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| 1 | Liver enzymes,metabolomics and genome-wide association studies:From systems biology to the personalized medicine显示文摘For several decades,serum levels of alanine(ALT) and aspartate(AST) aminotransferases have been regarded as markers of liver injury,including a wide range of etiologies from viral hepatitis to fatty liver.The increasing worldwide prevalence of metabolic syndrome and cardiovascular disease revealed that transaminases are strong predictors of type 2 diabetes,coronary heart disease,atherothrombotic risk profile,and overall risk of metabolic disease.Therefore,it is plausible to suggest that aminotransferases are surrogate biomarkers of 'liver metabolic functioning' beyond the classical concept of liver cellular damage,as their enzymatic activity might actually reflect key aspects of the physiology and pathophysiology of the liver function.In this study,we summarize the background information and recent findings on the biological role of ALT and AST,and review the knowledge gained from the application of genome-wide approaches and 'omics' technologies that uncovered new concepts on the role of aminotransferases in human diseases and systemic regulation of metabolic functions.Prediction of biomolecular interactions between the candidate genes recently discovered to be associated with plasma concentrations of liver enzymes showed interesting interconnectivity nodes,which suggest that regulation of aminotransferase activity is a complex and highly regulated trait.Finally,links between aminotransferase genes and metabolites are explored to understand the genetic contributions to the metabolic diversity. | Silvia Sookoian Carlos J Pirola | 2015 | World Journal of Gastroenterology2015，21，3： | 27 |
| 2 | Laparoscopic liver resection:Experience based guidelines显示文摘Laparoscopic liver resection(LLR) has been progressively developed along the past two decades. Despite initial skepticism, improved operative results made laparoscopic approach incorporated to surgical practice and operations increased in frequency and complexity. Evidence supporting LLR comes from case-series, comparative studies and meta-analysis. Despite lack of level 1 evidence, the body of literature is stronger and existing data confirms the safety, feasibility and benefits of laparoscopic approach when compared to open resection. Indications for LLR do not differ from those for open surgery. They include benign and malignant(both primary and metastatic) tumors and living donor liver harvesting. Currently, resection of lesions located on anterolateral segments and left lateral sectionectomy are performed systematically by laparoscopy in hepatobiliary specialized centers. Resection of lesions located on posterosuperior segments(1, 4a, 7, 8) and major liver resections were shown to be feasible but remain technically demanding procedures, which should be reserved to experienced surgeons. Hand-assisted and laparoscopy-assisted procedures appeared to increase the indications of minimally invasive liver surgery and are useful strategies applied to difficult and major resections. LLR proved to be safe for malignant lesions and offers some short-term advantages over open resection. Oncological results including resection margin status and long-term survival were not inferior to open resection. At present, surgical community expects high quality studies to base the already perceived better outcomes achieved by laparoscopy in major centers' practice. Continuous surgical training, as well as new technologies should augment the application of lap-aroscopic liver surgery. Future applicability of new technologies such as robot assistance and image-guided surgery is still under investigation. | fabricio ferreira coelho jaime arthur pirola kruger gilton marques fonseca raphael leonardo cunha araújo vagner birk jeismann marcos vinícius perini renato micelli lupinacci ivan cecconello paulo herman | 2016 | World Journal of Gastrointestinal Surgery2016，8，1： | 22 |
