tbuckley/cabot-search huggingface dataset:
Abstract 2129: Breast tumor microenvironment &amp; metastasis is controlled by activity of a2 isoform of V-ATPase in mammary epithelium
Authors: Gajendra K. Katara, Arpita Kulshrestha, Manoranjan Sahoo, Kenneth Beaman
Journal: Cancer Research (2018)

Abstract Extracellular matrix (ECM) critically impacts tumor progression and is influenced by both cancer and host tissue cells. While our understanding of cancer cell ECM remodeling is widespread, the importance of host tissue ECM, which provides an initial congenial environment for primary tumor formation, is only partly understood. Previously, we have shown that epithelial cell associated vacuolar (V)-ATPase ‘a2' isoform (a2V) regulates stiffness of mammary gland ECM. Here, we investigated how a2V mediated alterations in ECM of breast tissues affects the tumor microenvironment and metastasis of breast cancer. We also established the correlation of a2V expression in the normal breast tissue with metastatic occurrence in cancer patients. In this study, using the MMTV-Cre-Lox system, we deleted the a2V gene in epithelial cells of mouse mammary glands. Tumors were transplanted in mammary fat pads of a2V conditional knockout mice (a2VcKO) using E0771/Py230 mouse mammary cancer cells. These tumors were evaluated for the histopathology, ECM stiffness, immune cell populations, cytokines, angiogenic factors and metastasis. We show that in a2VcKO, breast tumors exhibit less tumor rigidity, increased inflammation and a more necrotic tumor microenvironment. These mice showed an increased metastasis of tumors compared to control evident by cytokeratin (Ck)14 staining of cancer cells in lung tissues (3.3 fold increase, P=0.004). Immuno-phenotyping of breast tumor microenvironment revealed increased infiltration of CD45 cells with higher number of anti-tumor M1 macrophages (2.1 fold increase, P=0.007) and elevated expression of inflammatory cytokines TNF-α and iNOS in a2VcKO mice compared to control (P=0.01). The tumors in a2VcKO mice were much more highly vascularized and angiogenic compared to control (P=0.01) evident by increased number of Meca32+SMA+ cells. Clinically, in cancer patients, low a2V expression levels in normal breast tissue correlated directly with lymph-node metastasis. Thus, this study has identified a2V expression in epithelial cells as a key modulator of tumor microenvironment and its expression levels can significantly modulate breast tumor dissemination. Citation Format: Gajendra K. Katara, Arpita Kulshrestha, Manoranjan Sahoo, Kenneth Beaman. Breast tumor microenvironment &amp; metastasis is controlled by activity of a2 isoform of V-ATPase in mammary epithelium [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 2129.
Abstract 1796: Repurposing CRISPR to study aberrant AR signaling in models of castration-resistant prostate cancer
Authors: Evangelia E. Kounatidou, Craig Robson, Luke Gaughan
Journal: Cancer Research (2018)

Abstract Prostate cancer (PC) is currently the most commonly diagnosed noncutaneous cancer affecting men worldwide. Despite the initial response to androgen ablation, patients relapse with tumors becoming refractory to clinically approved anti-androgens, resulting invariably in castration-resistant PC (CRPC). In CRPC, androgen receptor (AR) signaling is inappropriately restored. Resistance to available hormone therapies in PC has been linked to aberrant splicing of nascent AR transcripts and subsequent expression of constitutively active AR splice variants. Although we have information on the expression of receptor variants in advanced disease, the mechanisms that regulate these aberrantly functioning proteins are markedly understudied. Therefore, a better understanding of how splice variants are generated and function in this disease setting is critical for the development of more refined targeted therapies. By modeling clinically relevant AR splice variants, we will identify and exploit mechanisms of receptor regulation for advanced prostate cancer therapy. The CRISPR-Cas9 technology has been exploited to generate a CWR22Rv1 derivative cell line that lacks AR-FL and hence only expresses AR-Vs. This has allowed us to study the function of AR-Vs in an AR-FL-free background and therefore attribute the observed outcomes exclusively to AR splice variants. In addition, a novel CRISPR-based approach, currently developed in our lab, allows selective targeting of a catalytically inactive form of Cas9 (dead Cas9, dCas9) fused to a FLAG tag, to native chromatin regions and subsequent isolation of protein/RNA complexes associated with these sites. We have taken advantage of spatial mRNA splicing and transcription coupling in order to isolate splicing factors responsible for the generation of the AR variant 7 (AR-V7) in the CWR22Rv1 cell line and its AR-FL CRISPR knockout derivative. Three gRNAs were designed against the AR cryptic exon 3 genomic region. Targeting of FLAG-tagged dCas9 to that site was exploited for in situ capture and isolation of endogenous splicing factors specific to AR-V7, upon rapid FLAG immunoprecipitation and characterization by mass spectrometry. Identification of the AR-V7 spliceosome will fill a critical knowledge gap in our understanding of how AR-Vs are generated and provide key targets for future therapeutic intervention in advanced PC patients. Citation Format: Evangelia E. Kounatidou, Craig Robson, Luke Gaughan. Repurposing CRISPR to study aberrant AR signaling in models of castration-resistant prostate 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 1796.
Abstract 4873: Therapeutic targeting of LSD1 in Ewing sarcoma with SP-2509
Authors: Kathleen Pishas, Megann Boone, Sunil Sharma, Stephen Lessnick
Journal: Cancer Research (2018)

