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Chronic intestinal inflammation accompanies familial adenomatous polyposis (FAP) and is a major risk factor for colorectal cancer in patients with this disease, but the cause of such inflammation is unknown. Because retinoic acid (RA) plays a critical role in maintaining immune homeostasis in the intestine, we hypothesized that altered RA metabolism contributes to inflammation and tumorigenesis in FAP. To assess this hypothesis, we analyzed RA metabolism in the intestines of patients with FAP as well as APCMin/+ mice, a model that recapitulates FAP in most respects. We also investigated the impact of intestinal RA repletion and depletion on tumorigenesis and inflammation in APCMin/+ mice. Tumors from both FAP patients and APCMin/+ mice displayed striking alterations in RA metabolism that resulted in reduced intestinal RA. APCMin/+ mice placed on a vitamin A–deficient diet exhibited further reductions in intestinal RA with concomitant increases in inflammation and tumor burden. Conversely, restoration of RA by pharmacologic blockade of the RA-catabolizing enzyme CYP26A1 attenuated inflammation and diminished tumor burden. To investigate the effect of RA deficiency on the gut immune system, we studied lamina propria dendritic cells (LPDC) because these cells play a central role in promoting tolerance. APCMin/+ LPDCs preferentially induced Th17 cells, but reverted to inducing Tregs following restoration of intestinal RA in vivo or direct treatment of LPDCs with RA in vitro. These findings demonstrate the importance of intestinal RA deficiency in tumorigenesis and suggest that pharmacologic repletion of RA could reduce tumorigenesis in FAP patients. Cancer Immunol Res; 4(11); 917–26. ©2016 AACR.

beta-catenin, RA metabolic enzymes, retinyl esters, all-trans retinol and RA in APCMin/+ tissues.

Sorting strategy to obtain DCs and DC subsets from the LP.

RALDH1A2 in LPDCs from APCMin/+ and WT mice.

Failure of injected RA to increase intestinal RA in APCMin/+ mice, and characterization of DC subsets in the SI-LP of APCMin/+ mice.

Failure of injected RA to reverse the proinflammatory phenotype of APCMin/+LPDCs.

Supplementary Figure Legends

Supplementary Figure Legends

Pancreatic ductal adenocarcinoma (PDAC) after complete surgical resection is often followed by distant metastatic relapse for reasons that remain unclear. In this study, we investigated how the immune response at secondary sites affects tumor spread in murine models of metastatic PDAC. Early metastases were associated with dense networks of CD11b+CD11c+MHC-II+CD24+CD64lowF4/80low dendritic cells (DC), which developed from monocytes in response to tumor-released GM-CSF. These cells uniquely expressed MGL2 and PD-L2 in the metastatic microenvironment and preferentially induced the expansion of T regulatory cells (Treg) in vitro and in vivo. Targeted depletion of this DC population in Mgl2DTR hosts activated cytotoxic lymphocytes, reduced Tregs, and inhibited metastasis development. Moreover, blocking PD-L2 selectively activated CD8 T cells at secondary sites and suppressed metastasis, suggesting that the DCs use this particular pathway to inhibit CD8 T-cell–mediated tumor immunity. Phenotypically similar DCs accumulated at primary and secondary sites in other models and in human PDAC. These studies suggest that a discrete DC subset both expands Tregs and suppresses CD8 T cells to establish an immunosuppressive microenvironment conducive to metastasis formation. Therapeutic strategies to block the accumulation and immunosuppressive activity of such cells may help prevent PDAC progression and metastatic relapse after surgical resection. Cancer Res; 77(15); 4158–70. ©2017 AACR.

