bluuebunny/crossref_metadata_2025 huggingface dataset:
Altered Metabolism of Phospholipases, Diacylglycerols, Endocannabinoids, and N-Acylethanolamines in Patients with Mastocytosis
Authors: Ferrara Anne Lise , Piscitelli Fabiana , Petraroli Angelica , Parente Roberta , Galdiero Maria Rosaria , Varricchi Gilda , Marone Giancarlo , Triggiani Massimo , Di Marzo Vincenzo , Loffredo Stefania
Published: July 2019

Background. Mastocytosis is a condition characterized by the expansion and accumulation of mast cells (MCs) in various organs. The symptoms are related to the increased release of MC-derived mediators that exert local and distant effects. MCs are a source and target of phospholipase enzymes (PLs), which catalyze the cleavage of membrane phospholipids releasing lipid mediators (e.g., diacylglycerols (DAGs) and the endocannabinoid (EC) 2-arachidonoylglycerol (2-AG)). To date, there are no data on the role of these lipid mediators in mastocytosis. Here, we analyzed plasma levels of PLA2, PLC, DAG, ECs, and EC-related N-acylethanolamines in patients with mastocytosis. Methods. In 23 patients with mastocytosis and 23 healthy individuals, we measured plasma PLA2 and PLC activities, DAG, 2-AG, anandamide (AEA), palmitoylethanolamide (PEA), and oleoylethanolamide (OEA). Results. Plasma PLA2 and PLC activities were increased in mastocytosis patients compared to controls. Concentrations of DAG (18:1 20:4 and 18:0 20:4), two second messengers produced by PLC, were higher in mastocytosis compared to controls, whereas the concentrations of their metabolite, 2-AG, were not altered. AEA was decreased in mastocytosis patients compared to controls; by contrast, AEA congener, PEA, was increased. PLA2 and PLC activities were increased only in patients with mediator-related symptoms. Moreover, PLC activity was positively correlated with disease severity and tryptase concentrations. By contrast, AEA was negatively correlated with tryptase concentrations. Conclusions. PLs and some lipid mediators are altered in patients with mastocytosis. Our results may pave the way for investigating the functions of these mediators in the pathophysiology of mastocytosis and provide new potential biomarkers and therapeutic targets.
Impact of a Multichannel Blocker in Attenuating Intramyocardial Artery Remodeling in Hypertensive Rats through Increased Nitric Oxide Bioavailability
Authors: Quintana-Villamandos Begoña , Delgado-Martos María Jesús , Delgado-Baeza Emilio
Published: July 2019

Dronedarone is recommended for the treatment of atrial fibrillation. However, we do not know its effect on vascular remodeling. This study was designed to assess whether dronedarone has the potential to improve the intramyocardial artery remodeling induced by chronic hypertension. Ten-month-old male spontaneously hypertensive rats (SHR) were randomly assigned to receive dronedarone (100 mg/kg) or vehicle. Age-matched male Wistar-Kyoto rats served as controls. After 14 days of treatment, we studied the structure (geometry and fibrosis) of the intramyocardial artery using histological analysis. Nitric oxide (NO) in plasma was analyzed. In the untreated SHR, we observed a significant increase in external diameter, lumen diameter, wall width, cross-sectional area, and collagen volume density, as was expected in the experimental model. Dronedarone induced a significant decrease in wall width, cross-sectional area, and collagen volume density in SHR-D in comparison with untreated SHR. The values obtained in SHR-D were similar in the WKY control group. We found significantly higher NO levels in plasma in SHR-D than in untreated SHR. Dronedarone improves the intramyocardial artery remodeling induced by chronic hypertension in SHR through increased nitric oxide bioavailability.
Attenuation Law of Stress Waves in Cracked Rock Mass under Different Confining Pressures
Authors: Lou Xiaoming , Luo Rui , Yu Jin
Published: July 2019

Through theoretical analysis and indoor model tests, this paper explores the attenuation law of stress waves in the intact confined rock mass and cracked rock mass under different confining pressures, especially the relationship between the stress attenuation coefficient, crack width, and crack angle, respectively. The tests were carried out on a triaxial test system for deep rock mass, which supports both static and dynamic loading. The research results show that the physical attenuation of the stress wave in the intact rock mass first decreases and then increases with the increase of the confining pressure and decreases with the increase of crack width. The attenuation coefficient of stress waves in the cracked rock mass depends on the crack angle and crack width. Specifically, the coefficient is negatively correlated with crack width; under no confining pressure, the coefficient decreases with the increase of the crack angle; when the confining pressure is on a moderate level, the coefficient increases with the crack angle; when the confining pressure exceeds the uniaxial intensity by 34%, the coefficient decreases again with the increase of the crack angle. The theoretical propagation equation of stress waves at the crack, which was derived from the propagation attenuation mechanism of stress waves in the cracked rock mass, was proved feasible through the comparison against the experimental results.
N-Acetyltransferase 10 Enhances Doxorubicin Resistance in Human Hepatocellular Carcinoma Cell Lines by Promoting the Epithelial-to-Mesenchymal Transition
Authors: Zhang Xiuming , Chen Jiang , Jiang Shi , He Shilin , Bai Yanfeng , Zhu Linghua , Ma Rui , Liang Xiao
Published: July 2019

