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David Dreizin, Uttam Bodanapally, Alexis Boscak, Nikki Tirada, Ghada Issa, Jason W Nascone, Louis Bivona, Daniel Mascarenhas, Robert V O'Toole, Erika Nixon, Rong Chen, Eliot Siegel
Purpose To develop and test a computed tomography (CT)-based predictive model for major arterial injury after blunt pelvic ring disruptions that incorporates semiautomated pelvic hematoma volume quantification. Materials and Methods A multivariable logistic regression model was developed in patients with blunt pelvic ring disruptions who underwent arterial phase abdominopelvic CT before angiography from 2008 to 2013. Arterial injury at angiography requiring transarterial embolization (TAE) served as the outcome...
March 20, 2018: Radiology
Chiara Bellia, Martina Zaninotto, Chiara Cosma, Luisa Agnello, Giulia Bivona, Mariela Marinova, Bruna Lo Sasso, Mario Plebani, Marcello Ciaccio
OBJECTIVES: Glycated Albumin (GA) has been proposed as a screening marker for diabetes in Asian countries in the last years. Nevertheless, few studies have been conducted in Caucasian population. The aim of this study is to evaluate the clinical usefulness of GA in diabetes diagnosis in Caucasian asymptomatic subjects considered at risk of diabetes based on medical history and Fasting Plasma Glucose (FPG). DESIGN AND METHODS: Three hundred and thirty-four Caucasian subjects having one or more risk factor for diabetes, and/or FPG ranging from 5...
February 24, 2018: Clinical Biochemistry
Niki Karachaliou, Imane Chaib, Andres Felipe Cardona, Jordi Berenguer, Jillian Wilhelmina Paulina Bracht, Jie Yang, Xueting Cai, Zhigang Wang, Chunping Hu, Ana Drozdowskyj, Carles Codony Servat, Jordi Codony Servat, Masaoki Ito, Ilaria Attili, Erika Aldeguer, Ana Gimenez Capitan, July Rodriguez, Leonardo Rojas, Santiago Viteri, Miguel Angel Molina-Vila, Sai-Hong Ignatius Ou, Morihito Okada, Tony S Mok, Trever G Bivona, Mayumi Ono, Jean Cui, Santiago Ramón Y Cajal, Peng Cao, Rafael Rosell
Epidermal growth factor receptor (EGFR)-mutation-positive non-smallcell lung cancer (NSCLC) is incurable, despite high rates of response to EGFR tyrosine kinase inhibitors (TKIs). We investigated receptor tyrosine kinases (RTKs), Src family kinases and focal adhesion kinase (FAK) as genetic modifiers of innate resistance in EGFR-mutation-positive NSCLC. We performed gene expression analysis in two cohorts (Cohort 1 and Cohort 2) of EGFR-mutation-positive NSCLC patients treated with EGFR TKI. We evaluated the efficacy of gefitinib or osimertinib with the Src/FAK/Janus kinase 2 (JAK2) inhibitor, TPX0005 in vitro and in vivo...
February 5, 2018: EBioMedicine
Sungmi Park, Benjamin J Bivona, Lisa M Harrison-Bernard
We have previously reported significant increases in neuronal nitric oxide synthase (NOS) immunostaining in renal arterioles of angiotensin type 1A receptor (AT1A) knockout mice, and in arterioles and macula densa cells of AT1A/AT1B knockout mice. The contribution of nitric oxide derived from endothelial and macula densa cells in the maintenance of afferent arteriolar tone and acetylcholine-induced vasodilation were functionally determined in kidneys of wild-type, AT1A, and AT1A/AT1B knockout mice. Acetylcholine-induced changes in arteriolar diameters of in vitro blood perfused juxtamedullary nephrons were measured during control conditions, in the presence of the nonspecific NOS inhibitor, Nw-nitro-L-arginine methyl ester (NLA), or the highly selective neuronal NOS inhibitor, N5-(1-imino-3-butenyl)-L-ornithine (VNIO)...
February 7, 2018: American Journal of Physiology. Renal Physiology
Wei Wu, Franziska Haderk, Trever G Bivona
Anaplastic lymphoma kinase ( ALK ) gene rearrangements have been identified in lung cancer at 3-7% frequency, thus representing an important subset of genetic lesions that drive oncogenesis in this disease. Despite the availability of multiple FDA-approved small molecule inhibitors targeting ALK fusion proteins, drug resistance to ALK kinase inhibitors is a common problem in clinic. Thus, there is an unmet need to deepen the current understanding of genomic characteristics of ALK rearrangements and to develop novel therapeutic strategies that can overcome ALK inhibitor resistance...
