RESUMO
Chronic enteropathy associated with the SLCO2A1 gene (CEAS) is a complex gastroenterological condition characterized by multiple ulcers in the small intestine with chronic bleeding and protein loss. This review explores the potential mechanisms underlying the pathogenesis of CEAS, focusing on the role of SLCO2A1-encoded prostaglandin transporter OATP2A1 and its impact on prostaglandin E2 (PGE2) levels. Studies have suggested that elevated PGE2 levels contribute to mucosal damage, inflammation, and disruption of the intestinal barrier. The effects of PGE2 on macrophage activation and Maxi-Cl channel functionality, as well as its interaction with nonsteroidal anti-inflammatory drugs play crucial roles in the progression of CEAS. Understanding the balance between its protective and pro-inflammatory effects and the complex interactions within the gastrointestinal tract can shed light on potential therapeutic targets for CEAS and guide the development of novel, targeted therapies.
Assuntos
Dinoprostona , Mucosa Intestinal , Transportadores de Ânions Orgânicos , Humanos , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , Mucosa Intestinal/patologia , Mucosa Intestinal/metabolismo , Doença Crônica , Dinoprostona/metabolismo , Intestino Delgado/patologia , Intestino Delgado/metabolismo , Anti-Inflamatórios não Esteroides/uso terapêutico , Enteropatias/genética , Enteropatias/patologia , Animais , Hemorragia Gastrointestinal/genética , Hemorragia Gastrointestinal/etiologia , Úlcera/genética , Úlcera/patologiaRESUMO
The objective of this study was to discover clinical and pharmacogenetic factors associated with bevacizumab-related gastrointestinal hemorrhage in Cancer and Leukemia Group B (Alliance) 90401. Patients with metastatic castration-resistant prostate cancer received docetaxel and prednisone ± bevacizumab. Patients were genotyped using Illumina HumanHap610-Quad and assessed using cause-specific risk for association between single nucleotide polymorphisms (SNPs) and gastrointestinal hemorrhage. In 1008 patients, grade 2 or higher gastrointestinal hemorrhage occurred in 9.5% and 3.8% of bevacizumab (n = 503) and placebo (n = 505) treated patients, respectively. Bevacizumab (P < 0.001) and age (P = 0.002) were associated with gastrointestinal hemorrhage. In 616 genetically estimated Europeans (n = 314 bevacizumab and n = 302 placebo treated patients), grade 2 or higher gastrointestinal hemorrhage occurred in 9.6% and 2.0% of patients, respectively. One SNP (rs1478947; HR 6.26; 95% CI 3.19-12.28; P = 9.40 × 10-8) surpassed Bonferroni-corrected significance. Grade 2 or higher gastrointestinal hemorrhage rate was 33.3% and 6.2% in bevacizumab-treated patients with the AA/AG and GG genotypes, versus 2.9% and 1.9% in the placebo arm, respectively. Prospective validation of these findings and functional analyses are needed to better understand the genetic contribution to treatment-related gastrointestinal hemorrhage.
Assuntos
Farmacogenética , Neoplasias da Próstata , Masculino , Humanos , Bevacizumab/efeitos adversos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Hemorragia Gastrointestinal/induzido quimicamente , Hemorragia Gastrointestinal/genética , Fatores de RiscoRESUMO
The gastric epithelium is often exposed to injurious elements and failure of appropriate healing predisposes to ulcers, hemorrhage, and ultimately cancer. We examined the gastric function of CD36, a protein linked to disease and homeostasis. We used the tamoxifen model of gastric injury in mice null for Cd36 (Cd36-/-), with Cd36 deletion in parietal cells (PC-Cd36-/-) or in endothelial cells (EC-Cd36-/-). CD36 expresses on corpus ECs, on PC basolateral membranes, and in gastrin and ghrelin cells. Stomachs of Cd36-/- mice have altered gland organization and secretion, more fibronectin, and inflammation. Tissue respiration and mitochondrial efficiency are reduced. Phospholipids increased and triglycerides decreased. Mucosal repair after injury is impaired in Cd36-/- and EC-Cd36-/-, not in PC-Cd36-/- mice, and is due to defect of progenitor differentiation to PCs, not of progenitor proliferation or mature PC dysfunction. Relevance to humans is explored in the Vanderbilt BioVu using PrediXcan that links genetically-determined gene expression to clinical phenotypes, which associates low CD36 mRNA with gastritis, gastric ulcer, and gastro-intestinal hemorrhage. A CD36 variant predicted to disrupt an enhancer site associates (p < 10-17) to death from gastro-intestinal hemorrhage in the UK Biobank. The findings support role of CD36 in gastric tissue repair, and its deletion associated with chronic diseases that can predispose to malignancy.