Background. N-Acetyltransferase 10 (NAT10) has been reported to be expressed at high levels in hepatocellular carcinoma (HCC); however, its role in chemoresistance is unclear. This study is aimed at investigating whether NAT10 regulates the epithelial-mesenchymal transition (EMT) and chemoresistance in HCC. Methods. HCC cell lines (Huh-7, Bel-7402, SNU387, and SNU449) were treated with remodelin, an inhibitor of NAT10, or transfected with small inhibitory RNAs (siRNAs) targeting NAT10 or Twist. The EMT was induced by hypoxia. The CCK-8 assay was used to quantify cell viability, the EdU incorporation assay to assess cell proliferation. siRNA knockdown efficiency and epithelial/mesenchymal marker expression were assessed by western blotting. Results. Knockdown of NAT10 using siRNA or inhibition of NAT10 using remodelin increased the sensitivity of HCC cell lines to doxorubicin; similar effects were observed in cells transfected with the Twist siRNA. Inhibition of NAT10 using remodelin also reversed the ability of doxorubicin to induce the EMT in HCC cells. Furthermore, inhibiting NAT10 reversed the hypoxia-induced EMT. Finally, we confirmed that combining doxorubicin with remodelin delayed tumor growth and reduced tumor cell proliferation in a mouse xenograft model of HCC. Conclusions. NAT10 may contribute to chemoresistance in HCC by regulating the EMT. The mechanism by which NAT10 regulates the EMT and doxorubicin sensitivity in HCC cells merits further investigation.
Metabolic Disturbances Identified in Plasma Samples from ST-Segment Elevation Myocardial Infarction Patients
Authors: Goulart Vânia Aparecida Mendes , Santos Anderson Kenedy , Sandrim Valéria Cristina , Batista Josimar Marques , Pinto Mauro Cunha Xavier , Cameron Luiz Cláudio , Resende Rodrigo Ribeiro
Published: July 2019

ST-segment elevation myocardial infarction (STEMI) is the most severe form of myocardial infarction (MI) and the main contributor to morbidity and mortality caused by MI worldwide. Frequently, STEMI is caused by complete and persistent occlusion of a coronary artery by a blood clot, which promotes heart damage. STEMI impairment triggers changes in gene transcription, protein expression, and metabolite concentrations, which grants a biosignature to the heart dysfunction. There is a major interest in identifying novel biomarkers that could improve the diagnosis of STEMI. In this study, the phenotypic characterization of STEMI patients (n=15) and healthy individuals (n=19) was performed, using a target metabolomics approach. Plasma samples were analyzed by UPLC-MS/MS (ultra-high-performance liquid chromatography-tandem mass spectrometry) and FIA-MS (MS-based flow injection analysis). The goal was to identify novel plasma biomarkers and metabolic signatures underlying STEMI. Concentrations of phosphatidylcholines, lysophosphatidylcholines, sphingomyelins, and biogenic amines were altered in STEMI patients in relation to healthy subjects. Also, after multivariate analysis, it was possible to identify alterations in the glycerophospholipids, alpha-linolenic acid, and sphingolipid metabolisms in STEMI patients.
Synthesis, DNA Binding, and Molecular Docking Studies of Dimethylaminobenzaldehyde-Based Bioactive Schiff Bases
Authors: Almarhoon Zainab M. , Al-Onazi Wedad A. , Alothman Asma A. , Al-Mohaimeed Amal M. , Al-Farraj Eida S.
Published: July 2019

A new series of p-dimethylaminobenzaldehyde derivatives were tested for therapeutic potential by exploring their properties through characterization. The derivatives were synthesized by 1 : 1 condensation reaction of p-dimethylaminobenzaldehyde and substituted amines. The synthesized compounds 1–8 were characterized by different characterization techniques including IR, mass, 1H NMR, and 13C NMR spectroscopy, elemental analysis, and mass spectrometry. Furthermore, binding of these Schiff bases to Ct-DNA was examined by absorption spectroscopy, fluorescence quenching, circular dichroic, viscosity measurement, molecular docking, and molecular dynamics simulation methods. Schiff bases were tested for antimicrobial activity against bacterial species Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus by the disc diffusion method. The pharmacological treatment of Schiff bases showed that 1–8 have promising potential against tested bacterial strains. The molecular docking study of the target compounds was also carried out against B-DNA dodecamer d(CGCGAATTCGCG)2, and it has been found that 1–8 can bind to Ct-DNA via an intercalative mode. DPPH free radical and hydrogen peroxide scavenging assays were employed to assess the antioxidant potential of synthesized Schiff bases.
CLU Polymorphisms in Patients with Pseudoexfoliation Syndrome in Polish Population
Authors: Lesiewska Hanna , Linkowska Katarzyna , Stafiej Joanna , Grzybowski Tomasz , Swobodziński Jacek , Malukiewicz Grażyna
Published: July 2019

Purpose. To evaluate CLU polymorphisms in patients with pseudoexfoliation syndrome. Materials and Methods. We studied 81 patients (23 males and 58 females, the median age 76 years) and 91 control subjects (27 males and 64 females, the median age 75 years). Genotypes of the CLU polymorphisms (SNPs), rs3087554 and rs2279590, were determined using a commercially available validated genotyping assays. The χ2 test was performed to compare patient and control groups for possible associations between SNP genotype/allele frequency and disease state. Results. There were no significant differences for both allele and genotype frequencies between PEX patients and controls for rs3087554 and rs2279590 polymorphisms. The haplotypes distribution shows statistically significant difference between groups p=0.03. The haplotype (CT) more often was found in controls than in PEX patients, conferring an 18-fold decreased risk to the disease. Conclusion. Our results indicate that CLU variants may contribute to the risk of PEX in the Polish population.
Nonfatal Hyperammonemic Encephalopathy as a Late Complication of Roux-en-Y Gastric Bypass
Authors: Salcedo Juan D. , Goldstein Jordan S. , Quinonez Jose M. , Mosetti Maria Antonietta
Published: July 2019

