RESUMO
OBJECTIVE: In Alzheimer's disease (AD), angiotensin II receptor blockers (ARBs) could reduce cerebrovascular dysfunction, while angiotensin-converting enzyme inhibitors (ACEis) might increase brain amyloid-ß by suppressing effects of the angiotensin-converting enzyme 1, an amyloid-ß-degrading enzyme. However, ACEis could benefit patients with AD by reducing the amyloidogenic processing of the amyloid precursor protein, by central cholinergic and anti-inflammatory mechanisms, and by peripheral modulation of glucose homeostasis. We aimed to investigate whether the ACE insertion/deletion polymorphism is associated with clinical changes in patients with AD, while considering apolipoprotein E (APOE)-ϵ4 carrier status and blood pressure response to angiotensin modulators. METHODS: Consecutive outpatients with late-onset AD were screened with cognitive tests and anthropometric measurements, while their caregivers were queried for functional and caregiver burden scores. Prospective pharmacogenetic associations were estimated for 1 year, taking APOE-ϵ4 carrier status and genotypes of the ACE insertion/deletion polymorphism into account, along with treatment with ACEis or ARBs. RESULTS: For 193 patients (67.4% women, 53.4% APOE-ϵ4 carriers), the ACE insertion/deletion polymorphism was in Hardy-Weinberg equilibrium (p = 0.281), while arterial hypertension was prevalent in 80.3% (n = 124 used an ACEi, n = 21 used an ARB). ARBs benefitted mostly APOE-ϵ4 carriers concerning caregiver burden variations, cognitive and functional decline. ACEis benefitted APOE-ϵ4 non-carriers concerning cognitive and functional decline due to improved blood pressure control in addition to possible central mechanisms. The ACE insertion/deletion polymorphism led to variable response to angiotensin modulators concerning neurological outcomes and blood pressure variations. CONCLUSION: Angiotensin modulators may be disease-modifiers in AD, while genetic stratification of samples is recommended in clinical studies.
Assuntos
Doença de Alzheimer , Humanos , Feminino , Masculino , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/complicações , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Angiotensinas/genética , Angiotensinas/uso terapêutico , Farmacogenética , Alelos , Estudos Prospectivos , Apolipoproteínas E/genética , Apolipoproteínas E/uso terapêuticoRESUMO
OBJECTIVE: Neuropsychiatric syndromes have been associated with memory dysfunction and risk of and earlier onset of dementia, but how psychotropic drugs affect clinical changes in Alzheimer's disease is not entirely clear. This study aimed to assess the prospective effects of psychotropic drugs on cognitive and functional changes in Alzheimer's disease according to APOE ε4 carrier status. METHODS: The study included consecutive outpatients with late-onset Alzheimer's disease (N=193) and examined score variations at 1 year on the following tests: Clinical Dementia Rating sum of boxes, Mini-Mental State Examination, Severe Mini-Mental State Examination (SMMSE), Brazilian version of the Zarit Caregiver Burden Interview, Index of Independence in Activities of Daily Living, and Lawton's Instrumental Activities of Daily Living Scale. Analyses of score variations accounted for the use of psychotropic drugs or the number of different medications in use, as well as APOE ε4 carrier status, with significance at p<0.05. RESULTS: For APOE ε4 noncarriers (N=90), cholinesterase inhibitors were beneficial regarding caregiver burden (p=0.030) and basic functionality (p=0.046), memantine was harmful regarding SMMSE score changes (p=0.032), second-generation antipsychotics had nonsignificant harmful effects on SMMSE score changes (p=0.070), and antiepileptic therapy (p=0.001) and the number of different medications in use (p=0.006) were harmful in terms of basic functionality. APOE ε4 carriers (N=103) did not experience any effects of isolated psychotropic drugs on clinical changes, including antidepressants. CONCLUSIONS: Results support the harmful prospective effects of second-generation antipsychotics and antiepileptic drugs on cognitive and functional changes in Alzheimer's disease, particularly for APOE ε4 noncarriers, whereas antidepressants may be safer options for behavioral enhancement.
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Doença de Alzheimer , Atividades Cotidianas , Doença de Alzheimer/complicações , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Anticonvulsivantes/uso terapêutico , Apolipoproteína E4/genética , Inibidores da Colinesterase/uso terapêutico , Humanos , Memantina/uso terapêutico , Testes Neuropsicológicos , Psicotrópicos/uso terapêuticoRESUMO
Introduction: The inherited risk of late-onset Alzheimer's disease (AD) is genetically determined. We aimed to examine associations of genetic variants of APOE and ACE with age at AD onset and with neuropsychiatric symptoms according to each dementia stage.Methods: Consecutive outpatients with AD were assessed for demographic features, Clinical Dementia Rating scores, and the 10-item Neuropsychiatric Inventory, and genotyped for rs7412 and rs429358 (APOE haplotypes, Real-Time Polymerase Chain Reactions), and the ACE insertion/deletion polymorphism (Polymerase Chain Reactions). Combined genetic variants of APOE and ACE were associated with age at dementia onset, and with neuropsychiatric symptoms in each dementia stage (adjusted for sex and age at dementia onset).Results: Over two-thirds of the 238 patients were women, whereas the mean age at dementia onset was 73.82 ± 6.2 years-old. APOE-ϵ4/ϵ4 carriers had earlier dementia onset (p<.001). The ACE insertion/deletion polymorphism was in Hardy-Weinberg equilibrium (p=.37) but was not associated with age at dementia onset, regardless of APOE-ϵ4 carrier status. The only results that survived corrections for false discovery rates were higher scores of dysphoria for APOE-ϵ4 carriers (n=122) who also carried ACE deletion/deletion (p=.031). No results survived corrections for false discovery rates for APOE-ϵ4 non-carriers (n=116).Conclusions: Though only the APOE-ϵ4/ϵ4 haplotype affected AD onset, effects of the ACE insertion/deletion polymorphism over behavioural features might differ according to APOE-ϵ4 carrier status in genetic associations.
