RESUMEN
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.
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Enfermedad de Alzheimer , Humanos , Femenino , Masculino , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/complicaciones , Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Angiotensinas/genética , Angiotensinas/uso terapéutico , Farmacogenética , Alelos , Estudios Prospectivos , Apolipoproteínas E/genética , Apolipoproteínas E/uso terapéuticoRESUMEN
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.
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Enfermedad de Alzheimer , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Cognición , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Pruebas de Farmacogenómica , Estudios ProspectivosRESUMEN
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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Enfermedad de Alzheimer , Actividades Cotidianas , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Anticonvulsivantes/uso terapéutico , Apolipoproteína E4/genética , Inhibidores de la Colinesterasa/uso terapéutico , Humanos , Memantina/uso terapéutico , Pruebas Neuropsicológicas , Psicotrópicos/uso terapéuticoRESUMEN
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.
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Enfermedad de Alzheimer , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Apolipoproteínas E/genética , Femenino , Genotipo , Humanos , Masculino , Polimorfismo GenéticoRESUMEN
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.
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Enfermedad de Alzheimer/genética , Apolipoproteínas E/genética , Cognición , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipercolesterolemia/genética , Polimorfismo de Nucleótido Simple , Receptores de LDL/genética , Anciano , Anciano de 80 o más Años , Epistasis Genética , Femenino , Haplotipos , Heterocigoto , Humanos , Hipercolesterolemia/tratamiento farmacológico , Masculino , Resultado del TratamientoRESUMEN
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.
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Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/genética , Enfermedades Cardiovasculares/complicaciones , Enfermedades Cardiovasculares/genética , Pruebas de Farmacogenómica , Anciano , Alelos , Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Presión Sanguínea , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedad Coronaria/tratamiento farmacológico , Enfermedad Coronaria/genética , Exones , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Haplotipos , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Metabolismo de los Lípidos , Receptores X del Hígado/genética , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Receptores de LDL/genética , Sistema Renina-Angiotensina/genética , Factores de RiesgoRESUMEN
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.
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Enfermedad de Alzheimer/complicaciones , Trastornos del Conocimiento/etiología , Factores de Riesgo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/genética , Apolipoproteínas E/genética , Brasil/epidemiología , Trastornos del Conocimiento/epidemiología , Escolaridad , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas , Evaluación de Resultado en la Atención de Salud , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de TiempoRESUMEN
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.
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Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Peptidil-Dipeptidasa A/genética , Farmacogenética , Polimorfismo de Nucleótido Simple/genética , Anciano , Anciano de 80 o más Años , Apolipoproteína E4/genética , Femenino , Estudios de Seguimiento , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Evaluación de Resultado en la Atención de Salud , Estudios RetrospectivosRESUMEN
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.
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Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/genética , Apolipoproteína E4/genética , Trastornos del Conocimiento/etiología , Caracteres Sexuales , Anciano , Anciano de 80 o más Años , Índice de Masa Corporal , Enfermedades Cardiovasculares/complicaciones , Trastornos del Conocimiento/genética , Creatinina/metabolismo , Femenino , Haplotipos , Humanos , Modelos Lineales , Masculino , Escala del Estado Mental , Pacientes Ambulatorios , Factores de RiesgoRESUMEN
