Non-invasive diagnostic biomarkers may contribute to an early identification of gastric cancer(GC) and improve the clinical management.Unfortunately,no sensitive and specific screening biomarkers are available yet and...Non-invasive diagnostic biomarkers may contribute to an early identification of gastric cancer(GC) and improve the clinical management.Unfortunately,no sensitive and specific screening biomarkers are available yet and the currently available approaches are limited by the nature of the disease.GC is a heterogenic disease with various distinct genetic and epigenetic events that occur during the multifactorial cascade of carcinogenesis.Micro RNAs(mi RNAs) are commonly deregulated in gastric mucosa during the Helicobacter pylori infection and in stepwise manner from chronic gastritis,through preneoplastic conditions such as atrophic gastritis and intestinal metaplasia,to early dysplasia and invasive cancer.Identification of mi RNAs in blood in 2008 led to a great interest on mi RNA-based diagnostic,prognostic biomarkers in GC.In this review,we provide the most recent systematic review on the existing studies related to mi RNAs as diagnostic biomarkers for GC.Here,we systematically evaluate 75 studies related to differential expression of circulating mi RNAs in GC patients and provide novel view on various heterogenic aspects of the existing data and summarize the methodological differences.Finally,we highlight several important aspects crucial to improve the future translational and clinical research in the field.展开更多
To evaluate the frequency of Helicobacter pylori(H.pylori)CagA antibodies in H.pylori infected subjects and to identify potential histopathological and bacterial factors related to H.pylori CagA-immune response.METHOD...To evaluate the frequency of Helicobacter pylori(H.pylori)CagA antibodies in H.pylori infected subjects and to identify potential histopathological and bacterial factors related to H.pylori CagA-immune response.METHODSSystematic data to H.pylori isolates,blood samples,gastric biopsies for histological and molecular analyses were available from 99 prospectively recruited subjects.Serological profile(anti-H.pylori,anti-CagA)was correlated with H.pylori isolates(cagA,EPIYA,vacA s/m genotype),histology(Sydney classification)and mucosal interleukin-8(IL-8)mRNA and protein expression.Selected H.pylori strains were assessed for H.pylori CagA protein expression and IL-8 induction in co-cultivation model with AGS cells.RESULTSThirty point three percent of microbiologically confirmed H.pylori infected patients were seropositive for CagA.Majority of H.pylori isolates were cagA gene positive(93.9%)with following vacA polymorphisms:42.4%vacA s1m1,23.2%s1m2 and 34.3%s2m2.Anti-CagA-IgG seropositivity was strongly associated with atrophic gastritis,increased mucosal inflammation according to the Sydney score,IL-8 and cagA mRNA expression.VacA s and m polymorphisms were the major determinants for positive(vacA s1m1)or negative(vacA s2m2)anti-CagA serological immune response,which also correlated with the in vitro inflammatory potential in AGS cells.In vitro co-cultivation of representative H.pylori strains with AGS cells confirmed functional CagA translocation,which showed only partial correlation with CagA seropositivity in patients,supporting vacA as major co-determinant of the immune response.CONCLUSIONSerological immune response to H.pylori cagA+strain in H.pylori infected patients is strongly associated with vacA polymorphism,suggesting the crucial role of bacterial factors in immune and clinical phenotype of the infection.展开更多
Biomarkers for surveillance, diagnosis and prediction of prognosis in patients with hepatocellular carcinoma(HCC) are currently not ready for introduction into clinical practice because of limited sensitivity and spec...Biomarkers for surveillance, diagnosis and prediction of prognosis in patients with hepatocellular carcinoma(HCC) are currently not ready for introduction into clinical practice because of limited sensitivity and specificity. Especially for the early detection of small HCC novel biomarkers are needed to improve the current effectiveness of screening performed byultrasound. The use of high-throughput technologies in hepatocellular research allows to identify molecules involved in the complex pathways in hepatocarcinogenesis. Several invasive and non-invasive biomarkers have been identified already and have been evaluated in different clinical settings. Gene signatures with prognostic potential have been identified by gene expression profiling from tumor tissue. However, a single "all-in-one" biomarker that fits all-surveillance, diagnosis, prediction of prognosis-has not been found so far. The future of biomarkers most probably lies in a combination of non-invasive biomarkers, imaging and clinical parameters in a surveillance setting. Molecular profiling of tumorous and non-tumorous liver tissue may allow a prediction of prognosis for the individual patient and hopefully clear the way for individual treatment approaches. This article gives an overview on current developments in biomarker research in HCC with a focus on currently available and novel biomarkers, in particular on micro RNA.展开更多
