Arms race co-evolution of plant–pathogen interactions evolved sophisticated recognition mechanisms between host immune receptors and pathogen effectors. Different allelic haplotypes of an immune receptor in the host ...Arms race co-evolution of plant–pathogen interactions evolved sophisticated recognition mechanisms between host immune receptors and pathogen effectors. Different allelic haplotypes of an immune receptor in the host mount distinct recognition against sequence or non-sequence related effectors in pathogens. We report the molecular characterization of the Piks allele of the rice immune receptor Pik against rice blast pathogen, which requires two head-to-head arrayed nucleotide-binding sites and leucine-rich repeat proteins. Like other Pik alleles, both Piks-1 and Piks-2 are necessary and sufficient for mediating resistance. However, unlike other Pik alleles, Piks does not recognize any known AvrPik variants of Magnaporthe oryzae. Sequence analysis of the genome of an avirulent isolate V86010 further revealed that its cognate avirulence(Avr) gene most likely has no significant sequence similarity to known AvrPik variants. Piks-1 and Pikm-1 have only two amino acid differences within the integrated heavy metal-associated(HMA) domain. Pikm-HMA interacts with AvrPik-A,-D, and-E in vitro and in vivo,whereas Piks-HMA does not bind any AvrPik variants. Characterization of two amino acid residues differing Piks-1 from Pikm-1 reveal that Piks-E229Q derived from the exchange of Glu229 to Gln229 in Piks-1 gains recognition specificity against AvrPik-D but not AvrPik-A or-E, indicating that Piks-E229Q partially restores the Pikm spectrum. By contrast,Piks-A261V derived from the exchange of Ala261 to Val261 in Piks-1 retains Piks recognition specificity.We conclude that Glu229 in Piks-1 is critical for Piks breaking the canonical Pik/AvrPik recognition pattern. Intriguingly, binding activity and ectopic cell death induction is maintained between Piks-A261V and AvrPik-D, implying that positive outcomes from ectopic assays might be insufficient to deduce its immune activity against the relevant effectors in rice and rice blast interaction.展开更多
Objectives:Treatment of metastatic colorectal cancer(mCRC)includes resection of liver metastases(LM),however,no validated biomarker identifies patients most likely to benefit from this procedure.This meta-analysis aim...Objectives:Treatment of metastatic colorectal cancer(mCRC)includes resection of liver metastases(LM),however,no validated biomarker identifies patients most likely to benefit from this procedure.This meta-analysis aimed to assess the impact of the most relevant molecular alterations in cancer-related genes of CRC(i.e.,RAS,BRAF,SMAD4,PIK3CA)as prognostic markers of survival and disease recurrence in patients with mCRC surgically treated by LM resection.Methods:A systematic literature review was performed to identify studies reporting data regarding survival and/or recurrence in patients that underwent complete liver resection for CRC LM,stratified according to RAS,BRAF,PIK3CA,and SMAD4 mutational status.Hazard ratios(HRs)from multivariate analyses were pooled in the meta-analysis and various adjustment strategies for confounding factors were combined.The search was conducted in numerous databases,including MEDLINE(PubMed),Embase,Cumulative Index to Nursing and Allied Health Literature(CINAHL)(EBSCO host),and WHO Global Index Medicus,through March 18th,2022.Meta-analyses,editorials,letters to the editor,case reports,studies on other primary cancers,studies with primary metastatic sites other than the liver,studies lacking specific oncological outcome variables or genetic data,non-English language studies,and studies omitting residual disease data from liver metastasectomy were excluded.The remaining 47 studies were summarized in a descriptive table which outlines the key characteristics of each study and final results were graphically presented.Results:RAS mutation status was negatively associated with overall survival(OS)(HR,1.68;95%CI,1.54–1.84)and recurrence free survival(RFS)(HR,1.46;95%CI,1.33–1.61).A negative association was also found for BRAF regarding OS(HR,2.64;95%CI,2.15–3.24)and RFS(HR,1.89;95%CI,1.32–2.73)and SMAD4 regarding OS(HR,1.93;95%CI,1.56–2.38)and RFS(HR,1.95;95%CI,1.31–2.91).For PIK3CA only three studies were eligible and no significant association with either OS or RFS could be highlighted.Conclusion:RAS,BRAF,and SMAD4 are negatively associated with OS and RFS in patients undergoing curative liver metastasectomy from colorectal cancer.No conclusion can be drawn for PIK3CA due to the limited literature availability.These data support the integration of RAS,BRAF,and SMAD4 mutational status in the surgical decision-making for colorectal liver metastasis.Nevertheless,we have to consider several limitations,the major ones being the pooling of results from studies that evaluated patient outcomes as either disease-free survival(DFS)or RFS;the inclusion of patients with minimal residual disease and unconsidered potential confounding factors,such as variability in resectability definitions,chemotherapy use,and a potential interaction between biological markers and pre-and post-resection pharmacological treatments.展开更多