Assuntos
Antígenos CD36/genética , Mucosa Gástrica/metabolismo , Gastrite/genética , Hemorragia Gastrointestinal/genética , Úlcera Gástrica/genética , Animais , Antígenos CD36/metabolismo , Células Endoteliais/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
OBJECTIVE: We have previously revealed the clinical factors and genetic polymorphisms associated with gastrointestinal mucosal injury and bleeding, induced by low-dose aspirin (LDA). After performing genome-wide analysis of single nucleotide polymorphisms (SNPs) using the Drug Metabolizing Enzymes and Transporters (DMET) system among drug metabolism and transporter genes, certain SNPs were found to increase the risk for LDA-induced small bowel bleeding. The aim of this study was to identify the SNPs involved in LDA-induced small bowel bleeding. SUBJECTS AND METHODS: Subjects were patients taking LDA, with small bowel bleeding diagnosed using capsule endoscopy. We investigated the clinical characteristics and the previously identified SNPs, that were examined by the DNA direct sequence method. RESULTS: 56 patients with bleeding and 410 controls taking LDA were enrolled. The risk factors associated with small bowel bleeding included smoking, cerebrovascular diseases, chronic renal failure, non-steroidal anti-inflammatory drug (NSAID) or anticoagulants combination, and two SNPs (CYP4F11 20043G>A (D446N) rs1060463, GSTP1 313A>G rs1695). After propensity score matching, GSTP1 rs1695 was significantly associated with small bowel bleeding. CONCLUSION: The GSTP1 SNP may be a predictive marker for small bowel bleeding among patients taking LDA.
Assuntos
Aspirina/efeitos adversos , Família 4 do Citocromo P450/genética , Hemorragia Gastrointestinal/genética , Glutationa S-Transferase pi/genética , Enteropatias/genética , Variantes Farmacogenômicos/genética , Idoso , Aspirina/administração & dosagem , Endoscopia por Cápsula , Feminino , Hemorragia Gastrointestinal/induzido quimicamente , Estudo de Associação Genômica Ampla , Humanos , Enteropatias/induzido quimicamente , Intestino Delgado/patologia , Masculino , Polimorfismo de Nucleotídeo Único/genética , Pontuação de Propensão , Fatores de RiscoRESUMO
Non-variceal upper gastrointestinal bleeding (non-variceal UGIB) is a frequent and severe adverse drug reaction. Idiosyncratic responses due to genetic susceptibility to non-variceal UGIB has been suggested. A systematic review was conducted to assess the association between genetic polymorphisms and non-variceal UGIB. Twenty-one publications and 7134 participants were included. Thirteen studies evaluated genetic polymorphism in patients exposed to non-steroidal anti-inflammatory drugs, low-dose aspirin, and warfarin. Eight studies present at least one methodological problem. Only six studies clearly defined that the outcome evaluated was non-variceal UGIB. Genetic polymorphisms involved in platelet activation and aggregation, angiogenesis, inflammatory process, and drug metabolism were associated with risk of non-variceal UGIB (NOS3, COX-1; COX-2; PLA2G7; GP1BA; GRS; IL1RN; F13A1; CDKN2B-AS1; DPP6; TBXA2R; TNF-alpha; VKORC1; CYP2C9; and AGT). Further well-designed studies are needed (e.g., clear restriction to non-variceal UGIB; proper selection of participants; and adjustment of confounding factors) to provide strong evidence for pharmacogenetic and personalized medicine.
Assuntos
Hemorragia Gastrointestinal/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Hemorragia/genética , Hemorragia Gastrointestinal/patologia , Trato Gastrointestinal/patologia , Hemorragia/patologia , Humanos , Polimorfismo Genético/genética , Fatores de RiscoRESUMO
OBJECTIVE: To describe the clinical features, therapeutic interventions, and patient outcomes of gastrointestinal (GI) hemorrhage in individuals with a telomere biology disorder, including dyskeratosis congenita, Hoyeraal-Hreidarsson syndrome, Revesz syndrome, and Coats plus. STUDY DESIGN: Clinical Care Consortium for Telomere Associated Ailments members were invited to contribute data on individuals with telomere biology disorders at their institutions who experienced GI bleeding. Patient demographic, laboratory, imaging, procedural, and treatment information and outcomes were extracted from the medical record. RESULTS: Sixteen patients who experienced GI hemorrhage were identified at 11 centers. Among 14 patients who underwent genetic testing, 8 had mutations in TINF2, 4 had mutations in CTC1 or STN1, and 1 patient each had a mutation in TERC and RTEL1. Ten patients had a history of hematopoietic cell transplantation. The patients with Coats plus and those without Coats plus had similar clinical features and courses. Angiodysplasia of the stomach and/or small bowel was described in 8 of the 12 patients who underwent endoscopy; only 4 had esophageal varices. Various medical interventions were trialed. No single intervention was uniformly associated with cessation of bleeding, although 1 patient had a sustained response to treatment with bevacizumab. Recurrence was common, and the overall long-term outcome for affected patients was poor. CONCLUSIONS: GI bleeding in patients with telomere biology disorders is associated with significant morbidity and with vascular ectasias rather than varices.