BACKGROUND: Neoadjuvant chemotherapy is a standard treatment for stage II and III breast cancer. The identification of biomarkers that may help in the prediction of response to neoadjuvant therapies is necessary for a more precise definition of the best drug or drug combination to induce a better response. MATERIAL AND METHODS: We assessed the role of Ki67, hormone receptors expression, HER2, MYC genes and their protein status, and KRAS codon 12 mutations as predictor factors of pathologic response to anthracycline-cyclophosphamide (AC) followed by taxane docetaxel (T) neoadjuvant chemotherapy (AC+T regimen) in 51 patients with invasive ductal breast cancer. RESULTS: After neoadjuvant chemotherapy, 82.4% of patients showed pathologic partial response, with only 9.8% showing pathologic complete response. In multivariate analysis, MYC immunoreactivity and high MYC gain defined as MYC/nucleus ≥ 5 were significant predictor factors for pathologic partial response. Using the receiver operating characteristic curve analysis, the ratio of 2.5 MYC/CEP8 (sensitivity of 80% and specificity of 89.1%) or 7 MYC/nuclei copies (sensitivity of 80% and specificity of 73.9%) as the best cutoff in predicting a pathologic complete response was identified. Thus, MYC may have a role in chemosensitivity to AC and/or docetaxel drugs. Additionally, MYC amplification may be a predictor factor of pathologic response to the AC+T regimen in patients with breast cancer. Moreover, patients with an increased number of MYC copies showed pathologic complete response to this neoadjuvant treatment more frequently. CONCLUSION: The analysis of MYC amplification may help in the identification of patients that may have a better response to AC+T treatment.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias de la Mama/patología , Amplificación de Genes , Terapia Neoadyuvante , Proteínas Proto-Oncogénicas c-myc/genética , Adulto , Antraciclinas/administración & dosificación , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Estudios de Cohortes , Ciclofosfamida/administración & dosificación , Docetaxel , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Invasividad Neoplásica , Pronóstico , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Tasa de Supervivencia , Taxoides/administración & dosificaciónRESUMEN
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 Óseas/genética , Genes Supresores de Tumor , Histonas/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Acetilación , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adulto , Diferenciación Celular/genética , Línea Celular Tumoral , Epigénesis Genética , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ácidos Hidroxámicos/farmacología , Masculino , Persona de Mediana Edad , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Neoplásico/genética , ARN Neoplásico/metabolismo , Neoplasias Gástricas/tratamiento farmacológicoRESUMEN
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.
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Adenocarcinoma/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Regulación Neoplásica de la Expresión Génica , Histonas/genética , Neoplasias Gástricas/genética , Acetilación , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adulto , Inmunoprecipitación de Cromatina , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Epigénesis Genética , Femenino , Histonas/metabolismo , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Regiones Promotoras Genéticas , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transducción de Señal , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologíaRESUMEN
We previously observed reduced YWHAE (14-3-3ε) protein expression in a small set of gastric cancer samples. YWHAE may act as a negative regulator of the cyclin CDC25B, which is a transcriptional target of MYC oncogene. The understanding of YWHAE role and its targets is important for the better knowledge of gastric carcinogenesis. Thus, we aimed to evaluate the relationship among YWHAE, CDC25B, and MYC in vitro and in vivo. For this, we analyzed the YWHAE, CDC25B, and MYC expression in YWHA-silenced, CDC25B-silenced, and MYC-silenced gastric cancer cell lines, as well as in gastric cancer and non-neoplastic gastric samples. In gastric cancer cell lines, YWHAE was able to inhibit the cell proliferation, invasion and migration through the reduction of MYC and CDC25B expression. Conversely, MYC induced the cell proliferation, invasion and migration through the induction of CDC25B and the reduction of YWHAE. Most of the tumors presented reduced YWHAE and increased CDC25B expression, which seems to be important for tumor development. Increased MYC expression was a common finding in gastric cancer and has a role in poor prognosis. In the tumor initiation, the opposite role of YWHAE and CDC25B in gastric carcinogenesis seems to be independent of MYC expression. However, the inversely correlation between YWHAE and MYC expression seems to be important for gastric cancer cells invasion and migration. The interaction between YWHAE and MYC and the activation of the pathways related to this interaction play a role in the metastasis process.
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Proteínas 14-3-3/metabolismo , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Proteínas Proto-Oncogénicas c-myc/metabolismo , Neoplasias Gástricas/enzimología , Fosfatasas cdc25/metabolismo , Proteínas 14-3-3/genética , Adulto , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Proteínas Proto-Oncogénicas c-myc/genética , Interferencia de ARN , Transducción de Señal/efectos de los fármacos , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Factores de Tiempo , Transfección , Regulación hacia Arriba , Fosfatasas cdc25/genéticaRESUMEN
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.
