Oceans have become substantially noisier since the Industrial Revolution. Shipping, resource exploration, and infrastructure development have increased the anthrophony (sounds generated by human ...activities), whereas the biophony (sounds of biological origin) has been reduced by hunting, fishing, and habitat degradation. Climate change is affecting geophony (abiotic, natural sounds). Existing evidence shows that anthrophony affects marine animals at multiple levels, including their behavior, physiology, and, in extreme cases, survival. This should prompt management actions to deploy existing solutions to reduce noise levels in the ocean, thereby allowing marine animals to reestablish their use of ocean sound as a central ecological trait in a healthy ocean.
Immune checkpoint therapy (ICT) provides substantial clinical benefits to cancer patients, but a large proportion of cancers do not respond to ICT. To date, the genomic underpinnings of primary ...resistance to ICT remain elusive. Here, we performed immunogenomic analysis of data from TCGA and clinical trials of anti-PD-1/PD-L1 therapy, with a particular focus on homozygous deletion of 9p21.3 (9p21 loss), one of the most frequent genomic defects occurring in ~13% of all cancers. We demonstrate that 9p21 loss confers "cold" tumor-immune phenotypes, characterized by reduced abundance of tumor-infiltrating leukocytes (TILs), particularly, T/B/NK cells, altered spatial TILs patterns, diminished immune cell trafficking/activation, decreased rate of PD-L1 positivity, along with activation of immunosuppressive signaling. Notably, patients with 9p21 loss exhibited significantly lower response rates to ICT and worse outcomes, which were corroborated in eight ICT trials of >1,000 patients. Further, 9p21 loss synergizes with PD-L1/TMB for patient stratification. A "response score" was derived by incorporating 9p21 loss, PD-L1 expression and TMB levels in pre-treatment tumors, which outperforms PD-L1, TMB, and their combination in identifying patients with high likelihood of achieving sustained response from otherwise non-responders. Moreover, we describe potential druggable targets in 9p21-loss tumors, which could be exploited to design rational therapeutic interventions.
Pluripotency defines the unlimited potential of individual cells of vertebrate embryos, from which all adult somatic cells and germ cells are derived. Understanding how the programming of ...pluripotency evolved has been obscured in part by a lack of data from lower vertebrates; in model systems such as frogs and zebrafish, the function of the pluripotency genes NANOG and POU5F1 have diverged. Here, we investigated how the axolotl ortholog of NANOG programs pluripotency during development. Axolotl NANOG is absolutely required for gastrulation and germ-layer commitment. We show that in axolotl primitive ectoderm (animal caps; ACs) NANOG and NODAL activity, as well as the epigenetic modifying enzyme DPY30, are required for the mass deposition of H3K4me3 in pluripotent chromatin. We also demonstrate that all 3 protein activities are required for ACs to establish the competency to differentiate toward mesoderm. Our results suggest the ancient function of NANOG may be establishing the competence for lineage differentiation in early cells. These observations provide insights into embryonic development in the tetrapod ancestor from which terrestrial vertebrates evolved.
Prodrugs reliant on microbial activation are widely used but exhibit a range of efficacies that remain poorly understood. The anti-inflammatory compound 5-aminosalicylic acid (5-ASA), which is ...packaged in a variety of azo-linked prodrugs provided to most Ulcerative Colitis (UC) patients, shows confounding inter-individual variabilities in response. Such prodrugs must be activated by azo-bond reduction to form 5-ASA, a process that has been attributed to both enzymatic and non-enzymatic catalysis. Gut microbial azoreductases (AzoRs) are the first catalysts shown to activate azo-linked drugs and to metabolize toxic azo-chemicals. Here, we chart the scope of the structural and functional diversity of AzoRs in health and in patients with the inflammatory bowel diseases (IBDs) UC and Crohn's Disease (CD). Using structural metagenomics, we define the landscape of gut microbial AzoRs in 413 healthy donor and 1059 IBD patient fecal samples. Firmicutes encode a significantly higher number of unique AzoRs compared to other phyla. However, structural and biochemical analyses of distinct AzoRs from the human microbiome reveal significant differences between prevalent orthologs in the processing of toxic azo-dyes, and their generally poor activation of IBD prodrugs. Furthermore, while individuals with IBD show higher abundances of AzoR-encoding gut microbial taxa than healthy controls, the overall abundance of AzoR-encoding microbes is markedly low in both disease and health. Together, these results establish that gut microbial AzoRs are functionally diverse but sparse in both health and disease, factors that may contribute to non-optimal processing of azo-linked prodrugs and idiopathic IBD drug responses.