BACKGROUND Gastric cancer(GC)is one of the most frequently diagnosed tumor globally.In most cases,GC develops in a stepwise manner from chronic gastritis or atrophic gastritis(AG)to cancer.One of the major issues in c...BACKGROUND Gastric cancer(GC)is one of the most frequently diagnosed tumor globally.In most cases,GC develops in a stepwise manner from chronic gastritis or atrophic gastritis(AG)to cancer.One of the major issues in clinical settings of GC is diagnosis at advanced disease stages resulting in poor prognosis.Micro RNAs(mi RNAs)are small noncoding molecules that play an essential role in a variety of fundamental biological processes.However,clinical potential of mi RNA profiling in the gastric cancerogenesis,especially in premalignant GC cases,remains unclear.AIM To evaluate the AG and GC tissue mi RNomes and identify specific mi RNAs’potential for clinical applications(e.g.,non-invasive diagnostics).METHODS Study included a total of 125 subjects:Controls(CON),AG,and GC patients.All study subjects were recruited at the Departments of Surgery or Gastroenterology,Hospital of Lithuanian University of Health Sciences and divided into the profiling(n=60)and validation(n=65)cohorts.Total RNA isolated from tissue samples was used for preparation of small RNA sequencing libraries and profiled using next-generation sequencing(NGS).Based on NGS data,deregulated mi RNAs hsa-mi R-129-1-3 p and hsa-mi R-196 a-5 p were analyzed in plasma samples of independent cohort consisting of CON,AG,and GC patients.Expression level of hsa-mi R-129-1-3 p and hsa-mi R-196 a-5 p was determined using the quantitative real-time polymerase chain reaction and 2-ΔΔCt method.RESULTS Results of tissue analysis revealed 20 differentially expressed mi RNAs in AG group compared to CON group,129 deregulated mi RNAs in GC compared to CON,and 99 altered mi RNAs comparing GC and AG groups.Only 2 mi RNAs(hsa-mi R-129-1-3 p and hsa-mi R-196 a-5 p)were identified to be step-wise deregulated in healthy-premalignant-malignant sequence.Area under the curve(AUC)-receiver operating characteristic analysis revealed that expression level of hsa-mi R-196 a-5 p is significant for discrimination of CON vs AG,CON vs GC and AG vs GC and resulted in AUCs:88.0%,93.1%and 66.3%,respectively.Comparing results in tissue and plasma samples,hsa-mi R-129-1-3 p was significantly down-regulated in GC compared to AG(P=0.0021 and P=0.024,tissue and plasma,respectively).Moreover,analysis revealed that hsa-mi R-215-3 p/5 p and hsa-mi R-934 were significantly deregulated in GC based on Helicobacter pylori(H.pylori)infection status[log2 fold change(FC)=-4.52,P-adjusted=0.02;log2 FC=-4.00,P-adjusted=0.02;log2 FC=6.09,P-adjusted=0.02,respectively].CONCLUSION Comprehensive mi RNome study provides evidence for gradual deregulation of hsa-mi R-196 a-5 p and hsa-mi R-129-1-3 p in gastric carcinogenesis and found hsami R-215-3 p/5 p and hsa-mi R-934 to be significantly deregulated in H.pylori carrying GC patients.展开更多
BACKGROUND There is ongoing search for new noninvasive biomarkers to improve management of patients with hepatocellular carcinoma(HCC).Studies,mostly from the Asian-Pacific region,demonstrated differential expression ...BACKGROUND There is ongoing search for new noninvasive biomarkers to improve management of patients with hepatocellular carcinoma(HCC).Studies,mostly from the Asian-Pacific region,demonstrated differential expression of liverspecific microRNA-122(miR-122)in tissue as well as in sera of patients with hepatitis B virus-and hepatitis C virus-induced HCC.AIM To evaluate prognostic value of miR-122 in patients with HCC in a European population and determine potential factors related to alteration of miR-122 in sera.METHODS Patients with confirmed HCC(n=91)were included in the study over a two-year period.Patients were characterized according to Child-Pugh score,Barcelona clinic liver cancer(BCLC)staging system,etiology of liver disease,laboratory parameters and overall survival.MiR-122 was measured in sera using TaqMan assay normalized to spiked-in cel-miR-39.RESULTS Serum miR-122 quantity was independent of the Child-Pugh score,the BCLC stage or the underlying etiology.Significant positive correlation was found between miR-122 and alanine aminotransferase(P<0.0001),aspartate aminotransferase(P=0.0001),alpha-fetoprotein(AFP)(P=0.0034)and hemoglobin concentration(P=0.076).Negative correlation was observed between miR-122 level and creatinine concentration(P=0.0028).AFP,Child-Pugh score and BCLC staging system were associated with survival differences.In overall cohort low miR-122 in sera was only associated with a trend for a better overall survival without reaching statistical significance.Subgroup analysis revealed that low miR-122 was significantly associated with better prognosis in patients with advanced cirrhosis(Child-Pugh class B/C),advanced tumor stage(BCLC B/C/D)and normal AFP(<7 ng/mL).CONCLUSION Our results strongly support the value of miR-122 as potential biomarker of liver injury and probably prognosis.Nevertheless,the value of miR-122 in prediction of prognosis of HCC patients was limited to certain patients’subgroups.Since circulating miR-122 may be influenced by impaired renal function,AFP and hemoglobin concentration,those factors need to be considered while interpreting miR-122 level.展开更多
