Best practices for bioinformatic characterization of neoantigens for clinical utility

Neoantigens are newly formed peptides created from somatic mutations that are capable of inducing tumor-specific T cell recognition. Recently, researchers and clinicians have leveraged next generation sequencing technologies to identify neoantigens and to create personalized immunotherapies for cancer treatment. To create a personalized cancer vaccine, neoantigens must be computationally predicted from matched tumor-normal sequencing data, and then ranked according to their predicted capability in stimulating a T cell response. This candidate neoantigen prediction process involves multiple steps, including somatic mutation identification, HLA typing, peptide processing, and peptide-MHC binding prediction. The general workflow has been utilized for many preclinical and clinical trials, but there is no current consensus approach and few established best practices. In this article, we review recent discoveries, summarize the available computational tools, and provide analysis considerations for each step, including neoantigen prediction, prioritization, delivery, and validation methods. In addition to reviewing the current state of neoantigen analysis, we provide practical guidance, specific recommendations, and extensive discussion of critical concepts and points of confusion in the practice of neoantigen characterization for clinical use. Finally, we outline necessary areas of development, including the need to improve HLA class II typing accuracy, to expand software support for diverse neoantigen sources, and to incorporate clinical response data to improve neoantigen prediction algorithms. The ultimate goal of neoantigen characterization workflows is to create personalized vaccines that improve patient outcomes in diverse cancer types

Psychosocial factors involved in memory and cognitive failures in people with myalgic encephalomyelitis/chronic fatigue syndrome

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by persistent emotional, mental, and physical fatigue accompanied by a range of neurological, autonomic, neuroendocrine, immune, and sleep problems. Research has shown that psychosocial factors such as anxiety and depression as well as the symptoms of the illness, have a significant impact on the quality of life of people with ME/CFS. In addition, individuals may suffer from deficits in memory and concentration. This study set out to explore the relationships between variables which have been found to contribute to cognitive performance, as measured by prospective and retrospective memory, and cognitive failures. Methods: Eighty-seven people with ME/CFS answered questionnaires measuring fatigue, depression, anxiety, social support, and general self-efficacy. These were used in a correlational design (multiple regression) to predict cognitive function (self-ratings on prospective and retrospective memory), and cognitive failures. Results: Our study found that fatigue, depression, and general self-efficacy were directly associated with cognitive failures and retrospective (but not prospective) memory. Conclusion: Although it was not possible in this study to determine the cause of the deficits, the literature in this area leads us to suggest that although the pathophysiological mechanisms of ME/CFS are unclear, abnormalities in the immune system, including proinflammatory cytokines, can lead to significant impairments in cognition. We suggest that fatigue and depression may be a result of the neurobiological effects of ME/CFS and in addition, that the neurobiological effects of the illness may give rise to both fatigue and cognitive deficits independently

Membranous Glomerulonephritis With Crescents.

INTRODUCTION: Membranous glomerulonephritis (MGN) is rarely associated with necrotizing and crescentic glomerulonephritis (NCGN). METHODS: We report the clinical and pathologic findings in 15 patients with MGN and NCGN associated with anti-neutrophil cytoplasm antibodies (ANCAs), anti-glomerular basement membrane (GBM), or anti-phospholipase A2 receptor (PLA2R) antibodies. RESULTS: The cohort consisted of 15 patients: 7 males and 8 females with a median age of 63 years (range: 18-79). In 12 of 15 patients, MGN and NCGN were diagnosed at the time of the biopsy, and in 3 cases, MGN predated the NCGN. ANCA was positive in 7 cases (6 MPO myeloperoxidase (MPO)-ANCA and 1 PR3-ANCA), anti-GBM antibodies were detected in 5 cases, and anti-PLA2R antibodies were found in 2 cases. One case was negative for all antibodies. Microscopic hematuria was present in all but one patient who was anuric, and median urinary protein-to-creatinine ratio was 819.5 mg/mmol (range: 88-5600). Pathologic evaluation revealed MGN and NCGN with crescents involving 28% of glomeruli (median; range: 5%-100%). Follow-up was available for all 15 patients; all were treated with steroids; 10 with cyclophosphamide, and 6 also received rituximab. At a median follow-up of 72 months, 9 had stabilization or improvement of renal function, 6 had progressed to end-stage renal disease, and 4 died during the follow-up period. CONCLUSION: MGN with crescents associated with ANCAs or anti-GBM antibodies is a rare dual glomerulopathy. Patients present with heavy proteinuria, microscopic hematuria, and acute kidney injury and should be treated for a rapidly progressive glomerulonephritis. Prognosis is variable, and 40% of patients progress to end-stage renal disease