Assuntos
Hemorragia Gastrointestinal/etiologia , Telômero/genética , Adolescente , Adulto , Ataxia/complicações , Ataxia/genética , Doenças Ósseas Metabólicas/complicações , Doenças Ósseas Metabólicas/genética , Medula Óssea/anormalidades , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/genética , Calcinose/complicações , Calcinose/genética , Cistos do Sistema Nervoso Central/complicações , Cistos do Sistema Nervoso Central/genética , Criança , Pré-Escolar , Disceratose Congênita/complicações , Disceratose Congênita/genética , Feminino , Retardo do Crescimento Fetal/genética , Hemorragia Gastrointestinal/genética , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Leucoencefalopatias/complicações , Leucoencefalopatias/genética , Masculino , Microcefalia/complicações , Microcefalia/genética , Espasticidade Muscular/complicações , Espasticidade Muscular/genética , Mutação , Retina , Doenças Retinianas/complicações , Doenças Retinianas/genética , Convulsões/complicações , Convulsões/genética , Telômero/metabolismo , Telômero/patologia , Adulto JovemRESUMO
OBJECTIVE: Peptic ulcer disease is a condition in which an important role has infection with H. pylori. The most common complication of peptic ulcer is bleeding. The presence of H. pylori triggers local and systemic cytokine signaling which may affect processes such as healing, gastric or duodenal rupture, and carcinogenesis. In this study, we examined the concentrations of IL-1ß, IL-6, IL-10, TNF, TGF-ß and IL-17A in serum by enzyme immunoassay and their mRNA expressions in periulcer biopsies obtained from patients with bleeding peptic ulcer by means of real-time-PCR. RESULTS: We have shown that pro-inflammatory IL-6 and TNF concentrations in serum were significantly higher in patients who were infected with H. pylori, while the concentrations of TGF-ß and IL-17A were significantly lower compared to non-infected subjects. IL-17A expression in periulcer mucosa was significantly higher in patients who were infected with H. pylori, while the expression of other cytokines, there was no significant difference compared to non-infected controls. Considering higher serum concentrations in non-infected subjects and higher IL-17A expression in mucosal tissue of infected patients, our data support the studies that found IL-17A has protective role in eradication of H. pylori infection in infected patients.
Assuntos
Citocinas/genética , Úlcera Duodenal/microbiologia , Hemorragia Gastrointestinal/microbiologia , Regulação da Expressão Gênica , Infecções por Helicobacter/microbiologia , Helicobacter pylori/fisiologia , Citocinas/sangue , Citocinas/metabolismo , Úlcera Duodenal/sangue , Úlcera Duodenal/complicações , Úlcera Duodenal/genética , Feminino , Mucosa Gástrica/microbiologia , Mucosa Gástrica/patologia , Hemorragia Gastrointestinal/sangue , Hemorragia Gastrointestinal/complicações , Hemorragia Gastrointestinal/genética , Infecções por Helicobacter/sangue , Infecções por Helicobacter/complicações , Infecções por Helicobacter/genética , Humanos , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
AIM: The aim of this retrospective single-centre study was to evaluate whether mutations in the ENG, ACVRL1, and SMAD4 genes were associated with different phenotypes in hereditary haemorrhagic telangiectasia (HHT). METHODS: The case records of 21 HHT patients with verified mutations in ENG, ACVRL1, or SMAD4 genes were reviewed. The numbers of HHT diagnostic criteria fulfilled for the three genotypes were compared, as was the prevalence of complications such as iron deficiency anaemia, gastrointestinal haemorrhage, stroke, and cerebral abscess. RESULTS: Our results indicate that mutations in the ENG (HHT1), ACVRL1 (HHT2), and SMAD4 genes result in different HHT phenotypes. Epistaxis debuts earlier and may be more severe in HHT1 than in HHT2. The prevalence of pulmonary arteriovenous malformations (AVM) is higher in HHT type 1, whereas hepatic AVMs are more common in HHT2. One patient with mutations in both ENG and ACVRL1 genes was identified, as were two SMAD4-mutated patients suffering from the overlapping juvenile polyposis-HHT syndrome. Nearly one in five patients in our HHT population has been diagnosed with stroke or cerebral abscess, indicating a high prevalence of cerebral complications. CONCLUSION: Our results showing that ENG and ACVRL1 gene mutations result in different HHT phenotypes confirm the results from other HHT centres worldwide. Cerebral complications of HHT are common, underscoring the importance of regular screening for pulmonary AVMs and early intervention against such AVMs. We have identified an HHT patient with simultaneous mutations in the ENG and ACVRL1 genes. Surprisingly, this patient has had a mild course of the disease.
Assuntos
Receptores de Activinas Tipo II/genética , Endoglina/genética , Mutação , Proteína Smad4/genética , Telangiectasia Hemorrágica Hereditária/genética , Adolescente , Adulto , Anemia Ferropriva/genética , Abscesso Encefálico/genética , Criança , Pré-Escolar , Epistaxe/genética , Feminino , Hemorragia Gastrointestinal/genética , Genótipo , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Fenótipo , Prevalência , Estudos Retrospectivos , Acidente Vascular Cerebral/genética , SuéciaRESUMO
Previously, we generated mouse models of Rack1 deficiency to identify key functions for Rack1 in regulating growth of intestinal epithelia: suppressing crypt cell proliferation and regeneration, promoting differentiation and apoptosis, and repressing development of neoplasia. However, other than low body weight, we did not detect an overt phenotype in mice constitutively deleted of Rack1 in intestinal epithelia ( vil-Cre: Rack1fl/fl mice), presumably because Rack1 was deleted in <10% of the total surface area of the epithelia. To assess the effect of Rack1 loss throughout the entire intestinal epithelia, we generated another mouse model of Rack1 deficiency, vil-Cre-ERT2: Rack1fl/fl. Within 5-10 days of the initial tamoxifen treatment, the mice lost over 20% of their body weight, developed severe diarrhea that for some was bloody, became critically ill, and died, if not euthanized. Necropsies revealed mildly distended, fluid-, gas-, and sometimes blood-filled loops of small and large bowel, inguinal lymphadenopathy, and thrombocytosis. Rack1 was deleted in nearly 100% of the epithelia in both the small intestine and colon when assessed by immunofluorescent or immunoblot analyses. Rack1 expression in other tissues and organs was not different than in control mice, indicating tissue specificity of the recombination. Histopathology revealed a patchy, erosive, hemorrhagic, inflammatory enterocolitis with denuded, sloughed off surface epithelium, and crypt hyperplasia. These results suggest a protective function for Rack1 in maintaining the integrity of intestinal epithelia and for survival. NEW & NOTEWORTHY Our findings reveal a novel function for Rack1 in maintaining intestinal homeostasis by protecting the epithelial barrier. Rack1 loss results in a patchy, erosive, hemorrhagic, inflammatory enterocolitis, which resembles that of inflammatory bowel diseases (IBD) in humans. Understanding mechanisms that protect barrier function in normal intestine and how loss of that protection contributes to the pathogenesis of IBD could lead to improved therapies for these and other erosive diseases of the gastrointestinal tract.
Assuntos
Enterocolite/metabolismo , Células Epiteliais/metabolismo , Absorção Intestinal , Mucosa Intestinal/metabolismo , Receptores de Quinase C Ativada/metabolismo , Animais , Diarreia/genética , Diarreia/metabolismo , Diarreia/patologia , Enterocolite/genética , Enterocolite/patologia , Células Epiteliais/patologia , Hemorragia Gastrointestinal/genética , Hemorragia Gastrointestinal/metabolismo , Hemorragia Gastrointestinal/patologia , Predisposição Genética para Doença , Homeostase , Mucosa Intestinal/patologia , Camundongos Knockout , Permeabilidade , Fenótipo , Receptores de Quinase C Ativada/deficiência , Receptores de Quinase C Ativada/genética , Transdução de Sinais , Redução de PesoRESUMO
BACKGROUND AND AIMS: The mutations in the gene that encodes vitamin K epoxide reductase (VKOR) enzyme are responsible for low levels of vitamin K. The purpose of this study was to evaluate whether the presence of the VKORC1 -1639 G> A polymorphism is a risk factor for non-variceal upper gastrointestinal bleeding (UGIB) in patients without concomitant therapy with vitamin K antagonists. METHODS: This case-control study comprised 163 consecutive patients diagnosed with UGIB and 178 controls, in whom the diagnosis of UGIB was excluded. The following data were recorded: age, gender, alcohol consumption, smoking, history of UGIB, nonsteroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin consumption. Genetic analysis included genotyping for the VKORC1 -1639 G>A polymorphism. RESULTS: History of UGIB (OR 3.463, CI95% 1.463-8.198, p=0.005), smoking (OR 2.498, CI95% 1.358-4.597, p=0.003), alcohol consumption (OR 3.283, CI95% 1.796-6.000, p<0.001), use of NSAIDs (OR 4.542, CI95% 2.502-8.247, p<0.001) or of low-dose aspirin (OR 2.390, CI95% 1.326-4.310), and the VKORC1 -1639 G> A AA genotype (OR 1.364, CI95% 0.998-1.863, p=0.05) were associated with an increased risk of UGIB. The risk of UGIB was analyzed in patients with genotype AA who used aspirin or NSAIDs. The genotype AA has not kept its status of independent risk factor (p=0.3). In subjects with NSAIDs/aspirin therapy and genotype AA there was a two times higher chance of UGIB compared to those under NSAIDs/aspirin therapy alone (OR 7.6 vs. 3.6, p<0.001). CONCLUSION: Patients with non-variceal UGIB caused by the use of NSAIDs or low-dose aspirin are more frequent carriers of the VKORC1 -1639 G>A AA genotype, as compared to those without UGIB.