BACKGROUND Helicobacter pylori and the stomach microbiome play a crucial role in gastric carcinogenesis,and detailed characterization of the microbiome is necessary for a better understanding of the pathophysiology of...BACKGROUND Helicobacter pylori and the stomach microbiome play a crucial role in gastric carcinogenesis,and detailed characterization of the microbiome is necessary for a better understanding of the pathophysiology of the disease.There are two common modalities for microbiome analysis:DNA(16S rRNA gene)and RNA(16S rRNA transcript)sequencing.The implications from the use of one or another sequencing approach on the characterization and comparability of the mucosal microbiome in gastric cancer(GC)are poorly studied.AIM To characterize the microbiota of GC using 16S rRNA gene and its transcript and determine difference in the bacterial composition.METHODS In this study,316 DNA and RNA samples extracted from 105 individual stomach biopsies were included.The study cohort consisted of 29 healthy control individuals and 76 patients with GC.Gastric tissue biopsy samples were collected from damaged mucosa and healthy mucosa at least 5 cm from the tumor tissue.From the controls,healthy stomach mucosa biopsies were collected.From all biopsies RNA and DNA were extracted.RNA was reverse transcribed into cDNA.V1-V2 region of bacterial 16S rRNA gene from all samples were amplified and sequenced on an Illumina MiSeq platform.Bray-Curtis algorithm was used to construct sample-similarity matrices abundances of taxonomic ranks in each sample type.For significant differences between groups permutational multivariate analysis of variance and Mann-Whitney test followed by false-discovery rate test were used.RESULTS Microbial analysis revealed that only a portion of phylotypes(18%-30%)overlapped between microbial profiles obtained from DNA and RNA samples.Detailed analysis revealed differences between GC and controls depending on the chosen modality,identifying 17 genera at the DNA level and 27 genera at the RNA level.Ten of those bacteria were found to be different from the control group at both levels.The key taxa showed congruent results in various tests used;however,differences in 7 bacteria taxa were found uniquely only at the DNA level,and 17 uniquely only at the RNA level.Furthermore,RNA sequencing was more sensitive for detecting differences in bacterial richness,as well as differences in the relative abundance of Reyranella and Sediminibacterium according to the type of GC.In each study group(control,tumor,and tumor adjacent)were found differences between DNA and RNA bacterial profiles.CONCLUSION Comprehensive microbial study provides evidence for the effect of choice of sequencing modality on the microbiota profile,as well as on the identified differences between case and control.展开更多
AIM To evaluate associations between mi RNA target genes IL12B,INSR,CCND1 and IL10 polymorphisms and gastric cancer(GC)in European population.METHODS Gene polymorphisms were analyzed in 508 controls and474 GC patients...AIM To evaluate associations between mi RNA target genes IL12B,INSR,CCND1 and IL10 polymorphisms and gastric cancer(GC)in European population.METHODS Gene polymorphisms were analyzed in 508 controls and474 GC patients from 3 tertiary centers in Germany,Lithuania and Latvia.Controls were patients from the out-patient departments,who were referred for upper endoscopy because of dyspeptic symptoms and had no history of previous malignancy.Gastric cancer(GC)patients had histopathological verification of gastric adenocarcinoma.Genomic DNA was extracted using salting out method from peripheral blood mononuclear cells.IL12B T>G(rs1368439),INSR T>C(rs1051690),CCND1 A>C(rs7177)and IL10 T>C(rs3024498)SNPs were genotyped by the real-time polymerase chain reaction.Associations between gene polymorphism and GC were evaluated using multiple logistic regression analysis with adjustment for sex,age and country of birth.RESULTS We observed similar distribution of genotypes and allelic frequencies of all polymorphisms between GC patients and controls except of INSR rs1051690.The frequency of the T allele of INSR gene was significantly higher in GC patients than in controls(23.26%and 19.19%respectively,P=0.028).CT genotype was also more prevalent in patients compared to control group(38.48%and 30.12%respectively,P<0.021).Logistic regression analysis revealed that only one polymorphism(rs1051690 in INSR gene)was associated with increased risk of GC.Carriers of CT genotype had higher odds of GC when compared to CC genotype(OR=1.45,95%PI:1.08-1.95,P=0.01).Similar association was observed in a dominant model for INSR gene,where comparison of TT+CT vs CC genotypes showed an increased risk of GC(OR=1.44,95%PI:1.08-1.90,P=0.01).Other analyzed SNPs were not associated with the presence of GC.CONCLUSION INSR rs1051690 SNP is associated with increased risk of GC,while polymorphisms in IL12B,CCND1 and IL10genes are not linked with the presence of GC.展开更多
BACKGROUND Clinically significant portal hypertension(CSPH) and severe portal hypertension(SPH) increase the risk for decompensation and life-threatening complications in liver cirrhosis. Pathologic angiogenesis might...BACKGROUND Clinically significant portal hypertension(CSPH) and severe portal hypertension(SPH) increase the risk for decompensation and life-threatening complications in liver cirrhosis. Pathologic angiogenesis might contribute to the formation of these conditions. Placental growth factor(PlGF) and Nogo-A protein are biomarkers of pathological angiogenesis, but data on their role in liver cirrhosis and portal hypertension is scarce.AIM To determine plasma levels of PlGF and Nogo-A in patients with liver cirrhosis,CSPH, SPH and potential to predict portal hypertension.METHODS A cohort of 122 patients with hepatitis C virus and/or alcohol-induced liver cirrhosis with characterized hepatic venous pressure gradient(HVPG) were included in the study. Demographic data, medical history, Child-Turcotte-Pugh and Model of End Stage liver disease score, clinical chemistry, liver stiffnessvalues were recorded on the day of the procedure prior HVPG measurement. The degree of portal hypertension was determined