Hematopoietic Cell Transplantation in Patients With Primary Immune Regulatory Disorders (PIRD): A Primary Immune Deficiency Treatment Consortium (PIDTC) Survey.

Primary Immune Regulatory Disorders (PIRD) are an expanding group of diseases caused by gene defects in several different immune pathways, such as regulatory T cell function. Patients with PIRD develop clinical manifestations associated with diminished and exaggerated immune responses. Management of these patients is complicated; oftentimes immunosuppressive therapies are insufficient, and patients may require hematopoietic cell transplant (HCT) for treatment. Analysis of HCT data in PIRD patients have previously focused on a single gene defect. This study surveyed transplanted patients with a phenotypic clinical picture consistent with PIRD treated in 33 Primary Immune Deficiency Treatment Consortium centers and European centers. Our data showed that PIRD patients often had immunodeficient and autoimmune features affecting multiple organ systems. Transplantation resulted in resolution of disease manifestations in more than half of the patients with an overall 5-years survival of 67%. This study, the first to encompass disorders across the PIRD spectrum, highlights the need for further research in PIRD management

Mycobacterium lentiflavum in Drinking Water Supplies, Australia

Humans may acquire infection from potable water

Nontuberculous Mycobacteria–associated Lung Disease in Hospitalized Persons, United States, 1998–2005

This bacterium is an underappreciated cause of lung disease and infection rates appear to be increasing

A measurement of the millimetre emission and the Sunyaev-Zel'dovich effect associated with low-frequency radio sources

We present a statistical analysis of the millimetre-wavelength properties of 1.4GHz-selected sources and a detection of the Sunyaev–Zel’dovich (SZ) effect associated with the haloes that host them. We stack data at 148, 218 and 277GHz from the Atacama Cosmology Telescope at the positions of a large sample of radio AGN selected at 1.4GHz. The thermal SZ effect associated with the haloes that host the AGN is detected at the 5σ level through its spectral signature, representing a statistical detection of the SZ effect in some of the lowest mass haloes (average M 200 ≈ 10 13 M. h −1 70 ) studied to date. The relation between the SZ effect and mass (based on weak lensing measurements of radio galaxies) is consistent with that measured by Planck for local bright galaxies. In the context of galaxy evolution models, this study confirms that galaxies with radio AGN also typically support hot gaseous haloes. Adding Herschel observations allows us to show that the SZ signal is not significantly contaminated by dust emission. Finally, we analyse the contribution of radio sources to the angular power spectrum of the cosmic microwave background

