ADHEMAR LONGATTO FILHO

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LIM/14 - Laboratório de Investigação em Patologia Hepática, Hospital das Clínicas, Faculdade de Medicina

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  • article 1 Citação(ões) na Scopus
    Inflammation Is a Histological Characteristic of Skeletal Muscle in Chronic Limb Threatening Ischemia
    (2024) FERREIRA, Joana; AFONSO, Julieta; LONGATTO-FILHO, Adhemar; ROQUE, Susana; CARNEIRO, Alexandre; VILE, Isabel; SILVA, Cristina; CUNHA, Cristina; MESQUITA, Amilcar; COTTER, Jorge; CORREIA-NEVES, Margarida; MANSILHA, Armando; CUNHA, Pedro
    Background: The loss of skeletal muscle is a prognostic factor in several diseases including in patients with chronic limb threatening ischemia (CLTI). Patients with CLTI also have a lower skeletal mass and area when compared to those with claudication. However, there are no currently available data regarding the histological characteristics of core muscles in patients with CLTI. This study aims to determine the differences in core skeletal muscles between patients with claudication and those with CLTI. The second aim is to evaluate the differences in myokines, which are molecules secreted by skeletal muscle, between patients with claudication and those with CLTI. Methods: An observational, prospective study was conducted from January 2018 to July 2022 involving consecutive patients with peripheral arterial disease (PAD). The clinical characteristics were registered. In PAD patients with surgical indication for common femoral artery approach, samples of sartorius skeletal muscle (and not from the limb muscles directly involved in the ischemic process) were collected. The samples were submitted to histological characterization on hematoxylin-eosin and to immunohistochemical analysis to detect CD45+ leukocytes and CD163+ macrophages. The extent of the inflammatory cells (leukocytes and macrophages) was semiquantitatively assessed using a 0 -to -4 grade scale as follows: absent (0t), mild (t), moderate (tt), severe (ttt), and very severe (tttt). Serum levels of myokines: irisin, myostatin, IL -8, and lL-6 were determined with multiplex bead -based immunoassay. Results: 119 patients (mean age: 67.58 +/- 9.60 years old, 79.80% males) 64 with claudication and 54 with CLTI were enrolled in the study. No differences were registered between patients with claudication and those with CLTI on age, gender, cardiovascular risk factors, and medication, except on smoking habits. There was a significantly higher prevalence of smokers and a higher smoking load in the claudication group. Samples of sartorius skeletal muscle from 40 patients (14 with claudication and 26 with CLTI) were submitted to histological analysis. No differences were found in skeletal muscle fibers preservation, trauma, or hemorrhage (on hematoxylin-eosin staining). However, in the immunohistochemistry study, we found more inflammatory cells CD45+ leukocytes in patients with CLTI when compared to those with claudication [CD45+ > moderate (tt): claudication (n = 14): 4; 28.57%; CLTI (n = 25): 16; 64.00%; P = 0.034]. Patients with CLTI also had higher tissue levels of CD163+ macrophages, but this difference was not significant [CD163+ > moderate (tt): claudication (n = 13): 7; 53.85%; CLTI (n = 27): 21; 77.78%; P = 0.122]. The serum levels of the myokines, irisin, and myostatin were below the lower limit of detection, in the majority of patients, so no valid results were obtained. However, patients with CLTI had a higher serum level of Interleukin (IL) -6 and IL -8. Conclusions: CLTI patients exhibit increased quantities of leukocytes in their sartorius muscle, as well as elevated serum levels of myokines IL -8 and IL -6. Inflamed skeletal muscle can contribute to the loss of muscle mass and account for the lower density of skeletal muscle observed in CLTI. Additionally, inflamed skeletal muscle may contribute to the development of systemic inflammation through the secretion of pro -inflammatory cytokines into the systemic circulation. Halting the inflammatory process could eventually improve the prognosis of CLTI patients.
