tbuckley/cabot-search huggingface dataset:
In Situ Pluripotency Factor Expression Promotes Functional Recovery From Cerebral Ischemia
Authors: Jung Hwa Seo, Min-Young Lee, Ji Hea Yu, Myung-Sun Kim, Myungjae Song, Cheong Hoon Seo, Hyongbum (Henry) Kim, Sung-Rae Cho
Journal: Molecular Therapy (2016)

Recovery from ischemic tissue injury can be promoted by cell proliferation and neovascularization. Transient expression of four pluripotency factors (Pou5f1, Sox2, Myc, and Klf4) has been used to convert cell types but never been tested as a means to promote functional recovery from ischemic injury. Here we aimed to determine whether transient in situ pluripotency factor expression can improve neurobehavioral function. Cerebral ischemia was induced by transient bilateral common carotid artery occlusion, after which the four pluripotency factors were expressed through either doxycycline administration into the lateral ventricle in transgenic mice in which the four factors are expressed in a doxycycline-inducible manner. Histologic evaluation showed that this transient expression induced the proliferative generation of astrocytes and/or neural progenitors, but not neurons or glial scar, and increased neovascularization with upregulation of angiogenic factors. Furthermore, in vivo pluripotency factor expression caused neuroprotective effects such as increased numbers of mature neurons and levels of synaptic markers in the striatum. Dysplasia or tumor development was not observed. Importantly, neurobehavioral evaluations such as rotarod and ladder walking tests showed that the expression of the four factors dramatically promoted functional restoration from ischemic injury. These results provide a basis for novel therapeutic modality development for cerebral ischemia.
Abstract 470: Application of sequencing, liquid biopsies and patient derived xenografts for personalized medicine in melanoma
Authors: Maria R. Girotti, Gabriela Gremel, Rebecca Lee, Elena Galvani, Dominic Rothwell, Amaya Viros, Amit Kumar Mandal, Kok Haw Jonathan Lim, Grazia Saturno, Simon J Furney, Franziska Baenke, Malin Pedersen, Jane Rogan, Jacqueline Swan, Matthew Smith, Alberto Fusi, Deemesh Oudit, Nathalie Dhomen, Ged Brady, Caroline Dive, Richard Marais
Journal: Cancer Research (2016)

Abstract BRAF/MEK inhibitors and immunotherapies have revolutionized care for patients with advanced melanoma, improving expected median survival from 9 months to 25-30 months, but the majority of patients still die of their disease. Personalized medicine strives to individualize and improve patient care. To individualize treatment decisions in advanced melanoma we analyzed 364 samples from 214 patients. We performed whole exome sequencing (WES) and circulating tumor DNA (ctDNA) analysis, and we developed patient derived xenografts (PDX). WES and targeted sequencing of ctDNA allowed us to predict responses to therapy and to identify and monitor mechanisms of resistance. WES of tumors revealed new therapeutic strategies in BRAF V600 wild-type and BRAF inhibitor-resistant melanoma and we validated these in patient derived xenografts (PDX). Thus, we describe a powerful combination of techniques for personalized medicine to improve the management of melanoma patients. Citation Format: Maria R. Girotti, Gabriela Gremel, Rebecca Lee, Elena Galvani, Dominic Rothwell, Amaya Viros, Amit Kumar Mandal, Kok Haw Jonathan Lim, Grazia Saturno, Simon J Furney, Franziska Baenke, Malin Pedersen, Jane Rogan, Jacqueline Swan, Matthew Smith, Alberto Fusi, Deemesh Oudit, Nathalie Dhomen, Ged Brady, Caroline Dive, Richard Marais. Application of sequencing, liquid biopsies and patient derived xenografts for personalized medicine in melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 470.
