368 results on '"Calderaro, A."'
Search Results
2. Co-activation of PIK3CA and Yap promotes development of hepatocellular and cholangiocellular tumors in mouse and human liver
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Li, Xiaolei, Tao, Junyan, Cigliano, Antonio, Sini, Marcella, Calderaro, Julien, Azoulay, Daniel, Wang, Chunmei, Liu, Yan, Jiang, Lijie, Evert, Katja, Demartis, Maria I, Ribback, Silvia, Utpatel, Kirsten, Dombrowski, Frank, Evert, Matthias, Calvisi, Diego F, and Chen, Xin
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Rare Diseases ,Liver Cancer ,Liver Disease ,Cancer ,Digestive Diseases ,2.1 Biological and endogenous factors ,Aetiology ,Adaptor Proteins ,Signal Transducing ,Animals ,Carcinoma ,Hepatocellular ,Cell Cycle Proteins ,Cell Line ,Tumor ,Cell Proliferation ,Cholangiocarcinoma ,Class I Phosphatidylinositol 3-Kinases ,Humans ,Liver Neoplasms ,Liver Neoplasms ,Experimental ,Mice ,Phosphatidylinositol 3-Kinases ,Phosphoproteins ,Signal Transduction ,Transcription Factors ,YAP-Signaling Proteins ,HCC ,cholangiocarcinoma ,liver tumor ,PI3K ,hippo ,Hippo ,Oncology and carcinogenesis - Abstract
Activation of the PI3K and Yes-associated protein (Yap) signaling pathways has been independently reported in human hepatocellular carcinoma (HCC). However, the oncogenic interactions between these two cascades in hepatocarcinogenesis remain undetermined. To assess the consequences of the crosstalk between the PI3K and Yap pathways along liver carcinogenesis, we generated a mouse model characterized by combined overexpression of activated mutant forms of PIK3CA (PIK3CAH1047R) and Yap (YapS127A) in the mouse liver using hydrodynamic transfection (PIK3CA/Yap). In addition, suppression of PI3K and Yap pathways was conducted in human HCC and cholangiocarcinoma (CCA) cell lines. We found that concomitant activation of PI3K and Yap pathways triggered rapid liver tumor development in mice. Histologically, tumors were pure HCC, CCA, or mixed HCC/CCA. At the molecular level, PIK3CA/Yap tumors were characterized by activation of the mTORC1/2, ERK/MAPK, and Notch pathways. Simultaneous activation of PI3K and Yap pathways frequently occurred in human liver tumor specimens and their combined suppression was highly detrimental for the growth of HCC and CCA cell lines. In conclusion, our study demonstrates the oncogenic cooperation between PI3K and Yap pathways along liver carcinogenesis. The PIK3CA/Yap mouse represents an important preclinical liver tumor model for the development of novel therapeutics against this malignancy.
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- 2015
3. Is there a change in P300 evoked potential after 6 months in cochlear implant users?
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Miguel Angelo Hyppolito, Maria Stella Arantes do Amaral, Victor Goiris Calderaro, Ana Cláudia Mirândola Barbosa Reis, Eduardo Tanaka Massuda, and Henrique Furlan Pauna
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Adult ,medicine.medical_specialty ,Hearing loss ,medicine.medical_treatment ,Deafness ,Stimulus (physiology) ,Audiology ,Hearing ,Cochlear implant ,otorhinolaryngologic diseases ,medicine ,Humans ,Auditory system ,P300 ,Latency (engineering) ,Evoked potential ,business.industry ,Cochlear Implantation ,Cochlear implantation ,Electrophysiology ,Cochlear Implants ,medicine.anatomical_structure ,Otorhinolaryngology ,Evoked Potentials, Auditory ,Speech Perception ,Implant ,medicine.symptom ,business ,Event-related potentials - Abstract
Objective: There are few studies on long-latency auditory evoked potential (P300) in people with hearing loss who use a cochlear implant. Central auditory system evaluation with behavioral and electrophysiological tests is believed to help understand the neuroplasticity mechanisms involved in auditory functioning after cochlear implant surgery. This study investigated the electrophysiological processing of cortical level acoustic signals in a group of 21 adult individuals with postlingual bilateral severe-to-profound hearing loss who were submitted to cochlear implant surgery. Methods: Data were collected in three phases: pre-cochlear implant surgery, at cochlear implant activation, and 6 months after surgery. P300 measures were also registered during all phases. Tone-burst and speech stimuli were used to elicit P300 and were presented in free field. Results: Mean P3 component latency with tone-burst and speech stimuli were 352.9 and 321.9 ms in the pre-cochlear implant phase, 364.9 and 368.7 ms in the activation phase, 336.2 and 343.6 ms 6 months after the surgery. The P3 component mean latency values using tone-burst at activation were significantly different from those 6 months after cochlear implant. They were also significantly different using speech, between pre-cochlear implant and activation phases. Lower P3 component latency occurred 6 months after cochlear implant activation with tone-burst and pre-cochlear implant with speech stimulus. There was a weak correlation between mean P3 component latency with speech stimulus and time of hearing loss. There was no difference in amplitude between phases or in the comparison with the other variables. Conclusion: There were changes in P3 component latency during the period assessed, for both speech and pure-tone stimuli, with increased latency in the activation phase and similar lower results in the two other phases, Pre-CI and 6 months after CI use. Mean amplitude measures did not vary in the three phases.
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- 2022
4. Prevalence of T-cell antigen losses in mycosis fungoides and CD30-positive cutaneous T-cell lymphoproliferations in a series of 153 patients
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Janine Wechsler, Saskia Ingen-Housz-Oro, Lydia Deschamps, Florence Brunet-Possenti, Justin Deschamps, Marie-Hélène Delfau, Julien Calderaro, and Nicolas Ortonne
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Mycosis Fungoides ,Skin Neoplasms ,T-Lymphocytes ,Programmed Cell Death 1 Receptor ,Prevalence ,Humans ,Ki-1 Antigen ,Lymphoproliferative Disorders ,Lymphoma, T-Cell, Cutaneous ,Retrospective Studies ,Pathology and Forensic Medicine - Abstract
Mycosis fungoides (MF) and primary cutaneous CD30-positive T-cell lymphoproliferative disorders (CD30LPD) are the most frequent primary cutaneous T-cell lymphomas. Our objective was to study pan-T-cell antigens and PD-1 expression in a large cohort of MF and CD30LPD with a special interest in antigen losses as a diagnostic tool. We retrospectively reviewed 160 consecutive samples from 153 patients over a 3 year period, including 104 with MF and 49 with CD30LPD. As controls, benign inflammatory dermatoses (BID, n=19) were studied. A semi-quantitative evaluation of CD2, CD3, CD4, CD5, CD7, CD8 expression was performed. PD-1 and double stainings (CD3+CD7 and PD-1+CD7) were performed in a subset of MF cases. CD8+ MF was frequent (23%) and CD7 was the most frequently lost antigen in both MF (45%) and CD30LPD (86%), while no significant T-cell antigen loss was observed in BID. CD7 loss was less frequent in folliculotropic MF (p0.001). PD-1 was variably expressed in MF with no differences with BID. The CD3+/CD7- and PD-1+/CD7- neoplastic lymphocytes were highlighted by the use of chromogenic double staining experiments in MF with a CD7 loss identified with single staining. Multiple pan T-cell antigen losses were mostly seen in CD30LPD with CD2 being the most frequently preserved marker (90%). While PD-1 does not discriminate between MF and BID, CD7 is frequently lost in MF infiltrates as well as other pan-T-cell antigens in CD30LPD, which can be used as routine markers for diagnosis. We recommend the use of CD7 in addition to CD3, CD4 and CD8 as a minimal immunohistochemical panel for MF assessment, and the use of double stainings for CD3 and CD7 in difficult cases.
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- 2022
5. Artificial intelligence predicts immune and inflammatory gene signatures directly from hepatocellular carcinoma histology
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Qinghe Zeng, Christophe Klein, Stefano Caruso, Pascale Maille, Narmin Ghaffari Laleh, Daniele Sommacale, Alexis Laurent, Giuliana Amaddeo, David Gentien, Audrey Rapinat, Hélène Regnault, Cécile Charpy, Cong Trung Nguyen, Christophe Tournigand, Raffaele Brustia, Jean Michel Pawlotsky, Jakob Nikolas Kather, Maria Chiara Maiuri, Nicolas Loménie, and Julien Calderaro
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Carcinoma, Hepatocellular ,ROC Curve ,Hepatology ,Artificial Intelligence ,Liver Neoplasms ,Humans - Abstract
Patients with hepatocellular carcinoma (HCC) displaying overexpression of immune gene signatures are likely to be more sensitive to immunotherapy, however, the use of such signatures in clinical settings remains challenging. We thus aimed, using artificial intelligence (AI) on whole-slide digital histological images, to develop models able to predict the activation of 6 immune gene signatures.AI models were trained and validated in 2 different series of patients with HCC treated by surgical resection. Gene expression was investigated using RNA sequencing or NanoString technology. Three deep learning approaches were investigated: patch-based, classic MIL and CLAM. Pathological reviewing of the most predictive tissue areas was performed for all gene signatures.The CLAM model showed the best overall performance in the discovery series. Its best-fold areas under the receiver operating characteristic curves (AUCs) for the prediction of tumors with upregulation of the immune gene signatures ranged from 0.78 to 0.91. The different models generalized well in the validation dataset with AUCs ranging from 0.81 to 0.92. Pathological analysis of highly predictive tissue areas showed enrichment in lymphocytes, plasma cells, and neutrophils.We have developed and validated AI-based pathology models able to predict the activation of several immune and inflammatory gene signatures. Our approach also provides insights into the morphological features that impact the model predictions. This proof-of-concept study shows that AI-based pathology could represent a novel type of biomarker that will ease the translation of our biological knowledge of HCC into clinical practice.Immune and inflammatory gene signatures may be associated with increased sensitivity to immunotherapy in patients with advanced hepatocellular carcinoma. In the present study, the use of artificial intelligence-based pathology enabled us to predict the activation of these signatures directly from histology.
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- 2022
6. Fat in mass in primary liver lesions: are usual MRI diagnostic criteria of both malignant and benign liver lesions still applicable?
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Edouard Reizine, Azure Meurgey, Giuliana Amaddeo, Alexis Laurent, Julien Calderaro, Sebastien Mule, and Alain Luciani
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Carcinoma, Hepatocellular ,Radiological and Ultrasound Technology ,Digestive System Diseases ,Urology ,Angiomyolipoma ,Liver Neoplasms ,Gastroenterology ,Contrast Media ,Magnetic Resonance Imaging ,Adenoma, Liver Cell ,Diagnosis, Differential ,Liver ,Focal Nodular Hyperplasia ,Humans ,Radiology, Nuclear Medicine and imaging ,Retrospective Studies - Abstract
To evaluate the accuracy of the usual MRI diagnostic patterns of primary liver lesions applied to the diagnosis of pathologically proven fat-containing liver lesions.This monocentric IRB approved retrospective study included all patients with pathologically proven focal liver lesions and documented intra-tumoral fat on pathology and who underwent preoperative liver MRI for characterization. Both liver morphology and usual lesion MRI features were analyzed and their distribution correlated to the final pathological result (Khi-2 or Fisher exact tests, Student t-test or Mann-Whitney U test, as appropriate). The Sensitivity (Se) and Specificity (Sp) of MRI patterns known to be associated to both Hepatocellular Carcinoma (HCC), Focal Nodular Hyperplasia (FNH), and Hepatocellular Adenoma (HCA) subtypes were evaluated.Between March 2014 and November 2021, 66 lesions were included, corresponding to: 26 HCC, 32 HCA, 6 FNH and 2 hepatic angiomyolipoma (HAML). All lesions developed on a dysmorphic liver were HCC. A non-rim arterial phase hyperenhancement with a washout and an enhancing capsule had a 98% specificity for HCC diagnosis; A homogeneous dropout of signal on the opposed phase had a sensitivity of 92% and a specificity of 89% for the diagnosis of HNF1alpha inactivated subtype of HCA (HHCA). The FNH pattern was specific at 100% for the diagnosis of FNH with a 40% Se. Finally, the accuracy of inflammatory hepatocellular adenoma (IHCA) pattern had a low 60% Se but a high 89% Sp for IHCA diagnosis.Known MRI patterns remain reliable for the accurate diagnosis of primary liver tumors on MRI even in fat-containing lesions.
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- 2022
7. Artificial intelligence for the prevention and clinical management of hepatocellular carcinoma
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Julien, Calderaro, Tobias Paul, Seraphin, Tom, Luedde, and Tracey G, Simon
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Machine Learning ,Carcinoma, Hepatocellular ,Hepatology ,Artificial Intelligence ,Liver Neoplasms ,Humans ,Algorithms ,Article - Abstract
Hepatocellular carcinoma (HCC) currently represents the fifth most common malignancy and the third-leading cause of cancer-related death, worldwide, with incidence and mortality rates that are increasing. Recently, artificial intelligence (AI) has emerged as a unique opportunity to improve the full spectrum of HCC clinical care, by improving HCC risk prediction, diagnosis, and prognostication. AI approaches include computational search algorithms, machine learning (ML) and deep learning (DL) models. ML consists of a computer running repeated iterations of models, in order to progressively improve performance of a specific task, such as classifying an outcome. DL models are a subtype of ML, based on neural network (NN) structures that are inspired by the neuroanatomy of the human brain. A growing body of recent data now apply DL models to diverse data sources – including electronic health record data, imaging modalities, histopathology and molecular biomarkers – to improve the accuracy of HCC risk prediction, detection and prediction of treatment response. Despite the promise of these early results, future research is still needed to standardize AI data, and to improve both generalizability and the interpretability of results. If such challenges can be overcome, AI has the potential to profoundly change the way in which care is provided to patients with or at risk for HCC.
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- 2022
8. Reduction trend of mcr-1 circulation in Emilia-Romagna Region, Italy
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Simone Ambretti, Chiara Bracchi, Vittorio Sambri, Carlo Biagetti, Adriana Calderaro, Claudia Venturelli, Giuseppe Diegoli, Ilaria Menozzi, Maria Federica Pedna, Martina Tambassi, Rossella Buttazzi, Carlo Gagliotti, Stefano Pongolini, Mario Sarti, Enrico Ricchizzi, Marianna Meschiari, Maria Luisa Moro, Erika Scaltriti, Massimo Confalonieri, Agostino Barozzi, Marina Morganti, Laura Soliani, Roberta Schiavo, Edoardo Carretto, Luca Bolzoni, Fabio Tumietto, Chiara Casadio, Gagliotti C., Bolzoni L., Carretto E., Sarti M., Ricchizzi E., Ambretti S., Barozzi A., Bracchi C., Confalonieri M., Menozzi I., Morganti M., Pedna M.F., Sambri V., Scaltriti E., Schiavo R., Soliani L., Tambassi M., Venturelli C., Biagetti C., Buttazzi R., Calderaro A., Casadio C., Meschiari M., Tumietto F., Diegoli G., Pongolini S., and Moro M.L.
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Microbiology (medical) ,Veterinary medicine ,Antimicrobials for veterinary use ,Antibiotic resistance ,Clonal dissemination ,Klebsiella pneumoniae ,Population ,Drug Resistance ,Horizontal transfer ,Bacterial Protein ,Microbial Sensitivity Tests ,Minimum inhibitory concentration ,Enterobacterales ,One Health approach ,Plasmid ,Bacterial Proteins ,Enterobacteriaceae ,Enterobacterale ,Anti-Bacterial Agent ,Drug Resistance, Bacterial ,medicine ,Humans ,Colistin ,Mcr ,Anti-Bacterial Agents ,Enterobacteriaceae Infections ,Ethanolaminephosphotransferase ,Italy ,Phylogeny ,Retrospective Studies ,education ,education.field_of_study ,biology ,Microbial Sensitivity Test ,Bacterial ,General Medicine ,biology.organism_classification ,Enterobacteriaceae Infection ,Infectious Diseases ,Salmonella enterica ,MCR-1 ,Enterobacter cloacae ,hormones, hormone substitutes, and hormone antagonists ,Human ,medicine.drug - Abstract
This study aims to describe trends of mcr-positive Enterobacterales in humans based on laboratory surveillance with a defined catchment population. The data source is the Micro-RER surveillance system, established in Emilia-Romagna region (Italy), to monitor the trend of mcr resistance. Enterobacterales isolates from human clinical samples with minimum inhibitory concentration (MIC) ≥ 2mg/L for colistin were sent to the study reference laboratory for the detection of mcr genes. Isolates prospectively collected in the period 2018–2020 were considered for the assessment of population rates and trends; further analyses were carried out for the evaluation of clonality and horizontal mcr gene transfer. Previous isolates from local laboratory collection were also described. In the period 2018–2020, 1164 isolates were sent to the reference laboratory, and 51 (4.4%) were confirmed as mcr-positive: 50 mcr-1 (42 Escherichia coli, 6 Klebsiella pneumoniae, 2 Salmonella enterica) and 1 mcr-4 (Enterobacter cloacae). The number of mcr-positive isolates dropped from 24 in the first half of 2018 to 3 in the whole of 2020 (trend p value < 0.001). Genomic analyses showed the predominant role of the horizontal transfer of mcr genes through plasmids or dissemination of transposable elements compared to clonal dissemination of mcr-positive microorganisms. The study results demonstrate a substantial decrease in the circulation of mcr-1 plasmid genes in Emilia-Romagna Region.
