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    Tumor mutational burden is a determinant of immune-mediated survival in breast cancer
    (Taylor and Francis, England, 2018-07-30) Thomas A; Routh ED; Pullikuth A; Jin G; Su J; Chou JW; Hoadley KA; Print C; Knowlton N; Black MA; Demaria S; Wang E; Bedognetti D; Jones WD; Mehta GA; Gatza ML; Perou CM; Page DB; Triozzi P; Miller LD
    Mounting evidence supports a role for the immune system in breast cancer outcomes. The ability to distinguish highly immunogenic tumors susceptible to anti-tumor immunity from weakly immunogenic or inherently immune-resistant tumors would guide development of therapeutic strategies in breast cancer. Genomic, transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) breast cancer cohorts were used to examine statistical associations between tumor mutational burden (TMB) and the survival of patients whose tumors were assigned to previously-described prognostic immune subclasses reflecting favorable, weak or poor immune-infiltrate dispositions (FID, WID or PID, respectively). Tumor immune subclasses were associated with survival in patients with high TMB (TMB-Hi, P < 0.001) but not in those with low TMB (TMB-Lo, P = 0.44). This statistical relationship was confirmed in the METABRIC cohort (TMB-Hi, P = 0.047; TMB-Lo, P = 0.39), and also found to hold true in the more-indolent Luminal A tumor subtype (TMB-Hi, P = 0.011; TMB-Lo, P = 0.91). In TMB-Hi tumors, the FID subclass was associated with prolonged survival independent of tumor stage, molecular subtype, age and treatment. Copy number analysis revealed the reproducible, preferential amplification of chromosome 1q immune-regulatory genes in the PID immune subclass. These findings demonstrate a previously unappreciated role for TMB as a determinant of immune-mediated survival of breast cancer patients and identify candidate immune-regulatory mechanisms associated with immunologically cold tumors. Immune subtyping of breast cancers may offer opportunities for therapeutic stratification.
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    A Nunavut community-directed Inuit youth mental wellness initiative: making I-SPARX fly
    (Taylor & Francis Group, 2024-10-10) Bohr Y; Hankey J; Thomas A; Abdelmaseh M; Armour L; McCague H; Barnhardt J; Oskalns M; Garvey N; Singh Y; Danz C; Singoorie C; Qaunaq R; Oshoweetok I; Lucassen M; Merry S; Shepherd M; Bornstein MH; Ahmad F; Shulman S; Weiss J
    Inuit youth in Nunavut (NU) are resilient but face a protracted suicide crisis. The SPARX serious game and e-intervention, developed originally in New Zealand, teaches youth cognitive behavioural therapy (CBT) skills to ameliorate stress and depression. Inuit youth in NU reviewed and culturally adapted SPARX and an existing wellness outcome measure for Inuit. One hundred and twenty-one youth, aged 13 to 24, across NU then tested, played, and evaluated I(nuit)-SPARX, showing improvement in several areas of wellbeing post-play. Youth completed a CBT skills survey, engaged in sharing circles to assess CBT skill retention, and shared their thoughts about the usefulness and cultural fit of I-SPARX with Inuit Qaujimajatuqangit (IQ). Communication Skills, Listening Skills, and Problem Solving emerged as the most helpful learned CBT skills, and NU youth provided real-world examples of using I-SPARX skills to support their mental wellness. Several principles of IQ were exemplified and upheld in the content of the adapted SPARX tool and the process of the project as a whole. Empirically grounded, asynchronous e-tools, developed in collaboration with Inuit communities to ensure cultural specificity, may support psychological wellness in communities where mental health resources are scarce.
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    Peripheral astral microtubules ensure asymmetric furrow positioning in neural stem cells
    (Elsevier Inc, 2021-10-26) Thomas A; Gallaud E; Pascal A; Serre L; Arnal I; Richard-Parpaillon L; Savoian MS; Giet R
    Neuroblast division is characterized by asymmetric positioning of the cleavage furrow, resulting in a large difference in size between the future daughter cells. In animal cells, furrow placement and assembly are governed by centralspindlin that accumulates at the equatorial cell cortex of the future cleavage site and at the spindle midzone. In neuroblasts, these two centralspindlin populations are spatially and temporally separated. A leading pool is located at the basal cleavage site and a second pool accumulates at the midzone before traveling to the cleavage site. The cortical centralspindlin population requires peripheral astral microtubules and the chromosome passenger complex for efficient recruitment. Loss of this pool does not prevent cytokinesis but enhances centralspindlin signaling at the midzone, leading to equatorial furrow repositioning and decreased size asymmetry. These data show that basal furrow positioning in neuroblasts results from a competition between different centralspindlin pools in which the cortical pool is dominant.