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Despite sharing incretin activity with glucagon-like peptide 1 (GLP-1), the development of gastric inhibitory polypeptide (GIP)-based drugs has been hindered by the minor effects of native GIP on appetite and body weight and genetic studies associating loss-of-function with reduced obesity. Yet, pharmacologically optimized GIP-based molecules have demonstrated profound weight lowering benefits of GIPR agonism when combined with GLP-1-based therapies, which has re-energized deeper exploration of the molecular mechanisms and downstream signaling of GIPR. Interestingly, both GIPR agonism and antagonism offer metabolic benefits, leading to differing viewpoints on how to target GIPR therapeutically. Here we summarize the emerging evidence about the tissue-specific mechanisms that positions GIP-based therapies as important targets for the next generation of anti-obesity and metabolic therapies.
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BACKGROUND: Common variants of the max-like protein X (MLX)-interacting protein-like (MLXIPL) gene, encoding the transcription factor carbohydrate-responsive element-binding protein, have been shown to be associated with plasma triglyceride levels. However, the role of these variants in steatotic liver disease (SLD) is unclear. METHODS: We used a genome-first approach to analyze a variety of metabolic phenotypes and clinical outcomes associated with a common missense variant in MLXIPL, Gln241His, in 2 large biobanks: the UK Biobank and the Penn Medicine Biobank. RESULTS: Carriers of MLXIPL Gln241His were associated with significantly lower serum levels of triglycerides, apolipoprotein-B, gamma-glutamyl transferase, and alkaline phosphatase. Additionally, MLXIPL Gln241His carriers were associated with significantly higher serum levels of HDL cholesterol and alanine aminotransferase. Carriers homozygous for MLXIPL Gln241His showed a higher risk of SLD in 2 unrelated cohorts. Carriers of MLXIPL Gln241His were especially more likely to be diagnosed with SLD if they were female, obese, and/or also carried the PNPLA3 I148M variant. Furthermore, the heterozygous carriage of MLXIPL Gln241His was associated with significantly higher all-cause, liver-related, and cardiovascular mortality rates. Nuclear magnetic resonance metabolomics data indicated that carriage of MLXIPL Gln241His was significantly associated with lower serum levels of VLDL and increased serum levels of HDL cholesterol. CONCLUSIONS: Analyses of the MLXIPL Gln241His polymorphism showed a significant association with a higher risk of SLD diagnosis and elevated serum alanine aminotransferase as well as significantly lower serum triglycerides and apolipoprotein-B levels. MLXIPL might, therefore, be a potential pharmacological target for the treatment of SLD and hyperlipidemia, notably for patients at risk. More mechanistic studies are needed to better understand the role of MLXIPL Gln241His on lipid metabolism and steatosis development.
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Aciltransferases , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Fígado Gorduroso , Fosfolipases A2 Independentes de Cálcio , Triglicerídeos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Alanina Transaminase/sangue , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , HDL-Colesterol/sangue , Fígado Gorduroso/genética , Fígado Gorduroso/sangue , Predisposição Genética para Doença , Lipase/genética , Lipase/sangue , Lipídeos/sangue , Proteínas de Membrana/genética , Proteínas de Membrana/sangue , Mutação de Sentido Incorreto , Triglicerídeos/sangueRESUMO
BACKGROUND: The hepatoprotective effects of aspirin have been observed in individuals with viral hepatitis; however, its impact on the general population remains uncertain. Understanding the association between aspirin use and the development of liver diseases is crucial for optimizing preventive strategies. METHODS: We identified individuals with aspirin use in the UK Biobank and the Penn Medicine Biobank, as well as propensity-score-matched controls. Outcome measures included new liver disease development, diagnosed by MRI or "International Classification of Diseases and Related Health Problems" coding, and incidences of gastrointestinal bleeding and ulcers. RESULTS: In the UK Biobank cohort, regular aspirin use was associated with an 11.2% reduction in the risk of developing new liver diseases during the average 11.84 ± 2.01-year follow-up period (HR=0.888, 95% CI = 0.819-0.963; p = 4.1 × 10-3). Notably, the risk of metabolic dysfunction-associated steatotic liver disease (ICD-10 K76.0) and MRI-diagnosed steatosis was significantly lower among aspirin users (HR = 0.882-0.911), whereas no increased risk of gastrointestinal bleeding or ulcers was observed. These findings were replicated in the Penn Medicine Biobank cohort, in which the protective effect of aspirin appeared to be dependent on the duration of intake. The greatest risk reduction for new liver disease development was observed after at least 1 year of aspirin use (HR = 0.569, 95% CI = 0.425-0.762; p = 1.6 × 10-4). Intriguingly, when considering general risk factors, only men exhibited a lower risk of MRI-confirmed or ICD-coded steatosis with aspirin use (HRs = 0.806-0.906), while no significant protective effect of aspirin was observed in females. CONCLUSION: This cohort study demonstrated that regular aspirin use was associated with a reduced risk of liver disease in men without an elevated risk of gastrointestinal bleeding or ulcers. Further investigation is warranted to elucidate potential sex-related differences in the effects of aspirin and to inform tailored preventive strategies for liver diseases.