Assuntos
Doença de Alzheimer , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Feminino , Genótipo , Humanos , Masculino , Polimorfismo GenéticoRESUMO
Background & objectives: Neurodegeneration affects blood pressure variations, while renal function and cerebral perfusion are impaired by vascular risk factors. This study was aimed to estimate variations of measures of cardiovascular risk in Alzheimer's dementia by pharmacogenetic analyses of the effects of angiotensin-converting enzyme (ACE) inhibitors and statins. Methods: Consecutive patients were prospectively followed to study variations of creatinine clearance and blood pressure for one year, estimated by correlating the effects of ACE inhibitors with the ACE Alu I/D polymorphism and genotypes or haplotypes of rs1800764 or rs4291, and the effects of statins with LDLR (low-density lipoprotein receptor) genotypes or haplotypes of rs11669576 (exon 8) or rs5930 (exon 10), or genotypes of rs2695121 (liver X receptor ß gene). Variations of the coronary heart disease (CHD) risk according to these cardiovascular measures were also explored. Results: All polymorphisms of the 193 patients were in Hardy-Weinberg equilibrium. Genetic determinants of cardiovascular effects affected the individual variability of the response to ACE inhibitors and statins. ACE inhibitors, but not statins, reduced blood pressure for all patients. ACE inhibitors protected carriers of alleles that supposedly decrease serum ACE levels (rs1800764-T, rs4291-A, Alu II) regarding creatinine clearance variations (P <0.005), but carriers of Alu DD (P <0.02), rs1800764-C (P <0.05), or rs4291-AT (P <0.04) showed better blood pressure lowering effects. The presence of rs2695121-T (P=0.007) or rs5930-A (P=0.039) was associated with systolic blood pressure lowering, whereas rs5930-AA was protective against decrease in creatinine clearance (P=0.019). Statins lowered creatinine clearance for carriers of rs2695121-CT (P=0.026). Interpretation & conclusions: Pharmacological response of blood pressure and creatinine clearance to ACE inhibitors and statins may be genetically mediated.
Assuntos
Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/genética , Testes Farmacogenômicos , Idoso , Alelos , Doença de Alzheimer/tratamento farmacológico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Pressão Sanguínea , Doenças Cardiovasculares/tratamento farmacológico , Doença das Coronárias/tratamento farmacológico , Doença das Coronárias/genética , Éxons , Feminino , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Metabolismo dos Lipídeos , Receptores X do Fígado/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptores de LDL/genética , Sistema Renina-Angiotensina/genética , Fatores de RiscoRESUMO
BACKGROUND: Illiteracy, high cerebrovascular risk and copies of APOE-ϵ4 are risk factors for Alzheimer's disease dementia (AD). We aimed to investigate the impacts of gender, education, coronary heart disease (CHD) risk and creatinine clearance variations, body mass index (BMI) and APOE haplotypes over the rates of cognitive and functional decline of AD in one year. METHODS: Consecutive outpatients with late-onset AD were assessed for gender, schooling, BMI and APOE haplotypes, variations in one year of creatinine clearance and Framingham projections of the 10-year absolute CHD risk, and prospective scores of the Mini-Mental State Examination (MMSE), the Clinical Dementia Rating Sum-of-Boxes (CDR-SOB), the Index of Independence in Activities of Daily Living (ADL) and Lawton's Scale for Instrumental Activities of Daily Living (IADL). RESULTS: For 191 patients, mean age at AD onset was 73.26 ± 6.4 years-old, earlier for APOE-ϵ4/ϵ4 carriers (p = 0.0039). For women, higher BMI led to improvements in CDR-SOB (ß = -0.091; p = 0.037) and MMSE (ß = 0.126; p = 0.017) scores, while increased creatinine clearance was associated with improvements in ADL (ß = 0.028; p = 0.012) and MMSE (ß = 0.043; p = 0.039) scores and higher schooling led to faster worsening of IADL (ß = -0.195; p = 0.022) scores. No variables impacted cognitive or functional decline for men, whereas copies of APOE-ϵ4 and the CHD risk had no significant effects whatsoever. CONCLUSIONS: Higher BMI and creatinine clearance are protective regarding cognitive and functional decline for women, whereas higher cognitive reserve may lead to faster decline in instrumental functionality. APOE haplotypes affected the age at AD onset, but not cognitive or functional decline.
