tbuckley/cabot-search huggingface dataset:
The balance between mitotic death and mitotic slippage in acute leukemia: a new therapeutic window?
Authors: Andrea Ghelli Luserna di Rorà, Giovanni Martinelli, Giorgia Simonetti
Journal: Journal of Hematology & Oncology (2019)

Abstract Mitosis is the process whereby an eukaryotic cell divides into two identical copies. Different multiprotein complexes are involved in the fine regulation of cell division, including the mitotic promoting factor and the anaphase promoting complex. Prolonged mitosis can result in cellular division, cell death, or mitotic slippage, the latter leading to a new interphase without cellular division. Mitotic slippage is one of the causes of genomic instability and has an important therapeutic and clinical impact. It has been widely studied in solid tumors but not in hematological malignancies, in particular, in acute leukemia. We review the literature data available on mitotic regulation, alterations in mitotic proteins occurring in acute leukemia, induction of prolonged mitosis and its consequences, focusing in particular on the balance between cell death and mitotic slippage and on its therapeutic potentials. We also present the most recent preclinical and clinical data on the efficacy of second-generation mitotic drugs (CDK1-Cyclin B1, APC/CCDC20, PLK, Aurora kinase inhibitors). Despite the poor clinical activity showed by these drugs as single agents, they offer a potential therapeutic window for synthetic lethal combinations aimed to selectively target leukemic cells at the right time, thus decreasing the risk of mitotic slippage events.
PRMT5 Inhibition Modulates E2F1 Methylation and Gene Regulatory Networks Leading to Therapeutic Efficacy in JAK2VF Mutant MPN
Authors: Friederike Pastore, Neha Bhagwat, Aishwarya Krishnan, Alessandro Pastore, Bing Li, Robert L Bowman, Wenbin Xiao, Aaron D Viny, Abdul Karzai, Anouar Zouak, Young C Park, Keith Cordner, Stephanie Braunstein, Alexander Grego, Jaanvi Mehta, Benjamin H Durham, Richard P. Koche, Jesper Maag, Peggy Scherle, Kris Vaddi, Ross L. Levine
Journal: Blood (2019)
Abstract 135: N-Terminal Pro-B-Type Natriuretic Peptide May Serve as a Prognostic Indicator for 30-Day Mortality Following Out-Of-Hospital Cardiac Arrest, Whereas Both High-Sensitivity Cardiac Troponin-T and Copeptin Did Not Yield Prognostic Information
Authors: Reidun Aarsetoey, Torbjorn Omland, Helge Rosjo, Heidi Strand, Hildegunn Aarsetoey, Harry Staines, Dennis W Nilsen
Journal: Circulation (2019)

Introduction: Sudden cardiac arrest (SCA) may be due to different underlying conditions. Prior heart disease is a major risk factor, and coronary artery disease is the most common underlying cause. Hs-cTnT and copeptin are used for early diagnosis of acute myocardial infarction, and may also serve as prognostic indicators following an acute coronary syndrome. NT-proBNP is a marker of heart failure and may act as a predictor of mortality in SCA patients. These three biomarkers in relation to ventricular fibrillation (VF) and asystole on scene during resuscitation has not, to our knowledge, been evaluated. Hypothesis: We hypothesized that early-on levels of hs-cTnT, copeptin and NT-proBNP may relate to prognosis. Methods: From February 2007 until November 2010 blood samples were collected from patients aged &gt; 18 years with out-of-hospital cardiac arrest of assumed cardiac origin. EDTA-blood was drawn during or immediately after termination of cardiopulmonary resuscitation or at hospital admission. Hs-cTnT, copeptin and NT-proBNP were all measured by standardized methods. Patients were classified according to first recorded heart rhythm. Both univariate and multivariate analyses, adjusted for age and gender, were performed using a Cox Proportional-Hazards model. Results: A total of 115 patients were included, 77 patients with VF and 38 patients with asystole as first recorded heart rhythm. Forty-four patients (38,3%) survived to 30-day follow-up. There was no significant difference in hs-cTnT (p = 0.71) or copeptin (p = 0.43) between non-survivors and survivors. The mean NT-proBNP level was significantly elevated in non-survivors compared to survivors, p = 0.001. The hazard ratio (HR) in the univariate analysis for patients with NT-proBNP in the highest quartile (Q4) compared to the lowest quartile (Q1) was 4.68 (95% CI 2.05-10.68), p = &lt; 0.001, and in the multivariate analysis HR was 2.52 (95% CI 0.97-6.53), p = 0.058. All patients in the asystole group died. Only NT-proBNP differed between the two groups, with significantly higher values in the asystole group, p = &lt; 0.001. Conclusion: Applying hs-cTnT, copeptin and NT-proBNP for assessment of prognosis in SCA patients with either VF or asystole, only NT-proBNP was found to yield prognostic information.
Targeting PD-L1 Initiates Effective Antitumor Immunity in a Murine Model of Cushing Disease
Authors: Hanna R. Kemeny, Aladine A. Elsamadicy, S. Harrison Farber, Cosette D. Champion, Selena J. Lorrey, Pakawat Chongsathidkiet, Karolina I. Woroniecka, Xiuyu Cui, Steven H. Shen, Kristen E. Rhodin, Vadim Tsvankin, Jeffrey Everitt, Luis Sanchez-Perez, Patrick Healy, Roger E. McLendon, Patrick J. Codd, Ian F. Dunn, Peter E. Fecci
Journal: Clinical Cancer Research (2019)