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- 2021
9. Structure, Dynamics, and Impact of Replication Stress–Induced Structural Variants in Hepatocellular Carcinoma
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Quentin Bayard, Pierre Cordier, Camille Péneau, Sandrine Imbeaud, Theo Z. Hirsch, Victor Renault, Jean-Charles Nault, Jean-Frédéric Blanc, Julien Calderaro, Chantal Desdouets, Jessica Zucman-Rossi, Eric Letouzé, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Fondation Jean Dausset CEPH, Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine [Bobigny], Université Paris 13 (UP13)-Sorbonne Paris Cité, Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], CHU de Bordeaux Pellegrin [Bordeaux], Bordeaux Research In Translational Oncology [Bordeaux] (BaRITOn), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Henri Mondor, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), and Zucman-Rossi, Jessica
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Cancer Research ,Carcinoma, Hepatocellular ,Whole Genome Sequencing ,Oncology ,Cyclins ,Liver Neoplasms ,Humans ,[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,Oncogenes ,[SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology - Abstract
Oncogene activation leads to replication stress and promotes genomic instability. Here we combine optical mapping and whole-genome sequencing (WGS) to explore in depth the nature of structural variants (SV) induced by replication stress in cyclin-activated hepatocellular carcinomas (CCN-HCC). In addition to classical tandem duplications, CCN-HCC displayed frequent intra-chromosomal and interchromosomal templated insertion cycles (TIC), likely resulting from template switching events. Template switching preferentially involves active topologically associated domains that are proximal to one another within the 3D genome. Template sizes depend on the type of cyclin activation and are coordinated within each TIC. Replication stress induced continuous accumulation of SVs during CCN-HCC progression, fostering the acquisition of new driver alterations and large-scale copy-number changes at TIC borders. Together, this analysis sheds light on the mechanisms, dynamics, and consequences of SV accumulation in tumors with oncogene-induced replication stress. Significance: Optical mapping and whole-genome sequencing integration unravels a unique signature of replication stress–induced structural variants that drive genomic evolution and the acquisition of driver events in CCN-HCC.
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- 2022
10. Gene expression signature as a surrogate marker of microvascular invasion on routine hepatocellular carcinoma biopsies
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Aurélie Beaufrère, François Cauchy, Stefano Caruso, Nicolas Poté, Jessica Zucman-Rossi, Gabielle Couchy, Valérie Paradis, Valérie Vilgrain, Julien Calderaro, and Jean-Charles Bijot
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Adult ,Male ,Oncology ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,Multivariate analysis ,Adolescent ,Biopsy ,Gene Expression ,Cohort Studies ,Proto-Oncogene Proteins ,Internal medicine ,Gene expression ,ROS1 ,Humans ,Medicine ,fas Receptor ,Angiopoietin-Like Protein 7 ,Glucuronosyltransferase ,Risk factor ,Aged ,Aged, 80 and over ,Hepatology ,medicine.diagnostic_test ,business.industry ,Surrogate endpoint ,Liver Neoplasms ,Hazard ratio ,Geminin ,Middle Aged ,Protein-Tyrosine Kinases ,medicine.disease ,Angiopoietin-like Proteins ,Ki-67 Antigen ,Hepatocellular carcinoma ,Microvessels ,Female ,France ,business ,Biomarkers - Abstract
Background & Aims Microvascular invasion (MVI), a major risk factor for tumor recurrence after surgery in hepatocellular carcinoma (HCC), is only detectable by microscopic examination of the surgical specimen. We aimed to define a transcriptomic signature associated with MVI in HCC than can be applied to formalin-fixed paraffin-embedded (FFPE) biopsies for use in clinical practice. Methods To identify a gene expression signature related to MVI by using NanoString technology, we selected a set of 200 genes according to the literature and RNA-sequencing data obtained from a cohort of 150 frozen HCC samples previously published. We used 178 FFPE-archived HCC samples, including 109 surgical samples for the training set and 69 paired pre-operative biopsies for the validation set. In 14 cases of the training set, a paired biopsy was available and was also analyzed. Results We identified a 6-gene signature (ROS1, UGT2B7, FAS, ANGPTL7, GMNN, MKI67) strongly associated with MVI in the training set of FFPE surgical HCC samples, with 82% accuracy (sensitivity 82%, specificity 81%, AUC 0.82). The NanoString gene expression was highly correlated in 14 paired surgical/biopsy HCC samples (mean R: 0.97). In the validation set of 69 FFPE HCC biopsies, the 6-gene NanoString signature predicted MVI with 74% accuracy (sensitivity 73%, specificity 76%, AUC 0.74). Moreover, on multivariate analysis, the MVI signature was associated with overall survival in both sets (hazard ratio 2.29; 95% CI 1.03-5.07; p = 0.041). Conclusion We defined a 6-gene signature that can accurately predict MVI in FFPE HCC biopsy samples, which is also associated with overall survival, although its survival impact must be confirmed by extensive study with further clinical data. Lay summary Microvascular invasion, a major risk factor for tumor recurrence after surgery in hepatocellular carcinoma, is only detectable by microscopic examination of a surgical specimen. In this study, we defined a relevant surrogate signature of microvascular invasion in hepatocellular carcinoma that may be applied in clinical practice with routine tumor biopsy and integrated into the therapeutic strategy.
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- 2022
11. Offspring's risk for suicidal behaviour in relation to parental death by suicide: systematic review and meta-analysis and a model for familial transmission of suicide
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Meryam Schouler-Ocak, Christopher Baethge, Jonathan Henssler, Stefan Gutwinski, Felix Bermpohl, and Mara Calderaro
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Offspring ,Familial transmission ,Suicide, Attempted ,Parental Death ,Suicidal Ideation ,Psychiatry and Mental health ,Child of Impaired Parents ,Risk Factors ,Meta-analysis ,Humans ,Relation (history of concept) ,Psychology ,Clinical psychology - Abstract
BackgroundExposure to parental suicide has been associated with increased risk for suicide and suicide attempts, although the strength of this association is unclear as evidence remains inconsistent.AimsTo quantify this risk using meta-analysis and identify potential effect modifiers.MethodA systematic search in PubMed, PsycInfo and Embase databases to 2020 netted 3614 articles. Inclusion criteria were: observation of history of parental death by suicide, comparison with non-exposed populations and definition of suicide and suicide attempt according to standardised criteria. We focused on population-based studies. The primary outcome was the pooled relative risk (RR) for incidence of suicide attempt and suicide in offspring of a parent who died by suicide compared with offspring of two living parents. Additionally, we compared the RR for attempted and completed suicide after parental suicide with the RR for attempted and completed suicide after parental death by other causes.ResultsTwenty studies met our inclusion criteria. Offspring exposed to parental suicide were more likely to die by suicide (RR = 2.97, 95% CI 2.50–3.53) and attempt suicide (RR = 1.76, 95% CI 1.58–1.96) than offspring of two living parents. Furthermore, their risk of dying by or attempting suicide was significantly higher compared with offspring bereaved by other causes of death.ConclusionsThe experience of losing a parent to suicide is a strong and independent risk factor for suicidal behaviour in offspring. Our findings highlight the need for prevention strategies, outreach programmes and support interventions that target suicide-related outcomes in the exposed population.
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- 2021
12. Controle dos fatores de risco cardiovascular - o que há de novo para o neurologista?
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Luciana Dornfeld Bichuette, Marcos Pita Lottenberg, Francisco Akira Malta Cardozo, and Daniela Calderaro
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Stroke ,Neurology ,Aterosclerose ,Risk Factors ,Hypertension ,Acidente Vascular Cerebral ,Humans ,Neurology (clinical) ,Neurologists ,Atherosclerosis ,Fatores de Risco - Abstract
Stroke is the second leading cause of death worldwide and the vast majority can be attributed to modifiable risk factors, mainly behavioral and metabolic. The top six risk factors responsible for cardiovascular mortality in Brazil in 2019 were high systolic blood pressure, inadequate dietary exposure, high body mass index, high LDL cholesterol, high fasting blood glucose levels, and tobacco. We intend to discuss in this paper the evidence and recommendations in the approach of three essential risk factors for patients with a history of stroke: dyslipidemia, hypertension and diabetes. RESUMO O acidente vascular cerebral (AVC) é a segunda causa de morte no mundo e, em grande parte, pode ser atribuído a fatores de risco modificáveis, principalmente comportamentais e metabólicos. Os seis principais fatores de risco responsáveis pela mortalidade cardiovascular no Brasil em 2019 foram pressão arterial sistólica elevada, exposição alimentar inadequada, índice de massa corporal elevado, LDL -colesterol elevado, níveis alterados de glicemia e tabagismo. Pretendemos discutir neste artigo as evidências e recomendações na abordagem de três fatores de risco essenciais para pacientes com histórico de AVC: dislipidemia, hipertensão e diabetes.
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- 2022
13. Realistic simulation is associated with healthcare professionals’ increased self-perception of confidence in providing acute stroke care: a before-after controlled study
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M. B. Teixeira, Rogério da Hora Passos, Fernando Mendes Paschoal Junior, Adelmo Vinicius Lima Oliveira, André Luiz Nunes Gobatto, Michel Pordeus Ribeiro, Mariana Sampaio Motta Reis, Luis C. L. Correia, Suzete Nascimento Farias da Guarda, Octavio M. Pontes-Neto, João Gabriel Rosa Ramos, Paulo Benigno Pena Batista, Juliana Ribeiro Caldas, João Pedro Souza Santos, and Marcelo Calderaro
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medicine.medical_specialty ,Multivariate analysis ,Health Personnel ,030231 tropical medicine ,Neurosciences. Biological psychiatry. Neuropsychiatry ,Education ,03 medical and health sciences ,0302 clinical medicine ,Interquartile range ,medicine ,Humans ,Simulation Training ,Stroke ,Acute stroke ,ASSISTÊNCIA À SAÚDE ,Health professionals ,business.industry ,Confounding ,Neurointensive care ,medicine.disease ,Self Concept ,High Fidelity Simulation Training ,Educação ,Neurology ,Life support ,Acidente Vascular Cerebral ,Physical therapy ,Clinical Competence ,Neurology (clinical) ,Treinamento com Simulação de Alta Fidelidade ,business ,Delivery of Health Care ,030217 neurology & neurosurgery ,RC321-571 - Abstract
Background: Simulations are becoming widely used in medical education, but there is little evidence of their effectiveness on neurocritical care. Because acute stroke is a neurological emergency demanding prompt attention, it is a promising candidate for simulation training. Objective: To assess the impact of a stroke realistic simulation course on clinicians’ self-perception of confidence in the management of acute stroke. Methods: We conducted a controlled, before-after study. For our intervention, 17 healthcare professionals participated in a stroke realistic simulation course. As controls, participants were chosen from a convenience sample of attendees to the courses Emergency Neurologic Life Support (ENLS) (18 participants) and Neurosonology (20 participants). All participants responded pre- and post-test questionnaires evaluating their self-perception of confidence in acute stroke care, ranging from 10 to 50 points. We evaluated the variation between pre- and post-test results to assess the change on trainees’ self-perception of confidence in the management of acute stroke. Multivariate analysis was performed to control for potential confounders. Results: Forty-six (83.63%) subjects completed both questionnaires. The post-test scores were higher than those from the pretests in the stroke realistic simulation course group [pretest median (interquartile range - IQR): 41.5 (36.7-46.5) and post-test median (IQR): 47 (44.7-48); p=0.033], but not in the neurosonology [pretest median (IQR): 46 (44-47) and post-test median (IQR): 46 (44-47); p=0.739] or the ENLS [pretest median (IQR): 46.5 (39-48.2), post-test median (IQR): 47 (40.2-49); p=0.317] groups. Results were maintained after adjustment for covariates. Conclusions: This stroke realistic simulation course was associated with an improvement on trainees’ self-perception of confidence in providing acute stroke care. RESUMO Introdução: Simulações são amplamente utilizadas na educação médica, mas há pouca evidência de sua eficácia no tratamento de pacientes neurocríticos. Como o acidente vascular cerebral agudo (AVC) é uma patologia que requer atendimento imediato, o uso de simulação pode ser uma ferramenta útil no treinamento do manejo desses pacientes. Objetivo: Avaliar o impacto do uso de simulação realística na autopercepção de segurança no atendimento a pacientes vítimas de AVC agudo. Métodos: Estudo antes-depois controlado. No grupo da intervenção, 17 profissionais da área de saúde participaram de um curso de simulação realística de atendimento a pacientes com AVC. Como controles, os participantes foram escolhidos a partir de uma amostra de conveniência composta por 18 participantes do curso Emergency Neurologic Life Support (ENLS) e 20 participantes de um curso de Neurossonologia. Foram respondidos questionários antes e após o curso para avaliar a autopercepção de segurança no atendimento a pacientes vítimas de AVC agudo, variando de 10 a 50 pontos. Foi avaliada a variação entre os resultados pré- e pós-teste, para avaliar a mudança na autopercepção de confiança do trainee no manejo do AVC agudo. Análise multivariada foi realizada para controlar possíveis fatores de confusão. Resultados: Quarenta e seis (83,63%) participantes responderam aos questionários. A pontuação no questionário pós-curso foi maior do que a obtida no questionário pré-curso no grupo de participantes do curso de simulação realística em AVC [mediana do questionário pré-curso: 41,5 (36,7-46,5) e mediana do questionário pós-curso: 47,0 (44,7-48,0); p=0,033]. Essa diferença não foi observada no curso de Neurossonologia [mediana pré-curso (IQR): 46,0 (44,0-47,00), mediana pós-curso (IQR): 46,0 (44,0-47,0); p=0,739] nem no ENLS [mediana pré-curso (IQR): 46,5 (39,0-48,2) mediana pós-curso (IQR): 47,0 (40,2-49,0); p=0,317]. Esses resultados persistiram após ajuste das variáveis. Conclusão: O curso de simulação realística em AVC foi associado a um aumento na autopercepção de segurança dos participantes em atender pacientes vítimas de AVC agudo.
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- 2021
14. Indication and Contraindication of Endoscopic Transforaminal Lumbar Decompression
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Anthony Yeung, Marlon Sudário de Lima E Silva, Jorge Felipe Ramírez León, Thiago Soares dos Santos, Paulo Sérgio Teixeira de Carvalho, André Luiz Calderaro, Kai-Uwe Lewandrowski, and Álvaro Dowling
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,Visual analogue scale ,Decompression ,Spinal stenosis ,Young Adult ,03 medical and health sciences ,Spinal Stenosis ,0302 clinical medicine ,Lumbar ,Preoperative Care ,Humans ,Medicine ,Contraindication ,Aged ,Retrospective Studies ,Aged, 80 and over ,Lumbar Vertebrae ,business.industry ,Lumbar spinal stenosis ,Middle Aged ,Decompression, Surgical ,medicine.disease ,Oswestry Disability Index ,Surgery ,Stenosis ,030220 oncology & carcinogenesis ,Neuroendoscopy ,Female ,Neurology (clinical) ,business ,Low Back Pain ,030217 neurology & neurosurgery ,Follow-Up Studies - Abstract
Background The indications and contraindications to the endoscopic transforaminal approach for lumbar spinal stenosis are not well defined. Methods We performed a Kaplan-Meier durability survival analysis of patients with the following types of spinal stenosis: type I, central canal; type II, lateral recess; type III, foraminal; and type IV, extraforaminal. The 304 patients comprised 140 men and 164 women, with an average age of 51.68 ± 15.78 years. The average follow-up was 45.3 years (range, 18–90 years). The primary clinical outcome measures were the Oswestry Disability Index, visual analog scale, and the modified Macnab criteria. Results Of 304 study patients, 70 had type I (23.0%) stenosis, 42 type II (13.7%), 151 type III (49.7%), and 41 type IV (13.5%). Excellent outcomes were obtained in 114 patients (37.5%), good in 152 (50.0%), fair in 33 (10.9%), and poor in 5 (1.6%). Kaplan-Meier durability analysis of the clinical treatment benefit with the endoscopic transforaminal decompression surgery showed statistically significance differences (P Conclusions We recommend stratifying patients based on the underlying compressive disease and the skill level of the endoscopic spine surgeon to decide preoperatively whether more difficult central or complex foraminal stenotic lesions should be considered for alternative endoscopic approaches.
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- 2021
15. Human respiratory viruses, including SARS-CoV-2, circulating in the winter season 2019–2020 in Parma, Northern Italy
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Mirko Buttrini, Adriana Calderaro, Monica Martinelli, Maria Cristina Arcangeletti, Paolo Montagna, Giovanna Piccolo, F. Ferraglia, Flora De Conto, Alan Di Maio, Carlo Chezzi, Clara Maccari, Sara Montecchini, and F. Pinardi
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Adult ,Male ,0301 basic medicine ,Microbiology (medical) ,medicine.medical_specialty ,Epidemiology ,viruses ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Respiratory System ,030106 microbiology ,Biology ,medicine.disease_cause ,Virus ,lcsh:Infectious and parasitic diseases ,Tertiary Care Centers ,03 medical and health sciences ,0302 clinical medicine ,Diagnosis ,Pandemic ,medicine ,Humans ,lcsh:RC109-216 ,030212 general & internal medicine ,Respiratory system ,Child ,Respiratory Tract Infections ,Respiratory viruses ,Coinfection ,SARS-CoV-2 ,Age Factors ,Molecular assays ,COVID-19 ,Infant ,General Medicine ,Virology ,Infectious Diseases ,medicine.anatomical_structure ,Italy ,Viruses ,Respiratory virus ,Female ,Seasons ,Rhinovirus ,Respiratory tract - Abstract
Objectives The aim of this study was to determine the prevalence of respiratory virus infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), during the winter period December 2019 to March 2020, via a tertiary care hospital-based survey in Parma, Northern Italy. Methods A total of 906 biological samples from the respiratory tract were analysed by both conventional assays (including culture) and molecular assays targeting nucleic acids of SARS-CoV-2 and other respiratory viruses. Results Overall, 474 samples (52.3%) were positive for at least one virus, with a total of 583 viruses detected. Single infections were detected in 380 (80.2%) samples and mixed infections were detected in 94 (19.8%). Respiratory syncytial virus (138/583, 23.7%) and rhinovirus (130/583, 22.3%) were the most commonly identified viruses, followed by SARS-CoV-2 (82/583, 14.1%). Respiratory syncytial virus predominated until February, with 129 detections; it then decreased drastically in March to only nine detections. SARS-CoV-2 was absent in the study area until February 26, 2020 and then reached 82 detections in just over a month. SARS-CoV-2 was found in mixed infections in only three cases, all observed in children younger than 1 year old. Conclusions This study showed a completely different trend between SARS-CoV-2 and the ‘common’ respiratory viruses: the common viruses mostly affected children, without any distinction according to sex, while SARS-CoV-2 mostly affected adult males.
