tbuckley/cabot-search huggingface dataset:
Mitogen- and stress-activated kinase 1 (MSK1) is required for neoplastic cell transformation
Authors: Hong-Gyum Kim, Ki Won Lee, Yong-Yeon Cho, Sang-Muk Oh, Ann Bode, Zigang Dong
Journal: Cancer Research (2008)

3473  Mitogen- and stress-activated kinase 1 (MSK1) is a nuclear kinase that acts downstream of both ERK and p38 mitogen-activated protein (MAP) kinases and is activated in response to stress or mitogenic extracellular stimuli. However, the physiological role of MSK1 in malignant transformation and cancer development is not clear . Here, we report that MSK1 is involved in 12-O-tetradecanoylphorbol-13-acetate (TPA)- or epidermal growth factor (EGF)-induced cell transformation of JB6 Cl41 cells. H89, a potent inhibitor of MSK1, strongly suppressed TPA- or EGF-induced cell transformation. When cells overexpressing wildtype MSK1 were treated with TPA or EGF, colony formation increased markedly compared to untreated cells or cells that did not overexpress MSK1. In contrast, MSK1 C-terminal or N-terminal dead dominant negative mutants dramatically suppressed cell transformation. Introduction of small interfering (si) RNA-MSK1 into JB6 Cl41 cells resulted in suppressed TPA- or EGF-induced cell transformation. In addition, cell proliferation was inhibited in MSK1 knockdown cells compared to MSK1 wildtype cells. In wildtype MSK1-overexpressing cells, AP-1 activation increased after TPA or EGF stimulation, whereas AP-1 activation decreased in both MSK1 dominant-negative mutants and MSK1 knockdown cells. Moreover, TPA- or EGF-induced phosphorylation of histone H3 at Ser10 was increased in wildtype cells but the induced phosphorylation was abolished in MSK1 dominant-negative mutant or MSK1 knockdown cells. Histone H3 mutant (S10A) cells also inhibited EGF- or TPA-induced colony transformation. Thus, MSK1 is required for tumor promoter-induced cell transformation through its phosphorylation of histone H3 at Ser10 and AP-1 activation.
Next-Generation Sequencing to Diagnose Suspected Genetic Disorders
Authors: David R. Adams, Christine M. Eng
Journal: New England Journal of Medicine (2018)

Interview with Dr. David Adams on the use of clinical next-generation sequencing to obtain a genetic diagnosis. (06:23)Download The technologies and chemistries underlying next-generation sequencing of DNA are evolving rapidly. This review describes the three main approaches to obtaining a genetic diagnosis through next-generation sequencing, their advantages, and their limitations.
Abstract 13212: The Role of Macrophage STAT3 Signaling in Pathogenesis of Aortic Dissection
Authors: Satoko Ohno, Hiroki Aoki, Michihide Nishihara, Aya Furusho, Saki Hirakata, Norifumi Nishida, Sohei Ito, Makiko Hayashi, Yoshihiro Fukumoto
Journal: Circulation (2015)

Aortic dissection (AD) is a fatal disease caused by the disruption of the intimomedial layer. Recent studies showed that IL-6, a STAT3-activating cytokine, and macrophages play important roles in AD. However, it is unknown whether or how activation of macrophage STAT3 is involved in AD pathogenesis. To answer this question, we examined both mouse AD model and human AD tissue. We used macrophage-specific knockout of SOCS3 (mSOCS3-KO), a negative regulator of STAT3, to specifically sensitize macrophages to STAT3 activation, and compared them with wild type (WT) mice. We created a mouse model of aortic stiffening by periaortic CaCl2 treatment of abdominal aorta, and infused them with angiotensin II (Ca+AngII), which augmented hemodynamic stress to aortic walls. Both WT and mSOCS3-KO showed microscopic injuries in aorta with equal frequencies (40%) 1 week after Ca+AngII. Whereas WT showed fibrotic repair of the injury, mSOCS3-KO failed to show such reparative response and developed large AD in 6 weeks. We analyzed the aorta 1 week after the Ca+AngII stimulation, focusing on the changes in aorta preceding AD development. Transcriptome analysis showed higher activation of cell cycle followed by higher proinflammatory response in mSOCS3-KO than in WT aorta before AD development. Ki67 staining and BrdU uptake study confirmed the proliferative response of inflammatory cells in aorta. Flowcytometric analysis showed preferential differentiation of mSOCS3-KO macrophages to proinflammatory M1 with reduction in reparative M2 population (M1:M2 = 2:1), while WT macrophages differentiated equally to M1 and M2. Immunofluorescence study of human AD tissue showed the infiltration of CD68-positive macrophages in adventitia and outer media at the site of dissection and surrounding intact aortic walls. The infiltrating cells showed high phospho- (active) STAT3 and Ki67. Interestingly, STAT3 was less active in tissue with fibrotic changes, suggesting the negative association of STAT3 activation and tissue repair. Therefore, macrophage STAT3 activation resulted in higher proliferation and M1 differentiation, which is likely to promote AD development. Over activation of STAT3 in macrophages may be a therapeutic target to mitigate the destructive process in AD.
E-cadherin expression on multiple myeloma cells activates tumor-promoting properties in plasmacytoid DCs
Authors: Enguang Bi, Rong Li, Laura C. Bover, Haiyan Li, Pan Su, Xingzhe Ma, Chunjian Huang, Qiang Wang, Lintao Liu, Maojie Yang, Zhijuan Lin, Jianfei Qian, Weijun Fu, Yong-Jun Liu, Qing Yi
Journal: Journal of Clinical Investigation (2018)

Plasmacytoid dendritic cells (pDCs) play a key role in antiviral responses by producing type-1 IFNs. However, recent studies showed that pDCs induce immune suppression and promote tumor growth in human ovarian cancer and myeloma. The molecular mechanisms underlying pDC acquisition of these properties are unknown. Here we show that human pDCs activated by CpG inhibited growth and induced apoptosis in myeloma cells via secreted IFN-α, but direct contact with myeloma cells converted pDCs into tumor-promoting cells by suppressing pDC IFN-α production. E-cadherin, expressed on both myeloma cells and pDCs, mediated these effects via a homophilic interaction — activation of E-cadherin signaling upregulated and activated TNFAIP3 to interact with TLR9, resulting in TLR9 ubiquitination and degradation, and inhibition of IFN-α production in pDCs. These findings were supported by an in vivo study in which pDC depletion induced tumor regression and better survival in the Vk*MYC myeloma mouse model. Furthermore, IFNAR1 expression level positively correlated to overall survival of patients with multiple myeloma (MM), and the IFN-α level in patient bone marrow was significantly lower than that in marrow of healthy individuals. This study reveals a novel mechanism underlying how MM tumors educate pDCs in their microenvironment and provides new targets for improving the treatment of MM.
Acetylcholine signaling system in progression of lung cancers
Authors: Jamie R. Friedman, Stephen D. Richbart, Justin C. Merritt, Kathleen C. Brown, Nicholas A. Nolan, Austin T. Akers, Jamie K. Lau, Zachary R. Robateau, Sarah L. Miles, Piyali Dasgupta
Journal: Pharmacology & Therapeutics (2018)
Evaluation of the HIV Infant Tracking System (HITSystem) to optimise quality and efficiency of early infant diagnosis: a cluster-randomised trial in Kenya
Authors: Sarah Finocchario-Kessler, Brad Gautney, AnLin Cheng, Catherine Wexler, May Maloba, Niaman Nazir, Samoel Khamadi, Raphael Lwembe, Melinda Brown, Thomas A Odeny, Jacinda K Dariotis, Matthew Sandbulte, Natabhona Mabachi, Kathy Goggin
Journal: The Lancet HIV (2018)
Abstract 18082: Poor Fontan Geometry, Hemodynamics, and Computational Fluid Dynamics Are Associated With Worse Quality of Life
Authors: Bradley S Marino, Mark Fogel, Laura Mercer-Rosa Mercer-Rosa, Zhenglun Alan Wei Wei, Phillip M Trusty, Micheal Tree, Elaine Tang, Maria Restrepo, Kevin K Whitehead, Stephen M Paridon, Ajit Yoganathan
Journal: Circulation (2017)

Introduction: Fontan palliation results in favorable short-term outcomes but limited exercise tolerance and poor quality of life (QOL) years after completion. Vessel narrowing and power loss in Fon...
Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps
Authors: Anubha Mahajan, Daniel Taliun, Matthias Thurner, Neil R. Robertson, Jason M. Torres, N. William Rayner, Anthony J. Payne, Valgerdur Steinthorsdottir, Robert A. Scott, Niels Grarup, James P. Cook, Ellen M. Schmidt, Matthias Wuttke, Chloé Sarnowski, Reedik Mägi, Jana Nano, Christian Gieger, Stella Trompet, Cécile Lecoeur, Michael H. Preuss, Bram Peter Prins, Xiuqing Guo, Lawrence F. Bielak, Jennifer E. Below, Donald W. Bowden, John Campbell Chambers, Young Jin Kim, Maggie C. Y. Ng, Lauren E. Petty, Xueling Sim, Weihua Zhang, Amanda J. Bennett, Jette Bork-Jensen, Chad M. Brummett, Mickaël Canouil, Kai-Uwe Ec kardt, Krista Fischer, Sharon L. R. Kardia, Florian Kronenberg, Kristi Läll, Ching-Ti Liu, Adam E. Locke, Jian’an Luan, Ioanna Ntalla, Vibe Nylander, Sebastian Schönherr, Claudia Schurmann, Loïc Yengo, Erwin P. Bottinger, Ivan Brandslund, Cramer Christensen, George Dedoussis, Jose C. Florez, Ian Ford, Oscar H. Franco, Timothy M. Frayling, Vilmantas Giedraitis, Sophie Hackinger, Andrew T. Hattersley, Christian Herder, M. Arfan Ikram, Martin Ingelsson, Marit E. Jørgensen, Torben Jørgensen, Jennifer Kriebel, Johanna Kuusisto, Symen Ligthart, Cecilia M. Lindgren, Allan Linneberg, Valeriya Lyssenko, Vasiliki Mamakou, Thomas Meitinger, Karen L. Mohlke, Andrew D. Morris, Girish Nadkarni, James S. Pankow, Annette Peters, Naveed Sattar, Alena Stančáková, Konstantin Strauch, Kent D. Taylor, Barbara Thorand, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Jaakko Tuomilehto, Daniel R. Witte, Josée Dupuis, Patricia A. Peyser, Eleftheria Zeggini, Ruth J. F. Loos, Philippe Froguel, Erik Ingelsson, Lars Lind, Leif Groop, Markku Laakso, Francis S. Collins, J. Wouter Jukema, Colin N. A. Palmer, Harald Grallert, Andres Metspalu, Abbas Dehghan, Anna Köttgen, Goncalo R. Abecasis, James B. Meigs, Jerome I. Rotter, Jonathan Marchini, Oluf Pedersen, Torben Hansen, Claudia Langenberg, Nicholas J. Wareham, Kari Stefansson, Anna L. Gloyn, Andrew P. Morris, Michael Boehnke, Mark I. McCarthy
Journal: Nature Genetics (2018)
Clinical Significance of Extracellular Vesicles in Plasma from Glioblastoma Patients
Authors: Daniela Osti, Massimiliano Del Bene, Germana Rappa, Mark Santos, Vittoria Matafora, Cristina Richichi, Stefania Faletti, Galina V. Beznoussenko, Alexandre Mironov, Angela Bachi, Lorenzo Fornasari, Daniele Bongetta, Paolo Gaetani, Francesco DiMeco, Aurelio Lorico, Giuliana Pelicci
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Glioblastoma (GBM) is the most common primary brain tumor. The identification of blood biomarkers reflecting the tumor status represents a major unmet need for optimal clinical management of patients with GBM. Their high number in body fluids, their stability, and the presence of many tumor-associated proteins and RNAs make extracellular vesicles potentially optimal biomarkers. Here, we investigated the potential role of plasma extracellular vesicles from patients with GBM for diagnosis and follow-up after treatment and as a prognostic tool. Experimental Design: Plasma from healthy controls (n = 33), patients with GBM (n = 43), and patients with different central nervous system malignancies (n = 25) were collected. Extracellular vesicles were isolated by ultracentrifugation and characterized in terms of morphology by transmission electron microscopy, concentration, and size by nanoparticle tracking analysis, and protein composition by mass spectrometry. An orthotopic mouse model of human GBM confirmed human plasma extracellular vesicle quantifications. Associations between plasma extracellular vesicle concentration and clinicopathologic features of patients with GBM were analyzed. All statistical tests were two-sided. Results: GBM releases heterogeneous extracellular vesicles detectable in plasma. Plasma extracellular vesicle concentration was higher in GBM compared with healthy controls (P &amp;lt; 0.001), brain metastases (P &amp;lt; 0.001), and extra-axial brain tumors (P &amp;lt; 0.001). After surgery, a significant drop in plasma extracellular vesicle concentration was measured (P &amp;lt; 0.001). Plasma extracellular vesicle concentration was also increased in GBM-bearing mice (P &amp;lt; 0.001). Proteomic profiling revealed a GBM-distinctive signature. Conclusions: Higher extracellular vesicle plasma levels may assist in GBM clinical diagnosis: their reduction after GBM resection, their rise at recurrence, and their protein cargo might provide indications about tumor, therapy response, and monitoring.
ATAC-ing the mechanisms of renin regulation
Authors: Steven D. Crowley
Journal: Journal of Clinical Investigation (2018)

Renin-expressing cells have been conserved through evolution and maintain blood pressure and fluid homeostasis. Lack of availability of tools to study the specifics of renin regulation has limited advances in this field. In the current issue of the Journal of Clinical Investigation, Martinez and colleagues used the genome-wide assessment of the chromatin status of cells and uncovered a unique set of super-enhancers that determine the identity of renin cells. The renin super-enhancers play a key role in the molecular memory of renin cell function, a mechanism at the core of preserving homeostasis.
Abstract P173: Improvements in Adherence to Antihypertensive Medication Among Medicare Beneficiaries Initiating Treatment Between 2007 and 2012
Authors: Gabriel S Tajeu, Shia T Kent, Daichi Shimbo, Marie Krousel-Wood, Ian M Kronish, Adam P Bress, Lei Huang, Paul Muntner
Journal: Circulation (2016)

Introduction: Low antihypertensive medication adherence has been reported, leading to recommendations for interventions to improve adherence. We evaluated trends in low medication adherence and discontinuation among Medicare beneficiaries initiating antihypertensive medication from 2007 to 2012. Hypothesis: Low antihypertensive medication adherence has decreased over time. Methods: We analyzed data on beneficiaries with ≥ 2 diagnoses for hypertension (ICD-9, 401.xx) in the Medicare 5% random sample initiating antihypertensive medication. Initiation was defined by a pharmacy claim for antihypertensive medication with no claims within the previous 365 days. Beneficiaries were required to have full Medicare fee-for-service coverage (Parts A, B and D) for the 365 days prior to and following the date of initiation. Low adherence was defined as having a proportion of days covered &lt;80% during the 365 day following initiation. Discontinuation was defined as having no days of supply or fills during the final 73 days in the year following initiation. Results: Between 2007-2012, 44,147 Medicare beneficiaries initiated antihypertensive medication. In the overall sample, low adherence decreased from 36.4% in 2007 to 31.7% in 2012 (p&lt;0.001) (Table). After multivariable adjustment, the relative risk (RR) of low adherence for beneficiaries initiating treatment in 2012 compared with those initiating treatment in 2007 was 0.84 (95% CI 0.79-0.89). Throughout the study period, low adherence was more common in beneficiaries that were black (RR 1.41; 95% CI 1.35-1.48), Hispanic (RR 1.40; 95% CI 1.30-1.50), had low income (RR 1.19; 95% CI 1.08-1.32), depression (RR 1.06; 95% CI 1.01-1.12), or a serious fall injury following antihypertensive medication initiation (RR 1.34; 95% CI 1.23-1.47). Discontinuation did not decrease over time. Conclusion: Low adherence to antihypertensive medication among Medicare beneficiaries has decreased over time. Higher rates of low adherence remain for blacks compared with whites.
FA-based combinations to target the DNA damage response in glioblastoma
Authors: Mr Ola Rominiyi, Dr Natividad Gomez-Roman, Mr Yahia Al-Tamimi, Mr David A Jellinek, Prof Anthony J Chalmers, Mr Thomas A Carroll, Prof Beining Chen, Dr Spencer Collis
Journal: Neuro-Oncology (2018)

Despite surgical resection followed by DNA-damaging adjuvant therapies, glioblastoma multiforme (GBM) remains incurable with a median survival of just 15.6 months. Anomalies within the DNA damage response (DDR) contribute to treatment resistance. We have previously shown that the Fanconi Anaemia (FA) pathway, a key DDR process, remains inactive in normal brain but is re-activated in GBM, making it an appealing foundational target for cancer-specific combination therapies. AIM: To determine whether combined targeting of the FA pathway and interconnected DDR processes could form a basis for new, effective multimodal therapies. Bioinformatic analysis of mRNA expression data (REMBRANDT database) was used to investigate the relevance of FA pathway genes in glioma. Subsequently, immunofluorescence and cell viability assays were used to validate and establish the therapeutic potential of novel FA pathway inhibitors (nFAPi) and inhibition of related DDR targets in established GBM cell models. Finally, combinations targeting the DDR were optimised using immunoblotting, and assessed using clonogenic survival in a novel 3D patient-derived glioblastoma stem cell model. High expression of downstream FA pathway genes is strongly associated with poor survival (-17.1% 5-year OS, n=329, Log-rank, P<0.0001) and is a feature of more aggressive tumour biology (log2-relative expression, GBM vs WHO Grade I-III gliomas: 7.18 ± 0.02 vs 7.08 ± 0.02, unpaired t-test, P=0.0009). In established GBM models FAPi and nFAPi were demonstrated to attenuate key markers of FA pathway activity. Of translational importance, nFAPi sensitised GBM cells to temozolomide (comparison of fits F value 63.7, P<0.0001). Inhibitors of PARP1 (PARPi) and ATR also demonstrated potential as temozolomide-sensitising agents. Furthermore, combined FAPi and PARPi significantly reduced cell viability (F value 12.99, P<0.0001) and enhanced radiosensitisation in patient-derived 3D models with sensitiser enhancement ratios (SER0.37) of 1.51 (1.50–1.51, 95% CI) and 1.57 (1.52–1.61), respectively.
Early PREdiction of sepsis using leukocyte surface biomarkers: the ExPRES-sepsis cohort study
Authors: Manu Shankar-Hari, Deepankar Datta, Julie Wilson, Valentina Assi, Jacqueline Stephen, Christopher J. Weir, Jillian Rennie, Jean Antonelli, Anthony Bateman, Jennifer M. Felton, Noel Warner, Kevin Judge, Jim Keenan, Alice Wang, Tony Burpee, Alun K. Brown, Sion M. Lewis, Tracey Mare, Alistair I. Roy, John Wright, Gillian Hulme, Ian Dimmick, Alasdair Gray, Adriano G. Rossi, A. John Simpson, Andrew Conway Morris, Timothy S. Walsh
Journal: Intensive Care Medicine (2018)
Abstract 18003: Patients With Good Adherence to Study Medication Have Better Outcomes: Insights From the ARISTOTLE Trial
Authors: Denis Xavier, Michael Hanna, Lars Wallentin, John H Alexander, Renato D Lopes, Peter Merrill, Daniel Wojdyla, M. Cecilia Bahit, Stefan H Hohnloser, Christopher B Granger
Journal: Circulation (2017)