Although pituitary adenoma is classified as benign, Cushing disease is associated with significant morbidity due to the numerous sequelae of elevated cortisol levels. Successful therapy for Cushing disease remains elusive due to high rates of treatment-refractory recurrence. The frequent emergence of lymphocytic hypophysitis following checkpoint blockade for other cancers, as well as the expression of PD-L1 on pituitary adenomas, suggest a role for immunotherapy.This study confirms PD-L1 expression on functioning pituitary adenomas and is the first to evaluate the efficacy of checkpoint blockade (anti-PD-L1) therapy in a preclinical model of Cushing disease.Herein, treatment with anti-PD-L1 was successful in reducing adrenocorticotropic hormone plasma levels, decreasing tumor growth, and increasing survival in our model. Furthermore, tumor-infiltrating T cells demonstrated a pattern of checkpoint expression similar to other checkpoint blockade-susceptible tumors.This suggests that immunotherapy, particularly blockade of the PD1/PD-L1 axis, may be a novel therapeutic option for refractory Cushing disease. Clinical investigation is encouraged.
Comparison between CHOP like regimens and DAEPOCH with or without Rituximab in adult high grade B cell lymphoma NOS; A retrospective study from a tertiary cancer hospital in South India
Authors: L. Moharana, D. Lokanatha, L.A. Jacob, M. Sureshbabu, K. Lokesh, A. Rudresha, L. Rajeev, S. Smitha
Journal: Annals of Oncology (2019)
Technical standards for respiratory oscillometry
Authors: Gregory G. King, Jason Bates, Kenneth I. Berger, Peter Calverley, Pedro L. de Melo, Raffaele L. Dellacà, Ramon Farré, Graham L. Hall, Iulia Ioan, Charles G. Irvin, David W. Kaczka, David A. Kaminsky, Hajime Kurosawa, Enrico Lombardi, Geoffrey N. Maksym, François Marchal, Beno W. Oppenheimer, Shannon J. Simpson, Cindy Thamrin, Maarten van den Berge, Ellie Oostveen
Journal: European Respiratory Journal (2019)

Oscillometry (also known as the forced oscillation technique) measures the mechanical properties of the respiratory system (upper and intrathoracic airways, lung tissue and chest wall) during quiet tidal breathing, by the application of an oscillating pressure signal (input or forcing signal), most commonly at the mouth. With increased clinical and research use, it is critical that all technical details of the hardware design, signal processing and analyses, and testing protocols are transparent and clearly reported to allow standardisation, comparison and replication of clinical and research studies. Because of this need, an update of the 2003 European Respiratory Society (ERS) technical standards document was produced by an ERS task force of experts who are active in clinical oscillometry research. The aim of the task force was to provide technical recommendations regarding oscillometry measurement including hardware, software, testing protocols and quality control. The main changes in this update, compared with the 2003 ERS task force document are 1) new quality control procedures which reflect use of “within-breath” analysis, and methods of handling artefacts; 2) recommendation to disclose signal processing, quality control, artefact handling and breathing protocols ( e.g. number and duration of acquisitions) in reports and publications to allow comparability and replication between devices and laboratories; 3) a summary review of new data to support threshold values for bronchodilator and bronchial challenge tests; and 4) updated list of predicted impedance values in adults and children.
The elephant in the room: What matters cognitively in cumulative technological culture
Authors: François Osiurak, Emanuelle Reynaud
Journal: Behavioral and Brain Sciences (2019)