Abstract 4048: Stem cell properties of normal human keratinocytes influence transformation responses to HPV16
Authors: Yvon Woappi, Kim E. Creek, Lucia Pirisi
Journal: Cancer Research (2016)

Abstract Human papillomavirus (HPV) infection is the primary cause of cervical cancer. While HPV infection is very common, cervical cancer is a rare outcome. Why some women develop cervical cancer and others do not is not well understood, but likely involves host cell-specific factors and a woman's ability to get rid of HPV-infected cells. We have previously reported marked variability of epidermal growth factor receptor (EGFR) expression in normal human epidermal tissue from different individuals and demonstrated that increased immortalization by HPV16 E6 and E7 oncogenes correlated with lower basal levels of EGFR. We now report a significantly greater transformation response in stem cell-like keratinocytes after transfection with the full length HPV16 genome. Primary normal human keratinocyte strains (NHKc) from 59 individuals were cultured in 3-D anchorage-free suspension to assess spheroid forming ability and to determine resistance to anchorage-independent cell death. Only about 40% of NHKc strains survived and formed spheroids in 3-D culture and grew when plated back in monolayers as spheroid-derived NHKc (SD-NHKc). Fluorescence-activated cell sorting analysis found that SD-NHKc were enriched in cells expressing known keratinocyte stem cell markers: low levels of EGFR and high levels of integrin α6, while spheroid-non forming strains (SNF-NHKc) had dramatically reduced numbers of EGFRlo/ITGα6hi cells. Isolation and cultivation of EGFRlo/ITGα6hi keratinocytes isolated from primary monolayer NHKc cultures revealed this cell population to behave like SD-NHKc with respect to anchorage-independent survival, proliferative potential, cell morphology, and clonogenicity. Upon transfection with HPV16 DNA, most NHKc strains acquired anchorage-independence and exhibited increased expression of EGFR. Importantly, EGFRlo/ITGα6hi keratinocytes and SD-NHKc displayed exuberant growth responses after transfection with HPV16 DNA and significantly higher transformation efficiency by HPV16. In contrast, SNF-NHKc grew more sluggishly and were relatively resistant to HPV16-mediated immortalization. Our study indicates that stem cell-like keratinocytes are preferentially transformed by HPV16 DNA and that stemness is a phenotypic determinant of susceptibility to HPV16-mediated transformation in primary human keratinocytes. Citation Format: Yvon Woappi, Kim E. Creek, Lucia Pirisi. Stem cell properties of normal human keratinocytes influence transformation responses to HPV16. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4048.
P0293 : Targeting glucosylceramide synthase increases sorafenib efficacy and evades sorafenib resistance in HCC models
Authors: M. Stefanovic, A. Tutusaus, C. Barcena, G.A. Martinez-Nieto, M. Marí, C. Garcia-Ruiz, J.C. Fernandez-Checa, A. Morales
Journal: Journal of Hepatology (2015)
Temporal Trends in Late Preterm and Early Term Birth Rates in 6 High-Income Countries in North America and Europe and Association With Clinician-Initiated Obstetric Interventions
Authors: Jennifer L. Richards, Michael S. Kramer, Paromita Deb-Rinker, Jocelyn Rouleau, Laust Mortensen, Mika Gissler, Nils-Halvdan Morken, Rolv Skjærven, Sven Cnattingius, Stefan Johansson, Marie Delnord, Siobhan M. Dolan, Naho Morisaki, Suzanne Tough, Jennifer Zeitlin, Michael R. Kramer
Journal: JAMA (2016)