Assuntos
Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Apolipoproteína E4/genética , Transtornos Cognitivos/etiologia , Caracteres Sexuais , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Doenças Cardiovasculares/complicações , Transtornos Cognitivos/genética , Creatinina/metabolismo , Feminino , Haplótipos , Humanos , Modelos Lineares , Masculino , Entrevista Psiquiátrica Padronizada , Pacientes Ambulatoriais , Fatores de RiscoRESUMO
Different from genetic alterations, the reversible nature of epigenetic modifications provides an interesting opportunity for the development of clinically relevant therapeutics in different tumors. In this study, we aimed to screen and validate candidate genes regulated by the epigenetic marker associated with transcriptional activation, histone acetylation, in gastric cancer (GC). We first compared gene expression profile of trichostatin A-treated and control GC cell lines using microarray assay. Among the 55 differentially expressed genes identified in this analysis, we chose the up-regulated genes BMP8B and BAMBI for further analyses, that included mRNA and histone acetylation quantification in paired GC and nontumor tissue samples. BMP8B expression was reduced in GC compared to nontumor samples (P < 0.01). In addition, reduced BMP8B expression was associated with poorly differentiated GC (P = 0.02). No differences or histopathological associations were identified concerning BAMBI expression. Furthermore, acetylated H3K9 and H4K16 levels at BMP8B were increased in GC compared to nontumors (P < 0.05). However, reduced levels of acetylated H3K9 and H4K16 were associated with poorly differentiated GC (P < 0.05). Reduced levels of acetylated H3K9 was also associated with diffuse-type histological GC (P < 0.05). Notably, reduced BMP8B mRNA and acetylated H4K16 levels were positively correlated in poorly differentiated GC (P < 0.05). Our study demonstrated that BMP8B seems to be a tumor suppressor gene regulated by H4K16 acetylation in poorly differentiated GC. Therefore, BMP8B may be a potential target for TSA-based therapies in this GC sample subset. J. Cell. Biochem. 118: 869-877, 2017. © 2016 Wiley Periodicals, Inc.
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Proteínas Morfogenéticas Ósseas/genética , Genes Supressores de Tumor , Histonas/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Acetilação , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adulto , Diferenciação Celular/genética , Linhagem Celular Tumoral , Epigênese Genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Ácidos Hidroxâmicos/farmacologia , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Neoplasias Gástricas/tratamento farmacológicoRESUMO
Gastric cancer is a complex, heterogeneous, and multistep disease. Over the past decades, several studies have aimed to determine the molecular factors that lead to gastric cancer development and progression. After completing the human genome sequencing, proteomic technologies have presented rapid progress. Differently from the relative static state of genome, the cell proteome is dynamic and changes in pathologic conditions. Proteomic approaches have been used to determine proteome profiles and identify differentially expressed proteins between groups of samples, such as neoplastic and nonneoplastic samples or between samples of different cancer subtypes or stages. Therefore, proteomic technologies are a useful tool toward improving the knowledge of gastric cancer molecular pathogenesis and the understanding of tumor heterogeneity. This review aimed to summarize the proteins or protein families that are frequently identified by using high-throughput screening methods and which thus may have a key role in gastric carcinogenesis. The increased knowledge of gastric carcinogenesis will clearly help in the development of new anticancer treatments. Although the studies are still in their infancy, the reviewed proteins may be useful for gastric cancer diagnosis, prognosis, and patient management.
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Transformação Celular Neoplásica , Proteínas de Neoplasias/análise , Proteômica/métodos , Neoplasias Gástricas/etiologia , Ensaios de Triagem em Larga Escala , Humanos , Proteínas de Neoplasias/classificação , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/fisiologia , Processamento de Proteína Pós-Traducional , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Eletroforese em Gel Diferencial BidimensionalRESUMO
Anterior shoulder instability is a common orthopedic problem. After a traumatic shoulder dislocation, patients present a plastic deformation of the capsule. The shoulder instability biology remains poorly understood. We evaluated the expression of genes that encode the cartilage oligomeric matrix protein (COMP), fibronectin 1 (FN1), tenascin C (TNC) and tenascin XB (TNXB) in the glenohumeral capsule of anterior shoulder instability patients and controls. Moreover, we investigated the associations between gene expression and clinical parameters. The gene expression was evaluated by quantitative reverse transcription-polymerase chain reaction in the antero-inferior (macroscopically injured region), antero-superior and posterior regions of the capsule of 29 patients with shoulder instability and 8 controls. COMP expression was reduced and FN1 and TNC expression was increased in the antero-inferior capsule region of cases compared to controls (p < 0.05). TNC expression was increased in the posterior capsule portion of shoulder instability patients (p = 0.022). COMP expression was reduced in the antero-inferior region compared to the posterior region of shoulder instability patients (p = 0.007). In the antero-inferior region, FN1 expression was increased in the capsule of patients with more than one year of symptoms (p = 0.003) and with recurrent dislocations (p = 0.004) compared with controls. FN1 and TNXB expression was correlated with the duration of symptoms in the posterior region (p < 0.05). Thus, COMP, FN1, TNC and TNXB expression was altered across the capsule of shoulder instability patients. Dislocation episodes modify FN1, TNC and TNXB expression in the injured tissue. COMP altered expression may be associated with capsule integrity after shoulder dislocation, particularly in the macroscopically injured portion.
