tbuckley/cabot-search huggingface dataset:
Characteristics of Shiga toxin producing- and enteropathogenic Escherichia coli of the emerging serotype O80:H2 isolated from humans and diarrhoeic calves in Belgium
Authors: K. De Rauw, D. Thiry, B. Caljon, M. Saulmont, J. Mainil, D. Piérard
Journal: Clinical Microbiology and Infection (2018)
Abstract 2265: viSNE in Cytobank enables rapid exploratory data analysis for RNA-seq biomarker discovery
Authors: Ashu Sethi, Hannah Polikowsky, Katherine A. Drake
Journal: Cancer Research (2018)

Abstract Biomarkers provide great potential for understanding and predicting patient outcomes. However, the large numbers of putative biomarkers assayed by many discovery technologies can be difficult to parse quickly to understand their potential as predictors of an outcome of interest. viSNE is a non-linear dimensionality reduction algorithm available on the Cytobank informatics platform that can rapidly assess whether a set of biomarkers can meaningfully group samples. We establish a method for applying viSNE to RNA-seq data. We demonstrate this method using data from The Cancer Genome Atlas for 1,011 samples from 5 different types of kidney cancer and matched normal tissue samples for 139 of the subjects. The tumors ranged from stage I to stage IV, and subjects varied by age, gender, and whether they were living when the sample was taken. Using FPKM data from the 806 most variable transcripts in these samples, viSNE was able to group the samples into six distinct “islands” that separated cancer samples from each of the five disease types and the matched normal tissue. We demonstrate that viSNE is robust to noise and is able to group the samples even when variables that do not contribute to the signal are present in the data, and illustrate how this can be leveraged as part of a larger biomarker discovery workflow with RNA-seq and other data types. viSNE allows rapid exploratory data analysis that helps to build understanding of correlations between biomarkers and patient outcomes and improve overall time-to-results in biomarker discovery pipelines. Citation Format: Ashu Sethi, Hannah Polikowsky, Katherine A. Drake. viSNE in Cytobank enables rapid exploratory data analysis for RNA-seq biomarker discovery [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 2265.
Abstract 2384: Preclinical evaluation of PD and efficacy of novel potent selective and orally bioavailable CDK12 covalent inhibitors in TNBC model
Authors: Ramulu Poddutoori, Sujatha Rajagopalan, Subhendu Mukherjee, Sivapriya Marappan, Samiulla D S, Sasirekha Sivakumar, Shilpa S. Nayak, Ravindra M. V, Hadianawala Murtuza, Devaraja T. S, Srinivas Kondela, Suraj Tgore, Amit A. Dhudashiya, Charamanna K. B, Thomas Antony, Girish Daginakatte, Sanjeev Giri, Shekar Chelur, Murali Ramachandra, Chetan Pandit, Susanta Samajdar
Journal: Cancer Research (2018)

Abstract Cyclin-dependent kinase 12 (CDK12) is a transcription-associated kinase that participates in various cellular processes such as DNA damage response, splicing and pre-mRNA processing. In association with Cyclin K (CycK), CDK12 regulates transcription elongation by phosphorylating RNA polymerase II (RNAP II) at Serine 2 in the C-terminal domain (CTD). Overexpression of CDK12 in various tumor types suggests the possibility that CDK12 has oncogenic properties, similarly to other transcription-associated kinases. Considering its critical role in transcription and RNA processing CDK12 is emerging as a potential therapeutic target for cancer. Multiple series of potent and selective CDK12 covalent inhibitors were identified by iterative medicinal chemistry efforts and SAR-based approaches. Early compounds were optimized towards attaining good physicochemical properties, high potency, good selectivity and desirable pharmacokinetic profile to achieve anti-tumour activity. Very potent and highly selective CDK12 inhibitors have been identified from two distinct chemical series. The covalent mode of action for these biochemically potent compounds has been confirmed by CDK12 target engagement assay in the cellular context. These selective inhibitors showed significant anti-proliferative activity in TNBC and other cancer cell lines, which correlated with inhibition of pS2 (RNAP II), a bonafide CDK12 substrate and target engagement. In vivo target engagement, PD and efficacy data for optimized compounds with good oral bioavailability in a TNBC (HCC-70) xenograft model along with will be presented. Citation Format: Ramulu Poddutoori, Sujatha Rajagopalan, Subhendu Mukherjee, Sivapriya Marappan, Samiulla D S, Sasirekha Sivakumar, Shilpa S. Nayak, Ravindra M. V, Hadianawala Murtuza, Devaraja T. S, Srinivas Kondela, Suraj Tgore, Amit A. Dhudashiya, Charamanna K. B, Thomas Antony, Girish Daginakatte, Sanjeev Giri, Shekar Chelur, Murali Ramachandra, Chetan Pandit, Susanta Samajdar. Preclinical evaluation of PD and efficacy of novel potent selective and orally bioavailable CDK12 covalent inhibitors in TNBC model [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 2384.
Abstract 4318: Identifying drivers of SMARCA4/BRG1-deficient SCCOHT tumorigenesis by integrative multi-omic analysis
Authors: Krystal A. Orlando, Jesse R. Raab, Jessica D. Lang, William P. Hendricks, Yemin Wang, David G. Huntsman, Jeffrey M. Trent, Joel S. Parker, Bernard E. Weissman
Journal: Cancer Research (2018)

