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.

Research on damage failure mechanism and dynamic mechanical behavior of layered shale with different angles under confining pressure

The hydrostatic or confining pressure of deep rocks has a significant impact on the mechanical behavior of brittle materials.Especially when confining pressure is applied,the mechanical properties of rock materials will undergo significant changes.Considering that the process of shale sample subjected to impact load is in a closed container in the dynamic triaxial SHPB test,the failure process of the sample cannot be observed.Meanwhile,the activation volume of the shale sample would be large and local failure would occur in the test under the high strain rate loading.Therefore,thefinite element model of shale considering the bedding effect under confining pressure was established in this study.Taking shale materials with different bedding dip angles as simulation objects,the dynamic failure characteristics of shale were studied using the dynamic analysis software ANSYS/LS‐DYNA from three aspects:stress‐strain curve,failure growth process,and failure morphology.The research results obtained can serve as the key technical parameters for deep resource extraction.

Seismic Vulnerability Analysis of Single-Story Reinforced Concrete Industrial Buildings with Seismic Fortification

As there is a lack of earthquake damage data for factory buildings with seismic fortifications in China,seismic vulnerability analysis was performed by numerical simulation in this paper.The earthquake-structure analysis model was developed with considering the influence of uncertainties of the ground motion and structural model parameters.The small-size sampling was conducted based on the Latin hypercube sampling and orthogonal design methods.Using nonlinear analysis,the seismic vulnerability curves and damage probability matrix with various seismic fortification intensities(SFI)were obtained.The seismic capacity of the factory building was then evaluated.The results showed that,with different designs at different SFIs,the factory building could consistently achieve the three seismic fortification objectives.For the studied factory buildings with the SFI of 6,they satisfied the seismic fortification requirements of“no damage in moderate earthquakes,mendable in strong earthquakes”;for those buildings with SFIs of 7 and 8,the requirement of“no collapsing in super strong earthquakes”was generally met;while for those with SFIs of 9,the requirement of“mendable in moderate earthquakes”was almost satisfied.The results showed factory buildings designed with low SFIs are better at achieving the seismic fortification objectives than those designed with high SFIs.

rMVP: A Memory-efficient, Visualization-enhanced, and Parallel-accelerated Tool for Genome-wide Association Study

Along with the develoipment of high-throughput sequencing technologies,both sample size and SNP number are increasing rapidly in genome-wide association studies(GWAS),and the associated computation is more challenging than ever.Here,we present a memory-efficient,visualization-enhanced,and parallel-accelerated R package called“r MVP”to address the need for improved GWAS computation.r MVP can 1)effectively process large GWAS data,2)rapidly evaluate population structure,3)efficiently estimate variance components by Efficient Mixed-Model Association e Xpedited(EMMAX),Factored Spectrally Transformed Linear Mixed Models(Fa ST-LMM),and Haseman-Elston(HE)regression algorithms,4)implement parallel-accelerated association tests of markers using general linear model(GLM),mixed linear model(MLM),and fixed and random model circulating probability unification(Farm CPU)methods,5)compute fast with a globally efficient design in the GWAS processes,and 6)generate various visualizations of GWASrelated information.Accelerated by block matrix multiplication strategy and multiple threads,the association test methods embedded in r MVP are significantly faster than PLINK,GEMMA,and Farm CPU_pkg.r MVP is freely available at https://github.com/xiaolei-lab/r MVP.

Elevating H3K27me3 level sensitizes colorectal cancer to oxaliplatin

Histone methylation is a context-dependent modification that regulates gene expression,and the trimethylation of histone H3 lysine 27(H3K27me3)usually induces gene silencing.Overcoming colorectal cancer(CRC)chemoresistance is currently a huge challenge,but the relationship between H3K27me3 modification and chemoresistance remains largely unclear.Here,we found that H3K27me3 levels positively correlated with the metastasis-free survival of CRC patients and a low H3K27me3 level predicted a poor outcome upon chemotherapeutic drug treatment.Oxaliplatin stimulation significantly induced the expression of H3K27 lysine demethylase 6A/6B(KDM6A/6B),thus decreasing the level of H3K27me3 in CRC cells.Elevation of H3K27me3 level through KDM6A/6B depletion or GSK-J4(a KDM6A/6B inhibitor)treatment significantly enhanced oxaliplatin-induced apoptosis.Conversely,when inhibiting the expression of H3K27me3 by EPZ-6438,an inhibitor of the histone methyltransferase EZH2,the proportion of apoptotic cells remarkably decreased.In addition,the combination of GSK-J4 and oxaliplatin significantly inhibited tumor growth in an oxaliplatin-resistant patient-derived xenograft model.Importantly,we revealed that oxaliplatin treatment dramatically induced NOTCH2 expression,which was caused by downregulation of H3K27me3 level on the NOTCH2 transcription initiation site.Thus,the activated NOTCH signaling promoted the expression of stemness-related genes,which resulted in oxaliplatin resistance.Furthermore,oxaliplatin-induced NOTCH signaling could be interrupted by GSK-J4 treatment.Collectively,our findings suggest that elevating H3K27me3 level can improve drug sensitivity in CRC patients.

