The tumor microenvironment (TME) of nasopharyngeal carcinoma (NPC) harbors a heterogeneous and dynamic stromal population. A comprehensive understanding of this tumor-specific ecosystem is necessary to enhance cancer diagnosis, therapeutics, and prognosis. However, recent advances based on bulk RNA sequencing remain insufficient to construct an in-depth landscape of infiltrating stromal cells in NPC. Here we apply single-cell RNA sequencing to 66,627 cells from 14 patients, integrated with clonotype identification on T and B cells. We identify and characterize five major stromal clusters and 36 distinct subpopulations based on genetic profiling. By comparing with the infiltrating cells in the non-malignant microenvironment, we report highly representative features in the TME, including phenotypic abundance, genetic alternations, immune dynamics, clonal expansion, developmental trajectory, and molecular interactions that profoundly influence patient prognosis and therapeutic outcome. The key findings are further independently validated in two single-cell RNA sequencing cohorts and two bulk RNA-sequencing cohorts. In the present study, we reveal the correlation between NPC-specific characteristics and progression-free survival. Together, these data facilitate the understanding of the stromal landscape and immune dynamics in NPC patients and provides deeper insights into the development of prognostic biomarkers and therapeutic targets in the TME.
Epithelial-mesenchymal transition (EMT) is a critical step in the metastasis of hepatocellular carcinoma (HCC). BTB/POZ domain-containing protein 7 (BTBD7) regulates EMTassociated proteins implicated in HCC progression. However, the role(s) of BTBD7 in HCC have not been identified. Using highly metastatic HCC HCCLM3 cells, immortalized L02 hepatocytes, metastatic HCC animal models, and three independent cohorts of HCC patient specimens, we aimed to determine the involvement of BTBD7 in HCC metastasis. We show that BTBD7 messenger RNA and protein was highly expressed in HCC cells and tumor tissues, with such expression being associated with: enhanced cell motility, venous invasion, and poor prognosis. BTBD7 promoted HCC angiogenesis and metastasis in vitro and in vivo, but did not influence cell proliferation or colony formation. BTBD7 enhancement of HCC invasion and EMT phenotype occurred through activation of a RhoC-Rock2-FAK-signaling pathway, resulting in matrix metalloproteinase-2/9 production and microvessel formation. Applying a predictive risk score model, Cox regression analysis revealed that high BTBD7 expression integrated with high microvessel density was a powerful independent predictive factor of HCC clinical outcome. Conclusion: The present study identifies BTBD7 as a novel candidate prognostic factor and a potential therapeutic target of HCC. (HEPATOLOGY 2013; 57:2326-2337 H epatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Overall survival (OS) of HCC patients remains unsatisfactory because of a high incidence of recurrence and metastasis after hepatic resection. 1 Understanding the mechanisms of HCC recurrence and metastasis should improve HCC treatment and outcomes.Epithelial-mesenchymal transition (EMT) is an important physiological process contributing to HCC recurrence and metastasis. Expression of several EMTassociated genes is correlated with HCC recurrence and metastasis. HCCs with EMT features consistently exhibit more venous invasion, metastases, and a poorer prognosis than those without EMT characteristics. 2 Therefore, for the treatment of HCC, there exists significant clinical potential in targeting EMT-associated factors.Members of the BTB (bric-a-brac tramtrack broad complex) (also known as POZ) gene family, characterized by a conserved BTB/POZ protein-protein interaction motif, have been implicated in human cancer. 3,4 The promoter region of BTB/POZ domain-containing protein 7 (BTBD7) contains binding sites for notable transcription factors, including alpha-fetoprotein (AFP)-1, CAAT enhancer-binding protein beta, GATA,