by the invasive HVPG measurement. Nogo-A and PlGF plasma levels were evaluated using enzyme linked immunosorbent assay. The control group consisted of 30 healthy age-and sex-matched individuals.RESULTS Peripheral PlGF levels were higher and Nogo-A levels were lower in patients with liver cirrhosis(23.20 vs 9.85;P < 0.0001 and 2.19 vs 3.12;P = 0.004 respectively). There was a positive linear correlation between peripheral levels of PlGF and HVPG(r = 0.338, P = 0.001) and negative linear correlation between the peripheral Nogo-A levels and HVPG(r =-0.267, P = 0.007). PlGF levels were higher in CSPH and SPH(P = 0.006;P < 0.0001) whereas Nogo-A levels were lower(P = 0.01;P < 0.033). Area under the curve for the diagnosis of CSPH for PlGF was 0.68(P = 0.003) and for Nogo-A-0.67(P = 0.01);for SPH 0.714(P <0.0001) and 0.65(P = 0.014) respectively. PlGF levels were higher and Nogo-A levels were lower in patients with esophageal varices(P < 0.05). PlGF cut-off value of 25 pg/mL distinguished patients with CSPH at 55.7% sensitivity and76.7% specificity;whereas Nogo-A cut-off value of 1.12 ng/mL was highly specific(93.1%) for the diagnosis of CSPH.CONCLUSION Plasma PlGF levels were higher while Nogo-A levels were lower in patients with liver cirrhosis and portal hypertension. Biomarkers showed moderate predictive value in determining CSPH and SPH.展开更多
BACKGROUND MicroRNAs(miRNAs)have been suggested as biomarkers for malignant diseases including hepatocellular carcinoma(HCC).Specifically,hsa-miR-21-5p(miR-21)is among the most frequently deregulated miRNA in cancer.T...BACKGROUND MicroRNAs(miRNAs)have been suggested as biomarkers for malignant diseases including hepatocellular carcinoma(HCC).Specifically,hsa-miR-21-5p(miR-21)is among the most frequently deregulated miRNA in cancer.The diagnostic and prognostic value of miR-21 has been demonstrated in HCC tissue,mostly in the Asian population.Although the impact of various factors has been recently reported for circulating hsa-miR-122-5p(miR-122),at present only limited knowledge is available for miR-21.AIM To evaluate the value of miR-21 for the assessment of prognosis in HCC patients and to delineate the influence of clinical and preanalytical factors on miR-21 level in sera.METHODS Patients with confirmed HCC from our European cohort with predominantly alcohol-associated liver damage were included in the study.All subjects were characterized according to their clinical and laboratory work-up and overall survival data were obtained.Quantitative real-time polymerase chain reaction was performed for miR-21 and spiked-in cel-miR-39-3p.The results were compared to previously reported miR-122 data.RESULTS Survival of HCC patients was comparable between patients with low and high serum miR-21 concentration.No association was observed between miR-21 level in sera and Child-Pugh score,Barcelona Clinic Liver Cancer staging system,or etiology of HCC/liver disease.Age,gender,or pretreatment had no association with miR-21 level.A positive correlation was observed between miR-21 and aspartate aminotransferase(r=0.2854,P=0.0061),serum miR-122(r=0.2624,P=0.0120),and the International Normalized Ratio(r=0.2065,P=0.0496).Negative correlation of miR-21 with serum creatinine(r=-0.2215,P=0.0348)suggests renal function as a potential influencing factor in miR-21 biogenesis in blood.CONCLUSION The results from this work do not support clinically relevant prognostic value of circulating miR-21 in HCC patients in real-life settings.Following systematic evaluation,we identified renal function and aspartate aminotransferase as potential factors that may affect miR-21 concentration in blood.This knowledge should be considered in future miRNA-based biomarker studies not only for HCC but also for other diseases.展开更多
Fusobacterium nucleatum(F.nucleatum)is a Gram-negative anaerobic bacterium that plays a key role in the development of oral inflammation,such as periodontitis and gingivitis.In the last 10 years,F.nucleatum has been i...Fusobacterium nucleatum(F.nucleatum)is a Gram-negative anaerobic bacterium that plays a key role in the development of oral inflammation,such as periodontitis and gingivitis.In the last 10 years,F.nucleatum has been identified as a prevalent bacterium associated with colorectal adenocarcinoma and has also been linked to cancer progression,metastasis and poor disease outcome.While the role of F.nucleatum in colon carcinogenesis has been intensively studied,its role in gastric carcinogenesis is still poorly understood.Although Helicobacter pylori infection has histo-rically been recognized as the strongest risk factor for the development of gastric cancer(GC),with recent advances in DNA sequencing technology,other members of the gastric microbial community,and F.nucleatum in particular,have received increasing attention.In this review,we summarize the existing knowledge on the involvement of F.nucleatum in gastric carcinogenesis and address the potential translational and clinical significance of F.nucleatum in GC.展开更多