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- 2021
16. Artificial intelligence-based pathology for gastrointestinal and hepatobiliary cancers
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Jakob Nikolas Kather and Julien Calderaro
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0301 basic medicine ,medicine.medical_specialty ,Pathology ,03 medical and health sciences ,Tumour tissue ,0302 clinical medicine ,Artificial Intelligence ,Image Interpretation, Computer-Assisted ,Biomarkers, Tumor ,medicine ,Humans ,Gastrointestinal Neoplasms ,business.industry ,Liver Neoplasms ,Gastroenterology ,Reproducibility of Results ,Cancer ,Prognosis ,medicine.disease ,Biliary Tract Neoplasms ,030104 developmental biology ,030220 oncology & carcinogenesis ,Microsatellite Instability ,Histopathology ,Artificial intelligence ,Applications of artificial intelligence ,Liver cancer ,business - Abstract
Artificial intelligence (AI) can extract complex information from visual data. Histopathology images of gastrointestinal (GI) and liver cancer contain a very high amount of information which human observers can only partially make sense of. Complementing human observers, AI allows an in-depth analysis of digitised histological slides of GI and liver cancer and offers a wide range of clinically relevant applications. First, AI can automatically detect tumour tissue, easing the exponentially increasing workload on pathologists. In addition, and possibly exceeding pathologist’s capacities, AI can capture prognostically relevant tissue features and thus predict clinical outcome across GI and liver cancer types. Finally, AI has demonstrated its capacity to infer molecular and genetic alterations of cancer tissues from histological digital slides. These are likely only the first of many AI applications that will have important clinical implications. Thus, pathologists and clinicians alike should be aware of the principles of AI-based pathology and its ability to solve clinically relevant problems, along with its limitations and biases.
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- 2020
17. Imaging and histological features of tumor biopsy sample predict aggressive intrasegmental recurrence of hepatocellular carcinoma after radiofrequency ablation
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Elia Gigante, Yohann Haddad, Jean-Charles Nault, Olivier Sutter, Einas Abou Ali, Baptiste Bonnet, Gisèle N’Kontchou, Veronique Grando, Nathalie Ganne-Carrié, Pierre Nahon, Lorraine Blaise, Julien Calderaro, Nathalie Barget, Olivier Seror, and Marianne Ziol
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Male ,Radiofrequency Ablation ,Multidisciplinary ,Carcinoma, Hepatocellular ,Treatment Outcome ,Biopsy ,Liver Neoplasms ,Catheter Ablation ,Humans ,Neoplasm Recurrence, Local ,Aged ,Retrospective Studies - Abstract
Aggressive intrasegmental recurrence (AIR) is a form of local recurrence associated with a dismal prognosis and defined by multiple nodules or by an infiltrative mass with a tumor thrombus, occurring in the treated segment, after radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). We aimed to identify radiological and/or histological characteristics of tumor biopsy predictive of AIR. We retrospectively analyzed patients treated by No-Touch multi-bipolar RFA (mbpRFA) for a first HCC with a systematic per-procedural tumor biopsy positive for diagnosis of HCC. The first recurrence was classified as non-aggressive local recurrence, AIR or intrahepatic distant recurrence. 212 patients were included (168 men; mean age 67.1 years; mean tumor size 28.6 mm, 181 cirrhosis). AIR occurred in 21/212 patients (10%) and was associated with a higher risk of death (57% in patients with AIR vs 30% without AIR, p = 0.0001). Non-smooth tumor margins, observed in 21% of the patients and macro-trabecular massive histological subtype, observed in 12% of the patients were independently related to a higher risk of AIR (HR: 3.7[1.57;9.06], p = 0.002 and HR:3.8[2.47;10], p = 0.005 respectively). Non smooth margins at imaging and macro-trabecular massive histological subtype are associated with AIR and could be considered as aggressive features useful to stratify therapeutic strategy.
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- 2022
18. Effects of dabigatran versus warfarin on 2-year cognitive outcomes in old patients with atrial fibrillation: results from the GIRAF randomized clinical trial
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Bruno Caramelli, Pai Ching Yu, Francisco A. M. Cardozo, Iuri R. Magalhães, Raphael R. Spera, Daniel K. Amado, Maria C. Escalante-Rojas, Danielle M. Gualandro, Daniela Calderaro, Caio A. M. Tavares, Flavio A. Borges-Junior, Adriana F. Pastana, Mariana G. Matheus, Sonia M. D. Brucki, Ana Carolina O. Rodrigues, Ricardo Nitrini, and Paulo Caramelli
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Stroke ,Cognition ,Atrial Fibrillation ,Humans ,Anticoagulants ,General Medicine ,Warfarin ,Brazil ,Aged ,Dabigatran - Abstract
Background Observational studies support a role for oral anticoagulation to reduce the risk of dementia in atrial fibrillation patients, but conclusive data are lacking. Since dabigatran offers a more stable anticoagulation, we hypothesized it would reduce cognitive decline when compared to warfarin in old patients with atrial fibrillation. Methods The GIRAF trial was a 24-month, randomized, parallel-group, controlled, open-label, hypothesis generating trial. The trial was done in six centers including a geriatric care unit, secondary and tertiary care cardiology hospitals in São Paulo, Brazil. We included patients aged ≥ 70 years and CHA2DS2-VASc score > 1. The primary endpoint was the absolute difference in cognitive performance at 2 years. Patients were assigned 1:1 to take dabigatran (110 or 150 mg twice daily) or warfarin, controlled by INR and followed for 24 months. Patients were evaluated at baseline and at 2 years with a comprehensive and thorough cognitive evaluation protocol of tests for different cognitive domains including the Montreal Cognitive Assessment (MoCA), Mini-Mental State Exam (MMSE), a composite neuropsychological test battery (NTB), and computer-generated tests (CGNT). Results Between 2014 and 2019, 5523 participants were screened and 200 were assigned to dabigatran (N = 99) or warfarin (N = 101) treatment. After adjustment for age, log of years of education, and raw baseline score, the difference between the mean change from baseline in the dabigatran group minus warfarin group was − 0.12 for MMSE (95% confidence interval [CI] − 0.88 to 0.63; P = 0.75), 0.05 (95% CI − 0.07 to 0.18; P = 0.40) for NTB, − 0.15 (95% CI − 0.30 to 0.01; P = 0.06) for CGNT, and − 0.96 (95% CI − 1.80 to 0.13; P = 0.02) for MoCA, with higher values suggesting less cognitive decline in the warfarin group. Conclusions For elderly patients with atrial fibrillation, and without cognitive compromise at baseline that did not have stroke and were adequately treated with warfarin (TTR of 70%) or dabigatran for 2 years, there was no statistical difference at 5% significance level in any of the cognitive outcomes after adjusting for multiple comparisons. Trial registration Cognitive Impairment Related to Atrial Fibrillation Prevention Trial (GIRAF), NCT01994265.
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- 2022
19. Vestibular migraine
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Viviane Passarelli Ramin Silva, Luiz Henrique Martins Castro, and Marcelo Calderaro
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Transtornos de Enxaqueca ,Adult ,Diagnosis, Differential ,Epilepsy ,Neurology ,Migraine Disorders ,Headache ,Humans ,Neurology (clinical) ,Cefaleia ,Benign Paroxysmal Positional Vertigo - Abstract
Vestibular migraine (VM) remains an underdiagnosed condition, often mistaken with brainstem aura. VM is defined by recurrent vestibular symptoms in at least 50% of migraine attacks. Diagnosis is established by clinical criteria based on the International Classification of Headache Disorders (ICHD-3). Estimated prevalence of VM is 1 to 2.7% of the adult population. Vestibular symptoms usually appear after the headache. VM pathophysiology remains poorly understood. Vertigo may occur before, during, after the migraine attack, or even independently, and may last seconds to hours or days. Pathophysiological mechanisms for VM are still poorly understood and are usually extrapolated from migraines. Differential diagnoses include Ménière's disease, benign paroxysmal positional vertigo, brainstem aura, transient ischemic attack, persistent perceptual postural vertigo, and episodic type 2 ataxia. Specific treatment recommendations for vestibular migraine are still scarce. RESUMO Migrânea vestibular (MV) é pouco diagnosticada e comumente confundida com aura de tronco. A MV, definida por sintomas vestibulares recorrentes em até 50% das crises de migrânea. O diagnóstico baseia-se em critérios clínicos, descritos no International Classification of Headache Disorders (ICHD-3). Estima-se prevalência de MV em 1 a 2.7% da população adulta. Sintomas vestibulares geralmente ocorrem mais tardiamente comparados à cefaleia. A vertigem pode surgir antes, durante, depois, ou mesmo independentemente da crise de enxaqueca, com duração de segundos a horas ou dias. Pouco se conhece acerca da fisiopatologia da MV, que é geralmente extrapolada dos conhecimentos sobre migrânea. Diagnósticos diferenciais incluem: Doença de Ménière, Vertigem posicional paroxística benigna, aura de tronco, ataque isquêmico transitório, vertigem postural perceptual persistente e ataxia episódica tipo 2. Especialistas recomendam o mesmo tratamento que para enxaqueca. Estudos sobre o tratamento específico da migrânea vestibular ainda são escassos.
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- 2022
20. Oral and maxillofacial manifestations of IgG4-related disease: A clinicopathological study
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Glauce Guimarães Pereira, Flávia Sirotheau Corrêa Pontes, Ciro Dantas Soares, Maria Goretti Freire Carvalho, Tarcília Aparecida Silva, Débora Cerqueira Calderaro, Gilda Aparecida Ferreira, Leandro Augusto Tanure, Lucas Lacerda Souza, Carla Isabelly Rodrigues‐Fernandes, Oslei Paes Almeida, Felipe Paiva Fonseca, and Hélder Antônio Rebelo Pontes
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Cancer Research ,Otorhinolaryngology ,Immunoglobulin G ,Submandibular Gland ,Periodontics ,Humans ,Female ,Immunoglobulin G4-Related Disease ,Oral Surgery ,Middle Aged ,Lip ,Salivary Glands ,Pathology and Forensic Medicine - Abstract
IgG4-related disease is a fibroinflammatory and immune-mediated condition, which has extremely variable clinical manifestations. In this study, we aim to investigate the clinicopathological features of IgG4-related disease involving the oral and maxillofacial region.Cases of IgG4-related disease manifesting in the oral and maxillofacial region were retrieved from three Brazilian institutions. Clinical and serological data were obtained from the patients' medical charts, while microscopic and immunohistochemical findings were revised by oral pathologists. Diagnosis followed the American College of Rheumatology/European League against Rheumatism criteria.Seven patients diagnosed with IgG4-related disease were included in this study. Women were affected in all analysed cases, with a mean age of 55.4 years. Two patients presented with the clinical involvement of more than one oral and maxillofacial anatomic site. Therefore, our sample comprised nine oral and maxillofacial anatomic sites affected by IgG4-related disease. The submandibular gland was affected in four cases, the tongue and the parotid gland in two cases each, and the palate in one case. In a few cases, exploratory lower lip biopsy was used as a diagnostic approach. A moderate-to-severe lymphoid infiltrate containing plasma cells and lymphocytes, with an increased IgG4/IgG ratio, was common. Treatment varied and steroids were the most frequently used (57.4%). Six patients remained alive, while one died from unknown causes.Although major salivary glands are commonly affected by IgG4-related disease, the oral cavity can also be involved, and lower lip biopsy may be an auxiliary diagnostic tool.
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- 2022
21. Bi-allelic hydroxymethylbilane synthase inactivation defines a homogenous clinico-molecular subtype of hepatocellular carcinoma
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Laura Molina, Junjie Zhu, Eric Trépo, Quentin Bayard, Giuliana Amaddeo, Jean-Frédéric Blanc, Julien Calderaro, Xiaochao Ma, Jessica Zucman-Rossi, Eric Letouzé, Brigitte Le Bail, Laurence Chiche, Paulette Bioulac-Sage, Charles Balabaud, Laurent Possenti, Marie Decraecker, Valérie Paradis, and Alexis Laurent
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Carcinoma, Hepatocellular ,Hepatology ,Porphobilinogen ,Liver Neoplasms ,Heme ,Article ,Hydroxymethylbilane Synthase ,Oxygen ,Porphyria, Acute Intermittent ,Mutation ,Humans ,Genes, Tumor Suppressor ,Female ,beta Catenin - Abstract
Acute intermittent porphyria (AIP), caused by heterozygous germline mutations of the heme synthesis pathway enzyme HMBS (hydroxymethylbilane synthase), confers a high risk of hepatocellular carcinoma (HCC) development. Yet, the role of HMBS in liver tumorigenesis remains unclear.Herein, we explore HMBS alterations in a large series of 758 HCC cases, including 4 patients with AIP. We quantify the impact of HMBS mutations on heme biosynthesis pathway intermediates and we investigate the molecular and clinical features of HMBS-mutated tumors.We identify recurrent bi-allelic HMBS inactivation, both in patients with AIP acquiring a second somatic HMBS mutation and in sporadic HCC with 2 somatic hits. HMBS alterations are enriched in truncating mutations, in particular in splice regions, leading to abnormal transcript structures. Bi-allelic HMBS inactivation results in a massive accumulation of its toxic substrate porphobilinogen and synergizes with CTNNB1-activating mutations, leading to the development of well-differentiated tumors with a transcriptomic signature of Wnt/β-catenin pathway activation and a DNA methylation signature related to ageing. HMBS-inactivated HCC mostly affects females, in the absence of fibrosis and classical HCC risk factors.These data identify HMBS as a tumor suppressor gene whose bi-allelic inactivation defines a homogenous clinical and molecular HCC subtype.Heme (the precursor to hemoglobin, which plays a key role in oxygen transport around the body) synthesis occurs in the liver and involves several enzymes including hydroxymethylbilane synthase (HMBS). HMBS mutations cause acute intermittent porphyria, a disease caused by the accumulation of toxic porphyrin precursors. Herein, we show that HMBS inactivation is also involved in the development of liver cancers with distinct clinical and molecular characteristics.
