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- WNT6 is a novel oncogenic prognostic biomarker in human glioblastomaPublication . Gonçalves, CS; Vieira de Castro, J; Pojo, M; Martins, EP; Queirós, S; Chautard, E; Taipa, R; Pires, MM; Pinto, AA; Pardal, F; Custódia, C; Faria, CC; Clara, C; Reis, RM; Sousa, N; Costa, BMGlioblastoma (GBM) is a universally fatal brain cancer, for which novel therapies targeting specific underlying oncogenic events are urgently needed. While the WNT pathway has been shown to be frequently activated in GBM, constituting a potential therapeutic target, the relevance of WNT6, an activator of this pathway, remains unknown. Methods: WNT6 protein and mRNA levels were evaluated in GBM. WNT6 levels were silenced or overexpressed in GBM cells to assess functional effects in vitro and in vivo. Phospho-kinase arrays and TCF/LEF reporter assays were used to identify WNT6-signaling pathways, and significant associations with stem cell features and cancer-related pathways were validated in patients. Survival analyses were performed with Cox regression and Log-rank tests. Meta-analyses were used to calculate the estimated pooled effect. Results: We show that WNT6 is significantly overexpressed in GBMs, as compared to lower-grade gliomas and normal brain, at mRNA and protein levels. Functionally, WNT6 increases typical oncogenic activities in GBM cells, including viability, proliferation, glioma stem cell capacity, invasion, migration, and resistance to temozolomide chemotherapy. Concordantly, in in vivo orthotopic GBM mice models, using both overexpressing and silencing models, WNT6 expression was associated with shorter overall survival, and increased features of tumor aggressiveness. Mechanistically, WNT6 contributes to activate typical oncogenic pathways, including Src and STAT, which intertwined with the WNT pathway may be critical effectors of WNT6-associated aggressiveness in GBM. Clinically, we establish WNT6 as an independent prognostic biomarker of shorter survival in GBM patients from several independent cohorts. Conclusion: Our findings establish WNT6 as a novel oncogene in GBM, opening opportunities to develop more rational therapies to treat this highly aggressive tumor.
- Prospective Observational Study on acute Appendicitis Worldwide (POSAW)Publication . Sartelli, M; Baiocchi, GL; Di Saverio, S; Ferrara, F; Labricciosa, FM; Ansaloni, L; Coccolini, F; Vijayan, D; Abbas, A; Abongwa, HK; Agboola, J; Ahmed, A; Akhmeteli, L; Akkapulu, N; Akkucuk, S; Altintoprak, F; Andreiev, AL; Anyfantakis, D; Atanasov, B; Bala, M; Balalis, D; Baraket, O; Bellanova, G; Beltran, M; Melo, RB; Bini, R; Bouliaris, K; Brunelli, D; Castillo, A; Catani, M; Che Jusoh, A; Chichom-Mefire, A; Cocorullo, G; Coimbra, R; Colak, E; Costa, S; Das, K; Delibegovic, S; Demetrashvili, Z; Di Carlo, I; Kiseleva, N; El Zalabany, T; Faro, M; Ferreira, M; Fraga, GP; Gachabayov, M; Ghnnam, WM; Giménez Maurel, T; Gkiokas, G; Gomes, CA; Griffiths, E; Guner, A; Gupta, S; Hecker, A; Hirano, ES; Hodonou, A; Hutan, M; Ioannidis, O; Isik, A; Ivakhov, G; Jain, S; Jokubauskas, M; Karamarkovic, A; Kauhanen, S; Kaushik, R; Kavalakat, A; Kenig, J; Khokha, V; Khor, D; Kim, D; Kim, JI; Kong, V; Lasithiotakis, K; Leão, P; Leon, M; Litvin, A; Lohsiriwat, V; López-Tomassetti Fernandez, E; Lostoridis, E; Maciel, J; Major, P; Dimova, A; Manatakis, D; Marinis, A; Martinez-Perez, A; Marwah, S; McFarlane, M; Mesina, C; Pędziwiatr, M; Michalopoulos, N; Misiakos, E; Mohamedahmed, A; Moldovanu, R; Montori, G; Mysore Narayana, R; Negoi, I; Nikolopoulos, I; Novelli, G; Novikovs, V; Olaoye, I; Omari, A; Ordoñez, CA; Ouadii, Mt; Ozkan, Z; Pal, A; Palini, GM; Partecke, LI; Pata, F; Pędziwiatr, M; Pereira Júnior, GA; Pintar, T; Pisarska, M; Ploneda-Valencia, CF; Pouggouras, K; Prabhu, V; Ramakrishnapillai, P; Regimbeau, JM; Reitz, M; Rios-Cruz, D; Saar, S; Sakakushev, B; Seretis, C; Sazhin, A; Shelat, V; Skrovina, M; Smirnov, D; Spyropoulos, C; Strzałka, M; Talving, P; Teixeira Gonsaga, RA; Theobald, G; Tomadze, G; Torba, M; Tranà, C; Ulrych, J; Uzunoğlu, MY; Vasilescu, A; Occhionorelli, S; Venara, A; Vereczkei, A; Vettoretto, N; Vlad, N; Walędziak, M; Yilmaz, TU; Yuan, KC; Yunfeng, C; Zilinskas, J; Grelpois, G; Catena, FBACKGROUND: Acute appendicitis (AA) is the most common surgical disease, and appendectomy is the treatment of choice in the majority of cases. A correct diagnosis is key for decreasing the negative appendectomy rate. The management can become difficult in case of complicated appendicitis. The aim of this study is to describe the worldwide clinical and diagnostic work-up and management of AA in surgical departments. METHODS: This prospective multicenter observational study was performed in 116 worldwide surgical departments from 44 countries over a 6-month period (April 1, 2016-September 30, 2016). All consecutive patients admitted to surgical departments with a clinical diagnosis of AA were included in the study. RESULTS: A total of 4282 patients were enrolled in the POSAW study, 1928 (45%) women and 2354 (55%) men, with a median age of 29 years. Nine hundred and seven (21.2%) patients underwent an abdominal CT scan, 1856 (43.3%) patients an US, and 285 (6.7%) patients both CT scan and US. A total of 4097 (95.7%) patients underwent surgery; 1809 (42.2%) underwent open appendectomy and 2215 (51.7%) had laparoscopic appendectomy. One hundred eighty-five (4.3%) patients were managed conservatively. Major complications occurred in 199 patients (4.6%). The overall mortality rate was 0.28%. CONCLUSIONS: The results of the present study confirm the clinical value of imaging techniques and prognostic scores. Appendectomy remains the most effective treatment of acute appendicitis. Mortality rate is low.
- Relationships between neuropsychological and antisaccade measures in multiple sclerosis patientsPublication . Ferreira, MB; Pereira, PAl; Parreira, M; Sousa, I; Figueiredo, J; Cerqueira, JJ; Macedo, AFBACKGROUND: The Stroop test is frequently used to assess deficits in inhibitory control in people with multiple sclerosis (MS). This test has limitations and antisaccade eye movements, that also measure inhibitory control, may be an alternative to Stroop. OBJECTIVES: The aim of this study was twofold: (i) to investigate if the performance in the antisaccade task is altered in patients with MS and (ii) to investigate the correlation between performances in neuropsychological tests, the Stroop test and the antisaccade task. METHODS: We measured antisaccades (AS) parameters with an infrared eye tracker (SMIRED 250 Hz) using a standard AS paradigm. A total of 38 subjects diagnosed with MS and 38 age and gender matched controls participated in this study. Neuropsychological measures were obtained from the MS group. RESULTS: Patients with MS have higher error rates and prolonged latency than controls in the antisaccade task. There was a consistent association between the Stroop performance and AS latency. Stroop performance but not AS latency was associated with other neuropsychological measures in which the MS group showed deficits. CONCLUSIONS: Our findings suggest that AS may be a selective and independent measure to investigate inhibitory control in patients with MS. More studies are necessary to confirm our results and to describe brain correlates associated with impaired performance in the antisaccade task in people diagnosed with MS..
- Abernethy malformation: beware in cases of unexplained hepatic encephalopathy in adults-case report and review of the relevant literaturePublication . Mesquita, RD; Sousa, M; Vilaverde, F; Cardoso, RThe Abernethy malformation consists of a congenital extrahepatic portosystemic shunt and is believed to be extremely rare in humans. The potential implications of abnormal portovenous shunting and decreased hepatic portal flow are numerous and potentially serious. Although congenital extrahepatic portosystemic shunts are increasingly suspected and diagnosed in specialized centres, much of their clinical presentation and natural history is not fully understood. Symptoms of portosystemic shunt are mainly caused by increased levels of ammonia, which lead to signs of encephalopathy. Therapeutic options depend on the type of shunt and its clinical course, so the classification of the congenital portosystemic shunt is a key finding in these patients.