AIM:To study the impact of an endoscopy-based long-term study on the quality of life in healthy volunteers(HV).METHODS:Ten HV were included into a long-term prospective endoscopy-based placebo-controlled trial with 15...AIM:To study the impact of an endoscopy-based long-term study on the quality of life in healthy volunteers(HV).METHODS:Ten HV were included into a long-term prospective endoscopy-based placebo-controlled trial with 15 endoscopic examinations per person in 5 different drug phases.Participants completed short form-36(SF-36) and visual analog scale-based questionnaires(VAS) for different abdominal symptoms at days 0,7 and 14 of each drug phase.Analyses wereperformed according to short-and long-term changes and compared to the control group.RESULTS:All HV completed the study with duration of more than 6 mo.Initial quality of life score was comparable to a general population.Analyses of the SF-36 questionnaires showed no significant changes in physical,mental and total scores,either in a short-term perspective due to different medications,or to potentially endoscopic procedure-associated long-term cumulative changes.Analogous to SF-36,VAS revealed no significant changes in total scores for pathological abdominal symptoms and remained unchanged over the time course and when compared to the control population.CONCLUSION:This study demonstrates that quality of life in HV is not significantly affected by a longterm endoscopy-based study with multiple endoscopic procedures.展开更多
文摘Non-invasive diagnostic biomarkers may contribute to an early identification of gastric cancer(GC) and improve the clinical management.Unfortunately,no sensitive and specific screening biomarkers are available yet and the currently available approaches are limited by the nature of the disease.GC is a heterogenic disease with various distinct genetic and epigenetic events that occur during the multifactorial cascade of carcinogenesis.Micro RNAs(mi RNAs) are commonly deregulated in gastric mucosa during the Helicobacter pylori infection and in stepwise manner from chronic gastritis,through preneoplastic conditions such as atrophic gastritis and intestinal metaplasia,to early dysplasia and invasive cancer.Identification of mi RNAs in blood in 2008 led to a great interest on mi RNA-based diagnostic,prognostic biomarkers in GC.In this review,we provide the most recent systematic review on the existing studies related to mi RNAs as diagnostic biomarkers for GC.Here,we systematically evaluate 75 studies related to differential expression of circulating mi RNAs in GC patients and provide novel view on various heterogenic aspects of the existing data and summarize the methodological differences.Finally,we highlight several important aspects crucial to improve the future translational and clinical research in the field.
基金Supported by the BMBF No.BMBF-0315905D in the frame of ERA-NET Patho Geno Mics to Malfertheiner P
文摘To evaluate the frequency of Helicobacter pylori(H.pylori)CagA antibodies in H.pylori infected subjects and to identify potential histopathological and bacterial factors related to H.pylori CagA-immune response.METHODSSystematic data to H.pylori isolates,blood samples,gastric biopsies for histological and molecular analyses were available from 99 prospectively recruited subjects.Serological profile(anti-H.pylori,anti-CagA)was correlated with H.pylori isolates(cagA,EPIYA,vacA s/m genotype),histology(Sydney classification)and mucosal interleukin-8(IL-8)mRNA and protein expression.Selected H.pylori strains were assessed for H.pylori CagA protein expression and IL-8 induction in co-cultivation model with AGS cells.RESULTSThirty point three percent of microbiologically confirmed H.pylori infected patients were seropositive for CagA.Majority of H.pylori isolates were cagA gene positive(93.9%)with following vacA polymorphisms:42.4%vacA s1m1,23.2%s1m2 and 34.3%s2m2.Anti-CagA-IgG seropositivity was strongly associated with atrophic gastritis,increased mucosal inflammation according to the Sydney score,IL-8 and cagA mRNA expression.VacA s and m polymorphisms were the major determinants for positive(vacA s1m1)or negative(vacA s2m2)anti-CagA serological immune response,which also correlated with the in vitro inflammatory potential in AGS cells.In vitro co-cultivation of representative H.pylori strains with AGS cells confirmed functional CagA translocation,which showed only partial correlation with CagA seropositivity in patients,supporting vacA as major co-determinant of the immune response.CONCLUSIONSerological immune response to H.pylori cagA+strain in H.pylori infected patients is strongly associated with vacA polymorphism,suggesting the crucial role of bacterial factors in immune and clinical phenotype of the infection.
文摘Biomarkers for surveillance, diagnosis and prediction of prognosis in patients with hepatocellular carcinoma(HCC) are currently not ready for introduction into clinical practice because of limited sensitivity and specificity. Especially for the early detection of small HCC novel biomarkers are needed to improve the current effectiveness of screening performed byultrasound. The use of high-throughput technologies in hepatocellular research allows to identify molecules involved in the complex pathways in hepatocarcinogenesis. Several invasive and non-invasive biomarkers have been identified already and have been evaluated in different clinical settings. Gene signatures with prognostic potential have been identified by gene expression profiling from tumor tissue. However, a single "all-in-one" biomarker that fits all-surveillance, diagnosis, prediction of prognosis-has not been found so far. The future of biomarkers most probably lies in a combination of non-invasive biomarkers, imaging and clinical parameters in a surveillance setting. Molecular profiling of tumorous and non-tumorous liver tissue may allow a prediction of prognosis for the individual patient and hopefully clear the way for individual treatment approaches. This article gives an overview on current developments in biomarker research in HCC with a focus on currently available and novel biomarkers, in particular on micro RNA.