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Enfermedad de Alzheimer , Antihipertensivos/uso terapéutico , Apolipoproteínas E/genética , Presión Sanguínea , Hipertensión , Pruebas de Estado Mental y Demencia , Anciano , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/fisiopatología , Cognición/efectos de los fármacos , Femenino , Humanos , Hipertensión/diagnóstico , Hipertensión/tratamiento farmacológico , Hipertensión/genética , Hipertensión/psicología , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVES: We evaluated mRNA expression levels of genes that encode TGF-ß1; the TGF-ß1 receptor; the collagen-modifying enzymes LOX, PLOD1, and PLOD2; and the extracellular matrix proteins COMP, FN1, TNC and TNXB in synovial/capsule specimens from patients with idiopathic adhesive capsulitis. Possible associations between the measured mRNA levels and clinical parameters were also investigated. METHODS: We obtained glenohumeral joint synovium/capsule specimens from 9 patients with idiopathic adhesive capsulitis who had not shown improvement in symptoms after 5 months of physiotherapy. Adhesive capsulitis was confirmed in all patients by magnetic resonance imaging. We also obtained specimens from 8 control patients who had underwent surgery for acute acromioclavicular joint dislocation and who had radiological indication of glenohumeral capsule alteration based on arthroscopic evaluation. mRNA expression in the synovium/capsule specimens was analyzed by quantitative reverse transcription PCR. The B2M and HPRT1 genes were used as references to normalize target gene expression in the shoulder tissue samples. RESULTS: The synovium/capsule samples from the patients with adhesive capsulitis had significantly higher TNC and FN1 expression than those from the controls. Additionally, symptom duration directly correlated with expression of TGFß1 receptor I. CONCLUSION: Elevated levels of TNC and FN1 expression may be a marker of capsule injury. Upregulation of TGFß1 receptor I seems to be dependent on symptom duration; therefore, TGFß signaling may be involved in adhesive capsulitis. As such, TNC, FN1 and TGFß1 receptor I may also play roles in adhesive capsulitis by contributing to capsule inflammation and fibrosis.
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Bursitis/metabolismo , Fibronectinas/metabolismo , Articulación del Hombro/metabolismo , Membrana Sinovial/metabolismo , Tenascina/metabolismo , Factor de Crecimiento Transformador beta1/genética , Articulación Acromioclavicular/lesiones , Articulación Acromioclavicular/metabolismo , Adolescente , Adulto , Anciano , Bursitis/genética , Estudios de Casos y Controles , Proteínas de la Matriz Extracelular/metabolismo , Femenino , Expresión Génica , Humanos , Luxaciones Articulares/metabolismo , Masculino , Persona de Mediana Edad , Proyectos Piloto , ARN Mensajero/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Adulto JovenRESUMEN
OBJECTIVES: We evaluated mRNA expression levels of genes that encode TGF-β1; the TGF-β1 receptor; the collagen-modifying enzymes LOX, PLOD1, and PLOD2; and the extracellular matrix proteins COMP, FN1, TNC and TNXB in synovial/capsule specimens from patients with idiopathic adhesive capsulitis. Possible associations between the measured mRNA levels and clinical parameters were also investigated. METHODS: We obtained glenohumeral joint synovium/capsule specimens from 9 patients with idiopathic adhesive capsulitis who had not shown improvement in symptoms after 5 months of physiotherapy. Adhesive capsulitis was confirmed in all patients by magnetic resonance imaging. We also obtained specimens from 8 control patients who had underwent surgery for acute acromioclavicular joint dislocation and who had radiological indication of glenohumeral capsule alteration based on arthroscopic evaluation. mRNA expression in the synovium/capsule specimens was analyzed by quantitative reverse transcription PCR. The B2M and HPRT1 genes were used as references to normalize target gene expression in the shoulder tissue samples. RESULTS: The synovium/capsule samples from the patients with adhesive capsulitis had significantly higher TNC and FN1 expression than those from the controls. Additionally, symptom duration directly correlated with expression of TGFβ1 receptor I. CONCLUSION: Elevated levels of TNC and FN1 expression may be a marker of capsule injury. Upregulation of TGFβ1 receptor I seems to be dependent on symptom duration; therefore, TGFβ signaling may be involved in adhesive capsulitis. As such, TNC, FN1 and TGFβ1 receptor I may also play roles in adhesive capsulitis by contributing to capsule inflammation and fibrosis.
