AIM: To assess whether the polymorphisms of NOD2/ CARD15 , autophagy-related 16-like 1 (ATG16L1 ), and interleukin-23 receptor (IL23R ) genes play a more critical role in the susceptibility of childhood-onset than in ...AIM: To assess whether the polymorphisms of NOD2/ CARD15 , autophagy-related 16-like 1 (ATG16L1 ), and interleukin-23 receptor (IL23R ) genes play a more critical role in the susceptibility of childhood-onset than in adult-onset Crohn’s disease (CD). METHODS: Polymorphisms R702W, G908R, and 3020insC of NOD2/CARD15 ; rs2241880 A/G of ATG16L1 , and rs11209026 (R381Q) of IL23R gene were assessed in 110 childhood-onset CD, 364 adult-onset CD, and 539 healthy individuals. Analysis of polymorphisms R702W, G908R, and 3020insC of NOD2/CARD15 genotyping was performed by allele specific polymerase chain reaction (PCR) or by PCR-restriction fragment length polymor-phism analysis. The polymorphisms rs2241880 A/G of the ATG16L1 , and rs11209026 (R381Q) of the IL23R gene in the children’s cohort were genotyped by PCR and melting curve analysis whereas adult group genotyping was performed using the Affymetrix Genome-Wide Human SNP Array 5.0 (500K). RESULTS: The 3020insC allele in NOD2/CARD15 was significantly higher in childhood than in adult-onset CD (P = 0.0067). Association with at least 1 NOD2/CARD15 variant was specific for ileal disease (with or without co- lonic involvement). Even if the frequency of G allele of the rs2241880 ATG16L1 polymorphism was increased in both paediatric and adult CD patients compared to con- trols (P = 0.017 and P = 0.001, respectively), no difference was observed between the childhood and the adult cohort. The rare Q allele of IL23R rs11209026 polymorphism was underrepresented in both paediatric and adult CD cases (P = 0.0018 and P = 0.04, respectively) and no difference was observed between the childhood and the adult cohort. The presence of the rs2241880 ATG16L1 and rs11209026 IL23R polymorphisms did not influence disease phenotype. CONCLUSION: Polymorphism 3020insC in NOD2/ CARD15 occurs statistically significantly more often in patients with childhood-onset CD than in patients with adult-onset CD. The ATG16L1 and IL23R variants are associated with susceptibility to CD, but not earlyonset disease.展开更多
Inflammatory bowel disease is a group of diseases that includes Crohn＇s disease （CD） and ulcerative colitis. CD is characterized as a chronic inflammatory disease of the gastrointestinal tract, ranging from the mou...Inflammatory bowel disease is a group of diseases that includes Crohn＇s disease （CD） and ulcerative colitis. CD is characterized as a chronic inflammatory disease of the gastrointestinal tract, ranging from the mouth to the anus. Although there are gross pathological and histological similarities between CD and Johne＇s dis- ease of cattle, the cause of CD remains controversial. It is vital to understand fully the cause of this disease because it affects approximately 500 000 people in North America and Europe. It ranges from 27 to 48 cases per 100 000 people. There are many theories on the cause of CD ranging from possible association with environmental factors including microorganisms to imbalance in the intestinal normal flora of the pa- tients. Regardless of the environmental trigger, there is strong evidence that a genetic disposition is a major key in acquiring CD. Many studies have proven the link between mutations in the ATG16L, NOD2/CARD15, IBDS, CTLA4, TNFSF15 and IL23R genes, and CD. The purpose of this review is to examine all genetic aspects and theories of CD, including up to date multiple popu- lation studies performed worldwide.展开更多
AIM:To investigate the frequency of NOD2, IL23R and ATG16L1 genetic variants in a case-control panel for inflammatory bowel disease (IBD) from Lithuania.METHODS: One hundred and eighty unrelated IBD pa- tients [57 Cro...AIM:To investigate the frequency of NOD2, IL23R and ATG16L1 genetic variants in a case-control panel for inflammatory bowel disease (IBD) from Lithuania.METHODS: One hundred and eighty unrelated IBD pa- tients [57 Crohn's disease (CD) and 123 ulcerative colitis (UC)] and 186 healthy controls were genotyped for the following known genetic susceptibility variants:NOD2-Arg702Trp (rs2066844), Gly908Arg (rs2066845) and Leu1007insC (rs2066847), as well as IL23R-Arg381Gln (rs11209026) and ATG16L1-Thr300Ala (rs2241880).RESULTS:The effect that carriership of at least one NOD2 risk allele predisposes to CD was replicated in the Lithuanian population (41.1% CD vs 16.9% controls, P=2×10-4, OR=3.48,95% CI:1.81-6.72). In the allelic single marker analysis, Leu1007insC was strongly associated with CD (21.4% CD vs 4.7% controls, P=3.687×10-8, OR=5.54, 95% CI:2.85-10.75). Neither the other two NOD2 variants, nor the known variants in IL23R and ATG16L1 were found to be risk factors for CD, UC or IBD. However, our relatively small study population was underpowered to demonstrate such weak to moderate disease associations.CONCLUSION: The results support a strong association between CD susceptibility and the Leu1007insC variant in NOD2 in the Lithuanian study population.展开更多
Esophageal squamous cell carcinoma(ESCC),a malignancy of the digestive system,is highly prevalent and the primary cause of cancer-related deaths worldwide due to the lack of early diagnostic biomarkers and effective t...Esophageal squamous cell carcinoma(ESCC),a malignancy of the digestive system,is highly prevalent and the primary cause of cancer-related deaths worldwide due to the lack of early diagnostic biomarkers and effective therapeutic targets.Dysregulated ribonucleotide reductase(RNR)expression has been confirmed to be causally linked to tumorigenesis.This study demonstrated that ribonucleotide reductase small subunit M2(RRM2)is significantly upregulated in ESCC tissue and that its expression is negatively correlated with clinical outcomes.Mechanistically,HuR promotes RRM2 mRNA stabilization by binding to the adenine/uridine(AU)-rich elements(AREs)within the 3′UTR,resulting in persistent overexpression of RRM2.Furthermore,bifonazole is identified as an inhibitor of HuR via computational screening and molecular docking analysis.Bifonazole disrupts HuR-ARE interactions by competitively binding to HuR at F65,R97,I103,and R153 residues,resulting in reduced RRM2 expression.Furthermore,bifonazole exhibited antitumor effects on ESCC patient-derived xenograft(PDX)models by decreasing RRM2 expression and the dNTP pool.In summary,this study reveals the interaction network among HuR,RRM2,and bifonazole and demonstrated that bifonazole is a potential therapeutic compound for ESCC through inhibition of the HuR/RRM2 axis.展开更多
文摘AIM: To assess whether the polymorphisms of NOD2/ CARD15 , autophagy-related 16-like 1 (ATG16L1 ), and interleukin-23 receptor (IL23R ) genes play a more critical role in the susceptibility of childhood-onset than in adult-onset Crohn’s disease (CD). METHODS: Polymorphisms R702W, G908R, and 3020insC of NOD2/CARD15 ; rs2241880 A/G of ATG16L1 , and rs11209026 (R381Q) of IL23R gene were assessed in 110 childhood-onset CD, 364 adult-onset CD, and 539 healthy individuals. Analysis of polymorphisms R702W, G908R, and 3020insC of NOD2/CARD15 genotyping was performed by allele specific polymerase chain reaction (PCR) or by PCR-restriction fragment length polymor-phism analysis. The polymorphisms rs2241880 A/G of the ATG16L1 , and rs11209026 (R381Q) of the IL23R gene in the children’s cohort were genotyped by PCR and melting curve analysis whereas adult group genotyping was performed using the Affymetrix Genome-Wide Human SNP Array 5.0 (500K). RESULTS: The 3020insC allele in NOD2/CARD15 was significantly higher in childhood than in adult-onset CD (P = 0.0067). Association with at least 1 NOD2/CARD15 variant was specific for ileal disease (with or without co- lonic involvement). Even if the frequency of G allele of the rs2241880 ATG16L1 polymorphism was increased in both paediatric and adult CD patients compared to con- trols (P = 0.017 and P = 0.001, respectively), no difference was observed between the childhood and the adult cohort. The rare Q allele of IL23R rs11209026 polymorphism was underrepresented in both paediatric and adult CD cases (P = 0.0018 and P = 0.04, respectively) and no difference was observed between the childhood and the adult cohort. The presence of the rs2241880 ATG16L1 and rs11209026 IL23R polymorphisms did not influence disease phenotype. CONCLUSION: Polymorphism 3020insC in NOD2/ CARD15 occurs statistically significantly more often in patients with childhood-onset CD than in patients with adult-onset CD. The ATG16L1 and IL23R variants are associated with susceptibility to CD, but not earlyonset disease.
基金Supported by The Broad Foundation grant,No. IBD-0207R
文摘Inflammatory bowel disease is a group of diseases that includes Crohn＇s disease （CD） and ulcerative colitis. CD is characterized as a chronic inflammatory disease of the gastrointestinal tract, ranging from the mouth to the anus. Although there are gross pathological and histological similarities between CD and Johne＇s dis- ease of cattle, the cause of CD remains controversial. It is vital to understand fully the cause of this disease because it affects approximately 500 000 people in North America and Europe. It ranges from 27 to 48 cases per 100 000 people. There are many theories on the cause of CD ranging from possible association with environmental factors including microorganisms to imbalance in the intestinal normal flora of the pa- tients. Regardless of the environmental trigger, there is strong evidence that a genetic disposition is a major key in acquiring CD. Many studies have proven the link between mutations in the ATG16L, NOD2/CARD15, IBDS, CTLA4, TNFSF15 and IL23R genes, and CD. The purpose of this review is to examine all genetic aspects and theories of CD, including up to date multiple popu- lation studies performed worldwide.
基金Supported by The German Ministry of Education and Research through the National Genome Research Network
文摘AIM:To investigate the frequency of NOD2, IL23R and ATG16L1 genetic variants in a case-control panel for inflammatory bowel disease (IBD) from Lithuania.METHODS: One hundred and eighty unrelated IBD pa- tients [57 Crohn's disease (CD) and 123 ulcerative colitis (UC)] and 186 healthy controls were genotyped for the following known genetic susceptibility variants:NOD2-Arg702Trp (rs2066844), Gly908Arg (rs2066845) and Leu1007insC (rs2066847), as well as IL23R-Arg381Gln (rs11209026) and ATG16L1-Thr300Ala (rs2241880).RESULTS:The effect that carriership of at least one NOD2 risk allele predisposes to CD was replicated in the Lithuanian population (41.1% CD vs 16.9% controls, P=2×10-4, OR=3.48,95% CI:1.81-6.72). In the allelic single marker analysis, Leu1007insC was strongly associated with CD (21.4% CD vs 4.7% controls, P=3.687×10-8, OR=5.54, 95% CI:2.85-10.75). Neither the other two NOD2 variants, nor the known variants in IL23R and ATG16L1 were found to be risk factors for CD, UC or IBD. However, our relatively small study population was underpowered to demonstrate such weak to moderate disease associations.CONCLUSION: The results support a strong association between CD susceptibility and the Leu1007insC variant in NOD2 in the Lithuanian study population.
基金funded by National Natural Science Foundation of China(grant numbers:81872335,82303891 and 82303119)The Central Plains Science and Technology Innovation Leading Talents(No.224200510015,China)+1 种基金Key scientific research project plan of colleges and universities in Henan Province(grant number:24A310025,China)Science and Technology Project of Henan Province(No.242102310414,China).
文摘Esophageal squamous cell carcinoma(ESCC),a malignancy of the digestive system,is highly prevalent and the primary cause of cancer-related deaths worldwide due to the lack of early diagnostic biomarkers and effective therapeutic targets.Dysregulated ribonucleotide reductase(RNR)expression has been confirmed to be causally linked to tumorigenesis.This study demonstrated that ribonucleotide reductase small subunit M2(RRM2)is significantly upregulated in ESCC tissue and that its expression is negatively correlated with clinical outcomes.Mechanistically,HuR promotes RRM2 mRNA stabilization by binding to the adenine/uridine(AU)-rich elements(AREs)within the 3′UTR,resulting in persistent overexpression of RRM2.Furthermore,bifonazole is identified as an inhibitor of HuR via computational screening and molecular docking analysis.Bifonazole disrupts HuR-ARE interactions by competitively binding to HuR at F65,R97,I103,and R153 residues,resulting in reduced RRM2 expression.Furthermore,bifonazole exhibited antitumor effects on ESCC patient-derived xenograft(PDX)models by decreasing RRM2 expression and the dNTP pool.In summary,this study reveals the interaction network among HuR,RRM2,and bifonazole and demonstrated that bifonazole is a potential therapeutic compound for ESCC through inhibition of the HuR/RRM2 axis.
