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Sánchez ML, Mangas A, Coveñas R. Glioma and Peptidergic Systems: Oncogenic and Anticancer Peptides. Int J Mol Sci 2024; 25:7990. [PMID: 39063232 PMCID: PMC11277022 DOI: 10.3390/ijms25147990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 07/18/2024] [Accepted: 07/19/2024] [Indexed: 07/28/2024] Open
Abstract
Glioma cells overexpress different peptide receptors that are useful for research, diagnosis, management, and treatment of the disease. Oncogenic peptides favor the proliferation, migration, and invasion of glioma cells, as well as angiogenesis, whereas anticancer peptides exert antiproliferative, antimigration, and anti-angiogenic effects against gliomas. Other peptides exert a dual effect on gliomas, that is, both proliferative and antiproliferative actions. Peptidergic systems are therapeutic targets, as peptide receptor antagonists/peptides or peptide receptor agonists can be administered to treat gliomas. Other anticancer strategies exerting beneficial effects against gliomas are discussed herein, and future research lines to be developed for gliomas are also suggested. Despite the large amount of data supporting the involvement of peptides in glioma progression, no anticancer drugs targeting peptidergic systems are currently available in clinical practice to treat gliomas.
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Affiliation(s)
- Manuel Lisardo Sánchez
- Laboratory of Neuroanatomy of the Peptidergic Systems, Institute of Neurosciences of Castilla and León (INCYL), University of Salamanca, 37007 Salamanca, Spain
| | - Arturo Mangas
- Laboratory of Neuroanatomy of the Peptidergic Systems, Institute of Neurosciences of Castilla and León (INCYL), University of Salamanca, 37007 Salamanca, Spain
| | - Rafael Coveñas
- Laboratory of Neuroanatomy of the Peptidergic Systems, Institute of Neurosciences of Castilla and León (INCYL), University of Salamanca, 37007 Salamanca, Spain
- Grupo GIR USAL-BMD (Bases Moleculares del Desarrollo), University of Salamanca, 37007 Salamanca, Spain
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Willman M, Willman J, Figg J, Dioso E, Sriram S, Olowofela B, Chacko K, Hernandez J, Lucke-Wold B. Update for astrocytomas: medical and surgical management considerations. EXPLORATION OF NEUROSCIENCE 2023:1-26. [PMID: 36935776 PMCID: PMC10019464 DOI: 10.37349/en.2023.00009] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 12/10/2022] [Indexed: 02/25/2023]
Abstract
Astrocytomas include a wide range of tumors with unique mutations and varying grades of malignancy. These tumors all originate from the astrocyte, a star-shaped glial cell that plays a major role in supporting functions of the central nervous system (CNS), including blood-brain barrier (BBB) development and maintenance, water and ion regulation, influencing neuronal synaptogenesis, and stimulating the immunological response. In terms of epidemiology, glioblastoma (GB), the most common and malignant astrocytoma, generally occur with higher rates in Australia, Western Europe, and Canada, with the lowest rates in Southeast Asia. Additionally, significantly higher rates of GB are observed in males and non-Hispanic whites. It has been suggested that higher levels of testosterone observed in biological males may account for the increased rates of GB. Hereditary syndromes such as Cowden, Lynch, Turcot, Li-Fraumeni, and neurofibromatosis type 1 have been linked to increased rates of astrocytoma development. While there are a number of specific gene mutations that may influence malignancy or be targeted in astrocytoma treatment, O6-methylguanine-DNA methyltransferase (MGMT) gene function is an important predictor of astrocytoma response to chemotherapeutic agent temozolomide (TMZ). TMZ for primary and bevacizumab in the setting of recurrent tumor formation are two of the main chemotherapeutic agents currently approved in the treatment of astrocytomas. While stereotactic radiosurgery (SRS) has debatable implications for increased survival in comparison to whole-brain radiotherapy (WBRT), SRS demonstrates increased precision with reduced radiation toxicity. When considering surgical resection of astrocytoma, the extent of resection (EoR) is taken into consideration. Subtotal resection (STR) spares the margins of the T1 enhanced magnetic resonance imaging (MRI) region, gross total resection (GTR) includes the margins, and supramaximal resection (SMR) extends beyond the margin of the T1 and into the T2 region. Surgical resection, radiation, and chemotherapy are integral components of astrocytoma treatment.
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Affiliation(s)
- Matthew Willman
- College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Jonathan Willman
- College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - John Figg
- College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Emma Dioso
- School of Medicine, University of Utah, Salt Lake City, UT 84132, USA
| | - Sai Sriram
- College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Bankole Olowofela
- College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Kevin Chacko
- College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Jairo Hernandez
- College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Brandon Lucke-Wold
- Department of Neurosurgery, University of Florida, Gainesville, FL 32608, USA
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He D, Peng X, Xie H, Peng R, Li Q, Guo Y, Wang W, He H, Chen Y. Genetic Variations in Angiotensinogen Gene and Risk of Preeclampsia: A Pilot Study. J Clin Med 2023; 12:jcm12041509. [PMID: 36836041 PMCID: PMC9966751 DOI: 10.3390/jcm12041509] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Revised: 01/27/2023] [Accepted: 01/30/2023] [Indexed: 02/17/2023] Open
Abstract
Preeclampsia (PE) is a typical hypertensive disorders of pregnancy (HDP) which can cause substantial morbidity and mortality in both pregnant women and fetuses. The renin-angiotensin system (RAS) genes are the main HDP-causing genes, and Angiotensinogen (AGT) as the initial substrate can directly reflect the activity of the entire RAS. However, the association between AGT SNPs and PE risk has rarely been confirmed. This study was carried out to determine whether AGT SNPs could affect the risk of PE in 228 cases and 358 controls. The genotyping result revealed that the AGT rs7079 TT carrier was related to increased PE risk. Further stratified analysis illustrated that the rs7079 TT genotype significantly increased the PE risk in subgroups of Age < 35, BMI < 25, Albumin (ALB) ≥ 30 and Aspartate aminotransferase (AST) < 30. These findings demonstrated that the rs7079 might be a promising candidate SNP strongly associated with PE susceptibility.