- Non-invasive hemodynamic evaluation by Doppler echocardiographyPublication . Gaspar, A; Azevedo, P; Roncon-Albuquerque, RThe approach for treating a hemodynamically unstable patient remains a diagnostic and therapeutic challenge. Stabilization of the patient should be rapid and effective, but there is not much room for error. This narrow window of intervention makes it necessary to use rapid and accurate hemodynamic evaluation methods. Echocardiography is the method of choice for the bedside evaluation of patients in circulatory shock. In fact, it was intensive care physicians who recognized the potential of Doppler echocardiography for the initial approach to patients in circulatory failure. An echocardiogram allows rapid anatomical and functional cardiac evaluation, which may include non-invasive hemodynamic evaluation using a Doppler study. Such an integrated study may provide data of extreme importance for understanding the mechanisms underlying the hemodynamic instability of the patient to allow the rapid institution of appropriate therapeutic measures. In the present article, we describe the most relevant echocardiographic findings using a practical approach for critical patients with hemodynamic instability.
- Experiences During a Psychoeducational Intervention Program Run in a Pediatric Ward: A Qualitative StudyPublication . Magalhães, P; Mourão, R; Pereira, R; Azevedo, R; Pereira, A; Lopes, M; Rosário, PHospitalization, despite its duration, is likely to result in emotional, social, and academic costs to school-age children and adolescents. Developing adequate psychoeducational activities and assuring inpatients' own class teachers' collaboration, allows for the enhancement of their personal and emotional competences and the maintenance of a connection with school and academic life. These educational programs have been mainly designed for patients with long stays and/or chronic conditions, in the format of Hospital Schools, and typically in pediatric Hospitals. However, the negative effects of hospitalization can be felt in internments of any duration, and children hospitalized in smaller regional hospitals should have access to actions to maintain the connection with their daily life. Thus, this investigation aims to present a psychoeducational intervention program theoretically grounded within the self-regulated learning (SRL) framework, implemented along 1 year in a pediatric ward of a regional hospital to all its school-aged inpatients, regardless of the duration of their stay. The program counts with two facets: the psychoeducational accompaniment and the linkage to school. All the 798 school-aged inpatients (M age = 11.7; SD age = 3.71; Mhospital stay = 4 days) participated in pedagogical, leisure nature, and SRL activities designed to train transversal skills (e.g., goal-setting). Moreover, inpatients completed assigned study tasks resulting from the linkage between the students' own class teachers and the hospital teacher. The experiences reported by parents/caregivers and class teachers of the inpatients enrolling in the intervention allowed the researchers to reflect on the potential advantages of implementing a psychoeducational intervention to hospitalized children and adolescents that is: individually tailored, focused on leisure playful theoretically grounded activities that allow learning to naturally occur, and designed to facilitate school re-entry after hospital discharge. Parents/caregivers highlighted that the program helped in the preparation for surgery and facilitated the hospitalization process, aided in the distraction from the health condition, promoted SRL competences, and facilitated the communication and linkage with school life. Class teachers emphasized the relevance of the program, particularly in the liaison between hospital and school, in the academic and psycho-emotional and leisure-educational support provided, and in smoothing the school re-entry.
- Reed's SyndromePublication . Almeida, FT; Santos, R P; Carvalho, SD; Brito, CMultiple cutaneous and uterine leiomyomatosis (MCUL), also known as Reed's syndrome, is a rare genodermatosis, with an autosomal dominant pattern of inheritance. It results from a germline heterozygous mutation of fumarate hydratase gene, that is classified as a tumor suppressor gene. Hereditary leiomyomatosis and renal cell cancer is characterized by the association of MCUL with renal cell carcinoma. We report a case of a 57-year-old woman, with multiple cutaneous leiomyomas as the presenting sign of Reed's syndrome.
