FM - Contribuições em Revistas Científicas / Contribution to Journals
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- Resistance to tyrosine kinase inhibitors in chronic myeloid leukemia — from molecular mechanisms to clinical relevancePublication . Alves, Raquel; Gonçalves, Ana Cristina; Rutella, Sergio; Almeida, António M.; Rivas, Javier De Las; Trougakos, Ioannis P.; Ribeiro, Ana Bela SarmentoResistance to targeted therapies is a complex and multifactorial process that culminates in the selection of a cancer clone with the ability to evade treatment. Chronic myeloid leukemia (CML) was the first malignancy recognized to be associated with a genetic alteration, the t(9;22)(q34;q11). This translocation originates the BCR-ABL1 fusion gene, encoding the cytoplasmic chimeric BCR-ABL1 protein that displays an abnormally high tyrosine kinase activity. Although the vast majority of patients with CML respond to Imatinib, a tyrosine kinase inhibitor (TKI), resistance might occur either de novo or during treatment. In CML, the TKI resistance mechanisms are usually subdivided into BCR-ABL1-dependent and independent mechanisms. Furthermore, patients’ compliance/adherence to therapy is critical to CML management. Techniques with enhanced sensitivity like NGS and dPCR, the use of artificial intelligence (AI) techniques, and the development of mathematical modeling and computational prediction methods could reveal the underlying mechanisms of drug resistance and facilitate the design of more effective treatment strategies for improving drug efficacy in CML patients. Here we review the molecular mechanisms and other factors involved in resistance to TKIs in CML and the new methodologies to access these mechanisms, and the therapeutic approaches to circumvent TKI resistance.
- Moringa as a household water purification method – community perception and pilot study in Guinea-BissauPublication . Bancessi, Aducabe; Teodósio, Rosa; Duarte, Elizabeth; Baldé, Aladje; Catarino, Luís; Nazareth, TeresaBackground: Public perceptions of water-related issues are still under-researched topics. The current paper intends to explore a local community’s perceptions regarding household water purification (HWP) strategies, namely before and after trying a new method: moringa seeds powder (moringa-teabag). Methods: In September 2020, six focus group discussions (N = 65) assessing perceptions about the usefulness of Moringa oleifera Lam (Moringaceae) as a HWP method (before moringa-based HWP trials), and questionnaires (N = 104) evaluating successes and identifying difficulties (after one week of moringa-based HWP trials). Participants were all women aged over 18 years, living in Ondame, Biombo region, Guinea-Bissau. Data were analyzed using qualitative and quantitative approaches. Results: The focus group discussions revealed that people are aware of the fact that water can transmit diseases. Although certain persons showed concern about shallow well water safety, people generally underestimate the risk, as they trust tubewell water. Not everyone had an understanding of what water contamination is, or the concept of medical importance. Some respondents declared they use traditional methods such as boiling and bleach to treat water before drinking. However, those who reported no kind of treatment indicated reasons such as lack of time, cost, and bleach’s taste and smell. In the questionnaire, more than half of the participants (68%) reported treating water before consumption. Nevertheless, these results are not consistent with our field notes. Participants demonstrated a strong belief in the capacity of moringa-teabags to purify water and even consider them better or much better (81%) than other methods. Participants asked for more information on moringa-teabag for household water purification. Conclusion: More information on water treatment and water safety would help to raise public awareness about waterborne diseases. These findings could be used to promote greater adherence to moringa-based HWP as an alternative to household water treatment.