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Fígado Gorduroso , Hepatopatias , Feminino , Masculino , Humanos , Incidência , Estudos de Coortes , Úlcera , Hepatopatias/epidemiologia , Hemorragia Gastrointestinal/induzido quimicamente , Hemorragia Gastrointestinal/epidemiologia , Hemorragia Gastrointestinal/prevenção & controle , Aspirina/efeitos adversosRESUMO
Background: Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver-related morbidity in people with and without diabetes, but it is underdiagnosed, posing challenges for research and clinical management. Here, we determine if natural language processing (NLP) of data in the electronic health record (EHR) could identify undiagnosed patients with hepatic steatosis based on pathology and radiology reports. Methods: A rule-based NLP algorithm was built using a Linguamatics literature text mining tool to search 2.15 million pathology report and 2.7 million imaging reports in the Penn Medicine EHR from November 2014, through December 2020, for evidence of hepatic steatosis. For quality control, two independent physicians manually reviewed randomly chosen biopsy and imaging reports (n = 353, PPV 99.7%). Findings: After exclusion of individuals with other causes of hepatic steatosis, 3007 patients with biopsy-proven NAFLD and 42,083 patients with imaging-proven NAFLD were identified. Interestingly, elevated ALT was not a sensitive predictor of the presence of steatosis, and only half of the biopsied patients with steatosis ever received an ICD diagnosis code for the presence of NAFLD/NASH. There was a robust association for PNPLA3 and TM6SF2 risk alleles and steatosis identified by NLP. We identified 234 disorders that were significantly over- or underrepresented in all subjects with steatosis and identified changes in serum markers (e.g., GGT) associated with presence of steatosis. Interpretation: This study demonstrates clear feasibility of NLP-based approaches to identify patients whose steatosis was indicated in imaging and pathology reports within a large healthcare system and uncovers undercoding of NAFLD in the general population. Identification of patients at risk could link them to improved care and outcomes. Funding: The study was funded by US and German funding sources that did provide financial support only and had no influence or control over the research process.
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Importance: Given the burden of chronic liver disease on the health care system, more information on the hepatoprotective association of statins in the general population is needed. Objective: To examine whether regular statin use is associated with a reduction in liver disease, particularly hepatocellular carcinoma (HCC) and liver-related deaths, in the general population. Design, Setting, and Participants: This cohort study used data from the UK Biobank (UKB) (individuals aged 37-73 years) collected from baseline (2006-2010) to the end of follow-up in May 2021, from the TriNetX cohort (individuals aged 18-90 years) enrolled from baseline (2011-2020) until end of follow-up in September 2022, and from the Penn Medicine Biobank (PMBB) (individuals aged 18-102 years) with ongoing enrollment starting in 2013 to the end of follow-up in December 2020. Individuals were matched using propensity score matching according to the following criteria: age, sex, body mass index, ethnicity, diabetes with or without insulin or biguanide use, hypertension, ischemic heart disease, dyslipidemia, aspirin use, and number of medications taken (UKB only). Data analysis was performed from April 2021 to April 2023. Exposure: Regular statin use. Main Outcomes and Measures: Primary outcomes were liver disease and HCC development as well as liver-associated death. Results: A total of 1â¯785â¯491 individuals were evaluated after matching (aged 55 to 61 years on average, up to 56% men, and up to 49% women). A total of 581 cases of liver-associated death, 472 cases of incident HCC, and 98â¯497 new liver diseases were registered during the follow-up period. Individuals were aged 55-61 years on average, with a slightly higher proportion of men (up to 56%). In UKB individuals (n = 205â¯057) without previously diagnosed liver disease, statin users (n = 56â¯109) had a 15% lower hazard ratio (HR) for the association of developing a new liver disease (HR, 0.85; 95% CI, 0.78-0.92; P < .001). In addition, statin users demonstrated a 28% lower HR for the association with liver-related death (HR, 0.72; 95% CI, 0.59-0.88; P = .001) and a 42% lower HR for the development of HCC (HR, 0.58; 95% CI, 0.35-0.96; P = .04). In TriNetX individuals (n = 1â¯568â¯794), the HR for the association of HCC was reduced even further for statin users (HR, 0.26; 95% CI, 0.22-0.31; P = .003). The hepatoprotective association of statins was time and dose dependent, with a significant association in PMBB individuals (n = 11â¯640) for incident liver diseases after 1 year of statin use (HR, 0.76; 95% CI, 0.59-0.98; P = .03). Taking statins was particularly beneficial in men, individuals with diabetes, and individuals with a high Fibrosis-4 index at baseline. Carriers of the heterozygous minor allele of PNPLA3 rs738409 benefited from statin use and had a 69% lower HR for the association with HCC (UKB HR, 0.31; 95% CI, 0.11-0.85; P = .02). Conclusions and Relevance: This cohort study indicates substantial preventive associations of statins against liver disease, with an association with duration and dose of intake.
