👤 Amy Luke

To assess the association between hepatitis C virus (HCV) infection and cognitive impairment among seniors in Taiwan, building on our previous findings from a cross-sectional study. Retrospective cohort study. Taiwan Biobank. 326 participants with positive serum anti-HCV and a control group of 8753 with negative HCV free of cognitive impairment were assessed by the Mini-Mental State Examination at baseline. The association between HCV infection and cognitive impairment was evaluated using Cox proportional hazard models. The analysis was adjusted for age, sex, education, BMI, hypertension, cirrhosis, depression, estimated glomerular filtration rate, APOE genotype, and recruitment periods. Anti-HCV positive patients showed a significantly higher incidence of cognitive impairment compared to anti-HCV negative individuals (14.28 vs. 7.21 per 1000 person-years, P = 0.004). After adjusting for covariates, HCV infection was significantly associated with an increased risk of developing cognitive impairment (adjusted HR [aHR]: 1.80, 95% confidence interval [CI]: 1.12-2.90). Subgroup analyses for individuals diagnosed prior to the public direct-acting antivirals reimbursement in 2017 and with high antibody titres (sample/cutoff ratio ≥ 5), the elevated risk of cognitive impairment remained statistically significant, with aHRs of 1.69 (95% CI: 1.04-2.75) and 1.81 (95% CI: 1.11-2.96) respectively. Additionally, HCV patients carrying the APOE ɛ4 allele had a marginally higher risk (aHR: 2.60, 95% CI: 0.96-7.08, P = 0.06). In Taiwan, our findings strengthen evidence that individuals above the age of 60 with HCV infections are at a greater risk of developing cognitive impairment than their counterparts, who were HCV negative. Show less

First-line immune checkpoint inhibitor (ICI) combinations show responses in subsets of hepatocellular carcinoma (HCC) patients. Nearly half of HCCs are Wnt-active with mutations in CTNNB1 (encoding for β-catenin), AXIN1/2, or APC, and demonstrate heterogeneous and limited benefit to ICI due to an immune excluded tumor microenvironment. We show significant tumor responses in multiple β-catenin-mutated immunocompetent HCC models to a novel siRNA encapsulated in lipid nanoparticle targeting CTNNB1 (LNP-CTNNB1). Both single-cell and spatial transcriptomics reveal cellular and zonal reprogramming, along with activation of immune regulatory transcription factors IRF2 and POU2F1, re-engaged type I/II interferon signaling, and alterations in both innate and adaptive immunity upon β-catenin suppression with LNP-CTNNB1 at early- and advanced-stage disease. Moreover, ICI enhances response to LNP-CTNNB1 in advanced-stage disease by preventing T cell exhaustion and through formation of lymphoid aggregates (LA). In fact, expression of an LA-like gene signature prognosticates survival for patients receiving atezolizumab plus bevacizumab in the IMbrave150 phase III trial and inversely correlates with CTNNB1-mutatational status in this patient cohort. In conclusion, LNP-CTNNB1 is efficacious as monotherapy and in combination with ICI in CTNNB1-mutated HCCs through impacting tumor cell-intrinsic signaling and remodeling global immune surveillance, providing rationale for clinical investigations. Show less

The T-cell-inflamed phenotype correlates with efficacy of immune-checkpoint blockade, whereas non-T-cell-inflamed tumors infrequently benefit. Tumor-intrinsic WNT/β-catenin signaling mediates immune exclusion in melanoma, but association with the non-T-cell-inflamed tumor microenvironment in other tumor types is not well understood. Using The Cancer Genome Atlas (TCGA), a T-cell-inflamed gene expression signature segregated samples within tumor types. Activation of WNT/β-catenin signaling was inferred using three approaches: somatic mutations or somatic copy number alterations (SCNA) in β-catenin signaling elements including Across TCGA, 3,137/9,244 (33.9%) tumors were non-T-cell-inflamed, whereas 3,161/9,244 (34.2%) were T-cell-inflamed. Non-T-cell-inflamed tumors demonstrated significantly lower expression of T-cell inflammation genes relative to matched normal tissue, arguing for loss of a natural immune phenotype. Mutations of β-catenin signaling molecules in non-T-cell-inflamed tumors were enriched three-fold relative to T-cell-inflamed tumors. Across 31 tumors, 28 (90%) demonstrated activated β-catenin signaling in the non-T-cell-inflamed subset by at least one method. This included target molecule expression from somatic mutations and/or SCNAs of β-catenin signaling elements (19 tumors, 61%), pathway analysis (14 tumors, 45%), and increased β-catenin protein levels (20 tumors, 65%). Activation of tumor-intrinsic WNT/β-catenin signaling is enriched in non-T-cell-inflamed tumors. These data provide a strong rationale for development of pharmacologic inhibitors of this pathway with the aim of restoring immune cell infiltration and augmenting immunotherapy. Show less

Interest in mapping genetic variants that are associated with obesity remains high because of the increasing prevalence of obesity and its complications worldwide. Data on genetic determinants of obesity in African populations are rare. We have undertaken a genome-wide scan for body mass index (BMI) in 182 Nigerian families that included 769 individuals. The prevalence of obesity was only 5%, yet polygenic heritability for BMI was in the expected range (0.46 +/- 0.07). Tandem repeat markers (402) were typed across the genome with an average map density of 9 cM. Pedigree-based analysis using a variance components linkage model demonstrated evidence for linkage on chromosome 7 (near marker D7S817 at 7p14) with a logarithm of odds (LOD) score of 3.8 and on chromosome 11 (marker D11S2000 at 11q22) with an LOD score of 3.3. Weaker evidence for linkage was found on chromosomes 1 (1q21, LOD = 2.2) and 8 (8p22, LOD = 2.3). Several candidate genes, including neuropeptide Y, DRD2, APOA4, lamin A/C, and lipoprotein lipase, lie in or close to the chromosomal regions where strong linkage signals were found. The findings of this study suggest that, as in other populations with higher prevalences of obesity, positive linkage signals can be found on genome scans for obesity-related traits. Follow-up studies may be warranted to investigate these linkages, especially the one on chromosome 11, which has been reported in a population at the opposite end of the BMI distribution. Show less