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Affiliation(s)
- Dong He
- Guangdong Provincial Key Laboratory of Pathogenesis of Heart and Spleen and Prescription Drugs Research, Department of Pharmacology, School of Chinese Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Xianglan Peng
- Department of Obstetrics and Gynecology, Department of Gynecologic Oncology Research Office, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - Hongkai Xie
- Guangdong Provincial Key Laboratory of Pathogenesis of Heart and Spleen and Prescription Drugs Research, Department of Pharmacology, School of Chinese Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Rui Peng
- Department of Obstetrics and Gynecology, Department of Gynecologic Oncology Research Office, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - Qixuan Li
- Department of Obstetrics and Gynecology, Department of Gynecologic Oncology Research Office, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - Yitong Guo
- Guangdong Provincial Key Laboratory of Pathogenesis of Heart and Spleen and Prescription Drugs Research, Department of Pharmacology, School of Chinese Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Wei Wang
- Guangdong Provincial Key Laboratory of Pathogenesis of Heart and Spleen and Prescription Drugs Research, Department of Pharmacology, School of Chinese Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Hong He
- Department of Obstetrics and Gynecology, Department of Gynecologic Oncology Research Office, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
- Correspondence: (H.H.); (Y.C.)
| | - Yang Chen
- Guangdong Provincial Key Laboratory of Pathogenesis of Heart and Spleen and Prescription Drugs Research, Department of Pharmacology, School of Chinese Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
- Correspondence: (H.H.); (Y.C.)
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Carlos-Escalante JA, Mejía-Pérez SI, Soto-Reyes E, Guerra-Calderas L, Cacho-Díaz B, Torres-Arciga K, Montalvo-Casimiro M, González-Barrios R, Reynoso-Noverón N, Ruiz-de la Cruz M, Díaz-Velásquez CE, Vidal-Millán S, Álvarez-Gómez RM, Sánchez-Correa TE, Pech-Cervantes CH, Soria-Lucio JA, Pérez-Castillo A, Salazar AM, Arriaga-Canon C, Vaca-Paniagua F, González-Arenas A, Ostrosky-Wegman P, Mohar-Betancourt A, Herrera LA, Corona T, Wegman-Ostrosky T. Deep DNA sequencing of MGMT, TP53 and AGT in Mexican astrocytoma patients identifies an excess of genetic variants in women and a predictive biomarker. J Neurooncol 2023; 161:165-174. [PMID: 36525166 DOI: 10.1007/s11060-022-04214-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 12/07/2022] [Indexed: 12/23/2022]
Abstract
PURPOSE Astrocytomas are a type of malignant brain tumor with an unfavorable clinical course. The impact of AGT and MGMT somatic variants in the prognosis of astrocytoma is unknown, and it is controversial for TP53. Moreover, there is a lack of knowledge regarding the molecular characteristics of astrocytomas in Mexican patients. METHODS We studied 48 Mexican patients, men and women, with astrocytoma (discovery cohort). We performed DNA deep sequencing in tumor samples, targeting AGT, MGMT and TP53, and we studied MGMT gene promoter methylation status. Then we compared our findings to a cohort which included data from patients with astrocytoma from The Cancer Genome Atlas (validation cohort). RESULTS In the discovery cohort, we found a higher number of somatic variants in AGT and MGMT than in the validation cohort (10.4% vs < 1%, p < 0.001), and, in both cohorts, we observed only women carried variants AGT variants. We also found that the presence of either MGMT variant or promoter methylation was associated to better survival and response to chemotherapy, and, in conjunction with TP53 variants, to progression-free survival. CONCLUSIONS The occurrence of AGT variants only in women expands our knowledge about the molecular differences in astrocytoma between men and women. The increased prevalence of AGT and MGMT variants in the discovery cohort also points towards possible distinctions in the molecular landscape of astrocytoma among populations. Our findings warrant further study.
