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1. A child with duchenne muscular dystrophy: A case report of a rare diagnosis among Africans

Author

Lazaro Mboma, Seraphine Mushi, David D. Nassoro, Liset Torres, Rehema Marando, and Issakwisa Habakkuk Mwakyula

Subjects
medicine.medical_specialty, Pediatrics, Medicine (General), Neurology, business.industry, Duchenne muscular dystrophy, neurology, Case Report, Case Reports, General Medicine, 030204 cardiovascular system & hematology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, R5-920, 030220 oncology & carcinogenesis, medicine, Medicine, In patient, genetics, business
Abstract

In Africa, lack of awareness and low index of suspicion of rare diseases like dystrophinopathies, directly or indirectly, contributes to the increased morbidity and mortality. Therefore, even though the data on prevalence is limited, we need to have a high degree of suspicion in patients presenting with suggestive clinical features., In Africa, lack of awareness and low index of suspicion of rare diseases like dystrophinopathies, directly or indirectly, contributes to the increased morbidity and mortality. The picture is a muscle biopsy of an 11‐year‐old boy with Duchenne muscular dystrophy showing a transverse section with degenerated skeletal muscles of variable size and necrotic background.

Published
2020

2. Biosynthetic Glycan Labeling

Author

Laura L. Kiessling, Victoria M. Marando, Daria E. Kim, Phillip J. Calabretta, Bryan D. Bryson, and Matthew B. Kraft

Subjects
chemistry.chemical_classification, 0303 health sciences, Glycan, biology, 010405 organic chemistry, General Chemistry, 01 natural sciences, Biochemistry, Catalysis, Article, 0104 chemical sciences, Amino acid, Cell wall, 03 medical and health sciences, Colloid and Surface Chemistry, Enzyme, chemistry, Polysaccharides, Glycosyltransferase, biology.protein, Monosaccharide, Bioorthogonal chemistry, Function (biology), 030304 developmental biology
Abstract

Glycans are ubiquitous and play important biological roles, yet chemical methods for probing their structure and function within cells remain limited. Strategies for studying other biomacromolecules, such as proteins, often exploit chemoselective reactions for covalent modification, capture, or imaging. Unlike amino acids that constitute proteins, glycan building blocks lack distinguishing reactivity because they are composed primarily of polyol isomers. Moreover, encoding glycan variants through genetic manipulation is complex. Therefore, we formulated a new, generalizable strategy for chemoselective glycan modification that directly takes advantage of cellular glycosyltransferases. Many of these enzymes are selective for the products they generate yet promiscuous in their donor preferences. Thus, we designed reagents with bioorthogonal handles that function as glycosyltransferase substrate surrogates. We validated the feasibility of this approach by synthesizing and testing probes of d-arabinofuranose (d-Araf), a monosaccharide found in bacteria and an essential component of the cell wall that protects mycobacteria, including Mycobacterium tuberculosis. The result is the first probe capable of selectively labeling arabinofuranose-containing glycans. Our studies serve as a platform for developing new chemoselective labeling agents for other privileged monosaccharides. This probe revealed an asymmetric distribution of d-Araf residues during mycobacterial cell growth and could be used to detect mycobacteria in THP1-derived macrophages.

Published
2021

3. Exposing Small-Molecule Nanoentities by a Nuclear Magnetic Resonance Relaxation Assay

Author

Sacha Thierry Larda, Paul Coote, Louis Vaillancourt, Steven R LaPlante, Patricia Bouchard, Victoria M Marando, Gregory J. Heffron, and Yann Ayotte

Subjects
0303 health sciences, Magnetic Resonance Spectroscopy, Aqueous solution, Molecular Structure, Drug discovery, Chemistry, Relaxation (NMR), Context (language use), Nuclear magnetic resonance spectroscopy, 010402 general chemistry, 01 natural sciences, Micelle, Small molecule, 0104 chemical sciences, Small Molecule Libraries, 03 medical and health sciences, Chemical physics, Drug Discovery, Nanoparticles, Molecular Medicine, Molecule, 030304 developmental biology
Abstract

Small molecules can self-assemble in aqueous solution into a wide range of nanoentity types and sizes (dimers, n-mers, micelles, colloids, etc.), each having their own unique properties. This has important consequences in the context of drug discovery including issues related to nonspecific binding, off-target effects, and false positives and negatives. Here, we demonstrate the use of the spin-spin relaxation Carr-Purcell-Meiboom-Gill NMR experiment, which is sensitive to molecular tumbling rates and can expose larger aggregate species that have slower rotational correlations. The strategy easily distinguishes lone-tumbling molecules versus nanoentities of various sizes. The technique is highly sensitive to chemical exchange between single-molecule and aggregate states and can therefore be used as a reporter when direct measurement of aggregates is not possible by NMR. Interestingly, we found differences in solution behavior for compounds within structurally related series, demonstrating structure-nanoentity relationships. This practical experiment is a valuable tool to support drug discovery efforts.

Published
2019

4. Deciphering risk factors for blood stream infections, bacteria species and antimicrobial resistance profiles among children under five years of age in North-Western Tanzania: a multicentre study in a cascade of referral health care system

Author

Stephen E. Mshana, Jeremiah Seni, R. Marando, A. A. Mwakyoma, Rebekah DeVinney, Maimuna Ahmed, Florentina Mashuda, and Johann D. D. Pitout

Subjects
Male, medicine.medical_specialty, Referral, Klebsiella pneumoniae, Blood stream infections, Bacteremia, Risk Assessment, Tanzania, 03 medical and health sciences, 0302 clinical medicine, Antibiotic resistance, Blood culture positive, Risk Factors, 030225 pediatrics, Internal medicine, Health care, Drug Resistance, Bacterial, medicine, Humans, 030212 general & internal medicine, Prospective Studies, Referral and Consultation, Children, biology, Under-five, business.industry, Infant, Newborn, lcsh:RJ1-570, Infant, lcsh:Pediatrics, biology.organism_classification, Cross-Sectional Studies, Child, Preschool, Pediatrics, Perinatology and Child Health, Female, business, Blood stream, Delivery of Health Care, Research Article
Abstract

Background Blood stream infections (BSIs) cause a complex cascade of inflammatory events, resulting in significant morbidity and mortality in children in Tanzania. This study was designed to delineate circulating bacterial species, antimicrobial resistance (AMR) profiles and risk factors for BSIs and mortality among children in the cascade of referral health care facilities so as to guide comprehensive BSIs management. Methods A multiple cross sectional analytical study was conducted between July 20, 2016 to October 04, 2017 involving 950 children less than five years of age in the North-western part of Tanzania. Children with clinical features suggestive of BSIs were included. Demographic, clinical and laboratory information on culture and antimicrobial susceptibility testing was collected from children; and analyzed using STATA version 13.0 software. Results The prevalence of BSIs among children was 14.2% (95% CI: 12.1–16.6%), with specific prevalence in the district, regional and tertiary hospitals being 8.3, 6.4 and 20.0%, respectively. The most common bacterial pathogens isolated from 135 culture-positive children were Klebsiella pneumoniae (55, 40.4%), Staphylococcus aureus (23, 17.0%), and Escherichia coli (17, 12.6%). Multi-drug resistance (MDR) was higher in isolates from children at Bugando Medical Centre (BMC) tertiary hospital than isolates from district and regional hospitals [OR (95% CI): 6.36 (2.15–18.76); p = 0.001]. Independent risk factors for BSIs were neonatal period [OR (95% CI): 1.93 (1.07–3.48); p = 0.003] and admission at BMC [2.01 (1.08–3.74); p = 0.028)]. Approximately 6.6% (61/932) of children died, and risk factors for mortality were found to be children attending BMC [OR (95% CI): 4.95 (1.95–12.5); p = 0.001)], neonatal period [OR (95% CI): 2.25 (1.02–5.00); p = 0.045)], and children who had blood culture positive results [OR (95% CI): 1.95 (1.07–3.56); p = 0.028)]. Conclusions The prevalence of BSIs (14.2%) in this multi-centre study is high and predominantly caused by the MDR K. pneumoniae. Priority interventional measures to combat BSIs and mortality, specifically among neonates at BMC are urgently recommended.

Published
2019

5. Clinical, radiological and functional outcomes in patients with SARS-CoV-2 pneumonia: a prospective observational study

Author

Marco Pons, Adriana Tamburello, Marco Marando, Gianluca Argentieri, Alberto Pagnamenta, Lorenzo Grazioli Gauthier, Pietro Gianella, Carla Puligheddu, Tanja Fusi-Schmidhauser, and Elia Rigamonti

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, media_common.quotation_subject, 030218 nuclear medicine & medical imaging, Pulmonary function testing, 03 medical and health sciences, Diseases of the respiratory system, 0302 clinical medicine, 3-Month outcome, Chest CT, Quality of life, Internal medicine, Medicine, Prospective cohort study, media_common, Pulmonary function tests, Lung, RC705-779, business.industry, Convalescence, Research, COVID-19, medicine.disease, respiratory tract diseases, Pneumonia, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Radiological weapon, Observational study, business
Abstract

Background All over the world, SARS-CoV-2 pneumonia is causing a significant short-term morbidity and mortality, but the medium-term impact on lung function and quality of life of affected patients are still unknown. Methods In this prospective observational study, 39 patients with SARS-CoV-2 pneumonia were recruited from a single COVID-19 hospital in Southern Switzerland. At three months patients underwent radiological and functional follow-up through CT scan, lung function tests, and 6 min walking test. Furthermore, quality of life was assessed through self-reported questionnaires. Results Among 39 patients with SARS-CoV-2 pneumonia, 32 (82% of all participants) presented abnormalities in CT scan and 25 (64.1%) had lung function tests impairment at three months. Moreover, 31 patients (79.5%) reported a perception of poor health due to respiratory symptoms and all 39 patients showed an overall decreased quality of life. Conclusions Medium-term follow up at three months of patients diagnosed with SARS-CoV-2 pneumonia shows the persistence of abnormalities in CT scans, a significant functional impairment assessed by lung function tests and a decreased quality of life in affected patients. Further studies evaluating the long-term impact are warranted to guarantee an appropriate follow-up to patients recovering from SARS-CoV-2 pneumonia.

Published
2021

6. BETs Need Greens: Folate Deficiency and Resistance to MYC-Targeted Therapies

Author

Brian J. P. Huntly and Ludovica Marando

Subjects
0301 basic medicine, Kinase, Mechanism (biology), Cancer, Biology, medicine.disease, Article, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Folic Acid, Oncology, 030220 oncology & carcinogenesis, Cell Line, Tumor, Histone methylation, Cancer research, medicine, Cyclin-dependent kinase 7, Cell survival, Signal Transduction
Abstract

Deciphering the impact of metabolic intervention on response to anticancer therapy may elucidate a path toward improved clinical responses. Here, we identify amino acid-related pathways connected to the folate cycle whose activation predicts sensitivity to MYC-targeting therapies in acute myeloid leukemia (AML). We establish that folate restriction and deficiency of the rate-limiting folate cycle enzyme, MTHFR — which exhibits reduced-function polymorphisms in about 10% of Caucasians — induce resistance to MYC targeting by BET and CDK7 inhibitors in cell lines, primary patient samples, and syngeneic mouse models of AML. Further, this effect is abrogated by supplementation with the MTHFR enzymatic product, CH3-THF. Mechanistically, folate cycle disturbance reduces H3K27/K9 histone methylation and activates a SPI1 transcriptional program counteracting the effect of BET inhibition. Our data provide a rationale for screening MTHFR polymorphisms and the folate cycle status to nominate patients most likely to benefit from MYC-targeting therapies.

Published
2020

7. Long-Term GeneXpert Positivity after Treatment for Pulmonary Tuberculosis

Author

Pietro Gianella, Marco Marando, and Luisa Costantini

Subjects
0301 basic medicine, medicine.medical_specialty, Tuberculosis, 030106 microbiology, lcsh:Medicine, Mycobacterium tuberculosis, 03 medical and health sciences, 0302 clinical medicine, Pulmonary tuberculosis, Internal medicine, Internal Medicine, medicine, False positive paradox, false positives, 030212 general & internal medicine, GeneXpert MTB/RIF, medicine.diagnostic_test, biology, business.industry, lcsh:R, Diagnostic algorithms, Articles, retested patients, biology.organism_classification, medicine.disease, Bronchoalveolar lavage, tb, tuberculosis, genexpert, business, After treatment
Abstract

Tuberculosis (TB) is a cause of ill health and death worldwide. Since 2010, the diagnostic process has strongly relied on GeneXpert assays on biological specimens. Xpert MTB/RIF is an automated nucleic acid amplification test (NAAT) for Mycobacterium tuberculosis and rifampicin resistance, endorsed by the World Health Organization and the US Food and Drug Administration. Xpert is used in many countries as the initial diagnostic test for tuberculosis. Nevertheless, the reliability of GeneXpert positive tests in patients with a history of TB is largely unknown, due to possible false-positive results (i.e., GeneXpert-positive but culture-negative patients). We present a case report of a patient with a history of pulmonary TB, who was GeneXpert positive but culture negative on bronchoalveolar lavage 22 months after completion of appropriate antitubercular therapy. LEARNING POINTS: GeneXpert assays have a pivotal role in the diagnosis of tuberculosis (TB), with overall good sensitivity and excellent specificity. Patients with a history of TB can be GeneXpert positive up to several years after the end of appropriate antitubercular treatment. Further studies are warranted to fully understand the role of GeneXpert assays in the diagnostic algorithms of patients with a history of TB.

Published
2020

8. COVID-19 and Pulmonary Embolism: Not a Coincidence

Author

Giovanni Bruno, Adriana Tamburello, and Marco Marando

Subjects
Pediatrics, medicine.medical_specialty, pulmonary embolism, viruses, coronavirus, lcsh:Medicine, Disease, 030204 cardiovascular system & hematology, medicine.disease_cause, Virus, 03 medical and health sciences, tocilizumab, 0302 clinical medicine, Pandemic, Internal Medicine, medicine, Coagulopathy, 030212 general & internal medicine, Coronavirus, business.industry, lcsh:R, Outbreak, Articles, medicine.disease, Pulmonary embolism, Pneumonia, sars-cov-2, covid-19, coagulation abnormalities, business
Abstract

In December 2019, a novel coronavirus called SARS-CoV-2 was reported to be responsible for a cluster of acute atypical respiratory pneumonia cases in Wuhan, in Hubei province, China. The disease caused by this virus is called COVID-19 (coronavirus disease 2019). The virus is transmitted between humans and the outbreak was declared a pandemic by the World Health Organization (WHO) on 11 March 2020. Coagulopathy is a common abnormality in patients with COVID-19 due to inflammation, hypoxia, immobilisation, endothelial damage and diffuse intravascular coagulation. However, the data on this topic are still limited. Here we report the case of a man presenting with pneumonia complicated by bilateral pulmonary embolism LEARNING POINTS SARS-CoV-2 is a novel infectious agent that causes COVID-19, which can manifest in several ways, affecting endothelial cells and most organs. There is growing evidence that SARS-CoV-2-mediated endothelial damage is due to direct viral injury and the systemic inflammatory response, possibly together with a cytokine storm. As endothelial damage can manifest as thromboembolic disease, such as pulmonary thromboembolism, appropriate anti-thrombotic preventive strategies should be followed, and proper screening and treatment for thromboembolic complications should be implemented.

Published
2020

9. Immunoglobulins or convalescent plasma to tackle COVID-19: buying time to save lives - current situation and perspectives

Author

Marco Marando and Adriana Tamburello

Subjects
2019-20 coronavirus outbreak, Convalescent plasma, Coronavirus disease 2019 (COVID-19), business.industry, SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Pneumonia, Viral, Immunization, Passive, COVID-19, Immunoglobulins, General Medicine, 03 medical and health sciences, Betacoronavirus, 0302 clinical medicine, 030220 oncology & carcinogenesis, Medicine, Viral therapy, Humans, 030212 general & internal medicine, Marketing, business, Coronavirus Infections, Viral immunology, Pandemics, COVID-19 Serotherapy
Published
2020

10. False-Negative Nasopharyngeal Swab RT-PCR Assays in Typical COVID-19: Role of Ultra-low-dose Chest CT and Bronchoscopy in Diagnosis

Author

Adriana Tamburello, Marco Marando, and Pietro Gianella

Subjects
medicine.medical_specialty, bronchoscopy, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Chest ct, RT-PCR, lcsh:Medicine, medicine.disease_cause, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Tocilizumab, Bronchoscopy, Internal Medicine, Medicine, 030212 general & internal medicine, Coronavirus, medicine.diagnostic_test, business.industry, lcsh:R, COVID-19, Articles, Bronchoalveolar lavage, Real-time polymerase chain reaction, chemistry, Radiology, ultra-low-dose chest CT, business
Abstract

On 11 March 2020, the WHO declared COVID-19 a pandemic and global health emergency. We describe the clinical features and role of ultra-low-dose chest computed tomography (CT) and bronchoscopy in the diagnosis of coronavirus disease (COVID-19). In our patient, who was highly suggestive clinically and radiologically for COVID-19, we had two false-negative results for nasopharyngeal and oral swab reverse-transcriptase polymerase chain reaction (RT-PCR) assays for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Eventually, we confirmed the diagnosis using bronchoscopy and bronchoalveolar lavage (BAL). LEARNING POINTS Clinical and laboratory findings in COVID-19 are unspecific. Chest CT has a diagnostic sensitivity comparable to nasopharyngeal swab RT-PCR assay but lacks specificity. RT-PCR assays on biological specimens, particularly nasopharyngeal swabs, are considered the diagnostic gold standard. Bronchoscopy and bronchoalveolar lavage can help confirm the diagnosis and should be performed in patients in whom diagnostic-driven treatment for COVID-19, such as tocilizumab or remdesivir, is being considered.

Published
2020

11. Intravenous thrombolysis in stroke after dabigatran reversal with idarucizumab: case series and systematic review

Author

David Giannandrea, Sara Mastrocola, Stefano Ricci, Claudia Marando, Elisa Sacchini, Carla Caponi, Tatiana Mazzoli, Erica Marsili, Michele Romoli, Antongiulio Gallina, Silvia Cenciarelli, Anna Mengoni, and Chiara Padiglioni

Subjects
Male, medicine.medical_specialty, medicine.medical_treatment, Cochrane Library, Antibodies, Monoclonal, Humanized, Antithrombins, Dabigatran, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Modified Rankin Scale, medicine, Humans, Thrombolytic Therapy, Contraindication, Stroke, Aged, Aged, 80 and over, business.industry, Idarucizumab, Thrombolysis, Middle Aged, medicine.disease, Psychiatry and Mental health, Direct thrombin inhibitor, Emergency medicine, Female, Surgery, Neurology (clinical), business, 030217 neurology & neurosurgery, medicine.drug
Abstract

Idarucizumab can reverse the effect of the direct thrombin inhibitor dabigatran,1 a non-vitamin K oral anticoagulant (NOAC) available for primary and secondary prevention of cardioembolic stroke due to non-valvular atrial fibrillation. Ischaemic stroke may happen despite ongoing anticoagulation, a contraindication to intravenous thrombolysis (IVT).2 Thus, patients with ischaemic stroke while on dabigatran might be eligible for anticoagulation reversal with idarucizumab to allow IVT. Here, we report our case series and provide a systematic review to define outcomes of such treatment algorithm. Case series of patients undergoing IVT after dabigatran reversal was identified from our stroke registry (online supplementary file 1). Systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines3 and specified protocol (PROSPERO: http://www.crd.york.ac.uk/PROSPERO, registration no. CRD42017060274) (online supplementary file 2). Search strategy, performed on Cochrane Library, MEDLINE, EMBASE and PubMed, can be found in online supplementary file 1. ### Supplementary data [jnnp-2018-318658-supp1.pdf] ### Supplementary data [jnnp-2018-318658-supp2.pdf] ### Data extraction and outcome assessment All available data were collected (online supplementary file 1). According to National Institute of Health Stroke Scale (NIHSS) total score, stroke were divided into mild (1–4), moderate (5–15), moderate to severe (16–20) and severe (21–42 4). Unfavourable outcome was defined as an increase in NIHSS score or death. Additional outcomes included modified Rankin Scale (mRS) at follow-up, symptomatic intracerebral haemorrhage, systemic bleeding, allergic reactions to idarucizumab, recurrent stroke and venous thrombosis during post-acute phase. ### Statistical analysis Statistical analysis was performed with R software using …

Published
2018

12. Randomized controlled trial of acceptance and commitment therapy versus traditional cognitive behavior therapy for social anxiety disorder: Symptomatic and behavioral outcomes

Author

Staci A. Berkowitz, Lisa H. Glassman, Marina Gershkovich, Erica K. Yuen, Evan M. Forman, Stephanie Marando-Blanck, James D. Herbert, Elizabeth M. Goetter, Jena Shaw Tronieri, Peter F. Hitchcock, Joanna L. Kaye, and Stephanie P. Goldstein

Subjects
050103 clinical psychology, Organizational Behavior and Human Resource Management, Health (social science), medicine.medical_treatment, 05 social sciences, Social anxiety, Exposure therapy, Cognition, Acceptance and commitment therapy, 030227 psychiatry, law.invention, Replication trial, 03 medical and health sciences, Behavioral Neuroscience, 0302 clinical medicine, Quality of life (healthcare), Randomized controlled trial, law, medicine, 0501 psychology and cognitive sciences, Psychology, Applied Psychology, Ecology, Evolution, Behavior and Systematics, Clinical psychology
Abstract

Only two trials have compared acceptance and commitment therapy (ACT) and traditional cognitive behavior therapy (tCBT) in the treatment of social anxiety disorder (SAD), with both finding no significant differences. These trials did not examine effects on observer-rated behavioral outcomes and did not explicitly quantify the dose of exposure therapy within each treatment. In a replication trial, one hundred and two individuals with SAD (per DSM-IV criteria) were randomized to 12 sessions of ACT (n = 49) or tCBT (n = 53) controlling for exposure dose and assessing behavioral outcomes. Assessments were completed at pre- and post-treatment using clinician-rated and self-report measures of social anxiety, quality of life, and overall functioning. Observer-rated behavioral measures of social performance were completed for a subsample of participants. Results indicated that participants across conditions received equivalent doses of exposure. Those who received tCBT evidenced greater improvements in self-reported social anxiety symptoms and overall functioning, which contrasts with prior studies finding no differences between tCBT and ACT in the treatment of social anxiety. Medium effect sizes, while not statistically significant, indicate that ACT participants may have had greater improvements in observer-rated social behavior than tCBT participants. The discrepancy between these symptom and behavioral outcomes, building upon prior literature, calls for more research to assess the differences between tCBT and ACT treatments in behavioral domains.

