tbuckley/cabot-search huggingface dataset:
Abstract 18364: Partial Mechanical Unloading Distorts Cardiomyocyte Membrane Organization and Regional β2AR-cAMP Compartmentation
Authors: Carla Lucarelli, Peter Wright, Ivan Diakonov, Sean Bello, Giuseppe Faggian, Cesare Terracciano, Julia Gorelik
Journal: Circulation (2017)

Differences have been reported in the stringency of β2AR control along the left ventricle (LV). These may leave the apex relatively prone to catecholaminergic damage. In this study a rat model of p...
Impact of KRAS mutations in clinical features and survival in pancreatic cancer patients: a single institution experience
Authors: E. Inga, E. Perdomo Zaldivar, M. Gómez, T. Cano, B. Rodriguez Alonso, M. Ortiz, R. Rodriguez Alonso, M. Toledano Fonseca, A. Rodriguez Ariza, E. Aranda
Journal: Annals of Oncology (2019)
Advancing the development of new tuberculosis treatment regimens: The essential role of translational and clinical pharmacology and microbiology
Authors: Kelly E. Dooley, Debra Hanna, Vidya Mave, Kathleen Eisenach, Radojka M. Savic
Journal: PLoS Medicine (2019)

Translational and clinical pharmacology are the state-of-the-art tools used by drug developers to efficiently move compounds and regimens through all drug development phases.Tuberculosis drug and regimen development, though, has traditionally underutilized these modern, model-based drug development approaches, despite the urgent need to understand major pharmacological aspects not only of the new candidates but also of existing drugs.• Translational platforms that include drug combinations are critical and should encompass data from multiple preclinical drug development tools (in vitro and in vivo models) to select the best regimens to be moved forward into clinical development.• Quantitative pharmacokinetic (PK)-pharmacodynamic (PD) approaches should be incorporated into all phases of drug development and be used for selection of optimal dose and schedule, assessment of drug-drug interactions, and dose determination in key populations including pregnant women, children, and people living with HIV.Quantitative pharmacology models should further be utilized for clinical trial design using clinical trial simulations.• Microbiology determinants such as precisely assessed minimum inhibitory concentrations (MICs) as well as quantitative longitudinal cultures integrated with PK-PD assessment will substantially inform and enhance all phases of drug development.• Commitment of all stakeholders, data sharing, and resource investment are required for development and utilization of these tools, which are necessary for successful TB regimen development.
Abstract 1256: Validation of Ubiquitin specific peptidases 37 as a prognostic and diagnostic marker in osteosarcoma
Authors: Mayank Singh, Atul Batra, Sameer Bakhshi, Matthew Summers
Journal: Cancer Research (2019)

Abstract Osteosarcoma has been a challenge for the oncologist because even after surgical removal of tumors 80 percent patients go on to develop metastasis to the Lung. Systematic development of Drug has been literally on a standstill in osteosarcoma. The emergence of Adjuvant therapy after surgery for localized osteosarcoma has increased the long term survival in patients under age 40 by 60 to 70 percent however for patients who go on to develop metastasis the prognosis is poor as there are limited therapeutic options. Protein ubiquitination and deubiquitylation plays an important role in controlling protein stability. Initial studies by us points to a model in which Ubiquitin specific peptidase 37 regulates cell cycle progression. Our data indicates that USP37 expression correlates with transformation by preventing degradation of different oncoproteins. It was found that in osteosarcoma cell lines USP37 is elevated which gives survival advantage to these cells while its depletion leads to enhanced cell death in response to genotoxic stress. USP37 depletion results in reduced resolution of DNA damage foci like gamma H2AX and 53BP1 and increase in no of collapsed replication fork which indicate the reduced ability of cells to carry out constitutive DNA replication. Physically USP37 interacted with proteins involved in DNA damage repair and effected their stability. We tried to correlate our data with archived patient osteosarcoma samples by analyzing if USP37 levels corelate with patient prognosis at our center which will be further discussed. The current data adds a new dimension to this newly explored deubiquitinates and merits development of targeting strategies to explore its therapeutic potential in osteosarcoma. Citation Format: Mayank Singh, Atul Batra, Sameer Bakhshi, Matthew Summers. Validation of Ubiquitin specific peptidases 37 as a prognostic and diagnostic marker in osteosarcoma [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 1256.
Abstract CT085: Pharmacodynamic correlates in a phase I study of INCMGA00012, a PD-1 antagonistic monoclonal antibody
Authors: Thomas Condamine, Sherry Owens, Patricia Feldman, Ross La Motte-Mohs, John Muth, Bradley Sumrow, Paul Moore, Robert Newton
Journal: Cancer Research (2019)

