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

Processing and Transmission of Information

Contains research objectives and reports on two research projects.National Aeronautics and Space Administration (Grant NsG-334)National Aeronautics and Space Administration (Grant NsG-496)Joint Services Electronics Programs (U. S. Army, U.S. Navy, and U.S. Air Force) under Contract DA 36-039-AMC-03200(E)National Science Foundation (Grant GP-835)Sloan Fund for Basic Research (M.I.T. Grant

Metamodel-based model conformance and multiview consistency checking

Model-driven development, using languages such as UML and BON, often makes use of multiple diagrams (e.g., class and sequence diagrams) when modeling systems. These diagrams, presenting different views of a system of interest, may be inconsistent. A metamodel provides a unifying framework in which to ensure and check consistency, while at the same time providing the means to distinguish between valid and invalid models, that is, conformance. Two formal specifications of the metamodel for an object-oriented modeling language are presented, and it is shown how to use these specifications for model conformance and multiview consistency checking. Comparisons are made in terms of completeness and the level of automation each provide for checking multiview consistency and model conformance. The lessons learned from applying formal techniques to the problems of metamodeling, model conformance, and multiview consistency checking are summarized

Synthesis of novel piperazine-linked anthranilic acids as potential small molecule kinase inhibitors

Please cite as follows: Chakravorty, S. et al. 2014. Synthesis of novel piperazine-linked anthranilic acids as potential small molecule kinase inhibitors. South African Journal of Chemistry, 67:71–79.The original publication is available at http://www.journals.co.za/sajchemSubstituted anthranilic acid and piperazines were used as building blocks to prepare two libraries of compounds, with the aim being that they would exhibit biochemical activity as small molecule kinase inhibitors. The synthesized anthranilamidepiperazine compounds were subsequently tested against a panel of kinases including EGFR, Abl, Akt and Aurora B.http://www.scielo.org.za/scielo.php?script=sci_abstract&pid=S0379-43502014000100012&lng=en&nrm=iso&tlng=enPublisher's versio

Glycerol treatment as recovery procedure for cryopreserved human skin allografts positive for bacteria and fungi

Human donor skin allografts are suitable and much used temporary biological (burn) wound dressings. They prepare the excised wound bed for final autografting and form an excellent substrate for revascularisation and for the formation of granulation tissue. Two preservation methods, glycerol preservation and cryopreservation, are commonly used by tissue banks for the long-term storage of skin grafts. The burn surgeons of the Queen Astrid Military Hospital preferentially use partly viable cryopreserved skin allografts. After mandatory 14-day bacterial and mycological culture, however, approximately 15% of the cryopreserved skin allografts cannot be released from quarantine because of positive culture. To maximize the use of our scarce and precious donor skin, we developed a glycerolisation-based recovery method for these culture positive cryopreserved allografts. The inactivation and preservation method, described in this paper, allowed for an efficient inactivation of the colonising bacteria and fungi, with the exception of spore-formers, and did not influence the structural and functional aspects of the skin allografts

Statistical Communication Theory

Contains reports on six research project.National Institutes of Health (Grant MH-04737-03)National Science Foundation (Grant G-16526

A theory-based approach to understanding condom errors and problems reported by men attending an STI clinic

The official published version can be accessed from the link below - Copyright @ 2008 Springer VerlagWe employed the information–motivation–behavioral skills (IMB) model to guide an investigation of correlates for correct condom use among 278 adult (18–35 years old) male clients attending a sexually transmitted infection (STI) clinic. An anonymous questionnaire aided by a CD-recording of the questions was administered. Linear Structural Relations Program was used to conduct path analyses of the hypothesized IMB model. Parameter estimates showed that while information did not directly affect behavioral skills, it did have a direct (negative) effect on condom use errors. Motivation had a significant direct (positive) effect on behavioral skills and a significant indirect (positive) effect on condom use errors through behavioral skills. Behavioral skills had a direct (negative) effect on condom use errors. Among men attending a public STI clinic, these findings suggest brief, clinic-based, safer sex programs for men who have sex with women should incorporate activities to convey correct condom use information, instill motivation to use condoms correctly, and directly enhance men’s behavioral skills for correct use of condoms

Factors Associated With Sexual Coercion in a Representative Sample of Men in Australian Prisons