  • article 0 Citação(ões) na Scopus
    Peri-Carotid Adipose Tissue and Atherosclerosis at Carotid Bifurcation
    (2024) FERREIRA, Joana; LONGATTO-FILHO, Adhemar; DIONISIO, Ana; CORREIA-NEVES, Margarida; CUNHA, Pedro; MANSILHA, Armando
    Vulnerable carotid plaques are responsible for 20% of the ischemic strokes. The identification of these asymptomatic carotid plaques that will become symptomatic is essential but remains unclear. Our main goal was to investigate whether the amount of the peri-carotid adipose tissue, estimated by the extra-media thickness (EMT), is associated with the atherosclerotic characteristics at the carotid bifurcation in patients with PAD. An observational, prospective, single-center, longitudinal study was conducted. Overall, 177 patients were subjected to carotid Doppler ultrasound at the study admission. The following data were collected: EMT, intima-media thickness (IMT), the presence of carotid plaques, the area of the highest plaque, the presence of ""acute culprit"" carotid stenosis, and the grade of internal carotid stenosis. ""Acute culprit"" carotid stenosis was defined as a significant atherosclerotic plaque that leads to a neurologic event within 15 days. From each carotid bifurcation, a right and a left EMT were determined. We analyzed both the mean EMTs (calculated as the mean between the right and the left EMT) and the EMT ipsilateral to the carotid bifurcation. The presence of carotid plaques was associated with a higher mean EMT [Median = 1.14; IQR = 0.66 versus Median = 0.97; IQR = 0.40; p = 0.001]. A positive correlation was found between the mean EMT and IMT (right: rho = 0.20; p = 0.010; left: rho = 0.21; p = 0.007) and between the mean EMT and the area of the largest carotid plaque (right: rho = 0.17; p = 0.036; left: rho = 0.22; p = 0.004). Left carotid stenosis >= 70% was associated with higher ipsilateral EMT [Median = 1.56; IQR = 0.70 versus Median = 0.94; IQR = 0.42; p = 0.009]. Patients with ""acute culprit"" carotid stenosis had a higher ipsilateral EMT [left ipsilateral EMT: Median = 1.46; IQR = 0.63; ""non-acute"": Median = 0.94; IQR = 0.43; p = 0.009; right ipsilateral EMT: Median = 2.25; IQR = 0.62; ""non-acute"": Median = 1.00; IQR = 0.51; p = 0.015]. This difference was not found in the contra-lateral EMT. Six months after the neurologic event, EMT ipsilateral to an ""acute culprit"" carotid stenosis decreased (p = 0.036). The amount of peri-carotid adipose tissue, estimated with EMT, was associated with atherosclerosis at the carotid arteries. The mean EMT was associated with the features of chronic atherosclerosis lesions: the presence of carotid plaques, IMT, and the area of the highest plaque. Ipsilateral EMT was linked with ""acute culprit"" atherosclerotic plaque.
  • article 0 Citação(ões) na Scopus
    Exosomes modified with anti-MEK1 siRNA lead to an effective silencing of triple negative breast cancer cells
    (2023) FERREIRA, Debora; SANTOS-PEREIRA, Catia; COSTA, Marta; AFONSO, Julieta; YANG, Sujuan; HENSEL, Janine; MCANDREWS, Kathleen M.; LONGATTO-FILHO, Adhemar; FERNANDES, Rui; MELO, Joana B.; BALTAZAR, Fatima; MOREIRA, Joao N.; KALLURI, Raghu; RODRIGUES, Ligia R.
    Triple negative breast cancer (TNBC) is a highly heterogenous disease not sensitive to endocrine or HER2 therapy and standardized treatment regimens are still missing. Therefore, development of novel TNBC treatment approaches is of utmost relevance. Herein, the potential of MAPK/ERK downregulation by RNAi-based therapeutics in a panel of mesenchymal stem-like TNBC cell lines was uncovered. Our data revealed that suppression of one of the central nodes of this signaling pathway, MEK1, affects proliferation, migration, and invasion of TNBC cells, that may be explained by the reversion of the epithelial-mesenchymal transition phenotype, which is facilitated by the MMP-2/MMP-9 downregulation. Moreover, an exosome-based system was successfully generated for the siRNA loading (iExoMEK1). Our data suggested absence of modification of the physical properties and general integrity of the iExoMEK1 comparatively to the unmodified counterparts. Such exosome-mediated down-regulation of MEK1 led to a tumor regression accompanied by a decrease of angiogenesis using the chick chorioallantoic-membrane model. Our results highlight the potential of the targeting of MAPK/ERK cascade as a promising therapeutic approach against TNBC.