Roux-en-Y gastric bypass (RYGB) is the most common weight loss procedure performed in the US. Gastric bypass–related hyperammonemia (GaBHA) is a potentially fatal entity, characterized by encephalopathy associated with hyperammonemia and various nutritional deficiencies, which can present at variable time intervals after RYGB. Twenty-five cases of hyperammonemic encephalopathy after bariatric surgery have been previously reported in the literature. We describe the case of a 48-year-old Hispanic woman with no prior history of liver disease, presenting with nonfatal hyperammonemic encephalopathy as a late postoperative complication 20 years after undergoing a RYGB. Hyperammonemic encephalopathy in the absence of known hepatic dysfunction presents a diagnostic dilemma. An early diagnosis and intervention are crucial to decrease morbidity and mortality.
Long-Chain Fatty Acids and Inflammatory Markers Coaccumulate in the Skeletal Muscle of Sarcopenic Old Rats
Authors: Laurentius Thea , Kob Robert , Fellner Claudia , Nourbakhsh Mahtab , Bertsch Thomas , Sieber Cornel Christian , Bollheimer Leo Cornelius
Published: July 2019

Obesity and inflammation are reportedly associated with the pathogenesis of sarcopenia, which is characterized by age-related loss of skeletal muscle mass. Intramuscular fat deposits have been found to compromise muscle integrity; however, the relevant fat compounds and their roles as mediators of muscular inflammation are not known. The aim of this study was to identify potential correlations between inflammation markers and lipid compounds that accumulate in the quadriceps muscle of previously described Sprague-Dawley (SD) rat model for high-fat diet- (HFD-) induced muscle loss. Six-month-old SD rats were continuously fed a control (CD) or HFD until the age of 21 months. Magnetic resonance imaging (MRI) revealed a significant decline in muscle cross-sectional area in male SD rats as a result of HFD, but not in female rats. Here, we developed a new procedure to quantitatively identify and classify the fatty acid methyl esters (FAMEs) in rats’ quadriceps muscles from our former study using gas chromatography-mass spectrometry (GC-MS). Fatty acid analysis revealed accumulation of octadecadienoic (linoleic acid), octadecanoic (stearic acid), and octadecenoic (vaccenic acid) acids exclusively in the quadriceps muscles of male rats. The designated fatty acids were mainly incorporated into triacylglycerols (TAGs) or free fatty acids (FFAs), and their proportions were significantly elevated by consumption of a HFD. Furthermore, the number of resident immune cells and the levels of the chemokines RANTES, MCP-1, and MIP-2 were significantly increased in quadriceps muscle tissue of HFD-fed male, but not female rats. Together, HFD-induced muscle loss in aged male SD rats is associated with greater deposits of long-chain fatty acid esters and increased levels of the inflammatory markers RANTES, MCP-1, and MIP-2 in skeletal muscle tissue. This trend is further reinforced by long-term consumption of a HFD, which may provoke synergistic crosstalk between long-chain fatty acids and inflammatory pathways in sarcopenic muscle.
Multiple Molecular Targets Associated with Genomic Instability in Lung Cancer
Authors: Soca-Chafre Giovanny , Montiel-Dávalos Angelica , Rosa-Velázquez Inti Alberto De La , Caro-Sánchez Claudia Haydeé Saraí , Peña-Nieves Adriana , Arrieta Oscar
Published: July 2019

Lung cancer (LC) is the first cause of cancer-related deaths worldwide. Elucidating the pathogenesis of LC will give information on key elements of tumor initiation and development while helping to design novel targeted therapies. LC is an heterogeneous disease that has the second highest mutation rate surpassed only by melanoma, since 90% of LC occurs in tobacco smokers. However, only a small percent of smokers develops LC, indicating an inherent genomic instability. Additionally, LC in never smokers suggests other molecular mechanisms not causally linked to tobacco carcinogens. This review presents a current outlook of the connection between LC and genomic instability at the molecular and clinical level summarizing its implications for diagnosis, therapy, and prognosis. The genomic landscape of LC shows widespread alterations such as DNA methylation, point mutations, copy number variation, chromosomal translocations, and aneuploidy. Genome maintenance mechanisms including cell cycle control, DNA repair, and mitotic checkpoints open a window to translational research for finding novel diagnostic biomarkers and targeted therapies in LC.
Global Properties of a General Latent Pathogen Dynamics Model with Delayed Pathogenic and Cellular Infections
Authors: Elaiw A. M. , Almatrafi A. A. , Hobiny A. D. , Hattaf K.
Published: July 2019

This paper studies the global dynamics of a general pathogenic infection model with two ways of infections. The effect of antibody immune response is analyzed. We incorporate three discrete time delays and both latently infected cells and actively infected cells. The infection rate and production and clearance/death rates of the cells and pathogens are given by general functions. We determine two threshold parameters to investigate the global stability of three equilibria. We use Lyapunov method to establish the global stability. We support our theoretical results by numerical simulations.
Gut Microbiota: A New Strategy to Study the Mechanism of Electroacupuncture and Moxibustion in Treating Ulcerative Colitis
Authors: Wei Daneng , Xie Lushuang , Zhuang Zhiqi , Zhao Na , Huang Biao , Tang Yong , Yu Shuguang , Zhou Qizhi , Wu Qiaofeng
Published: July 2019

