BACKGROUND AND AIMS: Susceptibility genes and the underlying mechanisms for the majority of risk loci identified by genome-wide association studies (GWAS) for colorectal cancer (CRC) risk remain largely unknown. We conducted a transcriptome-wide association study (TWAS) to identify putative susceptibility genes. METHODS: Gene-expression prediction models were built using transcriptome and genetic data from the 284 normal transverse colon tissues of European descendants from the Genotype-Tissue Expression (GTEx), and model performance was evaluated using data from The Cancer Genome Atlas (n = 355). We applied the gene-expression prediction models and GWAS data to evaluate associations of genetically predicted gene-expression with CRC risk in 58,131 CRC cases and 67,347 controls of European ancestry. Dual-luciferase reporter assays and knockdown experiments in CRC cells and tumor xenografts were conducted. RESULTS: We identified 25 genes associated with CRC risk at a Bonferroni-corrected threshold of P < 9.1 × 10-6, including genes in 4 novel loci, PYGL (14q22.1), RPL28 (19q13.42), CAPN12 (19q13.2), MYH7B (20q11.22), and MAP1L3CA (20q11.22). In 9 known GWAS-identified loci, we uncovered 9 genes that have not been reported previously, whereas 4 genes remained statistically significant after adjusting for the lead risk variant of the locus. Through colocalization analysis in GWAS loci, we additionally identified 12 putative susceptibility genes that were supported by TWAS analysis at P < .01. We showed that risk allele of the lead risk variant rs1741640 affected the promoter activity of CABLES2. Knockdown experiments confirmed that CABLES2 plays a vital role in colorectal carcinogenesis. CONCLUSIONS: Our study reveals new putative susceptibility genes and provides new insight into the biological mechanisms underlying CRC development.

• MeSH
• alely MeSH
• celogenomová asociační studie MeSH
• genetická predispozice k nemoci * MeSH
• genový knockdown MeSH
• jednonukleotidový polymorfismus MeSH
• karcinogeneze genetika   MeSH
• kohortové studie MeSH
• kolorektální nádory epidemiologie   genetika   MeSH
• lidé MeSH
• modely genetické * MeSH
• nádorové biomarkery genetika   MeSH
• promotorové oblasti (genetika) genetika   MeSH
• rizikové faktory MeSH
• sekvenování transkriptomu MeSH
• studie případů a kontrol MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, N.I.H., Intramural MeSH

A collection of asbtracts of papers presented at a forum that focused on host pathogen interaction. Also contains the program of the meeting. Intended for professional public.

• MeSH
• interakce hostitele a parazita MeSH
• Publikační typ
• abstrakty MeSH
• kongresy MeSH
• programy MeSH
• sborníky MeSH
• zprávy MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• infekční lékařství

Extramedullary disease (EMD) is a high-risk feature of multiple myeloma (MM) and remains a poor prognostic factor, even in the era of novel immunotherapies. Here, we applied spatial transcriptomics (RNA tomography for spatially resolved transcriptomics [tomo-seq] [n = 2] and 10x Visium [n = 12]) and single-cell RNA sequencing (n = 3) to a set of 14 EMD biopsies to dissect the 3-dimensional architecture of tumor cells and their microenvironment. Overall, infiltrating immune and stromal cells showed both intrapatient and interpatient variations, with no uniform distribution over the lesion. We observed substantial heterogeneity at the copy number level within plasma cells, including the emergence of new subclones in circumscribed areas of the tumor, which is consistent with genomic instability. We further identified the spatial expression differences between GPRC5D and TNFRSF17, 2 important antigens for bispecific antibody therapy. EMD masses were infiltrated by various immune cells, including T cells. Notably, exhausted TIM3+/PD-1+ T cells diffusely colocalized with MM cells, whereas functional and activated CD8+ T cells showed a focal infiltration pattern along with M1 macrophages in tumor-free regions. This segregation of fit and exhausted T cells was resolved in the case of response to T-cell-engaging bispecific antibodies. MM and microenvironment cells were embedded in a complex network that influenced immune activation and angiogenesis, and oxidative phosphorylation represented the major metabolic program within EMD lesions. In summary, spatial transcriptomics has revealed a multicellular ecosystem in EMD with checkpoint inhibition and dual targeting as potential new therapeutic avenues.

