SARS-CoV-2 omicron BA.5 and XBB variants have increased neurotropic potential over BA.1 in K18-hACE2 mice and human brain organoids

The reduced pathogenicity of the omicron BA.1 sub-lineage compared to earlier variants is well described, although whether such attenuation is retained for later variants like BA.5 and XBB remains controversial. We show that BA.5 and XBB isolates were significantly more pathogenic in K18-hACE2 mice than a BA.1 isolate, showing increased neurotropic potential, resulting in fulminant brain infection and mortality, similar to that seen for original ancestral isolates. BA.5 also infected human cortical brain organoids to a greater extent than the BA.1 and original ancestral isolates. In the brains of mice, neurons were the main target of infection, and in human organoids neuronal progenitor cells and immature neurons were infected. The results herein suggest that evolving omicron variants may have increasing neurotropic potential

Oncogenic BRAF mutation induces DNA methylation changes in a murine model for human serrated colorectal neoplasia

Colorectal cancer is a major cause of cancer death and approximately 20% arises within serrated polyps, which are under-recognized and poorly understood. Human serrated colorectal polyps frequently exhibit both oncogenic BRAF mutation and widespread DNA methylation changes, which are important in silencing genes restraining neoplastic progression. Here, we investigated whether in vivo induction of mutant Braf is sufficient to result in coordinated promoter methylation changes for multiple cancer-related genes. The BrafV637E mutation was induced in murine intestine on an FVB;C57BL/6J background and assessed for morphological and DNA methylation changes at multiple time points from 10 days to 14 months. Extensive intestinal hyperplasia developed by 10 days post-induction of the mutation. By 8 months, most mice had murine serrated adenomas with dysplasia and invasive cancer developed in 40% of mice by 14 months. From 5 months onwards, Braf mutant mice showed extensive, gene-specific increases in DNA methylation even in hyperplastic mucosa without lesions. This demonstrates that persistent oncogenic Braf signaling is sufficient to induce widespread DNA methylation changes. This occurs over an extended period of time, mimicking the long latency followed by rapid progression of human serrated neoplasia. This study establishes for the first time that DNA methylation arises slowly in direct response to prolonged oncogenic Braf signaling in serrated polyps; this finding has implications both for chemoprevention and for understanding the origin of DNA hypermethylation in cancer generally.Catherine E. Bond, Cheng Liu, Futoshi Kawamata, Diane M. McKeone, Winnie Fernando, Saara Jamieson, Sally-Ann Pearson, Alexandra Kane, Susan L. Woods, Tamsin R.M. Lannagan, Roshini Somashekar, Young Lee, Troy Dumenil, Gunter Hartel, Kevin J. Spring, Jennifer Borowsky, Lochlan Fennell, Mark Bettington, Jason Lee, Daniel L. Worthley, Barbara A. Leggett and Vicki L.J. Whitehal

Copy number profiles of paired primary and metastatic colorectal cancers

This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Liver metastasis is the major cause of death following a diagnosis of colorectal cancer (CRC). In this study, we compared the copy number profiles of paired primary and liver metastatic CRC to better understand how the genomic structure of primary CRC differs from the metastasis. Paired primary and metastatic tumors from 16 patients and their adjacent normal tissue samples were analyzed using single nucleotide polymorphism arrays. Genome-wide chromosomal copy number alterations were assessed, with particular attention to 188 genes known to be somatically altered in CRC and 24 genes that are clinically actionable in CRC. These data were analyzed with respect to the timing of primary and metastatic tissue resection and with exposure to chemotherapy. The genomic differences between the tumor and paired metastases revealed an average copy number discordance of 22.0%. The pairs of tumor samples collected prior to treatment revealed significantly higher copy number differences compared to post-therapy liver metastases (P = 0.014). Loss of heterozygosity acquired in liver metastases was significantly higher in previously treated liver metastasis samples compared to treatment naive liver metastasis samples (P = 0.003). Amplification of the clinically actionable genes ERBB2, FGFR1, PIK3CA or CDK8 was observed in the metastatic tissue of 4 patients but not in the paired primary CRC. These examples highlight the intra-patient genomic discrepancies that can occur between metastases and the primary tumors from which they arose. We propose that precision medicine strategies may therefore identify different actionable targets in metastatic tissue, compared to primary tumors, due to substantial genomic differences

Association study of candidate variants of COMT with neuroticism, anxiety and depression

The Val158Met polymorphism of the gene encoding catechol-O-methyltransferase (COMT) is one of the most widely tested variants for association with psychiatric disorders, but replication has been inconsistent including both sex limitation and heterogeneity of the associated allele. In this study we investigate the association between three SNPs from COMT and anxiety and depression disorders and neuroticism. all measured within the same study sample. Participants were selected as sibling pairs (or multiples) that were either concordant or discordant for extreme neuroticism. scores from a total sample of 18,742 Australian twin individuals and their siblings. All participants completed the Composite International Diagnostic Interview (CIDI) from which diagnoses of DSM-IV depression and anxiety disorders were determined. Of the participants, 674 had a diagnosis of anxiety and/or depression from 492 families. Study participants (n = 2,045 from 987 families) plus, where possible, their parents were genotyped for rs737865, rs4680 (Val158Met), and rs165599. Using family based tests we looked for association between these variants and neuroticism, depression, anxiety, panic disorder and agarophobia (PDAG) and obsessive compulsive disorder. We found no convincing evidence for association either in allelic or genotypic tests for the total sample or when the sample was stratified by sex. Haplotype T-G-G showed weak association (P=0.042) with PDAG before correction for multiple testing, association between this haplotype and schizophrenia has been previously reported in an Australian sample. (C) 2008 Wiley-Liss, Inc