<h3>Importance</h3> Clinicians have been urged to delay the use of obstetric interventions (eg, labor induction, cesarean delivery) until 39 weeks or later in the absence of maternal or fetal indications for intervention. <h3>Objective</h3> To describe recent trends in late preterm and early term birth rates in 6 high-income countries and assess association with use of clinician-initiated obstetric interventions. <h3>Design</h3> Retrospective analysis of singleton live births from 2006 to the latest available year (ranging from 2010 to 2015) in Canada, Denmark, Finland, Norway, Sweden, and the United States. <h3>Exposures</h3> Use of clinician-initiated obstetric intervention (either labor induction or prelabor cesarean delivery) during delivery. <h3>Main Outcomes and Measures</h3> Annual country-specific late preterm (34-36 weeks) and early term (37-38 weeks) birth rates. <h3>Results</h3> The study population included 2 415 432 Canadian births in 2006-2014 (4.8% late preterm; 25.3% early term); 305 947 Danish births in 2006-2010 (3.6% late preterm; 18.8% early term); 571 937 Finnish births in 2006-2015 (3.3% late preterm; 16.8% early term); 468 954 Norwegian births in 2006-2013 (3.8% late preterm; 17.2% early term); 737 754 Swedish births in 2006-2012 (3.6% late preterm; 18.7% early term); and 25 788 558 US births in 2006-2014 (6.0% late preterm; 26.9% early term). Late preterm birth rates decreased in Norway (3.9% to 3.5%) and the United States (6.8% to 5.7%). Early term birth rates decreased in Norway (17.6% to 16.8%), Sweden (19.4% to 18.5%), and the United States (30.2% to 24.4%). In the United States, early term birth rates decreased from 33.0% in 2006 to 21.1% in 2014 among births with clinician-initiated obstetric intervention, and from 29.7% in 2006 to 27.1% in 2014 among births without clinician-initiated obstetric intervention. Rates of clinician-initiated obstetric intervention increased among late preterm births in Canada (28.0% to 37.9%), Denmark (22.2% to 25.0%), and Finland (25.1% to 38.5%), and among early term births in Denmark (38.4% to 43.8%) and Finland (29.8% to 40.1%). <h3>Conclusions and Relevance</h3> Between 2006 and 2014, late preterm and early term birth rates decreased in the United States, and an association was observed between early term birth rates and decreasing clinician-initiated obstetric interventions. Late preterm births also decreased in Norway, and early term births decreased in Norway and Sweden. Clinician-initiated obstetric interventions increased in some countries but no association was found with rates of late preterm or early term birth.
P1122 : Alternatively activated M2 macrophages promote hepatocyte differentiation in hepatic progenitor cell mediated liver regeneration in acute on chronic liver failure patients
Authors: A. Kumar, D. Kumar, S. Rooge, S. Shubham, A. Bhat, C. Syal, A. Rastogi, C. Bihari, V. Pamecha, S.K. Sarin
Journal: Journal of Hepatology (2015)
Dissection of Complementary Vs Unique Cntributions of Kit, Flt3 and IL-7R Signaling to Lymphohematopoietic Development in Vivo
Authors: Nivedita Shankar Saxena, Jing Huang, Yujun Yang, Dullei Min, Carmencita Nicolas, Sumana Shashidhar, Janice (Wes) Brown, Kenneth I Weinberg
Journal: Blood (2014)
Abstract 32: LincRNA-p21 Regulates Neointima Formation and Atherosclerosis by Enhancing p53 Activity
Authors: Gengze Wu, Yue Cai, Yujia Yang, Zaicheng Xu, Wei Eric Wang, Ken Chen, Chunyu Zeng
Journal: Circulation Research (2014)

Background: Long non-coding RNAs (lncRNAs) recently have been implicated in many biological processes and diseases. Atherosclerosis is a major risk factor for cardiovascular disease. However, the functional role of lncRNAs in atherosclerosis is largely unknown. Methods and Results: The downstream targets of p53 also been detected by un-bias mRNA array and specific qPCR. Furthermore, bioinformatics prediction, RNA-Immunoprecipitation, biotin-labeled RNA-pulldown and deletion mapping were performed to test the potential interaction between lincRNA-p21 and MDM2. Co-IP, genome-wide ChIP-seq and ChIP-qPCR were preformed to verify the possible influence on p53 transcriptional activity. We further investigated the function of lincRNA-p21 in vivo, therefore