  • article 0 Citação(ões) na Scopus
    Combined Oral Contraceptive Use and the Risk of Cervical Cancer: Literature Review
    (2023) BOVO, Adriane Cristina; PEDRAO, Priscila Grecca; GUIMARAES, Yasmin Medeiros; GODOY, Luani Rezende; RESENDE, Julio Cesar Possati; LONGATTO-FILHO, Adhemar; REIS, Ricardo dos
    Cervical cancer (CC) is caused by persistent infection of human papillomavirus of high oncogenic risk (hr-HPV); however, several cofactors are important in its carcinogenesis, such as smoking, multiparity, and prolonged use of oral hormonal contraceptives (COCs). Worldwide, 16% of women use COCs, whereas in Brazil this rate is of similar to 30%. The safety and adverse effects of COCs are widely discussed in the literature, including the increase in carcinogenic risk. Due to the existence of several drugs, combinations, and dosages of COCs, it is hard to have uniform information in epidemiological studies. Our objective was to perform a narrative review on the role of COCs use in the carcinogenesis of cervical cancer. Several populational studies have suggested an increase in the incidence of cervical cancer for those who have used COCs for > 5 years, but other available studies reach controversial and contradictory results regarding the action of COCs in the development of CC.
  • article 0 Citação(ões) na Scopus
    Diaphragmatic hernia repair porcine model to compare the performance of biodegradable membranes against Gore-Tex®
    (2023) SCUGLIA, Marianna; FRAZAO, Laura P.; MIRANDA, Alice; MARTINS, Albino; BARBOSA-SEQUEIRA, Joana; COIMBRA, Diana; LONGATTO-FILHO, Adhemar; REIS, Rui L.; NOGUEIRA-SILVA, Cristina; NEVES, Nuno M.; CORREIA-PINTO, Jorge
    Background: Patch repair of congenital diaphragmatic hernia (CDH) using Gore-Tex (R) is associated with infection, adhesions, hernia recurrence, long-term musculoskeletal sequels and poor tissue regeneration. To overcome these limitations, the performance of two novel biodegradable membranes was tested to repair CDH in a growing pig model.Methods: Twelve male pigs were randomly assigned to 3 different groups of 4 animals each, determined by the type of patch used during thoracoscopic diaphragmatic hernia repair (Gore-Tex (R), polycaprolactone electrospun membrane-PCLem, and decellularized human chorion membrane-dHCM). After 7 weeks, all animals were euthanized, followed by necropsy for diaphragmatic evaluation and histological analysis.Results: Thoracoscopic defect creation and diaphragmatic repair were performed without any technical difficulty in all groups. However, hernia recurrence rate was 0% in Gore-Tex (R), 50% in PCLem and 100% in dHCM groups. At euthanasia, Gore-Tex (R) patches appeared virtually unchanged and covered with a fibrotic capsule, while PCLem and dHCM patches were replaced by either floppy connective tissue or vascularized and floppy regenerated membranous tissue, respectively.Conclusion: Gore-Tex (R) was associated with a higher survival rate and lower recurrence. Nevertheless, the proposed biodegradable membranes were associated with better tissue integration when compared with Gore-Tex (R).
  • article 1 Citação(ões) na Scopus
    VEGF and Ki-67 Expression in Colorectal Cancer: The Long-Term Impact on Recurrence and Mortality
    (2022) SANTOS, Pedro Miguel Dias dos; PEREIRA, Ines Sa; LONGATO, Adhemar; MARTINS, Sandra F.