Previous studies have confirmed that acupuncture and moxibustion is an effective way for treating ulcerative colitis (UC). However, the exact mechanism is unclear yet. In this study, DSS-induced UC mice were treated by electroacupuncture and moxibustion, and the genome of intestinal flora was subsequently detected by high-throughput sequencing in order to explore the detailed mechanism in terms of intestinal flora. The results indicated that the alpha diversity indices and beta diversity of intestinal flora were improved by electroacupuncture and moxibustion treatments, especially by the moxibustion treatment. These treatments inhibited Streptococcus, Odoribacter, and Allobaculum whereas it facilitated Lactobacillus on genus level. Further correlation analysis showed that the alpha diversity indices were positively correlated with the percentage of Treg cells in CD4+ cells but negatively correlated with the percentage of Th17 in CD4+ cells. These data indicated that both electroacupuncture and moxibustion can promote the intestinal flora diversity, providing a new view to understand the relationship between host and microbiome when using some external therapies.
Trastorno de alimentación: identificación y primeras intervenciones para los profesionales de salud.
Authors: CORDELLA MASINI MARIA PATRICIA
Published: July 2019

los trastornos de la alimentación e ingesta (TAI) son un complejo conjunto interdimensional de enfermedades mentales que afectan el rendimiento corporal, mental y social. El núcleo de la enfermedad es el miedo a ganar peso. Las estrategias de control de ingesta varían entre: restricción, selección y purga alimentaria. Afectan diferentes sexos, razas, etnias y edades. Con mayor frecuencia en adolescentes y mujeres jóvenes (9: 1). Presentan alta mortalidad, comorbilidad mental y conflictos familiares asociados.Método: integrar información disponible y útil según criterio de experto, orientada al manejo clínico de los TAI. Resultado: debido a que los profesionales de salud de diferentes áreas podrían ser el único contacto que el/la paciente busca para aliviar alguna dolencia aparentemente no relacionada con TAI, es necesario lograr identificar y diagnosticar los estadios patológicos e indicar las primeras conductas, así como hacer una referencia exitosa. El retraso en el diagnóstico causa alteraciones severas y crónicas en la fisiología, el comportamiento, la cognición y el funcionamiento psicosocial. Los objetivos de este estudio son: a. Presentar, en forma integrada, la información disponible de modo de facilitar a los profesionales de la salud la detección precoz de los TAI; b. Ofrecer un conjunto de acciones útiles que faciliten el diagnóstico TAI; c.  Organizar la comprensión del riesgo TAI en un diagrama que facilite la construcción de la derivación utilizando las dimensiones:  cuerpo, mente, relaciones; d. Mostrar las alternativas psicoterapéuticas en uso e. Proveer información para realizar las primeras intervenciones. Conclusión: reconocer tempranamente el cuadro TAI puede detener el curso patológico y los potenciales daños.
Síndrome de Kounis como manifestación de anafilaxia
Authors: Orozco Chinome Javier Esteban , Picón Jaimes Yelson Alejandro , Ortega Uribe Leec Fabían-David
Published: July 2019

Introducción: el síndrome de Kounis corresponde a la isquemia miocárdica aguda relacionada con la liberación de mediadores inflamatorios que llevan a vasoespasmo coronario y/o complicación de una placa ateromatosa durante una reacción alérgica. La incidencia de eventos coronarios en procesos alérgicos en Estados Unidos es de 8 casos por 100000 habitantes por año. Métodos: describimos el caso de una mujer que desarrolla síndrome de Kounis, posterior a múltiples picaduras de abeja, recibiendo manejo en una unidad de cuidado intensivo de una institución de salud de Colombia. La paciente presentó un síndrome coronario agudo tipo infarto agudo de miocardio con elevación del segmento ST, con arteriografía coronaria en la cual se evidenció ausencia de lesiones vasculares o vasoespasmo, con presencia de un trombo flotante en la arteria descendente anterior, sin evidencia de enfermedad ateroesclerótica. Resultados: el síndrome de Kounis es frecuente en los pacientes con anafilaxia, sin embargo, se informa poco en la literatura, debido a la falta de sospecha diagnostica y al poco reconocimiento clínico.  Los síntomas de este síndrome pueden ser típicos como el dolor torácico opresivo de gran intensidad irradiado a miembro superior izquierdo o a cuello, o atípicos como disnea, nauseas o palpitaciones, los cuales pueden confundirse con las manifestaciones del proceso anafiláctico. Conclusiones: en la actualidad no existen guías para el tratamiento del síndrome y depende de la forma de presentación, comorbilidades y disponibilidad de un grupo médico interdisciplinar, que incluya monitoria y vigilancia en una unidad de cuidado intensivo.
Late diagnosis of tuberculosis and central nervous system infection
Authors: Dos Santos Vitorino Modesto , Dos Santos Lister Arruda Modesto
Published: July 2019

Dear Chief Editor,The migratory phenomenon in Latin America has significantly increased in recent decades, especially in Brazil and Chile. The frequent vulnerability of many of these migrants constitutes a major concern related to potential risks of emerging and re-emerging diseases. This is due to the poverty situation and the lack of resources for public health care, and current imported cases of measles from Venezuela are a major example of this social burden. Imported cases may increase the challenges related to the control of transmissible infections. In this scenery, pulmonary tuberculosis plays a main role among the communicable diseases. Chilean authors have properly suggested the utilization of basic screening of tuberculosis in migrants from countries of elevated prevalence, aiming to employ early treatment and to prevent infections associated with late diagnosis of an index case (Alarcón & Balcells, 2017).
Body Composition and Aspirin Dose for Colorectal Adenoma Prevention in a Randomized Clinical Trial
Authors: Passarelli Michael N. , Barry Elizabeth L. , Rees Judy R. , Mott Leila A. , Ahnen Dennis J. , Baron John A.
Published: July 2019

Background:

Visceral adiposity is a risk factor for colorectal adenomas, and aspirin is an established chemopreventive agent. Evidence from clinical trials suggests the effectiveness of aspirin at preventing cardiovascular disease and cancer may require higher doses for higher body weight.