- Temporal order of clinical and biomarker changes in familial frontotemporal dementiaPublication . Frontotemporal Dementia Prevention Initiative (FPI) Investigators; ALLFTD Investigators; GENFI investigators; Staffaroni, Adam M.; Quintana, Melanie; Wendelberger, Barbara; Heuer, Hilary W.; Russell, Lucy L.; Cobigo, Yann; Wolf, Amy; Goh, Sheng Yang Matt; Petrucelli, Leonard; Gendron, Tania F.; Heller, Carolin; Clark, Annie L.; Taylor, Jack Carson; Wise, Amy; Ong, Elise; Forsberg, Leah; Brushaber, Danielle; Rojas, Julio C.; VandeVrede, Lawren; Ljubenkov, Peter; Kramer, Joel; Casaletto, Kaitlin B.; Appleby, Brian; Bordelon, Yvette; Botha, Hugo; Dickerson, Bradford C.; Domoto-Reilly, Kimiko; Fields, Julie A.; Foroud, Tatiana; Gavrilova, Ralitza; Geschwind, Daniel; Ghoshal, Nupur; Goldman, Jill; Graff-Radford, Jonathon; Graff-Radford, Neill; Grossman, Murray; Hall, Matthew G.H.; Hsiung, Ging Yuek; Huey, Edward D.; Irwin, David; Jones, David T.; Kantarci, Kejal; Kaufer, Daniel; Knopman, David; Kremers, Walter; Lago, Argentina Lario; Lapid, Maria I.; Maruta, Carolina; Simões do Couto, Frederico; Almeida, Maria RosarioUnlike familial Alzheimer’s disease, we have been unable to accurately predict symptom onset in presymptomatic familial frontotemporal dementia (f-FTD) mutation carriers, which is a major hurdle to designing disease prevention trials. We developed multimodal models for f-FTD disease progression and estimated clinical trial sample sizes in C9orf72, GRN and MAPT mutation carriers. Models included longitudinal clinical and neuropsychological scores, regional brain volumes and plasma neurofilament light chain (NfL) in 796 carriers and 412 noncarrier controls. We found that the temporal ordering of clinical and biomarker progression differed by genotype. In prevention-trial simulations using model-based patient selection, atrophy and NfL were the best endpoints, whereas clinical measures were potential endpoints in early symptomatic trials. f-FTD prevention trials are feasible but will likely require global recruitment efforts. These disease progression models will facilitate the planning of f-FTD clinical trials, including the selection of optimal endpoints and enrollment criteria to maximize power to detect treatment effects.
- And the quest continues…Publication . Mendes, Lígia
- EBV and MSI status in gastric cancer: does it matter?Publication . Nascimento, Catarina Neto do; Mascarenhas-Lemos, Luís; Silva, João Ricardo; Marques, Diogo Sousa; Gouveia, Catarina Ferreira; Faria, Ana; Velho, Sónia; Garrido, Rita; Maio, Rui; Costa, Andreia; Pontes, Patrícia; Wen, Xiaogang; Gullo, Irene; Cravo, Marília; Carneiro, FátimaWe investigated the impactof microsatellite instability (MSI) and Epstein–Barr virus (EBV) status in gastric cancer (GC), regarding response to perioperative chemotherapy (POPChT), overall survival (OS), and progression-free survival (PFS). We included 137 cases of operated GC, 51 of which were submitted to POPChT. MSI status was determined by multiplex PCR and EBV status by EBV-encoded RNA in situ hybridization. Thirty-seven (27%) cases presented as MSI-high, and seven (5.1%) were EBV+. Concerning tumor regression after POPChT, no differences were observed between the molecular subtypes, but females were more likely to respond (p = 0.062). No significant differences were found in OS or PFS between different subtypes. In multivariate analysis, age (HR 1.02, IC 95% 1.002–1.056, p = 0.033) and positive lymph nodes (HR 1.82, IC 95% 1.034–3.211, p = 0.038) were the only prognostic factors for OS. However, females with MSI-high tumors treated with POPChT demonstrated a significantly increased OS compared to females with MSS tumors (p = 0.031). In conclusion, we found a high proportion of MSI-high cases. MSI and EBV status did not influence OS or PFS either in patients submitted to POPChT or surgery alone. However, superior survival of females with MSI-high tumors suggests that sex disparities and molecular classification may influence treatment options in GC.
