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https://www.readbyqxmd.com/read/29152593/resistance-is-futile-overcoming-resistance-to-targeted-therapies-in-lung-adenocarcinoma
#1
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 Precis Oncol
https://www.readbyqxmd.com/read/29125731/imaging-pd-l1-expression-with-immunopet
#2
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 that (89)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...
November 15, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/29106415/evolution-and-clinical-impact-of-co-occurring-genetic-alterations-in-advanced-stage-egfr-mutant-lung-cancers
#3
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...
November 6, 2017: Nature Genetics
https://www.readbyqxmd.com/read/29068003/understanding-and-targeting-resistance-mechanisms-in-nsclc
#4
REVIEW
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
https://www.readbyqxmd.com/read/29051483/ets-transcription-factor-gabp-controls-t-cell-homeostasis-and-immunity
#5
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
https://www.readbyqxmd.com/read/29018192/simultaneous-evolutionary-expansion-and-constraint-of-genomic-heterogeneity-in-multifocal-lung-cancer
#6
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
https://www.readbyqxmd.com/read/28945741/assessment-of-sesquiterpene-lactones-isolated-from-mikania-plants-species-for-their-potential-efficacy-against-trypanosoma-cruzi-and-leishmania-sp
#7
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
https://www.readbyqxmd.com/read/28905653/induction-of-cellular-and-molecular-immunomodulatory-pathways-by-vitamin-e-and-vitamin-c
#8
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
https://www.readbyqxmd.com/read/28871105/convergent-akt-activation-drives-acquired-egfr-inhibitor-resistance-in-lung-cancer
#9
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
https://www.readbyqxmd.com/read/28834557/association-of-cyp2r1-rs10766197-with-ms-risk-and-disease-progression
#10
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
https://www.readbyqxmd.com/read/28827353/foxp3-independent-mechanism-by-which-tgf-%C3%AE-controls-peripheral-t-cell-tolerance
#11
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
https://www.readbyqxmd.com/read/28801380/vitamin-d-and-immunomodulation-is-it-time-to-change-the-reference-values
#12
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
https://www.readbyqxmd.com/read/28650717/heart-type-fatty-acid-binding-protein-is-a-sensitive-biomarker-for-early-ami-detection-in-troponin-negative-patients-a-pilot-study
#13
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
https://www.readbyqxmd.com/read/28586301/definition-of-the-upper-reference-limit-of-glycated-albumin-in-blood-donors-from-italy
#14
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)...
June 6, 2017: Clinical Chemistry and Laboratory Medicine: CCLM
https://www.readbyqxmd.com/read/28537389/silsesquioxane-terpyridine-nano-building-blocks-for-the-design-of-three-dimensional-polymeric-networks
#15
Esther Carbonell, Lucia A Bivona, Luca Fusaro, Carmela Aprile
Novel polyhedral oligomeric silsesquioxanes (POSS) decorated with eight terpyridine moieties were synthesized in a one-pot procedure via Heck coupling reaction with the aim of investigating the possible formation of three-dimensional extended supramolecular organizations. The monosubstituted analogue was also prepared and used as a model compound. Both POSS-based nanostructures were extensively characterized via (1)H, (13)C, and (29)Si nuclear magnetic resonance (NMR), ultraviolet-visible spectroscopies and combustion chemical analysis...
May 24, 2017: Inorganic Chemistry
https://www.readbyqxmd.com/read/28521301/activation-of-signal-transducer-and-activator-of-transcription-3-stat3-signaling-in-egfr-mutant-non-small-cell-lung-cancer-nsclc
#16
Carles Codony-Servat, Jordi Codony-Servat, Niki Karachaliou, Miguel Angel Molina, Imane Chaib, Jose Luis Ramirez, Maria de Los Llanos Gil, Flavio Solca, Trever G Bivona, Rafael Rosell
Gefitinib, erlotinib or afatinib are the current treatment for non-small-cell lung cancer (NSCLC) harboring an activating mutation of the epidermal growth factor receptor (EGFR), but less than 5% of patients achieve a complete response and the median progression-free survival is no longer than 12 months. Early adaptive resistance can occur as soon as two hours after starting treatment by activating signal transducer and activation of transcription 3 (STAT3) signaling. We investigated the activation of STAT3 in a panel of gefitinib-sensitive EGFR mutant cell lines, and gefitinib-resistant PC9 cell lines developed in our laboratory...