Abstract Objective: Multimodal regimes remain the cornerstone treatment for Ewing sarcoma (ES), the second most common solid bone malignancy diagnosed in pediatric and young adolescent populations. We have reached a therapeutic ceiling with conventional cytotoxic agents, highlighting the need to adopt novel approaches specifically targeting the drivers of ES oncogenesis. As LSD1 (Lysine Specific Demethylase 1) is highly expressed in ES tumors, with elevated expression levels associated with worse overall survival, this study examined biomarkers of sensitivity/mechanisms of cytotoxicity to targeted LSD1 inhibition using SP-2509 (reversible LSD1 inhibitor). Methods: The antiproliferative effects of SP-2509 were determined through Cell Titre Glo assays following 72hrs of treatment in a panel of 17 ES cell lines with varying STAG2/TP53 mutational status and basal LSD1 expression levels. RNA-seq analysis of six ES cell lines -/+ SP-2509 treatment (2μM) was also conducted. Results: Innate resistance to SP-2509 was not observed in our cell line cohort (72hr IC50:81nM-1593nM). In contrast, resistance to the clinical next-generation LSD1 irreversible inhibitor GSK-LSD1 was observed across multiple cell lines (144hr IC50&amp;gt;300μM). Although TP53/STAG2 mutational status and basal LSD1 mRNA/protein levels did not correlate with SP-2509 response, induction of LSD2 (homologue of LSD1) following SP-2509 treatment was strongly associated with SP-2509 hypersensitivity (R2=0.562). shRNA mediated knockdown of LSD2 significantly reduced the cytotoxic effects of SP-2509 (4.3 fold IC50 increase) only in hypersensitive cell lines. Mechanistically, RNA-seq analysis revealed that SP-2509 imparts apoptosis through engagement of the endoplasmic reticulum stress pathway, with hypersensitive cell lines sharing similar transcriptomic profiles. In addition, ETS1/HIST1H2BM were specifically induced/repressed, respectively, following SP-2509 treatment only in our hypersensitive cell lines. Finally, we demonstrate that the transcriptional profile driven by SP-2509 strongly mirrors LSD1 genetic depletion. Conclusion: Our findings provide key insights into the mechanisms of SP-2509 cytotoxicity as well as biomarkers that can be used to predict LSD1 inhibitor sensitivity in ES. Citation Format: Kathleen Pishas, Megann Boone, Sunil Sharma, Stephen Lessnick. Therapeutic targeting of LSD1 in Ewing sarcoma with SP-2509 [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 4873.
Abstract 16702: Mitochondrial Mediated NLRP3 Inflammasome Promotes Cardiomyocyte Death
Authors: Jun Zhou, Xiongwen Zhen, Mingxin Tang, Xiaoji Ai, xiaofeng Yang, Hong Wang
Journal: Circulation (2017)

Introduction: Elevated level of serum homocysteine (Hcy) has been identified as a risk factor for accelerating progression of cardiovascular disease. The underlying mechanism by which NLRP3 inflamm...
Mechanical Stress–Induced Heat Shock Protein 70 Expression in Vascular Smooth Muscle Cells Is Regulated by Rac and Ras Small G Proteins but Not Mitogen-Activated Protein Kinases
Authors: QingboXu, GeorgSchett, ChaohongLi, YanhuaHu, GeorgWick
Journal: Circulation Research (2000)