Methods:

Body mass index, body surface area, fat-free mass, and fat mass were calculated from baseline height and weight in 1,121 participants of the Aspirin/Folate Polyp Prevention Study, a double-blind, placebo-controlled, 3 × 2 factorial randomized clinical trial of low-dose (81 mg/day) or high-dose (325 mg/day) aspirin and/or 1 mg/day folic acid to prevent metachronous colorectal adenomas. Participants were treated during a surveillance colonoscopy interval of approximately 3 years. Risk ratios (RR) with 95% confidence intervals (CI) for any colorectal neoplasia and high-risk adenoma (HRA, advanced or ≥3 adenomas) were estimated from log-linear regression.

Results:

We did not find evidence to suggest aspirin dose-response differed by body composition measurements, including weight alone. Among those weighing ≥ 80 kg, treatment effects for low-dose aspirin (RR for colorectal neoplasia, 0.75; 95% CI, 0.60–0.94; RR for HRA, 0.52; 95% CI, 0.31–0.86) and high-dose aspirin (RR for colorectal neoplasia, 0.88; 95% CI, 0.72–1.08; RR for HRA, 0.68; 95% CI, 0.43–1.09) were not meaningfully different than for those weighing 70–79 kg or <70 kg.

Conclusions:

Measurements of body composition calculated from height and weight did not modify aspirin treatment effects for colorectal adenoma prevention.

Impact:

Aspirin dosing strategies accounting for body weight suggested in previous trials of colorectal cancer may not apply to adenomas.
Oncogenic KRAS Induces NIX-Mediated Mitophagy to Promote Pancreatic Cancer
Authors: Humpton Timothy J. , Alagesan Brinda , DeNicola Gina M. , Lu Dan , Yordanov Georgi N. , Leonhardt Carl S. , Yao Melissa A. , Alagesan Priya , Zaatari Maya N. , Park Youngkyu , Skepper Jeremy N. , Macleod Kay F. , Perez-Mancera Pedro A. , Murphy Michael P. , Evan Gerard I. , Vousden Karen H. , Tuveson David A.
Published: July 2019

Activating KRAS mutations are found in nearly all cases of pancreatic ductal adenocarcinoma (PDAC), yet effective clinical targeting of oncogenic KRAS remains elusive. Understanding of KRAS-dependent PDAC-promoting pathways could lead to the identification of vulnerabilities and the development of new treatments. We show that oncogenic KRAS induces BNIP3L/NIX expression and a selective mitophagy program that restricts glucose flux to the mitochondria and enhances redox capacity. Loss of Nix restores functional mitochondria to cells, increasing demands for NADPH reducing power and decreasing proliferation in glucose-limited conditions. Nix deletion markedly delays progression of pancreatic cancer and improves survival in a murine (KPC) model of PDAC. Although conditional Nix ablation in vivo initially results in the accumulation of mitochondria, mitochondrial content eventually normalizes via increased mitochondrial clearance programs, and pancreatic intraepithelial neoplasia (PanIN) lesions progress to PDAC. We identify the KRAS–NIX mitophagy program as a novel driver of glycolysis, redox robustness, and disease progression in PDAC.

Significance:

NIX-mediated mitophagy is a new oncogenic KRAS effector pathway that suppresses functional mitochondrial content to stimulate cell proliferation and augment redox homeostasis. This pathway promotes the progression of PanIN to PDAC and represents a new dependency in pancreatic cancer.

This article is highlighted in the In This Issue feature, p. 1143
Mitochondrial Homeostasis in AML and Gasping for Response in Resistance to BCL2 Blockade
Authors: Savona Michael R. , Rathmell Jeffrey C.
Published: July 2019

Understanding resistance to BCL2 inhibition is a critical scientific and clinical challenge. In this issue of Cancer Discovery, two laboratories use unbiased approaches of large loss-of-function CRISPR/Cas 9 screens to discover targetable liabilities in cell signaling and metabolism to acute myeloid leukemia resistant to BCL2 inhibition.

See related article by Chen et al., p. 890.

See related article by Nechiporuk et al., p. 910.
The Estrogen-Induced miR-19 Downregulates Secretory Leucoprotease Inhibitor Expression in Monocytes
Authors: McKiernan Paul J. , Smith Stephen G.J. , Durham Andrew L. , Adcock Ian M. , McElvaney Noel G. , Greene Catherine M.
Published: July 2019

Compared to females, males are more susceptible to acute viral and other respiratory tract infections that display greater severity and higher mortality. In contrast, females tend to fare worse with chronic inflammatory diseases. Circulating 17β-estradiol (E2) is a female-specific factor that may influence the progression of human lung diseases. Here we hypothesize that E2 modulates the inflammatory response of monocytes through microRNA (miRNA)-based modulation of secretory leucoprotease inhibitor (SLPI), an antiprotease with immunomodulatory effects. Monocytic cells were treated ± E2, and differentially expressed miRNAs were identified using PCR profiling. Cells were transfected with miRNA mimics or antimiRs and SLPI mRNA and protein levels were quantified. Luciferase activity assay using wildtype and ΔmiR-19a/b-SLPI3′UTR reporter constructs and chromatin immunoprecipitation on E2-treated monocytes were performed. E2 downregulated SLPI and upregulated miR-19 expression in monocytes. Transfection with premiR-19b reduced SLPI mRNA and protein levels and this effect was abrogated using antimiRs against miR-19b. miR-19b directly binds the SLPI 3′UTR. The mechanism responsible for E2-mediated upregulation of miR-19 occurs via increased MIR17HG promoter activity mediated by c-MYC. Overall E2 decreases SLPI expression in human monocytic cells, via changes in miRNA expression and highlights the potential for estrogen to modulate the innate immune system.
Chimeric Antigen Receptor T-Cell Therapy: Reach to Solid Tumor Experience
Authors: Metzinger Matthew N. , Verghese Cherian , Hamouda Danae M. , Lenhard Amanda , Choucair Khalil , Senzer Neil , Brunicardi F. Charles , Dworkin Lance , Nemunaitis John
Published: July 2019