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Affiliation(s)
| | - Sonia Iliana Mejía-Pérez
- Departamento de Enseñanza, Instituto Nacional de Neurología y Neurocirugía "Manuel Velasco Suárez", 14269, Mexico City, Mexico
| | - Ernesto Soto-Reyes
- Departamento de Ciencias Naturales, Universidad Autónoma Metropolitana-Cuajimalpa, 05370, Mexico City, Mexico
| | - Lissania Guerra-Calderas
- Departamento de Ciencias Naturales, Universidad Autónoma Metropolitana-Cuajimalpa, 05370, Mexico City, Mexico
| | - Bernardo Cacho-Díaz
- Unidad de Neuro-Oncología, Instituto Nacional de Cancerología, 14080, Mexico City, Mexico
| | - Karla Torres-Arciga
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología-Instituto de Investigaciones Biomédicas, UNAM, 14080, Mexico City, Mexico
| | - Michel Montalvo-Casimiro
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología-Instituto de Investigaciones Biomédicas, UNAM, 14080, Mexico City, Mexico
| | - Rodrigo González-Barrios
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología-Instituto de Investigaciones Biomédicas, UNAM, 14080, Mexico City, Mexico
| | - Nancy Reynoso-Noverón
- Dirección de Investigación, Instituto Nacional de Cancerología, 14080, Mexico City, Mexico
| | - Miguel Ruiz-de la Cruz
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, 54090, Tlalnepantla, Mexico
- Departamento de Infectómica y Patogénsis Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), 07360, Mexico City, Mexico
| | - Clara Estela Díaz-Velásquez
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, 54090, Tlalnepantla, Mexico
- Laboratorio Nacional en Salud: Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, 54090, Tlalnepantla, Mexico
| | - Silvia Vidal-Millán
- Clínica de Cáncer Hereditario, Instituto Nacional de Cancerología, 14080, Mexico City, Mexico
| | | | - Thalía Estefanía Sánchez-Correa
- Departamento de Neurocirugía, Instituto Nacional de Neurología y Neurocirugía "Manuel Velasco Suarez", 14269, Mexico City, Mexico
| | - Claudio Hiram Pech-Cervantes
- Departamento de Neurocirugía, Instituto Nacional de Neurología y Neurocirugía "Manuel Velasco Suarez", 14269, Mexico City, Mexico
| | - José Antonio Soria-Lucio
- Departamento de Traumatología y Ortopedia, Hospital General Regional #2, Instituto Mexicano del Seguro Social, 14310, Mexico City, Mexico
| | - Areli Pérez-Castillo
- Departamento de Cirugía, Hospital General Regional #1, Instituto Mexicano del Seguro Social, 61303, Charo, Mexico
| | - Ana María Salazar
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico
| | - Cristian Arriaga-Canon
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología-Instituto de Investigaciones Biomédicas, UNAM, 14080, Mexico City, Mexico
| | - Felipe Vaca-Paniagua
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, 54090, Tlalnepantla, Mexico
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, 14080, Mexico City, Mexico
- Laboratorio Nacional en Salud: Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, 54090, Tlalnepantla, Mexico
| | - Aliesha González-Arenas
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico
| | - Patricia Ostrosky-Wegman
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico
| | - Alejandro Mohar-Betancourt
- Unidad de Epidemiología e Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas, UNAM-INCAN, 14080, Mexico City, Mexico
| | - Luis A Herrera
- Dirección General, Instituto Nacional de Medicina Genómica (INMEGEN), 14610, Mexico City, Mexico
| | - Teresa Corona
- Laboratorio Clínico de Enfermedades Neurodegenerativas, Instituto Nacional de Neurología y Neurocirugía, "Manuel Velasco Suárez", 14269, Mexico City, Mexico
- División de Estudios de Posgrado, Facultad de Medicina, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico
| | - Talia Wegman-Ostrosky
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, 14080, Mexico City, Mexico.
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Sapena V, Iavarone M, Boix L, Facchetti F, Guarino M, Sanduzzi Zamparelli M, Granito A, Samper E, Scartozzi M, Corominas J, Marisi G, Díaz A, Casadei-Gardini A, Gramantieri L, Lampertico P, Morisco F, Torres F, Bruix J, Reig M. Polymorphism AGT2 (rs4762) is involved in the development of dermatologic events: Proof-of-concept in hepatocellular carcinoma patients treated with sorafenib. World J Hepatol 2022; 14:1438-1458. [PMID: 36158918 PMCID: PMC9376774 DOI: 10.4254/wjh.v14.i7.1438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 01/24/2022] [Accepted: 07/06/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Dermatologic adverse events (DAEs) are associated with a better outcome in patients with hepatocellular carcinoma (HCC) irrespective of the therapeutic agent received. The exact mechanisms associated with the development of DAEs are unknown although several studies point to direct toxicity of tyrosine kinase inhibitors (TKIs) to the skin or an immune-mediated reaction triggered by the oncologic treatment. As is the case in other conditions, individual genetic variants may partially explain a higher risk of DAEs. AIM To evaluate the contribution of several gene variants to the risk of developing DAEs in HCC patients treated with TKIs. METHODS We first analyzed 27 single-nucleotide polymorphisms (SNPs) from 12 genes selected as potential predictors of adverse event (AE) development in HCC patients treated with sorafenib [Barcelona Clinic Liver Cancer 1 (BCLC1) cohort]. Three additional cohorts were analyzed for AGT1 (rs699) and AGT2 (rs4762) polymorphisms-initially identified as predictors of DAEs: BCLC2 (n = 79), Northern Italy (n = 221) and Naples (n = 69) cohorts, respectively. The relation between SNPs and DAEs and death were assessed by univariate and multivariate Cox regression models, and presented with hazard ratios and their 95% confidence intervals (95%CI). RESULTS The BCLC1 cohort showed that patients with arterial hypertension (AHT) (HR = 1.61; P value = 0.007) and/or AGT SNPs had an increased risk of DAEs. Thereafter, AGT2 (rs4762) AA genotype was found to be linked to a statistically significant increased probability of DAEs (HR = 5.97; P value = 0.0201, AA vs GG) in the Northern Italy cohort by multivariate analysis adjusted for BCLC stage, ECOG-PS, diabetes and AHT. The value of this genetic marker was externally validated in the cohort combining the BCLC1, BCLC2 and Naples cohorts [HR = 3.12 (95%CI: 1.2-8.14), P value = 0.0199, AGT2 (rs4762) AA vs AG genotype and HR = 2.73 (95%CI: 1.18-6.32) P value = 0.0188, AGT2 (rs4762) AA vs GG genotype]. None of the other gene variants tested were found to be associated with the risk of DAE development. CONCLUSION DAE development in HCC patients receiving TKIs could be explained by the AGT2 (rs4762) gene variant. If validated in other anti-oncogenic treatments, it might be considered a good prognosis marker.
