FM - Artigos em Revistas Internacionais
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- Sustained macrophage reprogramming is required for CD8+ T cell–dependent long-term tumor eradicationPublication . Jardim, Carolina; Bica, Marta; Reis-Sobreiro, Mariana; Mota, Afonso Teixeira da; Lopes, Raquel; Ferreira-Pinto, Miguel Alexandre; Sousa, Neuza S.; Mensurado, Sofia; Boekhoff, Henning; Scolaro, Tommaso; Reugebrink, Maud; Gonçalves-Sousa, Natacha; Kubo, Hiroshi; Leites, Elvira; Morais, Vanessa A.; Silva-Santos, Bruno; Barbosa-Morais, Nuno; Serre, KarineTumor-associated macrophages (TAM) exhibit a dual role in tumor progression and antitumor immunity. However, understanding the functional states and molecular mechanisms of antitumor TAMs remains a challenge. Herein, we show that intratumoral administration of a combination of agonists against TLR3 and CD40 [hereafter termed myeloid cell treatment (MCT)] reprogrammed TAMs in situ to adopt a protective antitumor phenotype in an orthotopic mouse breast cancer model, and that this led to tumor regression. Single-cell RNA sequencing of TAMs from different tumor stages and after MCT revealed a transient antitumor TAM phenotype, present at 12 hours after MCT and characterized by markers such as inducible nitric oxide synthase and CD38, which was replaced by TAMs coexpressing tumor-limiting and tumor-promoting features by 72 hours after MCT. Maintenance of antitumor TAMs required repeated MCT administration, and this promoted the activation of CD8+ T cells and long-term tumor eradication. Mechanistically, reactive oxygen species and TNF-α were pivotal in TAM-mediated tumor control. Our findings uncover the vulnerability of transient TAM reprogramming and show that it can be overcome by repeated MCT administrations to sustain efficient antitumor immune responses.
- How useful is contrast-enhanced ultrasound in rheumatoid arthritis? A systematic review with meta-analysis on the comparison between contrast-enhanced ultrasound and colour or power Doppler ultrasoundPublication . Polido Pereira, Joaquim; António, Manuel; Henriques, Susana Oliveira; Sabido, João; Fernandes, Ricardo M.; Vieira de Sousa, Elsa Cristina; D’Agostino, Maria Antonietta; Fonseca, João EuricoObjective The primary objective was to evaluate the additional benefits of contrast-enhanced ultrasound (CEUS) compared to unenhanced Doppler ultrasound (DUS) for the identification of active synovitis in rheumatoid arthritis (RA). Methods We searched PubMed/MEDLINE and EMBASE (February 2024) for all English-written published reports of human studies including the use of CEUS for the study of synovitis in RA. The risk of bias of included studies was evaluated using the QUADAS tool. DUS and CEUS semiquantitative scores were transformed in binomial, and these data were extracted for meta-analysis. Results that we were unable to quantitatively aggregate were summarised qualitatively. Results Twenty-three studies using CEUS to evaluate 1117 joints from 827 subjects were included, of which 898 joints were from 669 RA patients. We performed a meta-analysis of 9 studies in active RA patients showing that from 474 joints evaluated by either PDUS/CDUS and CEUS, the synovitis detection was 49.2% and 83.8%, respectively, corresponding to a relative detection ratio (RDR) of 1.49 (95% CI 1.23–1.81) favouring CEUS. Heterogeneity of the data was moderate. In healthy subjects, CEUS detected no vascularisation in 4 studies. Discussion CEUS detects more microvascularisation than PDUS in active RA with an RDR of 1.49.
- Radiologic clue to cavernous sinus hemangioma diagnosisPublication . Esteves, Cristiano; Berhanu, David; Guerreiro, CarlaWe describe a case of a 57-year-old woman presenting initially with diplopia who later developed retro-orbital and retroauricular pain. Examination showed right abducens nerve palsy and subsequent right trigeminal nerve hyperesthesia. Neuroimaging revealed a well-defined mass confined to the right cavernous sinus, with high T2 signal intensity and homogeneous enhancement on postgadolinium T1-weighted images. A meningioma was initially considered as the most likely diagnosis. The lesion grew over months, extending into the Meckel's cave and the pituitary fossa. Dynamic T1-weighted images revealed striking and progressive centripetal enhancement, leading to a revised diagnosis of cavernous sinus hemangioma (CSH). CSH is a rare benign extra-axial tumor, which is highly vascularized, and is frequently misdiagnosed as meningioma or schwannoma. The combination of very high T2 signal intensity and progressive centripetal contrast enhancement highly suggest CSH diagnosis. Given the significant risk of bleeding and mortality associated with surgical intervention, it is crucial to recognize CSH preoperatively to plan a meticulous surgical approach.