November 30, 2017: Cancers
Luisa Agnello, Chiara Bellia, Bruna Lo Sasso, Alessia Pivetti, Maddalena Muratore, Concetta Scazzone, Giulia Bivona, Giuseppe Lippi, Marcello Ciaccio
Introduction: Galectin-3 (Gal-3) is an independent predictor of poor outcomes and mortality in patients with heart failure (HF). Thus, it has been proposed as a reliable prognostic biomarker for HF. The definition of reference intervals is mandatory for interpreting the findings of experimental studies and encouraging the routine use of biomarkers in clinical practice. To date, no study assessed the reference intervals of Gal-3 and identified the biological variables that affect its concentration in a well-defined healthy population...
October 15, 2017: Biochemia Medica: časopis Hrvatskoga Društva Medicinskih Biokemičara
Dana S Neel, Trever G Bivona
The advent of genomics has led to the identification of specific "driver" mutations in oncogenic kinases, and the development of targeted small molecule inhibitors to block their tumor-driving functions. These specific inhibitors have been a clinical success, and often significantly prolong the lives of individuals with cancer. Inevitably, however, the treated tumors recur as resistance to these targeted therapies develops. Here, we review the major mechanisms by which a cancer cell can evade targeted therapy, focusing on mechanisms of resistance to kinase inhibitors in lung cancer...
2017: NPJ Precision Oncology
Charles Truillet, Hsueh Ling J Oh, Siok Ping Yeo, Chia-Yin Lee, Loc T Huynh, Junnian Wei, Matthew F L Parker, Collin Blakely, Natalia Sevillano, Yung-Hua Wang, Yuqin S Shen, Victor Olivas, Khaled M Jami, Anna Moroz, Benoit Jego, Emilie Jaumain, Lawrence Fong, Charles S Craik, Albert J Chang, Trever G Bivona, Cheng-I Wang, Michael J Evans
High sensitivity imaging tools could provide a more holistic view of target antigen expression to improve the identification of patients who might benefit from cancer immunotherapy. We developed for immunoPET a novel recombinant human IgG1 (termed C4) that potently binds an extracellular epitope on human and mouse PD-L1 and radiolabeled the antibody with zirconium-89. Small animal PET/CT studies showed that89 Zr-C4 detected antigen levels on a patient derived xenograft (PDX) established from a non-small-cell lung cancer (NSCLC) patient before an 8-month response to anti-PD-1 and anti-CTLA4 therapy...
January 17, 2018: Bioconjugate Chemistry
Collin M Blakely, Thomas B K Watkins, Wei Wu, Beatrice Gini, Jacob J Chabon, Caroline E McCoach, Nicholas McGranahan, Gareth A Wilson, Nicolai J Birkbak, Victor R Olivas, Julia Rotow, Ashley Maynard, Victoria Wang, Matthew A Gubens, Kimberly C Banks, Richard B Lanman, Aleah F Caulin, John St John, Anibal R Cordero, Petros Giannikopoulos, Andrew D Simmons, Philip C Mack, David R Gandara, Hatim Husain, Robert C Doebele, Jonathan W Riess, Maximilian Diehn, Charles Swanton, Trever G Bivona
A widespread approach to modern cancer therapy is to identify a single oncogenic driver gene and target its mutant-protein product (for example, EGFR-inhibitor treatment in EGFR-mutant lung cancers). However, genetically driven resistance to targeted therapy limits patient survival. Through genomic analysis of 1,122 EGFR-mutant lung cancer cell-free DNA samples and whole-exome analysis of seven longitudinally collected tumor samples from a patient with EGFR-mutant lung cancer, we identified critical co-occurring oncogenic events present in most advanced-stage EGFR-mutant lung cancers...
December 2017: Nature Genetics
Julia Rotow, Trever G Bivona
The expanding spectrum of both established and candidate oncogenic driver mutations identified in non-small-cell lung cancer (NSCLC), coupled with the increasing number of clinically available signal transduction pathway inhibitors targeting these driver mutations, offers a tremendous opportunity to enhance patient outcomes. Despite these molecular advances, advanced-stage NSCLC remains largely incurable due to therapeutic resistance. In this Review, we discuss alterations in the targeted oncogene ('on-target' resistance) and in other downstream and parallel pathways ('off-target' resistance) leading to resistance to targeted therapies in NSCLC, and we provide an overview of the current understanding of the bidirectional interactions with the tumour microenvironment that promote therapeutic resistance...