| 3 | Alanine and aspartate aminotransferase and glutamine-cycling pathway:Their roles in pathogenesis of metabolic syndrome显示文摘Although new research technologies are constantly used to look either for genes or biomarkers in the prediction of metabolic syndrome(MS),the pathogenesis and pathophysiology of this complex disease remains a major challenge.Interestingly,Cheng et al recently investigated possible pathways underlying MS by high-throughput metabolite profiling in two large and well characterized community-based cohorts.The authors explored by liquid chromatography and mass spectrometry the plasma concentrations of 45 distinct metabolites and examined their relation to cardiometabolic risk,and observed that metabolic risk factors such as obesity,insulin resistance(IR),high blood pressure,and dyslipidemia were associated with several metabolites,including branched-chain amino acids,other hydrophobic amino acids,tryptophan breakdown products,and nucleotide metabolites.In addition,the authors found a significant association of IR traits with glutamine,glutamate and the glutamineto-glutamate ratio.These data provide new insight into the pathogenesis of MS-associated phenotypes and introduce a crucial role of glutamine-cycling pathway as prominently involved in the development of metabolic risk.We consider that the hypothesis about the role of abnormal glutamate metabolism in the pathogenesis of the MS is certainly challenging and suggests the critical role of the liver in the global metabolic modulation as glutamate metabolism is linked with aminotransferase reactions.We discuss here the critical role of the 'liver metabolism' in the pathogenesis of the MS and IR,and postulate that before fatty liver develops,abnormal levels of liver enzymes,such as alanine and aspartate aminotransferases might reflect high levels of hepatic transamination of amino acids in the liver. | Silvia Sookoian Carlos J Pirola | 2012 | World Journal of Gastroenterology2012，18，29： | 11 |
| 4 | Role of pro-and anti-inflammatory phenomena in the physiopathology of type 2 diabetes and obesity显示文摘In obesity, persistent low-grade inflammation is considered as a major contributor towards the progression to insulin resistance and type 2 diabetes while in lean subjects the immune environment is non-inflammatory. Massive adipose tissue(AT) infiltration by pro-inflammatory M1 macrophages and several T cell subsets as obesity develops leads to the accumulation-both in the AT and systemically-of numerous pro-inflammatory cytokines, including interleukin-1β(IL-1β), tumor necrosis factor a, IL-17 and IL-6 which are strongly associated with the progression of the obese phenotype towards the metabolic syndrome. At the same time, anti-inflammatory M2 macrophages and Th subsets producing the antiinflammatory cytokines IL-10, IL-5 and interferon-γ, including Th2 and T-reg cells are correlated to the maintenance of AT homeostasis in lean individuals. Here, we discuss the basic principles in the control of the interaction between the AT and infiltrating immune cells both in the lean and the obese condition with a special emphasis on the contribution of pro-and antiinflammatory cytokines to the establishment of the insulinresistant state. In this context, we will discuss the current knowledge about alterations in the levels on pro-and antiinflammatory cytokines in obesity, insulin resistance and type 2 diabetes mellitus, in humans and animal models. Finally, we also briefly survey the recent novel therapeutic strategies that attempt to alleviate or reverse insulin resistance and type 2 diabetes via the administration of recombinant inhibitory antibodies directed towards some pro-inflammatory cytokines. | Luciano Pirola JoséCandido Ferraz | 2017 | World Journal of Biological Chemistry2017，8，2： | 10 |
| 5 | Multiomics biomarkers for the prediction of nonalcoholic fatty liver disease severity显示文摘This review intends to uncover how information from large-scale genetic profiling(whole genome sequencing, and whole exome sequencing) of nonalcoholic fatty liver disease(NAFLD), as well as information from circulating transcriptomics(cell-free mi RNAs) and metabolomics, contributes to the understanding of NAFLD pathogenesis. A further aim is to address the question of whether OMICs information is ready to be implemented in the clinics. The available evidence suggests that any new knowledge pertaining to molecular signatures associated with NAFLD and nonalcoholic steatohepatitis should be promptly translated into the clinical setting. Nevertheless, rigorous steps that must include validation and replication are mandatory before utilizing OMICs biomarkers in diagnostics to identify patients at risk of advanced disease, including liver cancer. | Carlos J Pirola Silvia Sookoian | 2018 | World Journal of Gastroenterology2018，24，15： | 8 |
| 6 | PNPLA3,the triacylglycerol synthesis/hydrolysis/storage dilemma,and nonalcoholic fatty liver disease显示文摘Genome-wide and candidate gene association studies have identified several variants that predispose individuals to developing nonalcoholic fatty liver disease(NAFLD).However,the gene that has been consistently involved in the genetic susceptibility of NAFLD in humans is patatin-like phospholipase domain containing 3(PNPLA3,also known as adiponutrin).A nonsynonymous single nucleotide polymorphism in PNPLA3(rs738409 C/G,a coding variant that encodes an amino acid substitution I148M) is significantly associated with fatty liver and histological disease severity,not only in adults but also in children.Nevertheless,how PNPLA3 influences the biology of fatty liver disease is still an open question.A recent article describes new aspects about PNPLA3 gene/protein function and suggests that the I148M variant promotes hepatic lipid synthesis due to a gain of function.We revise here the published data about the role of the I148M variant in lipogenesis/lipolysis,and suggest putative areas of future research.For instance we explored in silico whether the rs738409 C or G alleles have the ability to modify miRNA binding sites and miRNA gene regulation,and we found that prediction of PNPLA3 target miRNAs shows two miRNAs potentially interacting in the 3' UTR region(hsa-miR-769-3p and hsa-miR-516a-3p).In addition,interesting unanswered questions remain to be explored.For example,PNPLA3 lies between two CCCTC-binding factor-bound sites that could be tested for insulator activity,and an intronic histone 3 lysine 4 trimethylation peak predicts an enhancer element,corroborated by the DNase Ⅰ hypersensitivity site peak.Finally,an interaction between PNPLA3 and glycerol3-phosphate acyltransferase 2 is suggested by data miming. | Silvia Sookoian Carlos J Pirola | 2012 | World Journal of Gastroenterology2012，18，42： | 7 |
| 7 | Common genetic variations in CLOCK transcription factor are associated with nonalcoholic fatty liver disease显示文摘AIM: To investigate the role of gene variants and derived haplotypes of the CLOCK transcription factor in nonalcoholic fatty liver disease (NAFLD) and their relation with the disease severity. METHODS: A total of 136 patients with NAFLD and 64 healthy individuals were studied. Liver biopsy was performed in 91 patients. Six tag SNPs showing a minor allele frequency > 10% (rs1554483 C/G; rs11932595 A/G; rs4580704 C/G; rs6843722 A/C; rs6850524 C/G and rs4864548 A/G) encompassing 117 kb of chromosome 4 and representing 115 polymorphic sites (r2 > 0.8) were genotyped. RESULTS: rs11932595 and rs6843722 showed signifi cant associations with NAFLD (empiric P = 0.0449 and 0.023, respectively). A significant association was also observed between clinical or histologic spectrum of NAFLD and rs1554483 (empiric P = 0.0399), rs6843722 (empiric P = 0.0229) and rs6850524 (empiric P = 0.00899) and between fibrosis score and rs1554483 (empiric P = 0.02697), rs6843722 (empiric P = 0.01898) and rs4864548 (empiric P = 0.02697). Test of haplotypic association showed that CLOCK gene variant haplotypes frequencies in NAFLD individuals significantly differed from those in controls (empiric P = 0.0097). CONCLUSION: Our study suggests a potential role of the CLOCK polymorphisms and their haplotypes insusceptibility to NAFLD and disease severity. | Silvia Sookoian Gustavo Castao Carolina Gemma Tomas Fernández Gianotti Carlos Jose Pirola | 2007 | World Journal of Gastroenterology2007，13，31： | 5 |
| 8 | Role of ABCC2 common variants in intrahepatic cholestasis of pregnancy显示文摘The pathogenesis of intrahepatic cholestasis of pregnancy (ICP), a disorder that adversely affects maternal wellbeing and fetal outcome, is unclear. However, multiple factors probably interact along with a genetic predisposition. We would like to add some comments on a paper recently published concerning the role of ABCB11 and ABCC2 polymorphisms in both ICP and contraceptive-induced cholestasis, especially in the light of our recently published findings about a positive association between ICP and ABCC2 common variants. | Silvia Sookoian Gustavo Castao Carlos J Pirola | 2008 | World Journal of Gastroenterology2008，14，13： | 4 |