Sheep Updates 2008 - part 3

This session covers fiveteen papers from different authors: CONTROLLING FLY STRIKE 1. Breeding for Blowfly Resistance - Indicatoe Traits, LJE Karlsson, JC Greeff, L Slocombe, Department of Agriculture & Food, Western Australia 2.A practical method to select for breech strike resistance in non-pedigreed Merino flocks, LJE Karlsson, JC Greeff, L Slocombe, K. Jones, N. Underwood, Department of Agriculture & Food, Western Australia 3. Twice a year shearing - no mulesing, Fred Wilkinson, Producer, Brookton WA BEEF 4. Commercial testing of a new tool for prediction of fatness in beef cattle, WD HoffmanA, WA McKiernanA, VH OddyB, MJ McPheeA, Cooperative Research Centre for Beef Genetic Technologies, A N.S.W. Deptartment of Primary Industries, B University of New England 5. A new tool for the prediction of fatness in beef cattle, W.A. McKiernanA, V.H. OddyB and M.J. McPheeC; Cooperative Research Centre for Beef Genetic Technologies, A N.S.W. Dept of Primary Industries, B University of New England, C N.S.W. Dept of Primary Industries Beef Industry Centre of Excellence. 6. Effect of gene markers for tenderness on eating quality of beef, B.L. McIntyre, CRC for Beef Genetic Technologies, Department of Agriculture and Food WA 7. Accelerating beef industry innovation through Beef Profit Partnerships, Parnell PF1,2, Clark RA1,3, Timms J1,3, Griffith G1,2, Alford A1,2, Mulholland C1 and Hyland P1,4,1Co-operative Research Centre for Beef Genetic Technologies; 2NSW Department of Primary Industries; 3 Qld Department of Primary Industries and Fisheries; 4The University of Queensland. SUSTAINABILITY 8. The WA Sheep Industry - is it ethically and environmentally sustainable? Danielle England, Department of Agriculture and Food Western Australia 9. Overview of ruminant agriculture and greenhouse emissions, Fiona Jones, Department of Agriculture and Food Western Australia 10. Grazing for Nitrogen Efficiency, John Lucey, Martin Staines and Richard Morris, Department of Agriculture and Food Western Australia 11. Investigating potential adaptations to climate change for low rainfall farming system, Megan Abrahams, Caroline Peek, Dennis Van Gool, Daniel Gardiner, Kari-Lee Falconer, Department of Agriculture and Food Western Australia SHEEP 12. Benchmarking ewe productivity through on-farm genetic comparisons, Sandra Prosser, Mario D’Antuono and Johan Greeff; Department of Agriculture and Food Western Australia 13. Increasing profitability by pregnancy scanning ewes, John Young1, Andrew Thompson2 and Chris Oldham2; 1Farming Systems Analysis Service, Kojonup, WA, 2Department of Agriculture and Food Western Australia 14. Targeted treatment of worm-affected sheep - more efficient, more sustainable, Brown Besier, Department of Agriculture and Food Western Australia 15. Improving Weaner Sheep Survival, Angus Campbell and Ralph Behrendt, Cooperative Research Centre for Sheep Industry Innovatio

Using Evolutionary Conserved Modules in Gene Networks as a Strategy to Leverage High Throughput Gene Expression Queries

Background: Large-scale gene expression studies have not yielded the expected insight into genetic networks that control complex processes. These anticipated discoveries have been limited not by technology, but by a lack of effective strategies to investigate the data in a manageable and meaningful way. Previous work suggests that using a pre-determined seednetwork of gene relationships to query large-scale expression datasets is an effective way to generate candidate genes for further study and network expansion or enrichment. Based on the evolutionary conservation of gene relationships, we test the hypothesis that a seed network derived from studies of retinal cell determination in the fly, Drosophila melanogaster, will be an effective way to identify novel candidate genes for their role in mouse retinal development. Methodology/Principal Findings: Our results demonstrate that a number of gene relationships regulating retinal cell differentiation in the fly are identifiable as pairwise correlations between genes from developing mouse retina. In addition, we demonstrate that our extracted seed-network of correlated mouse genes is an effective tool for querying datasets and provides a context to generate hypotheses. Our query identified 46 genes correlated with our extracted seed-network members. Approximately 54% of these candidates had been previously linked to the developing brain and 33% had been previously linked to the developing retina. Five of six candidate genes investigated further were validated by experiments examining spatial and temporal protein expression in the developing retina. Conclusions/Significance: We present an effective strategy for pursuing a systems biology approach that utilizes an evolutionary comparative framework between two model organisms, fly and mouse. Future implementation of this strategy will be useful to determine the extent of network conservation, not just gene conservation, between species and will facilitate the use of prior biological knowledge to develop rational systems-based hypotheses