Assuntos
Proteínas da Matriz Extracelular/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Cápsula Articular/patologia , Luxação do Ombro/genética , Articulação do Ombro/patologia , Adulto , Estudos de Casos e Controles , Colágeno/genética , Colágeno/metabolismo , Matriz Extracelular/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Feminino , Fibronectinas/genética , Fibronectinas/metabolismo , Humanos , Masculino , Cuidados Pré-Operatórios , Luxação do Ombro/cirurgia , Tenascina/genética , Tenascina/metabolismoRESUMO
BACKGROUND: Midlife hypertension followed by late life hypotension resulting from neurodegeneration increases amyloidogenesis and tauopathy. METHODS: Consecutive outpatients with late-onset Alzheimer's disease (AD) at various stages and their respective caregivers were assessed for score variations in 1 year of tests assessing caregiver burden, functionality and cognition according to blood pressure (BP) variations and APOE haplotypes, while also taking into account differential effects of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, ß-blockers, calcium channel blockers, diuretics, or no antihypertensive medication on score changes. The diagnosis and treatment of arterial hypertension followed the JNC 7 report. RESULTS: Variations in systolic BP (-11.76 ± 17.1 mm Hg), diastolic BP (-4.92 ± 10.3 mm Hg) and pulse pressure (-6.84 ± 12.6 mm Hg) were significant after 1 year (n = 191; x03C1; < 0.01). For APOE4+ carriers, rises in systolic or diastolic BP improved Clinical Dementia Rating Scale Sum of Boxes scores (x03C1; < 0.04), with marginally significant improvements in Mini-Mental State Examination scores resulting from risen systolic (x03C1; = 0.069) or diastolic BP (x03C1; = 0.079), and in basic independence only regarding risen diastolic BP (x03C1; = 0.055). APOE4- carriers resisted any functional or cognitive effects of BP variations. No differences were found regarding any antihypertensive class for variations in BP or any test scores, regardless of APOE haplotypes. CONCLUSIONS: Targeting mild BP elevations brings better functional and cognitive results for APOE4+ carriers with AD.
Assuntos
Doença de Alzheimer , Anti-Hipertensivos/uso terapêutico , Apolipoproteínas E/genética , Pressão Sanguínea , Hipertensão , Testes de Estado Mental e Demência , Idoso , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Cognição/efeitos dos fármacos , Feminino , Humanos , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Hipertensão/genética , Hipertensão/psicologia , Masculino , Pessoa de Meia-IdadeRESUMO
Gastric cancer is still the second leading cause of cancer-related death worldwide, even though its incidence and mortality have declined over the recent few decades. Epigenetic control using histone deacetylase inhibitors, such as trichostatin A (TSA), is a promising cancer therapy. This study aimed to assess the messenger RNA (mRNA) levels of three histone deacetylases (HDAC1, HDAC2, and HDAC3), two histone acetyltransferases (GCN5 and PCAF), and two possible targets of these histone modifiers (MYC and CDKN1A) in 50 matched pairs of gastric tumors and corresponding adjacent nontumors samples from patients with gastric adenocarcinoma, as well as their correlations and their possible associations with clinicopathological features. Additionally, we evaluated whether these genes are sensitive to TSA in gastric cancer cell lines. Our results demonstrated downregulation of HDAC1, PCAF, and CDKN1A in gastric tumors compared with adjacent nontumors (P < 0.05). On the other hand, upregulation of HDAC2, GCN5, and MYC was observed in gastric tumors compared with adjacent nontumors (P < 0.05). The mRNA level of MYC was correlated to HDAC3 and GCN5 (P < 0.05), whereas CDKN1A was correlated to HDAC1 and GCN5 (P < 0.05 and P < 0.01, respectively). In addition, the reduced expression of PCAF was associated with intestinal-type gastric cancer (P = 0.03) and TNM stages I/II (P = 0.01). The increased expression of GCN5 was associated with advanced stage gastric cancer (P = 0.02) and tumor invasion (P = 0.03). The gastric cell lines treated with TSA showed different patterns of histone deacetylase and acetyltransferase mRNA expression, downregulation of MYC, and upregulation of CDKN1A. Our findings suggest that alteration of histone modifier genes play an important role in gastric carcinogenesis, contributing to MYC and CDKN1A deregulation. In addition, all genes studied here are modulated by TSA, although this modulation appears to be dependent of the genetic background of the cell line.