- Identification of a Novel Mutation in a Family with Pseudohypoparathyroidism Type 1aPublication . Moutinho, A; Carvalho, R; Ferreira-Reis, R; Tavares, SINTRODUCTION: Pseudohypoparathyroidism type 1a is caused by GNAS mutations leading to target organ resistance to multiple hormones rather than parathyroid hormone, resulting not only in hypocalcemia, but also in Albright's hereditary osteodystrophy phenotype. MATERIALS AND METHODS: DNA sequencing of the GNAS gene identified a novel heterozygous mutation in peripheral blood leukocytes in the family presented in this case report. RESULTS: We present a case of a 25-year-old woman with pseudohypoparathyroidism type 1a admitted with seizures, whose family presents an autosomal dominant transmission of a novel heterozygous GNAS mutation (c.524_530+3del). CONCLUSION: Pseudohypoparathyroidism type 1a is mostly caused by inactivating GNAS mutations that have been gradually reported in the literature that lead to a typical and complex clinical phenotype and resistance to multiple hormones. The deletion caused by the mutation identified in the presented case has not been reported previously.
- Palliative splenic irradiation for symptomatic splenomegaly in non-Hodgkin lymphomaPublication . Oliveira, LC; Fardilha, C; Louro, M; Pinheiro, C; Sousa, A; Marques, H; Costa, PINTRODUCTION AND AIMS: Splenic marginal zone lymphoma, an uncommon subtype of non-Hodgkin lymphoma (NHL), is usually present with symptomatic splenomegaly. Although splenectomy has long been considered the first-line therapy in symptomatic or cytopenic patients, it can lead to significant morbidity and mortality. Splenic irradiation is an option for patients who have a poor response to systemic therapy and/or are not surgical candidates. In this paper, we present a case report of a patient who received splenic radiotherapy for symptomatic splenomegaly. METHODS: An 85-year-old Caucasian man with a 4 year history of low-grade NHL presented with progressive pancytopenia, significant weight loss and symptomatic splenomegaly (abdominal discomfort, sense of fullness and limitation of mobility due to spleen size). The patient refused splenectomy and, in December 2017, was referred to palliative splenic radiotherapy. He was initially treated with five fractions of one Grey (Gy) in order to evaluate clinical and haematology response. After that, 1.5 Gy daily, 5 days a week for 3 weeks. 3D conformal radiotherapy, multiple fields and mixed energy (6 and 15 Mv) were used. RESULTS: Radiotherapy allowed significant splenic reduction to almost half the size, resolving abdominal discomfort and improving quality of life. There was no decline of haemoglobin, leukocytes and platelet counts; in fact, there was a marginal increase. CONCLUSION: Palliative splenic irradiation was well tolerated confirming that it is a safe treatment option for palliation of symptomatic splenomegaly. Thereby, splenic irradiation should be strongly considered in the management of symptomatic splenomegaly, for selected patients who are refractory to or unsuitable for other options or when the patient refuses other treatments.
- Drugs Involved in Dyslipidemia and Obesity Treatment: Focus on Adipose TissuePublication . Dias, S; Paredes, S; Ribeiro, LMetabolic syndrome can be defined as a state of disturbed metabolic homeostasis characterized by visceral obesity, atherogenic dyslipidemia, arterial hypertension, and insulin resistance. The growing prevalence of metabolic syndrome will certainly contribute to the burden of cardiovascular disease. Obesity and dyslipidemia are main features of metabolic syndrome, and both can present with adipose tissue dysfunction, involved in the pathogenic mechanisms underlying this syndrome. We revised the effects, and underlying mechanisms, of the current approved drugs for dyslipidemia and obesity (fibrates, statins, niacin, resins, ezetimibe, and orlistat; sibutramine; and diethylpropion, phentermine/topiramate, bupropion and naltrexone, and liraglutide) on adipose tissue. Specifically, we explored how these drugs can modulate the complex pathways involved in metabolism, inflammation, atherogenesis, insulin sensitivity, and adipogenesis. The clinical outcomes of adipose tissue modulation by these drugs, as well as differences of major importance for clinical practice between drugs of the same class, were identified. Whether solutions to these issues will be found in further adjustments and combinations between drugs already in use or necessarily in new advances in pharmacology is not known. To better understand the effect of drugs used in dyslipidemia and obesity on adipose tissue not only is challenging for physicians but could also be the next step to tackle cardiovascular disease.