Published
2018

13. Trusting homeostatic cues versus accepting hedonic cues: A randomized controlled trial comparing two distinct mindfulness-based intervention components

Author

Brittney C. Evans, Evan M. Forman, James D. Herbert, Stephanie Marando-Blanck, Ruth A. Baer, Ruth Q. Wolever, Meghan L. Butryn, Hallie Espel-Huynh, and Lindsay M. Martin

Subjects
0301 basic medicine, Organizational Behavior and Human Resource Management, 030109 nutrition & dietetics, Health (social science), Mindfulness, Calorie, Weight change, Overweight, medicine.disease, Obesity, law.invention, 03 medical and health sciences, Behavioral Neuroscience, Randomized controlled trial, Weight loss, law, Intervention (counseling), medicine, medicine.symptom, Psychology, Applied Psychology, Ecology, Evolution, Behavior and Systematics, Clinical psychology
Abstract

Objective Mindfulness-informed cognitive behavioral interventions for obesity are promising. However, results on the efficacy of such treatments are inconsistent which in part may be due to their substantially different methods of practice. This study is the first direct comparison of two theoretically distinct mindfulness-based weight loss approaches: increasing awareness of homeostatic/innate physiological cues versus hedonic/externally-driven cues for eating. Methods Overweight adults were randomized to one of three group-based workshops: Mindful Eating (ME; n = 21), Mindful Decision-Making (MD; n = 17), or active standard behavioral control (SC; n = 19). Outcome measures included percent weight change and reduction in caloric intake from baseline to 6 weeks. Results Differences in weight loss and calorie reduction did not differ significantly among groups. However, the difference in weight loss between the MD and ME groups trended towards significance, with medium-large effect sizes. Conclusions Results provide modest preliminary evidence for the utility of mindful decision-making strategies over mindful eating for short-term weight loss and calorie reduction.

Published
2017

14. Exenatide regulates pancreatic islet integrity and insulin sensitivity in the nonhuman primate baboon Papio hamadryas

Author

Subhash Kamath, Anthony G. Comuzzie, Stefano La Rosa, Eliana S. Di Cairano, Ana Maria Paez, Alberto O. Chavez, Francesca Casiraghi, Rodolfo Guardado-Mendoza, Paolo Fiorina, Ralph A. DeFronzo, Paul B. Higgins, Fausto Sessa, A.M. Davalli, Gregory A Abrahamian, Giuseppe Daniele, Livio Luzi, Carla Perego, Franco Folli, Amalia Gastaldelli, Francesco Andreozzi, Alessandro Marando, Giovanna Finzi, Patrice A. Frost, Glenn A. Halff, Raul A. Bastarrachea, Andrea Ricotti, Edward J. Dick, and Teresa Vanessa Fiorentino

Subjects
0301 basic medicine, Blood Glucose, Male, medicine.medical_treatment, Apoptosis, Animals, Apoptosis/drug effects, Blood Glucose/analysis, Cell Proliferation/drug effects, Cell Transdifferentiation/drug effects, Diabetes Mellitus, Type 2/blood, Diabetes Mellitus, Type 2/drug therapy, Diabetes Mellitus, Type 2/pathology, Disease Models, Animal, Exenatide/pharmacology, Exenatide/therapeutic use, Female, Glucose Clamp Technique, Humans, Hypoglycemic Agents/pharmacology, Hypoglycemic Agents/therapeutic use, Infusions, Intravenous, Insulin/metabolism, Insulin Resistance, Islets of Langerhans/drug effects, Islets of Langerhans/pathology, Papio, B cells, Endocrinology, Glucose metabolism, Insulin signaling, 0302 clinical medicine, Insulin, Receptor, geography.geographical_feature_category, biology, General Medicine, Islet, 030220 oncology & carcinogenesis, medicine.drug, Research Article, Agonist, medicine.medical_specialty, endocrine system, medicine.drug_class, 03 medical and health sciences, Islets of Langerhans, Insulin resistance, Internal medicine, biology.animal, medicine, Hypoglycemic Agents, Cell Proliferation, geography, business.industry, medicine.disease, Insulin receptor, 030104 developmental biology, Diabetes Mellitus, Type 2, Cell Transdifferentiation, biology.protein, Exenatide, business, Baboon
Abstract

The glucagon-like peptide-1 receptor agonist exenatide improves glycemic control by several and not completely understood mechanisms. Herein, we examined the effects of chronic intravenous exenatide infusion on insulin sensitivity, β cell and α cell function and relative volumes, and islet cell apoptosis and replication in nondiabetic nonhuman primates (baboons). At baseline, baboons received a 2-step hyperglycemic clamp followed by an l-arginine bolus (HC/A). After HC/A, baboons underwent a partial pancreatectomy (tail removal) and received a continuous exenatide (n = 12) or saline (n = 12) infusion for 13 weeks. At the end of treatment, HC/A was repeated, and the remnant pancreas (head-body) was harvested. Insulin sensitivity increased dramatically after exenatide treatment and was accompanied by a decrease in insulin and C-peptide secretion, while the insulin secretion/insulin resistance (disposition) index increased by about 2-fold. β, α, and δ cell relative volumes in exenatide-treated baboons were significantly increased compared with saline-treated controls, primarily as the result of increased islet cell replication. Features of cellular stress and secretory dysfunction were present in islets of saline-treated baboons and absent in islets of exenatide-treated baboons. In conclusion, chronic administration of exenatide exerts proliferative and cytoprotective effects on β, α, and δ cells and produces a robust increase in insulin sensitivity in nonhuman primates.

Published
2019

15. Identification of OTX1 and OTX2 As Two Possible Molecular Markers for Sinonasal Carcinomas and Olfactory Neuroblastomas

Author

Giovanni Porta, Francesco Pasquali, Alessia Rainero, Annalisa Grimaldi, Cristina Pirrone, Giorgia Millefanti, Giovanni Micheloni, Andrea Conti, Roberto Valli, Francesco Lo Curto, Andrea Pistochini, Lucia Tararà, Francesco Acquati, Paolo Castelnuovo, and Alessandro Marando

Subjects
0301 basic medicine, Nasal cavity, General Chemical Engineering, Esthesioneuroblastoma, Olfactory, Biology, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Esthesioneuroblastoma, Embryonic morphogenesis, medicine, Humans, Gene, Otx Transcription Factors, Olfactory Neuroblastoma, General Immunology and Microbiology, General Neuroscience, Genes, Homeobox, Gene Expression Regulation, Developmental, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, Homeobox, Carcinogenesis, Olfactory epithelium, Paranasal Sinus Neoplasms
Abstract

OTX homeobox (HB) genes are expressed during embryonic morphogenesis and during the development of olfactory epithelium in adult organisms. Mutations occurring in these genes are often related to tumorigenesis in human. No data are available today regarding the possible correlation between OTX genes and tumors of the nasal cavity. The aim of this work is to understand if OTX1 and OTX2 can be considered as molecular markers in the development of nasal tumors. We selected nasal and sinonasal adenocarcinomas to investigate the expression of OTX1 and OTX2 genes through immunohistochemical and real-time PCR analyses.Both OTX1 and OTX2 were absent in all the samples of sinonasal Intestinal-Type Adenocarcinomas (ITACs). OTX1 mRNA was identified only in Non-Intestinal Type Adenocarcinomas (NITACs) while OTX2 mRNA was expressed only in Olfactory Neuroblastomas (ONs). We have demonstrated that the differential gene expression for both OTX1 and OTX2 genes might be a useful molecular marker to distinguish the different types of sinonasal tumors.

Published
2019

16. Exposure to Residential Greenness as a Predictor of Cause-Specific Mortality and Stroke Incidence in the Rome Longitudinal Study

Author

Matteo Scortichini, Francesco Forastiere, Chiara Antonucci, Francesco Cerza, Marina Davoli, Giulia Cesaroni, Carla Ancona, Fausto Manes, Federica Marando, Paola Michelozzi, and Riccardo Orioli

Subjects
Adult, Male, Longitudinal study, public health, environmental and occupational health, health, toxicology and mutagenesis, Health, Toxicology and Mutagenesis, Rome, Myocardial Ischemia, MEDLINE, 010501 environmental sciences, Health outcomes, 01 natural sciences, 03 medical and health sciences, 0302 clinical medicine, Air Pollution, Environmental health, parasitic diseases, Humans, Medicine, Longitudinal Studies, Prospective Studies, 030212 general & internal medicine, Prospective cohort study, Aged, 0105 earth and related environmental sciences, Aged, 80 and over, business.industry, Incidence, Research, Incidence (epidemiology), Public Health, Environmental and Occupational Health, Cause specific mortality, Middle Aged, Stroke, Cerebrovascular Disorders, Motor Vehicles, Italy, Cardiovascular Diseases, Female, Particulate Matter, Noise, business, Stroke incidence
Abstract

BACKGROUND: Living in areas with higher levels of surrounding greenness and access to urban green areas have been associated with beneficial health outcomes. Some studies suggested a beneficial influence on mortality, but the evidence is still controversial. OBJECTIVES: We used longitudinal data from a large cohort to estimate associations of two measures of residential greenness exposure with cause-specific mortality and stroke incidence. METHODS: We studied a population-based cohort of 1,263,721 residents in Rome aged [Formula: see text], followed from 2001 to 2013. As greenness exposure, we utilized the leaf area index (LAI), which expresses the tree canopy as the leaf area per unit ground surface area, and the normalized difference vegetation index (NDVI) within 300- and [Formula: see text] buffers around home addresses. We estimated the association between the two measures of residential greenness and the outcomes using Cox models, after controlling for relevant individual covariates and contextual characteristics, and explored potential mediation by air pollution [fine particulate matter with aerodynamic diameter [Formula: see text] [Formula: see text] and [Formula: see text]] and road traffic noise. RESULTS: We observed 198,704 deaths from nonaccidental causes, 81,269 from cardiovascular diseases [CVDs; 29,654 from ischemic heart disease (IHD)], 18,090 from cerebrovascular diseases, and 29,033 incident cases of stroke. Residential greenness, expressed as interquartile range (IQR) increase in LAI within [Formula: see text], was inversely associated with stroke incidence {hazard ratio (HR) 0.977 [95% confidence interval (CI): 0.961, 0.994]} and mortality for nonaccidental [HR 0.988 (95% CI: 0.981, 0.994)], cardiovascular [HR 0.984 (95% CI: 0.974, 0.994)] and cerebrovascular diseases [HR 0.964 (95% CI: 0.943, 0.985)]. Similar results were obtained using NDVI with 300- or [Formula: see text] buffers. CONCLUSIONS: Living in greener areas was associated with better health outcomes in our study, which could be partly due to reduced exposure to environmental hazards. Further research is required to understand the underlying mechanisms. https://doi.org/10.1289/EHP2854.

Published
2019

17. Diagnostic yield, safety, and advantages of ultra-low dose chest CT compared to chest radiography in early stage suspected SARS-CoV-2 pneumonia

Author

Gianluca Vanini, Gianluca Argentieri, Marco Marando, L. Bellesi, Filippo Del Grande, Stefano Presilla, Pietro Gianella, and Alberto Pagnamenta

Subjects
medicine.medical_specialty, Lung, business.industry, Radiography, Retrospective cohort study, General Medicine, medicine.disease, Effective dose (radiation), respiratory tract diseases, 03 medical and health sciences, Pneumonia, 0302 clinical medicine, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Predictive value of tests, medicine, Dosimetry, 030212 general & internal medicine, Radiology, Stage (cooking), business
Abstract

To determine the role of ultra-low dose chest computed tomography (uld CT) compared to chest radiographs in patients with laboratory-confirmed early stage SARS-CoV-2 pneumonia.Chest radiographs and uld CT of 12 consecutive suspected SARS-CoV-2 patients performed up to 48 hours from hospital admission were reviewed by 2 radiologists. Dosimetry and descriptive statistics of both modalities were analyzed.On uld CT, parenchymal abnormalities compatible with SARS-CoV-2 pneumonia were detected in 10/12 (83%) patients whereas on chest X-ray in, respectively, 8/12 (66%) and 5/12 (41%) patients for reader 1 and 2. The average increment of diagnostic performance of uld CT compared to chest X-ray was 29%. The average effective dose was, respectively, of 0.219 and 0.073 mSv.Uld CT detects substantially more lung injuries in symptomatic patients with suspected early stage SARS-CoV-2 pneumonia compared to chest radiographs, with a significantly better inter-reader agreement, at the cost of a slightly higher equivalent radiation dose.

Published
2021

18. A Human Cellular Model for Colorectal Anastomotic Repair: The Effect of Localization and Transforming Growth Factor-β1 Treatment on Collagen Deposition and Biomarkers

Author

Jens Hannibal, Ceylan Türlü, Peter Schjerling, Debora Marando, Edyta Biskup, Nicholas Willumsen, Lars N. Jorgensen, and Magnus S. Ågren

Subjects
Male, collagen, Pathology, MMP2, Anastomotic Leak, wound healing, lcsh:Chemistry, Extracellular matrix, chemistry.chemical_compound, 0302 clinical medicine, Submucosa, rectum, Large intestine, lcsh:QH301-705.5, Cells, Cultured, Spectroscopy, Chemistry, Anastomosis, Surgical, General Medicine, Flow Cytometry, Computer Science Applications, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Female, 030211 gastroenterology & hepatology, Collagen, Growth factors, Type I collagen, medicine.medical_specialty, Colon, extracellular matrix, Primary Cell Culture, Wound healing, anastomotic leakage, Models, Biological, Article, Catalysis, Transforming Growth Factor beta1, Inorganic Chemistry, 03 medical and health sciences, growth factors, medicine, Humans, Anasto-motic leakage, Physical and Theoretical Chemistry, Molecular Biology, Sirius Red, colon, Organic Chemistry, Rectum, Fibroblasts, lcsh:Biology (General), lcsh:QD1-999, Culture Media, Conditioned, Colorectal Surgery, Biomarkers, Transforming growth factor
Abstract

Anastomotic leakage (AL) is a devastating complication after colorectal surgery, possibly due to the loss of stabilizing collagen fibers in the submucosa. Our aim was to assess the formation of collagen in the colon versus the rectum with or without transforming growth factor (TGF)-β1 exposure in a human cellular model of colorectal repair. Primary fibroblasts were isolated by an explant procedure from clinically resected tissue rings during anastomosis construction in 19 consecutive colorectal patients who underwent laparoscopy. The cells, identified as fibroblasts by morphologic characteristics and flow cytometry analysis (CD90+), were cultured for 8 days and in 12 patients in the presence of 1 ng/mL TGF-β1. Total collagen deposition was measured colorimetrically after Sirius red staining of fixed cell layers, and type I, III, and VI collagen biosynthesis and degradation were specifically determined by the biomarkers PINP, PRO-C3, PRO-C6, and C3M in conditioned media by competitive enzyme-linked immunosorbent assays. Total collagen deposition by fibroblasts from the colon and rectum did not significantly differ. TGF-β1 treatment increased PINP, PRO-C6, and total collagen deposition. Mechanistically, TGF-β1 treatment increased COL1A1 and ACTA2 (encoding α-smooth muscle actin), and decreased COL6A1 and MMP2 mRNA levels in colorectal fibroblasts. In conclusion, we found no effect of anatomic localization on collagen production by fibroblasts derived from the large intestine. TGF-β1 represents a potential therapeutic agent for the prevention of AL by increasing type I collagen synthesis and collagen deposition.

Published
2021

19. The adaptation of lipid profile of human fibroblasts to alginate 2D films and 3D printed scaffolds

Author

Carlo Bergonzi, Silvia Marando, Giulia Remaggi, Ruggero Bettini, Franco Bernini, Ilaria Zanotti, and Lisa Elviri

Subjects
0301 basic medicine, Scaffold, Alginates, Cell, Biophysics, Biocompatible Materials, 02 engineering and technology, Ceramides, Biochemistry, Cell membrane, 03 medical and health sciences, Lipidomics, medicine, Humans, Fibroblast, Molecular Biology, Cells, Cultured, Tissue Scaffolds, Chemistry, Biomaterial, Fibroblasts, Lipid Metabolism, 021001 nanoscience & nanotechnology, Lipids, 030104 developmental biology, medicine.anatomical_structure, Printing, Three-Dimensional, Self-healing hydrogels, lipids (amino acids, peptides, and proteins), Swelling, medicine.symptom, 0210 nano-technology
Abstract

Background The investigation of the interactions between cells and active materials is pivotal in the emerging 3D printing-biomaterial application fields. Here, lipidomics has been used to explore the early impact of alginate (ALG) hydrogel architecture (2D films or 3D printed scaffolds) and the type of gelling agent (CaCl2 or FeCl3) on the lipid profile of human fibroblasts. Methods 2D and 3D ALG scaffolds were prepared and characterized in terms of water content, swelling, mechanical resistance and morphology before human fibroblast seeding (8 days). Using a liquid chromatography-triple quadrupole-tandem mass spectrometry approach, selected ceramides (CER), lysophosphatidylcholines (LPC), lysophosphatidic acids (LPA) and free fatty acids (FFA) were analyzed. Results The results showed a clear alteration in the CER expression profile depending of both the geometry and the gelling agent used to prepare the hydrogels. As for LPCs, the main parameter affecting their distribution is the scaffold architecture with a significant decrease in the relative expression levels of the species with higher chain length (C20 to C22) for 3D scaffolds compared to 2D films. In the case of FFAs and LPAs only slight differences were observed as a function of scaffold geometry or gelling agent. Conclusions Variations in the cell membrane lipid profile were observed for 3D cell cultures compared to 2D and these data are consistent with activation processes occurring through the mutual interactions between fibroblasts and ALG support. These unknown physiologically relevant changes add insights into the discussion about the relationship between biomaterial and the variations of cell biological functions.

Published
2021

20. Examining the Interrelation Among Change Processes: Decentering and Anticipatory Processing Across Cognitive Behavioral Therapy for Social Anxiety Disorder

Author

Stephanie Marando-Blanck and Sarah A. Hayes-Skelton

Subjects
Adult, Male, 050103 clinical psychology, medicine.medical_treatment, Emotions, Anxiety, Affect (psychology), Article, Cognitive reappraisal, Group psychotherapy, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Cognitive resource theory, medicine, Humans, 0501 psychology and cognitive sciences, skin and connective tissue diseases, Cognitive Behavioral Therapy, Mechanism (biology), 05 social sciences, Social anxiety, Cognition, Phobia, Social, 030227 psychiatry, Cognitive behavioral therapy, Clinical Psychology, Treatment Outcome, Psychotherapy, Group, Female, sense organs, Psychology, Cognitive psychology
Abstract

As evidence grows supporting certain mechanisms of change in psychological treatments and we improve statistical approaches to measuring them, it is important that we also explore how mechanisms and processes are related to each other, and how they together affect treatment outcomes. To answer these questions about interrelating processes and mechanisms, we need to take advantage of frequent assessment and modeling techniques that allow for an examination of the influence of one mechanism on another over time. Within cognitive behavioral therapy, studies have shown support for both decentering, the ability to observe thoughts and feelings as objective events in the mind, and anticipatory processing, the repetitive thinking about upcoming social situations, as potentially related mechanisms of change. Therefore, the current study examined weekly ratings of decentering and a single-item anticipatory processing question to examine the interrelation among these change mechanisms in 59 individuals who received a 12-weeks of Cognitive Behavioral Group Therapy for social anxiety disorder. Overall, these results found that both anticipatory processing and decentering changed over the course therapy for clients. Change in both anticipatory processing and decentering was related to outcome. The bivariate latent difference score analysis showed that anticipatory processing was a leading indicator of change in decentering, but not the reverse, indicating that change in anticipatory processing is leading to change in decentering. It may be that with the focus on cognitive reappraisal in this treatment, that reducing anticipatory processing is freeing up the cognitive resources for decentering to occur.