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Carcinoma Hepatocelular , Diabetes Mellitus , Inibidores de Hidroximetilglutaril-CoA Redutases , Neoplasias Hepáticas , Masculino , Humanos , Feminino , Carcinoma Hepatocelular/epidemiologia , Estudos de Coortes , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/epidemiologiaRESUMO
Obesity is a chronic disease that increases morbidity and mortality and adversely affects quality of life. The rapid rise of obesity has outpaced the development and deployment of effective therapeutic interventions, thereby creating a global health crisis. The presentation, complications, and response to obesity treatments vary, yet lifestyle modification, which is the foundational therapeutic intervention for obesity, is often "one size fits all." The concept of personalized medicine uses genetic and phenotypic information as a guide for disease prevention, diagnosis, and treatment and has been successfully applied in diseases such as cancer, but not in obesity. As we gain insight into the pathophysiologic mechanisms of obesity and its phenotypic expression, specific pathways can be targeted to yield a greater, more sustained therapeutic impact in an individual patient with obesity. A phenotype-based pharmacologic treatment approach utilizing objective measures to classify patients into predominant obesity mechanism groups resulted in greater weight loss (compared with a non-phenotype-based approach) in a recent study by Acosta and colleagues. In this review, we discuss the application of lifestyle modifications, behavior therapy and pharmacotherapy using the obesity phenotype-based approach as a framework.
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Fármacos Antiobesidade , Qualidade de Vida , Humanos , Obesidade/complicações , Fármacos Antiobesidade/uso terapêutico , Redução de Peso , Estilo de VidaRESUMO
BACKGROUND: Genetic inactivation and pharmacologic inhibition of the microsomal triglyceride transfer protein (MTP; gene name MTTP) inhibits hepatic secretion of VLDL, thereby reducing serum lipids and apoB at the expense of increasing hepatic steatosis. AIM: To examine the effects of missense variants in MTTP on hepatic and circulating lipids. METHODS: We analysed the association of MTTP missense variants with metabolic, hepatic and clinical phenotypes in the Penn Medicine Biobank (PMBB; n = 37,960) and the UKBiobank (UKB; n = 451,444). RESULTS: We analysed 24 missense variants in MTTP in PMBB for association with biopsy-proven hepatic steatosis and found that an isoleucine 128 to threonine variant (I128T: rs3816873-A, frequency 26%) was associated with reduced steatosis (p < 0.001). PMBB subjects with imaging-proven steatosis also revealed significantly fewer carriers of MTTP I128T compared to controls. Analysis in UKB also showed that MTTP I128T was associated with reduced risk of hepatic steatosis. Unexpectedly, MTTP I128T was found to be associated with reduced plasma levels of LDL-cholesterol and apoB (all p < 0.001). Functional studies indicated that MTTP I128T is neither a classic loss nor gain of function allele. CONCLUSIONS: MTTP I128T is associated with reduced hepatic steatosis as well as reduced plasma lipids and apoB. This paradoxical profile is not consistent with a simple gain or loss of function in MTP activity and suggests a more complex effect on MTP function. Further investigation of MTTP I128T will provide insight into the structure-function of MTP and potentially new approaches to modulate MTP activity that could both reduce hepatic and circulating lipids.