Our modification of the traditional Newcastle-Ottawa scale enables urological researchers to effectively appraise and communicate the quality of genetic-based research in urology.
Saliva represents an ideal matrix for diagnostic biomarker development as it is readily available and requires no invasive collection procedures. However, salivary RNA is labile and rapidly degrades. ...Previous attempts to isolate RNA from saliva have yielded poor quality and low concentrations. Here we compare collection and processing methods and propose an approach for future studies. The effects of RNA stabilisers, storage temperatures, length of storage and fasting windows were investigated on pooled saliva samples from healthy volunteers. Isolated RNA was assessed for concentration and quality. Bacterial growth was investigated through RT-PCR using bacterial and human primers. Optimal conditions were implemented and quality controlled in a clinical setting. The addition of RNAlater increased mean RNA yield from 4912 ng/μl to 15,473 ng and RNA Integrity Number (RIN) from 4.5 to 7.0. No significant changes to RNA yield were observed for storage at room temperature beyond 1 day or at -80 °C. Bacterial growth did not occur in samples stored at ambient temperature for up to a week. There was a trend towards higher RNA concentration when saliva was collected after overnight fasting but no effect on RIN. In the clinic, RNA yields of 6307 ng and RINs of 3.9 were achieved, improving on previous reports. The method we describe here is a robust, clinically feasible saliva collection method using preservative that gives high concentrations and improved RINs compared to saliva collected without preservative.
Introduction
The population rate of familial cluster headache (CH) has been reported to be as high as 20% however this varies considerably across studies. To obtain a true estimate of family history ...in CH, we conducted a systematic review and meta-analysis of previously published data.
Methods
Our systematic review involved a search of electronic databases (Medline, EMBASE, PubMed, CINAHL) to identify and appraise studies of interest utilising the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) guidelines. To further ameliorate the accuracy of our analysis we included an additional unpublished cohort of CH patients recruited at a tertiary referral centre for headache, who underwent detailed family history with diagnostic verification in relatives. Data was extracted and meta-analysis conducted to provide a true estimation of family history.
Results
In total, we identified 7 studies which fulfilled our inclusion criteria. The estimated true prevalence of CH patients with a positive family history was 6.27% (95% CI:4.65–8.40%) with an overall I
2
of 73%. Fitted models for gender subgroups showed higher estimates 9.26% (95% CI: 6.29–13.43%) in females. However the I
2
for the female model was 58.42% and significant (
p
= 0.047).
Conclusion
Our findings estimate a rate of family history in CH to be approximately 6.27% (95% CI: 4.65–8.40%). While estimates were larger for female probands, we demonstrated high heterogeneity in this subgroup. These findings further support a genetic role in the aetiology of CH.
Neoantigens, mutated tumour-specific antigens, are key targets of anti-tumour immunity during checkpoint inhibitor (CPI) treatment. Their identification is fundamental to designing ...neoantigen-directed therapy. Non-canonical neoantigens arising from the untranslated regions (UTR) of the genome are an overlooked source of immunogenic neoantigens. Here, we describe the landscape of UTR-derived neoantigens and release a computational tool, PrimeCUTR, to predict UTR neoantigens generated by start-gain and stop-loss mutations.
We applied PrimeCUTR to a whole genome sequencing dataset of pre-treatment tumour samples from CPI-treated patients (n = 341). Cancer immunopeptidomic datasets were interrogated to identify MHC class I presentation of UTR neoantigens.
