MHC-I genotype drives early immune selection of oncogenic mutations.

MHC-I exposes the intracellular contents to immune cells for surveillance of cellular health. Due to high genomic variation, individuals' immune systems differ in their ability to expose and eliminate cancer-causing mutations. These personalized immune blind spots create specific oncogenic mutation predispositions within patients and influence their prevalence across populations

A taxonomy of event participants based on risk and security perceptions

Purpose: The purpose of this paper is to create a taxonomy of event participants based on risk and security perceptions. Design/methodology/approach: Two focus groups were established with British mothers, one with five mothers and the other with six, recruited through convenience and snowball sampling. A tree diagram was employed to uncover the taxonomic structure underlying risk and security perceptions. In creating the taxonomy, two critical issues were found to best categorise participants: the extent to which risks were considered before attending an event and whether or not participants showed an interest in knowing about security measures in advance of the event. Findings: Six taxonomy categories were created, based on the unique combination of attitude and reactions: overthinker, investigator, naïve, ignorer, survivalist and optimiser. Similarities and differences between the types of participants were examined across 12 typical traits and reactions to risk and security. Practical implications: The results provide event organisers with an understanding of whether they need to communicate their risk management strategy, and if so how they can best achieve this. Originality/value: Existing taxonomies have tended to identify customer types based on risk perceptions alone. This research expands such work by considering attitudes towards both risk and security and how these affect event attendance. Hence, the descriptive taxonomy developed in the paper provides empirical evidence of the diverse risk and security perceptions at public events

Network-based stratification of tumor mutations.

Many forms of cancer have multiple subtypes with different causes and clinical outcomes. Somatic tumor genome sequences provide a rich new source of data for uncovering these subtypes but have proven difficult to compare, as two tumors rarely share the same mutations. Here we introduce network-based stratification (NBS), a method to integrate somatic tumor genomes with gene networks. This approach allows for stratification of cancer into informative subtypes by clustering together patients with mutations in similar network regions. We demonstrate NBS in ovarian, uterine and lung cancer cohorts from The Cancer Genome Atlas. For each tissue, NBS identifies subtypes that are predictive of clinical outcomes such as patient survival, response to therapy or tumor histology. We identify network regions characteristic of each subtype and show how mutation-derived subtypes can be used to train an mRNA expression signature, which provides similar information in the absence of DNA sequence

How Early Mathematics Interventions Support Mathematics Vocabulary Learning: A Content Analysis

While there is a strong research base that supports intervening early in mathematics, research investigating the importance of mathematics vocabulary is still emerging. Practitioners and researchers may benefit from understanding how mathematics interventions support mathematics vocabulary acquisition, particularly for students who struggle with learning mathematics. Thus, the purpose of this study was to conduct a mathematics vocabulary content analysis across seven kindergarten and first-grade mathematics interventions. Across the intervention lessons, we recorded suggested teacher and student actions related to mathematics vocabulary instruction. The results indicated the most common instructional strategies used to teach mathematics vocabulary include: providing students with the opportunity to apply the meaning of the vocabulary term (94.7%), using representations (66.4%), and asking students to respond to teacher prompts using the term (44.7%). Overall, 29.7% of lessons clearly defined vocabulary terms, and 5.8% of lesson objectives addressed teaching the definition of the term. We discuss implications for researchers and practitioners to supplement interventions with opportunities for students to learn, practise, and apply mathematics vocabulary

Elevated neoantigen levels in tumors with somatic mutations in the HLA-A, HLA-B, HLA-C and B2M genes.

BackgroundThe major histocompatibility complex class I (MHC-I) molecule is a protein complex that displays intracellular peptides to T cells, allowing the immune system to recognize and destroy infected or cancerous cells. MHC-I is composed of a highly polymorphic HLA-encoded alpha chain that binds the peptide and a Beta-2-microglobulin (B2M) protein that acts as a stabilizing scaffold. HLA mutations have been implicated as a mechanism of immune evasion during tumorigenesis, and B2M is considered a tumor suppressor gene. However, the implications of somatic HLA and B2M mutations have not been fully explored in the context of antigen presentation via the MHC-I molecule during tumor development. To understand the effect that B2M and HLA MHC-I molecule mutations have on mutagenesis, we analyzed the accumulation of mutations in patients from The Cancer Genome Atlas according to their MHC-I molecule mutation status.ResultsSomatic B2M and HLA mutations in microsatellite stable tumors were associated with higher overall mutation burden and a larger fraction of HLA-binding neoantigens when compared to B2M and HLA wild type tumors. B2M and HLA mutations were highly enriched in patients with microsatellite instability. B2M mutations tended to occur relatively early during patients' respective tumor development, whereas HLA mutations were either early or late events. In addition, B2M and HLA mutated patients had higher levels of immune infiltration by natural killer and CD8+ T cells and higher levels of cytotoxicity.ConclusionsOur findings add to a growing body of evidence that somatic B2M and HLA mutations are a mechanism of immune evasion by demonstrating that such mutations are associated with a higher load of neoantigens that should be presented via MHC-I