Abstract—Previous studies have documented that acute elevation in blood pressure results in heat shock protein (hsp) 70–mRNA expression followed by hsp70-protein production in rat aortas. In this article, we provide evidence that mechanical forces evoke rapid activation of heat shock transcription factor (HSF) and hsp70 accumulation. In our study, Western blot analysis demonstrated that hsp70-protein induction peaked between 6 and 12 hours after treatment with cyclic stain stress (60 cycles/minute, up to 30% elongation). Elevated protein levels were preceded by hsp70-mRNA transcription, which was associated with HSF1 phosphorylation and activation stimulated by mechanical forces, suggesting that the response was regulated at the transcriptional level. Conditioned medium from cyclic strain–stressed vascular smooth muscle cells (VSMCs) did not result in HSF-DNA–binding activation. Furthermore, mitogen-activated protein kinases (MAPKs), including extracellular signal–regulated kinases, c-Jun NH2-terminal pro...
Abstract 5683: Value of new spontaneous and carcinogen-induced mouse-derived isograft (MDI) tumor models for drug development of novel immune therapeutic approaches
Authors: Janette Beshay, Peter Jantscheff, Cynthia Obodozie, Christoph Schaechtele, Holger Weber
Journal: Cancer Research (2018)

Abstract Checkpoint inhibitor treatment has already become a common therapy of various cancer types. However, there is still a growing need for well-characterized preclinical mouse models, as clinical data indicate that patients only partially respond to this regiment. Currently, cell lines cultured from the 1970s are used frequently to evaluate novel therapies. In a research development program, new mouse-derived isografts (MDI) were established from spontaneously occurring and carcinogen-induced tumors. These tumors are transplanted as tissue pieces in a PDX-like manner and tested for their solid growth. Furthermore, the efficacy of immune checkpoint inhibitor treatment is evaluated and the presence of different immune cell populations in the tumor is characterized by FACS analysis. In addition, RNA-seq data complete the first characterization of these models and will give insights into the expression level and genetic modification of genes in these models. Here, the spontaneous MDI model JA-0009 and two carcinogen-induced MDI models JA-2042 and JA-2011 are presented. Whereas JA-0009 and JA-2011 tumors are only partially affected by immune checkpoint inhibitor treatment, JA-2042 shows a significant response in a combined treatment of anti-PD-1/anti-CTLA-4. Characterization of the infiltrated immune populations revealed a high number of T cells, especially Treg cells. In contrast, the JA-0009 tumor is infiltrated mainly by macrophages of M2 type with a low number of CD8+ T cells and the JA-2011 tumor by neutrophils. Taken together, the new MDI models complement the existing GEMs and cell-line derived syngeneic tumor models by their new properties (low passage number, no tissue culture, conserved original tumor properties and intra-tumoral immune cell populations) to characterize novel immune-modulatory agents in drug development. Citation Format: Janette Beshay, Peter Jantscheff, Cynthia Obodozie, Christoph Schaechtele, Holger Weber. Value of new spontaneous and carcinogen-induced mouse-derived isograft (MDI) tumor models for drug development of novel immune therapeutic approaches [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 5683.
p53 activation: a checkpoint for precision genome editing?
Authors: Anastasia Conti, Raffaella Di Micco
Journal: Genome Medicine (2018)

Recent work has reported that the activation of the p53 pathway in primary cells hampers the efficiency of genome editing by CRISPR/Cas9 via induction of apoptosis or cell cycle arrest. These findings highlight the importance of wholly comprehending cellular responses to programmable nucleases in therapeutically relevant cell types to fulfill the promise of genome editing for therapeutic applications for human diseases.
Abstract 22: Experienced Impact and Post-Traumatic Stress Symptoms of Dispatched Local Lay Rescuers Performing Basic Life Support
Authors: Jolande Zijlstra, Stefanie Beesems, Rob de Haan, Rudolph Koster
Journal: Circulation (2014)

