Spatially organized multicellular immune hubs in human colorectal cancer.

Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd individuals. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across tumors from affected individuals and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T cell-attracting chemokines. By identifying interacting cellular programs, we reveal the logic underlying spatially organized immune-malignant cell networks.

Clinical Trial Participation: A Qualitative Study of Adolescents and Younger Adults Recently Diagnosed with Cancer.

Purpose: Although participation of adolescents and young adults (AYAs) in cancer clinical trials (CCTs, i.e., cancer-directed treatment studies) is low, their decision-making perspectives are not well understood, especially following recent diagnosis. Methods: Semistructured interviews with younger AYAs (15-21 years old) eligible for a CCT were to be held within 60 days of beginning treatment at Children's Hospital Los Angeles, an academic pediatric hospital. Using grounded theory methods, key themes regarding CCT participation, barriers, and facilitators were identified from interview transcripts. Thematic saturation was confirmed. Results: Of nine participants, three were <18 years old, four Hispanic, six male, six diagnosed with leukemia, eight enrolled in a CCT, and eight also enrolled in ancillary studies. Four overarching themes emerged: (1) Initial Consent encompassed the first discussion of CCT with patients reflecting positive and negative effects of timing, decisional role, and the emotional impact following cancer diagnosis; (2) Informing Participation involved decision-making processes, specific knowledge, comprehension, and external influences; (3) Participant Relationships emphasized the importance of communication and relationships with providers and parents; and (4) Patient Determinants centered on motives from different perspectives, pre-conceived attitudes, and understanding of CCTs. Conclusion: Recommendations for improving CCT participation among younger AYAs include separating the diagnosis/treatment and CCT discussions, assigning AYAs a meaningful decisional role, having ongoing provider conversations, designing trials to minimize burden, and developing age-appropriate decision aids.

Huntingtin fibrils with different toxicity, structure, and seeding potential can be interconverted.

The first exon of the huntingtin protein (HTTex1) important in Huntington's disease (HD) can form cross-ß fibrils of varying toxicity. We find that the difference between these fibrils is the degree of entanglement and dynamics of the C-terminal proline-rich domain (PRD) in a mechanism analogous to polyproline film formation. In contrast to fibril strains found for other cross-ß fibrils, these HTTex1 fibril types can be interconverted. This is because the structure of their polyQ fibril core remains unchanged. Further, we find that more toxic fibrils of low entanglement have higher affinities for protein interactors and are more effective seeds for recombinant HTTex1 and HTTex1 in cells. Together these data show how the structure of a framing sequence at the surface of a fibril can modulate seeding, protein-protein interactions, and thereby toxicity in neurodegenerative disease.