Assuntos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/administração & dosagem , Ácidos Hidroxâmicos/administração & dosagem , RNA Mensageiro/biossíntese , Neoplasias Gástricas/enzimologia , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/biossíntese , Inibidor de Quinase Dependente de Ciclina p21/genética , Regulação Neoplásica da Expressão Gênica/genética , Genes myc/genética , Histona Desacetilase 1/biossíntese , Histona Desacetilase 1/genética , Histona Desacetilase 2/biossíntese , Histona Desacetilase 2/genética , Histona Desacetilases/biossíntese , Histona Desacetilases/genética , Humanos , RNA Mensageiro/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Ativação Transcricional/efeitos dos fármacos , Fatores de Transcrição de p300-CBP/biossíntese , Fatores de Transcrição de p300-CBP/genéticaRESUMO
BACKGROUND: The process of gastric carcinogenesis still remains to be elucidated. The identification of genes related to this process may help to reduce mortality rates through early diagnosis and the development of new anticancer therapies. Nucleophosmin 1 (NPM1) acts in ribosome biogenesis, centrosome duplication, maintenance of genomic stability, and embryonic development. Recently, NPM1 has been implicated in the tumorigenesis processes. Here, we evaluated NPM1 gene and protein expression in gastric tumors and in corresponding non-neoplastic gastric samples. METHODS: NPM1 protein expression was determined by Western blot in 17 pairs of gastric tumors and corresponding non-neoplastic gastric tissue. The protein immunoreactivity was observed in 12 tumor samples. mRNA expression was evaluated by reverse transcription quantitative polymerase chain reaction (RT-qPCR) in 22 pairs of gastric tumors and in matched non-neoplastic gastric tissue. RESULTS: NPM1 protein expression was significantly reduced in gastric cancer samples compared to matched non-neoplastic gastric samples (P = 0.019). The protein level of NPM1 was reduced at least 1.5-fold in 35% of tumors compared to paired non-neoplastic gastric tissue. However, NPM1 immunoreactivity was detected in neoplastic and non-neoplastic cells, including in intestinal metaplastic, gastritis and inflammatory cells. NPM1 was mainly expressed in nucleus and nucleolus subcellular compartments. The staining intensity and the percentage of immunoreactive cells varied among the studied cases. The NPM1 mRNA level was reduced at least 1.5-fold in 45.5% of samples and increased in 27.3% of samples. An inverse correlation between protein and mRNA expression was detected (r = -0.509, P = 0.037). Intestinal-type gastric cancer presented higher mRNA levels than diffuse-type (P = 0.026). However, reduced NPM1 protein expression was associated with intestinal-type gastric cancer compared to matched non-neoplastic gastric samples (P = 0.018). In addition, tumors from patients with known distant metastasis presented reduced NPM1 protein levels compared to tumors from patients without distant metastasis (P < 0.001). CONCLUSION: Although the expression of NPM1 is heterogeneous in gastric tumors, our results suggest that NPM1 down-regulation may have a role in gastric carcinogenesis and may help in the selection of anticancer treatment strategies.
Assuntos
Mucosa Gástrica/patologia , Regulação Neoplásica da Expressão Gênica , Proteínas Nucleares/genética , RNA Mensageiro/metabolismo , Neoplasias Gástricas/genética , Adulto , Nucléolo Celular/química , Núcleo Celular/química , Feminino , Mucosa Gástrica/metabolismo , Gastrite/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Metaplasia/genética , Metaplasia/metabolismo , Pessoa de Meia-Idade , Metástase Neoplásica , Proteínas Nucleares/análise , Proteínas Nucleares/metabolismo , Nucleofosmina , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologiaRESUMO
BACKGROUND: Helicobacter pylori (HP) and Epstein-Barr virus (EBV) have been associated with cancer development. We evaluated the prevalence of HP, HP CagA+ and EBV infection in gastric cancer (GC) samples from adults and in gastric tissues from patients who underwent upper endoscopy (UE). METHODS: Samples from UE and GC were collected to investigate the presence of HP infection and the HP virulence factor CagA by a urease test and PCR. The presence of EBV was detected by Eber-1 in situ hybridization. RESULTS: In UE, 85.5% of juvenile patients showed some degree of gastritis (45.3% of patients with mild gastritis and 54.7% with moderate/severe gastritis) and patients with mild gastritis were younger than patients with moderate/severe gastritis. Among adults, 48.7% presented mild gastritis and 51.3% moderate/severe gastritis. HP infection was detected in 0% of normal mucosa, 58.5% of juvenile gastritis patients, 69.2% of adult gastritis patients and 88% of GC patients. In these same groups, HP CagA+ was detected in 0%, 37.7%, 61.5% and 67.2% of tissue samples, respectively. In juvenile patients, HP infection was more common in those with gastritis than in normal samples (p = 0.004). The patients with either HP or HP CagA+ were older than patients without these pathogens (p < 0.05). In juvenile patients, HP infection was more frequent in cases of moderate/severe gastritis than in cases of mild gastritis (p = 0.026). Moreover, in patients with GC, HP infection was more frequent in males than in females (p = 0.023). GC patients with HP CagA+ were older than patients with HP CagA- (p = 0.027). HP CagA+ was more common in intestinal-type than diffuse-type GC (p = 0.012). HP CagA+ was also associated with lymph-node (p = 0.024) and distal (p = 0.005) metastasis. No association between EBV infection and HP infection or any clinicopathological variable was detected. CONCLUSIONS: Our results suggest that HP is involved in the pathophysiology of severe gastric lesions and in the development of GC, particularly when CagA+ is present. EBV was not the primary pathogenic factor in our samples.