Abstract Background: The role of the PD-1 / PD-L1 axis in limiting T cell activity has been well established. Effective blockade of this pathway has been demonstrated to lead to an increase in T cell activity and to yield clinical activity in cancer patients. INCMGA00012 is a humanized IgG4 monoclonal antibody that binds to human PD-1 and blocks its interaction with PD-L1/PD-L2. This therapeutic antibody has demonstrated acceptable tolerability with evidence of clinical activity in a phase 1 study in patients with solid tumors (NCT03059823). Pharmacodynamic markers demonstrating biological activity of INCMGA0012 were assessed in samples collected during the study. Methods: Blood samples were collected at baseline and at various time points following treatment from patients receiving doses of either 3mg/Kg (Q2W) in the tumor-specific expansion cohort or a flat-dose of 500 or 750mg (Q4W) in the tumor-agnostic expansion cohort. Receptor occupancy was measured on circulating T cells by flow cytometry and serum cytokine levels were measured using either a proximity extension assay or immunoassays. In addition, circulating immune cell phenotyping was analyzed using flow cytometry and PBMC functionality evaluated using ex-vivo re-stimulation. Results: All tested doses of INCMGA0012 evaluated demonstrated a full saturation of the PD-1 receptor at trough on circulating CD4 and CD8 T cells. In all tested cohorts, an increase in serum CXCL9 and CXCL10 was observed following infusion with INCMGA0012. Moreover, an increase in the proliferation of circulating T cells was observed on treatment compared to baseline. Concurrently, following ex vivo re-stimulation, T cells isolated from peripheral blood mononuclear cells demonstrated an increased capacity to secrete cytokines. Conclusion: These results provide evidence that INCMGA0012 is biologically active and leads to an increase in IFNγ-related protein levels (i.e. CXCL9 and CXCL10) and in T cell proliferation. The clinical activity of INCMGA0012 is undergoing further evaluation in several indications, including endometrial cancer, Merkel cell carcinoma and squamous carcinoma of the anal canal. Several combination studies have also been initiated. Citation Format: Thomas Condamine, Sherry Owens, Patricia Feldman, Ross La Motte-Mohs, John Muth, Bradley Sumrow, Paul Moore, Robert Newton. Pharmacodynamic correlates in a phase I study of INCMGA00012, a PD-1 antagonistic monoclonal antibody [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 CT085.
Abstract 4315: UNC0642 inhibits G9a and induces apoptosis of human bladder cancer cells
Authors: Ruimin Huang, Jingya Sun, Meiqian Li, Yu Dong, Yuanheng Zhang, Jun Yan
Journal: Cancer Research (2019)