recombinant lincRNA-p21 knockdown lentivirus were injected into the injured area of carotid arteries injury mouse model. Then the expression of lincRNA-p21 in vascular samples of clinical coronary disease patients were also detected. We identified lincRNA-p21 as a key regulator of atherosclerosis. Expression of lincRNA-p21 was dramatically down-regulated in atherosclerotic plaques of ApoE-/- mice, an animal model for AS. Through loss- and gain-of function approaches, we showed that lincRNA-p21 represses cell proliferation and induces apoptosis in VSMCs in vitro. Moreover, we found that inhibition of lincRNA-p21 results in neointimal hyperplasia in vivo in a carotid artery injury model. Mechanistically, we revealed that lincRNA-p21, which is a transcriptional target of p53, feeds back to enhance p53 transcriptional activity via binding to mouse double minute 2 (MDM2), an E3 ubiquitin-protein ligase. The association of lincRNA-p21 and MDM2 releases MDM2 repression of p53, enabling p53 to interact with p300 to regulate apoptosis, cell proliferation and suppress neointima formation. Conclusions: Our studies identified lincRNA-p21 as a novel regulator of cell proliferation and apoptosis and suggest that this lncRNA could serve as a therapeutic target to treat atherosclerosis.
Decision tree for the diagnosis of upper tract urothelial carcinoma: Can selective upper-tract urine cytology be omitted in diagnosis?
Authors: Nozomi Hayakawa, Eiji Kikuchi, Kazuhiro Matshumoto, Shinya Morita, Kazunobu Shinoda, Takeo Kosaka, Ryuichi Mizuno, Toshiaki Shinojima, Hiroshi Asanuma, Akira Miyajima, Mototsugu Oya
Journal: Journal of Clinical Oncology (2015)

e15638 Background: Whether to perform selective upper-tract urine cytology (UTC) in all suspicious cases of upper tract urothelial carcinoma (UTUC) is still an open issue. The purpose of this study was to create a decision tree for the diagnosis of UTUC and to evaluate the diagnostic role of selective UTC, as well as those of voiding urine cytology (VUC) and imaging studies. Methods: We identified 182 patients who were evaluated by urine analysis, VUC, CT and/or MRI imaging, and selective UTC for the diagnosis of UTUC during the past 15 years at our institution. We performed decision tree analysis and logistic regression analysis, which could demonstrate when we could omit selective UTC for UTUC diagnosis. Results: Radical nephroureterectomy (RNU) was performed in 148 patients and 139 were diagnosed histologically as UTUC. Of 34 patients treated without RNU, 23 had no evidence of UTUC during their follow-up of longer than 2 years, and 11 were diagnosed as UTUC later. Consequently, 150 patients (82%) had UTUC during the follow-up period. First, excluding the factor of selective UTC, we performed decision tree analysis and found that a tumor in imaging was the root node and VUC III-V and gross hematuria proved to be the decision nodes. As shown in the figure below, 89 of 92 patients (97%) who had a tumor on imaging and VUC III-V or gross hematuria were diagnosed as UTUC regardless of selective UTC information. Therefore, the role of selective UTC for these patients seemed to be quite limited. On the other hand, in the remaining 90 patients multivariate logistic regression analysis demonstrated that selective UTC IV,V was significantly related to the existence of UTUC. Of 36 patients whose selective UTC was IV,V, 33 (92%) proved to have UTUC. Meanwhile, the negative predictive value in patients with selective UTC I-III was limited (approximately 50%). Conclusions: Tumor on imaging and VUC III-V or gross hematuria are strong indicators for identifying UTUC. Therefore, we concluded that in these patients UTUC could be diagnosed without selective UTC. In other cases selective UTC had a high positive but low negative predictive value. Therefore, selective UTC has a limited value for UTUC diagnosis.