- Nutritional counselling in adults promoting adherence to the Mediterranean diet as adjuvant in the treatment of major depressive disorder (INDEPT): a randomized open controlled trial study protocolPublication . Sousa-Santos, Nuno; Fialho, Mónica; Madeira, Teresa; Clara, Cátia; Veiga, Sofia; Martins, Raquel; Barros, Neuza; Santos, Gabriela; Santos, Osvaldo; Almeida, Carolina; Ganança, Licínia; Campos, Rui C.; Camolas, José; Silva, Alda Pereira da; Guarino, Maria Pedro Sucena; Heitor, Maria JoãoBackground: Major Depressive Disorder (MDD) is a leading cause of disability worldwide. Approximately one-third of patients with MDD do not respond to treatment, and often exhibit elevated inflammation biomarkers, which are associated with worse prognosis. Previous research has linked healthier dietary patterns, such as the Mediterranean Diet (MedDiet), with a lower risk of MDD and symptoms of depression, potentially due to their anti-inflammatory properties. The aim of this study is to evaluate the effectiveness of a nutritional counselling intervention promoting MedDiet to alleviate symptoms of depression in adults recently diagnosed with MDD and presenting with elevated inflammation biomarkers. Methods: This study is a randomized controlled trial (RCT) that will recruit adults from outpatient clinics, between the ages of 18 and 70 years who have been diagnosed with MDD and are currently receiving treatment with the first prescribed antidepressant, and who exhibit elevated inflammation biomarkers (interleukin-6 and/or C-reactive protein). The control group will receive treatment-as-usual (TAU) only. The primary outcome of the study will be the change in symptoms of depression, as measured by the Beck Depression Inventory 2 (BDI-II), after 12 weeks of intervention. Data analysis will follow an intention-to-treat approach. Secondary outcomes will include changes in inflammation biomarkers, quality of life, adherence to the MedDiet, and cost-effectiveness of nutritional counselling. All outcomes will be assessed at baseline, after the 12-week intervention, and at 6- and 12-months post-baseline. Discussion: This study will be the first RCT to evaluate the effect of a nutritional intervention with anti-inflammatory properties, as an adjuvant in the treatment of MDD, in individuals diagnosed with MDD and elevated inflammation biomarkers. The results of this study may contribute to the development of more effective and personalized interventions for MDD patients with elevated inflammation biomarkers.
- PET/CT in patients with breast cancer treated with immunotherapyPublication . Vaz, Sofia C.; Graff, Stephanie L.; Ferreira, Arlindo R.; Debiasi, Márcio; de Geus-Oei, Lioe FeeSignificant advances in breast cancer (BC) treatment have been made in the last decade, including the use of immunotherapy and, in particular, immune checkpoint inhibitors that have been shown to improve the survival of patients with triple negative BC. This narrative review summarizes the studies supporting the use of immunotherapy in BC. Furthermore, the usefulness of 2-deoxy-2-[18F]fluoro-D-glucose (2-[18F]FDG) positron emission/computerized tomography (PET/CT) to image the tumor heterogeneity and to assess treatment response is explored, including the different criteria to interpret 2-[18F]FDG PET/CT imaging. The concept of immuno-PET is also described, by explaining the advantages of mapping treatment targets with a non-invasive and whole-body tool. Several radiopharmaceuticals in the preclinical phase are referred too, and, considering their promising results, translation to human studies is needed to support their use in clinical practice. Overall, this is an evolving field in BC treatment, despite PET imaging developments, the future trends also include expanding immunotherapy to early-stage BC and using other biomarkers.
- The effects of peptide receptor radionuclide therapy on the neoplastic and normal pituitaryPublication . Marques, PedroPituitary neuroendocrine tumours (PitNETs) are usually benign and slow-growing; how- ever, in some cases, they may behave aggressively and become resistant to conventional treatments. Therapeutic options for aggressive or metastatic PitNETs are limited, and currently mainly consist of temozolomide, with little experience of other emerging approaches, including peptide receptor radionuclide therapy (PRRT). Somatostatin receptor expression in PitNETs explains the effectiveness of somatostatin analogues for treating PitNETs, particularly those hypersecreting pituitary hormones, such as growth hormone or adrenocorticotropic hormone. The expression of such receptors in pi- tuitary tumour cells has provided the rationale for using PRRT to treat patients with aggressive or metastatic PitNETs. However, the PRRT efficacy in this setting remains unestablished, as knowledge on this today is based only on few case reports and small series of cases, which are reviewed here. A total of 30 PRRT-treated patients have been thus far reported: 23 aggressive PitNETs, 5 carcinomas, and 2 of malignancy status unspecified. Of the 27 published cases with information regarding the response to PRRT, 5 (18%) showed a partial response, 8 (30%) had stable disease, and 14 (52%) had progressive disease. No major adverse effects have been reported, and there is also no increased risk of clinically relevant hypopituitarism in patients with pituitary or non-pituitary neuroendocrine tumours following PRRT. PRRT may be regarded as a safe option for patients with aggressive or metastatic PitNETs if other treatment approaches are not feasible or have failed in controlling the disease progression, with tumour shrinkage occurring in up to a fifth of cases, while about a third of aggressive pituitary tumours may achieve stable disease. Here, the data on PRRT in the management of patients with aggressive pituitary tumours are reviewed, as well as the effects of PRRT on the pituitary function in other PRRT-treated cancer patients.