Published
2018

21. Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial

Author

Scott E Kasner, Balakumar Swaminathan, Pablo Lavados, Mukul Sharma, Keith Muir, Roland Veltkamp, Sebastian F Ameriso, Matthias Endres, Helmi Lutsep, Steven R Messé, J David Spence, Krassen Nedeltechev, Kanjana Perera, Gustavo Santo, Veronica Olavarria, Arne Lindgren, Shrikant Bangdiwala, Ashkan Shoamanesh, Scott D Berkowitz, Hardi Mundl, Stuart J Connolly, Robert G Hart, N Abdelhamid, D Abdul Rahman, M Abdul-Saheb, P Abreu, M Abroskina, F Abu Ahmad, S Accassat, M Acciaresi, A Adami, N Ahmad, F Ahmed, M Alberto Hawkes, F Alemseged, A Ali, R Altavilla, L Alwis, P Amarenco, S Amaro, LE Amaya Sanchez, A Amelia Pinto, SF Ameriso, H Amin, T Amino, AK Amjad, E Anagnostou, G Andersen, C Anderson, DC Anderson, M Andrea Falco, F Andres Mackinnon, D Andreu, M Androulakis, M Angel Gamero, G Angel Saredo, R Angeles Diaz, M Angels Font, S Anticoli, A Arauz, AA Arauz Gongora, P Araya, JF Arenillas Lara, S Arias Rivas, M Arnold, S Augustin, W Avelar, E Azevedo, V Babikian, A Bacellar, K Badalyan, HJ Bae, EM Baez Martinez, H Bagelmann, P Bailey, Z Bak, M Baker, A Balazs, D Baldaranov, I Balogun, T Balueva, Z Bankuti, M Bar, A Baranowska, J Bardutzky, S Barker Trejo, J Barlinn, F Baronnet, C Barroso, M Barteys, T Bartolottiova, A Barulin, M Bas, S Bashir, V Basile, R Bathe-Peters, R Bathula, C Batista, H Batur Caglayan, P Baumgartner, R Bazan, O Bazhenova, M Beaudry, J Beer, Y Behnam, C Beilei, A Beinlich, Y Bejot, A Belkin, OR Benavente, A Benjamin, V Berardi, D Bereczki, SD Berkowitz, J Berlingieri, W Berrios, J Berrouschot, M Bhandari, M Bhargavah, H Bicker, T Bicsak, M Bilik, D Bindila, J Birchenall, L Birnbaum, T Black, D Blacker, D Blacquiere, C Blanc-Labarre, C Blank, B Blazejewska-Hyzorek, S Bloch, E Bodiguel, E Bogdanov, L Boos, L Borcsik, N Bornstein, S Bouly, G Braga, I Bragado, MC Bravi, C Brokalaki, W Brola, R Brouns, D Bruce, J Brzoska-Mizgalska, B Buck, M Buksinska-Lisik, J Burke, M Burn, G Bustamante, L Cabrejo, K Cai, S Cajaraville, M Calejo, D Calvet, J Campillo, E Campos Costa, P Camps, H Can Alaydin, E Candeloro, C Canepa, CG Cantu Brito, M Cappellari, C Carcel, P Cardona Portela, F Cardoso, M Carek, M Carletti, J Carlos Portilla, P Caruso, I Casado-Naranjo, P Castellini, D Castro, F Castro Meira, A Cavallini, N Cayuela Caudevilla, S Cenciarelli, C Cereda, P Cerrone, A Chakrabarti, P Chaloulos-Iakovidis, A Chamorro, D Chandrasena, DI Chang, C Che, J Chembala, J Chen, Z Chen, T Chen, H Chen, X Chen, G Chen, L Chen, S Chen, B Cheripelli, M Chin, E Chiquete Anaya, M Chorazy, H Christensen, T Christensen, L Christian, F Chu, CS Chung, W Clark, R Clarke, S Claverie, E Clemente Agostoni, B Clissold, J Coelho, D Cohen, S Colakoglu, D Collas, R Condurso, SJ Connolly, D Consoli, C Constantin, AB Constantino Silva, L Contardo, A Corlobe, M Correia, C Correia, E Cortijo Garcia, B Coull, S Coutts, S Coveney, P Cras, R Crols, S Crozier, A Csanyi, L Csiba, K Csontos, R Csuha, L Cui, L Cunha, S Curtze, M Czerska, A Czlonkowska, M Czurko, M Czuryszkiewicz, M Dagnino, C Dai, A Daineko, G Dalek, D Damgaard, A Danese, K Dani, V Danku, W Dario Toledo, A Dávalos, A De Havenon, J De Keyser, N De Klippel, J De La Torre, A De Pauw, A De Smedt, R De Torres, MM De Vries Basson, J Dearborn, R Deganutto, M Degeorgia, I Deguchi, A Del Giudice, C Delcourt, R Delgado-Mederos, G Della Marca, B Delpont, S Deltour, DL Demets, M Dennis, J Desai, J Devine, I Dhollander, MT Di Mascio, M Diaconu, F Diaz Otero, J Dietzel, E Diez-Tejedor, N Ding, J Ding, M Diomedi, P Dioszeghy, M Distefano, V Domigo, E Dorodnicov, D Dossi, F Doubal, I Druzenko, P Du, J Du, T Duman, Y Duodu, D Dutta, L Dylewicz, J Eckstein, E Ehrensperger, S Ehrlich, G Einer Allende, B Elena Halac, S Elyas, M Endres, JM Engelbrecht, S Engelter, M Epinat, F Eren, M Esbjornsson, B Escribano, I Escudero, B Esisi, B Essa, M Esterbauer, N Evans, D Eveson, S Fabio, L Fang, S Fanta, M Fares, M Fatar, K Faust, A Favate, F Fazekas, M Federica Denaro, A Fedin, P Felipe Amaya, J Feng, K Ferencova, M Fernanda Gilli, MD Fernandez, PN Fernandez Pirrone, J Fernandez Vera, J Ferrari, A Ferreira, G Ferreira Junior, M Fidler, D Field, T Field, C Figueroa, J Fiksa, A Filipov, A Firstenfeld, L Fisch, U Fischer, M Fisselier, U Fiszer, F Fluri, G Fortea, K Fotherby, A Fraczek, E France, G Freitas, S Frey, M Frick, A Friedman, M Friedrich, G Frisullo, W Fryze, B Fuentes Gimeno, H Fujigasaki, K Fukuyama, A Furlan, G Furlanis, J Furnace, M Gabriel, E Gabriel Reich, RJ Gagliardi, F Galati, E Galli Giqueauk, A Gallina, E Gallinella, J Gallo, S Gangadharan, Y Gao, R Garcia Lopez, A Garcia Pastor, SM Garcia Sanchez, M Garnauf, P Garnier, D Gasecki, K Gasic, K Gasiorek, S Gasser, M Gaugg, M Gebreyohanns, K Gebura, J Geng, M Geniz Clavijo, K Georg Haeusler, R Geran, M Geremek, Z Gerocs, D Ghia, D Giannandrea, F Giatsidis, JA Gien Lopez, A Gil Nunez, L Gimenez, E Giralt, A Glabinski, D Gladstone, M Gliem, M Gluszkiewicz, R Goddeau, E Gogoleva, M Gokce, D Goldemund, K Golikov, A Gomes Neto, M Gomez Schneider, M Gomez-Choco, M Gomis, JF Gongora-Rivera, Y Gonysheva, L Gonzalez, ME Gonzalez Toledo, M Gottschal, I Gozdzik, S Grabowski, S Graf, D Green, D Greer, T Gregorio, S Greisenegger, I Greshnova, M Griebe, M Grzesik, J Guan, S Guarda, A Gueguen, C Guidoux, P Guillermo Povedano, B Guillon, V Guiraudg, G Gunathilagan, N Guryanova, V Gusev, G Gustavo Persi, R Gutiérrez, P Guyler, N Gyuker, V Hachinski, A Hajas, H Hallevi, G Hankey, GJ Hankey, L Hanouskova, L Hao, K Haraguchi, Y Haralur Sreekantaiah, S Haratz, D Hargroves, K Harkness, P Harmel, M Harrasser, RG Hart, M Harvey, R Hasan, Y Hasegawa, A Hassan, M Hattori, A Hatzitolios, M Hauk, T Hayashi, H Hayhoe, VS Hedna, M Heine, V Held, S Hellwig, J Henkner, N Henninger, S Hermans, J Hernandez, D Herrero, M Hervieu-Begue, R Herzig, L Hicken, M Hieber, M Hill, M Hirose, MC Hobeanu, B Hobson, M Hochstetter, J Hoe Heo, M Hoffmann, C Holmstedt, P Hon, KS Hong, Y Honma, A Horev, G Horgan, L Horvath, M Horvath, C Hoyer, D Huang, H Huang, B Huber, J Huhtakangas, M Hussain, S Igarashi, AM Iglesias Mohedano, J Ignacio Tembl, M Impellizzeri, Y Inanc, P Ioli, A Irina Aniculaesei, K Ishida, R Itabashi, H Iversen, A Jagolino, K Jakab, S Jander, H Janka, J Jankovych, J Jansen, L Jasek, M Javier Alet, L Javor, X Jin, P Jing, B Joachim, M Joan Macleod, M Johnson, J Jose Martin, C Joyner, K Judit Szabo, A Jun-Oconnell, R Jura, B Kaczorowska, J Kadlcikova, T Kahles, N Kakaletsis, I Kakuk, K Kalinowska, K Kaminska, C Kaneko, I Kanellos, P Kapeller, K Kapica-Topczewska, O Karasz, M Karlinski, JE Karlsson, K Kasa, E Kashaeva, SE Kasner, M Kaste, J Kasza, A Katalin Iljicsov, M Katsurayama, S Kaur, M Kawanishi, S Kaygorodtseva, K Ke, A Kei, J Keilitz, J Kellner, P Kelly, S Kelly, D Kemlink, M Kerekgyarto, I Keskinarkaus, D Khairutdinova, A Khanna, A Khaw, M Kholopov, C Khoumri, S Kirpicheva, H Kirshner, K Kitagawa, S Kittner, R Kivioja, F Klein, D Kleindorfer, T Kleinig, P Klivenyi, S Knecht, Y Kobayashi, A Kobayashi, M Koch, L Koehler, M Koivu, V Kolianov, I Koltsov, T Kondo, I Konkov, S Kopecky, E Korompoki, J Korpela, K Kosarz-Lanczek, A Koutroubi, K Kovacs, T Kovacs, H Kovacs, K Kowalczyk, M Kowalska, D Krajickova, M Kral, C Krarup Hansen, J Kraska, S Krebs, V Krejci, C Kremer, R Kreuzpointer, M Krzyzanowska, D Kucken, A Kulakowska, J Kunzmann, N Kurenkova, A Kuris, I Kurkowska-Jastrzebska, N Kurtenkova, O Kurushina, G Kusnick, M Kustova, T Kuwashiro, J Kwan Cha, A Lago, M Lagutenko, B Lajos, J Lambeck, C Lamy, A Landolfi, S Lanfranconi, W Lang, LB Lara Lezama, B Lara Rodriguez, T Largo, A Lasek-Bal, L Latte, V Lauer, P Lavados, R Le Bouc, R Leal Cantu, H Lechner, K Lecouturier, S Leder, J Lee, BC Lee, A Leger, E Leira, I Leisse, R Leker, G Lembo, L Lenskaya, J Leyden, G Li, M Li, S Li, J Li, G Liamis, H Liang, Z Liang, N Ligot, H Lin, R Lindert, A Lindgren, M Linna, T Litwin, K Liu, X Liu, L Llull, B Lohninger, M Longoni, C Loomis, D Lopes, M Lopez Fernandez, N Lopez Garza, A Lord, S Louw, R Lovasz, T Lowenkopf, Z Lu, SC Lubke-Detring, R Luder, S Lujan, B Luo, L Lupinogina, G Luschin, H Lutsep, A Lvova, J Ly, G.M. Grosse, H Ma, C Ma, M Machado, C Machado, S Macher, J Machetanz, F Macian-Montoro, E Mackey, A Mackey, G Maclean, J Maestre-Moreno, A Magadan, T Magyar, A Mahagney, A Majid, A Majjhoo, K Makaritsis, J Mandzia, M Mangas Guijarro, D Mangion, E Manios, S Mann, L Manning, C Manno, J Manuel Garcia, V Maqueda, M Mar Castellanos, M Mar Freijo, C Marando, S Marcela Lepera, J Marcos Couto, G Maria Bruera, L Maria Greco, A Maria Lorenzo, S Maria Obmann, A Maria Roa, C Marini, I Marinkovic, G Mario Sumay, C Mario Torres, M Marko, S Markova, H Markus, R Marsh, E Marsili, M Marta Esnaola, J Marta Moreno, J Marti-Fabregas, S Martina Angelocola, P Martínez Sánchez, N Martinez-Majander, S Martins, O Marzelik, S Mastrocola, G Matamala, A Matoltsy, B Matosevic, S Matsumoto, A Maud, G Mauri Cabdevila, Z May, Y Mayasi, A Mayr, T Mazzoli, K Mcarthur, L Mccullough, CE Medina Pech, F Medlin, M Mehdiratta, S Mehta, D Mehta, B Mehta, M Melis, E Melnikova, B Mendez, T Mendonca, JJ Mengual Chirifie, N Menon, A Mensch, E Meseguer, S Messe, K Metcalf, N Meyer, F Michas, N Micheletti, R Mikulik, H Milionis, B Miller, T Milling, C Minelli, J Minhas, M Minns, D Mircea, S Mishra, A Mismas, A Mistri, N Mitrovic, H Miyake, B Modrau, A Moey, C Molina, J Molina, A Molis, J Moller, S Molnar, F Moniche, C Monosi, V Monzani, M Moonis, R Morais, L Morales, A Morales, D Morar-Precup, F Moreton, C Moro, E Morozova, M Morton, T Morvan, E Morvan, T Motko, A Mowla, E Mozhejko, G Muddegowda, O Mudhar, T Mueller, C Muhl, KW Muir, H Mundl, S Munoz, C Murphy, S Murphy, A Murtuzova, T Musuka, J Mutzenbach, M Myint, W Mysliwy, M Naccarato, G Naeije, Y Nagakane, I Natarajan, D Navaratnam, A Nave, B Nazliel, K Nedeltchev, J Nel, H Nell, R Nemeth, L Nemeth, O Neto, K Ng, J Ngeh, L Nicolas Chialvo, T Nieminen, M Nikkanen, J Nikl, M Nikoforova, S Nishino, Y Nishiyama, X Njovane, S Nogawa, F Nombela, B Norrving, K Nosek, B Nowak, E Nowakowska-Sledz, G Ntaios, H Numminen, F Nunez, M Obadia, S Oberndorfer, A Obrezan, J Ochiai, W Oczkowski, MJ O'Donnell, A Odyniec, K Oh, M Ohira, Y Okamoto, M Okpala, S Okubo, L Olah, V Olavarria, J Oleszek, N Onat Demirci, V Ondar, G Ongun, K Ooyama, V Orosz, R Ortiz, G Osseby, E Österlund-Tauriala, C Ovesen, S Ozcekic Demirhan, J Ozdoba-Rot, S Ozturk, E Ozyurt, M Pablo Grecco, G Pablo Povedano, M Paciaroni, C Padiglioni, J Pagola, W Palasik, G Panczel, L Panos, G Papadopoulos, E Papadopoulou, A Papagiannis, V Papavasileiou, M Papina, JR Pardo De Donlebun, V Parisi, JM Park, J Pasten, N Patel, O Pavlik, M Pawelczyk, WF Peacock, H Pei, T Peisker, LF Pena Sedna, A Penn, S Pentek, E Pepper, L Pereira, K Perera, Y Perez, S Perez, P Perez Leguizamon, M Pernicka, R Perry, A Persico, Y Pesant, S Peska, D Peters, G Peters, L Pettigrew, T Phan, S Philippi, T Phinney, F Pico, A Pidal, B Piechowski-Jozwiak, A Pieroni, S Pineiro, V Piras, N Pizova, J Polanco, M Polin, A Polyakov, E Polychronopoulou, A Polymeris, D Popov, A Poppe, P Postorino, C Pozzerese, M Pradhan, L Prats, E Prazdnichkova, B Prendl, M Pretorius, P Profice, S Prokopenko, E Pudov, V Pujol Lereis, G Punzo Bravo, F Purroy, J Qiu, X Qu, V Quenardelle, H Quesada Garcia, L Radrizzani, A Radtke, T Raffelsberger, JM Ramirez Moreno, C Ramos-Estebanez, A Rani, P Rapantova, K Rashed, A Rasheed Nihara, J Rasmussen, L Redondo Robles, M Reif, P Reiner, P Rekova, A Renu, M Repetto, P Reyes, S Reyes Morales, JH Rha, J Ribeiro, S Ricci, C Richard, R Rigual, C Rinaldi, C Riveira Rodriguez, B Rizzato, TG Robinson, A Rocco, M Rodrigues, G Rodriguez, A Rodriguez Campello, F Rodriguez Lucci, M Rodriguez Yanez, C Roesler, C Roffe, R Roine, S Roine, A Roldan, F Romana Pezzella, M Romano, JS Roos, C Rosso, C Rostrup Kruuse, Y Roth, R Roukens, L Roveri, D Rozanski, J Rozniecki, C Rozsa, S Rudilosso, G Ruiz Ares, A Ruiz Franco, G Rum, J Ruuskanen, I Rybinnik, K Ryota, J Saarinen, V Saavedra, C Sabben, A Sabet, D Sagris, J Sahlas, N Sakai, P Salamanca, P Salgado, S Salig, T Salletmayr, M Salnikov, O Samoshkina, Y Samson, D Sanak, M Sànchez Cerón, P Santalucia, M Santamaria Cadavid, P Santiago, G Santo, B Sanz Cuesta, J Sargento, A Sarraj, K Sas, A Sas, O Satoshi, S Satsoglou, N Sattar, S Savitz, C Savopoulos, J Saw, M Sawicka, R Sawyer, T Scandura, N Schillinger, J Schindler, F Schlachetzki, I Schneider, R Schuppner, J Schurig, CJ Schwarzbach, M Sebejova, G Seidel, L Sekaran, D Selcuk, J Selvarajah, A Semerano, J Semjen, D Semushina, S Sen, M Seok Park, J Serena, O Serhat Tokgoz, W Serles, F Serrano, M Sevin, L Seynaeve, S Shah, N Shamalov, T Shang, M Sharma, A Sharrief, M Shazam Hussain, I Shchukin, W Shen, E Shepeleva, I Shinsuke, A Shmonin, A Shoamanesh, A Shuaib, A Shulga, G Sibolt, I Sibon, I Sicilia, M Siebert, E Sieczkowska, C Sila, AA Silva, D Silva, P Silva, Y Silva, M Silvestrini, Z Simony, A Simpkins, B Singh, D Sinha, I Sipos, O Skoda, P Skowron, M Skowronska, B Sliwinska, J Slonkova, A Smolkin, A Smyth, P Sobolewski, A Sobota, SI Sohn, M Soldatov, I Solganov, L Soloveva, E Solovyeva, N Sonntag, P Soors, M Sorgun, C Soriano, D Spence, K Spengos, L Sposato, G Staaf, K Stadler, L Stakhovskaya, K Stamatelopoulos, S Steinert, I Stetkarova, M Stiehm, R Stocker, J Stoinski, A Stoll, G Stotts, A Stumpp, P Sucapane, T Suenaga, X Sun, S Sundararajan, J Sung Kim, H Suzuki, N Svaneborg, G Szasz, W Szczuchniak, S Szczyrba, N Szegedi, A Szekely, Z Szewczyk, G Szilagyi, S Szlufik, K Szoboszlai, L Szpisjak, R Sztajzel, L Sztriha, SE Ta Wil, J Taggeselle, K Takamatsu, M Takao, W Taki, S Takizawa, M Talahma, A Tamayo, J Tan, D Tanne, A Tapanainen, T Tapiola, J Tarasiuk, T Tatlisumak, A Tayal, S Tcvetkova, P Teal, J Tejada Garcia, H Tejada Meza, D Tenora, M Terceno, A Terentiou, S Tezcan, D Thaler, A Thomson, E Thouvenot, M Tiainen, I Timberg, S Timsit, A Tinchon, D Tirschwell, C Togay Isikay, K Tokunaga, M Tolino, C Toloza, G Tomelleri, K Tomoyuki, LM Tomppo, Z Tong, L Tong, D Toni, J Torres, C Tossavainen, G Toth, A Tountopoulou, E Touze, M Tovar, K Toyoda, S Trillo, A Trommer, D Tropepi, D Tryambake, H Tu, S Tuetuencue, R Tumova, O Tumpula, G Turc, A Tutaj, J Tynkkynen, S Uchiyama, U Uchwat, L Uhrinyakova, R Ulku Acar, D Uluduz Ugurlu, X Urra, S Urui, M Usero Ruiz, D Vaclavik, K Vahedi, A Valikovics, J Valpas, P Van Acker, W Van Daele, G Vanderschueren, L Vanina Jure, R Varela, Z Varga, J Varvat, N Varvyanskaya, A Vasco Salgado, P Vasko, L Vass, S Vassilopoulou, I Vastagh, P Vazquez, L Vecsei, R Veltkamp, M Venti, M Verdugo, V Verocai, M Veronica Marroquin, C Veronica Simonsini, T Veverka, M Vigl, A Vila, C Vilar, JA Villanueva Osorio, J Virta, E Vitkova, B Voglsperger, J Volna, PA Von Weitzel-Mudersbach, N Vora, I Voznyuk, A Wach-Klink, A Wacongne, D Walters, Y Wang, J Wang, L Wang, X Wang, W Wang, N Wang, D Wang, H Wang, W Warnack, K Wartenberg, R Waters, M Waters, T Webb, J Weber, G Weiss, K Weissenborn, JI Weitz, B Weller, G Wen, G Weng, P Werner, D Werring, P Wester, W Whiteley, R Whiting, T Wijeratne, C Willems, L Wilson, C Wilson, T Winder, J Windt, A Winkler, A Winska-Tereszkiewicz, A Wisniewska, M Wittayer, A Wlodek, A Wojnarowska-Arendt, M Wolf, V Wolff, C Wolter, A Wong, H Wook Nah, H Worthmann, W Wu, S Wu, S Wunderlich, H Wurzinger, DG Wyse, B Xiao, W Xiaopeng, A Ximenez-Carrillo, L Xiong, Y Xiong, W Xiong, Y Xu, J Xu, Z Xu, B Yalo, T Yamada, M Yamasaki, L Yang, Y Yang, X Yang, Q Yang, B Yang, J Yang, I Yasuhiro, M Yee Lam, C Yegappan, S Yip, E Ylikallio, P Ylikotila, A Yongwon Jin, BW Yoon, Y Yoshida, L Yperzeele, H Yuan, H Yuasa, J Zalewska, C Zanferrari, E Zapata, D Zboznovits, I Zelenka, C Zhang, B Zhang, S Zhang, M Zhang, X Zhang, J Zhang, L Zhao, O Zhirnova, L Zhou, J Zielinska-Turek, I Zinchenko, M Ziomek, A Zitzmann, R Zweifler, J Zwiernik, Yperzeele, Laetitia, and NAVIGATE ESUS Investigators

