Trinquand, Amelie; dos Santos, Nuno R.; Quang, Christine Tran; Rocchetti, Francesca; Zaniboni, Benedetta; Belhocine, Mohamed; de Jesus, Cindy Da Costa; Lhermitte, Ludovic; Tesio, Melania; Dussiot, Michael; Cosset, Francois-Loic; Verhoeyen, Els; Pflumio, Francoise; Ifrah, Norbert; Dombret, Herve; Spicuglia, Salvatore; Chatenoud, Lucienne; Gross, David-Alexandre; Hermine, Olivier; Macintyre, Elizabeth; Ghysdael, Jacques; Asnafi, Vahid
Cancer onset and progression involves the accumulation of multiple oncogenic hits, which are thought to dominate or bypass the physiologic regulatory mechanisms in tissue development and homeostasis. We demonstrate in T-cell acute lymphoblastic leukemia (T-ALL) that, irrespective of the complex oncogenic abnormalities underlying tumor progression, experimentally induced, persistent T-cell receptor (TCR) signaling has antileukemic properties and enforces a molecular program resembling thymic negative selection, a major developmental event in normal T-cell development. Using mouse models of T-ALL, we show that induction of TCR signaling by high-affinity self-peptide/MHC or treatment with monoclonal antibodies to the CD3 epsilon chain (anti-CD3) causes massive...
Castelo-Branco, Pedro; Leao, Ricardo; Lipman, Tatiana; Campbell, Brittany; Lee, Donghyun; Price, Aryeh; Zhang, Cindy; Heidari, Abolfazl; Stephens, Derek; Boerno, Stefan; Coelho, Hugo; Gomes, Ana; Domingos, Celia; Apolonio, Joana D.; Schaefer, Georg; Bristow, Robert G.; Schweiger, Michal R.; Hamilton, Robert; Zlotta, Alexandre; Figueiredo, Arnaldo; Klocker, Helmut; Sueltmann, Holger; Tabori, Uri
The identification of new biomarkers to differentiate between indolent and aggressive prostate tumors is an important unmet need. We examined the role of THOR (TERT Hypermethylated Oncological Region) as a diagnostic and prognostic biomarker in prostate cancer (PCa).We analyzed THOR in common cancers using genome-wide methylation arrays. Methylation status of the whole TERT gene in benign and malignant prostate samples was determined by MeDIP-Seq. The prognostic role of THOR in PCa was assessed by pyrosequencing on discovery and validation cohorts from patients who underwent radical prostatectomy with long-term follow-up data.Most cancers (n = 3056) including PCa (n = 300) exhibited...
Afonso, Joana; Lopes, Susana; Gonçalves, Raquel; Caldeira, Paulo; Lago, Paula; Sousa, Helena Tavares de; Ramos, Jaime; Goncalves, Ana Rita; Ministro, Paula; Rosa, Isadora; Vieira, Ana Isabel; Coelho, Rosa; Tavares, Patricia; Soares, João; Sousa, Ana Lúcia; Carvalho, Diana; Sousa, Paula; Silva, João Pereira da; Meira, Tânia; Ferreira, Filipa Silva; Dias, Cláudia Camila; Chowers, Yehuda; Ben-Horin, Shomron; Magro, Fernando
Background: There is scant information on the accuracy of different assays used to measure anti-infliximab antibodies (ADAs), especially in the presence of detectable infliximab (IFX). We thus aimed to evaluate and compare three different assays for the detection of IFX and ADAs and to clarify the impact of the presence of circulating IFX on the accuracy of the ADA assays.Methods: Blood samples from 79 ulcerative colitis (UC) patients treated with infliximab were assessed for IFX levels and ADAs using three different assays: an in-house assay and two commercial kits, Immundiagnostik and Theradiag. Sera samples with ADAs and undetectable levels of...
Ribeiro, Ana Luisa; Silva, Rui D.; Foyn, Havard; Tiago, Margarida N.; Rathore, Om Singh; Arnesen, Thomas; Martinho, Rui Gonçalo
The gene separation anxiety (san) encodes Naa50/San, a N-terminal acetyltransferase required for chromosome segregation during mitosis. Although highly conserved among higher eukaryotes, the mitotic function of this enzyme is still poorly understood. Naa50/San was originally proposed to be required for centromeric sister chromatid cohesion in Drosophila and human cells, yet, more recently, it was also suggested to be a negative regulator of microtubule polymerization through internal acetylation of beta Tubulin. We used genetic and biochemical approaches to clarify the function of Naa50/San during development. Our work suggests that Naa50/San is required during tissue proliferation for the correct interaction between the...
