding and drug activity) to estimate the human efficacious dosing of BAY 1834942. For this purpose, a physiologically-based pharmacokinetic (PBPK) model considering target binding of BAY 1834942 in tumor tissue and on blood granulocytes has been developed. The aim of the PBPK model was to estimate the dose range and regimen for humans leading to exposure level at the tumor site that allows sufficient target binding. The PBPK simulations were based on 1) an analysis of PD in vitro data in order to estimate the degree of saturation needed for maximum drug activity, 2) the assessment of CEACAM6 receptor numbers on tumor cells and blood granulocytes and 3) in vivo PK data in order to develop and evaluate the PBPK model. For the latter, plasma PK data of BAY 1834942 in monkeys were used as well as known tumor concentration-time profiles of the antibodies MOPC21 (non-targeting Ab) and ZCE025 (anti-CEA Ab) in mice and humans. Uncertainty of parameters which are relevant for CEACAM6 target saturation was considered by stochastic in silico simulations to estimate the CEACAM6 saturation at the tumor vs. dosing. This analysis revealed that the predicted human efficacious dose strongly depends on CEACAM6 density. Thus, a low CEACAM6 density scenario (25,000 CEACAM6/tumor cell) and a high CEACAM6 density scenario (250,000 CEACAM6/tumor cell) were simulated and used to support dose selection for the first-in-man (FIM) study of BAY 1834942. The FIM study is currently under preparation. Citation Format: Sabine Wittemer-Rump, Christoph Niederalt, Joerg Willuda, Mark Trautwein, Merlin Luetke-Eversloh, Wolf-Dietrich Doecke, Clemens Guenther, Christian Scheerans. Physiologically based pharmacokinetic modeling and simulations to estimate the efficacious dose of the CEACAM6 function-blocking antibody BAY 1834942 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2791.
Abstract 12871: High Sensitivity C-Reactive Protein is Associated with Coronary Plaque Burden as Measured by Intravascular Ultrasound and Adverse Cardiovascular Outcome
Authors: Jin M Cheng, Rohit Oemrawsingh, Hector M Garcia-Garcia, Isabella Kardys, Martijn Akkerhuis, Sanneke de Boer, Evelyn Regar, Robert-Jan van Geuns, Patrick W Serruys, Eric Boersma
Journal: Circulation (2013)

Background: High sensitivity C-reactive protein (hsCRP) is a prognostic marker in coronary artery disease (CAD). However, its relation with coronary plaque characteristics is not yet investigated. We studied the association between hsCRP, coronary plaque characteristics as measured in-vivo by intravascular ultrasound (IVUS) and 1-year cardiovascular outcome in CAD patients. Methods: In the ATHEROREMO-IVUS study, IVUS imaging of a non-culprit coronary artery was performed in 581 patients who underwent coronary angiography for acute coronary syndrome (ACS) or stable angina pectoris between 2008 and 2011. Primary endpoint was 1-year major adverse cardiac events (MACE), defined as all-cause mortality, non-fatal ACS or unplanned coronary revascularization. Definite culprit lesion related MACE were not counted. Results: Baseline hsCRP levels were associated with higher coronary plaque burden in the imaged coronary segment (p=0.013) (Figure) and tended to be associated with presence of large lesions (plaque burd...
Abstract 577: Oral microbiome biomarker panel to detect oral and oropharyngeal cancers in a clinical setting
Authors: Yenkai Lim, Naoki Fukuma, Makrina Totsika, Liz Kenny, Mark Morrison, Chamindie Punyadeera
Journal: Cancer Research (2018)

Abstract Oral microbiome plays a role in the instigation of oral diseases that affect other systemic conditions. These associations encourage the exploration of oral dysbiosis leading to the pathogenesis of cancers. In this study, saliva was used to characterise the oral microbiome fluctuation associated with oral and oropharyngeal cancers. The study cohort consists of normal healthy controls (n = 10, between 20 to 30 years of age; n = 10, above 50 years of age), high-risk individuals (n = 11, above 50 years of age with bad oral hygiene and/or oral diseases) and oral and oropharyngeal cancer patients (n = 31, HPV-positive; n = 21, HPV-negative). Saliva samples were analysed using 16S rRNA gene amplicon sequencing on the MiSeq platform. Kruskal-Wallis rank test was used to identify genera associated with oral and oropharyngeal cancers. A logistic regression analysis was carried out to determine the performance of these genera as a biomarker panel to detect oral and oropharyngeal cancers. In addition, a two-fold cross-validation with a bootstrap procedure was carried out on R to investigate how well the panel would perform in a real clinical scenario. Our data indicates that the oral microbiome is able to predict the presence of oral and oropharyngeal cancers with sensitivity and specificity of 100% and 90% respectively. With further validation, the panel could potentially be implemented into clinical workflow as oral and oropharyngeal cancers diagnostic and prognostic biomonitors. Citation Format: Yenkai Lim, Naoki Fukuma, Makrina Totsika, Liz Kenny, Mark Morrison, Chamindie Punyadeera. Oral microbiome biomarker panel to detect oral and oropharyngeal cancers in a clinical setting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 577.
Genetics Meets Therapy? Exome‐wide Association Study Reveals a Loss‐of‐Function Variant in 17‐Beta‐Hydroxysteroid Dehydrogenase 13 That Protects Patients From Liver Damage and Nonalcoholic Fatty Liver Disease Progression
Authors: Silvia Sookoian, Marco Arrese, Carlos J. Pirola
Journal: Hepatology (2018)