Abstract Urinary bladder cancer (UBC) is one of the most common malignancies in the world, with the characteristics of frequent recurrence and metastasis despite the standard chemotherapy with gemcitabine and cisplatin combination. Hence, it is needed to develop new drugs to tackle down UBC. Histone modifiers, which are frequently dysregulated in cancer development, are excellent drug targets for cancer treatment. Here, we found that G9a, one of the histone H3 methyltransferases, was overexpressed significantly in human UBC patients, using the expression data from public databases. In the TCGA Provisional dataset, the average expression level of G9a in primary UBC samples (n=408) was 1.6-fold as much as that in normal bladder samples (n=19; P &amp;lt; 0.001). Knockdown G9a by small interfering RNA decreased cell viability and induced apoptosis in human UBC cell lines. Thus, UNC0642, a small molecule inhibitor targeting G9a with high selectivity, low cytotoxicity, and excellent in vivo pharmacokinetic properties, was chosen to test the inhibitory effect on UBC cells. UNC0642 decreased the level of histone H3K9me2, the downstream target of G9a, and increase apoptosis of UBC cells in vitro in a dose-dependent manner. UNC0642 exhibited similar inhibitory effects on the J82 xenografts, without the loss of body weight of mice. Targeting G9a in vivo reduced Ki67 expression and increase the level of cleaved Caspase 3 and BIM protein by immunohistochemistry and Western blot analysis, respectively. Taken together, our data indicate that G9a may be a promising therapeutic target for UBC, and an epigenetics-based therapy by UNC0642 is suggested. Citation Format: Ruimin Huang, Jingya Sun, Meiqian Li, Yu Dong, Yuanheng Zhang, Jun Yan. UNC0642 inhibits G9a and induces apoptosis of human bladder cancer cells [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 4315.
Abstract 20396: N-Terminal Fragment of Cardiac Myosin Binding Protein-C Triggers Pro-Inflammatory Responses
Authors: Christoph Lipps, Jenine H Nguyen, Lukas Pyttel, Thomas Lynch, Christoph Liebetrau, Sandra Voss, Oliver Dörr, Holger M Nef, Helge Möllmann, Christian W Hamm, Sakthivel Sadayappan, Christian Troidl
Journal: Circulation (2017)

Introduction: Cardiac myosin binding protein-C (cMyBP-C) is detectable early after cardiac injury and has been described as a novel biomarker for cardiovascular diseases. Recently, it was shown tha...
Abstract 624: A case control study of benign breast disease and breast cancer among indigenous African women
Authors: BABATUNDE ADEDOKUN, Stella Odedina, Oladosu Ojengbede, Adeyinka Ademola, Temidayo Ogundiran, Dezheng Huo, Olufunmilayo Olopade, Imaria Agwai, Timothy Makumbi, Paul Ndom, Antony Gakwaya
Journal: Cancer Research (2019)

Abstract Purpose: To determine the association between benign breast disease (BBD) and breast cancer and if BBD is a mediator of the association between established risk factors and breast cancer among native African women Methods: We analysed data from 5154 women who participated in a case control study (2405 cases and 2749 controls) between March 1998 and December 2014 in three sub Saharan African countries: Nigeria (n= 4233), Uganda (n=477) and Cameroon (n=444). Breast cancer cases aged 18 years and older were enrolled in two tertiary hospitals in the two countries, unselected for age at diagnosis and family history. Controls who were free of breast cancer were enrolled in the same hospitals. Interviews were conducted to obtain data on potential epidemiological risk factors for breast cancer. We determined the association between breast cancer, history of BBD, age at diagnosis and types of BBD using logistic regression, while adjusting for socio-demographic characteristics and established risk factors. In addition, we estimated the proportion of the effects of other established risk factors mediated by BBD in the etiology of breast cancer. Results: Less than a tenth (8.1%, 420) of the study participants reported having a history of BBD, 87 of the 420 reported a biopsy diagnosed BBD. Among breast cancer cases, the proportions of BBD and biopsy-confirmed BBD were 10.4% and 3.8%, respectively, compared to 6.3% and 1.3% among controls (both p&amp;lt;0.001). Fibroadenoma (n=100, 45.2%) was the most commonly reported type of benign breast disease, followed by breast cyst (n=31, 15.2%) and fibrocystic diseases (n=19, 10.1%). Overall, the adjusted odds ratio of having breast cancer for those with benign breast disease relative to those without was 1.42 (95% CI 1.13-1.79). The odds ratios were also significantly higher among premenopausal (OR = 1.45, 95% CI: 1.07-1.95) and postmenopausal women (OR = 1.49, 95% CI 1.02-2.19). The proportion mediated by BBD in the association between age at menarche and breast cancer was 13.7%. Less than 1% of the effects of other risk factors that we examined was mediated by BBD. Conclusions: Benign breast disease is a risk factor for breast cancer among women in SSA. The mediator role of BBD in the effects of established risk factors on breast cancer risk appears very minimal. Citation Format: BABATUNDE ADEDOKUN, Stella Odedina, Oladosu Ojengbede, Adeyinka Ademola, Temidayo Ogundiran, Dezheng Huo, Olufunmilayo Olopade, Imaria Agwai, Timothy Makumbi, Paul Ndom, Antony Gakwaya. A case control study of benign breast disease and breast cancer among indigenous African women [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 624.
Abstract 5217: RB loss reprograms AR and E2F1 signaling in models of prostate cancer progression
Authors: Amy C. Mandigo, Chris McNair, Matthew J. Schiewer, Karen E. Knudsen
Journal: Cancer Research (2019)