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Affiliation(s)
- Víctor Sapena
- Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona 08036, Spain
- Universidad de Barcelona, Barcelona 08036, Spain
| | - Massimo Iavarone
- Division of Gastroenterology and Hepatology, Foundation Istituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica Ca' Granda Ospedale Maggiore Policlinico, Milano 20122, Italy
| | - Loreto Boix
- Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona 08036, Spain
| | - Floriana Facchetti
- Gastroenterology and Hepatology Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica Cà Granda Ospedale Maggiore Policlinico, University of Milan, Milan 20100, Italy
| | - Maria Guarino
- Department of Clinical Medicine and Surgery, Gastroenterology Unit, University of Naples "Federico II", Napoli 80100, Italy
| | - Marco Sanduzzi Zamparelli
- Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona 08036, Spain
- Universidad de Barcelona, Barcelona 08036, Spain
- Department of Clinical Medicine and Surgery, Gastroenterology and Hepatology, Federico II University of Naples, Naples 80131, Italy
| | - Alessandro Granito
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, Istituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica Azienda Ospedaliero-Universitaria di Bologna, Bologna 40139, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna 40139, Italy
| | - Esther Samper
- Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona 08036, Spain
| | - Mario Scartozzi
- Department of Medical Oncology, University of Cagliari, Cagliari 45698, Italy
| | - Josep Corominas
- Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona 08036, Spain
| | - Giorgia Marisi
- Biosciences Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica, Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori", Meldola 47014, Italy
| | - Alba Díaz
- Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona 08036, Spain
- Universidad de Barcelona, Barcelona 08036, Spain
- Department of Pathology, Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona 08036, Spain
| | - Andrea Casadei-Gardini
- School of Medicine, Vita-Salute San Raffaele University, Milan 20132, Italy
- Unit of Oncology, Università Vita-Salute, Istituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica-San Raffaele Scientific Institute, Milan 20132, Italy
| | - Laura Gramantieri
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, Istituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica Azienda Ospedaliero, Bologna 40138, Italy
| | - Pietro Lampertico
- Division of Gastroenterology and Hepatology, Foundation Istituto di Ricovero e Cura a Carattere Scientifico di Natura Pubblica Ca' Granda Ospedale Maggiore Policlinico, Milano 20122, Italy
- Department of Pathophysiology and Transplantation, Colorectal Cancer "A. M. and A. Migliavacca" Center for Liver Disease, University of Milan, Milano 20122, Italy
| | - Filomena Morisco
- Department of Clinical Medicine and Surgery, Gastroenterology Unit, University of Naples Federico II, Naples 80131, Italy
| | - Ferran Torres
- Medical Statistics Core Facility, Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Hospital Clinic Barcelona, Barcelona 08036, Spain
- Biostatistics Unit, Faculty of Medicine, Universitat Autònoma de Barcelona, Cerdanyola 08193, Spain
| | - Jordi Bruix
- Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona 08036, Spain
- Universidad de Barcelona, Barcelona 08036, Spain
| | - María Reig
- Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona 08036, Spain
- Universidad de Barcelona, Barcelona 08036, Spain
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Yee J, Song TJ, Yoon HY, Park J, Gwak HS. Genetic Factors of Renin–Angiotensin System Associated with Major Bleeding for Patients Treated with Direct Oral Anticoagulants. Pharmaceutics 2022; 14:pharmaceutics14020231. [PMID: 35213964 PMCID: PMC8877686 DOI: 10.3390/pharmaceutics14020231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/14/2022] [Accepted: 01/17/2022] [Indexed: 12/04/2022] Open
Abstract
The purpose of this study was to identify the renin–angiotensin system (RAS)-related genetic factors associated with bleeding and develop the bleeding risk scoring system in patients receiving direct oral anticoagulants (DOACs). This study was a retrospective analysis of prospectively collected samples from June 2018 to May 2020. To investigate the associations between RAS-related genetic factors and major bleeding, we selected 16 single nucleotide polymorphisms (SNPs) from five genes (namely, AGT, REN, ACE, AGTR1, and AGTR2). Multivariable logistic regression analysis was employed to investigate the independent risk factors for bleeding and to develop a risk scoring system. A total of 172 patients were included in the analysis, including 33 major bleeding cases. Both old age (≥65 years) and moderate to severe renal impairment (CrCl < 50 mL/min) increased the risk of bleeding in the multivariable analysis. Among RAS-related polymorphisms, patients carrying TT genotype of rs5050 and A allele of rs4353 experienced a 3.6-fold (95% CI: 1.4–9.3) and 3.1-fold (95% CI: 1.1–9.3) increase in bleeding, respectively. The bleeding risk increased exponentially with a higher score; the risks were 0%, 2.8%, 16.9%, 32.7%, and 75% in patients with 0, 1, 2, 3, and 4 points, respectively. Although this study is limited to a retrospective study design, this is the first study to suggest RAS-related genetic markers and risk scoring systems, including both clinical and genetic factors, for major bleeding in patients receiving DOAC treatment.