Chimeric antigen receptor (CAR) modified T-cell therapy, a unique platform technology highlighting precision medicine through utilization of molecular biology and cell-based therapeutics has shown unprecedented rates in patients with hematological malignancies such as acute lymphocyte leukemia, non-Hodgkin’s lymphoma and multiple myeloma (MM). With the approval of CD19-targeted CAR T-cells by the Food and Drug Administration in acute lymphoblastic leukemia (ALL) and NHL, this technology is positioned for aggressive expansion to combination therapeutic opportunities and proof of principle towards utility in other malignant disorders. However, despite the impressive results seen with hematological malignancies, CAR T-cells have shown limited efficacy in solid tumors with several unsuccessful preclinical studies. Regardless, these attempts have provided us with a better understanding of the imminent challenges specific to solid tumors even if they have not so far led to expanded clinical treatment opportunities outside ALL/NHL/MM. This review summarizes our current understanding of CAR T-cell mechanism of action, while presenting the major limitations of CAR T-cell derived treatments in solid tumors. We further discuss recent findings and present new potential strategies to overcome the challenges facing solid tumor targeting by CAR T-cell platforms.
Leukocyte Counts and Other Hematological Values in Twin-Twin Transfusion Syndrome and Twin Anemia-Polycythemia Sequence
Authors: Visser G. Laurien , Tollenaar Lisanne S.A. , Bekker Vincent , te Pas Arjan B. , Lankester Arjan C. , Oepkes Dick , Lopriore Enrico , Verbeek Lianne
Published: July 2019

Objective: The aim of this study was to evaluate the differences in leukocyte counts at birth between donors and recipients with twin-twin transfusion syndrome (TTTS) or twin anemia-polycythemia sequence (TAPS). Methods: We performed a retrospective cohort study in monochorionic twin pairs with TTTS or TAPS. TTTS and TAPS cases treated with fetoscopic laser surgery were excluded. Primary outcome was the difference in leukocyte levels at birth between donor and recipient twins and the presence of leukopenia (defined as leukocyte count <4 × 109/L). Secondary outcomes included early-onset sepsis, necrotizing enterocolitis, use of antibiotics during admission, and neonatal mortality. Results: We included 99 twins pairs, of which 61 twin pairs were affected by TAPS and 38 twin pairs by TTTS. The mean leukocyte count at birth in donors and recipients was 7.5 × 109/L versus 7.4 × 109/L (p = 0.936), respectively. Leukopenia was significantly more common in donor twins compared to recipient twins (7.1% [7/99] vs. 0% [0/99], p = 0.016). Of the 7 donors with leukopenia, 6 were affected by TAPS and 1 by TTTS. Overall, donors were more often affected by early-onset sepsis than recipients, 23.7% (23/97) versus 13% (13.7/95) (p = 0.049), respectively. Conclusions: Leukocyte counts at birth in twins with TTTS or TAPS are similar between donors and recipients, but TAPS donors are at an increased risk of leukopenia. Overall, TTTS and TAPS donors seem to be at an increased risk of early-onset neonatal sepsis compared to recipient twins.
A origem animal de deus: Flávio de Carvalho e a figura do artista enquanto um etnógrafo da mente
Authors: Cavalcanti Augusto Guimaraens
Published: July 2019

Este artigo tem por objetivo basilar problematizar a dimensão dialógica entre etnografia e arte na poética composicional de Flávio de Carvalho. Tendo como fio condutor o livro póstumo A origem animal de deus (1973), procuraremos investigar a instância etnográfica tal como a entendia Flávio e seu surrealismo particular; não apenas como uma prática circunscrita a um só gênero de escrita, mas também como uma forma de visão de mundo, um espaço teórico reinventor de tradições, um método de produção de conhecimento e um processo de crítica cultural.
Criminalização, racialização e patologização: as origens do sistema de justiça juvenil da Califórnia
Authors: Cornelius Eduardo Gutierrez
Published: July 2019

Resenha de Chávez-García, Miroslava. States of Delinquency: Race and Science in the Making of California’s Juvenile Justice System. Los Angeles: University of California Press, 2012.
Association of Total Medication Burden With Intensive and Standard Blood Pressure Control and Clinical Outcomes: A Secondary Analysis of SPRINT
Authors: Derington Catherine G. , Gums Tyler H. , Bress Adam P. , Herrick Jennifer S. , Greene Tom H. , Moran Andrew E. , Weintraub William S. , Kronish Ian M. , Morisky Donald E. , Trinkley Katy E. , Saseen Joseph J. , Reynolds Kristi , Bates Jeffrey T. , Berlowitz Dan R. , Chang Tara I. , Chonchol Michel , Cushman William C. , Foy Capri G. , Herring Charles T. , Katz Lois Anne , Krousel-Wood Marie , Pajewski Nicholas M. , Tamariz Leonardo , King Jordan B. ,   for the SPRINT Research Group
Published: July 2019