Sookoian, Silvia M.D., Ph.D., F.A.A.S.L.D.; Arrese, Marco M.D., F.A.A.S.L.D.; Pirola, Carlos J. Ph.D., F.A.H.A.Editor(s): Corey, Kathleen E.5; Malhi, Harmeet6 Author Information
Abstract 3544: Ras GTPases are modified by SUMOylation
Authors: Byeong Hyeok Choi, Changyan Chen, Mark Philips, Wei Dai
Journal: Cancer Research (2018)

Abstract RAS proteins are GTPases that participate in multiple signal cascades, regulating crucial cellular processes including cell survival, proliferation, differentiation, and autophagy. Mutations or deregulated activities of RAS are frequently the driving force for oncogenic transformation and tumorigenesis. Given the important roles of the small ubiquitin-related modifier (SUMO) pathway in controlling the stability, activity, or subcellular localization of key cellular regulators, we investigated here whether RAS proteins are post-translationally modified (i.e., SUMOylated) by the SUMO pathway. We observed that all three RAS protein isoforms (HRAS, KRAS, and NRAS) were modified by the SUMO3 protein. SUMOylation of KRAS protein, either endogenous or ectopically expressed, was observed in multiple cell lines. The SUMO3 modification of KRAS proteins could be removed by SUMO1/sentrin-specific peptidase 1 (SENP1) and SENP2, but not by SENP6, indicating that RAS SUMOylation is a reversible process. A conserved residue in RAS, Lys-42, was a site that mediates SUMOylation. Results from biochemical and molecular studies indicated that the SUMO-E3 ligase PIASγ specifically interacts with RAS and promotes its SUMOylation. Moreover, SUMOylation of RAS appeared to be associated with its activation. In summary, our study reveals a new post-translational modification for RAS proteins. Since we found that HRAS, KRAS, and NRAS can all be SUMOylated, we propose that SUMOylation might represent a mechanism by which RAS activities are controlled. Citation Format: Byeong Hyeok Choi, Changyan Chen, Mark Philips, Wei Dai. Ras GTPases are modified by SUMOylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3544.
Abstract 2376: AXL receptor tyrosine kinase stimulates cell softening and cancer progression via Rac signaling pathway
Authors: Masami Suganuma, Keisuke Iida, Shota Yokoyama, Anchalee Rawangkan, Kozue Namiki, Pattama Wongsirisin
Journal: Cancer Research (2018)

Abstract Cancer cells exhibit different biophysical properties, such as cell stiffness and elasticity, compared with normal cells. It is now well accepted that cell stiffness measured by atomic force microscope (AFM) is a quantitative indicator of cancer progression and metastasis. To study the role of cell softening in malignant progression, Using Transwell assays and AFM, six human non-small cell lung cancer cell lines were classified into two groups: a high motility-low stiffness (HMLS) group and a low motility-high stiffness (LMHS) group. We found a significant difference in expression of the AXL receptor tyrosine kinase, which belongs to the TAM (Tyro3, AXL, Mer) family, in the stimulation of motility and cell softening. HMLS cells expressed higher AXL and phosphorylated AXL levels than LMHS cells. Exogenous AXL gene expression in H1703 LMHS cells exhibited increased motility and decreased stiffness, along with lower levels of actin stress fibre formation. Conversely, the AXL-specific inhibitor R428 and AXL-targeting siRNA reduced motility and increased stiffness in H1299 HMLS cells. Knockdown of AXL gene stimulated both actin stress fibre formation and focal adhesion kinase phosphorylation, which inhibited tumour formation in a mouse xenograft model. Treatment with Ras/Rac inhibitor SCH 51344, which blocks disruption of actin stress fibres, exerted similar effects to AXL inactivation in H1299 and H1703-AXL cells, but not in H1703 cells (no AXL expression). Furthermore, treatment with an ROCK inhibitor, Y27632, did not show any effect in two AXL expressing cells, while it stimulated motility in H1703 cells. Considering all these results, we propose that the Ras/Rac pathway operates downstream of AXL and suppresses the Rho/ROCK pathway. Cell softening induced by AXL activation is a key biophysical property of cancer cells, and AXL is thus a new target for inhibition of malignant progression in non-small cell lung cancer. Citation Format: Masami Suganuma, Keisuke Iida, Shota Yokoyama, Anchalee Rawangkan, Kozue Namiki, Pattama Wongsirisin. AXL receptor tyrosine kinase stimulates cell softening and cancer progression via Rac signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2376.