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- 2022
22. Psoas muscle area and one-year mortality in a cohort of patients undergoing vascular surgery
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Caio Assis Moura Tavares, Danielle Menosi Gualandro, Francisco Akira Malta Cardozo, Marcelo Oranges Filho, Sabrina de Mello Ando, Daniela Calderaro, and Bruno Caramelli
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Cohort Studies ,Sarcopenia ,Humans ,Geriatrics and Gerontology ,Vascular Surgical Procedures ,Psoas Muscles ,Retrospective Studies - Published
- 2022
23. Common genetic variation in alcohol-related hepatocellular carcinoma: a case-control genome-wide association study
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Eric Trépo, Stefano Caruso, Jie Yang, Sandrine Imbeaud, Gabrielle Couchy, Quentin Bayard, Eric Letouzé, Nathalie Ganne-Carrié, Christophe Moreno, Abderrahim Oussalah, Cyrille Féray, Jean Frédéric Blanc, Bruno Clément, Patrick Hillon, Jérôme Boursier, Valérie Paradis, Julien Calderaro, Viviane Gnemmi, Jean-Charles Nault, Jean-Louis Guéant, Jacques Devière, Isabelle Archambeaud, Carole Vitellius, Bruno Turlin, Jean-Pierre Bronowicki, Thierry Gustot, Angela Sutton, Marianne Ziol, Pierre Nahon, Jessica Zucman-Rossi, Clément Meiller, Qian Cao, Théo Z. Hirsch, Sandra Rebouissou, Delphine Degré, Lukas Otero Sanchez, Nicolas Rosewick, Eric Quertinmont, Mireille Desille-Dugast, Muriel François-Vié, Cécile Moins, Emmanuelle Leteurtre, Guillaume Lassailly, Massih Ningarhari, Emmanuel Boleslawski, Vanessa Cottet, Université libre de Bruxelles (ULB), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), People's Hospital of Peking University (PKUPH), Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Hôpital Paul Brousse, CHU Bordeaux [Bordeaux], Bordeaux Research In Translational Oncology [Bordeaux] (BaRITOn), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHU Pontchaillou [Rennes], Centre de Ressources Biologiques Santé (CRB Santé), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-CRLCC Eugène Marquis (CRLCC), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Hôpital Beaujon [AP-HP], Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Henri Mondor, Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), CHU Lille, Institut des Maladies de l'Appareil Digestif, Université de Nantes (UN), Hôtel-Dieu de Nantes, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Hôpitaux Universitaires Paris Seine-Saint-Denis [Sevran] (HUP2SD), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), BB-0033-00027, H2020 Marie Skłodowska-Curie Actions, MSCA, University Hospitals, UH: NCT03311152, Bpifrance, Agence Nationale de la Recherche, ANR: ANR-11-LABX-0021, Institut National de la Santé et de la Recherche Médicale, Inserm, Assistance Publique - Hôpitaux de Paris, AP-HP, Ligue Contre le Cancer, Fondation de France, Institut National Du Cancer, INCa, Université Libre de Bruxelles, Conseil régional de Bourgogne-Franche-Comté, Korean Association for the Study of the Liver, KASL, GENTHEP Consortium: Clément Meiller, Qian Cao, Théo Z Hirsch, Sandra Rebouissou, Delphine Degré, Lukas Otero Sanchez, Nicolas Rosewick, Eric Quertinmont, Mireille Desille-Dugast, Muriel François-Vié, Cécile Moins, Emmanuelle Leteurtre, Guillaume Lassailly, Massih Ningarhari, Emmanuel Boleslawski, Vanessa Cottet, ANR-11-LABX-0021,Lipstic,Lipoprotéines et santé : prévention et traitement des maladies inflammatoires non vasculaires et du cancer(2011), École pratique des hautes études (EPHE), Jonchère, Laurent, Laboratoires d'excellence - Lipoprotéines et santé : prévention et traitement des maladies inflammatoires non vasculaires et du cancer - - Lipstic2011 - ANR-11-LABX-0021 - LABX - VALID, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-CRLCC Eugène Marquis (CRLCC), Faculté de Médecine [Bruxelles] [ULB], Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)], Biochimie – Biologie moléculaire et Nutrition [CHRU Nancy], Institut National de la Santé et de la Recherche Médicale [INSERM], Centre Hépato-Biliaire [Hôpital Paul Brousse] [CHB], Bordeaux Research In Translational Oncology [Bordeaux] [BaRITOn], Lipides - Nutrition - Cancer [Dijon - U1231] [LNC], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand [CHU Dijon], Centre Hospitalier Universitaire d'Angers [CHU Angers], Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques [HIFIH], Université Paris-Est Créteil Val-de-Marne - Paris 12 [UPEC UP12], Institut Mondor de Recherche Biomédicale [IMRB], Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER], Université Sorbonne Paris Nord, Centre Hospitalier Régional Universitaire de Nancy [CHRU Nancy], Nutrition-Génétique et Exposition aux Risques Environnementaux [NGERE], Nutrition, Métabolismes et Cancer [NuMeCan], Laboratoire de Recherche Vasculaire Translationnelle [LVTS (UMR_S_1148 / U1148)], Hôpital Européen Georges Pompidou [APHP] [HEGP], Thérapies Laser Assistées par l'Image pour l'Oncologie - U 1189 [ONCO-THAI], and Equipe EPICAD (LNC - U1231)
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Adult ,Male ,Carcinoma, Hepatocellular ,Genotype ,[SDV]Life Sciences [q-bio] ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Polymorphism, Single Nucleotide ,Young Adult ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Wnt3A Protein ,Humans ,Genetic Predisposition to Disease ,Aged ,Aged, 80 and over ,Liver Neoplasms ,Genetic Variation ,Middle Aged ,Wnt Proteins ,[SDV] Life Sciences [q-bio] ,Oncology ,Case-Control Studies ,Phospholipases A2, Calcium-Independent ,Female ,Alcohol-Related Disorders ,Acyltransferases ,Genome-Wide Association Study - Abstract
International audience; Background: Hepatocellular carcinoma is a frequent consequence of alcohol-related liver disease, with variable incidence among heavy drinkers. We did a genome-wide association study (GWAS) to identify common genetic variants for alcohol-related hepatocellular carcinoma. Methods: We conducted a two-stage case-control GWAS in a discovery cohort of 2107 unrelated European patients with alcohol-related liver disease aged 20–92 years recruited between Oct 22, 1993, and March 12, 2017. Cases were patients with alcohol-related hepatocellular carcinoma diagnosed by imaging or histology. Controls were patients with alcohol-related liver disease without hepatocellular carcinoma. We used an additive logistic regression model adjusted for the first ten principal components to assess genetic variants associated with alcohol-related hepatocellular carcinoma. We did another analysis with adjustment for age, sex, and liver fibrosis. New candidate associations (pandlt;1 × 10−6) and variants previously associated with alcohol-related hepatocellular carcinoma were evaluated in a validation cohort of 1933 patients with alcohol-related liver disease aged 29–92 years recruited between July 21, 1995, and May 2, 2019. We did a meta-analysis of the two case–control cohorts. Findings: The discovery cohort included 775 cases and 1332 controls. Of 7 962 325 variants assessed, we identified WNT3A-WNT9A (rs708113; p=1·11 × 10−8) and found support for previously reported regions associated with alcohol-related hepatocellular carcinoma risk at TM6SF2 (rs58542926; p=6·02 × 10−10), PNPLA3 (rs738409; p=9·29 × 10−7), and HSD17B13 (rs72613567; p=2·49 × 10−4). The validation cohort included 874 cases and 1059 controls and three variants were replicated: WNT3A-WNT9A (rs708113; p=1·17 × 10−3), TM6SF2 (rs58542926; p=4·06 × 10−5), and PNPLA3 (rs738409; p=1·17 × 10−4). All three variants reached GWAS significance in the meta-analysis: WNT3A-WNT9A (odds ratio 0·73, 95% CI 0·66–0·81; p=3·93 × 10−10), TM6SF2 (1·77, 1·52–2·07; p=3·84×10−13), PNPLA3 (1·34, 1·22–1·47; p=7·30 × 10−10). Adjustment for clinical covariates yielded similar results. We observed an additive effect of at-risk alleles on alcohol-related hepatocellular carcinoma. WNT3A-WNT9A rs708113 was not associated with liver fibrosis. Interpretation: WNT3A-WNT9A is a susceptibility locus for alcohol-related hepatocellular carcinoma, suggesting an early role of the Wnt–β-catenin pathway in alcohol-related hepatocellular carcinoma carcinogenesis.
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- 2022
24. Rivaroxaban versus no anticoagulation for post-discharge thromboprophylaxis after hospitalisation for COVID-19 (MICHELLE): an open-label, multicentre, randomised, controlled trial
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Eduardo Ramacciotti, Leandro Barile Agati, Daniela Calderaro, Valéria Cristina Resende Aguiar, Alex C Spyropoulos, Caroline Candida Carvalho de Oliveira, Jessica Lins dos Santos, Giuliano Giova Volpiani, Marcone Lima Sobreira, Edwaldo Edner Joviliano, Milton Sérgio Bohatch Júnior, Benedito Antônio Lopes da Fonseca, Maurício Serra Ribeiro, Cesar Dusilek, Kengi Itinose, Suzanna Maria Viana Sanches, Karine de Almeida Araujo Ramos, Nara Franzin de Moraes, Paulo Fernando Guimarães Morando Marzocchi Tierno, André Luiz Malavasi Longo de Oliveira, Adriano Tachibana, Rodrigo Caruso Chate, Marcus Vinícius Barbosa Santos, Bruno Bezerra de Menezes Cavalcante, Ricardo Cesar Rocha Moreira, Chiann Chang, Alfonso Tafur, Jawed Fareed, Renato D Lopes, Tania Benevenuto Caltabiano, Breno Hattori, Marcello da Silva Jardim, Igor Marinho, Ivan Silva Marinho, Liane Mara Melo Batista, Lucas Rivabem, Carlos Alberto Kenji Nakashima, Ana Carla Gois Franco, Renata Fernanda de Oliveira Pereira, Giana Caroline Strack Neves, Izara de Castro e Souza, Bruno Moraes Ribas, Flavia Ramos Tristão, Marcus Vinicius Barbosa Santos, Science Valley Research Institute, Santo André, Universidade de São Paulo (USP), Zucker School of Medicine at Hofstra/Northwell and the Feinstein Institutes for Medical Research, I M Sechenov First Moscow State Medical University, Universidade Estadual Paulista (UNESP), Hospital do Rocio, Salvador, Hospital Municipal de Barueri, São Paulo State Public Women's Health Reference Center, Hospital Israelita Albert Einstein, Institute of Teaching and Research Hapvida, Hospital Nossa Senhora das Graças, Northshore University Health System, Hemostasis and Thrombosis Research Laboratories at Loyola University Medical Center, and Duke University School of Medicine
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Adult ,Male ,Heparin ,SARS-CoV-2 ,Comment ,Aftercare ,Anticoagulants ,COVID-19 ,General Medicine ,Venous Thromboembolism ,Articles ,Middle Aged ,Patient Discharge ,COVID-19 Drug Treatment ,Hospitalization ,Treatment Outcome ,Rivaroxaban ,Humans ,Female ,Blood Coagulation ,Aged ,Factor Xa Inhibitors - Abstract
Made available in DSpace on 2022-04-29T08:46:13Z (GMT). No. of bitstreams: 0 Previous issue date: 2022-01-01 Background: Patients hospitalised with COVID-19 are at risk for thrombotic events after discharge; the role of extended thromboprophylaxis in this population is unknown. Methods: In this open-label, multicentre, randomised trial conducted at 14 centres in Brazil, patients hospitalised with COVID-19 at increased risk for venous thromboembolism (International Medical Prevention Registry on Venous Thromboembolism [IMPROVE] venous thromboembolism [VTE] score of ≥4 or 2–3 with a D-dimer >500 ng/mL) were randomly assigned (1:1) to receive, at hospital discharge, rivaroxaban 10 mg/day or no anticoagulation for 35 days. The primary efficacy outcome in an intention-to-treat analysis was a composite of symptomatic or fatal venous thromboembolism, asymptomatic venous thromboembolism on bilateral lower-limb venous ultrasound and CT pulmonary angiogram, symptomatic arterial thromboembolism, and cardiovascular death at day 35. Adjudication was blinded. The primary safety outcome was major bleeding. The primary and safety analyses were carried out in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT04662684. Findings: From Oct 8, 2020, to June 29, 2021, 997 patients were screened. Of these patients, 677 did not meet eligibility criteria; the remaining 320 patients were enrolled and randomly assigned to receive rivaroxaban (n=160 [50%]) or no anticoagulation (n=160 [50%]). All patients received thromboprophylaxis with standard doses of heparin during hospitalisation. 165 (52%) patients were in the intensive care unit while hospitalised. 197 (62%) patients had an IMPROVE score of 2–3 and elevated D-dimer levels and 121 (38%) had a score of 4 or more. Two patients (one in each group) were lost to follow-up due to withdrawal of consent and not included in the intention-to-treat primary analysis. The primary efficacy outcome occurred in five (3%) of 159 patients assigned to rivaroxaban and 15 (9%) of 159 patients assigned to no anticoagulation (relative risk 0·33, 95% CI 0·12–0·90; p=0·0293). No major bleeding occurred in either study group. Allergic reactions occurred in two (1%) patients in the rivaroxaban group. Interpretation: In patients at high risk discharged after hospitalisation due to COVID-19, thromboprophylaxis with rivaroxaban 10 mg/day for 35 days improved clinical outcomes compared with no extended thromboprophylaxis. Funding: Bayer. Science Valley Research Institute Hospital e Maternidade Christóvão da Gama Grupo Leforte Santo André Unidade de Medicina Interdisciplinar em Cardiologia Instituto do Coração Hospital das Clínicas HCFMUSP Faculdade de Medicina Universidade de São Paulo Zucker School of Medicine at Hofstra/Northwell and the Feinstein Institutes for Medical Research Department of Obstetrics and Gynecology I M Sechenov First Moscow State Medical University Universidade Estadual Paulista Hospital das Clínicas de Ribeirão Preto São Paulo University Medical School Ribeirão Preto Hospital do Rocio, Campo Largo Instituto Couto Maia Salvador Hospital Municipal de Barueri São Paulo State Public Women's Health Reference Center Hospital Israelita Albert Einstein Instituto do Coração Hospital das Clínicas HCFMUSP Faculdade de Medicina Universidade de São Paulo Institute of Teaching and Research Hapvida Hospital Nossa Senhora das Graças Department of Statistics Institute of Mathematics and Statistics University of São Paulo Northshore University Health System Hemostasis and Thrombosis Research Laboratories at Loyola University Medical Center Duke Clinical Research Institute Duke University School of Medicine Universidade Estadual Paulista
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- 2022
25. Non-invasive diagnosis and follow-up of benign liver tumours
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Thong Dao, Victor de Lédinghen, M. Bourlière, Jean-Frédéric Blanc, Julien Calderaro, Jean-Charles Nault, Arnaud Hocquelet, Boris Guiu, Ephrem Salamé, Christophe Bureau, Lucile Moga, Nathalie Ganne-Carrié, Valérie Paradis, Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Bordeaux Research In Translational Oncology [Bordeaux] (BaRITOn), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Beaujon [AP-HP], Hôpital Henri Mondor, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Hôpital Saint-Joseph [Marseille], Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), École pratique des hautes études (EPHE), and Malbec, Odile
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medicine.medical_specialty ,Carcinoma, Hepatocellular ,Biliary Cyst ,[SDV]Life Sciences [q-bio] ,Bile Duct Diseases ,Gallbladder Diseases ,Adenoma, Liver Cell ,Diagnosis, Differential ,medicine ,Humans ,Hepatology ,medicine.diagnostic_test ,Cysts ,business.industry ,Liver Diseases ,Liver Neoplasms ,Non invasive ,Gastroenterology ,Focal nodular hyperplasia ,Histology ,Hepatocellular adenoma ,medicine.disease ,digestive system diseases ,Benign liver tumours ,[SDV] Life Sciences [q-bio] ,Liver ,Focal Nodular Hyperplasia ,Liver biopsy ,Radiology ,Ultrasonography ,Hemangioma ,business ,Follow-Up Studies - Abstract
International audience; Hepatocellular benign liver tumours are mainly developed on normal liver and include hepatic hemangioma, focal nodular hyperplasia and hepatocellular adenoma from the most frequent to the less frequent. The diagnosis of hepatic hemangioma and of simple hepatic biliary cysts can be performed using non-invasive criteria using liver ultrasonography or contrast enhanced MRI. Most of the time the diagnosis of focal nodular hyperplasia can be achieved using contrast-enhanced ultrasonography or contrast enhanced MRI with an additional value of hepatobiliary contrast-agent in this setting. Rarely, if a doubt persists, a tumour and non-tumour liver biopsy can be required in order to establish the diagnosis. As hepatic hemangioma, simple hepatic biliary cysts and focal nodular hyperplasia are not associated with complications, they don't require any treatments or follow-up. Hepatocellular adenomas are mainly diagnosed at histology on surgical samples or liver biopsy even if some radiological features are highly suggestive of several subtypes of hepatocellular adenomas. Finally, the management of hepatocellular adenomas should be guided according to the tumour size, gender but also to the molecular subtypes.
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- 2022
26. Small-Molecule Inhibitors of Cyclophilins Block Opening of the Mitochondrial Permeability Transition Pore and Protect Mice From Hepatic Ischemia/Reperfusion Injury
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Muriel Gelin, Fred Allemand, Cong Trung Nguyen, Mathieu Panel, Abdelhakim Ahmed-Belkacem, Bijan Ghaleh, Rozenn Brillet, Isaac Ruiz, Julien Calderaro, Fouad Lafdil, Jean-François Guichou, Fatima Teixeira-Clerc, Didier Morin, Jean-Michel Pawlotsky, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre de Biochimie Structurale [Montpellier] (CBS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), morin, didier, and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)
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Male ,0301 basic medicine ,Isomerase activity ,[SDV.MHEP.CHI] Life Sciences [q-bio]/Human health and pathology/Surgery ,Ischemia ,Mitochondria, Liver ,[SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery ,Pharmacology ,Mitochondrion ,Mitochondrial Membrane Transport Proteins ,Mouse model ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Animals ,Humans ,Calcium Signaling ,Enzyme Inhibitors ,Inner mitochondrial membrane ,Cells, Cultured ,Mice, Knockout ,Hepatology ,Mitochondrial Permeability Transition Pore ,Chemistry ,Liver Diseases ,MPTP ,Gastroenterology ,PPIF ,[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,medicine.disease ,[SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,3. Good health ,PPIase activity ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Liver ,Mitochondrial permeability transition pore ,Cytoprotection ,[SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,Reperfusion Injury ,[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,030211 gastroenterology & hepatology ,Drug ,Mitochondrial Swelling ,Reperfusion injury ,Cyclophilin D ,Signal Transduction - Abstract
International audience; Background & Aims: Hepatic ischemia-reperfusion injury is a complication of liver surgery that involves mitochondrial dysfunction resulting from mitochondrial permeability transition pore (mPTP) opening. Cyclophilin D (PPIF or CypD) is a peptidyl-prolyl cis-trans isomerase that regulates mPTP opening in the inner mitochondrial membrane. We investigated whether and how recently created small-molecule inhibitors of CypD prevent opening of the mPTP in hepatocytes and the resulting effects in cell models and livers of mice undergoing ischemia/reperfusion injuryMethods: We measured the activity of 9 small-molecule inhibitors of cyclophilins in an assay of CypD activity. The effects of the small-molecule CypD inhibitors or vehicle on mPTP opening were assessed by measuring mitochondrial swelling and calcium retention in isolated liver mitochondria from C57BL/6J (wild-type) and Ppif–/– (CypD knockout) mice and in primary mouse and human hepatocytes by fluorescence microscopy. We induced ischemia/reperfusion injury in livers of mice given a small-molecule CypD inhibitor or vehicle before and during reperfusion and collected samples of blood and liver for histologic analysis.Results: The compounds inhibited peptidyl-prolyl isomerase activity (half maximal inhibitory concentration values, 0.2–16.2 μmol/L) and, as a result, calcium-induced mitochondrial swelling, by preventing mPTP opening (half maximal inhibitory concentration values, 1.4–132 μmol/L) in a concentration-dependent manner. The most potent inhibitor (C31) bound CypD with high affinity and inhibited swelling in mitochondria from livers of wild-type and Ppif–/– mice (indicating an additional, CypD-independent effect on mPTP opening) and in primary human and mouse hepatocytes. Administration of C31 in mice with ischemia/reperfusion injury before and during reperfusion restored hepatic calcium retention capacity and oxidative phosphorylation parameters and reduced liver damage compared with vehicle.Conclusions:Recently created small-molecule inhibitors of CypD reduced calcium-induced swelling in mitochondria from mouse and human liver tissues. Administration of these compounds to mice during ischemia/reperfusion restored hepatic calcium retention capacity and oxidative phosphorylation parameters and reduced liver damage. These compounds might be developed to protect patients from ischemia/reperfusion injury after liver surgery or for other hepatic or nonhepatic disorders related to abnormal mPTP opening.