Abstract Prostatic adenocarcinoma (PCa) is the most frequently diagnosed non-cutaneous malignancy, and the third leading cause of cancer death in males in the United States. A crucial component to the development and progression of PCa is the activity of the androgen receptor (AR). As such, targeting the AR-signaling axis through androgen deprivation therapy (ADT) is the first line of therapy for PCa. However, cells invariably become resistant to this therapy and men relapse with the incurable form of the disease termed, castration-resistant prostate cancer (CRPC). In addition to AR, another principal component aiding in the progression of disease is the retinoblastoma tumor suppressor protein (RB). RB functions to repress tumor development by negatively regulating the activity of the E2F family of transcription factors, preventing cell cycle progression. RB is lost in roughly 30% of CRPC tumors and is sufficient to induce a CRPC phenotype in hormone-sensitive cells under ADT conditions. Analyses into the molecular significance of RB loss on disease progression identified a potential cooperation between AR and the RB-E2F1 signaling axis. Biological assessment performed in isogenic RB knockdown (i.e. hormone-sensitive and CRPC models) identified distinct functional consequences of RB loss depending on AR status and disease state. Transcriptome analysis identified divergently regulated gene signatures between disease stages in the presence of AR activation, which were not seen under ADT conditions, implicating a unique role of AR in transcriptional regulation with the loss of RB. Data to be discussed will also include further comparison of the E2F1 and AR cistromes in the absence of RB to identify the mechanism by which the AR-RB-E2F1 signaling axis function in promoting the progression of disease. Citation Format: Amy C. Mandigo, Chris McNair, Matthew J. Schiewer, Karen E. Knudsen. RB loss reprograms AR and E2F1 signaling in models of prostate cancer progression [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 5217.
Abstract P201: Use of Medicare Claims Data for the Identification of Myocardial Infarction. The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study
Authors: Lisandro D Colantonio, Emily B Levitan, Huifeng Yun, Meredith L Kilgore, George Howard, Monika M Safford, Paul Muntner
Journal: Circulation (2017)