Aim: A text message (TM) alert system for OHCA has been implemented in part of the Netherlands. This system uses TM from EMS dispatch to alert local lay rescuers (TM-responders [TMRs]) living &lt;1000m radius of the OHCA victim, to either go directly to the victim and perform CPR, or to a nearby AED first. Over 14 000 TMRs and &gt;1500 AEDs were registered in a database residing with the dispatch center. We studied the level of experienced impact shortly after performing BLS and compared it with the Impact of Event Scale (IES) score 4-6 wks afterwards. Methods: With each TM-alert an email was sent to the TMRs with a link to an online questionnaire. We analyzed all questionnaires from 15-02-2013 to 21-04-2014 which were filled out median 5h after EMS call. We counted the experienced impact level (no, little, bearable, much, unbearable). All firstly arrived TMRs who provided BLS±AED use prior to EMS arrival, participated in a semi-structured interview by telephone median 4 days after resuscitation. To assess if TMRs had post-traumatic stress symptoms (PTSS), the IES was sent to all interviewees 4-6 wks after the resuscitation. Scores 0-8 indicated subclinical, 9-25 mild, 26-43 moderate, and ≥44 severe stress. A score &gt;25 indicated PTSS. Results: The dispatcher activated the TM-alert system 697 times, alerting 18 742 TMRs. 4799 completed the questionnaire. Of these, 1639 responded to the call and 353 arrived on scene, participating in the resuscitation. We interviewed 148 first arriving TMRs of whom 137 also completed the IES. Comparison between level of experienced impact and IES score is shown in the figure. None showed PTSS (median: 1, 25th-75th percentile: 0-8, max. 25). Of all TMRs experiencing no/little impact, 13% was grouped as mild. Of all TMRs experiencing bearable impact, 22% scored mild and of all TMRs experiencing much impact, 44% scored mild. Conclusion: TMRs do not show PTSS 4-6 wks after performing BLS, even if their experienced level of impact is considerable shortly after the event.
Abstract 18646: Safety Aspects of High Intensity Interval Training versus Moderate Intensity Continuous Exercise Training in Patients Post Acute Coronary Syndrome
Authors: DouglasHayami, MathieuGayda, MartinJuneau, EricThorin, Jean-FrançoisLarouche, GabrielLapierre, Jean-ClaudeTardif, AnilNigam
Journal: Circulation (2014)

Introduction: Exercise training in patients who have suffered an acute coronary syndrome is associated with a significant reduction in mortality and cardiovascular events. Moderate intensity continuous exercise training (MICET) is currently recommended. Recently, high-intensity interval training (HIIT), that utilizes short bursts of very intense efforts interspersed with periods of recovery, has been explored as an alternative to MICET. The safety aspects of HIIT in patients post acute coronary syndrome (ACS) have been poorly described. Methods: Thirty-seven low-risk patients post ACS (65% STEMI, fully revascularized, EF > 40%, age 61±9 years, 8 women) were randomized 4 weeks to 6 months post ACS; to 12 to 18 weeks of 2-3 sessions/week (total: 36 sessions) of isocaloric MICET or HIIT on cycle ergometer. VO2peak and maximal aerobic power (MAP) were determined using maximal cardiopulmonary exercise test (CPET) on cycle ergometer and continuous ECG and BP were monitored every 2 min. Cardiometabolic profile (...
Indicators of Poor Prognosis of Acute Pericarditis
Authors: MassimoImazio, EnricoCecchi, BrunellaDemichelis, SalvatoreIerna, DanielaDemarie, AldoGhisio, FrancoPomari, LuisellaCoda, RiccardoBelli, RitaTrinchero
Journal: Circulation (2007)

Background— The clinical search for indicators of poor prognosis of acute pericarditis may be useful for clinical triage of patients at high risk of specific causal conditions or complications. The aim of the present article is to assess the relationship between clinical features at presentation and specific causes or complications. Methods and Results— A total of 453 patients aged 17 to 90 years (mean age 52±18 years, 245 men) with acute pericarditis (post–myocardial infarction pericarditis was excluded) were prospectively evaluated from January 1996 to August 2004. A specific cause was found in 76 of 453 patients (16.8%): autoimmune in 33 patients (7.3%), neoplastic in 23 patients (5.1%), tuberculous in 17 patients (3.8%), and purulent in 3 patients (0.7%). In multivariable analysis, women (hazard ratio [HR] 1.67, 95% confidence interval [CI] 1.03 to 2.70; P=0.036) and patients with fever >38°C (HR 3.56, 95% CI 1.82 to 6.95; P<0.001), subacute course (HR 3.97, 95% CI 1.66 to 9.50; P=0.002), large effusi...
Abstract 3176: CD99 regulates ERK1/2-MSK1/2-CREB axis in Ewing sarcoma
Authors: Haydar Celik, Erin J. Conn, David V. Allegakoen, Jeff R. Petro, Jeffrey A. Toretsky, Aykut Uren
Journal: Cancer Research (2018)