Abstract 401: Preservation of cells in blood and culture
Authors: Cecille Browne, Dan Lu, Daniela Roth, Vasco Liberal
Journal: Cancer Research (2016)

Abstract Introduction: Liquid biopsies and cell-based therapies are emerging approaches for the treatment of cancer. Accuracy of diagnosis using liquid biopsies and effectiveness of treatment using cell-based therapies will rely upon the preservation cells for both viability and the information contained in them. Experimental procedures: Biomatrica's proprietary chemical library was used to develop formulations that could preserve cells in multiple formats. Cell preservation was assessed by a variety of cell-based and molecular techniques such as microscopy, flow cytometry and real-time PCR. Results: Blood samples spiked with circulating tumor cells (CTCs) were preserved for several days at room temperature to allow for downstream morphological and transcriptomic analyses. CTC recoveries in preserved samples were as much as 4 times those in non-protected samples over 4 days. Changes in RNA expression of CTC-specific genes in preserved samples ranged from 0 to +/- 2 delta Ct values, while in non-protected samples, changes ranged from 0 to +/-5 delta Ct values over 4 days. In some formulations, CTC viabilities were as much as twice the viabilities of CTCs in non-protected samples. Supporting these viability results was a demonstrated culturability of isolated CTCs. Furthermore, cell-free DNA in plasma of preserved blood samples changed by less than 2 Ct values over 4 days, whereas in control samples, plasma DNA changed by as much as 10 Ct values. Hemolysis in preserved blood samples was also lower by as much as 69% compared to non-protected samples. In a separate set of experiments, activated T-cells were stored in the presence of common buffers (RPMI, PBS) or formulations at room temperature. T-cells cultured with formulations displayed greater 40 to 60% greater cell viability after 3 days compared to those stored in common buffers. Conclusions: Biomatrica has developed a library of cell preservatives that can be used to preserve cells in blood samples and in cell culture. The ability to recover cells in blood samples and determine their genetic information would enable monitoring of a patient's cancer status and personalizing drug treatments. In addition, cell preservation may allow further advances in cell-based therapies as cells could be more reliably recovered from patients, modified (e.g. CAR-T, stem cells), and administered to patients. Citation Format: Cecille Browne, Dan Lu, Daniela Roth, Vasco Liberal. Preservation of cells in blood and culture. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 401.
Abstract 4709: Broad activity for the combination of BET and MEK inhibitors across solid and hematologic cancers
Authors: Anastasia Wyce, Daniel J. Felitsky, Xi-Ping Zhang, Jeanne J. Matteo, Susan Korenchuk, Lijoy K. Mathew, Melissa Musso, Sakina Khaku, Victoria Ortiz, Kathryn Keenan, Melissa Stern, Yan Degenhardt, Ramona Plant, Charles F. McHugh, Peter J. Tummino, Christopher Carpenter, Olena Barbash
Journal: Cancer Research (2016)

Abstract BET (bromodomain and extra-terminal) family proteins are epigenetic readers that modulate expression genes involved in cell growth and oncogenesis. Selective small molecule BET inhibitors, such as the GSK I-BETs (I-BET762, I-BET151), abrogate binding of BET proteins to acetylated chromatin and inhibit transcription of BET target genes. We and others have previously demonstrated single agent activity for BET inhibitors in a number of pre-clinical solid and hematologic tumor models. Transcriptomics and mechanistic studies from several of these tumor types indicate that BET inhibitors influence numerous signaling pathways at the transcriptional level, including RAS/RAF/MEK signaling. Here we describe the synergistic effects of combining BET and MEK inhibitors in various solid and hematologic cancer models. We observe synergistic growth inhibition and apoptosis in a subset of cell lines representing multiple tumor types, as well as patient-derived xenograft models treated with the combination ex vivo. Additionally, combination of BET and MEK inhibitors results in improved tumor growth inhibition in cell line xenograft models compared to either single agent therapy. Further exploration of the combination in sensitive tumor types highlights multiple mechanisms potentially driving synergy, and suggests possible markers associated with sensitivity to the combination. Taken together, our data highlight the potential of BET/MEK inhibitor combinations to improve upon the efficacy observed for these agents as monotherapies in a wide variety of preclinical cancer models. All studies were conducted in accordance with the GSK Policy on the Care, Welfare and Treatment of Laboratory Animals and were reviewed by the Institutional Animal Care and Use Committee either at GSK or by the ethical review process at the institution where the work was performed. Human biological samples were sourced ethically and their research use was in accord with the terms of the informed consents. Citation Format: Anastasia Wyce, Daniel J. Felitsky, Xi-Ping Zhang, Jeanne J. Matteo, Susan Korenchuk, Lijoy K. Mathew, Melissa Musso, Sakina Khaku, Victoria Ortiz, Kathryn Keenan, Melissa Stern, Yan Degenhardt, Ramona Plant, Charles F. McHugh, Peter J. Tummino, Christopher Carpenter, Olena Barbash. Broad activity for the combination of BET and MEK inhibitors across solid and hematologic cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4709.