Subjects
Male, International Cooperation, 030204 cardiovascular system & hematology, antiplatelet therapy, law.invention, Neurology (clinical), ischemic stroke, anticoagulation, Cohort Studies, 0302 clinical medicine, Randomized controlled trial, Rivaroxaban, law, Stroke, education.field_of_study, Aspirin, Anticoagulant, Settore BIO/14, Middle Aged, 3. Good health, Treatment Outcome, N/A, Cardiology, Platelet aggregation inhibitor, Settore MED/26 - Neurologia, Female, medicine.drug, medicine.medical_specialty, medicine.drug_class, MEDLINE, Population, Foramen Ovale, Patent, Subgroup analysis, Article, Statistics, Nonparametric, 03 medical and health sciences, Double-Blind Method, Internal medicine, medicine, Humans, education, Aged, business.industry, medicine.disease, Human medicine, business, 030217 neurology & neurosurgery, Platelet Aggregation Inhibitors, Factor Xa Inhibitors
Abstract

Background: \ud Patent foramen ovale (PFO) is a contributor to embolic stroke of undetermined source (ESUS). Subgroup analyses from previous studies suggest that anticoagulation could reduce recurrent stroke compared with antiplatelet therapy. We hypothesised that anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, would reduce the risk of recurrent ischaemic stroke compared with aspirin among patients with PFO enrolled in the NAVIGATE ESUS trial.\ud \ud Methods: \ud NAVIGATE ESUS was a double-blinded, randomised, phase 3 trial done at 459 centres in 31 countries that assessed the efficacy and safety of rivaroxaban versus aspirin for secondary stroke prevention in patients with ESUS. For this prespecified subgroup analysis, cohorts with and without PFO were defined on the basis of transthoracic echocardiography (TTE) and transoesophageal echocardiography (TOE). The primary efficacy outcome was time to recurrent ischaemic stroke between treatment groups. The primary safety outcome was major bleeding, according to the criteria of the International Society of Thrombosis and Haemostasis. The primary analyses were based on the intention-to-treat population. Additionally, we did a systematic review and random-effects meta-analysis of studies in which patients with cryptogenic stroke and PFO were randomly assigned to receive anticoagulant or antiplatelet therapy.\ud \ud Findings: \ud Between Dec 23, 2014, and Sept 20, 2017, 7213 participants were enrolled and assigned to receive rivaroxaban (n=3609) or aspirin (n=3604). Patients were followed up for a mean of 11 months because of early trial termination. PFO was reported as present in 534 (7·4%) patients on the basis of either TTE or TOE. Patients with PFO assigned to receive aspirin had a recurrent ischaemic stroke rate of 4·8 events per 100 person-years compared with 2·6 events per 100 person-years in those treated with rivaroxaban. Among patients with known PFO, there was insufficient evidence to support a difference in risk of recurrent ischaemic stroke between rivaroxaban and aspirin (hazard ratio [HR] 0·54; 95% CI 0·22–1·36), and the risk was similar for those without known PFO (1·06; 0·84–1·33; pinteraction=0·18). The risks of major bleeding with rivaroxaban versus aspirin were similar in patients with PFO detected (HR 2·05; 95% CI 0·51–8·18) and in those without PFO detected (HR 2·82; 95% CI 1·69–4·70; pinteraction=0·68). The random-effects meta-analysis combined data from NAVIGATE ESUS with data from two previous trials (PICSS and CLOSE) and yielded a summary odds ratio of 0·48 (95% CI 0·24–0·96; p=0·04) for ischaemic stroke in favour of anticoagulation, without evidence of heterogeneity.\ud \ud Interpretation: \ud Among patients with ESUS who have PFO, anticoagulation might reduce the risk of recurrent stroke by about half, although substantial imprecision remains. Dedicated trials of anticoagulation versus antiplatelet therapy or PFO closure, or both, are warranted.\ud \ud Funding: \ud Bayer and Janssen.

Published
2018

22. Hematopoietic stem cells made BETter by inhibition

Author

Brian J. P. Huntly and Ludovica Marando

Subjects
0301 basic medicine, BRD4, biology, Chemistry, Cell growth, Lysine, Hematology, Hematopoietic Stem Cells, Embryonic stem cell, Article, Cell biology, Bromodomain, Hematopoiesis, 03 medical and health sciences, 030104 developmental biology, Histone, Acetylation, biology.protein, Stem cell, Embryonic Stem Cells, Cell Proliferation
Abstract

Although inhibitors of bromodomain and extra terminal domain (BET) proteins show promising clinical activity in different hematologic malignancies, a systematic analysis of the consequences of pharmacological BET inhibition on healthy hematopoietic (stem) cells is urgently needed. We found that JQ1 treatment decreases the numbers of pre-, immature and mature B cells while numbers of early pro-B cells remain constant. In addition, JQ1 treatment increases apoptosis in T cells, all together leading to reduced cellularity in thymus, bone marrow and spleen. Furthermore, JQ1 induces proliferation of long-term hematopoietic stem cells, thereby increasing stem cell numbers. Due to increased numbers, JQ1-treated hematopoietic stem cells engrafted better after stem cell transplantation and repopulated the hematopoietic system significantly faster after sublethal myeloablation. As quantity and functionality of hematopoietic stem cells determine the duration of life-threatening myelosuppression, BET inhibition might benefit patients in myelosuppressive conditions.

Published
2018

23. Rivaroxaban for stroke prevention after embolic stroke of undetermined source

Author

Hart, Robert G, Sharma, Mukul, Mundl, Hardi, Kasner, Scott E, Bangdiwala, Shrikant I, Berkowitz, Scott D, Swaminathan, Balakumar, Lavados, Pablo, Wang, Yongjun, Wang, Yilong, Davalos, Antonio, Shamalov, Nikolay, Mikulik, Robert, Cunha, Luis, Lindgren, Arne, Arauz, Antonio, Lang, Wilfried, Czlonkowska, Anna, Eckstein, Jens, Gagliardi, Rubens J, Amarenco, Pierre, Ameriso, Sebastian F, Tatlisumak, Turgut, Veltkamp, Roland, Hankey, Graeme J, Toni, Danilo, Bereczki, Daniel, Uchiyama, Shinichiro, Ntaios, George, Yoon, Byung-Woo, Brouns, Raf, Endres, Matthias, Muir, Keith W, Bornstein, Natan, Ozturk, Serefnur, O'Donnell, Martin J, De Vries Basson, Matthys M, Pare, Guillaume, Pater, Calin, Kirsch, Bodo, Sheridan, Patrick, Peters, Gary, Weitz, Jeffrey I, Peacock, W Frank, Shoamanesh, Ashkan, Benavente, Oscar R, Joyner, Campbell, Themeles, Ellison, Connolly, Anderson DC, Stuart J., Demets, Dl, Kaste, M, Norrving, B, Wyse, Dg, Alet, M, Allende, G, Beinlich, A, Berrios, W, Bruera, G, Castro, D, Chialvo, L, Claverie, S, Contardo, L, Couto, J, Deganutto, R, Diaz, R, Dossi, D, Esnaola, M, Falco, M, Fernandez Pirrone, P, Ferrari, J, Firstenfeld, A, Galli Giqueauk, E, Gilli, M, Gonzalez, L, Gonzalez Toledo, M, Grecco, M, Halac, B, Hawkes, M, Ioli, P, Jure, L, Klein, F, Lepera, S, Lujan, S, Mackinnon, F, Marroquin, M, Martin, J, Parisi, V, Perez Leguizamon, P, Persi, G, Povedano, P, Povedano, G, Pujol Lereis, V, Radrizzani, L, Reich, E, Repetto, M, Rodriguez Lucci, F, Romano, M, Saredo, G, Schneider, M, Simonsini, C, Sumay, G, Thomson, A, Toledo, W, Torres, C, Vila, A, Abdul Rasheed, N, Anderson, C, Bailey, P, Blacker, D, Carcel, C, Clissold, B, Delcourt, C, Field, D, Gangadharan, S, Ghia, D, Kleinig, T, Leyden, J, Ly, J, Ma, H, Mackey, E, Mishra, S, Moey, A, Musuka, T, Pepper, E, Phan, T, Sabet, A, Saw, J, Singh, B, Tryambake, D, Tu, H, Wijeratne, T, Wong, A, Augustin, S, Esterbauer, M, Garnauf, M, Gasiorek, K, Gasser, S, Gaugg, M, Greisenegger, S, Harrasser, M, Heine, M, Huber, 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Kakaletsis, N, Kanellos, I, Kei, A, Korompoki, E, Koutroubi, A, Liamis, G, Makaritsis, K, Manios, E, Michas, F, Milionis, H, Papadopoulos, G, Papadopoulou, E, Papagiannis, A, Polychronopoulou, E, Sagris, D, Satsoglou, S, Savopoulos, C, Solganov, I, Spengos, K, Stamatelopoulos, K, Terentiou, A, Tountopoulou, A, Vassilopoulou, S, Amjad, A, Balazs, A, Bankuti, Z, Bicsak, T, Borcsik, L, Csanyi, A, Csiba, L, Csontos, K, Csuha, R, Czurko, M, Danku, V, Dioszeghy, P, Faust, K, Fazekas, F, Gerocs, Z, Gottschal, M, Gyuker, N, Hajas, A, Horvath, L, Horvath, M, Iljicsov, A, Jakab, K, Javor, L, Kakuk, I, Karasz, O, Kasa, K, Kasza, J, Kerekgyarto, M, Klivenyi, P, Kovacs, K, Kovacs, T, Kovacs, H, Lajos, B, Lovasz, R, Magyar, T, Matoltsy, A, May, Z, Molnar, S, Monosi, C, Motko, T, Nemeth, R, Nemeth, L, Nikl, J, Olah, L, Orosz, V, Panczel, G, Pentek, S, Prendl, B, Rozsa, C, Rum, G, Sas, K, Sas, A, Semjen, J, Simony, Z, Sipos, I, Szabo, K, Szasz, G, Szegedi, N, Szekely, A, Szilagyi, G, Szoboszlai, K, Szpisjak, L, Toth, G, Uhrinyakova, L, Valikovics, A, Varga, Z, Vass, L, Vastagh, I, Vecsei, L, Zboznovits, D, Coveney, S, Horgan, G, Kelly, P, Murphy, S, Smyth, A, Waters, R, Abu Ahmad, F, Bloch, S, Dorodnicov, E, Hallevi, H, Haratz, S, Horev, A, Kolianov, V, Leker, R, Mahagney, A, Marzelik, O, Rephaeli, G, Tanne, D, Weller, B, Acciarresi, M, Adami, A, Agostoni, E, Alemseged, F, Altavilla, R, Angelocola, S, Anticoli, S, Berardi, V, Bravi, M, Candeloro, E, Cappellari, M, Carletti, M, Caruso, P, Castellini, P, Cavallini, A, Cenciarelli, S, Cerrone, P, Condurso, R, Consoli, D, Danese, A, Della Marca, G, Denaro, M, Di Mascio, M, Diomedi, M, Distefano, M, Frisullo, G, Furlanis, G, Galati, F, Gallina, A, Gallinella, E, Giannandrea, D, Giatsidis, F, Greco, L, Impellizzeri, M, Landolfi, A, Lanfranconi, S, Latte, L, Lembo, G, Longoni, M, Marando, C, Marini, C, Marsili, E, Mastrocola, S, Mazzoli, T, Melis, M, Micheletti, N, Moller, J, Monzani, V, Naccarato, M, Paciaroni, M, Padiglioni, C, Persico, A, Pezzella, F, Pieroni, A, Piras, V, Postorino, P, Pozzerese, C, Profice, P, Ricci, S, Rinaldi, C, Rizzato, B, Rocco, A, Roveri, L, Santalucia, P, Semerano, A, Sicilia, I, Silvestrini, M, Sucapane, P, Tomelleri, G, Tropepi, D, Venti, M, Amino, T, Chin, M, Deguchi, I, Fujigasaki, H, Fukuyama, K, Haraguchi, K, Hasegawa, Y, Hattori, M, Hayashi, T, Hirose, M, Honma, Y, Igarashi, S, Irie, S, Itabashi, R, Ito, Y, Kamata, T, Kaneko, C, Kawanishi, M, Kimura, R, Kitagawa, K, Kobayashi, Y, Kondo, T, Kuwashiro, T, Matsumoto, S, Miyake, H, Nagakane, Y, Nishino, S, Nishiyama, Y, Nogawa, S, Ochiai, J, Ohira, M, Okamoto, Y, Okubo, S, Okuda, S, Ooyama, K, Sakai, N, Suenaga, T, Suzuki, H, Takamatsu, K, Takao, M, Taki, W, Takizawa, S, Tokunaga, K, Toyoda, K, Urui, S, Yamada, T, Yamasaki, M, Yoshida, Y, Yuasa, H, Bae, H, Cha, J, Chang, D, Chung, C, Heo, J, Hong, K, Kim, J, Lee, B, Nah, H, Oh, K, Park, M, Park, J, Rha, J, Sohn, S, Amaya Sanchez, L, Arauz Gongora, A, Cantu Brito, C, Chiquete Anaya, E, Felipe Amaya, P, Fernandez Vera, J, Garcia Lopez, R, Gien Lopez, J, Gongora-Rivera, J, Hernandez, J, Leal Cantu, R, Lopez Garza, N, Medina Pech, C, Mendez, B, Pena Sedna, L, Reyes Morales, S, Ruiz Franco, A, Serrano, F, Tovar, M, Uribe, R, Bak, Z, Baranowska, A, Bilik, M, Blazejewska-Hyzorek, B, Brola, W, Brzoska-Mizgalska, J, Buksinska-Lisik, M, Chorazy, M, Czerska, M, Czuryszkiewicz, M, Dalek, G, Dylewicz, L, Fiszer, U, Fraczek, A, Friedman, A, Fryze, W, Gasecki, D, Gębura, K, Geremek, M, Glabinski, A, Gluszkiewicz, M, Goździk, I, Grzesik, M, Jasek, L, Kaczorowska, B, Kalinowska, K, Kaminska, K, Kapica-Topczewska, K, Karlinski, M, Kobayashi, A, Kosarz-Lanczek, K, Kowalczyk, K, Kowalska, M, Kraska, J, Krzyzanowska, M, Kulakowska, A, Kurkowska-Jastrzebska, I, Lasek-Bal, A, Litwin, T, Morton, M, Myśliwy, W, Nosek, K, Nowak, B, Nowakowska-Śledź, E, Odyniec, A, Oleszek, J, Ozdoba-Rot, J, Palasik, W, Pawelczyk, M, Rozanski, D, Rozniecki, J, Sawicka, M, Sieczkowska, E, Skowron, P, Skowronska, M, Sliwinska, B, Sobolewski, P, Sobota, A, Stoiński, J, Szczuchniak, W, Szczyrba, S, Szewczyk, Z, Szlufik, S, Tarasiuk, J, Tutaj, A, Uchwat, U, Wach-Klink, A, Winska-Tereszkiewicz, A, Wisniewska, A, Włodek, A, Wojnarowska-Arendt, A, Zalewska, J, Zielinska-Turek, J, Ziomek, M, Zwiernik, J, Abreu, P, E Silva A, Amaral, Azevedo, E, Barroso, C, Calejo, M, Campillo, J, Campos Costa, E, Coelho, J, Correia, M, Correia, C, Gregorio, T, Lopes, D, Machado, C, Mendonca, T, Pereira, L, Pidal, A, Pineiro, S, Pinto, A, Ribeiro, J, Rodrigues, M, Salgado, P, Salgado, A, Santo, G, Sargento, J, Varela, R, Abroskina, M, Badalyan, K, Balueva, T, Barulin, A, Bazhenova, O, Belkin, A, Bogdanov, E, Daineko, A, Druzenko, I, Fedin, A, Fidler, M, Gogoleva, E, Golikov, K, Gonysheva, Y, Greshnova, I, Guryanova, N, Gusev, V, Kashaeva, E, Kaygorodtseva, S, Khairutdinova, D, Kholopov, M, Kirpicheva, S, Koltsov, I, Konkov, I, Kurenkova, N, Kurtenkova, N, Kurushina, O, Kustova, M, Lagutenko, M, Lenskaya, L, Lupinogina, L, Lvova, A, Melnikova, E, Meshkova, K, Morozova, E, Mozhejko, E, Nikoforova, M, Obrezan, A, Ondar, V, Pizova, N, Polyakov, A, Popov, D, Prazdnichkova, E, Prokopenko, S, Pudov, E, Salnikov, M, Samoshkina, O, Semushina, D, Shchukin, I, Shepeleva, E, Shmonin, A, Smolkin, A, Soldatov, M, Soloveva, L, Solovyeva, E, Stakhovskaya, L, Tcvetkova, S, Varvyanskaya, N, Voznyuk, I, Zhirnova, O, Ahmed, F, Basson, M, Engelbrecht, J, Hobson, B, Jansen, J, Nel, J, Nell, H, Njovane, X, Pretorius, M, Roos, J, Salig, S, Siebert, M, Amaro, S, Arenillas Lara, J, Arias Rivas, S, Baez Martinez, E, Bas, M, Bashir, S, Bragado, I, Cajaraville, S, Camps, P, Cardona Portela, P, Casado-Naranjo, I, Castellanos, M, Cayuela Caudevilla, N, Chamorro, A, Constantino Silva, A, Cortijo Garcia, E, De La Torre, J, De Torres, R, Diaz Otero, F, Diez-Tejedor, E, Escribano, B, Escudero, I, Fernandez, M, Font, M, Fortea, G, Freijo, M, Fuentes Gimeno, B, Gamero, M, Garcia, J, Garcia Pastor, A, Garcia Sanchez, S, Geniz Clavijo, M, Gil Nunez, A, Giralt, E, Gomez-Choco, M, Gomis, M, Gutiérrez, R, Iglesias Mohedano, A, Lago, A, Lara Lezama, L, Lara Rodriguez, B, Llull, L, Lopez Fernandez, M, Lorenzo, A, Maestre-Moreno, J, Marta Moreno, J, Marti-Fabregas, J, Martínez Sánchez, P, Mauri Cabdevila, G, Mengual Chirifie, J, Molina, C, Molina, J, Moniche, F, Morales, L, Morales, A, Nombela, F, Núñez, F, Pagola, J, Perez, S, Portilla, J, Prats, L, Purroy, F, Quesada Garcia, H, Ramirez Moreno, J, Redondo Robles, L, Renu, A, Riveira Rodriguez, C, Roa, A, Rodriguez Campello, A, Rodriguez Pardo De Donlebun, J, Rodriguez Yanez, M, Rudilosso, S, Ruiz Ares, G, Sànchez Cerón, M, Santamaria Cadavid, M, Sanz Cuesta, B, Serena, J, Silva, Y, Soriano Soriano, C, Tejada Garcia, J, Tejada Meza, H, Tembl, J, Terceno, M, Trillo, S, Urra, X, Usero Ruiz, M, Vazquez, P, Vilar, C, Villanueva Osorio, J, Ximenez-Carrillo, A, Zapata, E, Esbjornsson, M, Karlsson, J, Kremer, C, Kuris, A, Staaf, G, Stiehm, M, Timberg, I, Tossavainen, C, Wester, P, Arnold, M, Baumgartner, P, Beer, J, Bicker, H, Boos, L, Cereda, C, Chaloulos-Iakovidis, P, Christian, L, Engelter, S, Fisch, L, Fischer, U, Frey, S, Frick, M, Hauk, M, Hoffmann, M, Kahles, T, Manno, C, Medlin, F, Mircea, D, Nedeltchev, K, Panos, L, Polymeris, A, Schillinger, N, Stocker, R, Sztajzel, R, Alaydin, H, Batur Caglayan, H, Colakoglu, S, Demirci, N, Duman, T, Eren, F, Gokce, M, Inanc, Y, Nazliel, B, Ongun, G, Ozcekic Demirhan, S, Ozyurt, E, Selcuk, D, Sorgun, M, Tezcan, S, Togay Isikay, C, Tokgoz, O, Ulku Acar, R, Uluduz Ugurlu, D, Abdul-Saheb, M, Ahmad, N, Ali, A, Alwis, L, Balogun, I, Bathula, R, Behnam, Y, Bhandari, M, Bhargavah, M, Black, T, Blank, C, Bruce, D, Burn, M, Canepa, C, Chakrabarti, A, Chandrasena, D, Chembala, J, Cheripelli, B, Clarke, R, Cohen, D, Collas, D, Constantin, C, Dani, K, Del Giudice, A, Dennis, M, Devine, J, Dima, S, Doubal, F, Duodu, Y, Dutta, D, El Ta Wil, S, Elyas, S, Evans, N, Eveson, D, Fotherby, K, France, E, Furnace, J, Grabowski, S, Gunathilagan, G, Gutierrez, R, Guyler, P, Hargroves, D, Harkness, K, Harvey, M, Hayhoe, H, Hicken, L, Hussain, M, Kelly, S, Lam, M, Lindert, R, Louw, S, Luder, R, Macleod, M, Majid, A, Mangion, D, Markova, S, Markus, H, Marsh, R, Mcarthur, K, Menon, N, Metcalf, K, Minhas, J, Minns, M, Mistri, A, Moreton, F, Mpelembue, M, Muddegowda, G, Mudhar, O, Musarrat, K, Myint, M, Natarajan, I, Naylor, D, Ngeh, J, Papavasileiou, V, Perry, R, Piechowski-Jozwiak, B, Pradhan, M, Rani, A, Rashed, K, Robinson, T, Roffe, C, Saksena, R, Sattar, N, Sekaran, L, Selvarajah, J, Shah, S, Sinha, D, Sivakumar, R, Sztriha, L, Walters, D, Webb, T, Werring, D, Whiteley, W, Whiting, R, Abdelhamid, N, Abdul Rahman, D, Amin, H, Androulakis, M, Babikian, V, Baker, M, Barker Trejo, S, Benjamin, A, Birnbaum, L, Burke, J, Chen, S, Clark, W, Coull, B, De Havenon, A, Dearborn, J, Degeorgia, M, Essa, B, Fares, M, Favate, A, Furlan, A, Gebreyohanns, M, Goddeau, R, Green, D, Greer, D, Haralur Sreekantaiah, Y, Hasan, R, Hedna, V, Henninger, N, Holmstedt, C, Ishida, K, Jagolino, A, Johnson, M, Jun-Oconnell, A, Kaur, S, Khanna, A, Kirshner, H, Kittner, S, Kleindorfer, D, Leira, E, Loomis, C, Lord, A, Lowenkopf, T, Lutsep, H, Magadan, A, Majjhoo, A, Maud, A, Mayasi, Y, Mccullough, L, Mckinney, J, Mehta, S, Mehta, D, Mehta, B, Messe, S, Miller, B, Milling, T, Moonis, M, Navaratnam, D, Okpala, M, Patel, N, Pettigrew, L, Phinney, T, Ramos-Estebanez, C, Rasmussen, J, Rodriguez, G, Rybinnik, I, Santiago, P, Sarraj, A, Savitz, S, Sawyer, R, Scandura, T, Schindler, J, Sen, S, Shang, T, Sharrief, A, Sila, C, Simpkins, A, Sundararajan, S, Talahma, M, Tayal, A, Thaler, D, Tirschwell, D, Torres, J, Vora, N, Warnack, W, Waters, M, Wilson, C, Xiong, W, Zweifler, R, Zanferrari, C., St Marys Development Trust, Servicio de Neurologia (SANTIAGO - Neurologie), Universidad del Desarrollo, Department of Neurology (Dep Neuro - BEIJING), Tiantan Hospital, Neurology department, Universidade de Coimbra [Coimbra], Department of Internal Medicine, University Hospital Basel [Basel], Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Neurological Sciences, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Department of Neurology, Seoul National University Hospital, Institute of Neurosciences and Psychology [Glasgow], University of Glasgow, Neurology Department, Ichilov Medical Center, CIC Brest, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Cavale Blanche, Yperzeele, Laetitia, NAVIGATE ESUS Investigators, and Selçuk Üniversitesi