Abstract Cumulative technological culture (CTC) refers to the increase in the efficiency and complexity of tools and techniques in human populations over generations. A fascinating question is to understand the cognitive origins of this phenomenon. Because CTC is definitely a social phenomenon, most accounts have suggested a series of cognitive mechanisms oriented toward the social dimension (e.g., teaching, imitation, theory of mind, and metacognition), thereby minimizing the technical dimension and the potential influence of non-social, cognitive skills. What if we have failed to see the elephant in the room? What if social cognitive mechanisms were only catalyzing factors and not the sufficient and necessary conditions for the emergence of CTC? In this article, we offer an alternative, unified cognitive approach to this phenomenon by assuming that CTC originates in non-social cognitive skills, namely technical-reasoning skills which enable humans to develop the technical potential necessary to constantly acquire and improve technical information. This leads us to discuss how theory of mind and metacognition, in concert with technical reasoning, can help boost CTC. The cognitive approach developed here opens up promising new avenues for reinterpreting classical issues (e.g., innovation, emulation vs. imitation, social vs. asocial learning, cooperation, teaching, and overimitation) in a field that has so far been largely dominated by other disciplines, such as evolutionary biology, mathematics, anthropology, archeology, economics, and philosophy.
Autophagy protein NRBF2 has reduced expression in Alzheimer’s brains and modulates memory and amyloid-beta homeostasis in mice
Authors: Véronik Lachance, Qian Wang, Eric Sweet, Insup Choi, Cui-Zan Cai, Xu-Xu Zhuang, Yuanxi Zhang, Jessica Li Jiang, Robert D. Blitzer, Ozlem Bozdagi-Gunal, Bin Zhang, Jia-Hong Lu, Zhenyu Yue
Journal: Molecular Neurodegeneration (2019)

Abstract Background Dysfunctional autophagy is implicated in Alzheimer’s Disease (AD) pathogenesis. The alterations in the expression of many autophagy related genes (ATGs) have been reported in AD brains; however, the disparity of the changes confounds the role of autophagy in AD. Methods To further understand the autophagy alteration in AD brains, we analyzed transcriptomic (RNAseq) datasets of several brain regions (BA10, BA22, BA36 and BA44 in 223 patients compared to 59 healthy controls) and measured the expression of 130 ATGs. We used autophagy-deficient mouse models to assess the impact of the identified ATGs depletion on memory, autophagic activity and amyloid-β (Aβ) production. Results We observed significant downregulation of multiple components of two autophagy kinase complexes BECN1-PIK3C3 and ULK1/2-FIP200 specifically in the parahippocampal gyrus (BA36). Most importantly, we demonstrated that deletion of NRBF2 , a component of the BECN1-PIK3C3 complex, which also associates with ULK1/2-FIP200 complex, impairs memory in mice, alters long-term potentiation (LTP), reduces autophagy in mouse hippocampus, and promotes Aβ accumulation. Furthermore, AAV-mediated NRBF2 overexpression in the hippocampus not only rescues the impaired autophagy and memory deficits in NRBF2-depleted mice, but also reduces β-amyloid levels and improves memory in an AD mouse model. Conclusions Our data not only implicates NRBF2 deficiency as a risk factor for cognitive impairment associated with AD, but also support the idea of NRBF2 as a potential therapeutic target for AD.
NORTH/HGCSG1003: North Japan multicenter phase II study of oxaliplatin-containing regimen as adjuvant chemotherapy for stage III colon cancer: Final analysis
Authors: M. Nakamura, S. Yuki, N. Takahashi, T. Shichinohe, H. Nakatsumi, Y. Kawamoto, T. Kusumi, A. Ishiguro, K. Harada, I. Iwanaga, K. Hatanaka, K. Oomori, N. Senmaru, K. Iwai, M. Koike, N. Sakamoto, A. Taketomi, S. Hirano, N. Nishimoto, Y. Komatsu
Journal: Annals of Oncology (2019)
The prophylactic effect of 0.1% fluorometholone eye drops on eye disorders caused by high-dose cytarabine
Authors: T. Tsuchiya, T. Kume, K. Akiyama, K. Yoshitsugu, M. Fukaya, T. Enami, R. Tatara, M. Shino, T. Ikeda
Journal: Annals of Oncology (2019)
A Versatile ES Cell–Based Melanoma Mouse Modeling Platform
Authors: Ilah Bok, Olga Vera, Xiaonan Xu, Neel Jasani, Koji Nakamura, Jordan Reff, Arianna Nenci, Jose G. Gonzalez, Florian A. Karreth
Journal: Cancer Research (2019)