Assuntos
Hemorragia Gastrointestinal/genética , Polimorfismo Genético , Vitamina K Epóxido Redutases/genética , Idoso , Anti-Inflamatórios não Esteroides/efeitos adversos , Aspirina/efeitos adversos , Estudos de Casos e Controles , Estudos Transversais , Feminino , Hemorragia Gastrointestinal/induzido quimicamente , Frequência do Gene , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
OBJECTIVES: To investigate the association between polymorphisms of DNA repair genes and xenobiotic with acute adverse effects in locally advanced rectal cancer patients treated with neoadjuvant radiochemotherapy. METHODS: Sixty-seven patients were analyzed for the current study. Genotypes in DNA repair genes XRCC1 (G28152A), XRCC3 (A4541G), XRCC3 (C18067T), RAD51 (G315C), and GSTP1 (A313G) were determined by pyrosequencing technology. RESULTS: The observed grade ≥3 acute toxicity rates were 23.8%. Chemotherapy and radiotherapy were interrupted for 46 and 14 days, respectively, due to critical complications. Four patients were hospitalized, 6 patients had been admitted to the ER, and 5 patients received invasive procedures (2 bladder catheters, 2 blood transfusions, and 1 growth factor therapy).RAD51 correlated with acute severe gastrointestinal toxicity in heterozygosity (Aa) and homozygosity (AA) (P=0.036). Grade ≥3 abdominal/pelvis pain toxicity was higher in the Aa group (P=0.017) and in the Aa+AA group (P=0.027) compared with homozygous (aa) patients. Acute skin toxicity of any grade occurred in 55.6% of the mutated patients versus 22.8% in the wild-type group (P=0.04) for RAD51. XRCC1 correlated with skin toxicity of any grade in the Aa+AA group (P=0.03) and in the Aa group alone (P=0.044). Grade ≥3 urinary frequency/urgency was significantly higher in patients with AA (P=0.01), Aa (P=0.022), and Aa+AA (P=0.031) for XRCC3 compared with aa group. CONCLUSIONS: Our study suggested that RAD51, XRCC1, and XRCC3 polymorphisms may be predictive factors for radiation-induced acute toxicity in rectal cancer patients treated with preoperative combined therapy.
Assuntos
Adenocarcinoma/terapia , Antineoplásicos/uso terapêutico , Quimiorradioterapia/efeitos adversos , Lesões por Radiação/genética , Radioterapia Conformacional/efeitos adversos , Neoplasias Retais/terapia , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Capecitabina/uso terapêutico , Cistite/etiologia , Cistite/genética , Proteínas de Ligação a DNA/genética , Diarreia/etiologia , Diarreia/genética , Feminino , Fluoruracila/uso terapêutico , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Dor Pélvica/etiologia , Dor Pélvica/genética , Polimorfismo de Nucleotídeo Único , Proctite/etiologia , Proctite/genética , Rad51 Recombinase/genética , Lesões por Radiação/etiologia , Radiodermite/etiologia , Radiodermite/genética , Neoplasias Retais/patologia , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genéticaRESUMO
Pathophysiological mechanisms of the vitamin K impact, including those in the gut with ulcerative affection, are studied still insufficiently. Investigations of pharmacogenomics of the vitamin K gives a new approach to therapy in patients, suffering gastro-intestinal hemorrhage. Possibilities of titration of the vitamin K3 (menadione) doses, depending on level of estrogenemia and genetic constitution, concerning genes-candidates ESR1 (rs2234693) and VKORC1 (rs9923231), were studied. There were examined 36 patients, who were treated for the ulcer hemorrhage. The blood serum concentration of estradiol was investigated in accordance to method of solid phase enzyme immunoassay, the genotyping procedure was performed in accordance to indices of polymerase chain reaction with analysis of the restrictional fragments length. The initial daily dose of menadione have constituted 20 mg. After a genotype determination made (first-second day after admittance to hospital) in patients with normoestrogenemia in genotypes CC/GG, CC/GA, CT/GG, CT/GA a vitaminotherapy was prolonged in daily dose of 20 mg, and in a conditionally-pathological variant of genotype the dose of vitamin K was enhanced up to 30 mg. Determination of hormones and the patients' genetic constitution makes possible to apply a personified approach for the vitamin K3 application in the ulcerative hemorrhage.