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Proteínas de Transporte , Fígado Gorduroso , Humanos , Proteínas de Transporte/genética , Fígado Gorduroso/genética , Apolipoproteínas B/genética , Apolipoproteínas B/metabolismoRESUMO
INTRODUCTION: Vitamin E supplementation is recommended for the treatment of nonalcoholic fatty liver disease (NAFLD) for nondiabetic patients, but its preventative effects are unclear. METHODS: We assessed dietary vitamin E intake with disease phenotypes and evaluated vitamin E levels with the development of NAFLD. RESULTS: Data from >210,000 participants demonstrate that increased dietary vitamin E associates with reduced rates of several gastrointestinal diseases and reduced overall mortality. Diabetic and overweight subjects with increased vitamin E intake have fewer NAFLD diagnoses. DISCUSSION: Our findings reveal the relevance of vitamin E consumption for several gastrointestinal diseases and warrant further mechanistic and therapeutic investigations.
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Hepatopatia Gordurosa não Alcoólica , Dieta , Humanos , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Estado Nutricional , Vitamina E/uso terapêuticoRESUMO
BACKGROUND: Vancomycin is the drug of choice for treating Clostridioides difficile infection (CDI). We compare CDI resolution with vancomycin taper, pulse, and taper-and-pulse regimens. METHODS: We searched for Medline, Embase, Cochrane, and Scopus through October 9th, 2020. Taper regimen was defined as dose reduction over time; pulse was a regimen less frequent than daily. Studies assessing CDI resolution rates were included. Meta-analyses for resolution rates were performed using weighted proportion ratios (WPR). RESULTS: Ten studies with 675 patients treated with vancomycin regimens were included. Resolution rates were 83% (212/266, 95% CI 69-94%, I2 = 85%) for taper-and-pulse, 68% (264/383, 95% CI 57-78%, I2 = 72%) for taper alone, and 54% (11/26 95% CI 0-100%, I2 = 86%) for pulse alone regimens. Taper-and-pulse was superior to taper alone (WPR 83% vs 68%, p < 0.0001) and pulse alone (WPR 83% vs 54%, p < 0.0004), no significant difference between taper alone or pulse alone (WPR 68% vs 54%, p = 0.1). CONCLUSIONS: Limitations of our analysis are a small number of included studies and heterogeneity. Vancomycin taper-and-pulse seems superior to pulse alone or taper alone for recurrent CDI. A randomized controlled trial comparing vancomycin taper-and-pulse to fidaxomicin and microbiome restoration is needed.
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Infecções por Clostridium , Vancomicina , Antibacterianos/uso terapêutico , Clostridioides difficile , Infecções por Clostridium/tratamento farmacológico , Humanos , Resultado do Tratamento , Vancomicina/uso terapêuticoRESUMO
BACKGROUND: A coding variant in MTARC1 (rs2642438; p.Ala165Thr) was recently associated with protection from cirrhosis in European individuals. However, its impact on overall and cause-specific mortality remained elusive. METHODS: Using a genome-first approach, we explored a range of metabolic phenotypes and outcomes associated with MTARC1 p.Ala165Thr in the UKBiobank and the Penn-Medicine BioBank. FINDINGS: MTARC1 p.Ala165Thr was significantly associated with higher triglycerides, lower total cholesterol, lower LDL-C, lower ApoB, lower HDL-C, lower ApoA-I and higher IGF-1. Per each minor allele, the risk of NAFLD was reduced by ~15%. The ALT-lowering and NAFLD-protective effect of MTARC1 p.Ala165Thr was amplified by obesity, diabetes mellitus and presence of PNPLA3 rs738409:G. In African-American and Black-British individuals, the allele frequency of MTARC1 p.Ala165Thr was lower, but carriers showed the same distinctive lipid phenotype. Importantly, MTARC1 p.Ala165Thr carriers did not show higher cardiovascular disease burden as evidenced by cardiac MRI and carotid ultrasound. In prospective analyses, the homozygous minor allele was associated with up to 39% lower rates of liver-related mortality, while no risk of increased overall or cardiovascular death could be observed. Strikingly, liver-related mortality was more than 50% reduced in diabetic participants or carriers of PNPLA3 rs738409:G. CONCLUSIONS: Together these data highlight MTARC1 as an important liver disease modifier that influences plasma lipids in an allele-dose-dependent manner without increasing cardiovascular outcomes. Our results point toward potential mechanisms and reveal a remarkable association with liver-related mortality calling for future studies exploring its therapeutic potential. FUNDING: This study was funded by the German Research Foundation (DFG).
