Is it time for China to prioritize pan-genotypic regimens for treating patients with hepatitis C?

INTRODUCTION: The treatment of hepatitis C has entered the pan-genotypic era, but the effectiveness is not good for the genotype 3b patients who have a large proportion in China. The guidelines for hepatitis C recommend the use of gene-specific regimens when the regional 3b prevalence rate greater than 5%. This study is to explore rationality of this proportion and the cost-effectiveness to implement pan-genotypic regimens in China. METHODS: A decision Markov model was developed from the health system perspective to evaluate the effectiveness and cost-effectiveness between pan-genotypic and gene-specific treatment regimens for hepatitis C patients. Additionally, we set a regional genotype 3b patient proportion of 0-100% to explore at which proportion it is necessary to perform genotype identification and typing therapy on patients. Model parameters were derived from published literature and public databases. Effectiveness was measured by cured patient numbers, newly diagnosed cases of decompensated cirrhosis, hepatocellular carcinoma, need for liver transplantation, and quality-adjusted life years (QALYs). Cost-effectiveness outcomes included costs and the incremental cost-effectiveness ratio (ICER). The 1-3 times 2022 Chinese per capita gross domestic product was used as the willingness-to-pay threshold. One-way and probabilistic sensitivity analyses were performed to assess the uncertainty of the model parameters. RESULTS: Compared with gene-specific regimens, pan-genotypic regimens resulted in an additional 0.13 QALYs and an incremental cost of $165, the ICER was $1,268/QALY. From the view of efficacy, the pan-genotypic regimens cured 5,868 more people per 100,000 patients than gene-specific regimens, avoiding 86.5% of DC cases, 64.6% of HCC cases, and 78.2% of liver transplant needs. Identifying 3b patients before treatment was definitely cost-effectiveness when their prevalence was 12% or higher. The results remained robust in sensitivity analyses. CONCLUSIONS: In China, the prioritized recommendation of pan-genotypic therapeutics proves to be both cost-effective and efficacious. But, in regions where the prevalence of genotype 3b exceeds 12%, it is necessary to identify them to provision of more suitable therapies.

Dual Contrastive Learning Network for Graph Clustering.

Graph representation is an important part of graph clustering. Recently, contrastive learning, which maximizes the mutual information between augmented graph views that share the same semantics, has become a popular and powerful paradigm for graph representation. However, in the process of patch contrasting, existing literature tends to learn all features into similar variables, i.e., representation collapse, leading to less discriminative graph representations. To tackle this problem, we propose a novel self-supervised learning method called dual contrastive learning network (DCLN), which aims to reduce the redundant information of learned latent variables in a dual manner. Specifically, the dual curriculum contrastive module (DCCM) is proposed, which approximates the node similarity matrix and feature similarity matrix to a high-order adjacency matrix and an identity matrix, respectively. By doing this, the informative information in high-order neighbors could be well collected and preserved while the irrelevant redundant features among representations could be eliminated, hence improving the discriminative capacity of the graph representation. Moreover, to alleviate the problem of sample imbalance during the contrastive process, we design a curriculum learning strategy, which enables the network to simultaneously learn reliable information from two levels. Extensive experiments on six benchmark datasets have demonstrated the effectiveness and superiority of the proposed algorithm compared with state-of-the-art methods.

Polo-like kinase 1 (PLK1) O-GlcNAcylation is essential for dividing mammalian cells and inhibits uterine carcinoma.

The O-linked ß-N-acetylglucosamine (O-GlcNAc) transferase (OGT) mediates intracellular O-GlcNAcylation modification. O-GlcNAcylation occurs on Ser/Thr residues and is important for numerous physiological processes. OGT is essential for dividing mammalian cells and is involved in many human diseases; however, many of its fundamental substrates during cell division remain unknown. Here, we focus on the effect of OGT on polo-like kinase 1 (PLK1), a mitotic master kinase that governs DNA replication, mitotic entry, chromosome segregation, and mitotic exit. We show that PLK1 interacts with OGT and is O-GlcNAcylated. By utilizing stepped collisional energy/higher-energy collisional dissociation mass spectrometry, we found a peptide fragment of PLK1 that is modified by O-GlcNAc. Further mutation analysis of PLK1 shows that the T291A mutant decreases O-GlcNAcylation. Interestingly, T291N is a uterine carcinoma mutant in The Cancer Genome Atlas. Our biochemical assays demonstrate that T291A and T291N both increase PLK1 stability. Using stable H2B-GFP cells, we found that PLK1-T291A and PLK1-T291N mutants display chromosome segregation defects and result in misaligned and lagging chromosomes. In mouse xenograft models, we demonstrate that the O-GlcNAc-deficient PLK1-T291A and PLK1-T291N mutants enhance uterine carcinoma in animals. Hence, we propose that OGT partially exerts its mitotic function through O-GlcNAcylation of PLK1, which might be one mechanism by which elevated levels of O-GlcNAc promote tumorigenesis.

Centrosomes: Til O-GlcNAc Do Us Apart.

The centrosome apparatus is vital for spindle assembly and chromosome segregation during mitotic divisions. Its replication, disjunction and separation have to be fine-tuned in space and time. A multitude of post-translational modifications (PTMs) have been implicated in centrosome modulation, including phosphorylation, ubiquitination and acetylation. Among them is the emerging O-linked N-acetylglucosamine (O-GlcNAc) modification. This quintessential PTM has a sole writer, O-GlcNAc transferase (OGT), and the only eraser, O-GlcNAcase (OGA). O-GlcNAc couples glucose metabolism with signal transduction and forms a yin-yang relationship with phosphorylation. Evidence from proteomic studies as well as single protein investigations has pinpointed a role of O-GlcNAc in centrosome number and separation, centriole number and distribution, as well as the cilia machinery emanating from the centrosomes. Herein we review our current understanding of the sweet modification embedded in centrosome dynamics and speculate that more molecular details will be unveiled in the future.