Integration of pathologic characteristics, genetic risk and lifestyle exposure for colorectal cancer survival assessment.

The development of an effective survival prediction tool is key for reducing colorectal cancer mortality. Here, we apply a three-stage study to devise a polygenic prognostic score (PPS) for stratifying colorectal cancer overall survival. Leveraging two cohorts of 3703 patients, we first perform a genome-wide survival association analysis to develop eight candidate PPSs. Further using an independent cohort with 470 patients, we identify the 287 variants-derived PPS (i.e., PPS287) achieving an optimal prediction performance [hazard ratio (HR) per SD = 1.99, P = 1.76 × 10-8], accompanied by additional tests in two external cohorts, with HRs per SD of 1.90 (P = 3.21 × 10-14; 543 patients) and 1.80 (P = 1.11 × 10-9; 713 patients). Notably, the detrimental impact of pathologic characteristics and genetic risk could be attenuated by a healthy lifestyle, yielding a 7.62% improvement in the 5-year overall survival rate. Therefore, our findings demonstrate the integrated contribution of pathologic characteristics, germline variants, and lifestyle exposure to the prognosis of colorectal cancer patients.

Risk assessment for colorectal cancer via polygenic risk score and lifestyle exposure: a large-scale association study of East Asian and European populations.

BACKGROUND: The genetic architectures of colorectal cancer are distinct across different populations. To date, the majority of polygenic risk scores (PRSs) are derived from European (EUR) populations, which limits their accurate extrapolation to other populations. Here, we aimed to generate a PRS by incorporating East Asian (EAS) and EUR ancestry groups and validate its utility for colorectal cancer risk assessment among different populations. METHODS: A large-scale colorectal cancer genome-wide association study (GWAS), harboring 35,145 cases and 288,934 controls from EAS and EUR populations, was used for the EAS-EUR GWAS meta-analysis and the construction of candidate EAS-EUR PRSs via different approaches. The performance of each PRS was then validated in external GWAS datasets of EAS (727 cases and 1452 controls) and EUR (1289 cases and 1284 controls) ancestries, respectively. The optimal PRS was further tested using the UK Biobank longitudinal cohort of 355,543 individuals and ultimately applied to stratify individual risk attached by healthy lifestyle. RESULTS: In the meta-analysis across EAS and EUR populations, we identified 48 independent variants beyond genome-wide significance (P < 5 × 10-8) at previously reported loci. Among 26 candidate EAS-EUR PRSs, the PRS-CSx approach-derived PRS (defined as PRSCSx) that harbored genome-wide variants achieved the optimal discriminatory ability in both validation datasets, as well as better performance in the EAS population compared to the PRS derived from known variants. Using the UK Biobank cohort, we further validated a significant dose-response effect of PRSCSx on incident colorectal cancer, in which the risk was 2.11- and 3.88-fold higher in individuals with intermediate and high PRSCSx than in the low score subgroup (Ptrend = 8.15 × 10-53). Notably, the detrimental effect of being at a high genetic risk could be largely attenuated by adherence to a favorable lifestyle, with a 0.53% reduction in 5-year absolute risk. CONCLUSIONS: In summary, we systemically constructed an EAS-EUR PRS to effectively stratify colorectal cancer risk, which highlighted its clinical implication among diverse ancestries. Importantly, these findings also supported that a healthy lifestyle could reduce the genetic impact on incident colorectal cancer.

Mechanical and Acoustic Emission Characteristics of Coal-like Rock Specimens under Static Direct Shear and Dynamic Normal Load.

In underground engineering, shear failure is a common failure type in coal-rock mass under medium and low strain-rate disturbance loads. Analyzing the shear failure mechanical properties of coal-rock mass under dynamic normal load is significant. In order to reveal the influence of disturbance load on the shear mechanical properties of coal rock, a dynamic and static load coupling electro-hydraulic servo testing machine was used to conduct the shear tests of coal-like rock materials under dynamic and constant normal load. The amplitude of dynamic load is 10 kN and the frequency is 5 Hz. The damage process of the specimens was detected by the acoustic emission (AE) detection system. The results imply that the shear failure process of coal-like rock materials under constant normal load can be divided into four stages. The normal disturbance decreased the shear strength of the specimens and increased the shear modulus of the specimens. With the increase in normal load, the influence of disturbance on the shear strength of the specimen decreased. By analyzing the AE parameters, it was found that the dynamic load made the internal damage of the specimen more severe during the shear failure process. The damage variable was calculated by AE cumulative energy, and the damage evolution was divided into three stages. The shear failure mechanism of the specimen was judged by RA (rise time/amplitude) and AF (average frequency). It was found that from the elastic deformation stage to the unstable development fracture stage, the proportion of shear fracture increased. When the dynamic normal load was 10 kN and 30 kN, the fracture was mainly shear fracture; When the dynamic normal load was 50 kN, the fracture was mainly tensile or mixed fracture. The dynamic normal load affects the shear strength and failure mechanism. Therefore, the influence of disturbance load on coal-rock mass strength cannot be ignored in underground engineering.

