Distribution of COL9A2 and COL9A3 Gene Polymorphism in Male Chinese Singaporean - A Pilot Observational Study

The association between allelic variants and lumbar disc degenerative disease (DDD) has been investigated in Europe and Northern Asia. However, this has not been investigated in Southeast Asia. This observational study aims to compare the distribution of COL9A2 and COL9A3 gene polymorphism among male Chinese Singaporeans with and without lumbar DDD. COL9A2 gene polymorphism was investigated in p326 (tryptophan 2, Trp2 and glutamine 2, Gln2, alleles) and p335 (valine 2 or Val2 allele). COL9A3 gene polymorphism was investigated in p17 (glycine 3 or Gly3 allele) and p103 (tryptophan 3 or Trp3 allele). The Val2 allele was significantly decreased in the group with lumbar DDD (p < 0.05). No significant difference in allelic distributions of Trp2, Gln2 and Gly3 was found. The Trp3 allele was absent from all the subjects. The presence of at least one Val2 allele appears to have a protective effect against DDD. However, these should be interpreted with caution, given the limitations. Further investigations are warranted in order to verify such genetic predisposition prior to the potential development of preventative or therapeutic strategies in the near future

Retrospective analysis of hospital electronic health records reveals unseen cases of acute hepatitis with unknown aetiology in adults in Oxfordshire

Background: An outbreak of acute severe hepatitis of unknown aetiology (AS-Hep-UA) in children during 2022 was subsequently linked to infections with adenovirus-associated virus 2 and other ‘helper viruses’, including human adenovirus. It is possible that evidence of such an outbreak could be identified at a population level based on routine data captured by electronic health records (EHR). Methods: We used anonymised EHR to collate retrospective data for all emergency presentations to Oxford University Hospitals NHS Foundation Trust in the UK, between 2016–2022, for all ages from 18 months and older. We investigated clinical characteristics and temporal distribution of presentations of acute hepatitis and of adenovirus infections based on laboratory data and clinical coding. We relaxed the stringent case definition adopted during the AS-Hep-UA to identify all cases of acute hepatitis with unknown aetiology (termed AHUA). We compared events within the outbreak period (defined as 1st Oct 2021—31 Aug 2022) to the rest of our study period. Results: Over the study period, there were 903,433 acute presentations overall, of which 391 (0.04%) were classified as AHUA. AHUA episodes had significantly higher critical care admission rates (p < 0.0001, OR = 41.7, 95% CI:26.3–65.0) and longer inpatient admissions (p < 0.0001) compared with the rest of the patient population. During the outbreak period, significantly more adults (≥ 16 years) were diagnosed with AHUA (p < 0.0001, OR = 3.01, 95% CI: 2.20–4.12), and there were significantly more human adenovirus (HadV) infections in children (p < 0.001, OR = 1.78, 95% CI:1.27–2.47). There were also more HAdV tests performed during the outbreak (p < 0.0001, OR = 1.27, 95% CI:1.17–1.37). Among 3,707 individuals who were tested for HAdV, 179 (4.8%) were positive. However, there was no evidence of more acute hepatitis or increased severity of illness in HadV-positive compared to negative cases. Conclusions: Our results highlight an increase in AHUA in adults coinciding with the period of the outbreak in children, but not linked to documented HAdV infection. Tracking changes in routinely collected clinical data through EHR could be used to support outbreak surveillance

Pan-viral serology implicates enteroviruses in acute flaccid myelitis.

Since 2012, the United States of America has experienced a biennial spike in pediatric acute flaccid myelitis (AFM)1-6. Epidemiologic evidence suggests non-polio enteroviruses (EVs) are a potential etiology, yet EV RNA is rarely detected in cerebrospinal fluid (CSF)2. CSF from children with AFM (n = 42) and other pediatric neurologic disease controls (n = 58) were investigated for intrathecal antiviral antibodies, using a phage display library expressing 481,966 overlapping peptides derived from all known vertebrate and arboviruses (VirScan). Metagenomic next-generation sequencing (mNGS) of AFM CSF RNA (n = 20 cases) was also performed, both unbiased sequencing and with targeted enrichment for EVs. Using VirScan, the viral family significantly enriched by the CSF of AFM cases relative to controls was Picornaviridae, with the most enriched Picornaviridae peptides belonging to the genus Enterovirus (n = 29/42 cases versus 4/58 controls). EV VP1 ELISA confirmed this finding (n = 22/26 cases versus 7/50 controls). mNGS did not detect additional EV RNA. Despite rare detection of EV RNA, pan-viral serology frequently identified high levels of CSF EV-specific antibodies in AFM compared with controls, providing further evidence for a causal role of non-polio EVs in AFM

A clinical diagnostic model for predicting influenza among young adult military personnel with febrile respiratory illness in Singapore

10.1371/journal.pone.0017468PLoS ONE63

Optimized polyepitope neoantigen DNA vaccines elicit neoantigen-specific immune responses in preclinical models and in clinical translation

BACKGROUND: Preclinical studies and early clinical trials have shown that targeting cancer neoantigens is a promising approach towards the development of personalized cancer immunotherapies. DNA vaccines can be rapidly and efficiently manufactured and can integrate multiple neoantigens simultaneously. We therefore sought to optimize the design of polyepitope DNA vaccines and test optimized polyepitope neoantigen DNA vaccines in preclinical models and in clinical translation. METHODS: We developed and optimized a DNA vaccine platform to target multiple neoantigens. The polyepitope DNA vaccine platform was first optimized using model antigens in vitro and in vivo. We then identified neoantigens in preclinical breast cancer models through genome sequencing and in silico neoantigen prediction pipelines. Optimized polyepitope neoantigen DNA vaccines specific for the murine breast tumor E0771 and 4T1 were designed and their immunogenicity was tested in vivo. We also tested an optimized polyepitope neoantigen DNA vaccine in a patient with metastatic pancreatic neuroendocrine tumor. RESULTS: Our data support an optimized polyepitope neoantigen DNA vaccine design encoding long (≥20-mer) epitopes with a mutant form of ubiquitin (Ub CONCLUSIONS: We have developed and optimized a novel polyepitope neoantigen DNA vaccine platform that can target multiple neoantigens and induce antitumor immune responses in preclinical models and neoantigen-specific responses in clinical translation

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts