tbuckley/cabot-search huggingface dataset:
Abstract 16528: Activation of Classical Complement Pathway is Associated with the Development of Idiopathic Pulmonary Arterial Hypertension (IPAH)
Authors: Toshie Saito, Orr Sharpe, Daisuke Harada, Rasa Tamosiuniene, Caiyun G Li, Mark Nicolls, William H Robinson, Marlene Rabinovitch
Journal: Circulation (2012)

Background: Circulating autoantibodies and activation of the complement system were reported in patients with IPAH. However target antigens isolated from lung tissue of IPAH patients have not been ...
Abstract 15337: The Prevalence of Clinically Significant Ischemia in Patients Undergoing Percutaneous Coronary Intervention, a Report From the Multicenter Registry
Authors: Jun Fujita, Shun Kohsaka, Ikuko Ueda, Taku Inohara, Yuichiro Maekawa, Akio Kawamura, Hideaki Kanazawa, Kentaro Hayashida, Ryota Tabei, Shugo Tohyama, Tomohisa Seki, Masahiro Suzuki, Motoaki Sano, Keiichi Fukuda
Journal: Circulation (2015)

Background: Myocardial perfusion scintigraphy (MPS) plays an important role in the evaluation and quantification of myocardial ischemia, and those with significant ischemia (SI) benefit most from revascularization procedures. This study aimed to identify the clinical factors and anatomical features associated with SI in patients with stable ischemic heart disease (SIHD). Methods and Results: Data were analyzed from 4197 SIHD patients undergoing PCI in The Japan Cardiovascular Database (N = 11,258) between September 2008 and April 2013. MPS was used to evaluate 1070 (25.5%) patients. Significant ischemia (SI) was defined as more than 10% ischemic region. Logistic regression analysis was performed to identify any clinical factors associated with SI. Patients with a history of heart failure, stroke, or anginal symptoms with Canadian Cardiovascular Society class 2 or more were more likely to have SI (odds ratio [OR] 1.63, p = 0.025, OR: 1.85, p = 0.009, and OR: 1.49, p = 0.003, respectively). When angiographic variables were considered, a proximal left anterior descending artery (pLAD) lesion was the sole factor associated with SI (OR: 1.46, p = 0.012) (Table). Importantly, those with SI had more complications (p = 0.006), most notably post-PCI infarcts (p = 0.008) (Figure). Conclusions: Patients’ background data, such as stronger anginal symptoms or a pLAD lesion, were associated with SI. Since patients with SI are necessary to be treated with PCI to improve long-term prognosis, however procedure-related complications happen more frequently than non-SI patients. Physicians must give their full attention to the PCI procedure in SI patients to minimize their complication rate.
Abstract CT161: A Phase II study of the polo-like kinase (PLK1) inhibitor onvansertib in combination with abiraterone (abi) and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC)
Authors: David J. Einstein, Atish Choudhury, Philip Saylor, Lillian Werner, Mark Erlander, Maya Ridinger, Glenn Bubley
Journal: Cancer Research (2019)

Abstract Background: mCRPC remains a leading cause of cancer-related deaths worldwide. Although abi increases survival, resistance is universal and generally occurs within 9-16 months of initiating treatment. PLK1, a serine/threonine kinase, is a master regulator of cell-cycle progression and is highly upregulated in prostate cancer following castration. PLK1 inhibition enhances the efficacy of abi in cell line models and patient-derived tumor xenografts. Onvansertib (PCM-075; Trovagene, Inc.) is the first orally available PLK1-specific inhibitor. In Phase I testing, onvansertib demonstrated a manageable safety profile, with transient hematologic effects as its most prominent, yet reversible, toxicity. Methods: The goal of this Phase II study (NCT03414034) is to observe the effects of onvansertib in combination with abi + prednisone on disease control, as assessed by prostate-specific antigen (PSA) decline or stabilization after 12 weeks of study treatment, in subjects with mCRPC and early resistance to abi. Patients are enrolled at time of PSA progression while on standard abi and treated with onvansertib (24 mg/m2 orally on days 1-5 of a 21-day cycle) plus abi (administered orally and continuously once daily with prednisone) until time of radiographic or symptomatic progression. The safety lead-in of 3 subjects showed no dose-limiting toxicities or new toxicities from the combination of onvansertib with abi. A 29-patient expansion phase is ongoing, with 11 patients enrolled as of January 2019. With 32 patients, there will be 90% power to detect a change in disease-control rate from 10% (null) to 30% (alternative). Based on a Simon’s two-stage optimal design, the study will terminate early if &amp;lt;2 of the first 13 patients achieve disease control. Toxicity and PSA levels are monitored during treatment. Exploratory analyses include quantification of circulating tumor cells, evaluation of PLK1 inhibition in vivo and evaluation of predictive genomic biomarkers in circulating tumor DNA, such as alterations in oncogenes and tumor suppressors. Citation Format: David J. Einstein, Atish Choudhury, Philip Saylor, Lillian Werner, Mark Erlander, Maya Ridinger, Glenn Bubley. A Phase II study of the polo-like kinase (PLK1) inhibitor onvansertib in combination with abiraterone (abi) and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT161.
Abstract 1473: Dual oncolytic viral immunotherapy generates large polyfunctional tumour-specific CD8 + T cell responses that infiltrate immunosuppressive tumors
Authors: David Stojdl
Journal: Cancer Research (2019)

Abstract Generating effective T cell mediated clearance of solid tumors remains an unmet challenge in cancer therapy. Suppressive tumor microenvironments limit the generation of significant numbers of tumor specific T effector cells, their migration to tumor beds, and their subsequent functionality within tumors, thereby blocking the patient’s normally potent acquired immune response from contributing to tumor control. In an effort to meet this challenge, we have developed novel oncolytic viruses that were bioselected and engineered to cause cancer cell death through two distinct and complementary mechanisms-of-action, direct cancer lysis and tumor-antigen specific T cell generation. Specifically, we have selected and engineered MG1 Maraba virus which both infects tumor tissue to reverse immune suppressive programs while simultaneously delivering vector encoded tumor antigens to the spleen to vaccinate against the patient’s tumor. The result is a large increase in peripheral and tumor infiltrating CD8+ T effectors cells, strong intratumoral inflammatory signatures and ultimately curative efficacy in preclinical solid tumor models. This first-in-class therapeutic strategy is currently being evaluated in Phase 1 and Phase 2 clinical trials. In this new study, we describe the development of a novel viral immunotherapy platform based on Farmington virus that is: (1) oncolytic in solid tumor models, (2) a potent inducer of highly-functional antigen-specific T cells (expanding tumor specific CD8+ T effector pools over 1000 fold from pre-existing T central memory) and is (3) immunologically distinct from our clinical MG1 Maraba platform. We show that when used sequentially in a heterologous boosting regimen, T cell responses to encoded tumor antigens, either foreign (HPV E7), self (TRP2) or multi-neoantigen, can exceed greater than 50% of all CD8+ T cells in the periphery. The majority of these CD8+ T effectors show markers of polyfunctionality with little expression of the PD-1 exhaustion marker. We will describe our current data assessing the phenotype, localization and potency of these T cell responses in preclinical models of solid tumors and propose strategies to deploy our novel dual oncolytic viral immunotherapy boosting paradigm to the clinic. Citation Format: David Stojdl. Dual oncolytic viral immunotherapy generates large polyfunctional tumour-specific CD8 + T cell responses that infiltrate immunosuppressive tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1473.
Abstract 19013: Epidemiology of Out-of-Hospital Cardiac Arrest Within the Resuscitation Outcomes Consortium From 2011 to 2015: Improved Survival Though Site Differences Persist
Authors: Dana M Zive, Robert Schmicker, Mohamud Daya, Peter Kudenchuk, Jon C Rittenberger, Tom Aufderheide, Gary Vilke, Jim Christenson, Jason Buick, Ken Kaila, Susanne J May, Thomas Rea, Laurie J Morrison
Journal: Circulation (2017)

Background: The Resuscitation Outcomes Consortium (ROC) maintains an epidemiological registry (Epistry) of out-of-hospital cardiac arrest (OHCA), providing an opportunity to assess temporal trends ...
<i>在一组西班牙黑色素瘤家族中,与黑色素瘤易感性有关的是 POT1</i> 生殖系突变而非 TERT <i>启动子突变</i>
Authors: M. Potrony, J.A. Puig‐Butille, M. Ribera‐Sola, V. Iyer, C.D. Robles‐Espinoza, P. Aguilera, C. Carrera, J. Malvehy, C. Badenas, M.T. Landi, D.J. Adams, S. Puig
Journal: British Journal of Dermatology (2019)

黑色素瘤是一种侵袭性皮肤癌。全世界每年有超过 250,000 例新确诊病例。如果在早期诊断,黑色素瘤可以通过相对简单的手术治愈。在全球范围内,20% 的黑色素瘤患者将会死亡,但当被诊断为厚(更晚期/晚期)肿瘤时,死亡的可能性将增加高达 60%。提高生存率的最佳策略是提早诊断。识别处于危险中的人至关重要。大约 10% 的病例发生在家族环境中。这意味着这些个体有遗传性黑色素瘤的风险,而这可以通过特定基因的改变(突变)来解释。在一个已知突变的家族中,携带该突变的健康个体可以被纳入早期检测计划,从而能够在早期诊断出黑色素瘤。但是,在超过 70% 的家族中,造成这种风险的基因仍然未知。这项来自西班牙的研究旨在评估西班牙没有已知突变基因的、黑色素瘤易发家族中两个基因(POT1 和 TERT)突变的患病率。作者对 228 个家族的两种基因进行了测序(一种研究方法)。他们发现,在接受评估的家族中,有近 2% 发生了突变。他们还在两个家族中发现了两名同样患有甲状腺恶性肿瘤的患者。如果在其他研究中得到证实,那么这个基因突变的黑色素瘤易发家族也将受益于甲状腺肿瘤的早期诊断。TERT 启动子中未识别出突变,这表明该基因在西班牙家族性黑色素瘤易感性中不发挥重要作用。
<i>EN1</i> Is a Transcriptional Dependency in Triple-Negative Breast Cancer Associated with Brain Metastasis
Authors: Guillermo Peluffo, Ashim Subedee, Nicholas W. Harper, Natalie Kingston, Bojana Jovanović, Felipe Flores, Laura E. Stevens, Francisco Beca, Anne Trinh, Chandra Sekhar Reddy Chilamakuri, Evangelia K. Papachristou, Katherine Murphy, Ying Su, Andriy Marusyk, Clive S. D'Santos, Oscar M. Rueda, Andrew H. Beck, Carlos Caldas, Jason S. Carroll, Kornelia Polyak
Journal: Cancer Research (2019)

Abstract To define transcriptional dependencies of triple-negative breast cancer (TNBC), we identified transcription factors highly and specifically expressed in primary TNBCs and tested their requirement for cell growth in a panel of breast cancer cell lines. We found that EN1 (engrailed 1) is overexpressed in TNBCs and its downregulation preferentially and significantly reduced viability and tumorigenicity in TNBC cell lines. By integrating gene expression changes after EN1 downregulation with EN1 chromatin binding patterns, we identified genes involved in WNT and Hedgehog signaling, neurogenesis, and axonal guidance as direct EN1 transcriptional targets. Quantitative proteomic analyses of EN1-bound chromatin complexes revealed association with transcriptional repressors and coactivators including TLE3, TRIM24, TRIM28, and TRIM33. High expression of EN1 correlated with short overall survival and increased risk of developing brain metastases in patients with TNBC. Thus, EN1 is a prognostic marker and a potential therapeutic target in TNBC. Significance: These findings show that the EN1 transcription factor regulates neurogenesis-related genes and is associated with brain metastasis in triple-negative breast cancer.
Bacteriophages Improve Outcomes in Experimental <i>Staphylococcus aureus</i> Ventilator-associated Pneumonia
Authors: Josef Prazak, Manuela Iten, David R. Cameron, Jonathan Save, Denis Grandgirard, Gregory Resch, Christine Goepfert, Stephen L. Leib, Jukka Takala, Stephan M. Jakob, Yok-Ai Que, Matthias Haenggi
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rationale: Infections caused by multidrug-resistant bacteria are a major clinical challenge. Phage therapy is a promising alternative antibacterial strategy.Objectives: To evaluate the efficacy of intravenous phage therapy for the treatment of ventilator-associated pneumonia due to methicillin-resistant Staphylococcus aureus in rats.Methods: In a randomized, blinded, controlled experimental study, we compared intravenous teicoplanin (3 mg/kg, n = 12), a cocktail of four phages (2–3 × 109 plaque-forming units/ml of 2003, 2002, 3A, and K; n = 12), and a combination of both (n = 11) given 2, 12, and 24 hours after induction of pneumonia, and then once daily for 4 days. The primary outcome was survival at Day 4. Secondary outcomes were bacterial and phage densities in lungs and spleen, histopathological scoring of infection within the lungs, and inflammatory biomarkers in blood.Measurements and Main Results: Treatment with either phages or teicoplanin increased survival from 0% to 58% and 50%, respectively (P < 0.005). The combination of phages and antibiotics did not further improve outcomes (45% survival). Animal survival correlated with reduced bacterial burdens in the lung (1.2 × 106 cfu/g of tissue for survivors vs. 1.2 × 109 cfu/g for nonsurviving animals; P < 0.0001), as well as improved histopathological outcomes. Phage multiplication within the lung occurred during treatment. IL-1β increased in all treatment groups over the course of therapy.Conclusions: Phage therapy was as effective as teicoplanin in improving survival and decreasing bacterial load within the lungs of rats infected with methicillin-resistant S. aureus. Combining antibiotics with phage therapy did not further improve outcomes.
Abstract 1010: Extracellular matrix signaling modulates estrogen receptor activity in breast cancer
Authors: Josh W. DiGiacomo, Inês Godet, Michael Trautmann Rodriguez, I Chae Ye, Daniele M. Gilkes
Journal: Cancer Research (2019)

Abstract The tumor microenvironment plays a crucial role in cancer progression. In breast cancer, the extracellular matrix (ECM) is especially important as it contributes to mammographic breast density. Women with higher mammographic breast densities are at a greater risk for the development of breast cancer. Despite this, much knowledge of the ECM’s effects on breast cancer progression remains elusive. To better understand how ECM signaling affects breast cancer, we utilize fibroblast-deposited, decellularized ECM scaffolds. Scaffolds are produced for in vitro use by culturing a confluent layer of fibroblast cells over six days followed by decellularization with a detergent solution. RNA sequencing analysis of MCF7 human breast cancer cells cultured on ECM scaffolds versus uncoated dishes revealed differential expression of hundreds of genes. Most notably, genes within hallmark sets for early and late responses to estrogen were significantly enriched when cells were cultured on ECM. We confirm the expression of estrogen-responsive genes in breast cancer cells cultured on ECM even in the complete absence of estrogen, and also note that the estrogen receptor (ER) itself is downregulated at both the RNA and protein-level, consistent with results of estrogen stimulation. Treatment of breast cancer cells with ER inhibitors hydroxytamoxifen and fulvestrant reduces ECM-induced expression of estrogen-responsive genes. Likewise, culturing breast cancer cells on ECM enhances phosphorylation of Erk. Inhibition of phospho-Erk also reduces the expression of the same estrogen-responsive genes in cells cultured on ECM. Through luciferase, conditioned media, and estrogen-starvation assays, we demonstrate that ECM signaling activates estrogen receptor signaling in an estrogen-independent, nonclassical mechanism. In addition, we show that ER positive cells cultured on ECM are more resistant to ER-targeted therapeutics, but not other chemotherapeutic agents like paclitaxel or doxorubicin. Ultimately, we describe a pathway in which ECM can induce estrogen-independent activation of the ER as well as resistance to estrogen-targeted therapies in breast cancer. Clinical research into the effects of mammographic breast density beyond breast cancer predisposition is sparse, and this work provides incentive for investigators to better understand the relationship between breast fibrosis and clinical outcome. Citation Format: Josh W. DiGiacomo, Inês Godet, Michael Trautmann Rodriguez, I Chae Ye, Daniele M. Gilkes. Extracellular matrix signaling modulates estrogen receptor activity in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1010.
Abstract 3687: Colorectal cancer stem cell expressing POU5F1 promotes liver metastasis
Authors: Norikatsu Miyoshi, Shiki Fujino, Masaru Sasaki, Kazuhiro Saso, Hidekazu Takahashi, Naotsugu Haraguchi, Taishi Hata, Chu Matsuda, Tsunekazu Mizushima, Masaki Mori, Yuichiro Doki
Journal: Cancer Research (2019)

Abstract Background: The gene POU5F1, encoding the POU domain, class 5, is a transcription factor and the expression is found in embryonic stem cells. POU5F1 gene controls self-renewal and differentiation, and regulates pluripotency and proliferation in embryonic stem cells. However, the role of POU5F1 in metastatic CRC (mCRC) is not well known. We focused on the relationship between POU5F1 gene expression and liver metastasis of CRC and clarify the role and abilities of POU5F1-positive CRC cells. Methods: The study included 158 patients with CRC who underwent surgery from 2009 to 2011. The correlations between the POU5F1 gene expression and the clinical parameters were assessed, and liver-metastasis-free survival (LMFS) was evaluated in these patients. POU5F1-EGFP-positive cells were established by the construct with lentiviral vector, and we examine their sub-population and ability. The capacity to form liver metastasis in vivo was examined using CRC cell lines and primary cultured CRC cells. Results: In the survival analysis, LMFS was significantly poor in the high POU5F1 expression group compared to the low-expression group (P=0.008). Multivariate analyses showed that POU5F1 expression (P=0.015) and TNM stage (p&amp;lt;0.001) significantly correlated with LMFS. POU5F1-EGFP-positive cells highly expressed stem-cell-associated markers and they had self-renewal and differentiation abilities. POU5F1-high cells actively formed liver metastasis. Conclusion: The POU5F1expression correlated with liver metastasis in CRC patients. POU5F1-positive cells have the self-renewal and differentiation abilities as cancer stem cells. POU5F1 contributes to the ability forming liver metastasis in CRC. Citation Format: Norikatsu Miyoshi, Shiki Fujino, Masaru Sasaki, Kazuhiro Saso, Hidekazu Takahashi, Naotsugu Haraguchi, Taishi Hata, Chu Matsuda, Tsunekazu Mizushima, Masaki Mori, Yuichiro Doki. Colorectal cancer stem cell expressing POU5F1 promotes liver metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3687.
Abstract 17056: Validation of the Adult Hypertrophic Cardiomyopathy Sudden Death Risk Calculator in a Pediatric Population
Authors: Kathryn Armstrong, Julia Jeon, Chun-Po Steve Fan, Cedric Manlhiot, Judith Wilson, Kristen George, Elizabeth Stephenson, Seema Mital
Journal: Circulation (2016)

Background: Hypertrophic Cardiomyopathy (HCM) is a frequent cause of Sudden Cardiac Death (SCD) in children; however robust SCD risk predictors are lacking. Our study evaluated the adequacy of the ...
Pharmacological Management of Delirium
Authors: Bjørn Erik Neerland, Karin J. Neufeld, Arjen J. C. Slooter
Journal: JAMA Psychiatry (2019)

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Evaluation and Management of the Child and Adult With Fontan Circulation: A Scientific Statement From the American Heart Association
Authors: Jack Rychik, Andrew M. Atz, David S. Celermajer, Barbara J. Deal, Michael A. Gatzoulis, Marc H. Gewillig, Tain-Yen Hsia, Daphne T. Hsu, Adrienne H. Kovacs, Brian W. McCrindle, Jane W. Newburger, Nancy A. Pike, Mark Rodefeld, David N. Rosenthal, Kurt R. Schumacher, Bradley S. Marino, Karen Stout, Gruschen Veldtman, Adel K. Younoszai, Yves d’Udekem
Journal: Circulation (2019)

It has been 50 years since Francis Fontan pioneered the operation that today bears his name. Initially designed for patients with tricuspid atresia, this procedure is now offered for a vast array of congenital cardiac lesions when a circulation with 2 ventricles cannot be achieved. As a result of technical advances and improvements in patient selection and perioperative management, survival has steadily increased, and it is estimated that patients operated on today may hope for a 30-year survival of &gt;80%. Up to 70 000 patients may be alive worldwide today with Fontan circulation, and this population is expected to double in the next 20 years. In the absence of a subpulmonary ventricle, Fontan circulation is characterized by chronically elevated systemic venous pressures and decreased cardiac output. The addition of this acquired abnormal circulation to innate abnormalities associated with single-ventricle congenital heart disease exposes these patients to a variety of complications. Circulatory failure, ventricular dysfunction, atrioventricular valve regurgitation, arrhythmia, protein-losing enteropathy, and plastic bronchitis are potential complications of the Fontan circulation. Abnormalities in body composition, bone structure, and growth have been detected. Liver fibrosis and renal dysfunction are common and may progress over time. Cognitive, neuropsychological, and behavioral deficits are highly prevalent. As a testimony to the success of the current strategy of care, the proportion of adults with Fontan circulation is increasing. Healthcare providers are ill-prepared to tackle these challenges, as well as specific needs such as contraception and pregnancy in female patients. The role of therapies such as cardiovascular drugs to prevent and treat complications, heart transplantation, and mechanical circulatory support remains undetermined. There is a clear need for consensus on how best to follow up patients with Fontan circulation and to treat their complications. This American Heart Association statement summarizes the current state of knowledge on the Fontan circulation and its consequences. A proposed surveillance testing toolkit provides recommendations for a range of acceptable approaches to follow-up care for the patient with Fontan circulation. Gaps in knowledge and areas for future focus of investigation are highlighted, with the objective of laying the groundwork for creating a normal quality and duration of life for these unique individuals.