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Affiliation(s)
- Jeong Yee
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea; (J.Y.); (H.-Y.Y.)
| | - Tae-Jin Song
- Department of Neurology, Ewha Womans University Seoul Hospital, Ewha Womans University College of Medicine, Seoul 07804, Korea;
| | - Ha-Young Yoon
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea; (J.Y.); (H.-Y.Y.)
| | - Junbeom Park
- Division of Cardiology, Department of Internal Medicine, Ewha Womans University Mokdong Hospital, Ewha Womans University College of Medicine, Seoul 07985, Korea
- Correspondence: (J.P.); (H.-S.G.); Tel.: +82-2-2650-5826 (J.P.); +82-2-3277-4376 (H.-S.G.)
| | - Hye-Sun Gwak
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea; (J.Y.); (H.-Y.Y.)
- Correspondence: (J.P.); (H.-S.G.); Tel.: +82-2-2650-5826 (J.P.); +82-2-3277-4376 (H.-S.G.)
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Carlos-Escalante JA, Gómez-Flores-Ramos L, Bian X, Perdomo-Pantoja A, de Andrade KC, Mejía-Pérez SI, Cacho-Díaz B, González-Barrios R, Reynoso-Noverón N, Soto-Reyes E, Sánchez-Correa TE, Guerra-Calderas L, Yan C, Chen Q, Castro-Hernández C, Vidal-Millán S, Taja-Chayeb L, Gutiérrez O, Álvarez-Gómez RM, Gómez-Amador JL, Ostrosky-Wegman P, Mohar-Betancourt A, Herrera-Montalvo LA, Corona T, Meerzaman D, Wegman-Ostrosky T. Landscape of Germline Genetic Variants in AGT, MGMT, and TP53 in Mexican Adult Patients with Astrocytoma. Cell Mol Neurobiol 2021; 41:1285-1297. [PMID: 32535722 PMCID: PMC11448676 DOI: 10.1007/s10571-020-00901-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 06/06/2020] [Indexed: 12/20/2022]
Abstract
Astrocytoma is the most common type of primary brain tumor. The risk factors for astrocytoma are poorly understood; however, germline genetic variants account for 25% of the risk of developing gliomas. In this study, we assessed the risk of astrocytoma associated with variants in AGT, known by its role in angiogenesis, TP53, a well-known tumor suppressor and the DNA repair gene MGMT in a Mexican population. A case-control study was performed in 49 adult Mexican patients with grade II-IV astrocytoma. Sequencing of exons and untranslated regions of AGT, MGMT, and TP53 from was carried in an Ion Torrent platform. Individuals with Mexican Ancestry from the 1000 Genomes Project were used as controls. Variants found in our cohort were then assessed in a The Cancer Genome Atlas astrocytoma pan-ethnic validation cohort. Variants rs1926723 located in AGT (OR 2.74, 1.40-5.36 95% CI), rs7896488 in MGMT (OR 3.43, 1.17-10.10 95% CI), and rs4968187 in TP53 (OR 2.48, 1.26-4.88 95% CI) were significantly associated with the risk of astrocytoma after multiple-testing correction. This is the first study where the AGT rs1926723 variant, TP53 rs4968187, and MGMT rs7896488 were found to be associated with the risk of developing an astrocytoma.
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Affiliation(s)
| | | | - Xiaopeng Bian
- Computational Genomics and Bioinformatics Group, Center for Biomedical Informatics and Information Technology, National Cancer Institute, NIH, Rockville, MD, 20850, USA
| | | | - Kelvin César de Andrade
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA
| | - Sonia Iliana Mejía-Pérez
- Departamento de Enseñanza, Instituto Nacional de Neurología y Neurocirugía "Manuel Velasco Suárez", 13269, Mexico City, Mexico
- Departamento de Neurocirugía, Instituto Nacional de Neurología y Neurocirugía "Manuel Velasco Suarez", 14269, Mexico City, Mexico
| | - Bernardo Cacho-Díaz
- Unidad de Neurociencia, Instituto Nacional de Cancerología, 14080, Mexico City, Mexico
| | | | - Nancy Reynoso-Noverón
- Dirección de Investigación, Instituto Nacional de Cancerología, 14080, Mexico City, Mexico
| | - Ernesto Soto-Reyes
- Departamento de Ciencias Naturales, Universidad Autónoma Metropolitana-Cuajimalpa, 05370, Mexico City, Mexico
| | - Thalía Estefanía Sánchez-Correa
- Departamento de Neurocirugía, Instituto Nacional de Neurología y Neurocirugía "Manuel Velasco Suarez", 14269, Mexico City, Mexico
| | - Lissania Guerra-Calderas
- Departamento de Ciencias Naturales, Universidad Autónoma Metropolitana-Cuajimalpa, 05370, Mexico City, Mexico
| | - Chunhua Yan
- Computational Genomics and Bioinformatics Group, Center for Biomedical Informatics and Information Technology, National Cancer Institute, NIH, Rockville, MD, 20850, USA
| | - Qingrong Chen
- Computational Genomics and Bioinformatics Group, Center for Biomedical Informatics and Information Technology, National Cancer Institute, NIH, Rockville, MD, 20850, USA
| | - Clementina Castro-Hernández
- Unidad de Epidemiología E Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas, UNAM-INCAN, 14080, Mexico City, Mexico
| | - Silvia Vidal-Millán
- Clínica de Cáncer Hereditario, Instituto Nacional de Cancerología, 14080, Mexico City, Mexico
| | - Lucía Taja-Chayeb
- Dirección de Investigación, Instituto Nacional de Cancerología, 14080, Mexico City, Mexico
| | - Olga Gutiérrez
- Dirección de Investigación, Instituto Nacional de Cancerología, 14080, Mexico City, Mexico
| | | | - Juan Luis Gómez-Amador
- Departamento de Neurocirugía, Instituto Nacional de Neurología y Neurocirugía "Manuel Velasco Suarez", 14269, Mexico City, Mexico
| | - Patricia Ostrosky-Wegman
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico
| | - Alejandro Mohar-Betancourt
- Unidad de Epidemiología E Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas, UNAM-INCAN, 14080, Mexico City, Mexico
| | - Luis Alonso Herrera-Montalvo
- Unidad de Epidemiología E Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas, UNAM-INCAN, 14080, Mexico City, Mexico
- Dirección General, Instituto Nacional de Medicina Genómica, 14610, Mexico City, Mexico
| | - Teresa Corona
- Laboratorio Clínico de Enfermedades Neurodegenerativas, Instituto Nacional de Neurología y Neurocirugía, Manuel Velasco Suárez", 14269, Mexico City, Mexico
| | - Daoud Meerzaman
- Computational Genomics and Bioinformatics Group, Center for Biomedical Informatics and Information Technology, National Cancer Institute, NIH, Rockville, MD, 20850, USA
| | - Talia Wegman-Ostrosky
- Dirección de Investigación, Instituto Nacional de Cancerología, 14080, Mexico City, Mexico.
