172 research outputs found
Bridging Brain and Cognition: A Multilayer Network Analysis of Brain Structural Covariance and General Intelligence in a Developmental Sample of Struggling Learners.
Network analytic methods that are ubiquitous in other areas, such as systems neuroscience, have recently been used to test network theories in psychology, including intelligence research. The network or mutualism theory of intelligence proposes that the statistical associations among cognitive abilities (e.g., specific abilities such as vocabulary or memory) stem from causal relations among them throughout development. In this study, we used network models (specifically LASSO) of cognitive abilities and brain structural covariance (grey and white matter) to simultaneously model brain-behavior relationships essential for general intelligence in a large (behavioral, N = 805; cortical volume, N = 246; fractional anisotropy, N = 165) developmental (ages 5-18) cohort of struggling learners (CALM). We found that mostly positive, small partial correlations pervade our cognitive, neural, and multilayer networks. Moreover, using community detection (Walktrap algorithm) and calculating node centrality (absolute strength and bridge strength), we found convergent evidence that subsets of both cognitive and neural nodes play an intermediary role 'between' brain and behavior. We discuss implications and possible avenues for future studies
Functional immune characterization of HIV-associated non-small-cell lung cancer.
Dear Editor,
In the combined anti-retroviral therapy (cART) era, non-small cell lung cancer (NSCLC) is a highly incident cause of morbidity and mortality in people living with HIV (PLHIV)[1]. The immune-pathogenesis of NSCLC and HIV infection both rely on programmed-death 1 (PD-1) receptor-ligand interaction as a mechanism to induce T-cell exhaustion. To date, PLHIV have been excluded from clinical trials of immune-checkpoint inhibitors (ICPI), on the presumption that anti-tumour immunity might be compromised by HIV infection. To verify this, we evaluated the clinico-pathologic significance of PD-ligands expression in a consecutive series of 221 archival NSCLC samples, 24 of which were HIV-associated (Table S1)
Integrated phenotyping of the anti-cancer immune response in HIV-associated hepatocellular carcinoma
Phenotypic Characteristics of the Tumour Microenvironment in Primary and Secondary Hepatocellular Carcinoma
(1) Background: The intra-tumoural heterogeneity (ITH) of hepatocellular carcinoma (HCC) and its microenvironment (TME) across primary and secondary disease is poorly characterised. (2) Methods: Intra-tumoural (IT) and peri-tumoural (PT) staining of matched primary and secondary samples was conducted to evaluate the distribution of CD4+/FOXP3+ and CD8+/PD1+ T-cells. Samples underwent PD-L1/2 immunostaining, tumour mutational burden (TMB) evaluation, and high-resolution T-cell receptor (TCR) sequencing to derive T-cell clonality and targeted transcriptomics. (3) Results: We analysed 24 samples from matched primary (n = 11) and secondary (n = 13; 5 synchronous, 6 metachronous) deposits, 11 being extrahepatic (84.6%). IT CD8+ density was lower than PT in both primary (p = 0.005) and secondary deposits (p = 0.01), consistent with immune exclusion. PD-L1+ tumours displayed higher IT and PT CD8+/PD1+ cell density compared to PD-L1- (p < 0.05), and primary IT infiltrate was enriched in CD4+/FOXP3+ cells, compared to PT regions (p = 0.004). TCR-sequencing demonstrated enrichment of the top T-cell clonotype in secondary versus primary HCC (p = 0.02), without differences in overall productive clonality (p = 0.35). TMB was similar across primary versus secondary HCC (p = 0.95). While directed gene set analysis demonstrated the uniformity of transcriptional signatures of individual immune cell types, secondary deposits demonstrated higher COLEC12 (p = 0.004), CCL26 (p = 0.02), CD1E (p = 0.02) and CD36 (p = 0.03) expression with downregulation of CXCL1 (p = 0.03), suggesting differential regulation of innate immunity. (4) Conclusion: Immune exclusion is a defining feature of the HCC TME. Despite evidence of homogeneity in somatic TMB, secondary HCC is characterised by the expansion of a distinct T-cell clonotype and differential regulation of innate immune pathways
Novel markers in pediatric-type follicular lymphoma
The aim of this study was to review the histopathological, phenotypic, and molecular characteristics of pediatric-type follicular lymphoma (PTFL) and to assess the diagnostic value of novel immunohistochemical markers in distinguishing PTFL from follicular hyperplasia (FH). A total of 13 nodal PTFLs were investigated using immunohistochemistry, fluorescence in situ hybridization (FISH), and PCR and were compared with a further 20 reactive lymph nodes showing FH. Morphologically, PTFL cases exhibited a follicular growth pattern with irregular lymphoid follicles in which the germinal centers were composed of numerous blastoid cells showing a starry-sky appearance. Immunohistochemistry highlighted preserved CD10 (13/13) and BCL6 (13/13) staining, CD20 (13/13) positivity, a K light chain predominance (7/13), and partial BCL2 expression in 6/13 cases (using antibodies 124, E17, and SP66). The germinal center (GC)–associated markers stathmin and LLT-1 were positive in most of the cases (12/13 and 12/13, respectively). Interestingly, FOXP-1 was uniformly positive in PTFL (12/13 cases) in contrast to reactive GCs in FH, where only a few isolated positive cells were observed. FISH revealed no evidence of BCL2, BCL6, or MYC rearrangements in the examined cases. By PCR, clonal immunoglobulin gene rearrangements were detected in 100% of the tested PTFL cases. Our study confirmed the unique morphological and immunophenotypic features of PTFL and suggests that FOXP-1 can represent a novel useful diagnostic marker in the differential diagnosis between PTFL and FH
Regulatory T Cells Restrain Interleukin-2- and Blimp-1-Dependent Acquisition of Cytotoxic Function by CD4⁺ T Cells
In addition to helper and regulatory potential, CD4+ T cells also acquire cytotoxic activity marked by granzyme B (GzmB) expression and the ability to promote rejection of established tumors. Here, we examined the molecular and cellular mechanisms underpinning the differentiation of cytotoxic CD4+ T cells following immunotherapy. CD4+ transfer into lymphodepleted animals or regulatory T (Treg) cell depletion promoted GzmB expression by tumor-infiltrating CD4+, and this was prevented by interleukin-2 (IL-2) neutralization. Transcriptional analysis revealed a polyfunctional helper and cytotoxic phenotype characterized by the expression of the transcription factors T-bet and Blimp-1. While T-bet ablation restricted interferon-γ (IFN-γ) production, loss of Blimp-1 prevented GzmB expression in response to IL-2, suggesting two independent programs required for polyfunctionality of tumor-reactive CD4+ T cells. Our findings underscore the role of Treg cells, IL-2, and Blimp-1 in controlling the differentiation of cytotoxic CD4+ T cells and offer a pathway to enhancement of anti-tumor activity through their manipulation
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