Subjects
Stroke/etiology, Male, [SDV]Life Sciences [q-bio], Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, Brain Ischemia, Brain ischemia, 0302 clinical medicine, DESIGN, Rivaroxaban, Hemorrhage/chemically induced, Secondary Prevention, Medicine, Factor Xa Inhibitors/adverse effects, Stroke, Rivaroxaban/adverse effects, ComputingMilieux_MISCELLANEOUS, 11 Medical and Health Sciences, Aspirin, Atrial fibrillation, General Medicine, FORAMEN OVALE CLOSURE, Middle Aged, TRIALS, Intracranial Embolism, SAFETY, Aged, Factor Xa Inhibitors, Female, Hemorrhage, Humans, Platelet Aggregation Inhibitors, Medicine (all), Cardiology, Foramen ovale closure, Platelet aggregation inhibitor, Settore MED/26 - Neurologia, Life Sciences & Biomedicine, medicine.drug, medicine.medical_specialty, Platelet Aggregation Inhibitors/adverse effects, ANTITHROMBOTIC THERAPY, Aspirin/adverse effects, WARFARIN, 03 medical and health sciences, Secondary Prevention/methods, Medicine, General & Internal, Internal medicine, Intracranial Embolism/drug therapy, General & Internal Medicine, NAVIGATE ESUS Investigators, METAANALYSIS, Science & Technology, CRYPTOGENIC STROKE, business.industry, Warfarin, medicine.disease, EFFICACY, ATRIAL-FIBRILLATION, Human medicine, business, Brain Ischemia/prevention & control, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

WOS: 000434263000007, PubMed: 29766772, BACKGROUND Embolic strokes of undetermined source represent 20% of ischemic strokes and are associated with a high rate of recurrence. Anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, may result in a lower risk of recurrent stroke than aspirin. METHODS We compared the efficacy and safety of rivaroxaban (at a daily dose of 15 mg) with aspirin (at a daily dose of 100 mg) for the prevention of recurrent stroke in patients with recent ischemic stroke that was presumed to be from cerebral embolism but without arterial stenosis, lacune, or an identified cardioembolic source. The primary efficacy outcome was the first recurrence of ischemic or hemorrhagic stroke or systemic embolism in a time-to-event analysis; the primary safety outcome was the rate of major bleeding. RESULTS A total of 7213 participants were enrolled at 459 sites; 3609 patients were randomly assigned to receive rivaroxaban and 3604 to receive aspirin. Patients had been followed for a median of 11 months when the trial was terminated early because of a lack of benefit with regard to stroke risk and because of bleeding associated with rivaroxaban. The primary efficacy outcome occurred in 172 patients in the rivaroxaban group (annualized rate, 5.1%) and in 160 in the aspirin group (annualized rate, 4.8%) (hazard ratio, 1.07; 95% confidence interval [CI], 0.87 to 1.33; P=0.52). Recurrent ischemic stroke occurred in 158 patients in the rivaroxaban group (annualized rate, 4.7%) and in 156 in the aspirin group (annualized rate, 4.7%). Major bleeding occurred in 62 patients in the rivaroxaban group (annualized rate, 1.8%) and in 23 in the aspirin group (annualized rate, 0.7%) (hazard ratio, 2.72; 95% CI, 1.68 to 4.39; P, BayerBayer AG; Janssen Research and Development, Supported by Bayer and Janssen Research and Development.

Published
2018

24. Predictors of the extended-spectrum-beta lactamases producing Enterobacteriaceae neonatal sepsis at a tertiary hospital, Tanzania

Author

Linda Falgenhauer, Mariam M. Mirambo, Martha F. Mushi, Stephen E. Mshana, Trinad Chakraborty, Neema Kayange, Jeremiah Seni, Can Imirzalioglu, Nyambura Moremi, Festo Manyama, and Rehema Marando

Subjects
0301 basic medicine, Microbiology (medical), Male, medicine.medical_specialty, Klebsiella pneumoniae, 030106 microbiology, ESBL-PE, Microbial Sensitivity Tests, Microbiology, Tanzania, beta-Lactamases, Article, law.invention, Sepsis, Tertiary Care Centers, 03 medical and health sciences, ST45, law, Internal medicine, Intensive Care Units, Neonatal, medicine, polycyclic compounds, Infection control, Humans, Blood culture, Colonization, 2. Zero hunger, biology, medicine.diagnostic_test, Neonatal sepsis, Predictors, Infant, Newborn, General Medicine, biochemical phenomena, metabolism, and nutrition, biology.organism_classification, medicine.disease, bacterial infections and mycoses, Intensive care unit, 3. Good health, Anti-Bacterial Agents, Klebsiella Infections, Infectious Diseases, Treatment Outcome, Blood Culture, bacteria, Female
Abstract

Highlights • ESBL-PE sepsis was predicted by admission at ICU and ESBL-PE colonization. • Neonates infected with ESBL-PE had significantly high mortality. • ESBL-producing Klebsiella pneumoniae (ST45) carrying blaCTX-M-15 were predominant. • Whole genome SNP analysis revealed clonal origin in 50% of ESBL-PE paired cases with similar sequence type., The study was conducted to establish predictors of extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) neonatal sepsis and mortality in a tertiary hospital, Tanzania. Between July and December 2016, blood culture was performed in neonates with clinical features of sepsis and neonates/mothers/guardians were screened for ESBL colonization. Selected isolates underwent whole genome sequencing to investigate relatedness. Logistic regression analysis was performed to determine predictors for ESBL-PE associated neonatal sepsis and mortality. Neonatal ESBL-PE sepsis was detected in 32(10.5%) of the 304 neonates investigated. Neonatal ESBL-PE sepsis was independently predicted by admission at the Intensive care Unit and positive mother and neonate ESBL-PE colonization. Deaths occurred in 55(18.1%) of neonates. Neonates infected with ESBL-PE, admitted at ICU, increased age and those transferred from other centres had significantly high mortality rates. Gram-negative bacteria formed the majority (76%) of the isolates, of which 77% were ESBL-PE. Virulent Klebsiella pneumoniae ST45 carrying blaCTX-M-15 were commonly isolated from neonates. Klebsiella pneumoniae (ST45) were the predominant cause of ESBL-PE neonatal sepsis and mortality. Improved infection control and antibiotic stewardship are crucial in controlling the spread of resistant strains. Rapid diagnostic tests to detect ESBL-PE in low-income countries are needed to guide treatment and reduce ESBL-PE-associated mortality.

Published
2018

25. Recurrent stroke in Neurosyphilis treated with intravenous fibrinolysis

Author

David Giannandrea, Stefano Ricci, Claudia Marando, Sara Mastrocola, and Silvia Cenciarelli

Subjects
medicine.medical_specialty, business.industry, medicine.medical_treatment, General Medicine, General Chemistry, 030204 cardiovascular system & hematology, medicine.disease, Neurosyphilis, 03 medical and health sciences, 0302 clinical medicine, Recurrent stroke, Internal medicine, Fibrinolysis, medicine, Cardiology, business, 030217 neurology & neurosurgery
Published
2018

26. Discrepancies between physician's perception of depression in HIV patients and self-reported CES-D-20 assessment: the DHIVA study

Author

F. Marando, Giuliana Gualberti, A. Antinori, Marco Franzetti, Adriana Ammassari, Anna Maria Costanzo, Massimo Galli, and U. di Luzio Paparatti

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, Health (social science), Social Psychology, Cross-sectional study, media_common.quotation_subject, Concordance, Human immunodeficiency virus (HIV), HIV Infections, medicine.disease_cause, Article, 03 medical and health sciences, Internal medicine, Perception, Medicine, Humans, Psychiatry, Depression (differential diagnoses), media_common, Depressive Disorder, Major, business.industry, Depression, Disease progression, psychological evaluation, Public Health, Environmental and Occupational Health, HIV, Original Articles, Middle Aged, 030112 virology, Psychological evaluation, Cross-Sectional Studies, Italy, Hiv patients, Female, Self Report, business, CES-D-20 scale
Abstract

Depression in HIV/AIDS patients affects adherence and disease progression and often goes unnoticed. DHIVA is a cross-sectional epidemiologic survey, investigating the prevalence of depression in people living with HIV through use of a validated self-administered scale (CES-D-20), as well and the degree of concordance between the physician's perception and patients' reports. A total of 690 HIV-infected patients attending 24 centers across Italy were enrolled. Concordance was calculated by K statistics. Association between depression and subject characteristics were evaluated through univariate and multivariate logistic models (OR and 95%CI). The prevalence of depressive symptoms was 48.8% from patient's questionnaires and 49.5% from physicians' reports, with a low/fair concordance (K = .38, p

Published
2015

27. Pneumomediastinum as a complication of critical pertussis

Author

Monaco M, F. Nunnari, Francesco Monaco, Antonio David, Antonio Cascio, Valeria G. Manfredi, Rosario Marando, and Mario Barone

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, Bordetella pertussis, Disease, 030204 cardiovascular system & hematology, law.invention, 03 medical and health sciences, 0302 clinical medicine, law, medicine, Immunology and Allergy, Pneumomediastinum, Intensive care medicine, Genetics (clinical), biology, business.industry, Apnea, medicine.disease, biology.organism_classification, Intensive care unit, respiratory tract diseases, 030228 respiratory system, medicine.symptom, Differential diagnosis, Complication, business, Subcutaneous emphysema
Abstract

Background and Aims Pertussis is a common and potentially serious disease affecting mainly infants and young children. In its non-classic presentation, pertussis can be clinically indistinguishable from other respiratory illnesses. Pertussis today often remains underdiagnosed in adults. Our aims was to report a complicated cases of pertussis. Results A case of serologically confirmed pertussis occurred in an 18-year-old man presenting with pneumomediastinum, subcutaneous emphysema in the neck and chest, and persistent attacks of coughing with apnea that required treatment in the intensive care unit. Conclusion Pneumomediastinum and subcutaneous emphysema have never been described in adult patients with pertussis. Physicians should be aware that patients presenting with persistent cough and pneumomediastinum may have pertussis and include this in their differential diagnosis.

Published
2015

28. Revisiting the Cornea and Trabecular Meshwork Junction With 2-Photon Excitation Fluorescence Microscopy

Author

Roy S. Chuck, Jason A. Liao, Catherine M. Marando, Choul Yong Park, and Jimmy K. Lee

Subjects
0301 basic medicine, Materials science, genetic structures, Eye Banks, Cornea, Tendons, 03 medical and health sciences, 0302 clinical medicine, Ciliary body, Imaging, Three-Dimensional, Microscopy, Electron, Transmission, Trabecular Meshwork, Microscopy, medicine, Fluorescence microscope, Humans, biology, Anatomy, Fluorescence, eye diseases, Tissue Donors, Elastin, Ophthalmology, 030104 developmental biology, medicine.anatomical_structure, Microscopy, Fluorescence, Multiphoton, 030221 ophthalmology & optometry, Biophysics, biology.protein, sense organs, Trabecular meshwork, Collagen, Excitation
Abstract

To investigate the collagen and elastin architecture at the junction of the human cornea and trabecular meshwork (TM).The cornea, TM, and ciliary body (CB) tendons of unfixed human corneal buttons were imaged with an inverted 2-photon excited fluorescence microscope (FluoView FV-1000; Olympus, Central Valley, PA). The laser (Ti:sapphire) was tuned to 850 nm for 2-photon excitation. Backscatter signals of second harmonic generation and autofluorescence were collected through a 425/30-nm emission filter and a 525/45-nm emission filter, respectively. The second harmonic generation signal corresponds to collagen fibers, and the autofluorescence signal corresponds to elastin-containing tissue. Tissue structure representations were obtained through software-generated reconstructions of consecutive and overlapping (z-stack) images through a relevant sample depth.Collagen-rich CB tendons insert into the cornea between Descemet membrane (DM) and posterior stroma along with elastin fibers originating from the TM. The CB tendons directly abut DM, and their insertion narrows as they course centrally in the cornea, giving a wedge appearance to these parallel collagen fibers. Approximately 260 μm centrally from the edge of DM, the CB tendons fan out and merge with pre-DM collagen. As the CB tendons enter the cornea, they form a dense collagenous comb-like structure orthogonal to the edge of DM and supported by a delicate elastin network of interwoven fibers originating from the TM.Two-photon excited fluorescence microscopy has improved our understanding of the peripheral corneal architecture. CB tendon insertions in this region may contribute to the radial tears encountered when preparing DM endothelial keratoplasty grafts.

Published
2017

29. OTX1 and OTX2 as Possible Molecular Markers of Sinonasal Carcinomas and Olfactory Neuroblastomas

Author

Andrea Pistochini, Anna Maria Chiaravalli, Francesco Lo Curto, Francesco Pasquali, Alessia Rainero, Andrea Conti, Cristina Pirrone, Paolo Castelnuovo, Carlo Capella, Alessandro Marando, and Giovanni Porta

Subjects
0301 basic medicine, Nasal cavity, Adult, Male, Pathology, medicine.medical_specialty, Histology, sinonasal neoplasms, Nose Neoplasms, Biophysics, Esthesioneuroblastoma, Olfactory, Biology, Homeobox genes, Immunohistochemistry, Real-time PCR, Sinonasal neoplasms, Tumour marker, Cell Biology, Real-Time Polymerase Chain Reaction, Nose neoplasm, 03 medical and health sciences, 0302 clinical medicine, Embryonic morphogenesis, medicine, tumour marker, Biomarkers, Tumor, Humans, Gene, lcsh:QH301-705.5, Otx Transcription Factors, Olfactory Neuroblastoma, Brief Report, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, 030104 developmental biology, medicine.anatomical_structure, lcsh:Biology (General), 030220 oncology & carcinogenesis, immunohistochemistry, Cancer research, Homeobox, Female, Nasal Cavity, Olfactory epithelium
Abstract

OTX Homeobox genes are involved in embryonic morphogenesis and in the development of olfactory epithelium in adult. Mutations occurring in the OTX genes are reported to be associated to tumorigenisis in human. No reports correlate the expression of OTX genes and neoplasms of the nasal cavity. Thus, through immunohistochemical and Real-time PCR analysis we investigated OTX1 and OTX2 expression in the more frequent types of nasal and sinonasal tumours. Variable expression of both genes were found in normal sinonasal mucosa and in tumours. Interestingly, no expression of both OTX genes were detected in sinonasal intestinal-type adenocarcinomas; only OTX1 was found in non-intestinal-type adenocarcinomas and OTX2 was selectively expressed in olfactory neuroblastomas. In conclusion, OTX1 and OTX2 genes might have a role in the pathogenesis of different types of sinonasal neoplasms.

Published
2017

30. Expression of calretinin in high-grade hormone receptor-negative invasive breast carcinomas: correlation with histological and molecular subtypes

Author

Alberto Bossi, Fausto Sessa, Carlo Capella, Donata Micello, Alessandro Marando, and Emanuele Dainese

Subjects
0301 basic medicine, Adult, Calretinin, High-grade invasive breast carcinomas, Molecular subtypes of invasive breast cancer, 2734, Molecular Biology, Cell Biology, Pathology, medicine.medical_specialty, Proliferative index, Receptor, ErbB-2, Breast Neoplasms, Kaplan-Meier Estimate, Biology, Disease-Free Survival, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, medicine, Carcinoma, Biomarkers, Tumor, Humans, skin and connective tissue diseases, Lymph node, Aged, Carcinoma, Ductal, Breast, Apocrine, General Medicine, Middle Aged, medicine.disease, Phenotype, Immunohistochemistry, 030104 developmental biology, medicine.anatomical_structure, Receptors, Estrogen, nervous system, Hormone receptor, 030220 oncology & carcinogenesis, Calbindin 2, Female, Receptors, Progesterone
Abstract

Calretinin expression has been reported in neoplasms arising in various organs, including the breast. We investigated the relationship of calretinin expression with different histological and molecular subtypes of invasive breast carcinomas (IBCs) and its prognostic significance in high-grade female hormone receptor-negative IBCs. A total of 196 cases of IBCs of different histological subtypes were analyzed for immunohistochemical expression of calretinin, human epidermal growth factor receptor 2 (HER2), basal-like (BL), apocrine, and proliferative markers and grouped in different molecular subtypes. We found significant morphological differences in the group of formally classified invasive ductal carcinoma of no special type (IDC-NST), which we further subdivided into two types (type I IDC-NST and type II IDC-NST) according to their morphology. Calretinin expression was found in 55.1% of the IBCs and was strongly associated with carcinoma with medullary features (P = 0.014) and type II IDC-NST (P < 0.001), while type I IDC-NST correlated (P < 0.001) with a lack of calretinin expression. Among the molecular subtypes of IBC, calretinin expression was identified in a significant portion of BL breast cancers (BLBCs), while expression was poor in HER2-overexpressing and molecular-apocrine (MA) HER2-negative subtypes and even less in MA/HER2+ ones. Calretinin expression was significantly associated with high (>=50) Ki-67 (P = 0.02), but not with parameters like age, tumor size, lymph node status, overall survival (OS), and disease-free survival. Calretinin expression is most common in high-grade IBCs with histological medullary features, type II IDC-NST and BL phenotype, and is associated with high neoplastic proliferative index.

Published
2017

31. Viewpoint: 'Alcohol Consumption in Late Adolescence is Associated With an Increased Risk of Severe Liver Disease Later in Life'

Author

Adriana Tamburello, Stefano Bellentani, and Marco Marando

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, Adolescent, Alcohol Drinking, Epidemiology, Specialties of internal medicine, 03 medical and health sciences, Liver disease, 0302 clinical medicine, Environmental health, medicine, Humans, Liver damage, Prospective Studies, Prospective cohort study, Hepatology, business.industry, Alcohol Intake, Liver Diseases, General Medicine, Late adolescence, medicine.disease, Adolescence, 030104 developmental biology, Increased risk, RC581-951, ALD (alcoholic Liver Disease), 030211 gastroenterology & hepatology, Alcohol intake, business, Alcohol consumption
Abstract

Drinking alcohol during adolescence predispose to severe liver disease in the adult phase. This is the main message of this prospective study. Each daily gram of alcohol men consumed in their youth was linked with a two percent increase in the risk of severe liver disease. No threshold level emerged for liver damage and this is a warning for all the sociologists and politics. New legiferation and educational campaigns addressed to young people, with particular attention to the access to alcohol, prices and advertising are necessary.