Extracellular vesicles produced in B cells deliver tumor suppressor miR-335 to breast cancer cells disrupting oncogenic programming in vitro and in vivo.

The successful implementation of miRNA (miR) therapies in humans will ultimately rely on the use of vehicles with improved cellular delivery capability. Here we tested a new system that leverages extracellular vesicles (EVs) laden with a tumor suppressor miRNA (miR-335) produced in B cells by plasmid DNA induction (iEVs). We demonstrate that iEVs-335 efficiently and durably restored the endogenous miR-335 pool in human triple negative breast cancer cells, downregulated the expression of the miR-335 target gene SOX4 transcription factor, and markedly inhibited tumor growth in vivo. Remarkably, iEVs-335 mediated transcriptional effects that persisted in tumors after 60 days post orthotopic implantation. Genome-wide RNASeq analysis of cancer cells treated in vitro with iEVs-335 showed the regulation of a discrete number of genes only, without broad transcriptome perturbations. This new technology may be ideally suited for therapies aimed to restore tumor suppressor miRNAs in cancer cells, disrupting the oncogenic program established after escape from miRNA control

Challenges in identifying cancer genes by analysis of exome sequencing data.

Massively parallel sequencing has permitted an unprecedented examination of the cancer exome, leading to predictions that all genes important to cancer will soon be identified by genetic analysis of tumours. To examine this potential, here we evaluate the ability of state-of-the-art sequence analysis methods to specifically recover known cancer genes. While some cancer genes are identified by analysis of recurrence, spatial clustering or predicted impact of somatic mutations, many remain undetected due to lack of power to discriminate driver mutations from the background mutational load (13-60% recall of cancer genes impacted by somatic single-nucleotide variants, depending on the method). Cancer genes not detected by mutation recurrence also tend to be missed by all types of exome analysis. Nonetheless, these genes are implicated by other experiments such as functional genetic screens and expression profiling. These challenges are only partially addressed by increasing sample size and will likely hold even as greater numbers of tumours are analysed

S4E1: How does Cooperative Extension Help Mainers Thrive?

While University of Maine Cooperative Extension’s roots are in agriculture, the 106-year-old organization helps all Mainers thrive with its relevant research-based programs that promote child development, nutrition, robotics, entrepreneurship and more. Recently, “more” has included providing communities with much-needed resources during the pandemic. In this initial podcast of Season 4, host Ron Lisnet discusses Cooperative Extension’s past, present and future with UMaine and University of Maine at Machias President Joan Ferrini-Mundy and Cooperative Extension Dean Hannah Carter, who says the trusted organization can be like Google for Mainers seeking information

Immune DNA signature of T-cell infiltration in breast tumor exomes.

Tumor infiltrating lymphocytes (TILs) have been associated with favorable prognosis in multiple tumor types. The Cancer Genome Atlas (TCGA) represents the largest collection of cancer molecular data, but lacks detailed information about the immune environment. Here, we show that exome reads mapping to the complementarity-determining-region 3 (CDR3) of mature T-cell receptor beta (TCRB) can be used as an immune DNA (iDNA) signature. Specifically, we propose a method to identify CDR3 reads in a breast tumor exome and validate it using deep TCRB sequencing. In 1,078 TCGA breast cancer exomes, the fraction of CDR3 reads was associated with TILs fraction, tumor purity, adaptive immunity gene expression signatures and improved survival in Her2+ patients. Only 2/839 TCRB clonotypes were shared between patients and none associated with a specific HLA allele or somatic driver mutations. The iDNA biomarker enriches the comprehensive dataset collected through TCGA, revealing associations with other molecular features and clinical outcomes

P2_7 Outrunning Climate Change

In this paper we investigate the rate at which you would have to move Earth away from the Sun to combat the global temperature increase due to greenhouse gas emissions. By assuming the average global temperature increases linearly between 0.2 ◦C or 4.8 ◦C by the year 2100, we found that the Earth would need to be moved between 5.44 × 106 and 1.31 × 108 meters per year