Fragoso, E.; André, S.; Boleo-Tome, J. P.; Areias, V.; Munha, J.; Cardoso, J.
Chronic Obstructive Pulmonary Disease (COPD) phenotypes have become increasingly recognized as important for grouping patients with similar presentation and/or behavior, within the heterogeneity of the disease. The primary aim of identifying phenotypes is to provide patients with the best health care possible, tailoring the therapeutic approach to each patient.However, the identification of specific phenotypes has been hindered by several factors such as which specific attributes are relevant, which discriminant features should be used for assigning patients to specific phenotypes, and how relevant are they to the therapeutic approach, prognostic and clinical outcome. Moreover, the definition of phenotype is still not...
Hellquist, Henrik; Skalova, Alena; Barnes, Leon; Cardesa, Antonio; Thompson, Lester D. R.; Triantafyllou, Asterios; Williams, Michelle D.; Devaney, Kenneth O.; Gnepp, Douglas R.; Bishop, Justin A.; Wenig, Bruce M.; Suarez, Carlos; Rodrigo, Juan P.; Coca-Pelaz, Andres; Strojan, Primoz; Shah, Jatin P.; Hamoir, Marc; Bradley, Patrick J.; Silver, Carl E.; Slootweg, Pieter J.; Vander Poorten, Vincent; Teymoortash, Afshin; Medina, Jesus E.; Robbins, K. Thomas; Pitman, Karen T.; Kowalski, Luiz P.; de Bree, Remco; Mendenhall, William M.; Eloy, Jean Anderson; Takes, Robert P.; Rinaldo, Alessandra; Ferlito, Alfio
Adenoid cystic carcinoma (AdCC) is among the most common malignant tumors of the salivary glands. It is characterized by a prolonged clinical course, with frequent local recurrences, late onset of metastases and fatal outcome. High-grade transformation (HGT) is an uncommon phenomenon among salivary carcinomas and is associated with increased tumor aggressiveness. In AdCC with high-grade transformation (AdCC-HGT), the clinical course deviates from the natural history of AdCC. It tends to be accelerated, with a high propensity for lymph node metastasis. In order to shed light on this rare event and, in particular, on treatment implications, we undertook this review: searching...
Coca-Pelaz, Andres; Barnes, Leon; Rinaldo, Alessandra; Cardesa, Antonio; Shah, Jatin P.; Rodrigo, Juan P.; Suarez, Carlos; Eloy, Jean Anderson; Bishop, Justin A.; Devaney, Kenneth O.; Thompson, Lester D. R.; Wenig, Bruce M.; Strojan, Primoz; Hamoir, Marc; Bradley, Patrick J.; Gnepp, Douglas R.; Silver, Carl E.; Slootweg, Pieter J.; Triantafyllou, Asterios; Vander Poorten, Vincent; Williams, Michelle D.; Skalova, Alena; Hellquist, Henrik; Teymoortash, Afshin; Medina, Jesus E.; Robbins, K. Thomas; Pitman, Karen T.; Kowalski, Luiz P.; de Bree, Remco; Mendenhall, William M.; Takes, Robert P.; Ferlito, Alfio
Adenoid cystic carcinoma (AdCC) of the head and neck is a well-recognized pathologic entity that rarely occurs in the larynx. Although the 5-year locoregional control rates are high, distant metastasis has a tendency to appear more than 5 years post treatment. Because AdCC of the larynx is uncommon, it is difficult to standardize a treatment protocol. One of the controversial points is the decision whether or not to perform an elective neck dissection on these patients. Because there is contradictory information about this issue, we have critically reviewed the literature from 1912 to 2015 on all reported cases of AdCC...
Eusébio, Marta; Caldeira, Paulo; Antunes, Artur Gião; Ramos, André; Velasco, Francisco; Cadill, Jesús; Guerreiro, Horácio
We report a case of a 63-year-old-man presenting with chronic diarrhea and weight loss while on olmesartan treatment for hypertension. Investigation showed multiple nutritional deficiencies associated with diffuse intestinal villous atrophy. Serologies for celiac disease were negative and other causes of villous atrophy were excluded. Olmesartan as a precipitant agent was suspected and withdrawn. Clinical improvement occurred in days with no need for other therapeutic measures. Follow-up at three months showed clinical remission and almost complete recovery of intestinal atrophy. Olmesartan is an angiotensin receptor blocker commonly prescribed for the management of hypertension. Spruelike enteropathy associated with this drug is...