Published
2018

32. Mutational Synergy Coordinately Remodels Chromatin Accessibility, Enhancer Landscape and 3-Dimensional DNA Topology to Alter Gene Expression during Leukemia Induction

Author

Daniel Sasca, Malgorzata Gozdecka, George S. Vassiliou, Shabana Vohra, Paolo Gallipoli, Faisal Basheer, Brian J. P. Huntly, Cameron S. Osborne, Sarah J. Horton, Ludovica Marando, Haiyang Yun, Shuchi Agrawal-Singh, George Giotopoulos, Xiaonan Wang, Eshwar Meduri, Oliver M. Dovey, and Annalisa Mupo

Subjects
0301 basic medicine, Immunology, Wild type, Promoter, Cell Biology, Hematology, Biology, Topology, Biochemistry, Chromatin, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, CTCF, Epigenetics, Enhancer, Transcription factor, Gene, 030215 immunology
Abstract

Aberrant transcriptional programs are cardinal features of Acute Myeloid Leukemia (AML). Recently, it has been shown that specific distal cis-regulatory elements called enhancers communicate with promoters through 3-D DNA looping to regulate tissue-specific gene expression. Recurrent mutations in epigenetic regulators that modify enhancers, transcription factors that bind enhancers and the structural proteins that promote DNA looping, such as the Cohesin complex and its major binding partner CTCF have been demonstrated in AML. However, how these mutations regulate chromatin and alter 3D-DNA topology and communication between enhancers and promoters to generate leukemia-specific transcriptional programs remains poorly understood. In addition, many AML cases lack mutations in epigenetic regulators, transcription factors or DNA structural proteins, yet still demonstrate aberrant transcription, suggesting indirect effects of other mutations on enhancer function and the epigenetic landscape. To address these questions, we have utilized an allelic series of mice carrying the most common mutations in AML, namely Flt3-ITD and Npm1c (co-mutated in ~15% of all AMLs). These model different "transition states" (normal: wild type (WT), Pre-Malignant: single mutant (SM) with either Flt3-ITD or Npm1c mutations and Malignant: double mutant (DM)) during AML induction. Moreover, our design allows analysis of the SM mice to deconvolute the contribution of individual mutations to altered chromatin regulation. We have analyzed hematopoietic stem and progenitor cells (HSPCs) from WT and mutant mice for gene expression (RNA-seq), chromatin activation states (ChIP-seq for H3K4me1, H3K4me3, H3K27ac and H3K27me3), chromatin accessibility (ATAC-seq), and promoter-anchored 3-D chromatin interaction (promoter capture HiC, pCHiC)(Figure 1) and have integrated these analyses to determine the transcriptional, epigenetic and DNA-topological evolution of AML. Through pairwise comparisons between mutant and WT HSPCs, our data demonstrated that SM cells, with either Flt3-ITDor Npm1c mutations, alter gene expression only very modestly. However, when both mutations are present in DM cells, much larger gene programs that drive leukemia are both up- and downregulated. To examine the epigenetic regulation of these programs, we next built an enhancer compendium across all 4 allelic states using the H3K4me1 mark. Layering on H3K27ac activation, our data demonstrated that, in contrast to gene expression, significant alterations in enhancer specification and activation occur in advance of gene expression changes, to "prime" critical genes in Flt3-ITD, but not in Npm1c HSPCs. By contrast, Flt3-ITD and Npm1c mutations both altered global chromatin accessibility, with losses and gains evident at multiple critical genes. Similarly, our pCHiC data demonstrated significant alterations in DNA topology in mutant HSPCs that culminate in alterations in DNA "compartments" in DM HSPC. Moreover, they identified "hardwired" and "rewired" interactions between promoters and enhancers important for expression of critical leukemia programs. Analyses of all of these separate layers demonstrated a uniform pattern; progressive alterations in the transition from SM to DM HSPCs. Integrating these layers of analysis clearly demonstrated synergy between the mutations and a correlation between gene expression changes and chromatin dynamics in mutant cells. Furthermore, performing de novo motif analysis suggested a signal-specific transcription factor (TF) network downstream of Flt3-ITD that was amplified in the DM HSPC and that was corroborated by GSEA analysis. Our data had identified long-range regulatory control regions at the Spi1/PU.1 and Hoxa cluster loci amongst many others, and motif analysis had suggested Hox and Pu.1 to be important TFs in our malignant networks. Using these as examplars, we then perturbed the genes and regulatory elements at these loci by shRNA knockdown and CRISPR-mediated excision and could abrogate leukemic growth, validating the importance of our proposed networks. Taken together, these integrated analyses demonstrate a highly dynamic and coordinated process, where the effects of individual mutations synergize to remodel the chromatin landscape and 3D-DNA topology to generate networks that initiate and maintain AML transcriptional programs. Figure Disclosures Vassiliou: Kymab Ltd: Consultancy, Other: Minor Stockholder; Oxstem Ltd: Consultancy; Celgene: Research Funding.

Published
2019

33. Details of the Collagen and Elastin Architecture in the Human Limbal Conjunctiva, Tenon's Capsule and Sclera Revealed by Two-Photon Excited Fluorescence Microscopy

Author

Choul Yong Park, Ji-won Kwon, Jason A. Liao, Jimmy K. Lee, Roy S. Chuck, and Catherine M. Marando

Subjects
Adult, Male, Materials science, Conjunctiva, Tenon Capsule, 01 natural sciences, 010309 optics, 03 medical and health sciences, 0302 clinical medicine, Imaging, Three-Dimensional, Two-photon excitation microscopy, Tenon's capsule, 0103 physical sciences, Microscopy, medicine, Fluorescence microscope, Cadaver, Humans, Aged, biology, Reproducibility of Results, Anatomy, Middle Aged, eye diseases, Sclera, Elastin, Autofluorescence, medicine.anatomical_structure, Microscopy, Fluorescence, Multiphoton, 030221 ophthalmology & optometry, biology.protein, Female, sense organs, Collagen, Biomedical engineering
Abstract

Purpose To investigate the architecture and distribution of collagen and elastin in human limbal conjunctiva, Tenon's capsule, and sclera. Methods The limbal conjunctiva, Tenon's capsule, and sclera of human donor corneal buttons were imaged with an inverted two-photon excited fluorescence microscope. No fixation process was necessary. The laser (Ti:sapphire) was tuned at 850 nm for two-photon excitation. Backscatter signals of second harmonic generation (SHG) and autofluorescence (AF) were collected through a 425/30-nm and a 525/45-nm emission filter, respectively. Multiple, consecutive, and overlapping (z-stack) images were acquired. Collagen signals were collected with SHG, whereas elastin signals were collected with AF. Results The size and density of collagen bundles varied widely depending on depth: increasing from conjunctiva to sclera. In superficial image planes, collagen bundles were

Published
2016

34. Respiratory Syncytial Virus-associated hospitalization in premature infants who did not receive palivizumab prophylaxis in Italy: a retrospective analysis from the Osservatorio Study

Author

Umberto di Luzio Paparatti, Michela Silvestri, Giovanni A. Rossi, Francesca Marando, and Anna Maria Costanzo

Subjects
Palivizumab, Male, Pediatrics, medicine.medical_specialty, Respiratory Syncytial Virus Infections, Antiviral Agents, Virus, 03 medical and health sciences, 0302 clinical medicine, 030225 pediatrics, medicine, Late preterm, Retrospective analysis, Humans, 030212 general & internal medicine, Respiratory system, business.industry, Epidemiological Factors, Research, Infant, Newborn, Gestational age, medicine.disease, Acute lower respiratory tract infection, Hospitalization, Italy, Bronchiolitis, Female, business, Infant, Premature, medicine.drug
Abstract

Background Due to different social and epidemiological factors, the eligibility criteria to receive palivizumab prophylaxis may be different between countries, especially in “otherwise healthy” late preterm infants. Methods We analyzed an Italian database of young children referred to emergency departments for acute lower respiratory tract infection (ALRI) during the RSV season over a four year period, when the use of palivizumab as prophylaxis for RSV disease was not widespread in premature infants. The demographic and environmental characteristics and the RSV positivity (RSV+) in hospitalized and not-hospitalized patients were compared. In the data analysis we divided children according to their chronologic age (age) and their week gestational age (wGA). Results Out of the 100 children evaluated, 68 were infants (≤12 month-age): 7.5 and 20.6 % were in the 12 month-age group (N = 32), there was positive hospitalized-to-not-hospitalized ratio only in the 6–12 month-age. A positive hospitalized-to-not-hospitalized ratios was found in all wGA groups in ≤6 month-age infants, despite a low RSV+ frequency in the 29- 6-12 month-age group, all infants with a

Published
2016

35. Glaucoma Patient Treatment Preferences

Author

Catherine M. Marando, Jeffrey R. SooHoo, Leonard K. Seibold, Liliya Golas, Pradeep Y. Ramulu, Malik Y. Kahook, and Mina B. Pantcheva

Subjects
Male, Intraocular pressure, medicine.medical_specialty, Administration, Topical, Treatment outcome, MEDLINE, Glaucoma, 03 medical and health sciences, 0302 clinical medicine, Filtering surgery, medicine, Humans, Patient treatment, Antihypertensive Agents, Intraocular Pressure, Aged, business.industry, Patient Preference, medicine.disease, Patient preference, Surgery, Ophthalmology, Ophthalmic solutions, Treatment Outcome, Filtering Surgery, 030221 ophthalmology & optometry, Female, Ophthalmic Solutions, business, 030217 neurology & neurosurgery
Published
2015

36. Preclinical characterization of INCB053914, a novel pan-PIM kinase inhibitor, alone and in combination with anticancer agents, in models of hematologic malignancies

Author

Que T. Lambert, Kevin Bowman, Jason Boer, Gary W. Reuther, Valerie Roman, Peggy Scherle, Reid Huber, Krista Burke, Leslie Hall, Chu-Biao Xue, Kris Vaddi, Niu Shin, Yun-Long Li, Sharon Diamond, Alex Margulis, Qian Wang, Maryanne Covington, Greg Hollis, Swamy Yeleswaram, Holly Koblish, Hao Feng, Wenqing Yao, Cindy A. Marando, Richard Wynn, Ke Zhang, and Kathy Wang

Subjects
Kinase Inhibitors, Cancer Treatment, lcsh:Medicine, Apoptosis, Biochemistry, Hematologic Cancers and Related Disorders, Mice, 0302 clinical medicine, Cell Signaling, hemic and lymphatic diseases, Medicine and Health Sciences, Protein phosphorylation, Enzyme Inhibitors, Post-Translational Modification, Phosphorylation, lcsh:Science, Multidisciplinary, Chemistry, Kinase, Cytarabine, Myeloid leukemia, Hematology, Isozymes, Enzymes, Leukemia, Myeloid, Acute, Leukemia, Oncology, Proto-Oncogene Proteins c-bcl-2, Hematologic Neoplasms, 030220 oncology & carcinogenesis, Network Analysis, Research Article, Signal Transduction, Computer and Information Sciences, Signal Inhibition, PIM1, Antineoplastic Agents, 03 medical and health sciences, Proto-Oncogene Proteins c-pim-1, Cell Line, Tumor, medicine, Animals, Humans, Protein Kinase Inhibitors, Protein kinase B, PI3K/AKT/mTOR pathway, Cell Proliferation, Dose-Response Relationship, Drug, lcsh:R, Biology and Life Sciences, Proteins, Cancers and Neoplasms, Cell Biology, medicine.disease, Signaling Networks, Enzymology, Cancer research, lcsh:Q, 030215 immunology
Abstract

The Proviral Integration site of Moloney murine leukemia virus (PIM) serine/threonine protein kinases are overexpressed in many hematologic and solid tumor malignancies and play central roles in intracellular signaling networks important in tumorigenesis, including the Janus kinase-signal transducer and activator of transcription (JAK/STAT) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways. The three PIM kinase isozymes (PIM1, PIM2, and PIM3) share similar downstream substrates with other key oncogenic kinases and have differing but mutually compensatory functions across tumors. This supports the therapeutic potential of pan-PIM kinase inhibitors, especially in combination with other anticancer agents chosen based on their role in overlapping signaling networks. Reported here is a preclinical characterization of INCB053914, a novel, potent, and selective adenosine triphosphate-competitive pan-PIM kinase inhibitor. In vitro, INCB053914 inhibited proliferation and the phosphorylation of downstream substrates in cell lines from multiple hematologic malignancies. Effects were confirmed in primary bone marrow blasts from patients with acute myeloid leukemia treated ex vivo and in blood samples from patients receiving INCB053914 in an ongoing phase 1 dose-escalation study. In vivo, single-agent INCB053914 inhibited Bcl-2-associated death promoter protein phosphorylation and dose-dependently inhibited tumor growth in acute myeloid leukemia and multiple myeloma xenografts. Additive or synergistic inhibition of tumor growth was observed when INCB053914 was combined with selective PI3Kδ inhibition, selective JAK1 or JAK1/2 inhibition, or cytarabine. Based on these data, pan-PIM kinase inhibitors, including INCB053914, may have therapeutic utility in hematologic malignancies when combined with other inhibitors of oncogenic kinases or standard chemotherapeutics.

Published
2018

37. Abstract 5071: Preclinical characterization of the potent and selective BET inhibitor INCB057643 in models of hematologic malignancies

Author

Sharon Diamond-Fosbenner, Patricia Feldman, Mark Rupar, Swamy Yeleswaram, Wenqing Yao, Xiaoming Wen, Matthew C. Stubbs, Alla Volgina, Phillip Liu, Peggy Scherle, Reid Huber, Timothy Burn, Xuesong Mike Liu, Andrew P. Combs, Cindy A. Marando, Richard Wynn, Nina Zolotarjova, Bruce Ruggeri, Thomas Maduskuie, Maryanne Covington, Gregory Hollis, Nikoo Falahatpisheh, and Robert Collins

Subjects
0301 basic medicine, Bendamustine, Cancer Research, BRD4, business.industry, Cancer, Cell cycle, Pharmacology, medicine.disease, Bromodomain, BET inhibitor, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, medicine, business, Multiple myeloma, B cell, medicine.drug
Abstract

Inhibitors of the Bromodomain and Extra-Terminal (BET) family of bromodomain containing proteins regulate expression of key cell fate, cell cycle, and survival genes including c-myc. In preclinical models, BET inhibitors have demonstrated significant efficacy in a variety of different oncology indications, including hematological malignancies. Here we describe the preclinical profile of the novel, orally bioavailable BET inhibitor INCB057643 in preclinical models of hematologic malignancies. INCB057643 inhibited binding of BRD2/BRD3/BRD4 to an acetylated histone H4 peptide in the low nM range, and was selective against other bromodomain containing proteins. In vitro analyses showed that INCB057643 inhibited proliferation of human AML, DLBCL, and multiple myeloma cell lines, with a corresponding decrease in MYC protein levels. Cell cycle analyses indicated that G1 arrest and a concentration-dependent increase in apoptosis were seen within 48 hours of treatment with INCB057643. BRD proteins also regulate the expression of many pro-inflammatory genes. Production of several cytokines, including IL-6, IL-10 and MIP-1α, was repressed by INCB057643 in human and mouse whole blood stimulated ex vivo with LPS. Consistent with these effects, analyses of gene expression in cells treated with INCB057643 revealed that pathways involved in cell cycle progression, apoptosis, and IL-6 were among the most significantly altered in vitro. Oral administration of INCB057643 resulted in significant anti-tumor efficacy in xenograft models of AML, myeloma, and DLBCL. Additionally, combining INCB057643 with standard of care agents used for the treatment of DLBCL including rituximab and bendamustine resulted in enhanced anti-tumor efficacy relative to that achieved with single agent therapies at doses that were well tolerated. In addition, many B cell malignancies are reliant on the PI3Kδ pathway for proliferation and survival, suggesting that the combination of INCB057643 with the clinical stage PI3Kδ specific inhibitor INCB050465 may be a rational therapeutic strategy for DLBCL. Compared with single agent BETi or PI3Kδi therapy, the combination significantly potentiated tumor growth inhibition in DLBCL models representative of the ABC subtype (HBL-1), and the double hit GCB subtype (WILL2). These data suggest that clinical exploration of INCB057643 as a monotherapy or in combination in hematologic malignancies is warranted. Citation Format: Matthew C. Stubbs, Thomas Maduskuie, Timothy Burn, Sharon Diamond-Fosbenner, Nikoo Falahatpisheh, Alla Volgina, Nina Zolotarjova, Xiaoming Wen, Patricia Feldman, Mark Rupar, Robert Collins, Cindy Marando, Bruce Ruggeri, Maryanne Covington, Xuesong Mike Liu, Richard Wynn, Swamy Yeleswaram, Wenqing Yao, Reid Huber, Gregory Hollis, Peggy Scherle, Andrew P. Combs, Phillip C. Liu. Preclinical characterization of the potent and selective BET inhibitor INCB057643 in models of hematologic malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5071. doi:10.1158/1538-7445.AM2017-5071