Assuntos
Anticoagulantes/uso terapêutico , Úlcera Duodenal/tratamento farmacológico , Receptor alfa de Estrogênio/genética , Hemorragia Gastrointestinal/tratamento farmacológico , Úlcera Gástrica/tratamento farmacológico , Vitamina K Epóxido Redutases/genética , Vitamina K/uso terapêutico , Adulto , Cálculos da Dosagem de Medicamento , Úlcera Duodenal/sangue , Úlcera Duodenal/genética , Úlcera Duodenal/patologia , Estradiol/sangue , Receptor alfa de Estrogênio/sangue , Feminino , Hemorragia Gastrointestinal/sangue , Hemorragia Gastrointestinal/genética , Hemorragia Gastrointestinal/patologia , Expressão Gênica , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Polimorfismo de Nucleotídeo Único , Medicina de Precisão , Úlcera Gástrica/sangue , Úlcera Gástrica/genética , Úlcera Gástrica/patologia , Vitamina K Epóxido Redutases/sangueRESUMO
Thalidomide is used in clinical practice to treat gastrointestinal vascular malformation (GIVM), but the pathogenesis of GIVM is not clear. Hypoxia inducible factor 1 alpha (HIF-1α) and 2 alpha (HIF-2α/EPAS1) are in the same family and act as master regulators of the adaptive response to hypoxia. HIF-1α and HIF-2α are up-regulated in vascular malformations in intestinal tissues from GIVM patients, but not in adjacent normal vessels. Therefore, we investigated the role of HIF-1α and HIF-2α during angiogenesis and the mechanism of thalidomide action. In vitro experiments confirmed that vascular endothelial growth factor (VEGF) was a direct target of HIF-2α and that HIF-1α and HIF-2α regulated NOTCH1, Ang2, and DLL4, which enhanced vessel-forming of endothelial cells. Thalidomide down-regulated the expression of HIF-1α and HIF-2α and inhibited angiogenesis. In vivo zebrafish experiments suggested that HIF-2α overexpression was associated with abnormal subintestinal vascular (SIV) sprouting, which was reversed by thalidomide. This result indicated that thalidomide regulated angiogenesis via the inhibition of HIF-1α and HIF-2α expression, which further regulated downstream factors, including VEGF, NOTCH1, DLL4, and Ang2. The abnormally high expression of HIF-1α and HIF-2α may contribute to GIVM.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Hemorragia Gastrointestinal/tratamento farmacológico , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Talidomida/administração & dosagem , Malformações Vasculares/tratamento farmacológico , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Idoso , Inibidores da Angiogênese/farmacologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proteínas de Ligação ao Cálcio , Modelos Animais de Doenças , Feminino , Hemorragia Gastrointestinal/genética , Hemorragia Gastrointestinal/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Receptor Notch1/metabolismo , Talidomida/farmacologia , Regulação para Cima/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Malformações Vasculares/genética , Malformações Vasculares/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Peixe-ZebraRESUMO
Critically ill children can develop bleeding complications when treated with heparin-like drugs. These events are usually attributed to the anticoagulant activity of these drugs. However, previous studies showed that fibroblast growth factor-2 (FGF-2), a heparin-binding growth factor released in the circulation of these patients, could precipitate intestinal hemorrhages in mice treated with the heparin-like drug pentosan polysulfate (PPS). Yet very little is known about how FGF-2 induces bleeding complications in combination with heparin-like drugs. Here, we examined the mechanisms by which circulating FGF-2 induces intestinal hemorrhages in mice treated with PPS. We used a well-characterized mouse model of intestinal hemorrhages induced by FGF-2 plus PPS. Adult FVB/N mice were infected with adenovirus carrying Lac-Z or a secreted form of recombinant human FGF-2, and injected with PPS, at doses that do not induce bleeding complications per se. Mice treated with FGF-2 in combination with PPS developed an intestinal inflammatory reaction that increased the permeability and disrupted the integrity of submucosal intestinal vessels. These changes, together with the anticoagulant activity of PPS, induced lethal hemorrhages. Moreover, a genetically modified form of the endothelial ligand angiopoietin-1 (Ang-1*), which has powerful antipermeability and anti-inflammatory activity, prevented the lethal bleeding complications without correcting the anticoagulant status of these mice. These findings define new mechanisms through which FGF-2 and Ang-1* modulate the outcome of intestinal bleeding complications induced by PPS in mice and may have wider clinical implications for critically ill children treated with heparin-like drugs.