基金supported, in part, by grants from the National Natural Science Foundation of China to J.W. (U20A2021)Major Science and Technology Project of Hunan Province (2021NK1001)Talent promotion project of Hunan Association for Science and Technology (2019TJ-N03)。
文摘Arms race co-evolution of plant–pathogen interactions evolved sophisticated recognition mechanisms between host immune receptors and pathogen effectors. Different allelic haplotypes of an immune receptor in the host mount distinct recognition against sequence or non-sequence related effectors in pathogens. We report the molecular characterization of the Piks allele of the rice immune receptor Pik against rice blast pathogen, which requires two head-to-head arrayed nucleotide-binding sites and leucine-rich repeat proteins. Like other Pik alleles, both Piks-1 and Piks-2 are necessary and sufficient for mediating resistance. However, unlike other Pik alleles, Piks does not recognize any known AvrPik variants of Magnaporthe oryzae. Sequence analysis of the genome of an avirulent isolate V86010 further revealed that its cognate avirulence(Avr) gene most likely has no significant sequence similarity to known AvrPik variants. Piks-1 and Pikm-1 have only two amino acid differences within the integrated heavy metal-associated(HMA) domain. Pikm-HMA interacts with AvrPik-A,-D, and-E in vitro and in vivo,whereas Piks-HMA does not bind any AvrPik variants. Characterization of two amino acid residues differing Piks-1 from Pikm-1 reveal that Piks-E229Q derived from the exchange of Glu229 to Gln229 in Piks-1 gains recognition specificity against AvrPik-D but not AvrPik-A or-E, indicating that Piks-E229Q partially restores the Pikm spectrum. By contrast,Piks-A261V derived from the exchange of Ala261 to Val261 in Piks-1 retains Piks recognition specificity.We conclude that Glu229 in Piks-1 is critical for Piks breaking the canonical Pik/AvrPik recognition pattern. Intriguingly, binding activity and ectopic cell death induction is maintained between Piks-A261V and AvrPik-D, implying that positive outcomes from ectopic assays might be insufficient to deduce its immune activity against the relevant effectors in rice and rice blast interaction.
基金partially funded by Italian Ministry of Health—Ricerca Corrente(no grant number).
文摘Objectives:Treatment of metastatic colorectal cancer(mCRC)includes resection of liver metastases(LM),however,no validated biomarker identifies patients most likely to benefit from this procedure.This meta-analysis aimed to assess the impact of the most relevant molecular alterations in cancer-related genes of CRC(i.e.,RAS,BRAF,SMAD4,PIK3CA)as prognostic markers of survival and disease recurrence in patients with mCRC surgically treated by LM resection.Methods:A systematic literature review was performed to identify studies reporting data regarding survival and/or recurrence in patients that underwent complete liver resection for CRC LM,stratified according to RAS,BRAF,PIK3CA,and SMAD4 mutational status.Hazard ratios(HRs)from multivariate analyses were pooled in the meta-analysis and various adjustment strategies for confounding factors were combined.The search was conducted in numerous databases,including MEDLINE(PubMed),Embase,Cumulative Index to Nursing and Allied Health Literature(CINAHL)(EBSCO host),and WHO Global Index Medicus,through March 18th,2022.Meta-analyses,editorials,letters to the editor,case reports,studies on other primary cancers,studies with primary metastatic sites other than the liver,studies lacking specific oncological outcome variables or genetic data,non-English language studies,and studies omitting residual disease data from liver metastasectomy were excluded.The remaining 47 studies were summarized in a descriptive table which outlines the key characteristics of each study and final results were graphically presented.Results:RAS mutation status was negatively associated with overall survival(OS)(HR,1.68;95%CI,1.54–1.84)and recurrence free survival(RFS)(HR,1.46;95%CI,1.33–1.61).A negative association was also found for BRAF regarding OS(HR,2.64;95%CI,2.15–3.24)and RFS(HR,1.89;95%CI,1.32–2.73)and SMAD4 regarding OS(HR,1.93;95%CI,1.56–2.38)and RFS(HR,1.95;95%CI,1.31–2.91).For PIK3CA only three studies were eligible and no significant association with either OS or RFS could be highlighted.Conclusion:RAS,BRAF,and SMAD4 are negatively associated with OS and RFS in patients undergoing curative liver metastasectomy from colorectal cancer.No conclusion can be drawn for PIK3CA due to the limited literature availability.These data support the integration of RAS,BRAF,and SMAD4 mutational status in the surgical decision-making for colorectal liver metastasis.Nevertheless,we have to consider several limitations,the major ones being the pooling of results from studies that evaluated patient outcomes as either disease-free survival(DFS)or RFS;the inclusion of patients with minimal residual disease and unconsidered potential confounding factors,such as variability in resectability definitions,chemotherapy use,and a potential interaction between biological markers and pre-and post-resection pharmacological treatments.