基金Supported by the MULTIOMICS project that has received funding from European Social Fund(No.09.3.3-LMT-K-712-01-0130)under grant agreement with the Research Council of Lithuania(LMTLT)。
文摘BACKGROUND Gastric cancer(GC)is one of the most frequently diagnosed tumor globally.In most cases,GC develops in a stepwise manner from chronic gastritis or atrophic gastritis(AG)to cancer.One of the major issues in clinical settings of GC is diagnosis at advanced disease stages resulting in poor prognosis.Micro RNAs(mi RNAs)are small noncoding molecules that play an essential role in a variety of fundamental biological processes.However,clinical potential of mi RNA profiling in the gastric cancerogenesis,especially in premalignant GC cases,remains unclear.AIM To evaluate the AG and GC tissue mi RNomes and identify specific mi RNAs’potential for clinical applications(e.g.,non-invasive diagnostics).METHODS Study included a total of 125 subjects:Controls(CON),AG,and GC patients.All study subjects were recruited at the Departments of Surgery or Gastroenterology,Hospital of Lithuanian University of Health Sciences and divided into the profiling(n=60)and validation(n=65)cohorts.Total RNA isolated from tissue samples was used for preparation of small RNA sequencing libraries and profiled using next-generation sequencing(NGS).Based on NGS data,deregulated mi RNAs hsa-mi R-129-1-3 p and hsa-mi R-196 a-5 p were analyzed in plasma samples of independent cohort consisting of CON,AG,and GC patients.Expression level of hsa-mi R-129-1-3 p and hsa-mi R-196 a-5 p was determined using the quantitative real-time polymerase chain reaction and 2-ΔΔCt method.RESULTS Results of tissue analysis revealed 20 differentially expressed mi RNAs in AG group compared to CON group,129 deregulated mi RNAs in GC compared to CON,and 99 altered mi RNAs comparing GC and AG groups.Only 2 mi RNAs(hsa-mi R-129-1-3 p and hsa-mi R-196 a-5 p)were identified to be step-wise deregulated in healthy-premalignant-malignant sequence.Area under the curve(AUC)-receiver operating characteristic analysis revealed that expression level of hsa-mi R-196 a-5 p is significant for discrimination of CON vs AG,CON vs GC and AG vs GC and resulted in AUCs:88.0%,93.1%and 66.3%,respectively.Comparing results in tissue and plasma samples,hsa-mi R-129-1-3 p was significantly down-regulated in GC compared to AG(P=0.0021 and P=0.024,tissue and plasma,respectively).Moreover,analysis revealed that hsa-mi R-215-3 p/5 p and hsa-mi R-934 were significantly deregulated in GC based on Helicobacter pylori(H.pylori)infection status[log2 fold change(FC)=-4.52,P-adjusted=0.02;log2 FC=-4.00,P-adjusted=0.02;log2 FC=6.09,P-adjusted=0.02,respectively].CONCLUSION Comprehensive mi RNome study provides evidence for gradual deregulation of hsa-mi R-196 a-5 p and hsa-mi R-129-1-3 p in gastric carcinogenesis and found hsami R-215-3 p/5 p and hsa-mi R-934 to be significantly deregulated in H.pylori carrying GC patients.
文摘BACKGROUND There is ongoing search for new noninvasive biomarkers to improve management of patients with hepatocellular carcinoma(HCC).Studies,mostly from the Asian-Pacific region,demonstrated differential expression of liverspecific microRNA-122(miR-122)in tissue as well as in sera of patients with hepatitis B virus-and hepatitis C virus-induced HCC.AIM To evaluate prognostic value of miR-122 in patients with HCC in a European population and determine potential factors related to alteration of miR-122 in sera.METHODS Patients with confirmed HCC(n=91)were included in the study over a two-year period.Patients were characterized according to Child-Pugh score,Barcelona clinic liver cancer(BCLC)staging system,etiology of liver disease,laboratory parameters and overall survival.MiR-122 was measured in sera using TaqMan assay normalized to spiked-in cel-miR-39.RESULTS Serum miR-122 quantity was independent of the Child-Pugh score,the BCLC stage or the underlying etiology.Significant positive correlation was found between miR-122 and alanine aminotransferase(P<0.0001),aspartate aminotransferase(P=0.0001),alpha-fetoprotein(AFP)(P=0.0034)and hemoglobin concentration(P=0.076).Negative correlation was observed between miR-122 level and creatinine concentration(P=0.0028).AFP,Child-Pugh score and BCLC staging system were associated with survival differences.In overall cohort low miR-122 in sera was only associated with a trend for a better overall survival without reaching statistical significance.Subgroup analysis revealed that low miR-122 was significantly associated with better prognosis in patients with advanced cirrhosis(Child-Pugh class B/C),advanced tumor stage(BCLC B/C/D)and normal AFP(<7 ng/mL).CONCLUSION Our results strongly support the value of miR-122 as potential biomarker of liver injury and probably prognosis.Nevertheless,the value of miR-122 in prediction of prognosis of HCC patients was limited to certain patients’subgroups.Since circulating miR-122 may be influenced by impaired renal function,AFP and hemoglobin concentration,those factors need to be considered while interpreting miR-122 level.
基金the MULTIOMICS project that has received funding from European Social Fund(No.09.3.3-LMT-K-712-010130)under grant agreement with the Research Council of Lithuaniathe“LiLife”project as part of the“Autonomy in old Age”research group(No.ZS/2018/11/95324)under grant agreement with European Commission through the“European Funds for Regional development”.