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Humanos , Masculino , Femenino , Adolescente , Adulto , Persona de Mediana Edad , Anciano , Adulto Joven , Bursitis/metabolismo , Fibronectinas/metabolismo , Articulación del Hombro/metabolismo , Membrana Sinovial/metabolismo , Tenascina/metabolismo , Factor de Crecimiento Transformador beta1/genética , Articulación Acromioclavicular/lesiones , Articulación Acromioclavicular/metabolismo , Bursitis/genética , Estudios de Casos y Controles , Proteínas de la Matriz Extracelular/metabolismo , Expresión Génica , Luxaciones Articulares/metabolismo , Proyectos Piloto , ARN Mensajero/metabolismo , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
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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Transformación Celular Neoplásica , Proteínas de Neoplasias/análisis , Proteómica/métodos , Neoplasias Gástricas/etiología , Ensayos Analíticos de Alto Rendimiento , Humanos , Proteínas de Neoplasias/clasificación , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/fisiología , Procesamiento Proteico-Postraduccional , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Electroforesis Bidimensional Diferencial en GelRESUMEN
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.
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Proteínas de la Matriz Extracelular/genética , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Cápsula Articular/patología , Luxación del Hombro/genética , Articulación del Hombro/patología , Adulto , Estudios de Casos y Controles , Colágeno/genética , Colágeno/metabolismo , Matriz Extracelular/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Femenino , Fibronectinas/genética , Fibronectinas/metabolismo , Humanos , Masculino , Cuidados Preoperatorios , Luxación del Hombro/cirugía , Tenascina/genética , Tenascina/metabolismoRESUMEN
The molecular alterations involved in the capsule deformation presented in shoulder instability patients are poorly understood. Increased TGFß1 acts as a signal for production of matrix macromolecules by fibrogenic cells at joint injury sites. TGFß1, through its receptor TGFßR1, regulates genes involved in collagen cross-linking, such as LOX, PLOD1, and PLOD2. We evaluated TGFß1, TGFßR1, LOX, PLOD1, and PLOD2 gene expression in the antero-inferior (macroscopically injured region), antero-superior and posterior regions of the glenohumeral capsule of 29 shoulder instability patients and eight controls. We observed that PLOD2 expression was increased in the anterior-inferior capsule region of the patients compared to controls. LOX expression tended to be increased in the posterior portion of patients. Patients with recurrent shoulder dislocation presented upregulation of TGFßR1 in the antero-inferior capsule portion and of PLOD2 in the posterior region. Conversely, LOX was increased in the posterior portion of the capsule of patients with a single shoulder dislocation episode. In the antero-inferior, LOX expression was inversely correlated and TGFßR1 was directly correlated with the duration of symptoms. In the posterior region, PLOD2, TGFß1, and TGFßR1 were directly correlated with the duration of symptoms. In conclusion, PLOD2 expression was increased in the macroscopically injured region of the capsule of patients. Upregulation of TGFß1, TGFßR1, and PLOD2 seems to be related with the maintenance of disease symptoms, especially in the posterior region. LOX upregulation seems to occur only in the initial phase of the affection. Therefore, TGFß1, TGFßR1, LOX, and PLOD2 may play a role in shoulder instability.
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Colágeno/metabolismo , Luxación del Hombro/metabolismo , Articulación del Hombro/metabolismo , Adulto , Estudios de Casos y Controles , Femenino , Expresión Génica , Humanos , Masculino , Adulto JovenRESUMEN
Midlife cerebrovascular risk, low cognitive reserve and APOE4+ haplotypes are risk factors for Alzheimer's disease dementia (AD). We prospectively searched for factors that might be associated with yearly changes in caregiver burden, cognition, basic and instrumental functionality in 193 consecutive outpatients with late-onset AD, namely gender, APOE haplotypes, schooling, age at AD onset, marital status, depression, cerebrovascular risk factors, serum TSH levels, cognitive and physical activities, and treatment with cholinesterase inhibitors or anti-psychotics, while also investigating associations between APOE haplotypes and patient participation in cognitive or physical activities. Higher education led to greater declines in instrumental functionality, whereas increases in body mass index were associated with rises in basic functionality and cognitive test scores. Established cerebrovascular risk factors had no independent effects over cognitive or functional change, but their combinations led to cognitive improvement, possibly related to enhanced cerebral perfusion in late life. Cholinesterase inhibitors improved caregiver burden. Enhanced instrumental functionality and steeper cognitive decline by the use of anti-psychotics might be attributed to improved behavioural symptoms and neuropsychiatric side effects, respectively. Each copy of APOE-ε4 (ß=-0.102) led to cumulative decreased participation in physical activities (ρ=0.015). These results might impact public health policies and the interpretation of clinical trials for AD.