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8
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Khalili-Tanha G, Khalili-Tanha N, Nazari SE, Chaeichi-Tehrani N, Khazaei M, Aliakbarian M, Hassanian SM, Ghayour-Mobarhan M, Ferns GA, Avan A. The Therapeutic Potential of Targeting the Angiotensin Pathway as a Novel Therapeutic Approach to Ameliorating Post-Surgical Adhesions. Curr Pharm Des 2021; 28:180-186. [PMID: 34176457 DOI: 10.2174/1381612827666210625153011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 04/27/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Post-surgical adhesion is a common complication after abdominal or pelvic surgeries. Despite improvements in surgical techniques or the application of physical barriers, little improvements have been achieved. It causes bowel obstruction, pelvic pain, and infertility in women and has an adverse effect on the quality of life. Renin-Angiotensin System (RAS) is traditionally considered as a blood pressure regulator. However, recent studies also indicate that the RAS plays a vital role in other processes, including oxidative stress, fibrosis, proliferation, inflammation, and the wound healing process. Angiotensin II (Ang II) is the main upstream effector of the RAS that can bind to the AT1 receptor (ATIR). A growing body of evidence has revealed that targeting Angiotensin-Converting Enzyme Inhibitors (ACEIs), Angiotensin II type 1 Receptor Blockers (ARBs), and Direct Renin Inhibitors (DRIs) can prevent post-surgical adhesions. Here we provide an overview of the therapeutic effect of RAS antagonists for adhesion. METHODS PubMed, EMBASE, and the Cochrane library were reviewed to identify potential agents targeting the RAS system as a potential approach for post-surgical adhesion. RESULTS Available evidence suggests the involvement of the RAS signaling pathway in inflammation, proliferation, and fibrosis pathways as well as in post-surgical adhesions. Several FDA-approved drugs are being used for targeting the RAS system. Some of them are being tested in different models to reduce fibrosis and improve adhesion after surgery, including Telmisartan, valsartan, and enalapril. CONCLUSION Identification of the pathological causes of post-surgical adhesion and the potential role of targeting Renin-Angiotensin System may help prevent this problem. Based on the pathological function of RAS signaling after surgeries, the administration of ARBs may be considered as a novel and efficient approach to prevent postsurgical adhesions. Pre-clinical and clinical studies should be carried out to have better information on the clinical significance of this therapy against post-surgical adhesion formation.
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Affiliation(s)
- Ghazaleh Khalili-Tanha
- Metabolic Syndrome Research Centre, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Nima Khalili-Tanha
- Veterinary Medicine Student, Faculty of Veterinary Medicine, Ferdowsi University Mashhad, Iran
| | - Seyedeh Elnaz Nazari
- Metabolic Syndrome Research Centre, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Majid Khazaei
- Medical Genetics Research Centre, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohsen Aliakbarian
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Metabolic Syndrome Research Centre, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Gordon A Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex BN1 9PH, United Kingdom
| | - Amir Avan
- Metabolic Syndrome Research Centre, Mashhad University of Medical Sciences, Mashhad, Iran
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9
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Beltrán JQ, Ogando-Rivas E, Nettel-Rueda B, Velasco-Campos F, Navarro-Olvera JL, Aguado-Carrillo G, Soriano-Sánchez JA, Alpizar-Aguirre A, Carrillo-Ruiz JD. Women in Neurosurgery: First Neurosurgeon in Latin America and Current Mexican Leaders. World Neurosurg 2021; 150:114-120. [PMID: 33781943 DOI: 10.1016/j.wneu.2021.03.102] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 03/19/2021] [Accepted: 03/20/2021] [Indexed: 11/18/2022]
Abstract
BACKGROUND History has taught us that Mexican culture has been largely supported by women, despite gender prejudice from the society. Neurosurgery has not been the exception. Therefore, we investigated the challenges and influence of female neurosurgeons in Mexico. METHODS We conducted a review of the literature and an analysis of the internal database of the Mexican Society of Neurological Surgery focusing on 3 topics: 1) the historical presence of women and gender inequality in Mexico; 2) the life and legacy of the woman who became the first neurosurgeon in Mexico and in Latin America; and 3) the participation of women in neurosurgery in the past 3 decades. RESULTS In Latin America, the first woman in neurosurgery was María Cristina García-Sancho, who completed her neurosurgical training in 1951. Currently, women represent 6.2% of the total members of the Mexican Society of Neurological Surgery (MSNS). This percentage is still low, although data collected in this study suggest that it might increase in the next few years because 16.7% of Board Directors of the MSNS are women, the next elected president is a female neurosurgeon, and 14.5% of neurosurgery residents are women. CONCLUSIONS Although a steady increase has occurred of women in neurosurgery in Mexico, there is still work to do, especially to overcome the barriers related to the old assumptions of the cultural and social roles of women.