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- 2019
27. Angiogenesis and immune checkpoint inhibitors as therapies for hepatocellular carcinoma: current knowledge and future research directions
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Julien Calderaro, Fouad Lafdil, Benoit Rousseau, Jean-Michel Pawlotsky, Marc Hilmi, and Cindy Neuzillet
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0301 basic medicine ,Cancer Research ,Carcinoma, Hepatocellular ,Angiogenesis ,Hepatocellular carcinoma ,Immunology ,Angiogenesis Inhibitors ,Review ,lcsh:RC254-282 ,Immunomodulation ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Antineoplastic Agents, Immunological ,Checkpoint inhibitor ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers, Tumor ,Immunology and Allergy ,Medicine ,Cytotoxic T cell ,Animals ,Humans ,Molecular Targeted Therapy ,Drug combination ,Pharmacology ,Tumor microenvironment ,Clinical Trials as Topic ,Neovascularization, Pathologic ,business.industry ,Immunogenicity ,Liver Neoplasms ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Combined Modality Therapy ,Clinical trial ,Vascular endothelial growth factor A ,030104 developmental biology ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Molecular Medicine ,Disease Susceptibility ,business - Abstract
Hepatocellular carcinoma (HCC) is the second deadliest cancer worldwide, due to its high incidence and poor prognosis. Frequent initial presentation at advanced stages along with impaired liver function limit the use of a broad therapeutic arsenal in patients with HCC. Although main HCC oncogenic drivers have been deciphered in recent years (TERT, TP53, CTNNB1 mutations, miR122 and CDKN2A silencing), therapeutic applications derived from this molecular knowledge are still limited. Given its high vascularization and immunogenicity, antiangiogenics and immune checkpoint inhibitors (ICI), respectively, are two therapeutic approaches that have shown efficacy in HCC. Depending on HCC immune profile, combinations of these therapies aim to modify the protumoral/antitumoral immune balance, and to reactivate and favor the intratumoral trafficking of cytotoxic T cells. Combination therapies involving antiangiogenics and ICI may be synergistic, because vascular endothelial growth factor A inhibition increases intratumoral infiltration and survival of cytotoxic T lymphocytes and decreases regulatory T lymphocyte recruitment, resulting in a more favorable immune microenvironment for ICI antitumoral activity. First results from clinical trials evaluating combinations of these therapies are encouraging with response rates never observed before in patients with HCC. A better understanding of the balance and interactions between protumoral and antitumoral immune cells will help to ensure the success of future therapeutic trials. Here, we present an overview of the current state of clinical development of antitumoral therapies in HCC and the biological rationale for their use. Moreover, translational studies on tumor tissue and blood, prior to and during treatment, will help to identify biomarkers and immune signatures with predictive value for both clinical outcome and response to combination therapies.
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- 2019
28. Nestin as a diagnostic and prognostic marker for combined hepatocellular-cholangiocarcinoma
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Julien Calderaro, Luca Di Tommaso, Pascale Maillé, Aurélie Beaufrère, Cong Trung Nguyen, Lara Heij, Viviane Gnemmi, Rondell P. Graham, Frédéric Charlotte, Suzanne Chartier, Dominique Wendum, Mukul Vij, Daniela Allende, Alba Diaz, Carla Fuster, Benjamin Rivière, Astrid Herrero, Jérémy Augustin, Katja Evert, Diego Francesco Calvisi, Wei Qiang Leow, Howard Ho Wai Leung, Jan Bednarsch, Emmanuel Boleslawski, Mohamed Rela, Anthony Wing-Hung Chan, Alejandro Forner, Maria Reig, Anaïs Pujals, Loetitia Favre, Manon Allaire, Olivier Scatton, Arnaud Uguen, Eric Trépo, Lukas Otero Sanchez, Denis Chatelain, Myriam Remmelink, Camille Boulagnon-Rombi, Céline Bazille, Nathalie Sturm, Benjamin Menahem, Eric Frouin, David Tougeron, Christophe Tournigand, Emmanuelle Kempf, Haeryoung Kim, Massih Ningarhari, Sophie Michalak-Provost, Jakob Nikolas Kather, Annette S.H. Gouw, Purva Gopal, Raffaele Brustia, Eric Vibert, Kornelius Schulze, Darius F. Rüther, Sören A. Weidemann, Rami Rhaiem, Jean-Charles Nault, Alexis Laurent, Giuliana Amaddeo, Hélène Regnault, Eleonora de Martin, Christine Sempoux, Pooja Navale, Jayendra Shinde, Ketan Bacchuwar, Maria Westerhoff, Regina Cheuk-Lam Lo, Mylène Sebbagh, Catherine Guettier, Marie Lequoy, Mina Komuta, Marianne Ziol, Valérie Paradis, Jeanne Shen, Stefano Caruso, Hôpital Henri Mondor, Istituto Clinico Humanitas [Milan] (IRCCS Milan), Humanitas University [Milan] (Hunimed), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de Pathologie [Hôpital Beaujon - APHP], Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Molecular virology and immunology – Physiopathology and therapeutic of chronic viral hepatitis (Team 18) (Inserm U955), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), CHU Lille, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Thérapies Laser Assistées par l'Image pour l'Oncologie - U 1189 (ONCO-THAI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Henri Mondor [Créteil], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Université libre de Bruxelles (ULB), CHirurgie, IMagerie et REgénération tissulaire de l’extrémité céphalique - Caractérisation morphologique et fonctionnelle - UR UPJV 7516 (CHIMERE), Université de Picardie Jules Verne (UPJV), Laboratoire de Signalisation et Récepteurs Matriciels (SiRMa), Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Département de Pathologie [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Grenoble, Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Chirurgie Viscérale et Digestive [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé (LIMICS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, Groupe Henri Mondor-Albert Chenevier, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Johns Hopkins University (JHU), Hôpital Claude Huriez [Lille], Physiopathologie et traitement des maladies du foie, Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Centre Hospitalier Universitaire de Reims (CHU Reims), Génomique fonctionnelle des tumeurs solides = Functional Genomics of Solid Tumors [CRC] (FunGeST), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Labex OncoImmunology, Equipe labellisée Ligue Contre le Cancer, Université Paris Descartes - Paris 5 (UPD5), Service d'Hépatologie [Avicenne], Hôpital Avicenne [AP-HP], Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine [Bobigny], Université Paris 13 (UP13)-Sorbonne Paris Cité, Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Crosscope, University of Michigan [Ann Arbor], University of Michigan System, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Hôpital Bicêtre, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d’Anatomie Pathologique [CHU Beaujon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Labex Immuno-oncology [Paris] ( Université Paris Descartes - Paris 5 - PRES Sorbonne Paris Cité), Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité, Service d'Anatomie et cytologie pathologiques [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Anatomie et cytologie pathologiques = Service de Pathologie [CHU Pitié-Salpêtrière] (ACP), CHU Henri Mondor, Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École pratique des hautes études (EPHE), Service d'Hépato-gastro-entérologie [CHU Saint-Antoine], and Groningen Institute for Organ Transplantation (GIOT)
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Carcinoma, Hepatocellular ,Hepatology ,combined hepatocellular-cholangiocarcinoma ,Liver Neoplasms ,hepatocellular carcinoma ,liver ,Prognosis ,Nestin ,Cholangiocarcinoma ,Bile Ducts, Intrahepatic ,Bile Duct Neoplasms ,cancer ,Humans ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
Background & Aims: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer (PLC) associated with a poor prognosis. Given the challenges in its identification and its clinical implications, biomarkers are critically needed. We aimed to investigate the diagnostic and prognostic value of the immunohistochemical expression of Nestin, a progenitor cell marker, in a large multicentric series of PLCs.Methods: We collected 461 cHCC-CCA samples from 32 different clinical centers. Control cases included 368 hepatocellular carcinomas (HCCs) and 221 intrahepatic cholangiocarcinomas (iCCAs). Nestin immunohistochemistry was performed on whole tumor sections. Diagnostic and prognostic performances of Nestin expression were determined using receiver-operating characteristic curves and Cox regression modeling.Results: Nestin was able to distinguish cHCC-CCA from HCC with AUCs of 0.85 and 0.86 on surgical and biopsy samples, respectively. Performance was lower for the distinction of cHCC-CCA from iCCA (AUCs of 0.59 and 0.60). Nestin, however, showed a high prognostic value, allowing identification of the subset of cHCC-CCA (“Nestin High”, >30% neoplastic cells with positive staining) associated with the worst clinical outcome (shorter disease-free and overall survival) after surgical resection and liver transplantation, as well as when assessment was performed on biopsies.Conclusion: We show in different clinical settings that Nestin has diagnostic value and that it is a useful biomarker to identify the subset of cHCC-CCA associated with the worst clinical outcome. Nestin immunohistochemistry may be used to refine risk stratification and improve treatment allocation for patients with this highly aggressive malignancy. Lay summary: There are different types of primary liver cancers (i.e. cancers that originate in the liver). Accurately identifying a specific subtype of primary liver cancer (and determining its associated prognosis) is important as it can have a major impact on treatment allocation. Herein, we show that a protein called Nestin could be used to refine risk stratification and improve treatment allocation for patients with combined hepatocellular carcinoma, a rare but highly aggressive subtype of primary liver cancer.
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- 2021
29. Medically Ill hospitalized Patients for COVID-19 THrombosis Extended ProphyLaxis with rivaroxaban ThErapy: Rationale and Design of the MICHELLE Trial
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Adriano Tachibana, Eduardo Ramacciotti, Leandro Barile Agati, Alfonso Tafur, Rogério Aparecido Dedivitis, Daniela Calderaro, Marcus Vinicius Barbosa Santos, Paulo Fernando Guimarães Morando Marzocchi Tierno, Edwaldo Edner Joviliano, Alex C. Spyropoulos, Kenji Itinose, Renato D. Lopes, Suzanna Maria Viana Sanches, Bruno Bezerra de Menezes Cavalcante, André Sementilli Cortina, Nara Franzin de Moraes, Valéria Cristina Resende Aguiar, Giuliano Giova Volpiani, Ricardo Cesar Rocha Moreira, Rodrigo Caruso Chate, Caroline Candida Carvalho de Oliveira, Elizabeth Rodrigues, Cesar Dusilek, Marcone Lima Sobreira, Chang Chiann, André Luiz Malavasi Longo de Oliveira, Science Valley Research Institute, Universidade de São Paulo (USP), Universidade Estadual Paulista (UNESP), Irmandade da Santa Casa da Misericórdia de Santos, Hospital Ana Neri, Hospital Municipal de Barueri, São Paulo State Public Women's Health Reference Center, Hospital Israelita Albert Einstein, CE, Hospital Nossa Senhora das Graças, Northshore University Health System, and Duke University School of Medicine
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Adult ,Male ,medicine.medical_specialty ,venous thromboembolism ,Hemorrhage ,direct oral anticoagulants ,Drug Administration Schedule ,Article ,Thromboembolism ,medicine ,Humans ,Prospective Studies ,cardiovascular diseases ,anticoagulation ,Prospective cohort study ,rivaroxaban ,Stroke ,thrombosis ,Venous Thrombosis ,Rivaroxaban ,SARS-CoV-2 ,business.industry ,COVID-19 ,BIOESTATÍSTICA ,Bleed ,medicine.disease ,Thrombosis ,Pulmonary embolism ,Regimen ,Venous thrombosis ,Emergency medicine ,Female ,Pulmonary Embolism ,Cardiology and Cardiovascular Medicine ,business ,Brazil ,Factor Xa Inhibitors ,medicine.drug - Abstract
Made available in DSpace on 2022-04-29T08:46:11Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-12-01 BACKGROUND: The devastating Coronavirus disease (COVID-19) pandemic is associated with a high prothrombotic state. It is unclear if the coagulation abnormalities occur because of the direct effect of SARS-CoV-2 or indirectly by the cytokine storm and endothelial damage or by a combination of mechanisms. There is a clear indication of in-hospital pharmacological thromboprophylaxis for every patient with COVID-19 after bleed risk assessment. However, there is much debate regarding the best dosage regimen, and there is no consensus on the role of extended thromboprophylaxis. DESIGN: This study aims to evaluate the safety and efficacy of rivaroxaban 10 mg once daily for 35 ± 4 days versus no intervention after hospital discharge in COVID-19 patients who were at increased risk for VTE and have received standard parenteral VTE prophylaxis during hospitalization. The composite efficacy endpoint is a combination of symptomatic VTE, VTE-related death, VTE detected by bilateral lower limbs venous duplex scan and computed tomography pulmonary angiogram on day 35 ± 4 posthospital discharge and symptomatic arterial thromboembolism (myocardial infarction, nonhemorrhagic stroke, major adverse limb events, and cardiovascular death) up to day 35 ± 4 posthospital discharge. The key safety outcome is the incidence of major bleeding according to ISTH criteria. SUMMARY: The MICHELLE trial is expected to provide high-quality evidence around the role of extended thromboprophylaxis in COVID-19 and will help guide medical decisions in clinical practice.1. Science Valley Research Institute, Santo André, São Paulo, Brazil; Hospital e Maternidade Christóvão da Gama, Grupo Leforte, Santo André, São Paulo, Brazil Science Valley Research Institute Interdisciplinary Medicine in Cardiology Unit Heart Institute (InCor)- University of São Paulo Medical School Universidade Estadual Paulista (UNESP) Hospital das Clínicas de Ribeirão Preto São Paulo University Medical School (USP) Irmandade da Santa Casa da Misericórdia de Santos Hospital Ana Neri Hospital Municipal de Barueri São Paulo State Public Women's Health Reference Center Hospital Israelita Albert Einstein Heart Institute (InCor)- University of São Paulo Medical School Institute of Teaching and Research Hapvida CE Hospital Nossa Senhora das Graças Department of Statistics Institute of Mathematics and Statistics University of Sao Paulo Northshore University Health System Zucker School of Medicine at Hofstra/Northwell and the Feinstein Institutes for Medical Research, Manhasset, NY Duke Clinical Research Institute Duke University School of Medicine Universidade Estadual Paulista (UNESP)
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- 2021
30. Cardiology referral during the COVID-19 pandemic
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Iuri Resedá Magalhães, Henrique Trombini Pinesi, Fábio Cetinic Habrum, Fabio G Pitta, Maria Clara Saad Menezes, Rodrigo Freddi Miada, Nathalia Conci Santorio, Caio de Assis Moura Tavares, Francisco Akira Malta Cardozo, Daniela Calderaro, and Bruno Caramelli
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Cardiology Training ,medicine.medical_specialty ,Medicine (General) ,Referral ,Coronavirus disease 2019 (COVID-19) ,Cardiology ,Disease ,R5-920 ,Internal medicine ,Pandemic ,medicine ,Humans ,In patient ,Pandemics ,Referral and Consultation ,SARS-CoV-2 ,business.industry ,COVID-19 ,General Medicine ,Cardiology Referral ,Myocardial Injury ,Observational study ,Original Article ,business - Abstract
OBJECTIVES: This study presents the cardiology referral model adopted at the University of São Paulo-Hospital das Clínicas complex during the initial period of the coronavirus disease (COVID-19) pandemic, main reasons for requesting a cardiologic evaluation, and clinical profile of and prognostic predictors in patients with COVID-19. METHODS: In this observational study, data of all cardiology referral requests between March 30, 2020 and July 6, 2020 were collected prospectively. A descriptive analysis of the reasons for cardiologic evaluation requests and the most common cardiologic diagnoses was performed. A multivariable model was used to identify independent predictors of in-hospital mortality among patients with COVID-19. RESULTS: Cardiologic evaluation was requested for 206 patients admitted to the ICHC-COVID. A diagnosis of COVID-19 was confirmed for 180 patients. Cardiologic complications occurred in 77.7% of the patients. Among these, decompensated heart failure was the most common complication (38.8%), followed by myocardial injury (35%), and arrhythmias, especially high ventricular response atrial fibrillation (17.7%). Advanced age, greater need of ventilatory support on admission, and pre-existing heart failure were independently associated with in-hospital mortality. CONCLUSIONS: A hybrid model combining in-person referral with remote discussion and teaching is a viable alternative to overcome COVID-19 limitations. Cardiologic evaluation remains important during the pandemic, as patients with COVID-19 frequently develop cardiovascular complications or decompensation of the underlying heart disease.