文摘BACKGROUND Helicobacter pylori and the stomach microbiome play a crucial role in gastric carcinogenesis,and detailed characterization of the microbiome is necessary for a better understanding of the pathophysiology of the disease.There are two common modalities for microbiome analysis:DNA(16S rRNA gene)and RNA(16S rRNA transcript)sequencing.The implications from the use of one or another sequencing approach on the characterization and comparability of the mucosal microbiome in gastric cancer(GC)are poorly studied.AIM To characterize the microbiota of GC using 16S rRNA gene and its transcript and determine difference in the bacterial composition.METHODS In this study,316 DNA and RNA samples extracted from 105 individual stomach biopsies were included.The study cohort consisted of 29 healthy control individuals and 76 patients with GC.Gastric tissue biopsy samples were collected from damaged mucosa and healthy mucosa at least 5 cm from the tumor tissue.From the controls,healthy stomach mucosa biopsies were collected.From all biopsies RNA and DNA were extracted.RNA was reverse transcribed into cDNA.V1-V2 region of bacterial 16S rRNA gene from all samples were amplified and sequenced on an Illumina MiSeq platform.Bray-Curtis algorithm was used to construct sample-similarity matrices abundances of taxonomic ranks in each sample type.For significant differences between groups permutational multivariate analysis of variance and Mann-Whitney test followed by false-discovery rate test were used.RESULTS Microbial analysis revealed that only a portion of phylotypes(18%-30%)overlapped between microbial profiles obtained from DNA and RNA samples.Detailed analysis revealed differences between GC and controls depending on the chosen modality,identifying 17 genera at the DNA level and 27 genera at the RNA level.Ten of those bacteria were found to be different from the control group at both levels.The key taxa showed congruent results in various tests used;however,differences in 7 bacteria taxa were found uniquely only at the DNA level,and 17 uniquely only at the RNA level.Furthermore,RNA sequencing was more sensitive for detecting differences in bacterial richness,as well as differences in the relative abundance of Reyranella and Sediminibacterium according to the type of GC.In each study group(control,tumor,and tumor adjacent)were found differences between DNA and RNA bacterial profiles.CONCLUSION Comprehensive microbial study provides evidence for the effect of choice of sequencing modality on the microbiota profile,as well as on the identified differences between case and control.
基金Supported by Lithuanian Research Council Grant,No.MIP-14418
文摘AIM To evaluate associations between mi RNA target genes IL12B,INSR,CCND1 and IL10 polymorphisms and gastric cancer(GC)in European population.METHODS Gene polymorphisms were analyzed in 508 controls and474 GC patients from 3 tertiary centers in Germany,Lithuania and Latvia.Controls were patients from the out-patient departments,who were referred for upper endoscopy because of dyspeptic symptoms and had no history of previous malignancy.Gastric cancer(GC)patients had histopathological verification of gastric adenocarcinoma.Genomic DNA was extracted using salting out method from peripheral blood mononuclear cells.IL12B T>G(rs1368439),INSR T>C(rs1051690),CCND1 A>C(rs7177)and IL10 T>C(rs3024498)SNPs were genotyped by the real-time polymerase chain reaction.Associations between gene polymorphism and GC were evaluated using multiple logistic regression analysis with adjustment for sex,age and country of birth.RESULTS We observed similar distribution of genotypes and allelic frequencies of all polymorphisms between GC patients and controls except of INSR rs1051690.The frequency of the T allele of INSR gene was significantly higher in GC patients than in controls(23.26%and 19.19%respectively,P=0.028).CT genotype was also more prevalent in patients compared to control group(38.48%and 30.12%respectively,P<0.021).Logistic regression analysis revealed that only one polymorphism(rs1051690 in INSR gene)was associated with increased risk of GC.Carriers of CT genotype had higher odds of GC when compared to CC genotype(OR=1.45,95%PI:1.08-1.95,P=0.01).Similar association was observed in a dominant model for INSR gene,where comparison of TT+CT vs CC genotypes showed an increased risk of GC(OR=1.44,95%PI:1.08-1.90,P=0.01).Other analyzed SNPs were not associated with the presence of GC.CONCLUSION INSR rs1051690 SNP is associated with increased risk of GC,while polymorphisms in IL12B,CCND1 and IL10genes are not linked with the presence of GC.
基金Supported by the Research Fund of Lithuanian University of Health Sciences(SV5-074/BN17-99)No.LSMU-21
文摘BACKGROUND Clinically significant portal hypertension(CSPH) and severe portal hypertension(SPH) increase the risk for decompensation and life-threatening complications in liver cirrhosis. Pathologic angiogenesis might contribute to the formation of these conditions. Placental growth factor(PlGF) and Nogo-A protein are biomarkers of pathological angiogenesis, but data on their role in liver cirrhosis and portal hypertension is scarce.AIM To determine plasma levels of PlGF and Nogo-A in patients with liver cirrhosis,CSPH, SPH and potential to predict portal hypertension.METHODS A cohort of 122 patients with hepatitis C virus and/or alcohol-induced liver cirrhosis with characterized hepatic venous pressure gradient(HVPG) were included in the study. Demographic data, medical history, Child-Turcotte-Pugh and Model of End Stage liver disease score, clinical chemistry, liver stiffnessvalues were recorded on the day of the procedure prior HVPG measurement. The degree of portal hypertension was determined by the invasive HVPG measurement. Nogo-A and PlGF plasma levels were evaluated using enzyme linked immunosorbent assay. The control group consisted of 30 healthy age-and sex-matched individuals.RESULTS Peripheral PlGF levels were higher and Nogo-A levels were lower in patients with liver cirrhosis(23.20 vs 9.85;P < 0.0001 and 2.19 vs 3.12;P = 0.004 respectively). There was a positive linear correlation between peripheral levels of PlGF and HVPG(r = 0.338, P = 0.001) and negative linear correlation between the peripheral Nogo-A levels and HVPG(r =-0.267, P = 0.007). PlGF levels were higher in CSPH and SPH(P = 0.006;P < 0.0001) whereas Nogo-A levels were lower(P = 0.01;P < 0.033). Area under the curve for the diagnosis of CSPH for PlGF was 0.68(P = 0.003) and for Nogo-A-0.67(P = 0.01);for SPH 0.714(P <0.0001) and 0.65(P = 0.014) respectively. PlGF levels were higher and Nogo-A levels were lower in patients with esophageal varices(P < 0.05). PlGF cut-off value of 25 pg/mL distinguished patients with CSPH at 55.7% sensitivity and76.7% specificity;whereas Nogo-A cut-off value of 1.12 ng/mL was highly specific(93.1%) for the diagnosis of CSPH.CONCLUSION Plasma PlGF levels were higher while Nogo-A levels were lower in patients with liver cirrhosis and portal hypertension. Biomarkers showed moderate predictive value in determining CSPH and SPH.
