RESUMO
INTRODUCTION: Liver regeneration is a normal response to liver injury. The aim of this study was to determine the molecular basis of liver regeneration, through an integrative analysis of high-throughput gene expression datasets. METHODS: We identified and curated datasets pertaining to liver regeneration from the Gene Expression Omnibus, where regenerating liver tissue was compared to healthy liver samples. The key dysregulated genes and pathways were identified using Ingenuity Pathway Analysis software. There were three eligible datasets in total. RESULTS: In the early phase after hepatectomy, inflammatory pathways such as Nrf2 oxidative stress-mediated response and cytokine signaling were significantly upregulated. At peak regeneration, we discovered that cell cycle genes were predominantly expressed to promote cell proliferation. Using the Betweenness centrality algorithm, we discovered that Jun is the key central gene in liver regeneration. Calcineurin inhibitors may inhibit liver regeneration, based on predictive modeling. CONCLUSION: There is a paucity of human literature in defining the molecular mechanisms of liver regeneration along a time continuum. Nonetheless, using an integrative computational analysis approach to the available high-throughput data, we determine that the oxidative stress response and cytokine signaling are key early after hepatectomy, whereas cell cycle control is important at peak regeneration. The transcription factor Jun is central to liver regeneration and a potential therapeutic target. Future studies of regeneration in humans along a time continuum are needed to better define the underlying mechanisms, and ultimately enhance care of patients with acute and chronic liver failure while awaiting transplant.
Assuntos
Regulação da Expressão Gênica , Hepatectomia , Regeneração Hepática/genética , Transdução de Sinais/genética , Biologia de Sistemas/métodos , Animais , Coleta de Dados , Conjuntos de Dados como Assunto , Fator de Crescimento Epidérmico/genética , Feminino , Fatores de Crescimento de Fibroblastos/genética , Humanos , Transplante de Fígado/métodos , Masculino , Valores de Referência , Fator de Necrose Tumoral alfa/genéticaRESUMO
PURPOSE: The pathogenic association between Chlamydophila psittaci (Cp) and ocular adnexal marginal zone lymphoma (OAMZL) and the efficacy of doxycycline monotherapy have been investigated in retrospective series with variations in stage, management, and follow-up duration. To our knowledge, this is the first international phase II trial aimed at clarifying Cp prevalence and activity of first-line doxycycline in a homogeneous series of consecutive patients with newly diagnosed stage I OAMZL. PATIENTS AND METHODS: Forty-seven patients were registered. Tumor tissue, conjunctival swabs, and peripheral blood from 44 patients were assessed for seven Chlamydiaceae infections by three polymerase chain reaction protocols. Thirty-four patients with measurable or parametrable disease were treated with doxycycline and assessed for chlamydial eradication and lymphoma response (primary end point). RESULTS: Cp DNA was detected in biopsies of 39 patients (89%); no other Chlamydiaceae were detected. Twenty-nine patients had Cp DNA in baseline swabs and/or blood samples and were evaluable for chlamydial eradication, which was achieved in 14 patients (48%). Lymphoma regression was complete in six patients and partial in 16 (overall response rate, 65%; 95% CI, 49% to 81%); 11 had stable disease, and one had progressive disease. At a median follow-up of 37 months (range, 15 to 62 months), 20 patients remained relapse free (5-year progression-free survival [PFS] ± standard deviation, 55% ± 9%). Cp eradication was associated with improved response rate (86% v 47%; P = .02) and 5-year PFS (68% v 47%; P = .11). CONCLUSION: Upfront doxycycline is a rational and active treatment for patients with stage I Cp-positive OAMZL. Lymphoma regression is consequent to Cp eradication, which can easily be monitored on conjunctival and blood samples. Prospective trials aimed at identifying more effective administration schedules for doxycycline are warranted.