• MeSH
• lidé MeSH
• mnohočetný myelom * genetika   patologie   imunologie   MeSH
• nádorové mikroprostředí * imunologie   genetika   MeSH
• stanovení celkové genové exprese MeSH
• T-lymfocyty imunologie   patologie   metabolismus   MeSH
• transkriptom * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The mechanism of rotator cuff injury remains to be elucidated. And COX-2 plays a dual role in skeletal muscle injury and regeneration, would be associated with the development of rotator cuff injury. Therefore, we chose human skeletal muscle cells (HSKMC) as an in vitro muscle tissue model and transfected lentivirus with overexpressed COX-2 to simulate the in vitro environment of rotator cuff injury. To investigate the specific molecular biological mechanism of COX-2, transcriptome sequencing (RNA-Seq) was used to analyze the differentially expressed mRNAs in HSKMC overexpressing COX-2. Enrichment analysis was performed to analyze these differentially expressed genes and real-time quantitative PCR (RT-qPCR) was used to examine the mRNA levels of genes induced by overexpression. Subsequently, the role of COX-2 in cell proliferation was confirmed by cell counting kit-8 (CCK-8), and focal adhesion kinase (FAK) and signal transducer and activator of transcription 3 (STAT3) phosphorylation induced by COX-2 was utilized by western blotting (WB). The results showed that total of 30,759 differentially expressed genes were obtained, and the expression of CYP4F3 and GPR87 was significantly increased. COX-2 could bind CYP4F3 and GPR87 and co-localize with them in the cytoplasm. Finally, COX-2 promoted the proliferation of human skeletal muscle cells by activating the FAK and STAT3 pathways.

• MeSH
• cyklooxygenasa 2 * metabolismus   genetika   MeSH
• kosterní svalová vlákna metabolismus   enzymologie   patologie   MeSH
• kosterní svaly metabolismus   patologie   MeSH
• kultivované buňky MeSH
• lidé MeSH
• poranění rotátorové manžety * metabolismus   patologie   enzymologie   genetika   MeSH
• proliferace buněk MeSH
• transkripční faktor STAT3 metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

KEY MESSAGE: The new 4.2-kb transposable insertion in the intron of ZmCCT reversely responded relative to the known 5.1-kb transposable insertion to photoperiods between low- and high-latitude regions. Flowering time is a key trait for cereal adaptation that is controlled by a complex genetic background in maize. The effect of multiple alleles from a quantitative trait locus (QTL) on flowering time remains largely unknown. Here, we fine-mapped a major QTL for flowering time on maize chromosome 10 corresponding to ZmCCT, where a new allele with a 4.2-kilobase (kb) transposable insertion was present in the intron. The known allele with a 5.1-kb transposon insertion in the promoter of ZmCCT enhances flowering in high-latitude regions, but has no effect on flowering time in low-latitude regions in comparison with the null allele lacking this insertion. However, our new allele with a 4.2-kb insertion reduced flowering in the low-latitude region, but produced unchanged flowering time in the high-latitude region relative to the 5.1-kb transposable insertion. Transcription analysis revealed that the new allele with 4.2-kb insertion versus the 5.1-kb insertion repressed and unchanged the transcription of ZmCCT in the low- and high-latitude regions, respectively. Thus, the allele with the 4.2-kb transposable insertion showed a completely opposite response to photoperiods between these two regions. Phylogenetic analysis revealed that the 4.2-kb transposable insertion in the two Northern flint corns originated from tropical maize. RNA-seq analysis and dual-luciferase transient expression assays further identified a conserved gene regulation network of ZmCCT between maize and rice, in which ZmCCT directly repressed the transcription of the florigen gene ZCN8 via ZmEhd1. Our results suggest that transposable elements play an important role in maize adaptation.

• MeSH
• chromozomy rostlin genetika   MeSH
• fenotyp MeSH
• fotoperioda * MeSH
• fyziologická adaptace MeSH
• kukuřice setá genetika   růst a vývoj   účinky záření   MeSH
• květy genetika   růst a vývoj   účinky záření   MeSH
• lokus kvantitativního znaku MeSH
• mapování chromozomů metody   MeSH
• promotorové oblasti (genetika) MeSH
• regulace genové exprese u rostlin * MeSH
• rostlinné proteiny genetika   metabolismus   MeSH
• transpozibilní elementy DNA * MeSH
• Publikační typ
• časopisecké články MeSH