Abstract Over 94% of small cell carcinomas of the ovary, hypercalcemic type (SCCOHT), a rare and aggressive form of ovarian cancer, have mutations and concomitant protein loss in SMARCA4 (BRG1), one of the two mutually exclusive ATPases of the SWI/SNF chromatin remodeling complex. SCCOHT tumors rarely have secondary mutations, making them an excellent model for understanding the role BRG1 and SWI/SNF complexes play in tumor suppression. We hypothesize that BRG1 loss drives SCCOHT tumorigenesis by altering chromatin accessibility and gene expression. We have previously shown that BRG1 re-expression in SCCOHT cell lines suppresses cell growth and induces an elongated, neuronal-like morphology. To identify the top genes and transcription factors driving SCCOHT tumorigenesis, we performed ATAC-seq and RNA-seq in a SCCOHT cell line +/- BRG1 re-expression. BRG1 re-expression increased overall chromatin accessibly, shown by an increase in the number of ATAC-seq peaks. ATAC peaks gained following BRG1 re-expression were enriched in transcription factor binding motifs from FOS/JUN/AP-1, TEAD, and SOX family members. RNA-seq analysis demonstrated that BRG1 re-expression upregulated more genes than those downregulated, consistent with the increase in ATAC-seq peaks. Preliminary pathway analysis identified gene enrichments in epithelial-mesenchymal transition pathway and extracellular matrix remodeling following BRG1 re-expression, consistent with the observed morphology change. Cell types enrichment analysis (xCell) identified a shift from a mesenchymal stem cell-like gene signature in the control SCCOHT cells to an epithelial cell-like gene signature following BRG1 re-expression, further suggesting a possible mesenchymal-epithelial transition in SCCOHT cells after BRG1 re-expression. Future studies include integration of the ATAC/RNA-seq data to further identify correlations between gene expression changes and enriched transcription factor binding motifs, integrative ChIP-seq analysis for BRG1 following re-expression, and proteomic analyses. These studies will uncover the key genes, proteins, and transcription factors affected by BRG1 loss in other adult cancers, provide insight into BRG1's role in SCCOHT tumorigenesis, and potentially yield novel therapeutic targets. Citation Format: Krystal A. Orlando, Jesse R. Raab, Jessica D. Lang, William P. Hendricks, Yemin Wang, David G. Huntsman, Jeffrey M. Trent, Joel S. Parker, Bernard E. Weissman. Identifying drivers of SMARCA4/BRG1-deficient SCCOHT tumorigenesis by integrative multi-omic analysis [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 4318.
Abstract 4964: Metabolically activated macrophages mediate obesity-driven TNBC progression
Authors: Payal Tiwari, Ariane Blank, Chang Cui, Kelly Schoenfelt, Seema A. Khan, Marsha R. Rosner, Lev Becker
Journal: Cancer Research (2018)

