LDD is common, and its incidence increases with age. In a population setting, there is a significant association of LDD on MRI with back pain.

Interaction between tumor cells and immune cells in the tumor microenvironment is important in cancer development. Immune cells interact with the tumor cells to shape this process. Here, we use single-cell RNA sequencing analysis to delineate the immune landscape and tumor heterogeneity in a cohort of patients with HBV-associated human hepatocellular carcinoma (HCC). We found that tumor-associated macrophages suppress tumor T cell infiltration and TIGIT-NECTIN2 interaction regulates the immunosuppressive environment. The cell state transition of immune cells towards a more immunosuppressive and exhaustive status exemplifies the overall cancer-promoting immunocellular landscape. Furthermore, the heterogeneity of global molecular profiles reveals co-existence of intra-tumoral and inter-tumoral heterogeneity, but is more apparent in the latter. This analysis of the immunosuppressive landscape and intercellular interactions provides mechanistic information for the design of efficacious immune-oncology treatments in hepatocellular carcinoma.

Lumbar-disc degeneration (LDD) is a polygenic disease. Susceptibility genes reported so far are mainly extracellular matrix proteins. D14 allele of asporin (ASPN) is associated with osteoarthritis (OA). Candidate-gene association studies showed that the D14 allele is also significantly associated with LDD in Chinese and Japanese individuals. Meta-analysis showed that individuals harboring a D14 allele had higher risk with a summary odds ratio of 1.70 (p = 0.000013). ASPN expression in vertebral discs increased with age and degeneration. Our results indicate ASPN is a LDD gene in Asians, and common risk factors may be considered for OA and LDD.

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Lumbar disc degeneration (LDD) is associated with both genetic and environmental factors and affects many people worldwide. A hallmark of LDD is loss of proteoglycan and water content in the nucleus pulposus of intervertebral discs. While some genetic determinants have been reported, the etiology of LDD is largely unknown. Here we report the findings from linkage and association studies on a total of 32,642 subjects consisting of 4,043 LDD cases and 28,599 control subjects. We identified carbohydrate sulfotransferase 3 (CHST3), an enzyme that catalyzes proteoglycan sulfation, as a susceptibility gene for LDD. The strongest genome-wide linkage peak encompassed CHST3 from a Southern Chinese family-based data set, while a genome-wide association was observed at rs4148941 in the gene in a meta-analysis using multiethnic population cohorts. rs4148941 lies within a potential microRNA-513a-5p (miR-513a-5p) binding site. Interaction between miR-513a-5p and mRNA transcribed from the susceptibility allele (A allele) of rs4148941 was enhanced in vitro compared with transcripts from other alleles. Additionally, expression of CHST3 mRNA was significantly reduced in the intervertebral disc cells of human subjects carrying the A allele of rs4148941. Together, our data provide new insights into the etiology of LDD, implicating an interplay between genetic risk factors and miRNA.

ObjectiveWe investigated the mutational landscape of mammalian target of rapamycin (mTOR) signalling cascade in hepatocellular carcinomas (HCCs) with chronic HBV background, aiming to evaluate and delineate mutation-dependent mechanism of mTOR hyperactivation in hepatocarcinogenesis.DesignWe performed next-generation sequencing on human HCC samples and cell line panel. Systematic mutational screening of mTOR pathway-related genes was undertaken and mutant genes were evaluated based on their recurrence. Protein expressions of tuberous sclerosis complex (TSC)1, TSC2 and pRPS6 were assessed by immunohistochemistry in human HCC samples. Rapamycin sensitivity was estimated by colony-formation assay in HCC cell lines and the treatment was further tested using our patient-derived tumour xenograft (PDTX) models.ResultsWe identified and confirmed multiple mTOR components as recurrently mutated in HBV-associated HCCs. Of significance, we detected frequent (16.2%, n=18/111) mutations of TSC1 and TSC2 genes in the HCC samples. The spectrum of TSC1/2 mutations likely disrupts the endogenous gene functions in suppressing the downstream mTOR activity through different mechanisms and leads to more aggressive tumour behaviour. Mutational disruption of TSC1 and TSC2 was also observed in HCC cell lines and our PDTX models. TSC-mutant cells exhibited reduced colony-forming ability on rapamycin treatment. With the use of biologically relevant TSC2-mutant PDTXs, we demonstrated the therapeutic benefits of the hypersensitivity towards rapamycin treatment.ConclusionsTaken together, our findings suggest the significance of previously undocumented mutation-dependent mTOR hyperactivation and frequent TSC1/2 mutations in HBV-associated HCCs. They define a molecular subset of HCC having genetic aberrations in mTOR signalling, with potential significance of effective specific drug therapy.