Start-gain neoantigens were predicted in 72.7% of patients, while stop-loss mutations were found in 19.3% of patients. While UTR neoantigens only accounted 2.6% of total predicted neoantigen burden, they contributed 12.4% of neoantigens with high dissimilarity to self-proteome. More start-gain neoantigens were found in CPI responders, but this relationship was not significant when correcting for tumour mutational burden. While most UTR neoantigens are private, we identified two recurrent start-gain mutations in melanoma. Using immunopeptidomic datasets, we identify two distinct MHC class I-presented UTR neoantigens: one from a recurrent start-gain mutation in melanoma, and one private to Jurkat cells.
PrimeCUTR is a novel tool which complements existing neoantigen discovery approaches and has potential to increase the detection yield of neoantigens in personalised therapeutics, particularly for neoantigens with high dissimilarity to self. Further studies are warranted to confirm the expression and immunogenicity of UTR neoantigens.
Objective
This study was undertaken to identify susceptibility loci for cluster headache and obtain insights into relevant disease pathways.
Methods
We carried out a genome‐wide association study, ...where 852 UK and 591 Swedish cluster headache cases were compared with 5,614 and 1,134 controls, respectively. Following quality control and imputation, single variant association testing was conducted using a logistic mixed model for each cohort. The 2 cohorts were subsequently combined in a merged analysis. Downstream analyses, such as gene‐set enrichment, functional variant annotation, prediction and pathway analyses, were performed.
Results
Initial independent analysis identified 2 replicable cluster headache susceptibility loci on chromosome 2. A merged analysis identified an additional locus on chromosome 1 and confirmed a locus significant in the UK analysis on chromosome 6, which overlaps with a previously known migraine locus. The lead single nucleotide polymorphisms were rs113658130 (p = 1.92 × 10−17, odds ratio OR = 1.51, 95% confidence interval CI = 1.37–1.66) and rs4519530 (p = 6.98 × 10−17, OR = 1.47, 95% CI = 1.34–1.61) on chromosome 2, rs12121134 on chromosome 1 (p = 1.66 × 10−8, OR = 1.36, 95% CI = 1.22–1.52), and rs11153082 (p = 1.85 × 10−8, OR = 1.30, 95% CI = 1.19–1.42) on chromosome 6. Downstream analyses implicated immunological processes in the pathogenesis of cluster headache.
Interpretation
We identified and replicated several genome‐wide significant associations supporting a genetic predisposition in cluster headache in a genome‐wide association study involving 1,443 cases. Replication in larger independent cohorts combined with comprehensive phenotyping, in relation to, for example, treatment response and cluster headache subtypes, could provide unprecedented insights into genotype–phenotype correlations and the pathophysiological pathways underlying cluster headache. ANN NEUROL 2021;90:193–202
Pre‐biopsy multiparametric magnetic resonance imaging (mpMRI) has transformed the risk stratification and diagnostic approach for suspected prostate cancer. The majority of clinically significant ...prostate cancers are visible on pre‐biopsy mpMRI, however, there are a subset of significant tumors that are not detected by mpMRI. The radiobiological mechanisms underpinning mpMRI‐visibility and invisibility of these cancers remain uncertain. Emerging evidence suggests that mpMRI‐visible tumors are enriched with molecular features associated with increased disease aggressivity and poor clinical prognosis, which is supported by short‐term endpoints, such as biochemical recurrence following surgery. Furthermore, at the histopathological level, mpMRI‐visible tumors appear to exhibit increased architectural and vascular density compared to mpMRI‐invisible disease. It seems probable that the genomic, pathological, radiological, and clinical features of mpMRI‐visible and mpMRI‐invisible prostate cancers are interrelated. Here, we propose a novel cross‐disciplinary theory that links genomic and molecular evidence with cellular and histopathological appearances, elucidating both the mpMRI visibility and clinical status of significant prostate cancer.
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