    Objectives: Colorectal cancer is the most frequent and mortal cancer in Portugal. Both angiogenesis and cellular proliferation are core mechanisms to tumoral progression, with VEGF (Vascular Endothelial Growth Factor) and Ki-67, respectively, being widely known markers of those two processes. The purposes of this study are to comprehend VEGF and Ki-67's impact on colorectal cancer prognosis which include assessing its expression in primary colorectal cancer of patients who underwent surgery, establishing associations between the expression of VEGF and Ki-67 and discovering hypothetical associations between these biomarkers and clinicopathological aspects, relapse, and mortality of patients. Methods: A retrospective study was conducted in our hospital by including 512 patients submitted to surgery, from 2005 to 2010, with a post-operatory diagnosis of colorectal adenocarcinoma. The evaluation of expression of VEGF and Ki-67 in the obtained tissue was made through immunohistochemistry technique. The statistical analysis resourced to association tests and survival analysis. Results: VEGF-A showed association with the variable gender (p-value of 0.016), with its expression being more frequent in men. VEGF- C expression is more common in colon than in rectum (p- value of 0.042). VEGF-C is significantly associated with Ki-67 (p-value of 0.036), with 69.7% of cases where both are positive. All markers are significantly associated with the grade of differentiation, with the VEGF family generally more present in well or moderately differentiated tumours and Ki-67 in the poorly differentiated. While the survival time was generally lower in the presence of any marker or combination, no significant differences were found among the survival analysis. Conclusion: VEGF-A, VEGF- C and Ki-67 expression did not show impact on the prognosis of this sample of patients. There was no significant association with a poorer overall survival or a reduced disease-free survival.
  • article 7 Citação(ões) na Scopus
    Glucose Metabolism Reprogramming in Bladder Cancer: Hexokinase 2 (HK2) as Prognostic Biomarker and Target for Bladder Cancer Therapy
    (2023) AFONSO, Julieta; GONCALVES, Celine; COSTA, Marta; FERREIRA, Debora; SANTOS, Lucio; LONGATTO-FILHO, Adhemar; BALTAZAR, Fatima
    Simple Summary Urothelial bladder carcinoma entails significant health costs due to the high recurrence rates and poor response to standard cisplatin-based treatment. The glycolytic phenotype is a hallmark of proliferating cancer cells, but research is needed to validate the glycolysis-related proteins as prognostic and predictive biomarkers in the setting of bladder cancer. Here, we assessed the immunoexpression of several glycolysis-related biomarkers in bladder cancer tissues, demonstrating significant correlations with cancer aggressiveness and poor prognosis. Hexokinase 2 remained as an independent prognostic factor, which led us to further exploit the functional effects of the hexokinase 2 inhibitor 2-deoxy-D-glucose in ""in vitro"" and ""in vivo"" preclinical models of bladder cancer. The treatment impaired the classical aggressiveness features in the cancer cell lines and in the chick chorioallantoic membrane assay and also potentiated the cisplatin-induced inhibition of cell viability in a cisplatin-resistant subline. Thus, we demonstrated the potential use of 2-deoxy-D-glucose in inhibiting bladder cancer progression and potentiating cisplatin effects. Proliferating cancer cells are able to reprogram their energy metabolism, favouring glycolysis even in the presence of oxygen and fully functioning mitochondria. Research is needed to validate the glycolysis-related proteins as prognostic/predictive biomarkers in urothelial bladder carcinoma (UBC), a malignancy tagged by high recurrence rates and poor response to chemotherapy. Here, we assessed GLUT1, HK2, PFKL, PKM2, phospho-PDH, and LDHA immunoexpression in 76 UBC samples, differentiating among urothelial, fibroblast, and endothelial cells and among normoxic versus hypoxic areas. We additionally studied the functional effects of the HK2 inhibitor 2-deoxy-D-glucose (2DG) in ""in vitro"" and ""in vivo"" preclinical UBC models. We showed that the expression of the glycolysis-related proteins is associated with UBC aggressiveness and poor prognosis. HK2 remained as an independent prognostic factor for disease-free and overall survival. 2DG decreased the UBC cell's viability, proliferation, migration, and invasion; the inhibition of cell cycle progression and apoptosis occurrence was also verified. A significant reduction in tumour growth and blood vessel formation upon 2DG treatment was observed in the chick chorioallantoic membrane assay. 2DG potentiated the cisplatin-induced inhibition of cell viability in a cisplatin-resistant subline. This study highlights HK2 as a prognostic biomarker for UBC patients and demonstrates the potential benefits of using 2DG as a glycolysis inhibitor. Future studies should focus on integrating 2DG into chemotherapy design, as an attempt to overcome cisplatin resistance.