Published
2017

38. ESICM LIVES 2016: part two : Milan, Italy. 1-5 October 2016

Author

Sivakumar, S, Taccone, FS, Desai, KA, Lazaridis, C, Skarzynski, M, Sekhon, M, Henderson, W, Griesdale, D, Chapple, L, Deane, A, Williams, L, Ilia, S, Henderson, A, Hugill, K, Howard, P, Roy, A, Bonner, S, Monteiro, E, Baudouin, S, Ramírez, CS, Escalada, SH, Banaszewski, M, Sertedaki, A, Kaymak, Ç, Viera, MA, Santana, MC, Balcázar, LC, Monroy, NS, Campelo, FA, Vázquez, CF, Santana, PS, Cerejo, A, Santana, SR, Charmadari, E, Carteron, L, Kovach, L, Patet, C, Quintard, H, Solari, D, Bouzat, P, Oddo, M, Wollersheim, T, Malleike, J, Haas, K, Stratakis, CA, Rocha, AP, Carbon, N, Şencan, I, Schneider, J, Birchmeier, C, Fielitz, J, Spuler, S, Weber-Carstens, S, Enseñat, L, Pérez-Madrigal, A, Briassouli, E, Saludes, P, Proença, L, Elsayed, AA, Meço, B, Gruartmoner, G, Espinal, C, Mesquida, J, Huber, W, Eckmann, M, Elkmann, F, Goukos, D, Gruber, A, Lahmer, T, Mayr, U, Herner, A, Özçelik, M, Abougabal, AM, Schellnegger, R, Schmid, RM, Ayoub, W, Psarra, K, Samy, W, Esmat, A, Battah, A, Mukhtar, S, Mongkolpun, W, Ünal, N, Cortés, DO, Beshey, BN, Cordeiro, CP, Vincent, JL, Leite, MA, Creteur, J, Funcke, S, Groesdonk, H, Saugel, B, Wagenpfeil, G, Wagenpfeil, S, Reuter, DA, Fernandez, MM, Alzahaby, KM, Botoula, E, Fernandez, R, Magret, M, González-Castro, A, Bouza, MT, Ibañez, M, García, C, Balerdi, B, Jenni-Moser, B, Mas, A, Arauzo, V, Tsagarakis, S, Añón, JM, Pozzebon, S, Ruiz, F, Ferreres, J, Tomás, R, Alabert, M, Tizón, AI, Altaba, S, Jeitziner, MM, Llamas, N, Haroon, BA, Edul, VS, Goligher, EC, Fan, E, Herridge, M, Ortiz, AB, Vorona, S, Sklar, M, Dres, M, Rittayamai, N, Lanys, A, Schreiber, J, Mageira, E, Urrea, C, Tomlinson, G, Reid, WD, Rubenfeld, GD, Kavanagh, BP, Cristallini, S, Brochard, LJ, Ferguson, ND, Neto, AS, De Abreu, MG, Routsi, C, Imiela, J, Galassi, MS, Pelosi, P, Schultz, MJ, PRoVENT investigators and the PROVE Network, Guérin, C, Papazian, L, Reignier, J, Lheureux, O, Ayzac, L, Nanas, S, Loundou, A, Forel, JM, Sales, FL, Rolland-Debord, C, Bureau, C, Poitou, T, Clavel, M, Perbet, S, Terzi, N, Kouatchet, A, Briassoulis, G, Brasseur, A, Similowski, T, Demoule, A, De Moraes, KC, Hunfeld, N, Trogrlic, Z, Ladage, S, Osse, RJ, Koch, B, Rietdijk, W, Boscolo, A, Devlin, J, Van der Jagt, M, Picetti, E, Batista, CL, Ceccarelli, P, Mensi, F, Malchiodi, L, Risolo, S, Rossi, I, Bertini, D, Antonini, MV, Servadei, F, Caspani, ML, Roquilly, A, Júnior, JA, Lasocki, S, Seguin, P, Geeraerts, T, Perrigault, PF, Campello, E, Dahyot-Fizelier, C, Paugam-Burtz, C, Cook, F, Cinotti, R, Dit Latte, DD, Mahe, PJ, Marcari, TB, Fortuit, C, Feuillet, F, Lucchetta, V, Asehnoune, K, Marzorati, C, Spina, S, Scaravilli, V, Vargiolu, A, Riva, M, Giussani, C, Lobato, R, Sganzerla, E, Hravnak, M, Osaku, EF, Citerio, G, Barbadillo, S, De Molina, FJ, Álvarez-Lerma, F, Rodríguez, A, SEMICYUC/GETGAG Working Group, Zakharkina, T, Martin-Loeches, I, Castro, CS, Matamoros, S, Fuhrmann, V, Piasentini, E, Povoa, P, Yousef, K, Torres, A, Kastelijn, J, Hofstra, JJ, De Jong, M, Schultz, M, Sterk, P, Artigas, A, De Souza, LM, Aktepe, O, Bos, LJ, Moreau, AS, Chang, Y, Salluh, J, Rodriguez, A, Nseir, S, TAVeM study group, De Jong, E, Fildisis, G, Rodrigues, FF, Van Oers, JA, Beishuizen, A, Girbes, AR, Nijsten, MW, Crago, E, De Lange, DW, Bonvicini, D, Labate, D, Benacchio, L, Radu, CM, Olivieri, A, Stepinska, J, Wruck, ML, Pizzirani, E, Lopez-Delgado, JC, Gonzalez-Romero, M, Fuentes-Mila, V, Berbel-Franco, D, Friedlander, RM, Romera-Peregrina, I, Manesso, L, Martinez-Pascual, A, Perez-Sanchez, J, Abellan-Lencina, R, Correa, NG, Ávila-Espinoza, RE, Moreno-Gonzalez, G, Sbraga, F, Griffiths, S, Grocott, MP, Creagh-Brown, B, Simioni, P, Abdelmonem, SA, POPC-CB investigators, Doyle, J, Wilkerson, P, Pelegrini, AM, Soon, Y, Huddart, S, Dickinson, M, Riga, A, Zuleika, A, Ori, C, Miyamoto, K, Kawazoe, Y, Tahon, SA, Morimoto, T, Yamamoto, T, Eid, RA, Fuke, A, Hashimoto, A, Koami, H, Beppu, S, Su, H, Katayama, Y, Ito, M, Ohta, Y, Yamamura, H, Helmy, TA, DESIRE (DExmedetomidine for Sepsis in ICU Randomized Evaluation) Trial Investigators, Timenetsky, KT, Rygård, SL, Holst, LB, Wetterslev, J, Lam, YM, Johansson, PI, Perner, A, Soliman, IW, Van Dijk, D, Van Delden, JJ, Meligy, HS, Cazati, D, Cremer, OL, Slooter, AJ, Willis, K, Peelen, LM, McWilliams, D, Snelson, C, Neves, AD, Loudet, CI, Busico, M, Vazquez, D, Villalba, D, Lobato, M, Puig, F, Kott, M, Pullar, V, Veronesi, M, Lischinsky, A, López, FJ, Mori, LB, Plotnikow, G, Díaz, A, Giannasi, S, Hernandez, R, Krzisnik, L, Diniz, PS, Hubner, RP, Cecotti, C, Dunn-Siegrist, I, Viola, L, Lopez, R, Sottile, JP, Benavent, G, Estenssoro, E, Chen, CM, Lai, CC, Cheng, KC, Costa, CR, Rocha, LL, Chou, W, Chan, KS, Pugin, J, Roeker, LE, Horkan, CM, Gibbons, FK, Christopher, KB, Weijs, PJ, Mogensen, KM, Furche, M, Rawn, JD, Cavalheiro, AM, Robinson, MK, Tang, Z, Gupta, S, Qiu, C, Ouyang, B, Cai, C, Guan, X, Tsang, JL, Regueira, T, Cea, L, Topeli, A, Lucinio, NM, Carlos, SJ, Elisa, B, Puebla, C, Vargas, A, Govil, D, Poulsen, MK, De Guadiana-Romualdo, LG, Thomsen, LP, Kjærgaard, S, Rees, SE, Karbing, DS, Schwedhelm, E, Frank, S, Müller, MC, Carbon, NM, Skrypnikov, V, Rebollo-Acebes, S, Srinivasan, S, Pickerodt, PA, Falk, R, Mahlau, A, Santos, ER, Lee, A, Inglis, R, Morgan, R, Barker, G, Esteban-Torrella, P, Kamata, K, Abe, T, Patel, SJ, Saitoh, D, Tokuda, Y, Green, RS, Norrenberg, M, Butler, MB, Erdogan, M, Hwa, HT, Jiménez-Sánchez, R, Gil, LJ, Vaquero, RH, Rodriguez-Ruiz, E, Lago, AL, N, JK, Allut, JL, Gestal, AE, Gleize, A, Gonzalez, MA, Thomas-Rüddel, DO, Jiménez-Santos, E, Schwarzkopf, D, Fleischmann, C, Reinhart, K, Suwanpasu, S, Sattayasomboon, Y, Filho, NM, Gupta, A, Oliveira, JC, Preiser, JC, Ballalai, CS, Zitta, K, Ortín-Freire, A, De Lucia, CV, Araponga, GP, Veiga, LN, Silva, CS, Garrido, ME, Ramos, BB, Ricaldi, EF, Gomes, SS, Tomar, DS, Simón, IF, Hernando-Holgado, A, GEMINI, Gemmell, L, MacKay, A, Wright, C, Docking, RI, Doherty, P, Black, E, Stenhouse, P, Plummer, MP, Finnis, ME, Albaladejo-Otón, MD, Carmona, SA, Shafi, M, Phillips, LK, Kar, P, Bihari, S, Biradar, V, Moodie, S, Horowitz, M, Shaw, JE, Deane, AM, Coelho, L, Yatabe, T, Valhonrat, IL, Inoue, S, Harne, R, Sakaguchi, M, Egi, M, Abdelhamid, YA, Motta, MF, Domínguez, JP, Arora, DP, Hokka, M, Pattinson, KT, Mizobuchi, S, Pérez, AG, Abellán, AN, Plummer, M, Giersch, E, Talwar, N, Summers, M, Pelenz, M, Hatzinikolas, S, Heller, S, Chapman, M, Jones, K, Almudévar, PM, Schweizer, R, Jacquet-Lagreze, M, Portran, P, Rabello, L, Mazumdar, S, Junot, S, Allaouchiche, B, Fellahi, JL, Guerci, P, Ergin, B, Lange, K, Kapucu, A, Ince, C, Cioccari, L, Luethi, N, Crisman, M, Papakrivou, EE, Bellomo, R, Mårtensson, J, Shinotsuka, CR, Fagnoul, D, Kluge, S, Orbegozo, D, Makris, D, Thooft, A, Brimioulle, S, Dávila, F, Iwasaka, H, Brandt, B, Tahara, S, Nagamine, M, Ichigatani, A, Cabrera, AR, Zepeda, EM, Granillo, JF, Manoulakas, E, Sánchez, JS, Montoya, AA, Rubio, JJ, Montenegro, AP, Blanco, GA, Robles, CM, Drolz, A, Horvatits, T, Roedl, K, Rutter, K, Tsolaki, B, Funk, GC, Póvoa, P, Ramos, AJ, Schneeweiss, B, Sabetian, G, Pooresmaeel, F, Zand, F, Ghaffaripour, S, Farbod, A, Tabei, H, Taheri, L, TAVeM study Group, Karadodas, B, Reina, Á, Anandanadesan, R, Metaxa, V, Teixeira, C, Pereira, SM, Hernández-Marrero, P, Carvalho, AS, Beckmann, M, Hartog, CS, Varis, E, Raadts, A, López, NP, Zakynthinos, E, Robertsen, A, Førde, R, Skaga, NO, Helseth, E, Honeybul, S, Ho, K, Vazquez, AR, Lopez, PM, Gonzalez, MN, Ortega, PN, Pérez, MA, Sola, EC, Garcia, IP, Spasova, T, De la Torre-Prados, MV, Kopecky, O, Rusinova, K, Pettilä, V, Waldauf, P, Cepeplikova, Z, Balik, M, Ordoñez, PF, Apolo, DX, Almudevar, PM, Martin, AD, Muñoz, JJ, Poukkanen, M, Castañeda, DP, Villamizar, PR, Ramos, JV, Pérez, LP, Lucendo, AP, Villén, LM, Ejarque, MC, Estella, A, Camps, VL, Neitzke, NM, Encinares, VS, Martín, MC, Masnou, N, Bioethics work group of SEMICYUC, Barbosa, S, Varela, A, Palma, I, López, FM, Cristina, L, Nunes, E, Jacob, S, Pereira, I, Campello, G, Ibañez, MP, Granja, C, Pande, R, Pandey, M, Varghese, S, Chanu, M, García, IP, Van Dam, MJ, Schildhauer, C, Karlsson, S, Ter Braak, EW, Gracia, M, Viciana, R, Montero, JG, Recuerda, M, Fontaiña, LP, Tharmalingam, B, Kovari, F, Zöllner, C, Rose, L, Mcginlay, M, Amin, R, Burns, K, Connolly, B, Hart, N, Labrador, G, Jouvet, P, Katz, S, Leasa, D, Takala, J, Izurieta, JR, Mawdsley, C, Mcauley, D, Blackwood, B, Denham, S, Worrall, R, Arshad, M, Cangueiro, TC, Isherwood, P, Wilkman, E, Khadjibaev, A, Guerrero, JJ, Sabirov, D, Rosstalnaya, A, Parpibaev, F, Sharipova, V, Guzman, CI, FINNAKI Study Group, Poulose, V, Renal Transplantation HUVR, Lundberg, OH, Koh, J, Calvert, S, Cha, YS, Lee, SJ, Tyagi, N, Rajput, RK, Birri, PN, Taneja, S, Singh, VK, Sharma, SC, Mittal, S, Quint, M, Kam, JW, Rao, BK, Ayachi, J, Fraj, N, Romdhani, S, Bergenzaun, L, Khedher, A, Meddeb, K, Sma, N, Azouzi, A, Bouneb, R, Giribet, A, Adeniji, K, Chouchene, I, Yeter, H, El Ghardallou, M, Rydén, J, Boussarsar, M, Jennings, R, Walter, E, Ribeiro, JM, Moniz, I, Marçal, R, Santos, AC, Young, R, Candeias, C, E Silva, ZC, Rosenqvist, M, Kara, A, Gomez, SE, Nieto, OR, Gonzalez, JA, Cuellar, AI, Mildh, H, Korhonen, AM, Shevill, DD, Elke, G, Moraes, MM, Ala-Kokko, T, Reinikainen, M, Robertson, E, Garside, P, Tavladaki, T, Isotti, P, De Vecchi, MM, Perduca, AE, Cuervo, MA, Melander, O, Negro, A, Villa, G, Manara, DF, Cabrini, L, Zangrillo, A, Frencken, JF, Spanaki, AM, Van Baal, L, Donker, DW, Chew, MS, Cuervo, RA, Horn, J, Van der Poll, T, Van Klei, WA, Bonten, MJ, Menard, CE, Kumar, A, Dimitriou, H, Rimmer, E, Doucette, S, Esteban, MA, Turgeon, AF, Houston, BL, Houston, DS, Zarychanski, R, Pinto, BB, Carrara, M, Ferrario, M, Bendjelid, K, Kondili, E, Nunes, J, Fraile, LI, Diaz, P, Silva, G, Escórcio, S, Chaves, S, Jardim, M, Fernandes, N, Câmara, M, Duarte, R, Pereira, CA, Choulaki, C, Mittelbrum, CP, Vieira, J, Nóbrega, JJ, De Oca-Sandoval, MA, Sánchez-Rodríguez, A, Joya-Galeana, JG, Correa-Morales, A, Camarena-Alejo, G, Aguirre-Sánchez, J, Franco-Granillo, J, Albaiceta, GM, Meleti, E, Soliman, M, Al Azab, A, El Hossainy, R, Nagy, H, Nirmalan, M, Crippa, IA, Cavicchi, FZ, Koeze, J, Kafetzopoulos, D, Chaari, A, Hakim, KA, Hassanein, H, Etman, M, El Bahr, M, Bousselmi, K, Khalil, ES, Kauts, V, Tsolakoglou, I, Casey, WF, Imahase, H, Georgopoulos, D, Sakamoto, Y, Yamada, KC, Miike, T, Nagashima, F, Iwamura, T, Keus, F, Hummitzsch, L, Kishihara, Y, Heyland, D, Spiezia, L, Dieperink, W, Souza, RB, Yasuda, H, Martins, AM, Liberatore, AM, Kang, YR, Nakamae, MN, La Torre, AG, Vieira, JC, Koh, IH, Hanslin, K, Wilske, F, Van der Horst, IC, Jaskowiak, JL, Skorup, P, Sjölin, J, Lipcsey, M, Long, WJ, Zhen, CE, Vakalos, A, Avramidis, V, Wu, SH, Shyu, LJ, Rebollo, S, Van Meurs, M, Li, CH, Yu, CH, Chen, HC, Wang, CH, Lin, KH, Aray, ZE, Gómez, CF, Tsvetanova-Spasova, T, Tejero, AP, Monge, DD, Zijlstra, JG, Losada, VM, Tarancón, CM, Cortés, SD, Gutiérrez, AM, Álvarez, TP, Rouze, A, Jaffal, K, Six, S, Jimenez, R, Nuevo-Ortega, P, Stolz, K, Roberts, S, Cattoen, V, Arnal, JM, Saoli, M, Novotni, D, Garnero, A, Becher, T, Torrella, PE, Buchholz, V, Schädler, D, Rueda-Molina, C, Caballero, CH, Frerichs, I, Weiler, N, Eronia, N, Mauri, T, Gatti, S, Maffezzini, E, Fernandez, A, Bronco, A, Alban, L, Sasso, T, Marenghi, C, Isgro, G, Fernández-Porcel, A, Grasselli, G, Pesenti, A, Bellani, G, Al-Fares, A, Dubin, A, Del Sorbo, L, Anwar, S, Facchin, F, Azad, S, Zamel, R, Hall, D, Ferguson, N, Camara-Sola, E, Cypel, M, Keshavjee, S, Sanchez, S, Durlinger, E, Spoelstra-de Man, A, Smit, B, De Grooth, HJ, Girbes, A, Beitland, S, Straaten, HO, Smulders, Y, Salido-Díaz, L, Ortin, A, Alfaro, MA, Parrilla, F, Meli, A, Pellegrini, M, Rodriguez, N, Goyeneche, JM, Morán, I, Intas, G, Aguirre, H, Mancebo, J, Bassi, GL, Heines, SJ, García-Alcántara, A, Strauch, U, Bergmans, DC, Blankman, P, Shono, A, Hasan, D, Gommers, D, Trøseid, AM, Chung, WY, Prats, RG, Lee, KS, Jung, YJ, Park, JH, Sheen, SS, Park, KJ, Worral, R, Brusletto, BS, Larraza, S, Dey, N, Spadaro, S, Brohus, JB, Winding, RW, Volta, CA, Silva, MM, Waldum-Grevbo, BE, Ampatzidou, F, Vlachou, A, Kehagioglou, G, Karaiskos, T, Madesis, A, Mauromanolis, C, Michail, N, Drossos, G, Aguilera, E, Saraj, N, Berg, JP, Rijkenberg, S, Feijen, HM, Endeman, H, Donnelly, AA, Morgan, E, Garrard, H, Buckley, H, Russell, L, Marti, D, Haase, N, Sunde, K, Goh, C, Mouyis, K, Woodward, CL, Halliday, J, Encina, GB, Ros, J, Ranzani, OT, Lagunes, L, Tabernero, J, Huertas, DG, Bosch, F, Rello, J, Manzano, F, Morente-Constantin, E, Rivera-Ginés, B, Rigol, M, Colmenero-Ruiz, M, Meleti, DE, Sanz, JG, Dogliotti, A, Simon, IF, Valbuena, BL, Pais, M, Ramalingam, S, Quintana, MM, Díaz, C, Fox, L, Santafe, M, Fernandez, L, Barba, P, García, M, Leal, S, Pérez, M, Pérez, ML, Osuna, A, Ferrer, M, Veganzones, J, Martínez, N, Santiago-Ruiz, F, Moors, I, Mokart, D, Pène, F, Lambert, J, Mayaux, J, Vincent, F, Nyunga, M, Bruneel, F, Stergiannis, P, Laisne, L, Rabbat, A, Lebert, C, Perez, P, Suberviola, B, Chaize, M, Renault, A, Meert, AP, Hamidfar, R, Jourdain, M, Rodríguez-Mejías, C, Lanziotti, VS, Darmon, M, Schlemmer, B, Chevret, S, Lemiale, V, Azoulay, E, Rowland, MJ, Riera, J, Benoit, D, Martins-Branco, D, Sousa, M, Wangensteen, R, Marum, S, Bouw, MJ, Galstyan, G, Makarova, P, Parovichnikova, E, Kuzmina, L, Troitskaya, V, Rellan, L, Drize, N, Zaponi, RS, Gemdzhian, E, Jamaati, HR, Savchenko, V, Chao, HC, Kılıc, E, Demiriz, B, Uygur, ML, Sürücü, M, Cınar, K, Yıldırım, AE, Pulcheri, L, Sanchez, M, Kiss, K, Masjedi, M, Köves, B, Csernus, V, Molnár, Z, Ntantana, A, Matamis, D, Savvidou, S, Giannakou, M, Ribeiro, MO, Gouva, M, Nakos, G, Robles, JC, Koulouras, V, Gaffney, S, Docking, R, Judge, C, Drew, T, Barbosa, AP, Misran, H, Munshi, R, McGovern, L, Coyle, M, Hashemian, SM, Lopez, E, Dunne, L, Deasy, E, Lavin, P, Fahy, A, Antoniades, CA, Ramos, A, Darcy, DM, Donnelly, M, Ismail, NH, Hall, T, Wykes, K, Jack, J, Vicente, R, Ngu, WC, Morgan, P, E Silva, JR, Ruiz-Ramos, J, Ramirez, P, Gordon, M, Villarreal, E, Frasquet, J, Poveda-Andrés, JL, Abbasi, G, Castellanos, A, Ijssennagger, CE, Miñambres, E, Soares, M, Ten Hoorn, S, Van Wijk, A, Van den Broek, JM, Tuinman, PR, Elmenshawy, AM, Hammond, BD, Gibbon, G, Khaloo, V, Belcham, T, Burton, K, Salluh, JI, Taniguchi, LU, Santibañez, M, Ramos, FJ, Momma, AK, Martins-Filho, AP, Bartocci, JJ, Lopes, MF, Sad, MH, Tabei, SH, Rodrigues, CM, Pires, EM, Vieira, JM, Le Guen, M, Murbach, LD, Barreto, J, Duarte, ST, Taba, S, Kolaros, AA, Miglioranza, D, Gund, DP, Lordani, CF, Ogasawara, SM, Moore, J, Jorge, AC, Duarte, PA, Capuzzo, M, Marqués, MG, Kafilzadeh, A, Corte, FD, Terranova, S, Scaramuzzo, G, Fogagnolo, A, Bertacchini, S, Bellonzi, A, Garry, P, Mason, N, Ragazzi, R, Moreno, AP, Bakhodaei, HH, Cruz, C, Nunes, A, Pereira, FS, Aragão, I, Cardoso, AF, Santos, C, Malheiro, MJ, Castro, H, Abentroth, LR, Windpassinger, M, Cardoso, T, Diaz, JA, Paratz, J, Kenardy, J, Comans, 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Perchiazzi, G, Borges, JB, Queen Square Neuroanaesthesia and Neurocritical Care Resreach Group, Bayat, S, Porra, L, Mirek, S, Broche, L, Hedenstierna, G, Larsson, A, Kennedy, RM, Roneus, A, Segelsjö, M, Vestito, MC, Zeman, PM, Gremo, E, Nyberg, A, Castegren, M, Pikwer, A, Sharma, S, Monfort, B, Yoshida, T, Engelberts, D, Otulakowski, G, Katira, B, Post, M, Brochard, L, Amato, MB, Stazi, E, PLUG Working group, Koch, N, Hoellthaler, J, Mair, S, Phillip, V, Van Ewijk, CE, Beitz, A, González, LR, Roig, AL, Baladrón, V, Yugi, G, Calvo, FJ, Padilla, D, Villarejo, P, Villazala, R, Yuste, AS, Bejarano, N, Steenstra, RJ, Jacobs, GE, Banierink, H, Hof, J, Martika, A, Hoekstra, M, Sterz, F, Horvatits, K, Herkner, H, Magnoni, S, Marando, M, Faivre, V, Pifferi, S, Conte, V, Ortolano, F, Alonso, DC, Carbonara, M, Bertani, G, Scola, E, Cadioli, M, Triulzi, F, Colombo, A, Nevière, R, Stocchetti, N, Fatania, G, Hernández-Sánchez, N, Rotzel, HB, Lázaro, AS, Prada, DA, Guimillo, MR, Piqueras, CS, Guia, JR, Simon, MG, Thiébaut, PA, Arizmendi, AM, Carratalá, A, Sánchez, RDEP, El Maraghi, S, Yehia, A, Bakry, M, Shoman, A, Backes, FN, Bianchin, MM, Vieira, SR, Maupoint, J, De Souza, A, Lucas, JH, Backes, AN, Klein, C, García-Guillen, FJ, Arunkumar, AS, Lozano, A, Mulder, P, Gallaher, C, Cattlin, S, Ñamendys-Silva, SA, Gordon, S, Picard, J, Fontana, V, Bond, O, Coquerel, D, Nobile, L, Mrozek, S, Delamarre, L, Maghsoudi, B, Capilla, F, Al-Saati, T, Fourcade, O, Renet, S, Dominguez-Berrot, AM, Gonzalez-Vaquero, M, Vallejo-Pascual, ME, Gupta, D, Ivory, BD, Chopra, M, Emami, M, Khaliq, W, McCarthy, J, Felderhof, CL, Do Rego, JC, MacNeil, C, Maggiorini, M, Duska, F, Department of Professional Development, ESICM, Fumis, RR, Junior, JM, Khosravi, MB, Amarante, G, Rieusset, J, Skorko, A, Sanders, S, Aron, J, Kroll, RJ, Redfearn, C, Harish, MM, Krishnan, P, Khalil, JE, Kongpolprom, N, Richard, V, Gulia, V, Lourenço, E, Duro, C, Baptista, G, Alves, A, Arminda, B, Rodrigues, M, Tamion, F, Tabatabaie, HR, Hayward, J, Baldwin, F, Gray, R, Katinakis, PA, Stijf, M, Ten Kleij, M, Jansen-Frederiks, M, Broek, R, De Bruijne, M, Mengelle, C, Spronk, PE, Sinha, K, Luney, M, Palmer, K, Keating, L, Abu-Habsa, M, Bahl, R, Baskaralingam, N, Ahmad, A, Kanapeckaite, L, Bhatti, P, Strong, AJ, Sabetiyan, G, Glace, S, Jeyabraba, S, Lewis, HF, Kostopoulos, A, Raja, M, West, A, Ely, A, Turkoglu, LM, Zolfaghari, P, Baptista, JP, Mokri, A, Marques, MP, Martins, P, Pimentel, J, Su, YC, Singer, M, Villacres, S, Stone, ME, Parsikia, A, Medar, S, O'Dea, KP, Nurses of the Central and General ICUs of Shiraz Namazi Hospital, Porter, J, Tirlapur, N, Jonathan, JM, Singh, S, Takata, M, Critical Care Research Group, McWhirter, E, Lyon, R, Troubleyn, J, Hariz, ML, Ferlitsch, A, Azmi, E, Alkhan, J, Smulders, YM, Movsisyan, V, Petrikov, S, Marutyan, Z, Aliev, I, Evdokimov, A, Antonucci, E, Diltoer, M, Merz, T, Hartmann, C, De Waard, MC, Calzia, E, Radermacher, P, Nußbaum, B, Huber-Lang, M, Fauler, G, Gröger, M, Jacobs, R, Zaleska-Kociecka, M, Van Straaten, HM, Trauner, M, Svoren-Jabalera, E, Davenport, EE, Humburg, P, Nguyen, DN, Knight, J, Hinds, CJ, Jun, IJ, Prabu, NR, Kim, WJ, Lee, EH, Besch, G, Perrotti, A, Puyraveau, M, Baltres, M, Eringa, EC, De Waele, E, Samain, E, Chocron, S, Pili-Floury, S, Plata-Menchaca, EP, Sabater-Riera, J, Estruch, M, Boza, E, Toscana-Fernández, J, Man, AM, Bruguera-Pellicer, E, De Regt, J, Ordoñez-Llanos, J, Pérez-Fernández, XL, SIRAKI group, Cavaleiro, P, Tralhão, A, Arrigo, M, Lopes, JP, Lebrun, M, Favier, B, Pischke, S, Cholley, B, PerezVela, JL, Honoré, PM, MarinMateos, H, Rivera, JJ, Llorente, MA, De Marcos, BG, Fernandez, FJ, Laborda, CG, Zamora, DF, Fischer, L, Alegría, L, Grupo ESBAGA, Delgado, JC, Imperiali, C, Myers, RB, Van Gorp, V, Dastis, M, Thaiss, F, Soto, D, Górka, J, Spapen, HD, Górka, K, Iwaniec, T, Koch, M, Frołow, M, Polok, K, Luengo, C, Fronczek, J, Kózka, M, Musiał, J, Szczeklik, W, Contreras, RS, Bangert, K, Gomez, J, Sileli, M, Havaldar, AA, Toapanta, ND, Jarufe, N, Moursia, C, Maleoglou, H, Leleki, K, Uz, Z, Ince, Y, Papatella, R, Bulent, E, Moreno, G, Grabowski, M, Bruhn, A, De Mol, B, Vicka, V, Gineityte, D, Ringaitiene, D, Norkiene, I, Sipylaite, J, Möller, C, Sabater, J, Castro, R, Thomas-Rueddel, DO, Vlasakov, V, Lohse, AW, Rochwerg, B, Theurer, P, Al Sibai, JZ, Camblor, PM, Kattan, E, Torrado, H, Siddiqui, S, Fernandez, PA, Gala, JM, Guisasola, JS, Tamura, T, Miyajima, I, Yamashita, K, Yokoyama, M, Tapia, P, Nashan, B, Gonzalez, M, Dalampini, E, Nastou, M, Baddour, A, Ignatiadis, A, Asteri, T, Hathorn, KE, Sterneck, M, Rebolledo, R, Purtle, SW, Marin, M, Viana, MV, Tonietto, TA, Gross, LA, Costa, VL, Faenza, S, Tavares, AL, Payen, D, Lisboa, BO, Moraes, RB, Farigola, E, Viana, LV, Azevedo, MJ, Ceniccola, GD, Pequeno, RS, Siniscalchi, A, Holanda, TP, Mendonça, VS, Achurra, P, Araújo, WM, Carvalho, LS, Segaran, E, Vickers, L, Gonzalez, A, Brinchmann, K, Pierucci, E, Wignall, I, De Brito-Ashurst, I, Ospina-Tascón, G, Del Olmo, R, Esteban, MJ, Vaquerizo, C, Carreño, R, Gálvez, V, Kaminsky, G, Mancini, E, Fernandez, J, Nieto, B, Fuentes, M, De la Torre, MA, Bakker, J, Torres, E, Alonso, A, Velayos, C, Saldaña, T, Escribá, A, Krishna, B, Grip, J, Kölegård, R, Vera, A, Sundblad, P, Rooyackers, O, Hernández, G, Naser, B, Jaziri, F, Jazia, AB, Barghouth, M, Ricci, D, Hentati, O, Skouri, W, El Euch, M, Mahfoudhi, M, Gisbert, X, Turki, S, Dąbrowski, M, Bertini, P, Abdelghni, KB, Abdallah, B, Gemelli, C, Maha, BN, Cánovas, J, Sotos, F, López, A, Lorente, M, Burruezo, A, Torres, D, Juliá, C, Guarracino, F, Cuoghi, A, Włudarczyk, A, Hałek, A, Bargouth, M, Bennasr, M, Baldassarri, R, Magnani, S, Uya, J, Abdelghani, KB, Abdallah, TB, Geenen, IL, Parienti, JJ, Straaten, HM, Shum, HP, King, HS, Kulkarni, AP, Pinsky, MR, Chan, KC, Corral, L, Yan, WW, Londoño, JG, Cardenas, CL, Pedrosa, MM, Gubianas, CM, Bertolin, CF, Batllori, NV, Atti, M, Sirvent, JM, Sedation an Delirium Group Hospital Universitari de Bellvitge, Mukhopadhyay, A, Chan, HY, Kowitlawakul, Y, Remani, D, Leong, CS, Henry, CJ, Vera, M, Puthucheary, ZA, Mendsaikhan, N, Begzjav, T, Elias-Jones, I, Lundeg, G, Dünser, M, Espinoza, ED, Welsh, SP, Guerra, E, Poppe, A, Zerpa, MC, Zechner, F, Berdaguer, F, Risso-Vazquez, A, Masevicius, FD, Greaney, D, Dreyse, J, Magee, A, Fitzpatrick, G, Lugo-Cob, RG, Jermaine, CM, Tejeda-Huezo, BC, Cano-Oviedo, AA, Carpio, D, Aydogan, MS, Togal, T, Taha, A, Chai, HZ, Sriram, S, Kam, C, Razali, SS, Sivasamy, V, Randall, D, Kuan, LY, Henriquez, C, Morales, MA, Pires, T, Adwaney, A, Wozniak, S, Gajardo, D, Herrera-Gutierrez, ME, Azevedo, LC, Blunden, M, Prowle, JR, Kirwan, CJ, Thomas, N, Martin, A, Owen, H, Darwin, L, Robertson, CS, Bravo, S, Barrueco-Francioni, J, Conway, D, Atkinson, D, Sharman, M, Barbanti, C, Amour, J, Gaudard, P, Rozec, B, Mauriat, P, M'rini, M, Arias-Verdú, D, Rusin, CG, Leger, PL, Cambonie, G, Liet, JM, Girard, C, Laroche, S, Damas, P, Assaf, Z, Loron, G, Lozano-Saez, R, Lecourt, L, Pouard, P, Hofmeijer, J, Kim, SH, Divatia, JV, Na, S, Kim, J, Jung, CW, Sondag, L, Yoo, SH, Min, SH, Chung, EJ, Quesada-Garcia, G, Lee, NJ, Lee, KW, Suh, KS, Ryu, HG, Marshall, DC, Goodson, RJ, Tjepkema-Cloostermans, MC, Salciccioli, JD, Shalhoub, J, Seller-Pérez, G, Potter, EK, Kirk-Bayley, J, Karanjia, ND, Forni, LG, Kim, S, Creagh-Brown, BC, Bossy, M, Nyman, M, Tailor, A, Figueiredo, A, SPACeR group (Surrey Peri-operative, Anaesthesia and Critical Care Collaborative Research Group), D'Antini, D, Valentino, F, Winkler, MS, Sollitto, F, Cinnella, G, Mirabella, L, Anzola, Y, Bosch, FH, Baladron, V, Villajero, P, Lee, M, Redondo, J, Liu, J, Shen, F, Teboul, JL, Anguel, N, Van Putten, MJ, Beurton, A, Bezaz, N, Richard, C, Park, SY, Monnet, X, Fossali, T, Pereira, R, Colombo, R, Ottolina, D, Rossetti, M, Mazzucco, C, Marchi, A, Porta, A, Catena, E, Piotrowska, K, So, S, Bento, L, Tollisen, KH, Andersen, G, Heyerdahl, F, Jacobsen, D, Van IJzendoorn, MC, Buter, H, Kingma, WP, Navis, GJ, Boerma, EC, Rulisek, J, Zacharov, S, Kim, HS, Jeon, SJ, Namgung, H, Lee, E, Lai, M, Kačar, MB, Cho, YJ, Lee, YJ, Huang, A, Deiana, M, Forsberg, M, Edman, G, Kačar, SM, Höjer, J, Forsberg, S, Freile, MT, Hidalgo, FN, Molina, JA, Lecumberri, R, Rosselló, AF, Travieso, PM, Leon, GT, Uddin, I, Sanchez, JG, Ali, MA, Frias, LS, Rosello, DB, Verdejo, JA, Serrano, JA, Winterwerp, D, Van Galen, T, Vazin, A, Karimzade, I, Belhaj, AM, Zand, A, Ozen, E, Ekemen, S, Akcan, A, Sen, E, Yelken, BB, Kureshi, N, Fenerty, L, Thibault-Halman, G, Aydın, MA, Walling, S, Almeida, R, Seller-Perez, G, Clarke, DB, Briassoulis, P, Kalimeris, K, Ntzouvani, A, Nomikos, T, Papaparaskeva, K, Avsec, D, Politi, E, Kostopanagiotou, G, Crewdson, K, Vardas, K, Rehn, M, Vaz-Ferreira, A, Weaver, A, Brohi, K, Lockey, D, Wright, S, Thomas, K, Mudersbach, E, Baker, C, Mansfield, L, Pozo, MO, Stafford, V, Wade, C, Watson, G, Silva, J, Bryant, A, Chadwick, T, Shen, J, Wilkinson, J, Kapuağası, A, Furneval, J, and Clinical Neurophysiology