This study systematically evaluates the TCGA whole-transcriptome sequencing data of hepatocellular carcinoma (HCC) by comparing the global gene expression profiles between tumors and their corresponding nontumorous liver tissue. Based on the differential gene expression analysis, we identified a number of novel dysregulated genes, in addition to those previously reported. Top-listing upregulated (CENPF and FOXM1) and downregulated (CLEC4G, CRHBP, and CLEC1B) genes were successfully validated using qPCR on our cohort of 65 pairs of human HCCs. Further examination for the mechanistic overview by subjecting significantly upregulated and downregulated genes to gene set enrichment analysis showed that different cellular pathways were involved. This study provides useful information on the transcriptomic landscape and molecular mechanism of hepatocarcinogenesis for development of new biomarkers and further in-depth characterization.

Objective. Typically, age and abnormal physical loading ("wear and tear") have been associated with the development of intervertebral disc degeneration. In the past decade, various additional etiologic factors for disc degeneration have been sporadically reported in the literature; however, many investigators continue to place tremendous emphasis on the effects of age and biomechanics associated with disc degeneration. The aim of this study was to provide additional insight into the notion that age and biomechanics are key factors in the development of disc degeneration. To this end, we addressed the prevalence of and risk factors associated with a unique pattern of disc degeneration of the lumbar spine, "skipped" level (nonconsecutive) disc degeneration (SLDD).Methods. As part of a large genetics-based study in southern Chinese individuals (n ‫؍‬ 1,989), a crosssectional analysis was performed in subjects exhibiting disc degeneration in >2 levels (n ‫؍‬ 838) who were then categorized as having SLDD (n ‫؍‬ 174) or non-SLDD (contiguous, multilevel; n ‫؍‬ 664). Various radiographic parameters were assessed based on T2-weighted magnetic resonance imaging (MRI). Subject demographics were assessed, and univariate and multivariate logistic regression analyses were performed.Results. Overall, 8.7% of the whole population (n ‫؍‬ 1,989) had SLDD, while it was present in 20.8% of subjects with multilevel disc degeneration (n ‫؍‬ 838). SLDD was more prevalent in male subjects (adjusted odds ratio [OR] 1.48, 95% confidence interval [95% CI] 1.04-2.10, P ‫؍‬ 0.028). SLDD was significantly associated with the presence of Schmorl's nodes (adjusted OR 2.72, 95% CI 1.78-4.15, P < 0.001), which also presented in levels with no disc degeneration. A history of disc bulge/extrusion (P ‫؍‬ 0.004) and/or a history of back injury (P ‫؍‬ 0.010) was significantly associated with non-SLDD, and a greater degree of overall severity of disc degeneration was also associated with non-SLDD. Other demographic and MRI findings did not significantly differ between groups.Conclusion. To our knowledge, this report is the first to describe the prevalence and risk factors associated with SLDD. Our study challenges the paradigm that age and biomechanics are the key factors associated with the development of disc degeneration. Although age and biomechanical factors may play a role in the manifestation of disc degeneration, our novel findings of SLDD patterns provide further awareness of and support for the notion that additional etiologic factors may play a role in the development of disc degeneration. Such factors warrant further investigation to shed light on the cause of disc degeneration.