- Smoking status and vascular risk factors as predictors of disability in AQP4-NMOSD and MOGADPublication . Chan, Fiona; Berhanu, David; Samadzadeh, Sara; Francis, Anna; Asgari, Nasrin; Paul, Friedemann; Leite, M Isabel; Geraldes, Ruth; Palace, JacquelineBackground: Smoking and vascular risk factors (VRFs) are reported to have adverse effects in multiple sclerosis but data are limited in aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD). This study aimed to measure their impact on disability. Methods: Smoking status was defined as never, past or current smokers and VRF comprised of ⩾1: hypertension, dyslipidemia, high body mass index or diabetes. Logistic regression models were fitted to predict their influence on recovery from onset attack and first optic neuritis (ON) attack. Results: A total of 442 patients were included. Current MOGAD smokers had a higher risk of disability from onset attack and first ON attack than never smokers (odds ratio (OR) 2.9, 95% confidence interval (CI) 1.3-6.9; OR 3.3, 95% CI 1.4-7.8). VRF in MOGAD was not predictive of disability. Current AQP4-NMOSD smokers and VRFs had a higher risk of residual disability from onset attacks (OR 7.5, 95% CI 2.1-27.7; OR 1.9, 95% CI 1.0-3.4). VRF was associated with higher risk of visual disability (OR 2.6, 95% CI 1.08-6.46) while smoking status was not. Conclusions: Current smoking status detrimentally influenced onset attack recovery in AQP4-NMOSD and MOGAD patients, including visual recovery in MOGAD. Non-smoking VRFs influenced clinical and visual outcomes in AQP4-NMOSD.
- Thiamine compounds alleviate oxidative stress, over-expression of pro-inflammatory markers and behavioral abnormalities in a mouse predation model of PTSDPublication . Strekalova, Tatyana; Gorlova, Anna; Nunes, João; Litavrin, Aleksandr; Munter, Johannes P. M. de; Lyundup, Alexei; Umriukhin, Aleksei; Proshin, Andrey; Kalueff, Allan; Grünblatt, Edna; Walitza, SusannaExperiences of life-threatening stimuli can induce post-traumatic stress disorder (PTSD), which is associated with long-lasting behavioral and neurochemical abnormalities. Despite its increased global incidence, the current treatment options for PTSD remain limited, highlighting the need for novel therapeutic strategies. As oxidative stress and neuroinflammation contribute to PTSD, the use of powerful antioxidants such as thiamine (B1 vitamin) compounds may counteract disease development. Young C57BL/6 mice received thiamine or benfotiamine in drinking water (each at a dose of 200 mg/kg/day) for 21 days, and for the last five days, they were subjected to rat exposure. Mice were studied for anxiety-like behavior, exploration, locomotion, grooming, social interactions, pain sensitivity, brain changes in protein carbonyl (PC), total glutathione (TG), and gene expression of distress and inflammation markers. Rat exposure induced anxiety-like behavior, excessive grooming, and alteration in locomotion, along with other abnormalities. Stressed, untreated mice had elevated levels of PC and TG in the prefrontal cortex, hippocampus, amygdala, and striatum and increased expression of Il-1β, Tnf, c-Fos, Cox-1, and Cox-2. Treatment with thiamine or benfotiamine significantly ameliorated most of these changes in the stressed groups. Thus, thiamine compounds may have therapeutic potential in patients with PTSD, owing to their antioxidant and anti-inflammatory properties.
- PD-1 and ICOS are coexpressed in T follicular helper cells but define three stages of maturation of T follicular regulatory cellsPublication . Ribeiro, Filipa; Antunes, Diogo; Pires, Ana R.; Rino, José; Filipe, Beatriz; Jesus, Kátia; Correia, Ricardo; Fonseca, Válter R; Kumar, Saumya; Graca, LuisHumoral responses to infection or vaccination require T cell-B cell interactions. T follicular helper (TFH) cells drive germinal center (GC) responses by providing help to B cells, whereas T follicular regulatory (TFR) cells regulate them. Both mature GC-located TFH and TFR cells are widely characterized by the expression of ICOS and PD-1. However, although human TFR cells share many phenotypic characteristics with TFH cells, we found that ICOS and PD-1 are up-regulated differently in each. Although TFH cells express these proteins synchronously during maturation, they define three maturation stages in TFR cells. TFR cells in an intermediate maturation stage express ICOS, and it is only at the last stage of differentiation that both molecules are expressed at high levels. Although most TFR cells within the B cell follicle are PD-1-, the TFR within the GC are ICOS+PD-1+. These results show that TFH and TFR cells within human lymphoid tissue follow distinct maturation stages.