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Affiliation(s)
- Jesús Q Beltrán
- Unit for Stereotactic and Functional Neurosurgery, General Hospital of Mexico, Mexico City, Mexico; Direction of Research, General Hospital of Mexico, Mexico City, Mexico
| | - Elizabeth Ogando-Rivas
- Department of Neurosurgery, University of Florida, Gainesville, Florida, USA; Brain Tumor Immunotherapy Program, University of Florida, Gainesville, Florida, USA
| | - Barbara Nettel-Rueda
- Department of Neurosurgery, Hospital de Especialidades del Centro Médico Nacional Siglo XXI, Mexico City, Mexico
| | - Francisco Velasco-Campos
- Unit for Stereotactic and Functional Neurosurgery, General Hospital of Mexico, Mexico City, Mexico
| | - José L Navarro-Olvera
- Unit for Stereotactic and Functional Neurosurgery, General Hospital of Mexico, Mexico City, Mexico
| | - Gustavo Aguado-Carrillo
- Unit for Stereotactic and Functional Neurosurgery, General Hospital of Mexico, Mexico City, Mexico
| | - José A Soriano-Sánchez
- Spine Clinic, The American-British Cowdray Medical Center IAP, Campus Santa Fe, Mexico City, Mexico
| | | | - José D Carrillo-Ruiz
- Unit for Stereotactic and Functional Neurosurgery, General Hospital of Mexico, Mexico City, Mexico; Direction of Research, General Hospital of Mexico, Mexico City, Mexico; Direction of Faculty of Health Sciences, Anahuac University, Mexico City, Mexico.
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10
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Medina-Enríquez MM, Lopez-León S, Carlos-Escalante JA, Aponte-Torres Z, Cuapio A, Wegman-Ostrosky T. ACE2: the molecular doorway to SARS-CoV-2. Cell Biosci 2020; 10:148. [PMID: 33380340 PMCID: PMC7772801 DOI: 10.1186/s13578-020-00519-8] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 12/13/2020] [Indexed: 12/18/2022] Open
Abstract
The angiotensin-converting enzyme 2 (ACE2) is the host functional receptor for the new virus SARS-CoV-2 causing Coronavirus Disease 2019. ACE2 is expressed in 72 different cell types. Some factors that can affect the expression of the ACE2 are: sex, environment, comorbidities, medications (e.g. anti-hypertensives) and its interaction with other genes of the renin-angiotensin system and other pathways. Different factors can affect the risk of infection of SARS-CoV-2 and determine the severity of the symptoms. The ACE2 enzyme is a negative regulator of RAS expressed in various organ systems. It is with immunity, inflammation, increased coagulopathy, and cardiovascular disease. In this review, we describe the genetic and molecular functions of the ACE2 receptor and its relation with the physiological and pathological conditions to better understand how this receptor is involved in the pathogenesis of COVID-19. In addition, it reviews the different comorbidities that interact with SARS-CoV-2 in which also ACE2 plays an important role. It also describes the different factors that interact with the virus that have an influence in the expression and functional activities of the receptor. The goal is to provide the reader with an understanding of the complexity and importance of this receptor.
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Affiliation(s)
| | - Sandra Lopez-León
- Global Drug Development, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
| | | | | | - Angelica Cuapio
- Center of Infectious Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Talia Wegman-Ostrosky
- Department of Basic Research, Instituto Nacional de Cancerología, 22 San Fernando Avenue, Belisario Domínguez Sección XVI, 14080, Mexico City, Mexico.
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11
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The angiotensinogen gene polymorphism, lifestyle factors, associated diseases and gastric areas of inflammatory and preneoplastic lesions in a Romanian sample of patients. REV ROMANA MED LAB 2019. [DOI: 10.2478/rrlm-2019-0032] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Abstract
The aim of our study was to evaluate the association between variant genotype of angiotensinogen (AGT) c.-58A>C, lifestyle factors and clinical factors and corporeal extension of gastric inflammatory and preneoplastic lesions.
Methods: Our study included 209 subjects who underwent a complete set of gastric biopsies, followed by genotyping. They were included to study inflammatory gastric changes and preneoplastic lesions and were grouped according to the localization of changes.
Results: No significant statistical associations were noticed between AGT c.-58A>C genotypes and the corporeal extension of the inflammation or preneoplastic injury groups. Extending preneoplastic lesions to the gastric body was associated with smoking habits (p=0.01) and additionally, there was a significant association between nicotine consumption and the body extension of preneoplastic lesions (p=0.01). The use of acenocoumarol was frequently associated with the progression of histological lesions to preneoplastic lesions (p=0.01). Compared with the wild-type AA genotype, the combined genotypes AA+CC of AGT c.-58A>C were significantly associated with the progression of inflammatory gastric lesions’ according to the regular ingested doses of nonsteroidal anti-inflammatory drugs (NSAIDs).