Subjects
Queen Square Neuroanaesthesia and Neurocritical Care Resreach Group, TAVeM study Group, Renal Transplantation HUVR, Flow (psychology), lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Critical Care and Intensive Care Medicine, Grupo ESBAGA, GEMINI, 03 medical and health sciences, chemistry.chemical_compound, SPACeR group (Surrey Peri-operative, Anaesthesia and Critical Care Collaborative Research Group), 0302 clinical medicine, Critical Care Research Group, Journal Article, PRoVENT investigators and the PROVE Network, Medicine, Sedation an Delirium Group Hospital Universitari de Bellvitge, 030212 general & internal medicine, Bioethics work group of SEMICYUC, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), SEMICYUC/GETGAG Working Group, FINNAKI Study Group, POPC-CB investigators, business.industry, Other Research Radboud Institute for Health Sciences [Radboudumc 0], SIRAKI group, 030208 emergency & critical care medicine, EDISVAL Group, PLUG Working group, DESIRE (DExmedetomidine for Sepsis in ICU Randomized Evaluation) Trial Investigators, chemistry, Anesthesia, Carbon dioxide, Breathing, Department of Professional Development, ESICM, business, Nurses of the Central and General ICUs of Shiraz Namazi Hospital
Abstract

Contains fulltext : 172382.pdf (Publisher’s version ) (Open Access)

Published
2016

39. Analysis of Epstein-Barr virus reservoirs in paired blood and breast cancer primary biopsy specimens by real time PCR

Author

Stephen P. Dunn, Leslie J. Krueger, Nicholas J. Petrelli, Irving M Berkowitz, Patricia Soteropoulos, Gregory R Pahnke, Cindy Marando, Mark L Mitchell, Diana Dickson-Witmer, Katherine Sahm, Virginie Aris, and R. Serene Perkins

Subjects
Adult, Disease reservoir, Pathology, medicine.medical_specialty, Herpesvirus 4, Human, Biopsy, Population, Breast Neoplasms, medicine.disease_cause, Polymerase Chain Reaction, Virus, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, hemic and lymphatic diseases, medicine, Carcinoma, Humans, Breast, education, 030304 developmental biology, Disease Reservoirs, Medicine(all), 0303 health sciences, education.field_of_study, medicine.diagnostic_test, business.industry, Carcinoma, Ductal, Breast, Middle Aged, medicine.disease, Epstein–Barr virus, 3. Good health, Carcinoma, Lobular, Blood, Carcinoma, Intraductal, Noninfiltrating, 030220 oncology & carcinogenesis, DNA, Viral, Female, business, Breast carcinoma, Research Article
Abstract

Introduction Epstein-Barr virus (EBV) is present in over 90% of the world's population. This infection is considered benign, even though in limited cases EBV is associated with infectious and neoplastic conditions. Over the past decade, the EBV association with breast cancer has been constantly debated. Adding to this clinical and biological uncertainty, different techniques gave contradictory results for the presence of EBV in breast carcinoma specimens. In this study, minor groove binding (MGB)-TaqMan real time PCR was used to detect the presence of EBV DNA in both peripheral blood and tumor samples of selected patients. Methods Peripheral blood and breast carcinoma specimens from 24 patients were collected. DNA was extracted and then amplified by MGB-TaqMan real time PCR. Results Of 24 breast tumor specimens, 11 (46%) were positive for EBV DNA. Of these 11 breast tumor specimens, 7 (64%) were also positive for EBV DNA in the peripheral blood, while 4 (36%) were positive for EBV DNA in the tumor, but negative in the blood. Conclusion EBV was found at extremely low levels, with a mean of 0.00004 EBV genomes per cell (range 0.00014 to 0.00001 EBV genomes per cell). Furthermore, our finding of the presence of EBV in the tumor specimens coupled to the absence of detection of EBV genomic DNA in the peripheral blood is consistent with the epithelial nature of the virus. Because of the low levels of viral DNA in tumor tissue, further studies are needed to assess the biological input of EBV in breast cancer.

Published
2006

40. Glutaminolysis is a metabolic dependency in FLT3ITD acute myeloid leukemia unmasked by FLT3 tyrosine kinase inhibition

Author

Brian J. P. Huntly, João Lopes Dias, Christian Frezza, Paula Medina-Perez, George Giotopoulos, Paolo Gallipoli, Konstantinos Tzelepis, Daniel Sasca, Haiyang Yun, Faisal Basheer, Sarah J. Horton, Ludovica Marando, Ana S. H. Costa, George S. Vassiliou, Shabana Vohra, Lorena Di Lisio, Gallipoli, Paolo [0000-0001-7254-2253], Huntly, Brian JP [0000-0003-0312-161X], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, FLT3 Internal Tandem Duplication, THP-1 Cells, Glutamine, Immunology, medicine.disease_cause, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, medicine, Humans, Protein Kinase Inhibitors, Mutation, Glutaminolysis, business.industry, Myeloid leukemia, Cell Biology, Hematology, medicine.disease, 3. Good health, Enzyme Activation, Leukemia, Myeloid, Acute, Leukemia, 030104 developmental biology, fms-Like Tyrosine Kinase 3, 030220 oncology & carcinogenesis, Fms-Like Tyrosine Kinase 3, Cancer research, CRISPR-Cas Systems, K562 Cells, business, Tyrosine kinase, Genome-Wide Association Study, K562 cells
Abstract

FLT3 internal tandem duplication (FLT3ITD) mutations are common in acute myeloid leukemia (AML) associated with poor patient prognosis. Although new-generation FLT3 tyrosine kinase inhibitors (TKI) have shown promising results, the outcome of FLT3ITD AML patients remains poor and demands the identification of novel, specific, and validated therapeutic targets for this highly aggressive AML subtype. Utilizing an unbiased genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 screen, we identify GLS, the first enzyme in glutamine metabolism, as synthetically lethal with FLT3-TKI treatment. Using complementary metabolomic and gene-expression analysis, we demonstrate that glutamine metabolism, through its ability to support both mitochondrial function and cellular redox metabolism, becomes a metabolic dependency of FLT3ITD AML, specifically unmasked by FLT3-TKI treatment. We extend these findings to AML subtypes driven by other tyrosine kinase (TK) activating mutations and validate the role of GLS as a clinically actionable therapeutic target in both primary AML and in vivo models. Our work highlights the role of metabolic adaptations as a resistance mechanism to several TKI and suggests glutaminolysis as a therapeutically targetable vulnerability when combined with specific TKI in FLT3ITD and other TK activating mutation-driven leukemias.

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41. Bone Marrow Mesenchymal Stem Cells Support Acute Myeloid Leukemia Bioenergetics and Enhance Antioxidant Defense and Escape from Chemotherapy

Author

Juan Antonio López, Brian J. P. Huntly, Jesús Vázquez, Michael Barber, Laura Tronci, Ludovica Marando, Michele Cavo, Ana S. H. Costa, Juerg Schwaller, Simón Méndez-Ferrer, Carlos Lopez Fernandez de Castillejo, Christian Frezza, Sabine Dietmann, Antonio Curti, Paolo Gallipoli, María García-Fernández, Abel Sanchez-Aguilera, Efterpi Nikitopoulou, Vaia Stavropoulou, Daniel Martín-Pérez, Dorian Forte, Claire Fielding, Lucia Catani, Alexandar Tzankov, Forte D., Garcia-Fernandez M., Sanchez-Aguilera A., Stavropoulou V., Fielding C., Martin-Perez D., Lopez J.A., Costa A.S.H., Tronci L., Nikitopoulou E., Barber M., Gallipoli P., Marando L., Fernandez de Castillejo C.L., Tzankov A., Dietmann S., Cavo M., Catani L., Curti A., Vazquez J., Frezza C., Huntly B.J., Schwaller J., Mendez-Ferrer S., Wellcome Trust, MRC Cambridge Stem Cell Institute, Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades (España), Fundación ProCNIC, Fundación La Marató TV3, Fundación La Caixa, Medical Research Council (Reino Unido), Swiss National Research Foundation, Gertrude von Meissner Foundation, Comunidad de Madrid (España), National Health Service Blood and Transplant (Reino Unido), Cancer Research UK (Reino Unido), Howard Hughes Medical Institute, Frezza, Christian [0000-0002-3293-7397], Huntly, Brian [0000-0003-0312-161X], Apollo - University of Cambridge Repository, Cambridge Stem Cell Institute, Instituto de Salud Carlos III - ISCIII, Fundación La Mataró TV3, Medical Research Council (United Kingdom), Comunidad de Madrid, National Health Service Blood and Transplant (United Kingdom), and Cancer Research (United Kingdom)

Subjects
Male, 0301 basic medicine, antioxidant, Physiology, Hematopoietic stem cell niche, Antineoplastic Agents, acute myeloid leukemia, Biology, chemotherapy, Article, Antioxidants, Mice, 03 medical and health sciences, 0302 clinical medicine, Bone Marrow, hemic and lymphatic diseases, medicine, Animals, Humans, glutathione, TCA cycle, neoplasms, Molecular Biology, Cells, Cultured, Mesenchymal stem cell, bone marrow mesenchymal stem cells, Myeloid leukemia, Mesenchymal Stem Cells, hematopoietic stem cell niche, metabolic adaptation, Cell Biology, Middle Aged, Nestin, microenvironment, OXPHOS, 3. Good health, Mice, Inbred C57BL, Leukemia, Myeloid, Acute, Haematopoiesis, 030104 developmental biology, medicine.anatomical_structure, bone marrow mesenchymal stem cell, Cancer research, Female, Bone marrow, Stem cell, Energy Metabolism, Energy source, 030217 neurology & neurosurgery
Abstract

Summary Like normal hematopoietic stem cells, leukemic stem cells depend on their bone marrow (BM) microenvironment for survival, but the underlying mechanisms remain largely unknown. We have studied the contribution of nestin+ BM mesenchymal stem cells (BMSCs) to MLL-AF9-driven acute myeloid leukemia (AML) development and chemoresistance in vivo. Unlike bulk stroma, nestin+ BMSC numbers are not reduced in AML, but their function changes to support AML cells, at the expense of non-mutated hematopoietic stem cells (HSCs). Nestin+ cell depletion delays leukemogenesis in primary AML mice and selectively decreases AML, but not normal, cells in chimeric mice. Nestin+ BMSCs support survival and chemotherapy relapse of AML through increased oxidative phosphorylation, tricarboxylic acid (TCA) cycle activity, and glutathione (GSH)-mediated antioxidant defense. Therefore, AML cells co-opt energy sources and antioxidant defense mechanisms from BMSCs to survive chemotherapy., Graphical Abstract, Highlights • Nestin+ BMSCs support leukemogenesis and chemoresistance • BMSCs support metabolic requirements of LSCs • BMSCs provide LSCs with essential antioxidant defense from chemotherapy • GSH and GSH peroxidases underlie BMSC-derived antioxidant AML protection, Forte et al. reveal that nestin+ bone marrow stromal cells directly contribute to leukemogenesis and chemotherapy resistance in an in vivo model of acute myeloid leukemia. Nestin+ BMSCs support leukemic stem cells through a dual mechanism of increased bioenergetic capacity through OXPHOS and TCA and glutathione-dependent antioxidant defense.

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