  • article 1 Citação(ões) na Scopus
    Frequency of Human Papillomavirus Detection in Chagasic Megaesophagus Associated or Not with Esophageal Squamous Cell Carcinoma
    (2022) MUNARI, F. F.; SICHERO, L.; CARLONI, A. C.; LACERDA, C. F.; NUNES, E. M.; OLIVEIRA, A. T. T. De; SCAPULATEMPO-NETO, C.; SILVA, S. R. M. Da; CREMA, E.; ADAD, S. J.; RODRIGUES, M. A. M.; HENRY, M. A. C. A.; GUIMARãES, D. P.; REIS, R. M.; VILLA, L. L.; LONGATTO-FILHO, A.
    Background: Chagasic megaesophagus (CM) as well as the presence of human papillomavirus (HPV) has been reported as etiological factors for esophageal squamous cell carcinoma (ESCC). Objective: We assessed the prevalence of HPV DNA in a series of ESCCs associated or not with CM. Data obtained were further correlated to the pathological and clinical data of affected individuals. Methods: A retrospective study was performed on 92 formalin-fixed and paraffin-embedded tissues collected from patients referred to 3 different hospitals in São Paulo, Brazil: Barretos Cancer Hospital, Barretos, São Paulo; Federal University of Triângulo Mineiro, Uberaba, Minas Gerais; and São Paulo State University, Botucatu, São Paulo. Cases were divided into 3 groups: (i) 24 patients with CM associated with ESCC (CM/ESCC); (ii) 37 patients with ESCC without CM (ESCC); and (iii) 31 patients with CM without ESCC (CM). Detection of HPV DNA was assessed in all samples by a genotyping assay combining multiplex polymerase chain reaction and bead-based Luminex technology. Results: We identified a high prevalence of high-risk HPV in patients in the CM group (12/31, 38.8%) and CM/ESCC (8/24, 33.3%), compared to individuals in the ESCC group (6/37, 16.3%). The individuals in the groups with cancer (ESCC and CM/ESCC) had a higher frequency of HPV-16 (4/9, 44.5% and 2/8, 25.0%). The other types of high-risk HPVs detected were HPV-31, 45, 51, 53, 56, 66, and 73. We also observed in some samples HPV coinfection by more than one viral type. Despite the high incidence of HPV, it did not show any association with the patient's clinical-pathological and molecular (TP53 mutation status) characteristics. Conclusion: This is the first report of the presence of HPV DNA in CM associated with ESCC. HPV infection was more presence in megaesophagus lesions. Further studies are needed to confirm and better understand the role of persistent HPV infection in patients with CM.
  • article 2 Citação(ões) na Scopus
    Non-Alcoholic Fatty Liver Disease-Related Hepatocellular Carcinoma: Immunohistochemical Assessment of Markers of Cancer Cell Metabolism
    (2022) GRANJA, S. C.; LONGATTO-FILHO, A.; CAMPOS, P. B. De; OLIVEIRA, C. P.; STEFANO, J. T.; MARTINS-FILHO, S. N.; CHAGAS, A. L.; HERMAN, P.; D'ALBUQUERQUE, L. C.; ALVARES-DA-SILVA, M. Reis; CARRILHO, F. J.; BALTAZAR, F.; ALVES, V. A. F.