October 25, 2017: Nature Reviews. Cancer
Chong T Luo, Hatice U Osmanbeyoglu, Mytrang H Do, Michael R Bivona, Ahmed Toure, Davina Kang, Yuchen Xie, Christina S Leslie, Ming O Li
Peripheral T cells are maintained in the absence of vigorous stimuli, and respond to antigenic stimulation by initiating cell cycle progression and functional differentiation. Here we show that depletion of the Ets family transcription factor GA-binding protein (GABP) in T cells impairs T-cell homeostasis. In addition, GABP is critically required for antigen-stimulated T-cell responses in vitro and in vivo. Transcriptome and genome-wide GABP-binding site analyses identify GABP direct targets encoding proteins involved in cellular redox balance and DNA replication, including the Mcm replicative helicases...
October 20, 2017: Nature Communications
Pengfei Ma, Yujie Fu, Mei-Chun Cai, Ying Yan, Ying Jing, Shengzhe Zhang, Minjiang Chen, Jie Wu, Ying Shen, Liang Zhu, Hong-Zhuan Chen, Wei-Qiang Gao, Mengzhao Wang, Zhenyu Gu, Trever G Bivona, Xiaojing Zhao, Guanglei Zhuang
Recent genomic analyses have revealed substantial tumor heterogeneity across various cancers. However, it remains unclear whether and how genomic heterogeneity is constrained during tumor evolution. Here, we sequence a unique cohort of multiple synchronous lung cancers (MSLCs) to determine the relative diversity and uniformity of genetic drivers upon identical germline and environmental background. We find that each multicentric primary tumor harbors distinct oncogenic alterations, including novel mutations that are experimentally demonstrated to be functional and therapeutically targetable...
October 10, 2017: Nature Communications
Laura C Laurella, Natacha Cerny, Augusto E Bivona, Andrés Sánchez Alberti, Gustavo Giberti, Emilio L Malchiodi, Virginia S Martino, Cesar A Catalan, María Rosario Alonso, Silvia I Cazorla, Valeria P Sülsen
Four sesquiterpene lactones, mikanolide, deoxymikanolide, dihydromikanolide and scandenolide, were isolated by a bioassay-guided fractionation of Mikania variifolia and Mikania micrantha dichloromethane extracts. Mikanolide and deoxymikanolide were the major compounds in both extracts (2.2% and 0.4% for Mikania variifolia and 21.0% and 6.4% for Mikania micrantha respectively, calculated on extract dry weight). Mikanolide, deoxymikanolide and dihydromikanolide were active against Trypanosoma cruzi epimastigotes (50% inhibitory concentrations of 0...
September 2017: PLoS Neglected Tropical Diseases
Joseph J Bivona, Sapna Patel, Michael Vajdy
Vitamins E and C are well known small molecules that have been used to maintain health for decades. Recent studies of the cellular and molecular pathways leading to immunomodulation by these molecules have been of interest, as have their anti-oxidant properties and signal transduction pathways for curing or improving infectious diseases and cancer. Areas covered: Herein, the authors provide a definition and the structural classification of vitamins E and C and how these molecules influence cellular function...
September 14, 2017: Expert Opinion on Biological Therapy
Kirstine Jacobsen, Jordi Bertran-Alamillo, Miguel Angel Molina, Cristina Teixidó, Niki Karachaliou, Martin Haar Pedersen, Josep Castellví, Mónica Garzón, Carles Codony-Servat, Jordi Codony-Servat, Ana Giménez-Capitán, Ana Drozdowskyj, Santiago Viteri, Martin R Larsen, Ulrik Lassen, Enriqueta Felip, Trever G Bivona, Henrik J Ditzel, Rafael Rosell
Non-small-cell lung cancer patients with activating epidermal growth factor receptor (EGFR) mutations typically benefit from EGFR tyrosine kinase inhibitor treatment. However, virtually all patients succumb to acquired EGFR tyrosine kinase inhibitor resistance that occurs via diverse mechanisms. The diversity and unpredictability of EGFR tyrosine kinase inhibitor resistance mechanisms presents a challenge for developing new treatments to overcome EGFR tyrosine kinase inhibitor resistance. Here, we show that Akt activation is a convergent feature of acquired EGFR tyrosine kinase inhibitor resistance, across a spectrum of diverse, established upstream resistance mechanisms...