Vibrio parahaemolyticus is a major foodborne pathogen in China, Japan, and other Asian countries. In this study, we collected 437 strains of V. parahaemolyticus and investigated their serotypes, distribution of virulence genes, and presence of pandemic O3:K6 clone strains. A total of 327 strains were isolated from food and 110 strains were isolated from active surveillance hospitals or food outbreaks during 2005 to 2008. Presence of the tdh and trh genes is the key characteristic of virulent strains. Positive for both the tdh gene and group-specific polymerase chain reaction is the key characteristic of pandemic strains. A total of 9 O serogroups and 62 serovars were identified in all strains. Nine O serogroups and 56 serovars existed in 327 foodborne strains, and 6 O serogroups and 20 serovars existed in 110 clinical strains. Among the 327 food isolates, 6 isolates belonged to the pandemic clone with the orf8 gene (1 isolate was O1:KUT (untyped) and 5 isolates were O3:K6) and 4 isolates carried the trh gene (2 isolates belonged to O1:KUT and 2 isolates belonged to O5:KUT and O5:K17). Seventy-nine percent of the clinical isolates were pandemic strains, 9.4% of which lacked the orf8 gene. O3:K6 was the main serovar of the pandemic strains accounting for 83.5% of the clinical pandemic strains. Pandemic clonal serovars included O3:K6, O1:KUT, O1:K25, O1:K26, and O4:K68, and the newly emerging serovars O1:K36, O3:K25, and O3:K68 identified in the current study. O3:K6 was the dominant serovar in pandemic strains. All pandemic isolates had identical arbitrarily primed polymerase chain reaction fragment patterns, but did not share similar antibiotic sensitivity patterns. These results suggest that high serodiversity of V. parahaemolyticus was present in foodborne strains. Pathogenic isolates, especially pandemic isolates, were present in high-priced iced seafood and became the potential risk factor in food.
Purpose: Disruption of the balance of insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP3) has been implicated in the etiology and progression of lung and other cancers. Single nucleotide polymorphisms (SNP) in IGF1 and IGFBP3 have been reported to be associated with the expression of the IGF-I/IGFBP3 axis. Therefore, we hypothesized that SNPs in these two genes were associated with lung cancer survival.Experimental Design: We selected and genotyped 21 tagging and potentially functional SNPs in IGF1 and IGFBP3 by using Illumina Goldengate Genotyping Chip in a case cohort of 568 patients diagnosed with non-small cell lung cancer (NSCLC) in a Chinese population. Log-rank test and Cox proportional hazard models were used for the survival analyses.Results: We found that rs5742714C/G in the 3′-untranslated region of IGF1 was associated significantly with NSCLC survival after adjustment for demographic and clinicopathologic factors, showing an improved median survival time in patients carrying variant CG/GG genotypes [median survival time, 28.5 months for CG/GG and 23.0 for CC; crude hazard ratio (HR), 0.74; 95% confidence interval (95% CI), 0.57-0.95, and adjusted HR, 0.77; 95% CI, 0.60-0.99]. This protective effect was more predominant for patients receiving surgical operation (HR, 0.58; 95% CI, 0.40-0.85; P for heterogeneity test = 0.045), along with a significant multiplicative interaction between variant genotypes and operation status (P = 0.028).Conclusions: Our findings suggest that rs5742714 in IGF1 may be a genetic modifier for NSCLC prognosis in this Chinese population, especially among patients with surgical operation.
Background: Class C G protein-coupled receptors (GPCRs) represent a distinct group of the GPCR family, which structurally possess a characteristically distinct extracellular domain inclusive of the Venus flytrap module (VFTM). The VFTMs of the class C GPCRs is responsible for ligand recognition and binding, and share sequence similarity with bacterial periplasmic amino acid binding proteins (PBPs). An extensive phylogenetic investigation of the VFTMs was conducted by analyzing for functional divergence and testing for positive selection for five typical groups of the class C GPCRs. The altered selective constraints were determined to identify the sites that had undergone functional divergence via positive selection. In order to structurally demonstrate the pattern changes during the evolutionary process, three-dimensional (3D) structures of the GPCR VFTMs were modelled and reconstructed from ancestral VFTMs.
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