July 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28507205/a-case-of-metastatic-atypical-neuroendocrine-tumor-with-alk-translocation-and-diffuse-brain-metastases
#17
Victoria E Wang, Lauren Young, Siraj Ali, Vincent A Miller, Anatoly Urisman, John Wolfe, Trever G Bivona, Bertil Damato, Shannon Fogh, Emily K Bergsland
A challenge in precision medicine requires identification of actionable driver mutations. Critical to such effort is the deployment of sensitive and well-validated assays for mutation detection. Although identification of such alterations within the tumor tissue remains the gold standard, many advanced non-small cell lung cancer cases have only limited tissue samples, derived from small biopsies or fine-needle aspirates, available for testing. More recently, noninvasive methods using either circulating tumor cells or tumor DNA (ctDNA) have become an alternative method for identifying molecular biomarkers and screening patients eligible for targeted therapies...
July 2017: Oncologist
https://www.readbyqxmd.com/read/28456545/galectin-3-in-acute-coronary-syndrome
#18
REVIEW
Luisa Agnello, Giulia Bivona, Bruna Lo Sasso, Concetta Scazzone, Viviana Bazan, Chiara Bellia, Marcello Ciaccio
Acute coronary syndrome (ACS) is a very common cause of hospitalizations worldwide each year. In the past decades biomarkers have become an indispensable tool for diagnosis, risk stratification and prognosis of cardiovascular disease, including ACS. Despite Troponin is considered the gold standard in diagnosis of ACS, several molecules have been investigated to identify predictive biomarkers of prognosis. Among these, Gal-3 has emerged as a promising prognostic marker. It has a pivotal role in inflammation and fibrosis...
September 2017: Clinical Biochemistry
https://www.readbyqxmd.com/read/28376152/co-activation-of-stat3-and-yes-associated-protein-1-yap1-pathway-in-egfr-mutant-nsclc
#19
Imane Chaib, Niki Karachaliou, Sara Pilotto, Jordi Codony Servat, Xueting Cai, Xuefei Li, Ana Drozdowskyj, Carles Codony Servat, Jie Yang, Chunping Hu, Andres Felipe Cardona, Guillermo Lopez Vivanco, Alain Vergnenegre, Jose Miguel Sanchez, Mariano Provencio, Filipo de Marinis, Antonio Passaro, Enric Carcereny, Noemi Reguart, Charo Garcia Campelo, Christina Teixido, Isabella Sperduti, Sonia Rodriguez, Chiara Lazzari, Alberto Verlicchi, Itziar de Aguirre, Cristina Queralt, Jia Wei, Roger Estrada, Raimon Puig de la Bellacasa, Jose Luis Ramirez, Kirstine Jacobson, Henrik J Ditzel, Mariacarmela Santarpia, Santiago Viteri, Migual Angel Molina, Caicun Zhou, Peng Cao, Patrick C Ma, Trever G Bivona, Rafael Rosell
Background: The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) is limited by adaptive activation of cell survival signals. We hypothesized that both signal transducer and activator of transcription 3 (STAT3) and Src-YES-associated protein 1 (YAP1) signaling are dually activated during EGFR TKI treatment to limit therapeutic response. Methods: We used MTT and clonogenic assays, immunoblotting, and quantitative polymerase chain reaction to evaluate the efficacy of EGFR TKI alone and in combination with STAT3 and Src inhibition in three EGFR-mutant NSCLC cell lines...
September 1, 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/28361810/educational-action-in-the-rehabilitation-of-severe-acquired-brain-injuries-the-role-of-self-awareness
#20
Daniela Silvestro, Maria Mazzetti, Chiara Melia, Maria Teresa Stagno, Giovanni Augusto Carlesimo, Umberto Bivona, Rita Formisano
Severe acquired brain injuries (ABI) cause a range of short-or long-term limitations in physical and neuropsychological abilities. The aim of rehabilitation is to promote the harmonious development of the individual through collaboration between medical and educational sciences, involved in the educability of the whole person, in which the aim is not only functional recovery but also social-reintegration. This "functional synergy" permits the development of the person, and establishes an indissoluble link between functions and attitudes, thus allowing the achievement of the greater possible autonomy...
January 2017: Annali Dell'Istituto Superiore di Sanità
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