Abstract The cumbersome and time-consuming process of generating new mouse strains and multiallelic experimental animals often hinders the use of genetically engineered mouse models (GEMM) in cancer research. Here, we describe the development and validation of an embryonic stem cell (ESC)-GEMM platform for rapid modeling of melanoma in mice. The platform incorporates 12 clinically relevant genotypes composed of combinations of four driver alleles (LSL-BrafV600E, LSL-NrasQ61R, PtenFlox, and Cdkn2aFlox) and regulatory alleles to spatiotemporally control the perturbation of genes of interest. The ESCs produce high-contribution chimeras, which recapitulate the melanoma phenotypes of conventionally bred mice. Using the ESC-GEMM platform to modulate Pten expression in melanocytes in vivo, we highlighted the utility and advantages of gene depletion by CRISPR-Cas9, RNAi, or conditional knockout for melanoma modeling. Moreover, complementary genetic methods demonstrated the impact of Pten restoration on the prevention and maintenance of Pten-deficient melanomas. Finally, we showed that chimera-derived melanoma cell lines retain regulatory allele competency and are a powerful resource to complement ESC-GEMM chimera experiments in vitro and in syngeneic grafts in vivo. Thus, when combined with sophisticated genetic tools, the ESC-GEMM platform enables rapid, high-throughput, and versatile studies aimed at addressing outstanding questions in melanoma biology. Significance: This study presents a high-throughput and versatile ES cell-based mouse modeling platform that can be combined with state-of-the-art genetic tools to address unanswered questions in melanoma in vivo. See related commentary by Thorkelsson et al., p. 655
Treatment with inhaled α1-antitrypsin: a square peg in a round hole?
Authors: Miriam Barrecheguren, Marc Miravitlles
Journal: European Respiratory Journal (2019)

α1-Antitrypsin deficiency (AATD) is a genetic disorder that predisposes to the development of early pulmonary emphysema, especially in smokers. Episodes of exacerbations are frequent in patients with emphysema due to AATD and are associated with a deficient antiprotease screen in the airways compared with that of non-deficient COPD patients [1]. As a consequence, exacerbations have great impact on the evolution of the lung disease in AATD, measured in terms of decline in gas transfer [2], in health status [2, 3], and in lung function over time [4, 5]. Inhaled α1-antitrypsin may reduce severity of exacerbations in COPD <http://bit.ly/2OtJx8b>
Defining the biological responses of IL-6 by the study of a novel IL-6 receptor chain immunodeficiency
Authors: Amit Nahum, Nigel Sharfe, Arnon Broides, Harjit Dadi, Zahra Naghdi, Amarilla B. Mandola, Linda Vong, Adi Arbiv, Ilan Dalal, Ido Brami, Ohad Wormser, Jacov Levy, Chaim M. Roifman
Journal: Journal of Allergy and Clinical Immunology (2019)
Updated Results from the German Mpnsg-0212 Combination Trial: Ruxolitinib Plus Pomalidomide in Myelofibrosis with Anemia
Authors: Frank Stegelmann, Steffen Koschmieder, Susanne Isfort, Andreas Hochhaus, Florian H. Heidel, Holger Hebart, Markus Bangerter, Denise Wolleschak, Christoph Scheid, Joachim R Göthert, Philippe Schafhausen, Thomas Kindler, Markus P. Radsak, Robert Möhle, Cornelius Waller, Nikolas von Bubnoff, Andreas Reiter, Hartmut Döhner, Martin Griesshammer, Konstanze Döhner
Journal: Blood (2019)
Global Transcriptional Analysis of Nontransformed Human Intestinal Epithelial Cells (FHs 74 Int) after Exposure to Selected Drinking Water Disinfection By-Products
Authors: Erik Procházka, Steven D. Melvin, Beate I. Escher, Michael J. Plewa, Frederic D.L. Leusch
Journal: Environmental Health Perspectives (2019)