| 9 | Acute coronary syndrome: a rare case of multiple endocrine neoplasia syndromes with pheochromocytoma and medullary thyroid carcinoma显示文摘Pheochromocytoma is a tumor arising from neuroectodermal chromaffin tissues in the adrenal gland or extra-adrenal paraganglia(paragangliomas). The prevalence of the tumor is 0.1%-0.6% in the hypertensive population, of which 10%-20% are malignant. Pheochromocytoma produces, stores, and secretes catecholamines, as well as leads to hypertensive crisis, arrhythmia, angina, and acute myocardial infarction without coronary artery diseases. We report a case of acute coronary syndrome(ACS) with a final diagnosis of multiple endocrine neoplasia with pheochromocytoma and medullary thyroid carcinoma(MTC). | Alessadro Maloberti Paolo Meani Roberto Pirola Marisa Varrenti Marco Boniardi Anna Maria De Biase Paola Vallerio Edgardo Bonacina Giuseppe Mancia Paola Loli Cristina Giannattasio | 2015 | Cancer Biology & Medicine2015，12，3： | 4 |
| 10 | Effects of ketogenic diet and ketone bodies on the cardiovascular system:Concentration matters显示文摘Ketone bodies have emerged as central mediators of metabolic health,and multiple beneficial effects of a ketogenic diet,impacting metabolism,neuronal pathologies and,to a certain extent,tumorigenesis,have been reported both in animal models and clinical research.Ketone bodies,endogenously produced by the liver,act pleiotropically as metabolic intermediates,signaling molecules,and epigenetic modifiers.The endothelium and the vascular system are central regulators of the organism’s metabolic state and become dysfunctional in cardiovascular disease,atherosclerosis,and diabetic micro-and macrovascular complications.As physiological circulating ketone bodies can attain millimolar concentrations,the endothelium is the first-line cell lineage exposed to them.While in diabetic ketoacidosis high ketone body concentrations are detrimental to the vasculature,recent research revealed that ketone bodies in the low millimolar range may exert beneficial effects on endothelial cell(EC)functioning by modulating the EC inflammatory status,senescence,and metabolism.Here,we review the long-held evidence of detrimental cardiovascular effects of ketoacidosis as well as the more recent evidence for a positive impact of ketone bodies—at lower concentrations—on the ECs metabolism and vascular physiology and the subjacent cellular and molecular mechanisms.We also explore arising controversies in the field and discuss the importance of ketone body concentrations in relation to their effects.At low concentration,endogenously produced ketone bodies upon uptake of a ketogenic diet or supplemented ketone bodies(or their precursors)may prove beneficial to ameliorate endothelial function and,consequently,pathologies in which endothelial damage occurs. | Souad Nasser Varvara Vialichka Marta Biesiekierska Aneta Balcerczyk Luciano Pirola | 2020 | World Journal of Diabetes2020，11，12： | 4 |
| 11 | Obstructive Sleep Apnea Is Associated with Fatty Liver and Abnormal Liver Enzymes: a Meta-analysis显示文摘 | Silvia Sookoian Carlos J. Pirola | 2013 | Obesity Surgery2013，，11： | 3 |
| 12 | The Genetic Epidemiology of Nonalcoholic Fatty Liver Disease显示文摘 | Silvia Sookoian Carlos J. Pirola | 2012 | Clinics in Liver Disease2012，，3： | 3 |
| 13 | Activation of Pancreatic Stellate Cells in Human and Experimental Pancreatic Fibrosis显示文摘 | Paul S. Haber Gregory W. Keogh Minoti V. Apte Corey S. Moran Nancy L. Stewart Darrell H.G. Crawford Romano C. Pirola Geoffrey W. McCaughan Grant A. Ramm Jeremy S. Wilson | 1999 | The American Journal of Pathology1999，，4： | 2 |
| 14 | Role of Pancreatic Stellate Cells in Pancreatic Cancer Metastasis显示文摘 | Zhihong Xu Alain Vonlaufen Phoebe A. Phillips Eva Fiala-Beer Xuguo Zhang Lu Yang Andrew V. Biankin David Goldstein Romano C. Pirola Jeremy S. Wilson Minoti V. Apte | 2010 | The American Journal of Pathology2010，，5： | 2 |
| 15 | Pleiotropy within gene variants associated with nonalcoholic fatty liver disease and traits of the hematopoietic system显示文摘Genome-wide association studies of complex diseases,including nonalcoholic fatty liver disease(NAFLD),have demonstrated that a large number of variants are implicated in the susceptibility of multiple traits—a phenomenon known as pleiotropy that is increasingly being explored through phenome-wide association studies.We focused on the analysis of pleiotropy within variants associated with hematologic traits and NAFLD.We used information retrieved from large public National Health and Nutrition Examination Surveys,Genome-wide association studies,and phenome-wide association studies based on the general population and explored whether variants associated with NAFLD also present associations