September 4, 2017: Nature Communications
Concetta Scazzone, Luisa Agnello, Paolo Ragonese, Bruna Lo Sasso, Chiara Bellia, Giulia Bivona, Rosaria Schillaci, Giuseppe Salemi, Marcello Ciaccio
BACKGROUND: MS is a neurodegenerative autoimmune disease resulting from a complex interaction of genetic and environmental factors. Among these, vitamin D and genetic variants associated with vitamin D-metabolism gain great attention. The aim of our study was to assess five SNPs in NADSYN1 and CYP2R1 genes in relation to serum 25-OH-vitamin D3 levels in MS patients and controls. METHODS: 25-OH-vitamin D3 levels and genotyping of CYP2R1- and NADSYN1-SNPs were investigated both in MS patients and in healthy controls...
August 23, 2017: Journal of Neuroscience Research
Soyoung A Oh, Ming Liu, Briana G Nixon, Davina Kang, Ahmed Toure, Michael Bivona, Ming O Li
Peripheral T cell tolerance is promoted by the regulatory cytokine TGF-β and Foxp3-expressing Treg cells. However, whether TGF-β and Treg cells are part of the same regulatory module, or exist largely as distinct pathways to repress self-reactive T cells remains incompletely understood. Using a transgenic model of autoimmune diabetes, here we show that ablation of TGF-β receptor II (TβRII) in T cells, but not Foxp3 deficiency, resulted in early-onset diabetes with complete penetrance. The rampant autoimmune disease was associated with enhanced T cell priming and elevated T cell expression of the inflammatory cytokine GM-CSF, concomitant with pancreatic infiltration of inflammatory monocytes that triggered immunopathology...
September 5, 2017: Proceedings of the National Academy of Sciences of the United States of America
Giulia Bivona, Luisa Agnello, Marcello Ciaccio
The term "vitamin D" refers to two chemical compounds - ergosterol, or vitamin D2, and cholecalciferol, or vitamin D3. Active vitamin D3 is correctly regarded as a neurohormone due to its pleiotropic biological activities. Although the relation between vitamin D and calcium-phosphorus metabolism has never been discussed, the knowledge on many other roles vitamin D plays is growing fast. Briefly, vitamin D immunomodulation includes attenuation and stimulation of Th1 and Th2 cell proliferation, respectively. Similarly, vitamin D can induce or inhibit the synthesis, secretion, and release of anti- inflammatory (IL-4 and IL-10) and pro-inflammatory (IL-1, TNF-α, IFN-γ) cytokines, respectively...
August 2017: Annals of Clinical and Laboratory Science
Luisa Agnello, Giulia Bivona, Giuseppina Novo, Concetta Scazzone, Roberto Muratore, Piero Levantino, Chiara Bellia, Bruna Lo Sasso, Marcello Ciaccio
BACKGROUND: Early detecting AMI in individuals presenting to the ED with chest pain continues to be a challenge. cTn is the gold standard for AMI diagnosis but early presenters (<1 hours from symptom onset) maybe cTn negative on admission. We analysed the diagnostic value of h-FABP and hs-TnI in patients presenting to ED with chest pain and no cTnI elevations. METHODS: 28 AMI and 28 no-AMI individuals both presented to ED within one hour from pain onset were included...
June 26, 2017: Scandinavian Journal of Clinical and Laboratory Investigation
Chiara Bellia, Martina Zaninotto, Chiara Cosma, Luisa Agnello, Bruna Lo Sasso, Giulia Bivona, Mario Plebani, Marcello Ciaccio
BACKGROUND: Glycated Albumin (GA) has been proposed as a short-term indicator of glycemic homeostasis. The aim of this study is to describe the distribution of GA in a large sample of blood donors from Italy to evaluate whether demographic features, namely age and sex, could influence GA levels and define specific reference limits. METHODS: The study included 1334 Italian blood donors. GA was measured using an enzymatic method (quantILab Glycated Albumin, IL Werfen, Germany)...
November 27, 2017: Clinical Chemistry and Laboratory Medicine: CCLM
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