Background: Administrative claims are used to conduct epidemiology research. However, few studies have compared results using administrative claims versus primary data collection. Objective: To compare myocardial infarction (MI) rates using primary data collection and Medicare claims in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. Methods: We included 9,951 REGARDS study participants ≥65 years of age with Medicare Part A (inpatient) fee-for-service coverage at baseline in 2003-2007. Participants were asked every 6 months to report heart-related hospitalizations which were subsequently adjudicated to detect definite or probable MIs (MI Definition 1, see Table footnotes). Events detected through surveillance in REGARDS were supplemented with adjudicated definite or probable MIs detected through Medicare inpatient claims with a diagnosis code for MI (i.e., ICD-9 code 410.x0 or 410.x1) in any position (Definition 2) and in the primary position (Definition 3). MIs were also defined by a Medicare inpatient claim with a code for MI in any position (Definition 4) and in the primary position (Definition 5), without further adjudication. MIs were ascertained through December 2012. Results: REGARDS study procedures detected and adjudicated 669 definite or probable MIs over a mean follow-up of 6.3 years, representing 10.7 MIs per 1,000 person-years (Definition 1, Table ). Supplementing adjudicated MIs with Medicare inpatient claims resulted in a 12% (any diagnosis position, Definition 2) and 6% (primary diagnosis position, Definition 3) higher rate for MI. Using only Medicare claims without adjudication underestimated the rate for MI by 8% (any diagnosis position, Definition 4) and 32% (primary diagnosis position, Definition 5), compared with REGARDS study procedures. Conclusion: Supplementing MIs detected through participant self-report with those identified in claims could improve event detection. Using only Medicare claims to identify events may underestimate MI rates.
New Perspectives on the Aging Lexicon
Authors: Dirk U. Wulff, Simon De Deyne, Michael N. Jones, Rui Mata
Journal: Trends in Cognitive Sciences (2019)

The field of cognitive aging has seen considerable advances in describing the linguistic and semantic changes that happen during the adult life span to uncover the structure of the mental lexicon (i.e., the mental repository of lexical and conceptual representations). Nevertheless, there is still debate concerning the sources of these changes, including the role of environmental exposure and several cognitive mechanisms associated with learning, representation, and retrieval of information. We review the current status of research in this field and outline a framework that promises to assess the contribution of both ecological and psychological aspects to the aging lexicon.
Abstract 697: Degradation of cancer mitochondria by the mitochondria-eating protein induces iron-dependent cancer cell death
Authors: Yasuyuki Nakamura, Naoki Ikari, Hirofumi Arakawa
Journal: Cancer Research (2019)

Abstract Parkin/Pink1-mediated mitophagy plays a critical role in mitochondrial quality control, in which the unhealthy mitochondria are sequestered by autophagosomes, and degraded by fusion between autophagosomes and lysosomes. Here, we report non-canonical mitophagy as a new function of tumor suppressor p53. The mitochondria-eating protein (Mieap) was originally identified as a p53-target gene. Mieap induced large vacuole-like structures (Mieap-induced vacuoles: MIVs) in cancer cells. MIVs were generated from around the mitochondria, and directly ate and degraded cancer mitochondria without autophagosomes. Therefore, we defined the function as the Mieap-regulated non-canonical mitophagy. UVRAG was found to be a Mieap-interacting protein that mediates the MIVs formation. Interestingly, degradation of cancer mitochondria by the MIVs induced cell death via iron-dependent production of reactive oxygen species. Introduction of exogenous Mieap strikingly suppressed in vivo tumor growth of Mieap-deficient colorectal cancer cells. Deficiency of endogenous Mieap dramatically promoted cancer development, malignancy, and aggressiveness in colorectal and gastric cancer model mice. The Mieap-induced cell death was found to occur in in vivo hypoxic tumor microenvironment of colorectal cancer tissues. These results suggest that degradation of cancer mitochondria by Mieap-regulated non-canonical mitophagy plays a critical role in p53 tumor suppression via iron-dependent cancer cell death. Citation Format: Yasuyuki Nakamura, Naoki Ikari, Hirofumi Arakawa. Degradation of cancer mitochondria by the mitochondria-eating protein induces iron-dependent cancer cell death [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 697.
A novel through-the-scope twin endoclip for a large mucosal closure in a live pig model
Authors: Qiang Zhang, Zhen Wang, Yang Bai
Journal: Endoscopy (2019)

A novel through-the-scope twin endoclip (TTS-TC) has been developed by our team. The TTS-TC can be delivered directly through an endoscope working channel of 3.2 mm in diameter and contributes to the closure of large mucosal wounds.