Conclusion: The AGT c.-58A>C polymorphism is not associated with extension of the gastric lesions. In accordance with nicotine and alcohol consumption, the acenocoumarol co-treatment and multiple cardiac pathologies are associated with the corporeal progression of these injuries. The age below 70 years and NSAIDs treatment for the patients with heterozygous AC genotype and variant homozygous CC genotype for the mentioned SNP have been associated with the corporeal extension of gastric inflammation.
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12
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Beitia M, Solano-Iturri JD, Errarte P, Sanz B, Perez I, Etxezarraga MC, Loizate A, Asumendi A, Larrinaga G. Altered expression of renin-angiotensin system receptors throughout colorectal adenoma-adenocarcinoma sequence. Int J Med Sci 2019; 16:813-821. [PMID: 31337954 PMCID: PMC6643103 DOI: 10.7150/ijms.32599] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Accepted: 03/27/2019] [Indexed: 12/24/2022] Open
Abstract
Background and Objective: Colorectal cancer (CRC) is a major health problem in developed countries. Adenomatous lesions in the large bowel are the main precursors of CRC and the adenoma-adenocarcinoma sequence still provides a solid model for research on carcinogenesis. The finding of local renin-angiotensin systems (RAS) has been crucial to understand the role of this peptidergic system in cancer and has opened new perspectives in the study of colorectal carcinogenetic processes. Methods: In this study we analyzed the immunohistochemical expression of three main RAS receptors (AT1, AT2 and MAS) in a large series of CRC samples (n=161), including uninvolved intestinal mucosa-adenoma-adenocarcinoma sequences from the same patients (n=50). Results: 1) AT1 and AT2 showed a biphasic expression pattern along the sequence. The expression significantly decreased in adenomas with respect to uninvolved mucosa but increased in CRCs. 2) AT2 expression was lower in advanced CRCs with high local invasion (pT4), high stage (IV), high nodal (N2) and vascular invasion. 3) MAS receptor was moderately expressed in the uninvolved mucosa and in adenomas. This expression increased very significantly in CRC tissues. Conclusions: These results suggest that: 1) RAS receptors are differentially regulated as the genetic and epigenetic alterations accumulate throughout the uninvolved mucosa-adenoma-CRC sequence. 2) Loss of AT2 expression could contribute to the aggressive behavior of advanced CRC cells.
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MESH Headings
- Adenocarcinoma/genetics
- Adenocarcinoma/mortality
- Adenocarcinoma/pathology
- Adenoma/genetics
- Adenoma/mortality
- Adenoma/pathology
- Adult
- Aged
- Aged, 80 and over
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinogenesis/genetics
- Carcinogenesis/pathology
- Colorectal Neoplasms/genetics
- Colorectal Neoplasms/mortality
- Colorectal Neoplasms/pathology
- Epigenesis, Genetic
- Female
- Follow-Up Studies
- Gene Expression Regulation, Neoplastic
- Humans
- Intestinal Mucosa/pathology
- Kaplan-Meier Estimate
- Male
- Middle Aged
- Prognosis
- Proto-Oncogene Mas
- Proto-Oncogene Proteins/genetics
- Proto-Oncogene Proteins/metabolism
- Receptor, Angiotensin, Type 1/genetics
- Receptor, Angiotensin, Type 1/metabolism
- Receptor, Angiotensin, Type 2/genetics
- Receptor, Angiotensin, Type 2/metabolism
- Receptors, G-Protein-Coupled/genetics
- Receptors, G-Protein-Coupled/metabolism
- Renin-Angiotensin System/genetics
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Affiliation(s)
- Maider Beitia
- Department of Nursing I, School of Nursing, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain
- Department of Physiology, Faculty of Medicine and Dentistry, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain
- BioCruces Health Research Institute, Barakaldo, Bizkaia, Spain
| | - Jon Danel Solano-Iturri
- Department of Anatomic Pathology, Cruces University Hospital, University of the Basque Country (UPV/EHU), Barakaldo, Bizkaia, Spain
- BioCruces Health Research Institute, Barakaldo, Bizkaia, Spain
| | - Peio Errarte
- Department of Physiology, Faculty of Medicine and Dentistry, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain
- BioCruces Health Research Institute, Barakaldo, Bizkaia, Spain
| | - Begoña Sanz
- Department of Physiology, Faculty of Medicine and Dentistry, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain
- BioCruces Health Research Institute, Barakaldo, Bizkaia, Spain
| | - Itxaro Perez
- Department of Nursing I, School of Nursing, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain
- BioCruces Health Research Institute, Barakaldo, Bizkaia, Spain
| | - María C. Etxezarraga
- Department of Anatomic Pathology, Basurto University Hospital, University of the Basque Country (UPV/EHU), Bilbao, Bizkaia, Spain
- BioCruces Health Research Institute, Barakaldo, Bizkaia, Spain
| | - Alberto Loizate
- Department of Surgery, Basurto University Hospital, University of the Basque Country (UPV/EHU), Bilbao, Bizkaia, Spain
| | - Aintzane Asumendi
- Department of Cell Biology and Histology, School of Medicine and Dentistry, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain
| | - Gorka Larrinaga
- Department of Nursing I, School of Nursing, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain
- Department of Physiology, Faculty of Medicine and Dentistry, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain
- BioCruces Health Research Institute, Barakaldo, Bizkaia, Spain
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