Abstract Ewing sarcoma (ES) is an aggressive malignancy of bone and soft tissue that affects predominantly children and young adults with a high propensity to metastasize and poor prognosis. ES cells express high levels of a cell surface protein CD99, which is routinely used as a marker antigen in the histological diagnosis of ES, and contributes to its pathogenesis. We performed a phospho-kinase array to uncover specific cellular responses evoked by CD99 inhibition in ES cells. The treatment of ES cells with CD99 antibody or a small molecule CD99 inhibitor (clofarabine) resulted in strong activation of mitogen- and stress-activated kinases 1 and 2 (MSK1/2) as well as its substrate CREB and its upstream kinase ERK1/2. These findings were further confirmed with western blot analysis in ES cells treated with either different CD99 antibodies or clofarabine. The treatment of osteosarcoma (OS) cells with clofarabine or the forced expression of CD99 in OS cells did not change their phosphorylation levels, suggesting that CD99-mediated ERK1/2-MSK1/2-CREB signaling cascade is specific to ES cells. Interestingly, knock-down of the CD99 protein in ES cells led to a significant decrease in ERK1/2 phosphorylation without any effect on the downstream phosphorylation of MSK1/2 and CREB. Cytarabine, a structurally similar pyrimidine analog that has been identified as an inhibitor of EWS/FLI1 transcriptional activity but failed in clinical trials on ES patients, did not activate ERK1/2-MSK1/2-CREB axis unlike clofarabine in ES cells. These findings suggest that clofarabine functions through alternative mechanisms on ES cells that are different than cytarabine. Clofarabine induced a significant increase in phosphorylation levels of MSK1/2 in a small cohort of TC-71 xenografts, supporting its use as a potential pharmacodynamic marker of CD99 inhibitor activity. In conclusion, our findings suggest that CD99 regulates ERK1/2-MSK1/2-CREB axis in ES, which represents an intracellular pathway that may be responsible for CD99's biological activities in ES. Citation Format: Haydar Celik, Erin J. Conn, David V. Allegakoen, Jeff R. Petro, Jeffrey A. Toretsky, Aykut Uren. CD99 regulates ERK1/2-MSK1/2-CREB axis in Ewing sarcoma [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 3176.
Abstract 4442: Wilms' tumor 1-associating protein increases cancer cell proliferation and stem-cell like properties through RNA modification
Authors: Sae Whan Park, Young Taek Oh, Jong Bae Park, Jong Heon Kim
Journal: Cancer Research (2018)

Abstract Purpose: Wilms' tumor 1-associating protein (WTAP) which is known for its role in RNA methylation machinery, is highly upregulated in the necrotic region of glioblastoma multiforme (GBM). The highly heterogenic nature of GBM is associated with the necrotic region within the brain, where many types of cells such as the stromal cell, immune cells, and cancer stem cells co-localize. The complex cellular network within the necrotic region is believed to cause the resistance of the conventional chemotherapy and radiotherapy. Here we attempted to identify the role of WTAP in GBM and what kind of RNA modification is associated with the proliferation and stemness in GBM. Improvement of our understanding about post-transcriptional regulation in GBM will allow us to find out the key oncogenic switch in GBM, and development of therapeutics targeting this mechanism will provide better survival benefits. Methods: 23 Patient-derived cell lines, two established GBM cell lines, and astrocyte was arrayed to find out the correlation between WTAP and cancer stem cells. shWTAP and WTAP overexpression vector were infected into patient-derived GBM cancer stem cell lines to test the effect of WTAP. Western blot and polymerase chain reaction analysis was performed to find out the change in genes which are related to cell proliferation and stemness. Limiting dilution assay was performed to validate the function of WTAP in sphere-forming ability. RNA sequencing was performed on shWTAP infected patient-derived cancer stem cell to identify the type of RNA modification made by knocking down WTAP. Results: Knocking down of WTAP using shWTAP in patient-derived cancer stem cell lines, we were able to see the decrease in cell proliferation and stemness-related genes while overexpressing WTAP in these cells slightly increased cell proliferation and stemness. WTAP knockdown cells had a significant decrease in sphere-forming ability. RNA sequencing of shWTAP cells has revealed the increase in intron retention and the decrease in exon skipping, which shows that WTAP has a role in decreasing intron retention while increasing exon skipping. Conclusion: We have revealed that WTAP has an important role in increasing proliferation and maintaining stemness in GBM. We have also identified that WTAP decreases intron retention and increasing exon skipping. Citation Format: Sae Whan Park, Young Taek Oh, Jong Bae Park, Jong Heon Kim. Wilms' tumor 1-associating protein increases cancer cell proliferation and stem-cell like properties through RNA modification [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 4442.
Cis-dimeric architecture of Pcdh15 critical for mechanotransduction
Authors: G. Dionne, X. Qiu, M. Rapp, X. Liang, B. Zhao, G. Peng, P.S. Katsamba, G. Ahlsen, R. Rubinstein, C.S. Potter, B. Carragher, B. Honig, U. Mueller
Journal: Neuron (2018)