Navarro-Costa, Paulo; McCarthy, Alicia; Prudêncio, Pedro; Greer, Christina; Guilgur, Leonardo G.; Becker, Jorg D.; Secombe, Julie; Rangan, Prashanth; Martinho, Rui Gonçalo
Oocytes are arrested for long periods of time in the prophase of the first meiotic division (prophase I). As chromosome condensation poses significant constraints to gene expression, the mechanisms regulating transcriptional activity in the prophase I-arrested oocyte are still not entirely understood. We hypothesized that gene expression during the prophase I arrest is primarily epigenetically regulated. Here we comprehensively define the Drosophila female germ line epigenome throughout oogenesis and show that the oocyte has a unique, dynamic and remarkably diversified epigenome characterized by the presence of both euchromatic and heterochromatic marks. We observed that the perturbation of the oocyte's epigenome...
Morgado, Bruno; Madeira, Catarina; Pinto, Joana; Pestana, Joana
A 71-year-old woman presented with constitutional signs and lower extremity palpable purpura after being prescribed a four-day course of 500 mg of ciprofloxacin two times daily for a gastrointestinal infection. She was admitted for inpatient treatment. During the third hospital day, she presented with an episode of abundant hematemesis while her skin lesions remained unchanged. Upper endoscopy revealed multiple lesions consistent with vasculitis and histological examination of the skin biopsy disclosed a leukocytoclastic vasculitis. The patient was successfully treated with prednisone following ciprofloxacin discontinuation. Complete resolution of the lesions on drug withdrawal strongly suggested drug toxicity, which was further supported...
Cardeira, João; Gavaia, Paulo J.; Fernandez, Ignacio; Cengiz, Ibrahim Fatih; Moreira-Silva, Joana; Oliveira, Joaquim Miguel; Reis, Rui L.; Cancela, Leonor; Laizé, Vincent
The ability of zebrafish to fully regenerate its caudal fin has been explored to better understand the mechanisms underlying de novo bone formation and to develop screening methods towards the discovery of compounds with therapeutic potential. Quantifying caudal fin regeneration largely depends on successfully measuring new tissue formation through methods that require optimization and standardization. Here, we present an improved methodology to characterize and analyse overall caudal fin and bone regeneration in adult zebrafish. First, regenerated and mineralized areas are evaluated through broad, rapid and specific chronological and morphometric analysis in alizarin red stained fins. Then, following a more refined...
Jacob, Miguel; Ramos, Helena C.; Morgado, Bruno
The most significantoutbreak of Legionella pneumophila, or Legionnaires' Disease, ever registered in Portugal occurred in 2014, and was considered one of the largest in European history. This relatively rare infection has a dire prognosis if not timely identified and correctly treated, presenting with a high lethality rate. We describe a case of infection by Legionella pneumophila in a previously healthy individual during an outbreak that originated 300 kilometers away from our hospital. The patient presented to the Emergency Department and after an initial assessment, was admitted to the Intensive Care Unit (ICU). He underwent supportive treatment with invasive mechanical ventilation...
Rathore, Om Singh; Faustino, Alexandra; Prudêncio, Pedro; Van Damme, Petra; Cox, Cymon J.; Martinho, Rui Gonçalo
Protein N-terminal acetylation is an ancient and ubiquitous co-translational modification catalyzed by a highly conserved family of N-terminal acetyltransferases (NATs). Prokaryotes have at least 3 NATs, whereas humans have six distinct but highly conserved NATs, suggesting an increase in regulatory complexity of this modification during eukaryotic evolution. Despite this, and against our initial expectations, we determined that NAT diversification did not occur in the eukaryotes, as all six major human NATs were most likely present in the Last Eukaryotic Common Ancestor (LECA). Furthermore, we also observed that some NATs were actually secondarily lost during evolution of major eukaryotic lineages; therefore,...
Camacho, A.; Simão, M.; Ea, H. -K.; Cohen-Solal, M.; Richette, P.; Branco, J.; Cancela, Leonor
Objective: Hereditary hemochromatosis (HH) is a disease caused by mutations in the Hfe gene characterised by systemic iron overload and associated with an increased prevalence of osteoarthritis (OA) but the role of iron overload in the development of OA is still undefined. To further understand the molecular mechanisms involved we have used a murine model of HH and studied the progression of experimental OA under mechanical stress.Design: OA was surgically induced in the knee joints of 10-week-old C57BL6 (wild-type) mice and Hfe-KO mice. OA progression was assessed using histology, micro CT, gene expression and immunohistochemistry at 8 weeks after surgery.Results:...