- Quantitative assessment of myocardial fibrosis by digital image analysis: an adjunctive tool for pathologist “ground truth”Publication . Abecasis, João; Cortez-Dias, Nuno; Pinto, Daniel Gomes; Lopes, Pedro; Madeira, Márcio; Ramos, Sancia; Gil, Victor; Cardim, Nuno; Félix, AnaAIMS: Myocardial fibrosis (MF) is a common pathological process in a wide range of cardiovascular diseases. Its quantity has diagnostic and prognostic relevance. We aimed to assess if the complementary use of an automated artificial intelligence software might improve the precision of the pathologist´s quantification of MF on endomyocardial biopsies (EMB). Methods and results: Intraoperative EMB samples from 30 patients with severe aortic stenosis submitted to surgical aortic valve replacement were analysed. Tissue sections were stained with Masson´s trichrome for collagen/fibrosis and whole slide images (WSI) from the experimental glass slides were obtained at a resolution of 0.5 μm using a digital microscopic scanner. Three experienced pathologists made a first quantification of MF excluding the subendocardium. After two weeks, an algorithm for Masson´s trichrome brightfield WSI (at QuPath software) was applied and the automatic quantification was revealed to the pathologists, who were asked to reassess MF, blinded to their first evaluation. The impact of the automatic algorithm on the inter-observer agreement was evaluated using Bland-Altman type methodology. Median values of MF on EMB were 8.33% [IQR 5.00-12.08%] and 13.60% [IQR 7.32-21.2%], respectively for the first pathologist´s and automatic algorithm quantification, being highly correlated (R2: 0.79; p < 0.001). Interobserver discordance was relevant, particularly for higher percentages of MF. The knowledge of the automatic quantification significantly improved the overall pathologist´s agreement, which became unaffected by the degree of MF severity. Conclusions: The use of an automated artificial intelligence software for MF quantification on EMB samples improves the reproducibility of measurements by experienced pathologists. By improving the reliability of the quantification of myocardial tissue components, this adjunctive tool may facilitate the implementation of imaging-pathology correlation studies.
- Online information search by people with Multiple Sclerosis: a systematic reviewPublication . Berhanu, David; Leal Rato, Miguel; Canhoto, Ana Isabel; Vieira da Cunha, João; Geraldes, RuthBackground: People with Multiple Sclerosis (pwMS) search for information online about various aspects of living with their disease, but details about patterns of searching and outcomes are unclear. This means that opportunities to leverage online resources to support pwMS, and to enhance shared decision making, may be missed. We aimed to do a systematic review of the literature on digital information searching by pwMS. Methods: We performed a systematic search for studies assessing online information seeking of pwMS in MEDLINE and JSTOR databases. Studies were screened and selected by two investigators. All study designs were included, risk of bias was assessed using the Critical Appraisal Skills Programme qualitative checklist. Reports were assessed for the proportion of patients searching information online about MS, type of information sought, online tools used by patients, perceived quality of the information acquired, and impact of online searching in pwMS. Results: We identified 5 studies, including 10,090 patients. Most pwMS search for information online (53.8–82 %), which they rarely discuss with physicians. The most common topics are treatment, general disease information, symptoms, lifestyle recommendations, prognosis, and coping strategies. Patients that are younger, have a shorter disease duration, primary progressive MS, and during periods of disease worsening, are more likely to use online resources. Online information is perceived as low quality by pwMS. Conclusions: Online information search is prevalent among pwMS. Despite concerns with the quality of the available information, only a minority of pwMS will discuss the information found with their physician. These findings highlight the importance of developing and providing quality online information resources for pwMS.