Total medication burden (antihypertensive and nonantihypertensive medications) may be associated with poor systolic blood pressure (SBP) control. We investigated the association of baseline medication burden and clinical outcomes and whether the effect of the SBP intervention varied according to baseline medication burden in SPRINT (Systolic Blood Pressure Intervention Trial). Participants were randomized to intensive or standard SBP goal (below 120 or 140 mm Hg, respectively); n=3769 participants with high baseline medication burden (≥5 medications) and n=5592 with low burden (<5 medications). Primary outcome: differences in SBP. Secondary outcomes: 8-item Morisky Medication Adherence Scale and modified Treatment Satisfaction Questionnaire for Medications measured at baseline and 12 months and incident cardiovascular disease events and serious adverse events throughout the trial. Participants in the intensive group with high versus low medication burden were less likely to achieve their SBP goal at 12 months (risk ratio, 0.91; 95% CI, 0.85–0.97) but not in the standard group (risk ratio, 0.98; 95% CI, 0.93–1.03;
P
interaction
<0.001). High medication burden was associated with increased cardiovascular disease events (hazard ratio, 1.39; 95% CI, 1.14–1.70) and serious adverse events (hazard ratio, 1.34; 95% CI, 1.24–1.45), but the effect of intensive versus standard treatment did not vary between medication burden groups (
P
interaction
>0.5). Medication burden had minimal association with adherence or satisfaction. High baseline medication burden was associated with worse intensive SBP control and higher rates of cardiovascular disease events and serious adverse events. The relative benefits and risks of intensive SBP goals were similar regardless of medication burden.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01206062
Vergilius Astronomiae Ignarus?
Authors: Bakker Frederik A.
Published: July 2019

Both in antiquity and today Virgil is sometimes accused of ignorance in astronomy. This paper argues that, on the contrary, Virgil’s treatment of astronomical topics in Georgics 1.231-258 shows that he was quite familiar with the subject, and was able (when he wished to) to combine information from different sources (Aratus, Eratosthenes and other, unidentified ones) into a sensible and harmonious whole. On the other hand, the omission of essential steps between the various parts of his account, and the deliberate confusion of science and myth show us that his ultimate aim was not to inform the ignorant but to amuse and surprise readers who were just as familiar with astronomy as Virgil himself.
Greek and the Indo-European Verb
Authors: Kölligan Daniel
Published: July 2019

This article reviews Andreas Willi’s study of the history and prehistory of the Greek and Proto-Indo-European (PIE) verbal system which tries to put the data of one of the ‘classical’ languages of PIE reconstruction back onto the centre stage after much attention has been given to Anatolian (Hittite, etc.) and Tocharian in recent decades. It argues that in the earliest reconstructable phase PIE had ergative alignment and that the switch to nominative-accusative alignment triggered a series of changes leading to the distribution of stem formations found in Greek and other ancient PIE languages (root aorists, reduplicated aorists and presents, thematic aorists and presents, s-aorists and s-futures, etc.). The review tries to show that the study presents a series of thought-provoking and well-argued hypotheses, while with its focus on prehistory its philological analyses tend to rely on a few chosen examples.
Self-Knowledge in the Eye-Soul Analogy of the Alcibiades
Authors: Ferguson Daniel
Published: July 2019

The kind of self-knowledge at issue in the eye-soul analogy of the Alcibiades (132d5-133c7) is knowledge of one’s epistemic state, i.e. what one knows and does not know, rather than knowledge of what one is. My evidence for this is the connection between knowledge of one’s epistemic state and self-improvement, the equivalence of self-knowledge to moderation, and the fact that ‘looking’ into the soul of another is a metaphor for elenctic discussion. The final lines of the analogy (133c1-7) clarify that the part of the soul one ‘looks’ into and the part one learns about when learning about one’s epistemic state is divine.
The Carabao and the Encounter of the Law in Nineteenth-Century Philippines
Authors: Ludovice Nicolo Paolo P.
Published: July 2019

The place of the non-human animal in the legal world has been questioned. Animals’ legal status as property has been probed on how to best protect their welfare. While this is significant for animals who are not on the farm, it might not be effective when considering animals raised for food. The case of the carabao, or the water buffalo, in the Philippines is seen as a hybrid. This article traces the development of the carabao in Philippine history during the nineteenth century. Through historical, archival, and legal research on animals, the carabao is situated as private property. Colonial instruments of control were introduced to protect the carabao from criminals. In its proper historical context, the classification of carabaos as property indeed highlighted the animal’s status as legally owned, which did not necessarily demean the animal’s relationship with the human peasant nor the carabao’s quality as an animal.
You Speak What They Wear
Authors: Li Larry Hong-lin
Published: July 2019

We manipulated persona features characterising US and Taike subcultures, and examined its impact on preference toward Chinese-English alternated uses among Taiwanese youngsters. We conducted (i) a literature survey to identify the features iconic of US and Taike subcultures, (ii) a norming task to verify the subculture icons obtained, (iii) a multi-choice task to survey preference for six relevant non-/mixed forms of language, (iv) a forced-choice task to inspect “relative” code choices between Chinese versus its code-mix with English elements under the cues of the probe features. We found that visual cues and the stereotypical generalisations thereof play a role in language negotiation in first meeting contexts; cultural personae manifest themselves in the language alternation; with code mixing as an accommodative move, language users self-categorise themselves with the interlocutor that is stereotyped as having a linguistic preference associated to their persona character; linguistic convergence to stereotypes is driven by unconscious need.
Articulation of Movement Demands and the Politics of Solidarity against Extractive Capital in Bangladesh
Authors: Faruque M. Omar
Published: July 2019