- Genetic characterization of the dihydrofolate reductase gene of Pneumocystis jirovecii isolates from PortugalPublication . Costa, Marina C.; Esteves, Francisco; Antunes, Francisco; Matos, OlgaObjectives: The aim of the present study was to evaluate the genetic variation of Pneumocystis jirovecii dihydrofolate reductase (DHFR) gene in an immunocompromised Portuguese population and to investigate the possible association between DHFR genotypes and P. jirovecii pneumonia (PcP) prophylaxis with co-trimoxazole. Methods: One hundred and thirty-eight P. jirovecii isolates were submitted to DHFR genetic characterization by PCR and sequencing. Results: In the studied population, 72.7% of the patients presented sequences identical to the wild-type sequence of the P. jirovecii DHFR gene and 27.3% presented point substitutions. A total of nine substitution sites were identified; four synonymous substitutions at nucleotide positions 201, 272, 312 and 381 were detected in 31 patients. Five non-synonymous substitutions were observed, leading to the DHFR mutations Leu-13→Ser, Asn-23→Ser, Ser-31→Phe, Met-52→Leu and Ala-67→Val. With the exception of the polymorphism at position 312 and the mutation at codon 52, all polymorphisms were reported in this study for the first time. Conclusions: Our results suggest that DHFR gene polymorphisms are frequent in the Portuguese immunocompromised population but do not seem to be associated with PcP prophylaxis failure (P = 0.748 and P = 0.730).
- Identification of potentially human-pathogenic Enterocytozoon bieneusi genotypes in various birdsPublication . Lobo, Maria Luísa; Xiao, Lihua; Cama, Vitaliano; Magalhães, Nuno; Antunes, Francisco; Matos, OlgaEnterocytozoon bieneusi was detected in 24 of 83 samples from birds of the orders Columbiformes, Passeriformes, and Psittaciformes. It was identical to or closely related to the Peru6 genotype, which was previously found in humans in Peru. Thus, various birds can be a significant source of environmental contamination by potentially human-pathogenic E. bieneusi.
- Distribution of Cryptosporidium subtypes in humans and domestic and wild ruminants in PortugalPublication . Alves, Margarida; Xiao, Lihua; Antunes, Francisco; Matos, OlgaTo investigate the transmission of cryptosporidiosis in Portugal, Cryptosporidium hominis and Cryptosporidium parvum from HIV-infected patients, cattle, and wild ruminants were characterized by sequence analysis of the 60-kDa glycoprotein (GP60) gene. Fourteen subtypes within nine subtype families were identified, and three of the subtype families (If, IIb, and IId) were restricted or largely limited to Portugal. Parasites from cattle from various regions in Portugal and wild ruminants in Lisbon showed limited genetic heterogeneity (only two subtype families). All wild ruminants had the same subtype, which was also the predominant subtype in cattle all over Portugal and was found in nine HIV-infected patients in Lisbon. Two other C. parvum subtypes were only restricted to limited locations. In contrast, human parasites displayed 13 subtypes in nine subtype families, with most of the infections caused by parasites in Ib, IIa, IIc, and IId families. Two of the C. parvum subtype families (IIc and IIb) had only been found in humans. The high overall parasite diversity and high percentage of C. hominis infections attributable to Ib and C. parvum infections to IId represent unique characteristics of Cryptosporidium transmission in humans in Portugal.
- Distribution of Cryptosporidium species and subtypes in water samples in Portugal: a preliminary studyPublication . Alves, Margarida; Ribeiro, Ana M.; Neto, Célia; Ferreira, Elisabete; Benoliel, Maria J.; Antunes, Francisco; Matos, OlgaCryptosporidium is a significant cause of diarrhoeal disease in the general population and a major cause for morbidity and mortality in immunocompromised persons. Cryptosporidiosis is a major public health concern and the role of water in disease transmission is now well recognized. The ingestion of oocyst-contaminated drinking water has led to large outbreaks of disease, mostly in North America, the United Kingdom, Japan, and Australia (Fayer, Morgan, and Upton 2000). The most important causative agents of human cryptosporidiosis are C. parvum (found in domestic livestock, wild animals, and humans) and C. hominis (found almost exclusively in humans; Alves et al. 2003; Leoni et al. 2006; Matos et al. 2004; Xiao and Ryan 2004).