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Proteínas Mitocondriais/metabolismo , Hepatopatia Gordurosa não Alcoólica , Oxirredutases/metabolismo , Heterozigoto , Homozigoto , Humanos , Lipase/genética , Proteínas de Membrana/genética , Hepatopatia Gordurosa não Alcoólica/complicações , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Estudos ProspectivosRESUMO
BACKGROUND & AIMS: Previous studies have identified physical activity as an important lifestyle factor in the pathogenesis of chronic liver diseases (CLD). However, most studies were short in follow-up, and based on self-reported activity. Moreover, it is unknown whether physical activity affects the risk of liver disease development in the general population. Herein, we aimed to clarify the association between physical activity and CLD by examining the risk of liver disease and progression in relation to accelerometer-based physical activity in a large subset of prospectively recruited participants in the UK Biobank. METHODS: We analysed data from 96,688 participants that recorded their physical activity through the use of a wrist accelerometer. Relative risks for development of liver diseases were calculated using multivariable-adjusted Cox regression models. In a subgroup of participants without any previously diagnosed liver disease (n = 95,974), a total of 374 liver disease cases were diagnosed during follow-up (mean = 5.5 years). RESULTS: Participants in the top compared with the bottom quartile of physical activity had a reduced risk of both overall CLD (hazard ratio [HR]: 0.41 [0.29-0.59]) and NAFLD (HR: 0.39 [0.21-0.70]). An activity increase of an additional 2,500 steps per day, was associated with a 38% reduction in CLD and a 47% reduction in NAFLD development, independent of adiposity. In the subgroup of participants with previously diagnosed liver disease (n = 714), participants in the top compared with the bottom quartile of physical activity had a striking 89% risk reduction in liver-related death (HR: 0.11 [0.02-0.86]), and 85% risk reduction in all-cause mortality (adjusted HR: 0.15 [0.05-0.44]). Walking an additional 2,500 steps per day was associated with 44% reduction in liver disease progression. CONCLUSIONS: Greater physical activity is associated with a dose-dependent reduction in liver disease, which appears to be independent of adiposity. LAY SUMMARY: In this study, we aimed to clarify the association between accelerometer-measured physical activity and chronic liver disease by examining risk of overall and specific liver diseases and their progression in relation to accelerometer-based physical activity in 96,688 participants in the UK Biobank. Our results show a clear, dose-dependent protective association between accelerometer-measured physical activity and liver disease development and progression. The linkage of device-measured activity could therefore create a framework for using wearables for personalised prevention of liver diseases.
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BACKGROUND: The bile acid (BA) pathway plays a role in regulation of food intake and glucose metabolism, based mainly on findings in animal models. Our aim was to determine whether the BA pathway is altered and correctable in human obesity and diabetes. METHODS: We conducted 3 investigations: 1) BA receptor pathways were studied in NCI-H716 enteroendocrine cell (EEC) line, whole human colonic mucosal tissue and in human colonic EEC isolated by Fluorescence-activated Cell Sorting (ex vivo) from endoscopically-obtained biopsies colon mucosa; 2) We characterized the BA pathway in 307 participants by measuring during fasting and postprandial levels of FGF19, 7αC4 and serum BA; 3) In a placebo-controlled, double-blind, randomised, 28-day trial, we studied the effect of ileo-colonic delivery of conjugated BAs (IC-CBAS) on glucose metabolism, incretins, and lipids, in participants with obesity and diabetes. FINDINGS: Human colonic GLP-1-producing EECs express TGR5, and upon treatment with bile acids in vitro, human EEC differentially expressed GLP-1 at the protein and mRNA level. In Ussing Chamber, GLP-1 release was stimulated by Taurocholic acid in either the apical or basolateral compartment. FGF19 was decreased in obesity and diabetes compared to controls. When compared to placebo, IC-CBAS significantly decreased postprandial glucose, fructosamine, fasting insulin, fasting LDL, and postprandial FGF19 and increased postprandial GLP-1 and C-peptide. Increase in faecal BA was associated with weight loss and with decreased fructosamine. INTERPRETATIONS: In humans, BA signalling machinery is expressed in colonic EECs, deficient in obesity and diabetes, and when stimulated with IC-CBAS, improved glucose homeostasis. ClinicalTrials.gov number, NCT02871882, NCT02033876. FUNDING: Research support and drug was provided by Satiogen Pharmaceuticals (San Diego, CA). AA, MC, and NFL report grants (AA- C-Sig P30DK84567, K23 DK114460; MC- NIH R01 DK67071; NFL- R01 DK057993) from the NIH. JR was supported by an Early Career Grant from Society for Endocrinology.
