Screening of significant biomarkers related with prognosis of liver cancer by lncRNA-associated ceRNAs analysis

This study aimed to identify significant biomarkers related to the prognosis of liver cancer using long noncoding RNA (lncRNA)-associated competing endogenous RNAs (ceRNAs) analysis. Differentially expressed mRNA and lncRNAs between liver cancer and paracancerous tissues were screened, and the functions of these mRNAs were predicted by gene ontology and pathway enrichment analyses. A ceRNA network consisting of differentially expressed mRNAs and lncRNAs was constructed. LncRNA FENDRR and lncRNA HAND2-AS1 were hub nodes in the ceRNA network. A risk score assessment model consisting of eight genes (PDE2A, ESR1, FBLN5, ALDH8A1, AKR1D1, EHHADH, ADRA1A, and GNE) associated with prognosis were developed. Multivariate Cox regression suggested that both pathologic_T and risk group could be regarded as independent prognostic factors. Furthermore, a nomogram model consisting of pathologic_T and risk group showed a good prediction ability for predicting the survival rate of liver cancer patients. The nomogram model consisting of pathologic_T and a risk score assessment model could be regarded as an independent factor for predicting prognosis of liver cancer.     

A Conservative Point Mutation in a Dynamic Antigen-binding Loop of Human Immunoglobulin λ6 Light Chain Promotes Pathologic Amyloid Formation

Immunoglobulin light chain (LC) amyloidosis (AL) is a life-threatening human disease wherein free mono-clonal LCs deposit in vital organs. To determine what makes some LCs amyloidogenic, we explored patient-based amyloidogenic and non-amyloidogenic recombinant LCs from the λ6 subtype prevalent in AL. Hydrogen-deuterium exchange mass spectrometry, structural stability, proteolysis, and amyloid growth studies revealed that the antigen-binding CDR1 loop is the least protected part in the variable domain of λ6 LC, particularly in the AL variant. N32T substitution in CRD1 is identified as a driver of amyloid formation. Substitution N32T increased the amyloidogenic propensity of CDR1 loop, decreased its protection in the native structure, and accelerated amyloid growth in the context of other AL substitutions. The destabilizing effects of N32T propagated across the molecule increasing its dynamics in regions ∼30 Å away from the substitution site. Such striking long-range effects of a conservative point substitution in a dynamic surface loop may be relevant to Ig function. Comparison of patient-derived and engineered proteins showed that N32T interactions with other substitution sites must contribute to amyloidosis. The results suggest that CDR1 is critical in amyloid formation by other λ6 LCs.     

Deep mutational scanning identifies SARS-CoV-2 Nucleocapsid escape mutations of currently available rapid antigen tests

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Critical role of bioanalytical strategies in investigation of clinical PK observations,a Phase I case study

RG7652 is a human immunoglobulin 1 (IgG1) monoclonal antibody (mAb) targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) and is designed for the treatment of hypercholesterolemia. A target-binding enzyme-linked immunosorbent assay (ELISA) was developed to measure RG7652 levels in human serum in a Phase I study. Although target-binding assay formats are generally used to quantify free therapeutic, the actual therapeutic species being measured are affected by assay conditions, such as sample dilution and incubation time, and levels of soluble target in the samples. Therefore, in the presence of high concentrations of circulating target, the choice of reagents and assay conditions can have a significant effect on the observed pharmacokinetic (PK) profiles. Phase I RG7652 PK analysis using the ELISA data resulted in a nonlinear dose normalized exposure. An investigation was conducted to characterize the ELISA to determine whether the assay format and reagents may have contributed to the PK observation. In addition, to confirm the ELISA results, a second orthogonal method, liquid chromatography tandem mass spectrometry (LC-MS/MS) using a signature peptide as surrogate, was developed and implemented. A subset of PK samples, randomly selected from half of the subjects in the 6 single ascending dose (SAD) cohorts in the Phase I clinical study, was analyzed with the LC-MS/MS assay, and the data were found to be comparable to the ELISA data. This paper illustrates the importance of reagent characterization, as well as the benefits of using an orthogonal approach to eliminate bioanalytical contributions when encountering unexpected observations.     

A novel hypoxia gene signature indicates prognosis and immune microenvironments characters in patients with hepatocellular carcinoma

Due to the lack of a suitable gene signature, it is difficult to assess the hypoxic exposure of HCC tissues. The clinical value of assessing hypoxia in HCC is short of tissue-level evidence. We tried to establish a robust and HCC-suitable hypoxia signature using microarray analysis and a robust rank aggregation algorithm. Based on the hypoxia signature, we obtained a hypoxia-associated HCC subtypes system using unsupervised hierarchical clustering and a hypoxia score system was provided using gene set variation analysis. A novel signature containing 21 stable hypoxia-related genes was constructed to effectively indicate the exposure of hypoxia in HCC tissues. The signature was validated by qRT-PCR and compared with other published hypoxia signatures in multiple large-size HCC cohorts. The subtype of HCC derived from this signature had different prognosis and other clinical characteristics. The hypoxia score obtained from the signature could be used to indicate clinical characteristics and predict prognoses of HCC patients. Moreover, we reveal a landscape of immune microenvironments in patients with different hypoxia score. In conclusion, we identified a novel HCC-suitable 21-gene hypoxia signature that could be used to estimate the hypoxia exposure in HCC tissues and indicated prognosis and a series of important clinical features in HCCs. It may enable the development of personalized counselling or treatment strategies for HCC patients with different levels of hypoxia exposure.     

Stem cell competition driven by the Axin2-p53 axis controls brain size during murine development

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Minority of mammalian orthologs can be regarded as physiologically closest genes

Orthologs are genes from different genomes that originate from a common ancestor gene by speciation event. They are most similar by the structure of encoded proteins and therefore should have a similar function. Here I apply the principle used for detection of structural orthology for a genome-wide analysis of gene expression. For this purpose, I determine the mutual similarity rank in all-by-all comparison of among-tissues expression patterns. The expression of most part of human–mouse orthologs in homologous tissues is poorly correlated (average mutual coexpression rank is only 4835 out of 18,092). Genes from evolutionarily labile gene families, which experience rapid turnover of family composition, are among those with the strongest expression change. However, the revealed phenomenon is not limited to them. There is no or very weak relationship between protein sequence divergence and mutual coexpression rank. Also, generally there is no relationship between the ratio of nonsynonymous to synonymous nucleotide substitutions and coexpression rank. This relationship is tangible only within evolutionarily labile gene families. These results indicate that despite of a similar biochemical function of orthologs reflected in the conserved protein sequence, the physiological (systemic) context of this function can be changed. Also, these results suggest that gene biochemical function and its physiological role in the organism can evolve independently.     

Cancer: Towards a general theory of the target

General theories (GT) are reductionist explications of apparently independent facts. Here, in reviewing the literature, I develop a GT to simplify the cluttered landscape of cancer therapy targets by revealing they cluster parsimoniously according to only a few underlying principles. The first principle is that targets can be only exploited by either or both of two fundamentally different approaches: causality‐inhibition, and ‘acausal’ recognition of some marker or signature. Nonetheless, each approach must achieve both of two separate goals, efficacy (reduction in cancer burden) and selectivity (sparing of normal cells); if the mechanisms are known, this provides a definition of rational treatment. The second principle is target fragmentation, whereby the target may perform up to three categoric functions (cytoreduction, modulation, cytoprotection), potentially mediated by physically different target molecules, even on different cell types, or circulating freely. This GT remains incomplete until the minimal requirements for cure, or alternatively, proof that cure is impossible, become predictable.