Association study of candidate variants from brain-derived neurotrophic factor and dystrobrevin-binding protein 1 with neuroticism, anxiety, and depression

Objectives Association of the valine/methionine variant at codon 66 (Val66Met) of brain derived neurotrophic factor (BDNF) has been reported inconsistently across a spectrum of psychiatric disorders. Haplotypes of six tagging single nucleotide polymorphisms (SNPs) of a 37-kb region of dystrobrevin-binding protein 1 (DTNBP1) were found to be associated with schizophrenia. These haplotypes have not been studied extensively for other psychiatric disorders but are plausible candidates for anxiety and depression disorders. Here, association between variants of BDNF and DTNBP1, and multiple anxiety and depression phenotypes is explored

The association between MC1R genotype and BRAF mutation status in cutaneous melanoma: Findings from an Australian population

There is increasing epidemiologic and molecular evidence that cutaneous melanomas arise through multiple causal pathways. The purpose of this study was to explore the relationship between germline and somatic mutations in a population-based series of melanoma patients to reshape and refine the divergent pathway model for melanoma. Melanomas collected from 123 Australian patients were analyzed for MC1R variants and mutations in the BRAF and NRAS genes. Detailed phenotypic and sun exposure data were systematically collected from all patients. We found that BRAF-mutant melanomas were significantly more likely from younger patients and those with high nevus counts, and were more likely in melanomas with adjacent neval remnants. Conversely, BRAF¬-mutant melanomas were significantly less likely in people with high levels of life-time sun exposure. We observed no association between germline MC1R status and somatic BRAF mutations in melanomas from this population. BRAF-mutant melanomas have different origins from other cutaneous melanomas. These data support the divergent pathways hypothesis for melanoma, which may require a reappraisal of targeted cancer prevention activities

Percentage of scoDEGs in each group that correlate with viral load.

(XLSX)</p

Wu-exclusive up-regulated DEGs.

(A) Overlap between all human groups for human-exclusive up-regulated DEGs (up-regulated in any human group, but no mouse group). 1298 genes were upregulated only in Wu and no other human or mouse groups. (B) Although only up-regulated in Wu these 1298 DEGs, nevertheless, return very similar IPA Cytokine USR pathways as those shown in Fig 4A and 4B. (C) The 3%, 18% and 21% of DEGs in the IL6R, TNF and IFNg networks (Fig 4D IL6R, S5 Fig TNF, and S6 Fig IFNG) that were up-regulated only in human (green) comprised 194 genes. Of these DEGs, 73% were found up-regulated exclusively in the Wu dataset. (D) When these 143 DEGs were analysed by IPA Diseases or Functions the highest and lowest annotation by z-score suggest more cell survival and less cell death, consistent with Fig 3C. Thus IL6R, TNF, and IFNG networks contain genes that are also associated with cell survival. The presence of DEGs in these later networks that are only up-regulated in humans (Fig 4D IL6R, S5 Fig TNF, and S6 Fig IFNG, green) is largely due to the Wu dataset. The RNA-Seq data suggests that the tissues used to generate the Wu dataset had less virus (Fig 2A) and less cell death (as also seen in Fig 3C), with pathways somewhat distinct (Fig 3A), perhaps because these samples were collected at a later time point when recovery was well underway and/or because a series of medication were used by the patients. The 3%, 18% and 21% of network genes up-regulated in humans might suggest humans up-regulate these network genes in response to SARS-CoV2 infection, whereas mice do not. However, this may largely be due to the fact that no comparable mouse data set was available (e.g. medicated in the same way). (PDF)</p

Pair-wise comparisons between groups of differential gene expression.

Upper-left Euler diagrams show the amount of overlap between groups regarding DEGs (green and purple circles) and scoDEGs (red and blue circles) for all possible group-wise combinations. Green and red circles relate to row names, while purple and blue circles relate to column names. Size of circles indicates the number of DEGs/scoDEGs, as produced by EdgeR analysis or, in the case of Ackermann and Blanco-Melo, as obtained from the authors. Lower-right Each cell contains information pertaining to the group-wise comparison indicated by the row and column names. Overlap—for each pair-wise comparison between groups the number of scoDEGs that were common to both groups is shown as a percentage of the total number of scoDEGs in the comparison.–log p and r—for each pair-wise comparison, gene expression was compared using the union of scoDEGs for those groups (i.e. single-copy orthologues that were differentially expressed in one or both groups, and that were present in the gene lists for both groups). Pearson correlations were then performed using the log2 fold-changes (log2FC) of those single-copy orthologues to provide–log p and r values. Ackerman provides high r values as this analysis only evaluated expression of 249 inflammation genes (see Table 1). Cells are colored using scales on the right. For upper left and lower right, colored boarders indicate whether comparisons are mouse-human (green), human-human (blue), or mouse-mouse (orange). (PDF)</p