Study on Mechanical Properties and Weakening Mechanism of Acid Corrosion Lamprophyre.

In order to study the weakening mechanism and mechanical behaviors of hard lamprophyre of Carboniferous Permian coal-bearing strata in China's mining area, lamprophyre samples were subjected to static rock dissolution experiments with pH values of 0, 2, and 4. The acid corrosion mechanism of lamprophyre was revealed from the weight changes of samples, characteristics of solution ion concentration, and macro-mechanical properties. The experimental results show that reaction occurred between lamprophyre and acid solution. With the increasing concentration of H+, the reaction was more intense, the degree of acid etching was higher, and the weight loss was greater. The internal damage induced by acid etching results in the slow extension of the compaction stage of stress-strain curve of uniaxial compression, and the obvious deterioration of mechanical properties of the lamprophyre. The uniaxial compressive strength of the lamprophyre in the dry state is 132 MPa, which decreased to 39 MPa under the acid etching condition, showing significant mudding characteristics. Dolomite (CaMg(CO3)2 with 19.63%) and orthoclase (KAlSi3O8 with 31.4%) in lamprophyre are the major minerals constituents involved in acidification reaction. Photomicrograph recorded from SEM studies reveals that the dissolution effect was directly related to the concentration of H+ in the solution. The dissolution effect was from the surface to the inside. The small dissolution pores became larger and continuously expanded, then finally formed a skeleton structure dominated by quartz. The content of K+, Ca2+, and Mg2+ in the solution after acid etching reaction indicates that the acidified product of orthoclase is colloidal H2SiO3, which adhered to the surface of samples during acid etching and hinders the further acidification of minerals. The dissolution of dolomite and orthoclase under acidic conditions directly leads to the damage of their structure and further promotes the water-rock interaction, which is the fundamental reason for the weakening of the mechanical properties of lamprophyre.

Genetic variants in noncoding PIWI-interacting RNA and colorectal cancer risk.

BACKGROUND: PIWI-interacting RNAs (piRNAs), which are a novel type of identified small noncoding RNA (ncRNA), play a crucial role in germline development and carcinogenesis. METHODS: By systematically screening all known piRNAs, the authors identified 7 common single nucleotide polymorphisms (SNPs) in 9 piRNAs. Associations between these selected SNPs and the risk of colorectal cancer (CRC) were detected in a case-control study. A quantitative real-time polymerase chain reaction assay was used to evaluate messenger RNA (mRNA) expression levels of piR-015551 and of the long ncRNA (lncRNA) LNC00964-3 in 88 pairs of tissue samples. RESULTS: The assay revealed that reference SNP rs11776042 in piR-015551 was significantly associated with a decreased risk of CRC in an additive model (P = .020). However, this protective effect was not significant after correction for multiple comparisons (test for the false discovery rate; P = .140). Furthermore, the authors observed that mRNA expression levels of LNC00964-3 (an lncRNA that included the piR-015551 sequence but not piR-015551) were significantly lower in CRC tissues than in corresponding normal tissues (P = 1.5 × 10(-5) for LNC00964-3; P = .899 for piR-015551). Correlation analysis revealed that piR-015551 expression was positively correlated with expression levels of LNC00964-3 (CRC tissues: r = 0.574, P = 5.13 × 10(-9) ; normal tissues: r = 0.601, P = 5.76 × 10(-10)). Moreover, rs11776042 was not significantly correlated with mRNA expression levels of piR-015551 or LNC00964-3 (all P > .05). CONCLUSIONS: The current findings reveal the possibility that piR-015551 may be generated from LNC00964-3, which may be involved in the development of CRC.