Anthrax vaccine design: strategies to achieve comprehensive protection against spore, bacillus, and toxin

The successful use of Bacillus anthracis as a lethal biological weapon has prompted renewed research interest in the development of more effective vaccines against anthrax. The disease consists of three critical components: spore, bacillus, and toxin, elimination of any of which confers at least partial protection against anthrax. Current remedies rely on postexposure antibiotics to eliminate bacilli and pre- and postexposure vaccination to target primarily toxins. Vaccines effective against toxin have been licensed for human use, but need improvement. Vaccines against bacilli have recently been developed by us and others. Whether effective vaccines will be developed against spores is still an open question. An ideal vaccine would confer simultaneous protection against spores, bacilli, and toxins. One step towards this goal is our dually active vaccine, designed to destroy both bacilli and toxin. Existing and potential strategies towards potent and effective anthrax vaccines are discussed in this review

The dawn of the liquid biopsy in the fight against cancer

ABSTRACT Cancer is a molecular disease associated with alterations in the genome, which, thanks to the highly improved sensitivity of mutation detection techniques, can be identified in cell-free DNA (cfDNA) circulating in blood, a method also called liquid biopsy. This is a non-invasive alternative to surgical biopsy and has the potential of revealing the molecular signature of tumors to aid in the individualization of treatments. In this review, we focus on cfDNA analysis, its advantages, and clinical applications employing genomic tools (NGS and dPCR) particularly in the field of oncology, and highlight its valuable contributions to early detection, prognosis, and prediction of treatment response

The marker quantification of the Shared Socioeconomic Pathway 2: A middle-of-the-road scenario for the 21st century

AbstractStudies of global environmental change make extensive use of scenarios to explore how the future can evolve under a consistent set of assumptions. The recently developed Shared Socioeconomic Pathways (SSPs) create a framework for the study of climate-related scenario outcomes. Their five narratives span a wide range of worlds that vary in their challenges for climate change mitigation and adaptation. Here we provide background on the quantification that has been selected to serve as the reference, or ‘marker’, implementation for SSP2. The SSP2 narrative describes a middle-of-the-road development in the mitigation and adaptation challenges space. We explain how the narrative has been translated into quantitative assumptions in the IIASA Integrated Assessment Modelling Framework. We show that our SSP2 marker implementation occupies a central position for key metrics along the mitigation and adaptation challenge dimensions. For many dimensions the SSP2 marker implementation also reflects an extension of the historical experience, particularly in terms of carbon and energy intensity improvements in its baseline. This leads to a steady emissions increase over the 21st century, with projected end-of-century warming nearing 4°C relative to preindustrial levels. On the other hand, SSP2 also shows that global-mean temperature increase can be limited to below 2°C, pending stringent climate policies throughout the world. The added value of the SSP2 marker implementation for the wider scientific community is that it can serve as a starting point to further explore integrated solutions for achieving multiple societal objectives in light of the climate adaptation and mitigation challenges that society could face over the 21st century

Towards the introduction of the ‘Immunoscore’ in the classification of malignant tumours

The American Joint Committee on Cancer/Union Internationale Contre le Cancer (AJCC/UICC) TNM staging system provides the most reliable guidelines for the routine prognostication and treatment of colorectal carcinoma. This traditional tumour staging summarizes data on tumour burden (T), the presence of cancer cells in draining and regional lymph nodes (N) and evidence for distant metastases (M). However, it is now recognized that the clinical outcome can vary significantly among patients within the same stage. The current classification provides limited prognostic information and does not predict response to therapy. Multiple ways to classify cancer and to distinguish different subtypes of colorectal cancer have been proposed, including morphology, cell origin, molecular pathways, mutation status and gene expression-based stratification. These parameters rely on tumour-cell characteristics. Extensive literature has investigated the host immune response against cancer and demonstrated the prognostic impact of the in situ immune cell infiltrate in tumours. A methodology named ‘Immunoscore’ has been defined to quantify the in situ immune infiltrate. In colorectal cancer, the Immunoscore may add to the significance of the current AJCC/UICC TNM classification, since it has been demonstrated to be a prognostic factor superior to the AJCC/UICC TNM classification. An international consortium has been initiated to validate and promote the Immunoscore in routine clinical settings. The results of this international consortium may result in the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-Immune). © 2013 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland

Innovations for Sustainability: Pathways to an efficient and post-pandemic future

3rd Report prepared by The World in 2050 initiativ

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

A master autoantigen-ome links alternative splicing, female predilection, and COVID-19 to autoimmune diseases

Chronic and debilitating autoimmune sequelae pose a grave concern for the post-COVID-19 pandemic era. Based on our discovery that the glycosaminoglycan dermatan sulfate (DS) displays peculiar affinity to apoptotic cells and autoantigens (autoAgs) and that DS-autoAg complexes cooperatively stimulate autoreactive B1 cell responses, we compiled a database of 751 candidate autoAgs from six human cell types. At least 657 of these have been found to be affected by SARS-CoV-2 infection based on currently available multi-omic COVID data, and at least 400 are confirmed targets of autoantibodies in a wide array of autoimmune diseases and cancer. The autoantigen-ome is significantly associated with various processes in viral infections, such as translation, protein processing, and vesicle transport. Interestingly, the coding genes of autoAgs predominantly contain multiple exons with many possible alternative splicing variants, short transcripts, and short UTR lengths. These observations and the finding that numerous autoAgs involved in RNA-splicing showed altered expression in viral infections suggest that viruses exploit alternative splicing to reprogram host cell machinery to ensure viral replication and survival. While each cell type gives rise to a unique pool of autoAgs, 39 common autoAgs associated with cell stress and apoptosis were identified from all six cell types, with several being known markers of systemic autoimmune diseases. In particular, the common autoAg UBA1 that catalyzes the first step in ubiquitination is encoded by an X-chromosome escape gene. Given its essential function in apoptotic cell clearance and that X-inactivation escape tends to increase with aging, UBA1 dysfunction can therefore predispose aging women to autoimmune disorders. In summary, we propose a model of how viral infections lead to extensive molecular alterations and host cell death, autoimmune responses facilitated by autoAg-DS complexes, and ultimately autoimmune diseases. Overall, this master autoantigen-ome provides a molecular guide for investigating the myriad of autoimmune sequalae to COVID-19 and clues to the rare adverse effects of the currently available mRNA and viral vector-based COVID vaccines

A repertoire of 124 potential autoantigens for autoimmune kidney diseases identified by dermatan sulfate affinity enrichment of kidney tissue proteins.

Autoantigens are the molecular targets in autoimmune diseases. They are a cohort of seemingly unrelated self-molecules present in different parts of the body, yet they can trigger a similar chain of autoimmune responses such as autoantibody production. We previously reported that dermatan sulfate (DS) can bind self-molecules of dying cells to stimulate autoreactive CD5+ B cells to produce autoantibodies. The formation of autoantigen-DS complexes converts the normally non-antigenic self-molecules to none-self antigens, and thus DS-affinity represents a common underlying biochemical property for autoantigens. This study sought to apply this property to identify potential autoantigens in the kidney. Total proteins were extracted from mouse kidney tissues and loaded onto DS-Sepharose resins. Proteins without affinity were washed off the resins, whereas those with increasing DS-affinity were eluted with step gradients of increasing salt strength. Fractions with strong and moderate DS-affinity were sequenced by mass spectrometry and yielded 25 and 99 proteins, respectively. An extensive literature search was conducted to validate whether these had been previously reported as autoantigens. Of the 124 proteins, 79 were reported autoantigens, and 19 out of 25 of the strong-DS-binding ones were well-known autoantigens. Moreover, these proteins largely fell into the two most common autoantibody categories in autoimmune kidney diseases, including 40 ANA (anti-nuclear autoantibodies) and 25 GBM (glomerular basement membrane) autoantigens. In summary, this study compiles a large repertoire of potential autoantigens for autoimmune kidney diseases. This autoantigen-ome sheds light on the molecular etiology of autoimmunity and further supports our hypothesis DS-autoantigen complexes as a unifying principle of autoantigenicity