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- 2021
31. The Neuroprotective Potentiality of Flavonoids on Alzheimer’s Disease
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Antonella Calderaro, Giuseppe Tancredi Patanè, Ester Tellone, Davide Barreca, Silvana Ficarra, Francesco Misiti, and Giuseppina Laganà
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Antioxidants ,Catalysis ,Inorganic Chemistry ,Alzheimer Disease ,Naringenin ,Humans ,Apigenin ,Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy ,Flavonoids ,Neuroprotection ,Quercetin ,Myricetin ,Epicatechin-3-gallate ,Cyanidin 3-o-glucoside ,Genistein ,Gossypetin ,Organic Chemistry ,General Medicine ,Computer Science Applications ,Neuroprotective Agents ,Butyrylcholinesterase ,Acetylcholinesterase ,Amyloid Precursor Protein Secretases - Abstract
Alzheimer’s disease (AD), due to its spread, has become a global health priority, and is characterized by senile dementia and progressive disability. The main cause of AD and other neurodegenerations (Huntington, Parkinson, Amyotrophic Lateral Sclerosis) are aggregated protein accumulation and oxidative damage. Recent research on secondary metabolites of plants such as polyphenols demonstrated that they may slow the progression of AD. The flavonoids’ mechanism of action in AD involved the inhibition of acetylcholinesterase, butyrylcholinesterase, Tau protein aggregation, β-secretase, oxidative stress, inflammation, and apoptosis through modulation of signaling pathways which are implicated in cognitive and neuroprotective functions, such as ERK, PI3-kinase/Akt, NFKB, MAPKs, and endogenous antioxidant enzymatic systems. This review focuses on flavonoids and their role in AD, in terms of therapeutic potentiality for human health, antioxidant potential, and specific AD molecular targets.
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- 2022
32. Liver resection for single large hepatocellular carcinoma: a prognostic factors study
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Vincent Nguyen-Khac, Raffaele Brustia, Rami Rhaiem, Hélène Regnault, Anna Sessa, Sebastien Mule, Christophe Duvoux, Alexis Laurent, Vincent Leroy, Julien Calderaro, Alain Luciani, Francoise Roudot-Thoraval, Giuliana Amaddeo, and Daniele Sommacale
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Male ,Liver Cirrhosis ,Carcinoma, Hepatocellular ,Hepatology ,Liver Neoplasms ,General Medicine ,Prognosis ,Severity of Illness Index ,End Stage Liver Disease ,Humans ,Hepatectomy ,Female ,Neoplasm Recurrence, Local ,Aged ,Retrospective Studies - Abstract
Liver resection is the only curative therapeutic option for large hepatocellular carcinoma (gt; 5 cm), but survival is worse than in smaller tumours, mostly due to the high recurrence rate. There is currently no proper tool for stratifying relapse risk. Herein, we investigated prognostic factors before hepatectomy in patients with a single large hepatocellular carcinoma (HCC).We retrospectively identified 119 patients who underwent liver resection for a single large HCC in 2 tertiary academic French centres and collected pre- and post-operative clinical, biological and radiological features. The primary outcome was overall survival at five years. Secondary outcomes were recurrence-free survival at five years and prognostic factors for recurrence.A total of 84% of the patients were male, and the median age was 66 years old (IQR 58-74). Thirty-nine (33%) had Child-Pugh A cirrhosis, and the mean Model for End-Stage Liver Disease (MELD) score was 6 (6-6). The aetiology of liver disease was predominantly alcohol-related (48%), followed by nonalcoholic steatohepatitis (22%), hepatitis B (18%) and hepatitis C (10%). The mean tumour size was 70 mm (55-110). The median overall survival was 72.5 months (IC 95%: 56.2-88.7), and the five-year overall survival was 55.1 ± 5.5%. The median recurrence-free survival was 26.6 months (95% CI: 16.0-37.1), and the five-year recurrence-free survival rate was 37.8 ± 5%. In multivariate analysis, preoperative prognostic factors for recurrence were baseline alpha-fetoprotein (AFP)gt; 7 ng/mL (plt;0.001), portal veinous invasion (p=0.003) and cirrhosis (p=0.020). Using these factors, we created a simple recurrence-risk scoring system that classified three groups with distinct disease-free survival medians (plt;0.001): no risk factors (65 months), 1 risk factor (36 months), and ≥2 risk factors (8.9 months).Liver resection is the only curative option for large HCC, and we confirmed that survival could be acceptable in experienced centres. Recurrence is the primary issue of surgery, and we proposed a simple preoperative score to help identify patients with the most worrisome prognosis and possible candidates for combined therapy.
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- 2022
33. Detection of occult hepatitis B virus infection among subjects with isolated hepatitis B core antibodies: Results from a 3-year survey in an Italian tertiary-care hospital
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Flora De Conto, Mirko Buttrini, Maria Loretana Dell'Anna, Clara Maccari, Giulia Montanari, Maria Cristina Arcangeletti, Monica Martinelli, Carlo Chezzi, and Adriana Calderaro
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Male ,Hepatitis B virus ,Hepatitis B Surface Antigens ,Hepatology ,Coinfection ,Gastroenterology ,HIV Infections ,Hepacivirus ,Hepatitis B ,Hepatitis B Core Antigens ,Tertiary Care Centers ,Hepatitis B, Chronic ,Seroepidemiologic Studies ,DNA, Viral ,Humans ,Female ,Hepatitis B Antibodies - Abstract
Hepatitis B virus (HBV) infection causes hepatitis, liver cirrhosis, hepatocellular carcinoma, and death. This study examines the subjects with isolated anti-HBV core antigen antibody (anti-HBcAg), a pattern characterized by the persistent HBV carriage in the absence of HBV surface antigen (HBsAg) and anti-HBsAg antibody.Based on medical orders, from 2017 to 2019, serological and molecular assays were performed on serum/plasma samples of 33,048 subjects (71.4% Italians, 28.6% foreigners), who referred to the Virology Unit of the University-Hospital of Parma (Northern Italy) for the laboratory diagnosis of HBV infection.The seroprevalence was 4.6% for HBsAg and 11% for anti-HBcAg. The occurrence of the isolated anti-HBcAg status was 3.1%, with higher frequency in males than in females (66.3% vs. 33.7%, P 0.0001), in Italians than in foreigners (54.8% vs. 45.2%, P 0.001), and in outpatients than in inpatients (57.4% vs. 42.6%, P 0.0001). Foreigners with isolated anti-HBcAg came mostly from Africa (67.9%) and Eastern Europe (26.2%). Among subjects with isolated anti-HBcAg, 14.8% had occult HBV infection, 26.3% hepatitis C virus co-infection, 2% human immunodeficiency virus co-infection, and 3.3% both of these latter co-infections.The anti-HBcAg assay accurately evaluates the HBV exposure; subjects with isolated anti-HBcAg antibody should be further analysed for HBV DNA. The HBV infection prevalence in Italy is increasing, due to growing migratory flows from endemic areas.
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- 2021
34. Utility of Early Posttreatment PET/CT Evaluation Using FDG or
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Edouard, Reizine, Julia, Chalaye, Sebastien, Mule, Helene, Regnault, Clara, Perrin, Julien, Calderaro, Alexis, Laurent, Giuliana, Amaddeo, Hicham, Kobeiter, Vania, Tacher, Emmanuel, Itti, and Alain, Luciani
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Male ,Carcinoma, Hepatocellular ,Brachytherapy ,Liver Neoplasms ,Choline ,Treatment Outcome ,Liver ,Fluorodeoxyglucose F18 ,Positron Emission Tomography Computed Tomography ,Humans ,Female ,Yttrium Radioisotopes ,Radiopharmaceuticals ,Aged ,Retrospective Studies - Published
- 2021
35. [Liver tumor pathology seminar. Introduction]
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Julien, Calderaro
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Liver Neoplasms ,Humans - Published
- 2021
36. Molecular Basis of Interactions between the Antibiotic Nitrofurantoin and Human Serum Albumin: A Mechanism for the Rapid Drug Blood Transportation
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Michele Navarra, Davide Barreca, Salvatore Magazù, Antonella Calderaro, Giuseppina Laganà, and Alessandro Maugeri
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Antibiotics ,Fluorescence ,FTIR ,Human serum albumin ,Molecular interactions ,Nitrofurantoin ,Molecular model ,QH301-705.5 ,Hydantoin ,Serum Albumin, Human ,nitrofurantoin ,Article ,Catalysis ,antibiotics ,Inorganic Chemistry ,chemistry.chemical_compound ,Spectroscopy, Fourier Transform Infrared ,medicine ,Humans ,Physical and Theoretical Chemistry ,Binding site ,Biology (General) ,Molecular Biology ,Protein secondary structure ,QD1-999 ,Spectroscopy ,Binding Sites ,Hydrogen bond ,Organic Chemistry ,General Medicine ,Combinatorial chemistry ,Computer Science Applications ,Molecular Docking Simulation ,Chemistry ,chemistry ,Docking (molecular) ,human serum albumin ,fluorescence ,Protein Binding ,medicine.drug ,molecular interactions - Abstract
Nitrofurantoin is an antimicrobial agent obtained through the addition of a nitro group and a side chain containing hydantoin to a furan ring. The interactions of the antibiotic with human serum albumin (HSA) have been investigated by fluorescence, UV-VIS, Fourier transform infrared spectroscopy (FTIR) spectroscopy, and protein-ligand docking studies. The fluorescence studies indicate that the binding site of the additive involves modifications of the environment around Trp214 at the level of subdomain IIA. Fluorescence and UV-VIS spectroscopy, displacement studies, and FTIR experiments show the association mode of nitrofurantoin to HSA, suggesting that the primary binding site of the antibiotic is located in Sudlow’s site I. Molecular modeling suggests that nitrofurantoin is involved in the formation of hydrogen bonds with Trp214, Arg218, and Ser454, and is located in the hydrophobic cavity of subdomain IIA. Moreover, the curve-fitting results of the infrared Amide I’ band indicate that the binding of nitrofurantoin induces little change in the protein secondary structure. Overall, these data clarify the blood transportation process of nitrofurantoin and its rapid transfer to the kidney for its elimination, hence leading to a better understanding of its biological effects and being able to design other molecules, based on nitrofurantoin, with a higher biological potential.
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- 2021
37. The Italian arm of the PREPARE study: an international project to evaluate and license a maternal vaccine against group B streptococcus
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Berardi A., Cassetti T., Creti R., Vocale C., Ambretti S., Sarti M., Facchinetti F., Cose S., van Bijlsma M., van De Beek D., Poyart C., French N., Nielsen M., Musoke P., Davies H., Ovale S., Lugli L., Capretti M. G., Lanari M., Dondi A., Ciccia M., Francavilla R., Lanzoni A., Baroni L., Fornaciari S., Carretto E., Alessandrini C., Lucia G., Perrone S., Calderaro A., Bacchini P., Giugno C., Rota C., Pagano R., Guidi B., Biasucci G., Benenati B., Schiavo R., Piccinini G., Pulvirenti R., Rizzo V., Ancora G., China C., Papa I., Viola L., Pedna M. F., Bua J., Travan L., Busetti M., Santori D., Merazzi D., Papa A., Laura L., Auriti C., Bernaschi P., Vento G., Giordano L., Spanu T., Haass C., Margiotta M. C., Nardella G., De Nittis R., Laforgia N., Loprieno S., Giuseppe L., Moramarco A. M., Tzialla C., Fasolato V., Orlandini S., Decembrino L., Del Campo G., Maiocchi A., Cuttano A., Tuoni C., Barnini S., Carnielli V., Perrone B., Orecchioni F., Visintini F., Arzese A., Heath P., Le Doare K., Neurology, Amsterdam Neuroscience - Neuroinfection & -inflammation, AII - Infectious diseases, Berardi A., Cassetti T., Creti R., Vocale C., Ambretti S., Sarti M., Facchinetti F., Cose S., van Bijlsma M., van De Beek D., Poyart C., French N., Nielsen M., Musoke P., Davies H., Ovale S., Lugli L., Capretti M.G., Lanari M., Dondi A., Ciccia M., Francavilla R., Lanzoni A., Baroni L., Fornaciari S., Carretto E., Alessandrini C., Lucia G., Perrone S., Calderaro A., Bacchini P., Giugno C., Rota C., Pagano R., Guidi B., Biasucci G., Benenati B., Schiavo R., Piccinini G., Pulvirenti R., Rizzo V., Ancora G., China C., Papa I., Viola L., Pedna M.F., Bua J., Travan L., Busetti M., Santori D., Merazzi D., Papa A., Laura L., Auriti C., Bernaschi P., Vento G., Giordano L., Spanu T., Haass C., Margiotta M.C., Nardella G., De Nittis R., Laforgia N., Loprieno S., Giuseppe L., Moramarco A.M., Tzialla C., Fasolato V., Orlandini S., Decembrino L., Del Campo G., Maiocchi A., Cuttano A., Tuoni C., Barnini S., Carnielli V., Perrone B., Orecchioni F., Visintini F., Arzese A., Heath P., and Le Doare K.
- Subjects
0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Group B streptococcus ,Sepsi ,International Cooperation ,030106 microbiology ,Disease ,Abortion ,Group B ,Streptococcus agalactiae ,Sepsis ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,Streptococcal Infections ,medicine ,Humans ,Meningitis ,030212 general & internal medicine ,Newborn ,Prevention ,Vaccine ,Pregnancy Complications, Infectious ,Antibiotic prophylaxis ,reproductive and urinary physiology ,Group B streptococcu ,business.industry ,Streptococcal Vaccines ,Infant, Newborn ,lcsh:RJ1-570 ,lcsh:Pediatrics ,Antibiotic Prophylaxis ,medicine.disease ,Infectious Disease Transmission, Vertical ,Meningiti ,Pneumonia ,Italy ,Immunization ,Commentary ,Female ,business - Abstract
Background Group B streptococcus (GBS) is a leading cause of sepsis, pneumonia and meningitis in infants, with long term neurodevelopmental sequelae. GBS may be associated with poor pregnancy outcomes, including spontaneous abortion, stillbirth and preterm birth. Intrapartum antibiotic prophylaxis (IAP) is currently the only way to prevent early-onset disease (presenting at 0 to 6 days of life), although it has no impact on the disease presenting over 6 days of life and its implementation is challenging in resource poor countries. A maternal vaccine against GBS could reduce all GBS manifestations as well as improve pregnancy outcomes, even in low-income countries. Main body The term “PREPARE” designates an international project aimed at developing a maternal vaccination platform to test vaccines against neonatal GBS infections by maternal immunization. It is a non-profit, multi-center, interventional and experimental study (promoted by the St George University of London. [UK]) with the aim of developing a maternal vaccination platform, determining pregnancy outcomes, and defining the extent of GBS infections in children and mothers in Africa. PREPARE also aims to estimate the protective serocorrelates against the main GBS serotypes that cause diseases in Europe and Africa and to conduct two trials on candidate GBS vaccines. PREPARE consists of 6 work packages. In four European countries (Italy, UK, Netherlands, France) the recruitment of cases and controls will start in 2020 and will end in 2022. The Italian PREPARE network includes 41 centers. The Italian network aims to collect: GBS isolates from infants with invasive disease, maternal and neonatal sera (cases); cord sera and GBS strains from colonized mothers whose infants do not develop GBS infection (controls). Short conclusion PREPARE will contribute information on protective serocorrelates against the main GBS serotypes that cause diseases in Europe and Africa. The vaccine that will be tested by the PREPARE study could be an effective strategy to prevent GBS disease.
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- 2020
38. Insights into the knowledge of complex diseases: Environmental infectious/toxic agents as potential etiopathogenetic factors of systemic sclerosis
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Maria D'Accolti, Gianluca Sighinolfi, Elisabetta Caselli, Clodoveo Ferri, Maria Cristina Arcangeletti, Dilia Giuggioli, Adriana Calderaro, K. Zakrzewska, Clara Maccari, Irene Soffritti, Erica Artoni, and Rosaria Arvia
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Human cytomegalovirus ,Herpesvirus 6, Human ,Immunology ,Cytomegalovirus ,Roseolovirus Infections ,Pathogenesis ,Disease ,Systemic sclerosis, Scleroderma, Human cytomegalovirus, Human parvovirus B19, Human herpesvirus-6, Retroviruses, SARS-CoV-2, Silica, Environmental, Pathogenesis ,Scleroderma ,NO ,Environmental ,Parvoviridae Infections ,Fibrosis ,Occupational Exposure ,Retroviruses ,medicine ,Parvovirus B19, Human ,Immunology and Allergy ,Humans ,LS6_8 ,skin and connective tissue diseases ,Pathological ,Scleroderma, Systemic ,integumentary system ,business.industry ,SARS-CoV-2 ,Microangiopathy ,COVID-19 ,LS6_12 ,Silica ,Human herpesvirus-6 ,medicine.disease ,Connective tissue disease ,Retroviridae ,Cytomegalovirus Infections ,Systemic sclerosis ,business ,Human parvovirus B19 ,Retroviridae Infections - Abstract
Systemic sclerosis (SSc) is a connective tissue disease secondary to three cardinal pathological features: immune-system alterations, diffuse microangiopathy, and fibrosis involving the skin and internal organs. The etiology of SSc remains quite obscure; it may encompass multiple host genetic and environmental -infectious/chemical-factors. The present review focused on the potential role of environmental agents in the etiopathogenesis of SSc based on epidemiological, clinical, and laboratory investigations previously published in the world literature. Among infectious agents, some viruses that may persist and reactivate in infected individuals, namely human cytomegalovirus (HCMV), human herpesvirus-6 (HHV-6), and parvovirus B19 (B19V), and retroviruses have been proposed as potential causative agents of SSc. These viruses share a number of biological activities and consequent pathological alterations, such as endothelial dysfunction and/or fibroblast activation. Moreover, the acute worsening of pre-existing interstitial lung involvement observed in SSc patients with symptomatic SARS-CoV-2 infection might suggest a potential role of this virus in the overall disease outcome. A variety of chemical/occupational agents might be regarded as putative etiological factors of SSc. In this setting, the SSc complicating silica dust exposure represents one of the most promising models of study. Considering the complexity of SSc pathogenesis, none of suggested causative factors may explain the appearance of the whole SSc; it is likely that the disease is the result of a multifactorial and multistep pathogenetic process. A variable combination of potential etiological factors may modulate the appearance of different clinical phenotypes detectable in individual scleroderma patients. The in-deep investigations on the SSc etiopathogenesis may provide useful insights in the broad field of human diseases characterized by diffuse microangiopathy or altered fibrogenesis.
