DNA damage response-related immune activation signature predicts the response to immune checkpoint inhibitors: from gastrointestinal cancer analysis to pan-cancer validation

Objective: DNA damage response(DDR) deficiency has emerged as a prominent determinant of tumor immunogenicity. This study aimed to construct a DDR-related immune activation(DRIA) signature and evaluate the predictive accuracy of the DRIA signature for response to immune checkpoint inhibitor(ICI) therapy in gastrointestinal(GI) cancer.Methods: A DRIA signature was established based on two previously reported DNA damage immune response assays. Clinical and gene expression data from two published GI cancer cohorts were used to assess and validate the association between the DRIA score and response to ICI therapy. The predictive accuracy of the DRIA score was validated based on one ICI-treated melanoma and three pan-cancer published cohorts.Results: The DRIA signature includes three genes(CXCL10, IDO1, and IFI44L). In the discovery cancer cohort, DRIA-high patients with gastric cancer achieved a higher response rate to ICI therapy than DRIA-low patients(81.8% vs. 8.8%;P < 0.001), and the predictive accuracy of the DRIA score [area under the receiver operating characteristic curve(AUC) = 0.845] was superior to the predictive accuracy of PD-L1 expression, tumor mutational burden, microsatellite instability, and Epstein–Barr virus status. The validation cohort demonstrated that the DRIA score identified responders with microsatellite-stable colorectal and pancreatic adenocarcinoma who received dual PD-1 and CTLA-4 blockade with radiation therapy. Furthermore, the predictive performance of the DRIA score was shown to be robust through an extended validation in melanoma, urothelial cancer, and pan-cancer.Conclusions: The DRIA signature has superior and robust predictive accuracy for the efficacy of ICI therapy in GI cancer and pancancer, indicating that the DRIA signature may serve as a powerful biomarker for guiding ICI therapy decisions.

Development and validation of novel inflammatory response-related gene signature for sepsis prognosis

Due to the low specificity and sensitivity of biomarkers in sepsis diagnostics,the prognosis of sepsis patient outcomes still relies on the assessment of clinical symptoms.Inflammatory response is crucial to sepsis onset and progression;however,the significance of inflammatory response-related genes(IRRGs)in sepsis prognosis is uncertain.This study developed an IRRG-based signature for sepsis prognosis and immunological function.The Gene Expression Omnibus(GEO)database was retrieved for two sepsis microarray datasets,GSE64457 and GSE69528,followed by gene set enrichment analysis(GSEA)comparing sepsis and healthy samples.A predictive signature for IRRGs was created using least absolute shrinkage and selection operator(LASSO).To confirm the efficacy and reliability of the new prognostic signature,Cox regression,Kaplan-Meier(K-M)survival,and receiver operating characteristic(ROC)curve analyses were performed.Subsequently,we employed the GSE95233 dataset to independently validate the prognostic signature.A single-sample GSEA(ssGSEA)was conducted to quantify the immune cell enrichment score and immune-related pathway activity.We found that more gene sets were enriched in the inflammatory response in sepsis patient samples than in healthy patient samples,as determined by GSEA.The signature of nine IRRGs permitted the patients to be classified into two risk categories.Patients in the low-risk group showed significantly better 28-d survival than those in the high-risk group.ROC curve analysis corroborated the predictive capacity of the signature,with the area under the curve(AUC)for 28-d survival reaching 0.866.Meanwhile,the ss GSEA showed that the two risk groups had different immune states.The validation set and external dataset showed that the signature was clinically predictive.In conclusion,a signature consisting of nine IRRGs can be utilized to predict prognosis and influence the immunological status of sepsis patients.Thus,intervention based on these IRRGs may become a therapeutic option in the future.

The correlation of drug resistance and virulence in Mycobacterium tuberculosis

The low success rates in the treatment of multidrug-resistant tuberculosis(MDR-TB)and extensively drug-resistant TB(XDR-TB),which account for 55%and 34%respectively,led the WHO to conclude that MDR/XDR-TB is a serious public health crisis.However,the virulence of MDR/XDR-Mycobacterium Tuberculosis(Mtb)has not been analyzed in details,which could provide a specific guidance for the control and prevention.In this review,we discuss different aspects of MDR/XDR-Mtb virulence and its relationship to fitness cost by probing the following questions:(1)what mediates the virulence of MDR/XDR-Mtb?(What is the relationship between fitness and virulence of Mtb?(2)Is it possible that drug-resistant Mtb(DR Mtb)can show higher fitness?(3)What is the definite effect on fitness of each drug-resistant mutant?(4)What other important factors affecting fitness in the mutant strain?(5)How to study the virulence of a large number of DR Mtb?And what prevention and control measures will be taken in the future,especially for the high virulent DR Mtb?We therefore summarized the congruent relationship between drug resistance and fitness from the global response-related genes to antibiotic resistance-contributing mutation,provided methods to explore the virulence of DR Mtb.This review may offer some critical information and concise guide to creating strategies for the prevention and control of drug-resistant Mtb.