Assuntos
Infecções por Vírus Epstein-Barr/diagnóstico , Gastrite/diagnóstico , Infecções por Helicobacter/diagnóstico , Helicobacter pylori , Neoplasias Gástricas/microbiologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antígenos de Bactérias/análise , Proteínas de Bactérias/análise , Criança , Pré-Escolar , Infecções por Vírus Epstein-Barr/patologia , Gastrite/patologia , Gastroscopia , Infecções por Helicobacter/patologia , Helicobacter pylori/isolamento & purificação , Herpesvirus Humano 4/isolamento & purificação , Humanos , Lactente , Pessoa de Meia-Idade , Estômago/química , Estômago/microbiologia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/virologia , Adulto JovemRESUMO
OBJECTIVE: In view of the mild effects of pharmacological treatment for dementia due to Alzheimer's disease (AD), the search for modifiable risk factors is an important challenge. Although risk factors for AD are widely recognized, elements that influence the time of onset of the dementia syndrome have not been comprehensively reported. We aimed to investigate which risk factors might be associated with the age at onset of AD in a sample of patients with low mean schooling from São Paulo, Brazil. METHODS: We included 210 consecutive patients with late-onset AD to investigate whether education, gender, nationality, urban living and sanitation, occupation, cognitive and physical inactivity, head trauma, depression, systemic infections, surgical interventions, cerebrovascular risk factors, family history of neurodegenerative diseases or cardiovascular diseases and apolipoprotein E gene (APOE) haplotypes might be related to the age at AD onset. RESULTS: Each copy of APOE-ε4 led to onset of AD almost 2 years earlier, while depression, smoking, higher body mass index and family history of cardiovascular diseases were also highly significant. Protective factors included non-Brazilian nationality, use of a pacemaker and waist circumference. Cerebrovascular risk factors had a mild combined effect for earlier onset of AD. CONCLUSION: APOE haplotypes, depression, nationality and cerebrovascular risk factors were the most important elements to influence the age at AD onset in this sample, whereas gender, education, occupation and physical activities had no isolated effects over the age at onset of this dementia syndrome.
Assuntos
Doença de Alzheimer/etiologia , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Apolipoproteína E4/genética , Brasil , Demência/etiologia , Escolaridade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Fatores de Risco , Fatores SocioeconômicosRESUMO
BACKGROUND: Pharmacological treatment has mild effects for patients with Alzheimer's disease dementia (AD); therefore, the search for modifiable risk factors is an important challenge. Though risk factors for AD are widely recognized, elements that influence the time of dementia onset have not been comprehensively reported. We aimed to investigate which risk factors might be related to the age of onset of AD in a sample of patients with highly variable educational levels, taking into account the Framingham risk scoring as the sole measure of vascular risk. SUBJECTS AND METHODS: We included 209 consecutive late-onset AD patients to find out which factors among educational levels, coronary heart disease risk estimated by way of Framingham risk scores, history of head trauma or depression, surgical procedures under general anesthesia, family history of neurodegenerative diseases, gender, marital status and APOE haplotypes might be related to the age of dementia onset in this sample of patients with low mean schooling. RESULTS: Mean age of AD onset was 73.38±6.5 years old, unaffected by schooling or family history of neurodegenerative diseases. Patients who were APOE-ε4 carriers, married, or with history of depression, had earlier onset of AD, particularly when they were women. Coronary heart disease risk was marginally significant for later onset of AD. CONCLUSIONS: APOE haplotypes, marital status and history of depression were the most important factors to influence the age of AD onset in this sample. While midlife cerebrovascular risk factors may increase incidence of AD, they may lead to later dementia onset when present in late life.
Assuntos
Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Apolipoproteína E4/genética , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Demência/epidemiologia , Demência/genética , Escolaridade , Feminino , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
BACKGROUND: Pharmacogenetic effects of statins on clinical changes in Alzheimer's disease (AD) could be mediated by epistatic interactions among relevant genetic variants involved in cholesterol metabolism. OBJECTIVE: To investigate associations of HMGCR (rs3846662), NR1H2 (rs2695121), or CETP (rs5882&rs708272) with cognitive and functional changes in AD, with stratification according to APOEÉ4 carrier status and lipid-lowering treatment with lipophilic statins. METHODS: Consecutive outpatients with late-onset AD were screened with cognitive tests, while caregivers scored functionality and global ratings, with prospective neurotranslational associations documented for one year. RESULTS: Considering nâ=â190:142 had hypercholesterolemia, 139 used lipophilic statins; minor allele frequencies were 0.379 (rs2695121-T:46.3% heterozygotes), 0.368 (rs5882-G:49.5% heterozygotes), and 0.371 (rs708272-A:53.2% heterozygotes), all in Hardy-Weinberg equilibrium. For APOEÉ4 carriers: rs5882-GG protected from cognitive decline; rs5882-AA caused faster cognitive decline; carriers of rs2695121-CC or rs5882-AA were more susceptible to harmful cognitive effects of lipophilic statins; carriers of rs5882-GG or rs708272-AG had functional benefits when using lipophilic statins. APOEÉ4 non-carriers resisted any cognitive or functional effects of lipophilic statins, while invariability of rs3846662 (all AA) prevented the assessment of HMGCR effects. When assessing CETP haplotypes only: rs5882-GG protected from cognitive and functional decline, regardless of lipophilic statin therapy; lipophilic statins usually caused cognitive and functional harm to carriers of rs5882-A and/or rs708272-A; lipophilic statins benefitted cognition and functionality of carriers of rs5882-G and/or rs708272-G. CONCLUSION: Reportedly protective variants of CETP and NR1H2 also slowed cognitive and functional decline particularly for APOEÉ4 carriers, and regardless of cholesterol variations, while therapy with lipophilic statins might affect carriers of specific genetic variants.