Abstract Triple-negative breast cancer (TNBC) patients have the poor prognosis due to their high metastatic potential and lack of targeted therapies. Emerging epidemiological data suggest that obesity is associated with increased incidence of more aggressive triple-negative breast cancer; however, mechanisms are unclear. During obesity, adipocytes within breast tissues recruit macrophages. M2-like macrophages can exacerbate TNBC progression; however, obese breast tissue is reported to be enriched with M1-like adipose tissue macrophages (ATMs), which are anti-tumorigenic. These results raise a paradox: how does obesity promote tumor progression if it activates an anti-tumorigenic macrophage phenotype? Here we show that obesity promotes a distinct pro-inflammatory phenotype (metabolically activated macrophages; MMe) in breast ATMs, which promotes TNBC progression. We showed that ATMs isolated from obese women express cell surface markers of MMe (CD36, ABCA1) but not M1 (CD38, CD319) macrophages. We further found that pretreating TNBC cells with MMe (but not M1) derived conditioned media increase tumorsphere growth, and frequency of tumor-incidence when injected into mice in limited dilutions. Remarkably, we saw the same effect with obesity on tumor-incidence in both spontaneous and syngeneic TNBC mouse models. Moreover, blocking cytokine expression specifically in MMe using myeloid specific genetic knockout mice diminishes the effect of obesity on tumor-incidence. Interestingly, a subset of these MMe-secreted cytokines shared a common signal transducer, gp130, which led us to investigate the role of gp130 in tumors. Knocking down gp130 in cancer cells inhibits the MMe-induced stat-3 phosphorylation and tumorsphere growth in vitro, and diminishes the MMe-mediated effect of obesity on tumor-incidence in mice. Together these findings suggest that obesity-induced metabolically activated macrophages (MMe) in breast adipose tissue secrete inflammatory cytokines that promotes the TNBC tumor-progression by activating gp130 in cancer cells. A comprehensive understanding of the signaling mechanism(s) involved in metabolic activation of mammary ATMs would enable development of targeted therapies towards this specific pro-tumorigenic macrophage phenotype, thereby leaving the immune system of cancer patients intact. Citation Format: Payal Tiwari, Ariane Blank, Chang Cui, Kelly Schoenfelt, Seema A. Khan, Marsha R. Rosner, Lev Becker. Metabolically activated macrophages mediate obesity-driven TNBC progression [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 4964.
Abstract 4196: Aspirin inhibits metastasis in the intravascular phase through the blockade of COX-1-TXA2pathway in platelets
Authors: Serena Lucotti, Camilla Cerutti, Magali Soyer, Ana M. Gil-Bernabé, Ana L. Gomes, Philip D. Allen, Sean Smart, Bostjan Markelc, Karla Watson, Paul C. Armstrong, Jane A. Mitchell, Timothy D. Warner, Anne J. Ridley, Ruth J. Muschel
Journal: Cancer Research (2018)

Abstract Evidence from experimental studies and clinical trials has shown that aspirin reduces the incidence of distant metastases. Aspirin inhibits cyclooxygenase (COX)-1 and COX-2, triggering anti-thrombotic and anti-inflammatory effects, respectively. However, the mechanisms underlying the anti-metastatic effect of aspirin are still largely unknown. By employing mouse models of experimental and spontaneous metastasis, we have shown that aspirin and a selective COX-1 inhibitor dramatically reduced metastatic lung nodules, an effect that was not replicated by selective inhibition of COX-2. Metastasis was impaired in COX-1 deficient mice as well, suggesting a pivotal role of microenvironmental COX-1 in the metastatic process. In particular, COX-1 activity was essential during the intravascular phase of pulmonary metastasis. Using a model of platelet depletion and re-infusion we identified platelet-derived thromboxane A2 (TXA2) as the main product of COX-1 responsible for its permissive effect on metastasis. The inhibition of the COX-1-TXA2 pathway in platelets decreased the aggregation of platelets on tumor cells and was associated with a reduction in endothelial activation, in tumor cell adhesion to the endothelium, in recruitment of metastasis-promoting monocytes/macrophages and in transendothelial migration. Thus, platelet-derived TXA2 orchestrates the generation of a favorable intravascular metastatic niche that promotes tumor cell seeding and metastasis. Taken together, our data suggest that COX-1 inhibition in platelets by aspirin is sufficient to exert an anti-metastatic effect and shed a new light on COX-1-TXA2 signalling in the context of tumor cell dissemination. From this perspective, TXA2 might present a more selective therapeutic target for the prevention of metastasis. Citation Format: Serena Lucotti, Camilla Cerutti, Magali Soyer, Ana M. Gil-Bernabé, Ana L. Gomes, Philip D. Allen, Sean Smart, Bostjan Markelc, Karla Watson, Paul C. Armstrong, Jane A. Mitchell, Timothy D. Warner, Anne J. Ridley, Ruth J. Muschel. Aspirin inhibits metastasis in the intravascular phase through the blockade of COX-1-TXA2 pathway in platelets [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 4196.
Abstract 19757: Comparison of Contemporary Bleeding Risk Scores in Patients With Non-Valvular Atrial Fibrillation Treated With Dabigatran or Warfarin: Insights From the RE-LY Trial
Authors: Marco Proietti, Ziad Hijazi, Ulrika Andersson, Stuart J Connolly, John W Eikelboom, Michael D Ezekowitz, Deirdre A Lane, Jonas Oldgren, Vanessa Roldan, Salim Yusuf, Lars Wallentin
Journal: Circulation (2016)