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- 2021
39. Incidence and risk factors for moderate/severe COVID-19 in rheumatic diseases patients on hydroxychloroquine: a 24-week prospective cohort
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Marcelo M. Pinheiro, Gecilmara S. Pileggi, Adriana M. Kakehasi, Ana Paula M. Gomides Reis, Edgard Torres Reis-Neto, Mirhelen M. Abreu, Cleandro P. Albuquerque, Nafice C. Araújo, Ana Beatriz Bacchiega, Dante V. Bianchi, Blanca Bica, Eloisa Bonfa, Eduardo F. Borba, Danielle C.S. Egypto Brito, Debora C. Calderaro, Ângela L.B. Pinto Duarte, Rafaela C. Espírito Santo, Paula R. Fernandes, Mariana P. Guimarães, Kirla W. Poti Gomes, Gabriela G. Faustino Ilana, Evandro M. Klumb, Claudia D.L. Marques, Ana Karla Guedes de Melo, Odirlei A. Monticielo, Licia M.H. Mota, Gabriela A. Munhoz, Eduardo S. Paiva, Helena L. Alves Pereira, José Roberto Provenza, Sandra L. Euzébio Ribeiro, Laurindo F. Rocha Jr, Emilia I. Sato, Telma Skare, Viviane A. de Souza, Valeria Valim, Marcus V.G. Lacerda, Ricardo M. Xavier, and Gilda A. Ferreira
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SARS-CoV-2 ,Incidence ,Immunology ,COVID-19 ,COVID-19 Drug Treatment ,COVID-19 Testing ,Treatment Outcome ,Rheumatology ,Risk Factors ,Rheumatic Diseases ,Humans ,Immunology and Allergy ,Prospective Studies ,Hydroxychloroquine - Abstract
To evaluate the incidence of COVID-19 and its main outcomes in rheumatic disease (RD) patients on hydroxychloroquine (HCQ) compared to household cohabitants (HC).This is a 24-week nationwide prospective multi-centre cohort with a control group without RD and not using HCQ. All participants were monitored through scheduled phone interviews performed by health professionals. Details regarding COVID-19 symptoms, and epidemiological, clinical, and demographic data were recorded on a specific web-based platform. COVID-19 was defined according to the Brazilian Ministry of Health criteria and classified as mild, moderate or severe.A total of 9,585 participants, 5,164 (53.9%) RD patients on HCQ and 4,421 (46.1%) HC were enrolled from March 29th, 2020 to September 30th, 2020, according to the eligibility criteria. COVID-19 confirmed cases were higher in RD patients than in cohabitants [728 (14.1%) vs. 427 (9.7%), p0.001] in a 24-week follow-up. However, there was no significant difference regarding outcomes related to moderate/ severe COVID-19 (7.1% and 7.3%, respectively, p=0.896). After multiple adjustments, risk factors associated with hospitalisation were age over 65 (HR=4.5; 95%CI 1.35-15.04, p=0.014) and cardiopathy (HR=2.57; 95%CI 1.12-5.91, p=0.026). The final survival analysis demonstrated the probability of dying in 180 days after a COVID-19 diagnosis was significantly higher in patients over 65 years (HR=20.8; 95%CI 4.5-96.1) and with 2 or more comorbidities (HR=10.8; 95%CI 1.1-107.9 and HR=24.8; 95%CI 2.5-249.3, p=0.006, respectively).Although RD patients have had a higher COVID-19 incidence than individuals from the same epidemiological background, the COVID-19 severity was related to traditional risk factors, particularly multiple comorbidities and age, and not to underlying RD and HCQ.
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- 2021
40. Sinusoidal obstruction syndrome: a warning about autologous stem cell transplantation preceded by regimens containing oxaliplatin
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Frédérique Kuhnowski, Jean Philippe Richardet, Marie-Pierre Moles, Sébastien Mulé, Sylvie Glaisner, Manel Bedoui, Jehane Fadlallah, Julien Calderaro, Luc-Matthieu Fornecker, Pierre-Edouard Debureaux, Daniel Azoulay, Delphine Le Febvre de Nailly, Jerome Tamburini, Jehan Dupuis, Emmanuelle Tavernier, Corinne Haioun, David Sibon, and Vincent Camus
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Transplantation ,medicine.medical_specialty ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hepatic Veno-Occlusive Disease ,Hematology ,Transplantation, Autologous ,Oxaliplatin ,Surgery ,Autologous stem-cell transplantation ,medicine ,Humans ,business ,medicine.drug - Published
- 2020
41. Pulmonary Hypertension in General Cardiology Practice
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Jose Leonidas Alves Junior, Rogério Souza, Daniela Calderaro, and Caio Julio Cesar dos Santos Fernandes
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medicine.medical_specialty ,Pulmonary Circulation ,Heart Diseases ,Hypertension, Pulmonary ,Pulmonary Fibrosis ,Prostacyclin ,Review Article ,030204 cardiovascular system & hematology ,Echocardiography/methods ,Risk Assessment ,Pulmonary heart disease ,03 medical and health sciences ,Pulmonary Disease, Chronic Obstructive ,0302 clinical medicine ,Pulmonary Heart Disease ,Internal medicine ,Pulmonary fibrosis ,medicine ,Humans ,Diseases of the circulatory (Cardiovascular) system ,business.industry ,medicine.disease ,Pulmonary hypertension ,Pulmonary Emphysema ,Echocardiography ,RC666-701 ,Etiology ,Cardiology ,Invasive hemodynamic monitoring ,Left heart disease ,Cardiology and Cardiovascular Medicine ,Endothelin receptor ,business ,medicine.drug - Abstract
The finding of pulmonary hypertension (PH) by echocardiography is common and of concern. However, echocardiography is just a suggestive and non-diagnostic assessment of PH. When direct involvement of pulmonary circulation is suspected, invasive hemodynamic monitoring is recommended to establish the diagnosis. This assessent provides, in addition to the diagnostic confirmation, the correct identification of the vascular territory predominantly involved (arterial pulmonary or postcapillary). Treatment with specific medication for PH (phosphodiesterase type 5 inhibitors, endothelin receptor antagonists and prostacyclin analogues) has been proven effective in patients with pulmonary arterial hypertension, but its use in patients with PH due to left heart disease can even be damaging. In this review, we discuss the diagnosis criteria, how etiological investigation should be carried out, the clinical classification and, finally, the therapeutic recommendations for PH.
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- 2019
42. ESM1 as a Marker of Macrotrabecular-Massive Hepatocellular Carcinoma
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Stefano Caruso, Valérie Paradis, Alexis Laurent, Marouane Boubaya, Nathalie Ganne-Carrié, Marianne Ziol, Valérie Vilgrain, Georges Philippe Pageaux, Cong Trung Nguyen, Hélène Regnault, Mohamed Bouattour, Boris Guiu, Giuliana Amaddeo, Léa Meunier, Christophe Aubé, Julien Calderaro, Jean-Charles Nault, Nathalie Barget, Olivier Seror, Jeanne Ramos, Justine Cohen, Alain Luciani, Frédéric Oberti, Sophie Michalak, Jean-Michel Pawlotsky, and Jessica Zucman-Rossi
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Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,Antigens, Neoplasm ,Internal medicine ,ESM1 ,Biopsy ,Biomarkers, Tumor ,Tumor Microenvironment ,Carcinoma ,Humans ,Medicine ,Carbonic Anhydrase IX ,medicine.diagnostic_test ,business.industry ,Gene Expression Profiling ,Liver Neoplasms ,Middle Aged ,Prognosis ,medicine.disease ,digestive system diseases ,Subtyping ,Neoplasm Proteins ,3. Good health ,Gene expression profiling ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Immunohistochemistry ,Female ,Proteoglycans ,030211 gastroenterology & hepatology ,business - Abstract
Purpose: Macrotrabecular-massive hepatocellular carcinoma (MTM-HCC) is a novel morphological subtype of HCC associated with early relapse after resection or percutaneous ablation, independently of classical clinical and radiological prognostic factors. The aim of the present study was to identify immunohistochemical markers of MTM-HCC, to ease its diagnosis and implementation into clinical practice. Experimental Design: To identify potential biomarkers of MTM-HCC, we first analyzed gene expression profiling data from The Cancer Genome Atlas study and further selected two candidate biomarkers. Performance of both biomarkers for diagnosis of MTM-HCC was further tested by immunohistochemistry in two independent series of 67 and 132 HCC biopsy samples. Results: Analysis of RNA sequencing data showed that MTM-HCC was characterized by a high expression of neoangiogenesis-related genes. Two candidate biomarkers, Endothelial-Specific Molecule 1 (ESM1) and Carbonic Anhydrase IX (CAIX), were selected. In the discovery series, sensitivity and specificity of ESM1 expression by stromal endothelial cells for the detection of MTM-HCC were 97% (28/29), and 92% (35/38), respectively. Sensitivity and specificity of CAIX were 48% (14/29) and 89% (34/38). In the validation set, sensitivity and specificity of ESM1 for the identification of MTM-HCC were 93% (14/15) and 91% (107/117), respectively. Interobserver agreement for ESM1 assessment was good in both series (Cohen Kappa 0.77 and 0.76). Conclusions: Using a molecular-driven selection of biomarkers, we identified ESM1 as a reliable microenvironment immunohistochemical marker of MTM-HCC. The results represent a step toward the implementation of HCC morpho-molecular subtyping into clinical practice.
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- 2019
43. Lactate Dehydrogenase Inhibition: Biochemical Relevance and Therapeutical Potential
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Giuseppina Laganà, Ersilia Bellocco, Antonella Calderaro, and Davide Barreca
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Azoles ,Indoles ,Plasmodium falciparum ,Biochemistry ,Antimalarials ,03 medical and health sciences ,chemistry.chemical_compound ,Lactate dehydrogenase, bifunctional inhibitor, enzyme inhibitor, galloflavin, miRNA and shRNAs, oxamate and derivatives, quinoline derivatives ,0302 clinical medicine ,Functional importance ,Lactate dehydrogenase ,Drug Discovery ,Animals ,Humans ,Enzyme Inhibitors ,Organic Chemicals ,Peptide sequence ,030304 developmental biology ,Pharmacology ,chemistry.chemical_classification ,0303 health sciences ,L-Lactate Dehydrogenase ,biology ,Organic Chemistry ,Gossypol ,biology.organism_classification ,DNA metabolism ,Enzyme ,Isocoumarins ,chemistry ,Gluconeogenesis ,030220 oncology & carcinogenesis ,Quinolines ,Molecular Medicine ,Anaerobic exercise - Abstract
Lactate dehydrogenase (LHD) is a key enzyme of anaerobic metabolism in almost all living organisms and it is also a functional checkpoint for glucose restoration during gluconeogenesis and single-stranded DNA metabolism. This enzyme has a well preserved structure during evolution and among the species, with little, but sometimes very useful, changes in the amino acid sequence, which makes it an attractive target for the design and construction of functional molecules able to modulate its catalytic potential and expression. Research has focused mainly on the selection of modulator especially as far as LDH isozymes (especially LDH-5) and lactate dehydrogenases of Plasmodium falciparum (pfLDH) are concerned. This review summarizes the recent advances in the design and development of inhibitors, pointing out their specificity and therapeutic potentials.
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- 2019
44. Analysis of Liver Cancer Cell Lines Identifies Agents With Likely Efficacy Against Hepatocellular Carcinoma and Markers of Response
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Quentin Bayard, Eric Letouzé, Jill Pilet, Jean-Charles Nault, Léa Meunier, Bettina Grasl-Kraupp, Camille Péneau, Nataliya Rohr-Udilova, Tiziana La Bella, Gabrielle Couchy, J. Calderaro, Stefano Caruso, Leanne de Koning, Jessica Zucman-Rossi, Sandrine Imbeaud, Bérengère Ouine, Anna-Line Calatayud, Sandra Rebouissou, Samia Rekik, Paulette Bioulac-Sage, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Sorbonne Paris Cité (USPC), Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Medizinische Universität Wien = Medical University of Vienna, Institut Curie [Paris], Université Paris sciences et lettres (PSL), Physiopathologie du cancer du foie, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and Gestionnaire, Hal Sorbonne Université
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0301 basic medicine ,chemistry.chemical_compound ,0302 clinical medicine ,MEK Inhibitor ,Antineoplastic Combined Chemotherapy Protocols ,Gene expression ,Gene Regulatory Networks ,Protein Interaction Maps ,Precision Medicine ,Response to Therapy ,Hepatocyte differentiation ,MEK inhibitor ,Liver Neoplasms ,Gastroenterology ,3. Good health ,Gene Expression Regulation, Neoplastic ,Phenotype ,[SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Liver Tumor ,030211 gastroenterology & hepatology ,Signal transduction ,Signal Transduction ,medicine.drug ,Sorafenib ,Carcinoma, Hepatocellular ,Tumor suppressor gene ,Cell Survival ,Clinical Decision-Making ,Antineoplastic Agents ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biology ,03 medical and health sciences ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Cell Line, Tumor ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,microRNA ,Biomarkers, Tumor ,medicine ,Humans ,Genetic Predisposition to Disease ,Hepatology ,Patient Selection ,[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,Biomarker ,[SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,030104 developmental biology ,chemistry ,Alisertib ,Cancer research ,Drug Screening Assays, Antitumor ,Transcriptome - Abstract
International audience; BACKGROUND AND AIMS: Hepatocellular carcinomas (HCCs) are heterogeneous aggressive tumors with low rates of response to treatment at advanced stages. We screened a large panel of liver cancer cell lines (LCCLs) to identify agents that might be effective against HCC and markers of therapeutic response.METHODS: We performed whole-exome RNA and microRNA sequencing and quantification of 126 proteins in 34 LCCLs. We screened 31 anticancer agents for their ability to decrease cell viability. We compared genetic, RNA, and protein profiles of LCCLs with those of primary HCC samples and searched for markers of response.RESULTS: The protein, RNA and mutational signatures of the LCCLs were similar to those of the proliferation class of HCC, which is the most aggressive tumor type. Cell lines with alterations in genes encoding members of the Ras-MAPK signaling pathway and that required fibroblast growth factor (FGF)19 signaling via FGF receptor 4 for survival were more sensitive to trametinib than to FGF receptor 4 inhibitors. Amplification of FGF19 resulted in increased activity of FGF19 only in tumor cells that kept a gene expression pattern of hepatocyte differentiation. We identified single agents and combinations of agents that reduced viability of cells with features of the progenitor subclass of HCC. LCCLs with inactivating mutations in TSC1 and TSC2 were sensitive to the mammalian target of rapamycin inhibitor rapamycin, and cells with inactivating mutations in TP53 were sensitive to the Aurora kinase A inhibitor alisertib. Amplification of MET was associated with hypersensitivity to cabozantinib and the combination of sorafenib and inhibitors of MAP kinase 1 and MAP kinase2 had a synergistic antiproliferative effect.CONCLUSION: LCCLs can be screened for drugs and agents that might be effective for treatment of HCC. We identified genetic alterations and gene expression patterns associated with response to these agents. This information might be used to select patients for clinical trials.
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- 2019
45. Clinical Impact of Genomic Diversity From Early to Advanced Hepatocellular Carcinoma
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Stefano Caruso, Théo Z. Hirsch, Julien Calderaro, Pierre Nahon, Christophe Duvoux, Yoann Martin, Sandrine Faivre, Jean-Frédéric Blanc, Josep M. Llovet, Quentin Bayard, Nathalie Ganne-Carrié, Cécile Charpy, Alexis Laurent, Eric Letouzé, Marianne Ziol, Paulette Bioulac-Sage, Guillaume Morcrette, Sandra Rebouissou, Christiane Copie-Bergman, Laurence Chiche, Jessica Zucman-Rossi, Giuliana Amaddeo, Jean-Charles Nault, Olivier Seror, Gabrielle Couchy, and Sandrine Imbeaud
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Adult ,Male ,Oncology ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,Adolescent ,ARID1A ,Gene mutation ,Young Adult ,Internal medicine ,Exome Sequencing ,medicine ,Carcinoma ,Humans ,Telomerase reverse transcriptase ,Aged ,Neoplasm Staging ,Aged, 80 and over ,Hepatology ,business.industry ,Liver Neoplasms ,Genomics ,Genetic Profile ,Middle Aged ,medicine.disease ,BCLC Stage ,Tumor progression ,Hepatocellular carcinoma ,Mutation ,Female ,Liver cancer ,business - Abstract
To date, genomic analyses of hepatocellular carcinoma (HCC) have been limited to early stages obtained from liver resection. We aim to describe the genomic profiling of HCC from early to advanced stages. We analyzed 801 HCC from 720 patients (410 resections, 137 transplantations, 122 percutaneous ablations, and 52 noncurative) for 190 gene expressions and for 31 gene mutations. Forty-one advanced HCC and 156 whole exome of Barcelona Clinic Liver Cancer (BCLC) 0/A were analyzed by whole-exome sequencing. Genomic profiling was correlated with tumor stages, clinical features, and survival. Our cohort included patients classified in BCLC stage 0 (9.4%), A (59.5%), B (16.2%), and C (14.9%). Among the overall 801 HCC, the most frequently mutated genes were telomerase reverse transcriptase (TERT) (58.1%), catenin beta 1 (CTNNB1) (30.7%), tumor protein 53 (TP53; 18.7%), AT-rich interaction domain 1A (ARID1A) (13%), albumin (11.4%), apolipoprotein B (APOB) (9.4%), and AXIN1 (9.2%). Advanced-stage HCC (BCLC B/C) showed higher frequencies of splicing factor 3b subunit 1 (SF3B1) (P = 0.0003), TP53 (P = 0.0006), and RB Transcriptional Corepressor 1 mutations (P = 0.03). G1-G6 transcriptomic classification and the molecular prognostic 5-gene score showed different distributions according to the stage of the disease and the type of treatment with an enrichment of G3 (P < 0.0001), poor prognostic score (P < 0.0001), and increased proliferation and dedifferentiation at the transcriptomic level in advanced HCC. The 5-gene score predicted survival in patients treated by resection (P < 0.0001) and ablation (P = 0.01) and in advanced HCC (P = 0.04). Twenty-two percent of advanced HCC harbored potentially druggable genetic alterations, and MET amplification was associated with complete tumor response in patients with advanced HCC treated by a specific MET inhibitor. Conclusion: Genomic analysis across the different stages of HCC revealed the mechanisms of tumor progression and helped to identify biomarkers of response to targeted therapies.