How do disparate grievances join to form an agenda for collective action? This article analyses the articulation of movement demands and solidarity building during the formative phase of a popular mobilisation against a multinational mining company in Bangladesh. Drawing on a conceptual framework derived from Laclauian discourse theory, I explain how local community resistance inspired various social groups to support an anti-corporate social movement, ultimately defeating the mining company. I explain how the construction of an empty signifier had the capacity to connect disparate groups to oppose a common enemy. This analysis is based on a set of interviews with activists and a close reading of organisational documents. The examination of how movement demands are articulated emphasises the role of movement intellectuals and enriches the theorising of social movements in the Global South.
The Historical Development of Indonesian Social Security
Authors: Murphy John
Published: July 2019

Indonesia’s National Social Security System (SJSN) aspires to universal coverage of insurance for health, retirement, and occupational benefits, such as employment injury. This article surveys the successive layers of policy development since the 1960s, in pensions and health benefits for some, and in social assistance programmes for the poor in the Reformasi era. Clarifying the nature of prior developments helps to understand the challenges facing the SJSN. These initiatives are assessed in terms of the literature on welfare regimes, applied as an interpretative tool, rather than in the expectation Indonesia fits the often-rigid categories of welfare typologies.
From the Demise of Social Democracy to the ‘End of Capitalism’
Authors: Roos Jerome
Published: July 2019

Over the past decade, Wolfgang Streeck has emerged as one of the most prominent voices in the debate on the crisis of democratic capitalism. This article provides a critical appraisal of Streeck’s recent writings in light of his wider intellectual trajectory, tracing the evolutions and continuities in his work over time; highlighting its important contributions to our understanding of the present crisis; and presenting a fourfold critique of his latest book on the end of capitalism. The main argument is that Streeck’s work, while very valuable for its elucidation of the dynamics behind the demise of social democracy, ultimately remains plagued by a corporatist residue that keeps him from drawing his increasingly radical critique of capitalism to its logical conclusions. As a result, Streeck’s embrace of an exceedingly catastrophist worldview, devoid of any emancipatory potential, has tempted him to veer dangerously close to the welfare chauvinism of the nationalist right.
God and His Works from an Entrepreneurship Perspective
Authors: van der Kooi Cornelis , Rietveld Cornelius A.
Published: July 2019

This article explores to what extent God and his works can be understood in terms of entrepreneurship. We give several theological reasons for using this lens, and we survey briefly the use of the word ‘oikonomia’ in the New Testament, the early church, and Reformed theology. Thereafter, we investigate how the entrepreneurship metaphor fits the narrative of the Bible. We argue that by looking at how features of entrepreneurship can be found in the way in which the triune God acts, we obtain a more comprehensive view on our history as a risky drama between God and humanity. The metaphor also highlights the important role played by humans in letting creation flourish.
Epistemic modality, particles and the potential optative in Classical Greek
Authors: la Roi Ezra
Published: July 2019

This paper challenges the commonly held view that the Classical Greek potential optative has a subjective epistemic semantics, the result of a conceptual confusion of subjectivity and epistemic modality inherited from our standard grammars. I propose that this view becomes less convincing when the optative’s unique interaction with the subjective particles ἦ and ἄρα is incorporated into the analysis. Rather, the potential optative has a non-subjective epistemic semantics presenting an epistemic judgment as interpersonally accessible to the conversational participants. Frequencies of combination with ἦ and ἄρα, linguistic tests for subjectivity on the potential optative, and contrastive contextual analyses corroborate this view.
Acclimatory responses of thermal physiological performances in hatchling yellow pond turtles (Mauremys mutica)
Authors: Lu Hongliang , Hu Yingchao , Li Shuran , Dang Wei , Zhang Yongpu
Published: July 2019

Temperature is a crucial environmental factor that can strongly impact animal physiology. Here, we acclimated hatchling of Asian yellow pond turtles (Mauremys mutica) to one of two different temperatures (25 or 30°C) for four weeks to determine temperature acclimation effects on their physiology. All four measured physiological variables (righting time, resting metabolic rate, critical thermal minimum and critical thermal maximum) were significantly affected by temperature acclimation. Turtles acclimated to 25°C righted themselves more slowly and had a lower mean metabolic rate than 30°C-acclimated turtles. Turtles acclimated to 25°C were more resistant to low temperatures, but less resistant to high temperatures than 30°C-acclimated turtles, as measured by critical thermal limits. The thermal resistance range (i.e., the difference between critical thermal minimum and maximum) did not differ between the two acclimation groups. Compared with other semi-aquatic turtles, M. mutica had relatively higher acclimation response ratios for its critical thermal minimum and critical thermal maximum. Our results indicate that acclimation to relatively moderate temperatures could also produce significant responses in the thermal physiology of turtles.
How to Do Things with Things: Craft at the Edge of Buber’s Philosophical Anthropology
Authors: Atlas Dustin
Published: July 2019

This article offers an alternative reading of Martin Buber (1878–1956), one guided by his writings on craft and artistic creation. Rather than view Buber as a philosopher of dialogue, it views him as a philosopher of relationships, including relationships to nonhuman things. His writings on craft and artistic creation are taken to exemplify these nonhuman relationships. After sketching out the general structure of Buber’s thought, and the role that nonhuman relationships play in it, this article traces a trajectory through Buber’s work, showing the ever-increasing importance of these relationships through an analysis of his treatments of art and craft. It ends with an analysis of his late anthropological work on craft and images, which demonstrates that this was a longstanding, if not central, concern of Buber’s that guided not only his treatment of material things, but his understanding of Judaism as well.