Introduction: Oral anticoagulation (OAC) is the mainstay of stroke prevention in patients with atrial fibrillation (AF), but has to be balanced against the associated bleeding risk. We compared the performance of contemporary clinical bleeding risk scores in 18,113 patients with AF randomized to dabigatran 110 mg or 150 mg BD or warfarin and followed for a median of 2 years in the RELY trial. Methods: The HAS-BLED, ORBIT, ATRIA and HEMORR2HAGES bleeding risk scores were calculated based on clinical information at baseline. Major bleeding events were centrally adjudicated. Event rates in relation to subcategories of bleeding scores were evaluated by Cox regression. C indices were used to evaluate and compare discriminatory performance. Results: In the overall trial cohort of 18,113 patients, there were 1,162 (translating into an overall annual event rate of 3.25%) major bleeding events. Subgroups with higher scores were associated with a raised risk of major bleeding (all p<0.001). Discriminatory performan...
Abstract 1095: Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) regulates mitochondrial dynamics, EMT and angiogenesis in progression of prostate cancer
Authors: Arpit Dheeraj, Dhanir Tailor, Gagan Deep, Rana P. Singh
Journal: Cancer Research (2018)

Abstract Prostate cancer (PCa) is a major epithelial cancer among men and with the second highest incidence rate, worldwide. The high ratio of IGF-1/IGFBP-3 correlates with increased risk of many cancers including prostate cancer. In present study, we have evaluated the role of IGFBP-3 and effect of fisetin, a phytochemical, active constituent of strawberry, apple etc. in the progression of prostate cancer. The exogenous expression of IGFBP-3 moderately decreased the cell growth and it further decreased with addition of fisetin in DU145 and LNCaP cells. The restoration of IGFBP-3 in DU145 cells inhibited the clonogenic potential which is further decreased with fisetin treatment. Increased ROS content was observed in IGFBP-3 overexpression condition, however fisetin treatment reversed the ROS content in DU145, shows antioxidant behaviour. Morphological examination of mitochondria revealed that IGFBP-3 overexpression destabilizes the mitochondrial dynamics by reduction in active DRP1 level which has been reversed by fisetin treatment. We evaluated the effect on mitochondrial mass which was decreased in IGFBP-3 overexpressing DU145 cells which further decreased with addition of fisetin at 12 and 24 h. IGFBP-3 overexpression decreased the migratory potential of DU145 cells under normoxic conditions and under hypoxic condition it increased the migration of DU145 cells. Furthermore, IGFBP-3 overexpression decreased the VEGF expression as compared to vector control which can inhibit the expansion of tumor cells. Under the hypoxic conditions (1% oxygen), cells showed increased levels of IGFBP-3 when compared to normoxic conditions (21% Oxygen) in time dependent manner. The down-regulation of IGFBP-3 in PC3 cells, increased the expression of E-cadherin, a biomarker of epithelial to mesenchymal transition. The wound scratch assay showed the pro-migratory role of IGFBP-3 in PC3 cells and treatment with fisetin inhibited the migration of these cells under the hypoxic condition. The knockdown of IGFBP3 resulted in the decreased invasive potential of PC3 in comparison to cells in hypoxic state. Together with these observation, IGFBP-3 have shown biphasic character depending on normoxic and hypoxic condition in controlling the prostate cancer progression. Citation Format: Arpit Dheeraj, Dhanir Tailor, Gagan Deep, Rana P. Singh. Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) regulates mitochondrial dynamics, EMT and angiogenesis in progression of 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 1095.
Abstract 12405: Left Ventricular Phasic Strain Rate and Slice Rotation by Novel One-beat Real-time Three-dimensional Speckle Tracking Echocardiography With High Volume Rates
Authors: Shingo Minatoguchi, Masanori Kawasaki, Ryuhei Tanaka, Helen Houle, Takahiro Ueno, Hirotaka Miwa, Takatomo Watanabe, Maki Nagaya, Noriaki Sato, Mayumi Kaneda, Tomoko Fujii, Tai Kojima, Shunichiro Warita, Shintaro Abe, Koji Ono, Yoshiaki Goto, Kazuo Amano, Toshiyuki Noda, Sachiro Watanabe, Shinya Minatoguchi
Journal: Circulation (2015)