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- 2019
46. Oral microbial dysbiosis linked to worsened periodontal condition in rheumatoid arthritis patients
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Tarcília Aparecida Silva, Gabriel Fernandes, Gilda Aparecida Ferreira, Fernando Q Cunha, Chiranjit Mukherjee, E. Xiao, Jôice Dias Corrêa, Mayra Laino Albiero, Débora Cerqueira Calderaro, Antônio Lúcio Teixeira, Dana T. Graves, Santuza Maria Souza de Mendonça, Eugene J. Leys, and Janine Mayra da Silva
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0301 basic medicine ,Male ,Periodontium ,Arthritis ,lcsh:Medicine ,Systemic inflammation ,Anti-Citrullinated Protein Antibodies ,Arthritis, Rheumatoid ,0302 clinical medicine ,RNA, Ribosomal, 16S ,Prevotella ,lcsh:Science ,Multidisciplinary ,biology ,Microbiota ,Interleukin-17 ,Middle Aged ,Rheumatoid arthritis ,Cytokines ,Periodontics ,Female ,medicine.symptom ,Adult ,Bleeding on probing ,Dental plaque ,Microbiology ,Article ,03 medical and health sciences ,medicine ,Rheumatoid factor ,Humans ,Parvimonas micra ,Periodontitis ,Mouth ,business.industry ,PERIODONTITE ,lcsh:R ,Aggregatibacter actinomycetemcomitans ,biology.organism_classification ,medicine.disease ,030104 developmental biology ,Clinical attachment loss ,Immunology ,Dysbiosis ,lcsh:Q ,Fusobacterium nucleatum ,business ,030217 neurology & neurosurgery - Abstract
Rheumatoid arthritis (RA) is an autoimmune disorder associated with increased periodontal destruction. It is thought that RA increases the risk of periodontal disease; it is not known how it influences the oral microbiota. Our aim was to analyze the impact of RA on subgingival microbiota and its association with periodontal inflammation and RA activity. Forty-two patients with RA were compared to 47 control subjects without RA. Patients were screened for probing depth, clinical attachment level, bleeding on probing and classified as with or without periodontitis. Subgingival plaque was examined by Illumina MiSeq Sequencing of 16S rRNA gene V4 region and inflammatory cytokines were measured in saliva. RA was associated to severe periodontal disease. In addition, the severity of RA, reflected by the number of tender and swollen joints, was significantly correlated with the presence of pathogenic oral bacteria (i.e. Fusobacterium nucleatum and Treponema socransky). Non-periodontitis RA patients compared to healthy controls had increased microbial diversity and bacterial load, higher levels of pathogenic species (Prevotella, Selenomonas, Anaeroglobus geminatus, Parvimonas micra, Aggregatibacter actinomycetemcomitans) and reduction of health-related species (Streptococcus, Rothia aeria, Kingela oralis). Genes involved with bacterial virulence (i.e. lipopolysaccharide biosynthesis, peptidases) were more prevalent in the subgingival metagenome of subjects with RA. In addition, the degree of oral inflammation reflected by IL-2, IL-6, TNF-α, IFN-γ salivary levels was increased in non-periodontitis RA patients in comparison with controls. Our findings support the hypothesis that RA triggers dysbiosis of subgingival microbiota, which may contribute to worsening periodontal status.Author SummaryRheumatoid arthritis (RA) is an autoimmune disease characterized by joints inflammation, swelling, pain and stiffness. Exactly what starts this disease is still unclear. Some recent studies have suggested mucosal surfaces in the body, like those in the gums, could affect the disease process. It has been observed that people with RA have higher risk of periodontitis (a bacterial inflammatory disease of the gums), compared with the general population, and this may be the start of the autoimmune process. Also, periodontitis increases the severity of RA while interventions by treating periodontitis can improve the symptoms of RA. One of the possible mechanisms that link the higher prevalence of periodontitis in RA patients is the dysbiosis of the oral microbiota triggered by the chronic inflammation in RA. Increased levels of molecules of inflammation may affect the oral environment and change the type of bacteria that live there. Here, we examined RA patients and healthy subjects, screening their oral health and inflammatory markers. We collected their saliva and the dental plaque from the space between the teeth and the gum. We found that RA patients exhibited severe periodontitis, increased levels of inflammatory mediators on their saliva and distinct bacterial communities, with higher proportions of bacteria species linked to periodontal disease, even in patients without periodontitis. We also found that the presence of these bacteria species was linked to worse RA conditions. Our study provides new insights to understand the bi-directional mechanisms linking periodontal disease to the development of RA, showing that we need to pay attention to the oral cavity in patients with RA and refer people for dental evaluation. This practice might have a positive impact in the course of RA.
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- 2019
47. Epidemiology of human respiratory viruses in children with acute respiratory tract infection in a 3-year hospital-based survey in Northern Italy☆
- Author
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Flora De Conto, F. Ferraglia, Maria Cristina Medici, Maria Cristina Arcangeletti, Adriana Calderaro, Carlo Chezzi, F. Pinardi, and Francesca Conversano
- Subjects
0301 basic medicine ,Male ,Microbiological Techniques ,Epidemiology ,viruses ,BAL, bronchial alveolar lavage ,Acute respiratory tract infections ,0302 clinical medicine ,PCR, polymerase chain reaction ,HEP-2, human larynx epidermoid carcinoma ,Surveys and Questionnaires ,rt-RT-PCR, reverse transcription RT-PCR ,030212 general & internal medicine ,Respiratory system ,Child ,Acute respiratory tract infection ,HMPV, human metapneumovirus ,Respiratory Tract Infections ,Respiratory tract infections ,ARTI, acute respiratory tract infection ,Coinfection ,Incidence (epidemiology) ,Incidence ,HBOV, human bocavirus ,Molecular assays ,SP, sputum ,General Medicine ,Hospital based ,IBV, influenza virus B ,IAV, influenza virus A ,Hospitals ,Infectious Diseases ,CPE, cytopathic effect ,Italy ,HCOV, human coronavirus ,Virus Diseases ,Child, Preschool ,Viruses ,IV, influenza virus ,HEV, human enterovirus ,Female ,LLC-MK2, rhesus monkey-kidney ,RT-PCR, real-time PCR ,Microbiology (medical) ,medicine.medical_specialty ,Adolescent ,030106 microbiology ,PBS, phosphate-buffered saline ,MDCK-SIAT1, Madin-Darby Canine Kidney with enhanced expression of 6-linked sialic acids ,MRC-5, human lung fibroblasts ,Virus ,Article ,TS, throat swab ,03 medical and health sciences ,medicine ,NS, nasal swab ,Humans ,mAb, monoclonal antibody ,HADV, human adenovirus ,IIF, indirect immunofluorescence assay ,Respiratory viruses ,Virus isolation in cell culture ,business.industry ,Diagnostic Tests, Routine ,Vero, African green monkey kidney ,Intestine 407, embryonic human intestine ,Infant, Newborn ,ECHO, echovirus ,Infant ,HPIV, human parainfluenza virus ,Virology ,BAS, bronchial aspirate ,Northern italy ,HRSV, human respiratory syncytial virus ,NPA, nasopharyngeal aspirate ,Laboratory diagnosis ,BSA, bovine serum albumin ,business ,CV, coxsackievirus - Abstract
Acute respiratory tract infections (ARTIs) are among the leading causes of morbidity and mortality in children. The viral etiology of ARTIs was investigated over 3 years (October 2012–September 2015) in 2575 children in Parma, Italy, using indirect immunofluorescent staining of respiratory samples for viral antigens, cell culture, and molecular assays. Respiratory viruses were detected in 1299 cases (50.44%); 1037 (79.83%) were single infections and 262 (20.17%) mixed infections. The highest infection incidence was in children aged >6 months to ≤3 years (57.36%). Human respiratory syncytial virus (27.12%) and human adenovirus (23.58%) were the most common viruses identified. The virus detection rate decreased significantly between the first and third epidemic season (53.9% vs. 43.05%, P, Highlights • Respiratory viruses were assessed in children from October 2012 to September 2015. • Viruses were detected using antigen and molecular assays, and cell culture. • Respiratory syncytial virus and adenovirus were the most common viruses detected. • Influenza virus and respiratory syncytial virus detection showed seasonal variation. • Respiratory virus detection was highest in children aged >6 months to ≤3 years.
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- 2019
48. Cyclin A2/E1 activation defines a hepatocellular carcinoma subclass with a rearrangement signature of replication stress
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Bayard, Quentin, Meunier, Léa, Peneau, Camille, Renault, Victor, Shinde, Jayendra, Nault, Jean-Charles, Mami, Iadh, Couchy, Gabrielle, Amaddeo, Giuliana, Tubacher, Emmanuel, Bacq, Delphine, Meyer, Vincent, La Bella, Tiziana, Debaillon-Vesque, Audrey, Bioulac-Sage, Paulette, Seror, Olivier, Blanc, Jean-Frédéric, Calderaro, Julien, Deleuze, Jean-François, Imbeaud, Sandrine, Zucman-Rossi, Jessica, and Letouzé, Eric
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Adult ,Aged, 80 and over ,Gene Rearrangement ,Male ,Oncogene Proteins ,Hepatitis B virus ,Carcinoma, Hepatocellular ,Science ,Liver Neoplasms ,Dependovirus ,Middle Aged ,Survival Analysis ,Article ,Gene Expression Regulation, Neoplastic ,Mutagenesis, Insertional ,Parvovirinae ,Cyclin E ,Humans ,lcsh:Q ,Female ,lcsh:Science ,Promoter Regions, Genetic ,Cyclin A2 ,Aged - Abstract
Cyclins A2 and E1 regulate the cell cycle by promoting S phase entry and progression. Here, we identify a hepatocellular carcinoma (HCC) subgroup exhibiting cyclin activation through various mechanisms including hepatitis B virus (HBV) and adeno-associated virus type 2 (AAV2) insertions, enhancer hijacking and recurrent CCNA2 fusions. Cyclin A2 or E1 alterations define a homogenous entity of aggressive HCC, mostly developed in non-cirrhotic patients, characterized by a transcriptional activation of E2F and ATR pathways and a high frequency of RB1 and PTEN inactivation. Cyclin-driven HCC display a unique signature of structural rearrangements with hundreds of tandem duplications and templated insertions frequently activating TERT promoter. These rearrangements, strongly enriched in early-replicated active chromatin regions, are consistent with a break-induced replication mechanism. Pan-cancer analysis reveals a similar signature in BRCA1-mutated breast and ovarian cancers. Together, this analysis reveals a new poor prognosis HCC entity and a rearrangement signature related to replication stress., Cyclins A2 and E1 are known to regulate the cell cycle by promoting S phase entry and progression. Here, they identify an aggressive hepatocellular carcinoma subgroup exhibiting cyclin activation through various mechanisms and find this subgroup to display replication stress-induced structural rearrangements frequently activating TERT promoter.
- Published
- 2018
49. Patients with <scp>COVID</scp> ‐19 who experience a myocardial infarction have complex coronary morphology and high in‐hospital mortality: Primary results of a nationwide angiographic study
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Adriano Caixeta, Daniela Calderaro, Carlos M. Campos, Renata do Val, Cristiano Guedes Bezerra, Patrícia O. Guimarães, Fabio Sandoli de Brito, Francis R. de Souza, Roberto Kalil Filho, Alexandre Abizaid, Ludhmila Abrahão Hajjar, Fernanda Mangione, Jose de Ribamar Costa, Felipe G. Lima, Breno de Alencar Araripe Falcão, Bruno Caramelli, Henrique Barbosa Ribeiro, Ricardo Cavalcante, Pedro A. Lemos, Leandro A Côrtes, Roxana Mehran, and Natassja Huemer
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medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,Myocardial Infarction ,Context (language use) ,Disease ,030204 cardiovascular system & hematology ,Coronary Angiography ,Original Studies ,Lesion ,coronavirus disease 2019 ,03 medical and health sciences ,COVID-19 Testing ,Percutaneous Coronary Intervention ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Hospital Mortality ,Prospective Studies ,030212 general & internal medicine ,Myocardial infarction ,Thrombus ,Prospective cohort study ,SARS-CoV-2 ,business.industry ,COVID-19 ,General Medicine ,medicine.disease ,Treatment Outcome ,Concomitant ,Cardiology ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business - Abstract
Objectives We aimed to explore angiographic patterns and in‐hospital outcomes of patients with concomitant coronavirus disease‐19 (COVID‐19) and myocardial infarction (MI). Background Patients with COVID‐19 may experience MI during the course of the viral infection. However, this association is currently poorly understood. Methods This is a multicenter prospective study of consecutive patients with concomitant COVID‐19 and MI who underwent coronary angiography. Quantitative and qualitative coronary angiography were analyzed by two observers in an independent core lab. Results A total of 152 patients were included, of whom 142 (93.4%) had COVID‐19 diagnosis confirmation. The median time between symptom onset and hospital admission was 5 (1–10) days. A total of 83 (54.6%) patients presented with ST‐elevation MI. The median angiographic Syntax score was 16 (9.0–25.3) and 69.0% had multi‐vessel disease. At least one complex lesion was found in 73.0% of patients, 51.3% had a thrombus containing lesion, and 57.9% had myocardial blush grades 0/1. The overall in‐hospital mortality was 23.7%. ST‐segment elevation MI presentation and baseline myocardial blush grades 0 or 1 were independently associated with a higher risk of death (HR 2.75, 95%CI 1.30–5.80 and HR 3.73, 95%CI 1.61–8.61, respectively). Conclusions Patients who have a MI in the context of ongoing COVID‐19 mostly present complex coronary morphologies, implying a background of prior atherosclerotic disease superimposed on a thrombotic milieu. The in‐hospital prognosis is poor with a markedly high mortality, prompting further investigation to better clarify this newly described condition.
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- 2021
50. Active surveillance for carbapenemase-producing
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Adriana, Calderaro, Mirko, Buttrini, Monica, Martinelli, Sara, Montecchini, Silvia, Covan, Alberto, Ruggeri, Isabella, Rodighiero, Alan, Di Maio, Mariapia, Galullo, Sandra, Larini, Maria Cristina, Arcangeletti, Carlo, Chezzi, and Flora, De Conto
- Subjects
diagnostic microbiology ,beta-Lactamases ,Klebsiella Infections ,Tertiary Care Centers ,molecular diagnostics ,Klebsiella pneumoniae ,Infectious Diseases ,Bacterial Proteins ,Italy ,Humans ,epidemiology ,Watchful Waiting ,Retrospective Studies - Abstract
Objectives The distribution of carbapenemase-producing Klebsiella pneumoniae (CPKP) phenotypes and genotypes in samples collected during 2011–2018 was evaluated. The association between patients with CPKP-positive rectal swab and those with CPKP infection, as well as the overall analysis of CPKP-infected patients, was performed. Setting The study was performed in a tertiary-care hospital located in Northern Italy. Participants Two groups were considered: 22 939 ‘at-risk’ patients submitted to active surveillance for CPKP detection in rectal swabs/stools and 1094 CPKP-infected patients in which CPKP was detected in samples other than rectal swabs. Results CPKP-positive rectal swabs were detected in 5% (1150/22 939). A CPKP infection was revealed in 3.1% (719/22 939) of patients: 582 with CPKP-positive rectal swab (50.6% of the 1150 CPKP-positive rectal swabs) and 137 with CPKP-negative rectal swab. The 49.4% (568/1150) of the patients with CPKP-positive rectal swab were carriers. The overall frequency of CPKP-positive patients (carriers and infected) was almost constant from 2012 to 2016 (excluding the 2015 peak) and then increased in 2017–2018. blaKPC was predominant followed by blaVIM. No difference was observed in the frequency of CPKP-positive rectal swab patients among the different material groups. Among the targeted carbapenemase genes, blaVIM was more significantly detected from urine than from other samples. Conclusions The high prevalence of carriers without evidence of infection, representing a potential reservoir of CPKP, suggests to maintain the guard about this problem, emphasising the importance of active surveillance for timely detection and separation of carriers, activation of contact precautions and antibiotic treatment guidance on suspicion of infection.
- Published
- 2021
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