Optimization of a doxycycline hydroxypropyl-β-cyclodextrin inclusion complex based on computational modeling

To prepare a stable complex of doxycycline(Doxy)and hydroxypropy-β-cyclodextrin(HP-β-CD)for ophthalmic delivery,the optimum formulation and preparation conditions were investigated using response surface methodology(RSM),artificial neural network(ANN)and support vector machine(SVM)modeling.The molar ratios of HP-β-CD/Doxy and Mg^(2+)/Doxy,inclusion time and temperature were selected as independent variables (X_(1)-X_(4)) and inclusion efficiency and stability of the Doxy-HP-β-CD complex were selected as dependent(response)variables(Y_(1) and Y_(2)).The optimal formulation predicted by genetic algorithm(GA)combined with the models was characterized by microscopy and nuclear magnetic resonance spectrometry,and the stability of Doxy in the complex was evaluated.The highest values of Y_(1) and Y_(2) were obtained using an ANN model combined with GA which predicted the values of X_(1)-X_(4) to be 4,10.8,12 h and 25℃,respectively.The modeling and optimization results indicated that a feed-forward back-propagation ANN with one hidden layer and 10 hidden units showed better fitting to both responses compared to the RSM and SVM models.GA proved to be an efficient tool in multi­objective optimization of a pharmaceutical formulation.

Bcl-3 promotes Wnt signaling by maintaining the acetylation ofβ-catenin at lysine 49 in colorectal cancer

Wnt/β-catenin signaling plays a critical role in colorectal cancer(CRC)tumorigenesis and the homeostasis of colorectal cancer stem cells(CSCs),but its molecular mechanism remains unclear.B-cell lymphoma 3(Bcl-3),a member of the IκB family,is overexpressed in CRC and promotes tumorigenicity.Here,we report a novel function of Bcl-3 in maintaining colorectal CSC homeostasis by activating Wnt/β-catenin signaling.Silencing Bcl-3 suppresses the self-renewal capacity of colorectal CSCs and sensitizes CRC cells to chemotherapeutic drugs through a decrease in Wnt/β-catenin signaling.Moreover,our data show that Bcl-3 is a crucial component of Wnt/β-catenin signaling and is essential forβ-catenin transcriptional activity in CRC cells.Interestingly,Wnt3a increases the level and nuclear translocation of Bcl-3,which binds directly toβ-catenin and enhances the acetylation ofβ-catenin at lysine 49(Ac-K49-β-catenin)and transcriptional activity.Bcl-3 depletion decreases the Ac-K49-β-catenin level by increasing the level of histone deacetylase 1 to remove acetyl groups fromβ-catenin,thus interrupting Wnt/β-catenin activity.In CRC clinical specimens,Bcl-3 expression negatively correlates with the overall survival of CRC patients.A significantly positive correlation was found between the expression of Bcl-3 and Ac-K49-β-catenin.Collectively,our data reveal that Bcl-3 plays a crucial role in CRC chemoresistance and colorectal CSC maintenance via its modulation of the Ac-K49-β-catenin,which serves as a promising therapeutic target for CRC.

Characteristics of gut microbiota determine effects of specific probiotics strains in patients with functional constipation

To the Editor:Probiotics are a promising treatment modality for functional constipation(FC);however,the factors affecting individual responses to probiotics remain unclear.Growing evidence has identified that there is a strong relationship among the gut microbiota and constipation and related gut-brain axis.[1]The gut microbiota may modulate the gut functions via gut metabolites or trigger the release of gut hormones,such as peptide YY,gastric inhibitory polypeptide,and 5-hydroxytryptamine.[2]In turn,gut hormones affect gut secretion,motility,and sensation through their receptors located on epithelial,enteric,and smooth muscle cells.[2]Based on these findings,exogenous probiotics have been used in patients with constipation;however,few have produced consistent results.[3]In this study,we investigated the efficacy and safety of several specific probiotics strains for constipation,and also examined the potential reasons for the individualized effects of probiotics,which may facilitate interventional decisionmaking for FC patients.