Background: Apixaban is effective in preventing stroke in atrial fibrillation in the diverse populations enrolled in clinical trials. Less is known about how outcomes and treatment effects relate t...
STEREOTACTIC RADIOSURGERY FOR PATIENTS WITH MELANOMA AND MULTIPLE BRAIN METASTASES: EXPERIENCE DURING THE ERA OF IMMUNOTHERAPY AND TARGETED AGENTS
Authors: Paul Sanghera, Richard Fox, Helen Benghiat, Sara Meade, Andrew Hartley, Garth Cruickshank, Vijay Sawlani, Neil Steven
Journal: Neuro-Oncology (2018)

There has been significant progress in the treatment of metastatic melanoma, however the impact of new agents on patients with brain metastases remains poorly understood. We report outcomes using SRS for patients with melanoma brain metastases exposed to BRAF targeted agents and/or immunotherapy. METHODS Consecutive patients with metastatic melanoma and brain metastases undergoing SRS without routine whole brain radiotherapy were identified. Selection was restricted to patients having systemic therapy within the same centre. Follow-up included 3monthly MRI scans. All patients were treated using Cyberknife. The target volume was neuroradiology approved without an uncertainty margin. A review of electronic records and follow up imaging was undertaken. Survival data were summarized using Kaplan-Meier curves and compared via a logrank test. RESULTS 49 patients with 148 target metastases were identified. Median number of lesions was 2 (range 1–12), median dose 21Gy, median volume 0.31cc (range 0.01–6.71cc) and 94% had extracranial disease at 2 or more sites. Three patients did not have follow up MRI. One patient required long-term steroids, 1 had transient symptomatic swelling at 11months and 3 patients experienced bleeds (1 symptomatic- post-SRS treated lesion). 12-month local disease free survival was 71% (CI 53, 84). Distant brain progression occurred in 28 patients (57%), with a median time to progression of 8months (95% CI 5, 15). Distant brain progression was less frequent in patients with a single metastasis (p=0.03). Median overall survival (OS) was 11months (95% CI 8, 17). Median OS was 20months (95% CI 5, NR), 10months (95% CI 4, 12) and 11months (95% CI 3, NR) for patients with 1, 2–4 and ≥ 5 metastases respectively (p=0.07). CONCLUSION Beyond a single metastasis, the number of brain metastases did not correlate with OS. Patients with multiple brain metastases and active systemic disease may benefit from SRS however prospective evaluation is recommended.
18F-FDG PET/CT in Isolated Primary Extraskeletal Osteosarcoma
Authors: Ashwin Singh Parihar, Bhagwant Rai Mittal, Shelvin Kumar Vadi, Apurva Sood, Rajender Kumar, Vijay Goni
Journal: Clinical Nuclear Medicine (2018)

Abstract Extraskeletal osteosarcoma is a rare, high-grade soft tissue malignancy, accounting for approximately 1% of all soft tissue sarcomas. Despite the histologic resemblance to osteogenic osteosarcoma, it is considered as a distinct entity because of the differences in clinical behavior and response to treatment. Hence, imaging plays a vital role in establishing the nonskeletal origin of the tumor, differentiating it from osteogenic osteosarcoma. We present 18 F-FDG PET/CT findings in a case of isolated primary extraskeletal osteosarcoma confirmed on histopathology.