Assuntos
Angiopoietina-1/biossíntese , Fator 2 de Crescimento de Fibroblastos/biossíntese , Hemorragia Gastrointestinal/prevenção & controle , Terapia Genética/métodos , Intestino Delgado/metabolismo , Adenoviridae/genética , Angiopoietina-1/genética , Animais , Coagulação Sanguínea , Permeabilidade Capilar , Modelos Animais de Doenças , Fator 2 de Crescimento de Fibroblastos/genética , Hemorragia Gastrointestinal/induzido quimicamente , Hemorragia Gastrointestinal/genética , Hemorragia Gastrointestinal/metabolismo , Hemorragia Gastrointestinal/patologia , Técnicas de Transferência de Genes , Vetores Genéticos , Mediadores da Inflamação/metabolismo , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/prevenção & controle , Intestino Delgado/irrigação sanguínea , Intestino Delgado/patologia , Macrófagos/metabolismo , Masculino , Metaloproteinases da Matriz/metabolismo , Camundongos , Poliéster Sulfúrico de PentosanaRESUMO
BACKGROUND AND PURPOSE: Late rectal bleeding is one of the severe adverse events after radiotherapy for prostate cancer. New biomarkers are needed to allow a personalized treatment. MATERIALS AND METHODS: Four patients each with grade 0-1 or grade 2-3 rectal bleeding were randomly selected for miRNA array to examine miRNA expression in peripheral blood lymphocytes (PBLs). Based on results of miRNA array, 1 of 348 miRNAs was selected for microRNA assays. Then, expression of DNA-dependent protein kinase mRNA and miR-99a was analyzed in the PBLs of 97 patients. PBLs were exposed to 4Gy of X-ray ex-vivo. RESULTS: In the discovery cohort, grade 2-3 rectal bleeding was significantly higher in the Ku80 <1.09 expression group compared with ⩾1.09 group (P=0.011). In radiation-induced expression of miR-99a, grade 2-3 rectal bleeding was significantly higher in the miR-99a IR(+)/IR(-) >0.93 group compared with ⩽0.93 group (P=0.013). Most patients with grade 2-3 rectal bleeding were in the group with low Ku80 and high miR-99a expression. In the validation cohort, similar results were obtained. CONCLUSION: A combination of low Ku80 expression and highly-induced miR-99a expression could be a promising marker for predicting rectal bleeding after radiotherapy.
Assuntos
Antígenos Nucleares/genética , Proteínas de Ligação a DNA/genética , Hemorragia Gastrointestinal/genética , MicroRNAs/genética , Neoplasias da Próstata/radioterapia , Lesões por Radiação/genética , Reto/lesões , Idoso , Hemorragia Gastrointestinal/etiologia , Regulação da Expressão Gênica , Humanos , Autoantígeno Ku , Masculino , Radioterapia/efeitos adversosRESUMO
We describe a patient with a severe juvenile polyposis phenotype, due to a de novo deletion of chromosome 10q22.3-q24.1. He was initially diagnosed with Juvenile polyposis syndrome (JPS) at age four after presenting with hematochezia due to multiple colonic juvenile polyps. He then re-presented at 23 years with recurrent hematochezia from juvenile polyps in his ileoanal pouch. He is one of the earliest reported cases of JPS associated with a large deletion of chromosome 10. Since his initial diagnosis of JPS further studies have confirmed an association between JPS and mutations in BMPR1A in chromosome band 10q23.2, which is in close proximity to PTEN. Mutations in PTEN cause Cowden syndrome (CS) and other PTEN hamartoma tumor syndromes. Due to the chromosome 10 deletion involving contiguous portions of BMPR1A and PTEN in our patient, he may be at risk for CS associated cancers and features, in addition to the polyps associated with JPS. This case presents new challenges in developing appropriate surveillance algorithms to account for the risks associated with each syndrome and highlights the importance of longitudinal follow-up and transitional care between pediatric and adult gastroenterology for patients with hereditary polyposis syndromes.
Assuntos
Receptores de Proteínas Morfogenéticas Ósseas Tipo I/genética , Deleção Cromossômica , Cromossomos Humanos Par 10 , Hemorragia Gastrointestinal/genética , Síndrome do Hamartoma Múltiplo/genética , Polipose Intestinal/congênito , Síndromes Neoplásicas Hereditárias/genética , PTEN Fosfo-Hidrolase/genética , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/deficiência , Hemorragia Gastrointestinal/patologia , Hemorragia Gastrointestinal/cirurgia , Expressão Gênica , Genótipo , Síndrome do Hamartoma Múltiplo/patologia , Síndrome do Hamartoma Múltiplo/cirurgia , Humanos , Polipose Intestinal/genética , Polipose Intestinal/patologia , Polipose Intestinal/cirurgia , Masculino , Monitorização Fisiológica , Síndromes Neoplásicas Hereditárias/patologia , Síndromes Neoplásicas Hereditárias/cirurgia , PTEN Fosfo-Hidrolase/deficiência , Fenótipo , Adulto JovemAssuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Encefalopatias Metabólicas/terapia , Proteína de Domínio de Morte Associada a Fas/deficiência , Hemorragia Gastrointestinal/terapia , Transplante de Células-Tronco Hematopoéticas , Imunoglobulinas Intravenosas/uso terapêutico , Encefalopatias Metabólicas/genética , Encefalopatias Metabólicas/imunologia , Encefalopatias Metabólicas/patologia , Pré-Escolar , Proteína de Domínio de Morte Associada a Fas/genética , Proteína de Domínio de Morte Associada a Fas/imunologia , Feminino , Hemorragia Gastrointestinal/genética , Hemorragia Gastrointestinal/imunologia , Hemorragia Gastrointestinal/patologia , Expressão Gênica , Humanos , Mutação , Linhagem , Rituximab , Resultado do TratamentoRESUMO