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Ácidos e Sais Biliares/administração & dosagem , Glicemia/metabolismo , Colo/efeitos dos fármacos , Diabetes Mellitus Tipo 2/terapia , Íleo/efeitos dos fármacos , Obesidade/terapia , Administração Oral , Ácidos e Sais Biliares/química , Ácidos e Sais Biliares/metabolismo , Transporte Biológico , Cápsulas , Linhagem Celular , Colestenonas/sangue , Colo/metabolismo , Colo/patologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Cultura em Câmaras de Difusão , Células Enteroendócrinas/citologia , Células Enteroendócrinas/efeitos dos fármacos , Células Enteroendócrinas/metabolismo , Jejum/fisiologia , Fatores de Crescimento de Fibroblastos/sangue , Frutosamina/sangue , Expressão Gênica , Peptídeo 1 Semelhante ao Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/genética , Homeostase/efeitos dos fármacos , Homeostase/fisiologia , Humanos , Íleo/metabolismo , Íleo/patologia , Insulina/sangue , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Período Pós-Prandial , Cultura Primária de Células , Receptores Acoplados a Proteínas G/sangue , Receptores Acoplados a Proteínas G/genéticaAssuntos
Exantema/virologia , Hepatite/virologia , Herpesvirus Humano 3/patogenicidade , Hospedeiro Imunocomprometido , Leucemia Linfocítica Crônica de Células B/imunologia , Infecções Oportunistas/virologia , Pancreatite/virologia , Infecção pelo Vírus da Varicela-Zoster/virologia , Aciclovir/uso terapêutico , Idoso , Antineoplásicos/efeitos adversos , Antivirais/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Exantema/diagnóstico , Exantema/tratamento farmacológico , Exantema/imunologia , Feminino , Hepatite/diagnóstico , Hepatite/tratamento farmacológico , Hepatite/imunologia , Herpesvirus Humano 3/efeitos dos fármacos , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Infecções Oportunistas/diagnóstico , Infecções Oportunistas/tratamento farmacológico , Infecções Oportunistas/imunologia , Pancreatite/diagnóstico , Pancreatite/tratamento farmacológico , Pancreatite/imunologia , Recidiva , Sulfonamidas/efeitos adversos , Resultado do Tratamento , Infecção pelo Vírus da Varicela-Zoster/diagnóstico , Infecção pelo Vírus da Varicela-Zoster/tratamento farmacológico , Infecção pelo Vírus da Varicela-Zoster/imunologiaRESUMO
The application of next-generation sequencing in clinical practice is increasing as accuracy and interpretation have improved and the cost continues to decline rapidly. Cell-free DNA is a unique source for next-generation sequencing that could change routine clinical practice in gastroenterology and hepatology. Testing of cell-free DNA in blood and fecal samples is an easy, rapid, and noninvasive method to assess for premalignant, malignant, metabolic, infectious, inflammatory, and autoimmune gastrointestinal and liver diseases. In this review, we describe cell-free DNA technologies, current applications of cell-free DNA testing, and proposed cell-free DNA targets for gastrointestinal and hepatic diseases, with a specific focus on malignancy. In addition, we provide commentary on how cell-free DNA can be integrated into clinical practice and help guide diagnosis, prognosis, disease management, and therapeutic response.
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Numerous cellular studies have indicated that RhoA signaling is required for oncogenic Ras-induced transformation, suggesting that RhoA is a useful target in Ras induced neoplasia. However, to date very limited data exist to genetically attribute RhoA function to Ras-mediated tumorigenesis in mammalian models. In order to assess whether RhoA is required for K-Ras-induced lung cancer initiation, we utilized the K-RasG12D Lox-Stop-Lox murine lung cancer model in combination with a conditional RhoAflox/flox and RhoC-/- knockout mouse models. Deletion of the floxed Rhoa gene and expression of K-RasG12D was achieved by either CCSP-Cre or adenoviral Cre, resulting in simultaneous expression of K-RasG12D and deletion of RhoA from the murine lung. We found that deletion of RhoA, RhoC or both did not adversely affect normal lung development. Moreover, we found that deletion of either RhoA or RhoC alone did not suppress K-RasG12D induced lung adenoma initiation. Rather, deletion of RhoA alone exacerbated lung adenoma formation, whereas dual deletion of RhoA and RhoC together significantly reduced K-RasG12D induced adenoma formation. Deletion of RhoA appears to induce a compensatory mechanism that exacerbates adenoma formation. The compensatory mechanism is at least partly mediated by RhoC. This study suggests that targeting of RhoA alone may allow for compensation and a paradoxical exacerbation of neoplasia, while simultaneous targeting of both RhoA and RhoC is likely to lead to more favorable outcomes.
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Adenoma/genética , Adenoma/patologia , Genes ras/fisiologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteína rhoA de Ligação ao GTP/genética , Animais , Western Blotting , Genes ras/genética , Imuno-Histoquímica , Camundongos , Proteínas ras/genética , Proteínas ras/metabolismo , Proteína rhoA de Ligação ao GTP/deficiência , Proteína de Ligação a GTP rhoCRESUMO
BACKGROUND: Molecular screening for BRCA1 and BRCA2 mutations is now an established component of risk evaluation and management of familial breast cancer. Features of hereditary breast cancer include an early age-of-onset and over-representation of the 'triple-negative' phenotype (negative for estrogen-receptor, progesterone-receptor and HER2). The decision to offer genetic testing to a breast cancer patient is usually based on her family history, but in the absence of a family history of cancer, some women may qualify for testing based on the age-of-onset and/or the pathologic features of the breast cancer. METHODS: We studied 54 women who were diagnosed with high-grade, triple-negative invasive breast cancer at or before age 40. These women were selected for study because they had little or no family history of breast or ovarian cancer and they did not qualify for genetic testing using conventional family history criteria. BRCA1 screening was performed using a combination of fluorescent multiplexed-PCR analysis, BRCA1 exon-13 6 kb duplication screening, the protein truncation test (PTT) and fluorescent multiplexed denaturing gradient gel electrophoresis (DGGE). All coding exons of BRCA1 were screened. The two large exons of BRCA2 were also screened using PTT. All mutations were confirmed with direct sequencing. RESULTS: Five deleterious BRCA1 mutations and one deleterious BRCA2 mutation were identified in the 54 patients with early-onset, triple-negative breast cancer (11%). CONCLUSION: Women with early-onset triple-negative breast cancer are candidates for genetic testing for BRCA1, even in the absence of a family history of breast or ovarian cancer.
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Proteína BRCA1/genética , Neoplasias da Mama/diagnóstico , Testes Genéticos/métodos , Mutação , Adulto , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Análise Mutacional de DNA , Feminino , Frequência do Gene , Humanos , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Adulto JovemRESUMO
Most of the breast cancer susceptibility genes identified to date are involved in DNA repair, including BRCA1, BRCA2, PALB2, CHEK2 and BRIP1. RAP80 works upstream of BRCA1 and is essential for the localization of BRCA1 to the site of damaged DNA. To investigate whether or not RAP80 is also a breast cancer susceptibility gene, we sequenced the entire exonic regions of RAP80 in the germline DNA of 152 women with familial breast cancer, who were previously found to be negative for BRCA1 and BRCA2 mutations. No truncating mutation was identified. Eleven potentially deleterious RAP80 variants were identified; these 11 variants were genotyped in 424 more familial cases and in 726 healthy controls. Three novel p.Ala342Thr, p.Met353Thr and p.Tyr575Asp rare missense variants and a novel haplotype composed of two variants in the CpG island (c.-24149G > T and c.-24001A > G) and a variant in the 5'UTR (c.-8A > G) and a variant in the 3'UTR (c.*27A > C) were detected in 26 of 571 (4.6%) individuals with familial breast cancer, compared to 14 of 725 (1.9%) controls (P = 0.01; OR = 2.4, 95% CI = 1.2-5.1). In summary, we did not find truncating mutations of the RAP80 gene to be a cause of familial breast cancer. A novel RAP80 haplotype or rare missense mutations may be associated with a modest increased risk of breast cancer, but this observation needs to be confirmed by additional studies.