    Introduction: Hepatocellular carcinoma (HCC) has been associated to non-alcoholic fatty liver disease (NAFLD). We sought to investigate the immunoexpression of several glycolytic metabolism-associated markers in patients with HCC associated to NAFLD and associate these factors to their clinical-pathological characteristics. Methods: We evaluated 35 HCC specimens from 21 patients diagnosed with non-alcoholic steatohepatitis (NASH) undergoing liver resection (12 patients), liver transplantation (8 patients), or both (1 patient). Histological features, clinical aspects, demographic and biochemical data, as well as the immunohistochemical reactivity for monocarboxylate transporters 1, 2, and 4; their chaperone CD147; carbonic anhydrase IX; and glucose transporter-1 (GLUT1) were assessed. Results: Metabolic-associated cirrhosis was present in 12 of the 21 patients (8 child A and 4 child B scores). From 9 patients without cirrhosis, 3 presented NASH F3 and 6 NASH F2. Sixteen (76%) had diabetes mellitus, 17 (81%) arterial hypertension, and 19 (90%) body mass index above 25 kg/m2; 8 (38%) had dyslipidemia. From 35 nodules, steatosis was found in 26, ballooning in 31 nodules, 25 of them diagnosed as steatohepatitic subtype of HCC. MCT4 immunoexpression was associated with extensive intratumoral fibrosis, advanced clinical stages, and shorter overall survival. GLUT1 was noticeable in nodules with extensive intratumoral steatosis, higher intratumoral fibrosis, and advanced clinical stages. Immunohistochemical expression of the metabolic biomarkers MCT4 and GLUT1 was higher in patients with Barcelona-clinic liver cancer B or C. GLUT1 correlated with higher degree of steatosis, marked ballooning, intratumoral fibrosis, and higher parenchymal necroinflammatory activity. Conclusion: Our data indicate that the expression of the glycolytic phenotype of metabolic markers, especially GLUT1 and MCT4, correlates with a more severe course of HCC occurring in NASH patients.
  • article 2 Citação(ões) na Scopus
    Immunoexpression profile of hypoxia- inducible factor (HIF) targets in potentially malignant and malignant oral lesions: a pilot study
    (2023) GHOLAMI, Shakiba; CHAMORRO-PETRONACCI, Cintia; PEREZ-SAYANS, Mario; PENARANDA, Jose Suarez; LONGATTO-FILHO, Adhemar; BALTAZAR, Fatima; AFONSO, Julieta
    Oral potentially malignant disorders (OPMD) are associated with an increased risk of oral squamous cell carcinoma (OSCC). OSCC has an aggressive profile and is the most prevalent among different head and neck malignancies. Most OSCC patients are diagnosed with advanced stage tumors and have a poor prognosis. Cancer cells are able to reprogram their metabolism, even in the presence of oxygen, enhancing the conversion of glucose to lactate via the glycolytic pathway, a phenomenon mainly regulated by hypoxia-inducible factor (HIF) signaling. Thus, several glycometabolism-related biomarkers are upregulated. Objectives: This study aimed to evaluate the immunoexpression of the HIF targets GLUT1, GLUT3, HK2, PFKL, PKM2, pPDH, LDHA, MCT4, and CAIX in OPMD and OSCC samples, in order to identify potential correlations between biomarkers' immunoexpression, clinicopathological features, and prognostic parameters. Methodology: OSCC and OPMD samples from 21 and 34 patients (respectively) were retrospectively collected and stained for the different biomarkers by immunohistochemistry. Results: CAIX and MCT4 expressions were significantly higher in OSCC samples when compared with OPMD samples, while the rest were also expressed by OPMD. GLUT3 and PKM2 alone, and the concomitant expression of more than four glycometabolism-related biomarkers were significantly correlated with the presence of dysplasia in OPMD. When considering OSCC cases, a trend toward increased expression of biomarkers and poor clinicopathological features was observed, and the differences regarding HK2, PFKL, LDHA and MCT4 expression were significant. Moreover, HK2 and CAIX were correlated with low survival rates. GLUT1 and GLUT3 were significantly associated with poor outcome when their expression was observed in the hypoxic region of malignant lesions. Conclusion: OPMD and OSCC cells overexpress glycolysis-related proteins, which is associated with aggressive features and poor patient outcome. Further research is needed to deeply understand the glycolic phenotype in the process of oral carcinogenesis.