Orwelius, Lotti; Teixeira-Pinto, Armando; Lobo, Cristina; Costa-Pereira, Altamiro; Granja, Cristina
Background: Decreased health-related quality of life (HRQoL) is a significant problem after an intensive care stay and is affected by several known factors such as age, sex, and previous health-state. The objective of this study was to assess the association between memory and self-reported perceived HRQoL of patients discharged from the intensive care unit (ICU).Methods: A prospective, multicenter study involving nine general ICUs in Portugal. All adult patients with a length of stay >48 hours were invited to participate in a 6-month follow-up after ICU discharge by answering a set of structured questionnaires, including EuroQol 5-Dimensions and ICU memory tool.Results:...
Marques, Cátia L.; Cancela, Leonor; Laizé, Vincent
Bone morphogenetic protein (BMP) 2 belongs to the transforming growth factor (3 (TGF(3) superfamily of cytokines and growth factors. While it plays important roles in embryo morphogenesis and organogenesis, BMP2 is also critical to bone and cartilage formation. Protein structure and function have been remarkably conserved throughout evolution and BMP2 transcription has been proposed to be tightly regulated, although few data is available. In this work we report the cloning and functional analysis of gilthead seabream BMP2 promoter. As in other vertebrates, seabream BMP2 gene has a 5' non-coding exon, a feature already present in DPP gene, the fruit fly...
Divisato, Giuseppina; Formicola, Daniela; Esposito, Teresa; Merlotti, Daniela; Pazzaglia, Laura; Del Fattore, Andrea; Siris, Ethel; Orcel, Philippe; Brown, Jacques P.; Nuti, Ranuccio; Strazzullo, Pasquale; Benassi, Maria Serena; Cancela, Leonor; Michou, Laetitia; Rendina, Domenico; Gennari, Luigi; Gianfrancesco, Fernando
Paget disease of bone (PDB) is a skeletal disorder characterized by focal abnormalities of bone remodeling, which result in enlarged and deformed bones in one or more regions of the skeleton. In some cases, the pagetic tissue undergoes neoplastic transformation, resulting in osteosarcoma and, less frequently, in giant cell tumor of bone (GCT). We performed whole-exome sequencing in a large family with 14 PDB-affected members, four of whom developed GCT at multiple pagetic skeletal sites, and we identified the c.2810C>G (p.Pro937Arg) missense mutation in the zinc finger protein 687 gene (ZNF687). The mutation precisely co-segregated with the clinical phenotype in...
Correia, Elizabeth; Conceição, Natércia; Cancela, Leonor; Belo, José
MGP (Matrix Gla Protein) is an extracellular matrix vitamin K dependent protein previously identified as a physiological inhibitor of calcification and shown to be well conserved among vertebrates during evolution. MGP is involved in other mechanisms such as TGF-beta and BMP activity, and a proposed modulator of cell-matrix interactions. MGP is expressed early in vertebrate development although its role has not been clarified. Previous work in the chicken embryo found MGP localization predominantly in the aorta and aortic valve base, but no data is available earlier in development. Here we examined MGP expression pattern using whole-mount in situ hybridization and...
Bidarian Moniri, Armin
Otitis media with effusion (OME) is defined as accumulation of fluid in the middle ear in absence of signs or symptoms of an acute ear infection.1 OME is usually associated with a conductive hearing loss that may affect the quality of life.1 Surgical treatment of OME with grommets is associated with substantial healthcare costs and is usually considered after a period of watchful waiting, leaving most children with OME untreated during this period.1 This raises the need for an efficient, non-invasive treatment option that can be offered to children with OME at an early stage.
In 1968, Hunt-Williams presented a new...
Mello, Ramon Andrade de
Over 1.5 million new cases of non-small cell lung cancer
(NSCLC), a highly aggressive disease, are registered
worldwide every year (1). Until the 1980s, treatment
generally yielded poor outcomes (2), and prognosis was
only good for early stages of operable disease. However,
advances in targeted molecular therapy since 2005 have
brought new hope to patients with advanced NSCLC,
especially those harboring the epidermal growth factor receptor
(EGFR) mutation in exons 18, 19 and 21 (3). As a result, the
median overall survival (OS) of a small group of patients with
advanced NSCLC increased from 10 to 18–36 months (2).