GOALS: To identify putative angiogenic factors associated with sporadic small bowel angiodysplasia (SBA). BACKGROUND: SBAs account for 50% of obscure gastrointestinal bleeding and due to delays in diagnosis and ineffective treatments, are associated with high levels of morbidity and mortality. Treatment development is impeded by a limited knowledge of the pathophysiology behind SBA formation. STUDY: We identified patients with definite sporadic SBA, and fecal immunochemical-negative controls were recruited from our institution's colorectal cancer screening program. Serum levels of VEGF, endoglin, Angiopoietin-2 (Ang-2), PDGF, Angiopoietin-1 (Ang-1), and TNF-α were measured using commercially available enzyme-linked immunosorbent assay kits. On the basis of serum results, we measured gene expression of target angiogenic factors in small bowel biopsy samples from angiodysplasias and unaffected tissue by quantitative PCR assessment. RESULTS: Serum samples were analyzed from 40 SBA patients and 40 controls. Median serum levels of Ang-2 were significantly higher in patients than controls with levels of Ang-1 and TNF-α significantly lower. There were no differences in serum levels of VEGF, endoglin, or PDGF. Gene expression levels of Ang-1, Ang-2, and their receptor Tie2 were all significantly higher in biopsies from areas of angiodysplasia compared with normal small bowel. CONCLUSIONS: This study, the first to explore the role of angiogenic factors in SBA, has identified a positive association between SBA and the Angiopoietin pathway, with increased serum and mucosal expression of Ang-2, which could potentially be used as a serum biomarker and future therapeutic target to improve outcome in affected patients.
Assuntos
Angiodisplasia/sangue , Indutores da Angiogênese/metabolismo , Enteropatias/sangue , Intestino Delgado/irrigação sanguínea , Adulto , Idoso , Idoso de 80 Anos ou mais , Angiodisplasia/complicações , Angiodisplasia/genética , Antígenos CD/sangue , Biópsia , Estudos de Casos e Controles , Endoglina , Ensaio de Imunoadsorção Enzimática , Feminino , Hemorragia Gastrointestinal/sangue , Hemorragia Gastrointestinal/genética , Humanos , Enteropatias/complicações , Enteropatias/genética , Masculino , Pessoa de Meia-Idade , Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptor TIE-2/metabolismo , Receptores de Superfície Celular/sangue , Ribonuclease Pancreático/sangue , Fator de Necrose Tumoral alfa/sangue , Fator A de Crescimento do Endotélio Vascular/sangue , Proteínas de Transporte Vesicular/sangueAssuntos
Hemorragia Gastrointestinal/genética , Mutação , Polimorfismo de Nucleotídeo Único , Inibidores da Bomba de Prótons , Fator de Necrose Tumoral alfa/genética , Biomarcadores/metabolismo , Medicina Baseada em Evidências , Hemorragia Gastrointestinal/diagnóstico , Genótipo , Infecções por Helicobacter/tratamento farmacológico , Humanos , Valor Preditivo dos Testes , Inibidores da Bomba de Prótons/uso terapêutico , Fatores de Risco , Sensibilidade e EspecificidadeRESUMO
Assessment of the bleeding risk of antithrombotic agents is usually performed in healthy animals with some form of vascular injury to peripheral organs to induce bleeding. However, bleeding observed in patients with currently marketed antithrombotic drugs is typically spontaneous in nature such as intracranial haemorrhage (ICH) and gastrointestinal (GI) bleeding, which happens most frequently on top of preexisting pathologies such as GI ulcerations and polyps. Apc(min/+) mice are reported to develop multiple adenomas through the entire intestinal tract and display progressive anaemia.In this study, we evaluated the potential utility of Apc(min/+) mice as a model for assessing spontaneous GI bleeding with antithrombotic agents. Apc(min/+) mice exhibited progressive blood loss starting at the age of nine weeks. Despite the increase in bleeding, Apc(min/+) mice were in a hypercoagulable state and displayed an age-dependent increase in thrombin generation and circulating fibrinogen as well as a significant decrease in clotting times. We evaluated the effect of warfarin, dabigatran etexilate, apixaban and clopidogrel in this model by administering them in diet or in the drinking water to mice for 1-4 weeks. All of these marketed drugs significantly increased GI bleeding in Apc(min/+) mice, but not in wild-type mice. Although different exposure profiles of these antithrombotic agents make it challenging to compare the bleeding risk of compounds, our results indicate that the Apc(min/+) mouse may be a sensitive preclinical model for assessing the spontaneous GI bleeding risk of novel antithrombotic agents.