Background: Left ventricular (LV) strain rate (SR) at systole (S) and isovolumic relaxation (IVR) by speckle tracking echocardiography (STE) are reported as an index of LV contractility and relaxation. LV rotation contributes a part of LV ejection fraction. However, heart is a complex organ that undergoes cyclic changes in multiple directions, thus mechanics seem to be best represented by 3D-STE. We developed a novel software and 3D-STE with high volume rates to measure LV phasic and global SR and rotation. Methods: We examined the reproducibility of the novel 3D-STE in 20 subjects. We measured 5 phasic SRs {SR at isovolumic contraction (IC), S, IVR, early diastole (ED) and atrial contraction (AC)} in longitudinal, circumferential and radial direction and slice rotation in 60 controls (age 69±10), 90 hypertensive patients (HTN) and 17 hypertensive heart failure (HHF) (age 70±12). HTN was divided into 2 groups; A: HTN without hypertrophy (LVH) (n=45, age 70±8) and B: HTN with LVH (n=45, age 70±5). LV slice rotation was measured dividing LV into 9 slices from base to apex according to long axis. Results: The interobserver correlation coefficient and variability in radial SR-S from data format by 2 operators were 0.92 and 6.7±22.4%. LV radial SR-IC and SR-S in HTN reduced compared to control and those in HHF further reduced (SR-IC; control: 1.16±0.57, A: 1.05±0.44*, B: 0.82±0.32*. HHF: 0.75±0.39*. SR-S; 2.59±0.61, 2.27±0.55*, 1.88±0.34*, 1.72±0.34*, *p&lt;0.05 vs control). LV radial SR-IVR and SR-ED in HTN reduced and those in HHF further reduced (SR-IVR; -0.94±0.58, -0.66±0.39*, -0.50±0.34*, -0.34±0.23*. SR-ED; -1.28±0.51, -1.05±0.42*, -0.82±0.25, -0.68±0.23*). LV circumferential SR-AC reduced in HHF. LV slice rotation angle decreased from apex to base (Figure). Conclusion: The phasic and global SR and slice rotation of LV myocardium could be assessed by 3D-STE with high volume rates. This method may be useful to evaluate LV properties including contractility and relaxation.
Upregulation of TRPM7 Channels by Angiotensin II Triggers Phenotypic Switching of Vascular Smooth Muscle Cells of Ascending Aorta
Authors: ZhengZhang, MiWang, Xiao-HanFan, Jing-HuiChen, Yong-YuanGuan, Yong-BoTang
Journal: Circulation Research (2012)

Rationale:Angiotensin II (Ang II) has pleiotropic effects on vascular smooth muscle cells (VSMCs). It has been demonstrated to promote the proliferative phenotype of VSMCs in mouse ascending aorta, but the underlying mechanisms remain incompletely understood. Objective:The present study was designed to explore whether the Ca2+-permeable transient receptor potential melastatin 7 (TRPM7) channel is involved in Ang II–induced phenotype switching of ascending aortic VSMCs and to dissect the molecular mechanisms by which TRPM7 modulates VSMC phenotype. Methods and Results:As revealed by current recording, Ang II infusion increased TRPM7 whole-cell currents in ascending aortic VSMCs. The increase in TRPM7 currents was found to result from enhanced expression of TRPM7 protein rather than elevated single-channel activity (open probability and slope conductance) and/or reduced Mg2+-mediated channel block. Mechanistically, Ang II elevated TRPM7 expression via Ang II type 1 receptor–mediated ERK1/2 signaling. As ind...
Abstract IA25: Epigenetic regulation of cancer immune surveillance processes
Authors: Ricky W. Johnstone
Journal: Clinical Cancer Research (2017)

Abstract Altered expression, function, or localization of epigenetic enzymes and/or their partner proteins can play a crucial role in cancer onset and progression. Histone writers and erasers that regulate histone acetylation or methylation, or histone readers that recognize specific histone marks, play important roles in tightly regulating gene expression through the remodeling of chromatin and these proteins are promising targets for therapeutic interventions intended to reverse aberrant epigenetic states associated with cancer. The effects of HDAC inhibitors (HDACi) and BET bromodomain inhibitors (BETi) on tumor cell growth and survival have been well documented. However, HDACi and BETi also have immunomodulatory properties that could be important for antitumor responses and could be harnessed to enhance the activities of other anticancer agents. I will present data showing that HDACi and BETi can activate different components of the innate and adaptive immune response through effects on both the target tumor cells and on immune cells. These properties are important for the antitumor effects of HDACi and BETi and can be exploited to devise novel combination regimes involving epigenetic regulators and immune modulators. Citation Format: Ricky W. Johnstone. Epigenetic regulation of cancer immune surveillance processes [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr IA25.
Relationship between Retinal Thickness Profiles and Visual Outcomes in Young Adults Born Extremely Preterm
Authors: Siva Balasubramanian, Joanne Beckmann, Hemal Mehta, SriniVas R. Sadda, Karntida Chanwimol, Marco Nassisi, Irena Tsui, Neil Marlow, Saurabh Jain
Journal: Ophthalmology (2018)