Assuntos
Doença de Alzheimer , Inibidores de Hidroximetilglutaril-CoA Redutases , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Cognição , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Testes Farmacogenômicos , Estudos ProspectivosRESUMO
Effects of statins over clinical changes in Alzheimer's disease (AD) are usually non-significant, but epistatic interactions between genetic variants involved in cholesterol metabolism could be important for such effects. We aimed to investigate whether LDLR single-nucleotide polymorphisms rs11669576 (LDLR8), rs5930 (LDLR10), and rs5925 (LDLR13) are associated with cognitive and functional changes in AD, while also considering APOE haplotypes and lipid-lowering treatment with lipophilic statins for stratification. Consecutive outpatients with late-onset AD were screened with cognitive tests, while caregivers scored functionality and caregiver burden, with prospective neurotranslational correlations documented for 1 year. For 179 patients, minor allele frequencies were 0.078 for rs11669576-A (14.5% heterozygotes), 0.346 for rs5930-A (42.5% heterozygotes), and 0.444 for rs5925-C (56.4% heterozygotes), all in Hardy-Weinberg equilibrium; 134 patients had hypercholesterolemia, and 133 used lipophilic statins. Carriers of rs11669576-G had faster cognitive decline, while functional decline was slower for carriers of rs11669576-A who used lipophilic statins. APOE-ε4 carriers who also carried rs5930-AA had improved caregiver burden, while carriers of haplotypes that included rs5930-AG had worse cognitive and functional outcomes, though carriers of the A allele of rs5930 had better cognitive and functional response to lipophilic statins. APOE-ε4 non-carriers who carried rs5925-TT had slower cognitive decline, while lipophilic statins protected carriers of the other genotypes. We preliminarily conclude that reportedly protective variants of LDLR and APOE against risk of AD also slowed cognitive decline, regardless of cholesterol variations, while therapy with lipophilic statins might benefit carriers of specific genetic variants.
Assuntos
Doença de Alzheimer/genética , Apolipoproteínas E/genética , Cognição , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/genética , Polimorfismo de Nucleotídeo Único , Receptores de LDL/genética , Idoso , Idoso de 80 Anos ou mais , Epistasia Genética , Feminino , Haplótipos , Heterozigoto , Humanos , Hipercolesterolemia/tratamento farmacológico , Masculino , Resultado do TratamentoRESUMO
BACKGROUND: While the angiotensin-converting enzyme degrades amyloid-ß, angiotensinconverting enzyme inhibitors (ACEis) may slow cognitive decline by way of cholinergic effects, by increasing brain substance P and boosting the activity of neprilysin, and by modulating glucose homeostasis and augmenting the secretion of adipokines to enhance insulin sensitivity in patients with Alzheimer's disease dementia (AD). We aimed to investigate whether ACE gene polymorphisms rs1800764 and rs4291 are associated with cognitive and functional change in patients with AD, while also taking APOE haplotypes and anti-hypertensive treatment with ACEis into account for stratification. METHODS: Consecutive late-onset AD patients were screened with cognitive tests, while their caregivers were queried for functional and caregiver burden scores. Prospective pharmacogenetic correlations were estimated for one year, considering APOE and ACE genotypes and haplotypes, and treatment with ACEis. RESULTS: For 193 patients, minor allele frequencies were 0.497 for rs1800764 - C (44.6% heterozygotes) and 0.345 for rs4291 - T (38.9% heterozygotes), both in Hardy-Weinberg equilibrium. Almost 94% of all patients used cholinesterase inhibitors, while 155 (80.3%) had arterial hypertension, and 124 used ACEis. No functional impacts were found regarding any genotypes or pharmacological treatment. Either for carriers of ACE haplotypes that included rs1800764 - T and rs4291 - A, or for APOE4- carriers of rs1800764 - T or rs4291 - T, ACEis slowed cognitive decline independently of blood pressure variations. APOE4+ carriers were not responsive to treatment with ACEis. CONCLUSION: ACEis may slow cognitive decline for patients with AD, more remarkably for APOE4- carriers of specific ACE genotypes.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Peptidil Dipeptidase A/genética , Farmacogenética , Polimorfismo de Nucleotídeo Único/genética , Idoso , Idoso de 80 Anos ou mais , Apolipoproteína E4/genética , Feminino , Seguimentos , Frequência do Gene , Genótipo , Humanos , Masculino , Avaliação de Resultados em Cuidados de Saúde , Estudos RetrospectivosRESUMO
Lifetime risk factors for cognitive and functional decline in Alzheimer's disease (AD) are not fully understood, and were prospectively evaluated in patients with low mean schooling from São Paulo, Brazil. Consecutive outpatients with late-onset AD were assessed for APOE haplotypes and the following potential baseline predictors: gender, schooling, age at dementia onset, lifetime urban living and sanitary conditions, occupational complexity, cognitive and physical activities, cerebrovascular risk factors (obesity, lifetime alcohol use and smoking, length of arterial hypertension, diabetes mellitus, and a dyslipidemic profile), use of a pacemaker, creatinine clearance, body mass index, waist circumference, head traumas with unconsciousness, treated systemic bacterial infections, amount of surgical procedures under general anesthesia, and family history of AD. Participants were followed from October 2010 to May 2017 for baseline risk factor associations with time since dementia onset for Clinical Dementia Rating and Mini-Mental State Examination score changes. For 227 patients (154 women, 119 APOE ε 4 carriers), later AD onset (mean 73.60±6.4 years-old, earlier for APOE ε 4/ε 4 carriers, p < 0.001) was the only variable hastening all endpoints, baseline creatinine clearance and lifetime alcohol use were hazardous for earlier cognitive and functional endpoints, women had earlier cognitive endpoints only, and schooling had a cumulative protective effect over later cognitive endpoints, particularly for carriers of APOE ε 4. Exclusively for carriers of APOE ε 4, head traumas with unconsciousness were hazardous for earlier cognitive endpoints, while lifetime sanitary conditions were protective regarding later cognitive endpoints. Functional and cognitive outcomes in AD represent probable interactions between effects of brain reserve and cerebral perfusion over neurodegeneration.