Very little research has focused on men or prisoners as victims of sexual violence. This study provides the first population-based analysis of factors associated with sexual coercion of men in Australian prisons, and the first to use a computer-assisted telephone interview to collect this information in a prison setting. A random sample of men in New South Wales and Queensland prisons were surveyed using computer-assisted telephone interviewing. We asked participants about sexual coercion, defined as being forced or frightened into doing something sexually that was unwanted while in prison. Associations between sexual coercion in prison and sociodemographics, sexual coercion history outside of prison, and prison-related factors were examined. Logistic regression was used to estimate adjusted odds ratios in examining factors associated with sexual coercion in prisons. Of 2626 eligible men, 2000 participated. Participants identifying as non-heterosexual and those with a history of sexual coercion outside prison were found to be most at risk. Those in prison for the first time and those who had spent more than 5 years in prison ever were also more likely to report sexual coercion. Although prison policies and improving prison officer training may help address immediate safety and health concerns of those at risk, given the sensitivity of the issue and likely under-reporting to correctional staff, community-based organizations and prisoner peer-based groups arguably have a role too in providing both preventive and trauma-focused support

Personalized ctDNA micro-panels can monitor and predict clinical outcomes for patients with triple-negative breast cancer

Circulating tumor DNA (ctDNA) in peripheral blood has been used to predict prognosis and therapeutic response for triple-negative breast cancer (TNBC) patients. However, previous approaches typically use large comprehensive panels of genes commonly mutated across all breast cancers. Given the reduction in sequencing costs and decreased turnaround times associated with panel generation, the objective of this study was to assess the use of custom micro-panels for tracking disease and predicting clinical outcomes for patients with TNBC. Paired tumor-normal samples from patients with TNBC were obtained at diagnosis (T0) and whole exome sequencing (WES) was performed to identify somatic variants associated with individual tumors. Custom micro-panels of 4-6 variants were created for each individual enrolled in the study. Peripheral blood was obtained at baseline, during Cycle 1 Day 3, at time of surgery, and in 3-6 month intervals after surgery to assess variant allele fraction (VAF) at different timepoints during disease course. The VAF was compared to clinical outcomes to evaluate the ability of custom micro-panels to predict pathological response, disease-free intervals, and patient relapse. A cohort of 50 individuals were evaluated for up to 48 months post-diagnosis of TNBC. In total, there were 33 patients who did not achieve pathological complete response (pCR) and seven patients developed clinical relapse. For all patients who developed clinical relapse and had peripheral blood obtained ≤ 6 months prior to relapse (n = 4), the custom ctDNA micro-panels identified molecular relapse at an average of 4.3 months prior to clinical relapse. The custom ctDNA panel results were moderately associated with pCR such that during disease monitoring, only 11% of patients with pCR had a molecular relapse, whereas 47% of patients without pCR had a molecular relapse (Chi-Square; p-value = 0.10). In this study, we show that a custom micro-panel of 4-6 markers can be effectively used to predict outcomes and monitor remission for patients with TNBC. These custom micro-panels show high sensitivity for detecting molecular relapse in advance of clinical relapse. The use of these panels could improve patient outcomes through early detection of relapse with preemptive intervention prior to symptom onset

Characterization of the genomic and immunologic diversity of malignant brain tumors through multisector analysis

Despite some success in secondary brain metastases, targeted or immune-based therapies have shown limited efficacy against primary brain malignancies such as glioblastoma (GBM). Although the intratumoral heterogeneity of GBM is implicated in treatment resistance, it remains unclear whether this diversity is observed within brain metastases and to what extent cancer cell-intrinsic heterogeneity sculpts the local immune microenvironment. Here, we profiled the immunogenomic state of 93 spatially distinct regions from 30 malignant brain tumors through whole-exome, RNA, and T-cell receptor sequencing. Our analyses identified differences between primary and secondary malignancies, with gliomas displaying more spatial heterogeneity at the genomic and neoantigen levels. In addition, this spatial diversity was recapitulated in the distribution of T-cell clones in which some gliomas harbored highly expanded but spatially restricted clonotypes. This study defines the immunogenomic landscape across a cohort of malignant brain tumors and contains implications for the design of targeted and immune-based therapies against intracranial malignancies. SIGNIFICANCE: This study describes the impact of spatial heterogeneity on genomic and immunologic characteristics of gliomas and brain metastases. The results suggest that gliomas harbor significantly greater intratumoral heterogeneity of genomic alterations, neoantigens, and T-cell clones than brain metastases, indicating the importance of multisector analysis for clinical or translational studies