with blood cell-related traits.Next,we applied systems biology approaches to assess the potential biological connection/s between genes that predispose affected individuals to NAFLD and nonalcoholic steatohepatitis,and genes that modulate hematological-related traits—specifically platelet count.We reasoned that this analysis would allow the identification of potential molecular mediators that link NAFLD with platelets.Genes associated with platelet count are most highly expressed in the liver,followed by the pancreas,heart,and muscle.Conversely,genes associated with NAFLD presented high expression levels in the brain,lung,spleen,and colon.Functional mapping,gene prioritization,and functional analysis of the most significant loci(P<1×10-8)revealed that loci involved in the genetic modulation of platelet count presented significant enrichment in metabolic and energy balance pathways.In conclusion,variants in genes influencing NAFLD exhibit pleiotropic associations with hematologic traits,particularly platelet count.Likewise,significant enrichment of related genes with variants influencing platelet traits was noted in metabolic-related pathways.Hence,this approach yields novel mechanistic insights into NAFLD pathogenesis. | Carlos Jose Pirola Adrian Salatino Silvia Sookoian | 2021 | World Journal of Gastroenterology2021，27，4： | 2 |
| 16 | Non-alcoholic fatty liver disease is strongly associated with carotid atherosclerosis: A systematic review显示文摘 | Silvia Sookoian Carlos J. Pirola | 2008 | Journal of Hepatology2008，，4： | 2 |
| 17 | Epigenetic modification of liver mitochondrial DNA is associated with histological severity of nonalcoholic fatty liver disease显示文摘 | Carlos Jose Pirola Tomas Fernández Gianotti Adriana Laura Burgue?o Manuel Rey-Funes Cesar Fabian Loidl Pablo Mallardi Julio San Martino Gustavo Osvaldo Casta?o S Sookoian | 2013 | Gut2013，，9： | 2 |
| 18 | Repeat hepatectomy for recurrent colorectal liver metastases:A comparative analysis of short-and long-term results显示文摘Background: Liver recurrence after resection of colorectal liver metastases(CRLM) is frequent. Repeat hepatectomy has been shown to have satisfactory perioperative results. However, the long-term outcomes and the benefts for patients with early recurrence have not been clarifed. The aim of this study was to compare the short-and long-term outcomes of patients undergoing single hepatectomy and repeat hepatectomy for CRLM. Additionally, the oncological outcomes of patients with early( ≤ 6 months) and late recurrence who underwent repeat hepatectomy were compared. Methods: Consecutive adult patients undergoing hepatectomy for CRLM between June 20 0 0 and February 2020 were included and divided into two groups: single hepatectomy and repeat hepatectomy. Results: A total of 709 patients were included: 649 in the single hepatectomy group and 60 in the repeat hepatectomy group. Patients in the repeat hepatectomy group underwent more cycles of preoperative chemotherapy [4(3-6) vs. 3(2-4), P = 0.003]. Patients in the single hepatectomy group more frequently underwent major hepatectomies(34.5% vs. 16.7%, P = 0.004) and had a greater number of lesions resected(2.9 ± 3.6 vs. 1.9 ± 1.8, P = 0.011). There was no increase in operative time, estimated blood loss, length of hospital stay, complications, or mortality in the repeat hepatectomy group. There were no differences in overall survival( P = 0.626) and disease-free survival( P = 0.579) between the two groups. Similarly, for patients underwent repeat hepatectomy, no difference was observed between the early and late recurrence groups in terms of overall survival( P = 0.771) or disease-free survival( P = 0.350). Conclusions: Repeat hepatectomy is feasible and safe, with similar short-and long-term outcomes when compared to single hepatectomy. Surgical treatment of early liver recurrence offers similar oncological outcomes to those obtained for late recurrence. | Paulo Figueiredo Costa Fabricio Ferreira Coelho Vagner Birk Jeismann Jaime Arthur Pirola Kruger Gilton Marques Fonseca Ivan Cecconello Paulo Herman | 2022 | Hepatobiliary & Pancreatic Diseases International2022，21，2： | 2 |
| 19 | Fine needle cytology of complex thyroid nodules显示文摘 | Cappelli C Pirola 1 Castellano M | | 0，，4： | 1 |
| 20 | Gene therapy of experimental brain tumors using neural progenitor cells显示文摘 | Benedetti S Pirola B Pollo B | 2000 | Nature Med2000，6，4： | 1 |
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