Development of V617F JAK2 Associated Myeloproliferative Neoplasms Is a Non-Random Event That Is Strongly Dependent on JAK2 Haplotype
Authors: Nicholas C.P. Cross, Amy V. Jones, Richard T. Silver, David Oscier, Georgia Metzgeroth, Y. Lynn Wang, Andrew Collins, Andreas Reiter, Francis Grand, Andrew Chase
Journal: Blood (2008)
AN INVESTIGATION INTO THE EFFECT OF CYTOCHROME P450 (CYP) 2D6 GENOTYPE ON PHARMACOKINETICS, PHARMACODYNAMICS AND OUTCOMES DURING METOPROLOL CR/XL THERAPY IN A HEART FAILURE COHORT
Authors: Jonathan Adam Batty, Anthony Balmforth, Hazel L. White, John Wikstrand, de Rudolf Boer, van Dirk Veldhuisen, van der Pim Harst, Ake Hjalmarson, John Kjekshus, Alistair Hall, Merit-Hf Study Grp
Journal: Journal of the American College of Cardiology (2013)
Case 46-1973
Authors: Richard C. Cabot, Benjamin Castleman, Robert E. Scully, Betty U. McNeely, Charles Trey, James J. Galdabini
Journal: New England Journal of Medicine (1973)

Presentation or CaseA 56-year-old man was admitted to the hospital for replacement of an electronic cardiac pacemaker generator.He was well until 18 months before admission, when he was brought to the hospital because of chest pain followed by collapse. An electrocardiogram disclosed acute inferior myocardial infarction with complete heart block. A temporary pacing electrode was inserted but failed, and ventricular fibrillation occurred, with circulatory arrest. He was resuscitated, and examination disclosed for the first time a Grade 3 holosystolic murmur along the lower left sternal border, with radiation to the cardiac apex. Thrombophlebitis developed about the temporary pacing . . .
EZH2 Is Aberrantly Expressed and Plays a Pro-Proliferative Role Independent of Its Methyltransferase Activity in Natural Killer/T-Cell Lymphoma
Authors: Wee-Joo Chng, Junli Yan, Siok-Bian NG, Jim Tay, Baohong Lin, Tze-Loong Koh, Joy Tan, Viknesvaran Selvarajan, Shaw-Cheng Liu, Chonglei Bi, Gaofeng Huang, Qiang Yu
Journal: Blood (2012)
Relationship between Overall Survival and Response or Progression-Free Survival in Advanced Non–Small Cell Lung Cancer Patients Treated with Anti–PD-1/PD-L1 Antibodies
Authors: Takehito Shukuya, Keita Mori, Joseph M. Amann, Erin M. Bertino, Gregory A. Otterson, Peter G. Shields, Satoshi Morita, David P. Carbone
Journal: Journal of Thoracic Oncology (2016)