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Many of the responses that occurred after the protracted schedule suggest that adaptive mechanisms may be being triggered following persistent exposure to radiation.

Previous workers have reported a range of structural variations occurring along the length of small intestine. These studies have concentrated on the major intestinal components with little information available on the intersite variation of other members of a highly heterogeneous population. Using resin histology, the current study has collected data per circumference for all definable structural features within the murine intestinal wall, along with measurements for epithelial, muscle, nerve and connective tissue areas, and villous height and cryptal depth. Seven different sites along the length of the small intestine were examined. Following statistical comparisons a number of features exhibited no intersite variation; these were numbers of villi, submucosal vessels, myenteric nerve plexus profiles, inner muscle nuclei and apoptotic bodies as well as measurements for tissue areas and cryptal depth. Variations were seen between sites for crypts, enterocytes, villous and cryptal stromal cells, cryptal goblet cells, cryptal non-secretory epithelial cells, Paneth cells, endocrine cells, intra-epithelial lymphocytes, submucosal nerve plexus profiles, outer muscle nuclei and mitotic figures. A reduced villous height was observed caudally. Certain correlations between villous height/crypt number and constituent parameters have been noted. The results provide a complete description of how each definable structural feature within the gut wall varies at regular intervals along the length of the small intestine in C57 BL mice. A number of previously unreported variations have been described. The work provides a comprehensive data bank for future intestinal investigations.

Phosphoinositide 3-kinase δ (PI3Kδ) plays a key role in lymphocytes and inhibitors targeting this PI3K have been approved for hematological malignancies. While studies in hematological and solid tumor models in mice have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumor immunity, the impact of PI3Kδi on solid tumors in humans remains unclear. Here, we assessed the effects of the PI3Kδi AMG319 in patients with resectable head and neck cancer in a neoadjuvant, double-blind, placebo-controlled randomised phase-II trial. We find that PI3Kδ inhibition decreases tumor-infiltrating immunosuppressive TREG cells and causes heightened cytotoxic potential of tumor-infiltrating CD8+ and CD4+ T cells. Loss of intratumoral TREG cells and an increase in the frequency of activated TREG cells in the blood post-treatment are indicative of systemic effects on TREG tissue retention and maintenance. At the tested AMG319 doses, immune-related adverse events caused treatment discontinuation in 12/21 of AMG319-treated patients, further suggestive of systemic effects on TREG cells. Consistent with this notion, in a murine syngeneic tumor model, PI3Kδi decreased TREG cells in both tumor and non-malignant tissues and affected TREG subtype composition, maintenance and functionality. Our data demonstrate the cancer-immunotherapy potential of PI3Kδ inhibition in humans, but its modulation will need to be carefully balanced to harness its anti-tumor capacity while minimizing immune related toxicity.

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