Supplementary Figures S1-8. Fig. S1: CD11b+CD11c+MHC-II+ cells exhibit DC phenotype and accumulate at multiple metastatic sites. Fig. S2: PDAC cells produce large amounts of GM-CSF and stimulate Mo-DC differentiation. Fig. S3: Liver DC from tumor-bearing mice efficiently activate T cells in conventional assays. Fig. S4: Metastasis-associated DC stimulate nTreg proliferation while suppressing CD8 T cells through PD-1 ligand expression. Fig. S5: MGL2+ cells exhibit DC phenotype and their depletion activates multiple lymphocyte populations. Fig. S6: Blocking PD-L2 reduces metastasis without affecting primary tumor burden. Fig. S7: PD-L2+ and MGL+ cells are present in human PDAC tissues. Fig. S8: Development and function of CD11b+ DC in PDAC metastasis.

Supplementary Materials and Methods

FlowNMR spectroscopy has become a popular and powerful technique for online reaction monitoring. DOSY NMR is an established technique for obtaining information about diffusion rates and molecular size on static samples. This work extends the FlowNMR toolbox to include FlowDOSY based on convection compensation and use of a low-pulsation pump or flow effect correction, allowing accurate and precise diffusion coefficients to be obtained at flow rates up to 4.0 mL min

This paper reports the synthesis of high molecular weight semi-aromatic polyamides containing renewable furanic monomer by a scalable melt polycondensation method using eco-friendly titanium-based catalysts.

A D-Xylose 3,5 anyhydrosugar (D-Ox) has been applied in the ring-opening copolymerisation (ROCOP) with isothiocyanates to form alternating AB-type copolymers with imidothiocarbonate linkages (Mn ≥ 34,900 g mol−1). Catalysed by...

International audience; he ‘acanthodian’ fishes provide key anatomical insights into the deepest branches of the chondrichthyan stem group. We review the anatomy of the acanthodian Vernicomacanthus uncinatus from the Lochkovian (Lower Devonian, 419.2–410.8 Ma) of Scotland based on eight articulated fossils, one of which is newly described. Broadly, the anatomy of V. uncinatus fits with that of contemporaneous acanthodians such as Climatius and Parexus, with a head covered by robust tesserae, an enlarged postorbital scale, an armoured shoulder girdle, and many pairs of ventrolateral spines. However, it departs from this anatomy in key respects. Its pectoral fin spines are obliquely ridged and posteriorly denticulated, similarly to Carboniferous gyracanth stem-group chondrichthyans. Its scales consist of multiple anteroposteriorly aligned odontodes, similarly to many Palaeozoic ‘sharks’. And its endoskeletal shoulder girdle may have a posterolateral angle, previously observed only in shark-like chondrichthyans. We propose that the differences between V. uncinatus and its congeneric, V. waynensis, which include potentially phylogenetically significant characters of the shoulder girdle and spines, are sufficient to erect a new genus for V. waynensis:Dobunnacanthus gen. nov. The scales of Vernicomacanthus are identical to those of the ‘shark’ scale genus Altholepis, suggesting that some such scales may instead belong to taxa with acanthodian-like gross anatomies. Based on these scales we highlight potential patterns in chondrichthyan scale evolution, in particular the axial addition of odontodes. Anatomical similarities between Vernicomacanthus and gyracanths, highlighted by previous authors, may indicate the existence of a grade including these and similar acanthodian-grade taxa placed relatively crownwards in the chondrichthyan stem-group

A study was performed to determine which transport events should be used to initiate a weight window lookup to achieve the best variance reduction performance. A weight window lookup potentially triggers particle splitting (in important regions of phase space) or rouletting (in unimportant regions), thereby optimizing computational effort. Potential initiating transport events include collisions (both pre- and post-collision), geometry surface crossings, traversing a mean-free path, and streaming across a weight window boundary. Permutations of these initiating events were tested on an urban model with background radiation sources and a spent fuel cask with a neutron dose mesh tally. Generally, all methods perform better with finer weight window meshes. Tracking on weight windows performs well for coarse weight window meshes, while a combination of splitting each mean-free path, geometric surface crossing, and before collisions performs well for fine weight window meshes.