Assuntos
Doença de Alzheimer/complicações , Transtornos Cognitivos/etiologia , Fatores de Risco , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Brasil/epidemiologia , Transtornos Cognitivos/epidemiologia , Escolaridade , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Avaliação de Resultados em Cuidados de Saúde , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de TempoRESUMO
Hypercholesterolemia and statin use have been unevenly associated with clinical change in Alzheimer's disease dementia. In this longitudinal study, 192 consecutive outpatients with late-onset Alzheimer's disease dementia were stratified according to APOE haplotypes, and followed for one year to investigate associations of lipid profile variations and lipophilic statin therapy with changes in cognition, caregiver burden, basic and instrumental functionality. Overall, 102 patients (53.1%) carried APOE4+ haplotypes and 90 (46.9%) carried APOE4- haplotypes; 189 patients (98.4%) used either a cholinesterase inhibitor, or Memantine, or both; 144 patients had dyslipidemias and 143 of them received statin therapy. Total cholesterol, LDL-cholesterol, Mini-Mental State Examination scores, and functional independence scores were significantly lower at the end of the follow-up, while Clinical Dementia Rating sum-of-boxes scores were higher. Exclusively for APOE4- carriers, rising LDL-cholesterol levels were associated with a trend toward improvements in the Index of Independence in Activities of Daily Living (ß=0.010; ρ=0.16), whereas rising HDL-cholesterol levels were associated with lowered scores (ß=-0.051; ρ=0.04). Lipophilic statin therapy had non-significant protective effects over Clinical Dementia Rating sum-of-boxes score variations only for APOE4- carriers. APOE4- haplotypes might enhance lipid availability to protect neuronal membranes, thus overcoming their supposed dysfunction in cholesterol metabolism, while APOE4+ carriers have inefficient neural repair mechanisms. In conclusion, APOE haplotypes seem to influence the protective effects of lipid profile variations for patients with Alzheimer's disease dementia, but current evidence is insufficient to propose lipid-lowering drugs as specific anti-dementia therapy.
Assuntos
Doença de Alzheimer/metabolismo , Metabolismo dos Lipídeos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/tratamento farmacológico , Apolipoproteína E4/metabolismo , Inibidores da Colinesterase/farmacologia , Cognição/efeitos dos fármacos , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Estudos Longitudinais , Masculino , Memantina/farmacologiaRESUMO
CDKN1A is a tumor suppressor gene involved in gastric carcinogenesis and is a potential target for histone deacetylase inhibitor-based therapies. Upregulation of CDKN1A is generally observed in several cell lines after histone deacetylase inhibitor treatment; however, little is known about the histone acetylation status associated with this gene in clinical samples, including gastric tumor tissue samples. Therefore, our goal was to quantify the H3K9 and H4K16 acetylation levels associated with three CDKN1A regions in 21 matched pairs of gastric adenocarcinoma and corresponding adjacent non-tumor samples by chromatin immunoprecipitation and to correlate these data with the gene expression. Our results demonstrated that the -402, -20, and +182 CDKN1A regions showed a significantly increased acetylation level in at least one of the histones evaluated (p < 0.05, for all comparisons), and these levels were positively correlated in gastric tumors. However, an inverse correlation was detected between both H3K9 and H4K16 acetylation at the -402 CDKN1A region and mRNA levels in gastric tumors (r = -0.51, p = 0.02; r = -0.60, p < 0.01, respectively). Furthermore, increased H4K16 acetylation at the -20 CDKN1A region was associated with gastric tumors of patients without lymph node metastasis (p = 0.04). These results highlight the complexity of these processes in gastric adenocarcinoma and contribute to a better understanding of CDKN1A regulation in carcinogenesis.