文摘BACKGROUND MicroRNAs(miRNAs)have been suggested as biomarkers for malignant diseases including hepatocellular carcinoma(HCC).Specifically,hsa-miR-21-5p(miR-21)is among the most frequently deregulated miRNA in cancer.The diagnostic and prognostic value of miR-21 has been demonstrated in HCC tissue,mostly in the Asian population.Although the impact of various factors has been recently reported for circulating hsa-miR-122-5p(miR-122),at present only limited knowledge is available for miR-21.AIM To evaluate the value of miR-21 for the assessment of prognosis in HCC patients and to delineate the influence of clinical and preanalytical factors on miR-21 level in sera.METHODS Patients with confirmed HCC from our European cohort with predominantly alcohol-associated liver damage were included in the study.All subjects were characterized according to their clinical and laboratory work-up and overall survival data were obtained.Quantitative real-time polymerase chain reaction was performed for miR-21 and spiked-in cel-miR-39-3p.The results were compared to previously reported miR-122 data.RESULTS Survival of HCC patients was comparable between patients with low and high serum miR-21 concentration.No association was observed between miR-21 level in sera and Child-Pugh score,Barcelona Clinic Liver Cancer staging system,or etiology of HCC/liver disease.Age,gender,or pretreatment had no association with miR-21 level.A positive correlation was observed between miR-21 and aspartate aminotransferase(r=0.2854,P=0.0061),serum miR-122(r=0.2624,P=0.0120),and the International Normalized Ratio(r=0.2065,P=0.0496).Negative correlation of miR-21 with serum creatinine(r=-0.2215,P=0.0348)suggests renal function as a potential influencing factor in miR-21 biogenesis in blood.CONCLUSION The results from this work do not support clinically relevant prognostic value of circulating miR-21 in HCC patients in real-life settings.Following systematic evaluation,we identified renal function and aspartate aminotransferase as potential factors that may affect miR-21 concentration in blood.This knowledge should be considered in future miRNA-based biomarker studies not only for HCC but also for other diseases.
基金Supported by The European Union’s“Horizon Europe Framework Program”Grant Agreement,No.101095359(AIDA project under the call"HORIZON-HLTH-2022-STAYHLTH-02).
文摘Fusobacterium nucleatum(F.nucleatum)is a Gram-negative anaerobic bacterium that plays a key role in the development of oral inflammation,such as periodontitis and gingivitis.In the last 10 years,F.nucleatum has been identified as a prevalent bacterium associated with colorectal adenocarcinoma and has also been linked to cancer progression,metastasis and poor disease outcome.While the role of F.nucleatum in colon carcinogenesis has been intensively studied,its role in gastric carcinogenesis is still poorly understood.Although Helicobacter pylori infection has histo-rically been recognized as the strongest risk factor for the development of gastric cancer(GC),with recent advances in DNA sequencing technology,other members of the gastric microbial community,and F.nucleatum in particular,have received increasing attention.In this review,we summarize the existing knowledge on the involvement of F.nucleatum in gastric carcinogenesis and address the potential translational and clinical significance of F.nucleatum in GC.
基金Supported by A Research Grant of Astra-Zeneca (Wedel,Germany)
文摘AIM:To study the impact of an endoscopy-based long-term study on the quality of life in healthy volunteers(HV).METHODS:Ten HV were included into a long-term prospective endoscopy-based placebo-controlled trial with 15 endoscopic examinations per person in 5 different drug phases.Participants completed short form-36(SF-36) and visual analog scale-based questionnaires(VAS) for different abdominal symptoms at days 0,7 and 14 of each drug phase.Analyses wereperformed according to short-and long-term changes and compared to the control group.RESULTS:All HV completed the study with duration of more than 6 mo.Initial quality of life score was comparable to a general population.Analyses of the SF-36 questionnaires showed no significant changes in physical,mental and total scores,either in a short-term perspective due to different medications,or to potentially endoscopic procedure-associated long-term cumulative changes.Analogous to SF-36,VAS revealed no significant changes in total scores for pathological abdominal symptoms and remained unchanged over the time course and when compared to the control population.CONCLUSION:This study demonstrates that quality of life in HV is not significantly affected by a longterm endoscopy-based study with multiple endoscopic procedures.