Drinking water disinfection inadvertently leads to the formation of numerous disinfection by-products (DBPs), some of which are cytotoxic, mutagenic, genotoxic, teratogenic, and potential carcinogens both in vitro and in vivo.We investigated alterations to global gene expression (GE) in nontransformed human small intestine epithelial cells (FHs 74 Int) after exposure to six brominated and two chlorinated DBPs: bromoacetic acid (BAA), bromoacetonitrile (BAN), 2,6-dibromo-p-benzoquinone (DBBQ), bromoacetamide (BAM), tribromoacetaldehyde (TBAL), bromate (BrO3-), trichloroacetic acid (TCAA), and trichloroacetaldehyde (TCAL).Using whole-genome cDNA microarray technology (Illumina), we examined GE in nontransformed human cells after 4h exposure to DBPs at predetermined equipotent concentrations, identified significant changes in gene expression (p≤0.01), and investigated the relevance of these genes to specific toxicity pathways via gene and pathway enrichment analysis.Genes related to activation of oxidative stress-responsive pathways exhibited fewer alterations than expected based on prior work, whereas all DBPs induced notable effects on transcription of genes related to immunity and inflammation.Our results suggest that alterations to genes associated with immune and inflammatory pathways play an important role in the potential adverse health effects of exposure to DBPs. The interrelationship between these pathways and the production of reactive oxygen species (ROS) may explain the common occurrence of oxidative stress in other studies exploring DBP toxicity. Finally, transcriptional changes and shared induction of toxicity pathways observed for all DBPs caution of additive effects of mixtures and suggest further assessment of adverse health effects of mixtures is warranted. https://doi.org/10.1289/EHP4945.
Risk factors associated with suicide in patients with prostate cancer in the United States.
Authors: Manojna Konda, Rohan Sharma, Arya Mariam Roy, Rashmi Verma
Journal: Journal of Clinical Oncology (2019)

84 Background: For a patient, receiving a diagnosis of cancer can be quite challenging and is often associated with depression and increased suicidal ideation. Previous studies have indicated that the risk of suicide in cancer patients is twice that of general population. Prostate cancer is the most common cancer in men. It has also been found to be associated with highest rates of suicide in genitourinary malignancies. We sought to evaluate the incidence and identify risk factors associated with suicide among men with prostate cancer. Methods: Patients with prostate cancer between the years 1973 and 2016 were identified in the Surveillance, Epidemiology, and End Results database (SEER). Multivariate logistic regression analysis was performed to identify independent risk factors for suicide death only on variables that were statistically significant in univariate statistical analysis. Results: In 1,307,625 patients with prostate cancer, 3,435 patients had committed suicide. Younger age (≤50 vs &gt; 70: OR = 4.73 , P &lt; 0.0001; 51-70 vs &gt; 70: OR = 1.93, P &lt; 0.04), Caucasian race (OR: 3.61, P &lt; 0.0001) and not undergoing surgery (OR: 1.33, P &lt; 0.0001) were significantly associated with increased risk of suicide. Furthermore, patients with &lt; 1 year since the diagnosis of prostate cancer were also found to be associated with increased risk of suicide death ( &lt; 1 vs &gt; 5 years: OR = 1.46, P &lt; 0.0001). Conclusions: Addressing mental health in patients with prostate cancer is an important issue. We found that several factors such as younger age, Caucasian race were significantly associated with risk of suicide. Patients who did not undergo surgery likely had advanced disease, which could explain their increased risk of suicide. Patients with &lt; 1 year since the diagnosis of prostate cancer are more vulnerable and at increased risk of suicide which emphasizes the necessity of identifying and treating patients at risk of suicide as early as possible. It is vital that health care providers recognize these patients and offer them appropriate support.
Prognostic value of patient-reported outcomes from international randomised clinical trials on cancer: a systematic review
Authors: Justyna Mierzynska, Claire Piccinin, Madeline Pe, Francesca Martinelli, Carolyn Gotay, Corneel Coens, Murielle Mauer, Alexander Eggermont, Mogens Groenvold, Kristin Bjordal, Jaap Reijneveld, Galina Velikova, Andrew Bottomley
Journal: The Lancet Oncology (2019)
Are There Islands of Awareness?
Authors: Tim Bayne, Anil K. Seth, Marcello Massimini
Journal: Trends in Neurosciences (2019)

Ordinary human experience is embedded in a web of causal relations that link the brain to the body and the wider environment. However, there might be conditions in which brain activity supports consciousness even when that activity is fully causally isolated from the body and its environment. Such cases would involve what we call islands of awareness: conscious states that are neither shaped by sensory input nor able to be expressed by motor output. This Opinion paper considers conditions in which such islands might occur, including ex cranio brains, hemispherotomy, and in cerebral organoids. We examine possible methods for detecting islands of awareness, and consider their implications for ethics and for the nature of consciousness.
Clinical utility of ctDNA genomic alterations (GA) based on ESMO scale for clinical actionability of molecular targets (ESCAT) in advanced NSCLC
Authors: L. Mezquita, D. Planchard, M. Dorta Suarez, M. Aldea, C. Naltet, V. Lamberts, M. Grecea, P. Martin-Romano, F. de Kievit, C. Jovelet, L. Lacroix, J. Remon Masip, P. Lavaud, A. Gazzah, C. Morris, K. Howarth, E. Green, G. Vassal, C. Massard, B. Besse
Journal: Annals of Oncology (2019)