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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

The intention of extracorporeal membrane oxygenation (ECMO) support in children with respiratory failure is to rest the lungs, give them time to heal, and prevent further lung injury while ensuring adequate oxygen delivery to the entire body. This chapter reviews the available evidence for lung-protective ventilation on ECMO, how to monitor recovery of lung function, and when and how to wean the patient off extracorporeal life support. Achieving adequate weaning from ECMO depends fully on the recovery of the lungs. It is essential that when ECMO is initiated in children with respiratory failure every attempt is made to rest the lungs, prevent secondary injury and give enough time to heal.

The CASL reactor simulation package VERA has been adapted to provide high-fidelity simulation capabilities for modeling source range detector response during subcritical reactor configurations. New...

The controls that affect the degree of spatio-temporal change to foredunes following scarping are reviewed herein. As sea-levels rises and climate changes, dune scarping will become more common. Thus, it is critical to understand what factors contribute to the magnitude of scarping, and what effect this has on dune systems to better manage coastal erosion into the future. Scarping occurs when foredunes are partially eroded by waves, generally during periods of high water level. The controls on the degree and magnitude of scarping examined include water level, foredune vegetation cover and species present, plant root mass, height and volume of the foredune, the original foredune morphology, surfzone–beach type, and compaction of sediment. Water-level height and duration of high water is the most significant control as it determines the elevation at which wave action can erode the dune and, therefore, the extent of scarping and dune volumetric loss. Higher plant density, greater rooting depth, high root mass, and greater compaction aid in reducing the degree of scaping. The presence of large woody debris and wrack may also influence the degree of scarping. The effects scarping has on the morphology of a foredune after the initial erosion event can range from small changes (e.g. minor, small scarps and slight slumping), to moderate changes such as the foredune translating landwards, to large change such as the transition of an entire dune system into a new transgressive dunefield phase. A new model summarising the key controls and their relationship/significance to the magnitude and extent of scarping is presented.

The selective catalytic synthesis of limonene‐derived monofunctional cyclic carbonates and their subsequent functionalisation via thiol–ene addition and amine ring‐opening is reported. A phosphotungstate polyoxometalate catalyst used for limonene epoxidation in the 1,2‐position is shown to also be active in cyclic carbonate synthesis, allowing a two‐step, one‐pot synthesis without intermittent epoxide isolation. When used in conjunction with a classical halide catalyst, the polyoxometalate increased the rate of carbonation in a synergistic double‐activation of both substrates. The cis isomer is shown to be responsible for incomplete conversion and by‐product formation in commercial mixtures of 1,2‐limomene oxide. Carbonation of 8,9‐limonene epoxide furnished the 8,9‐limonene carbonate for the first time. Both cyclic carbonates underwent thiol–ene addition reactions to yield linked di‐monocarbonates, which can be used in linear non‐isocyanate polyurethanes synthesis, as shown by their facile ring‐opening with N‐hexylamine. Thus, the selective catalytic route to monofunctional limonene carbonates gives straightforward access to monomers for novel bio‐based polymers., Biopolymers: The selective catalytic synthesis of limonene‐derived monofunctional cyclic carbonates and their subsequent functionalisation via thiol–ene addition and amine ring‐opening is reported. The selective catalytic route to monofunctional limonene carbonates gives straightforward access to monomers for novel bio‐based polymers.

Titanium(IV) complexes of amino-tris(phenolate) ligands (LTiX, X = chloride, isopropoxide) together with bis(triphenylphosphine)iminium chloride (PPNCl) are active catalyst systems for the ring-opening copolymerization of carbon dioxide and cyclohexene oxide. They show moderate activity, with turnover frequency values of ∼60 h–1(0.02 mol % of catalyst, 80 °C, 40 bar of CO2) and high selectivity (carbonate linkages >90%), but their absolute performances are lower than those of the most active Ti(IV) catalyst systems. The reactions proceed with linear evolution of polycarbonate (PCHC) molar mass with epoxide conversion, consistent with controlled polymerizations, and evolve bimodal molar mass distributions of PCHC (up toMn= 42 kg mol–1). The stoichiometric reaction between [LTiOiPr] and tetraphenylphosphonium chloride, PPh4Cl, allows isolation of the putative catalytic intermediate [LTi(OiPr)Cl]−, which is characterized using single-crystal X-ray diffraction techniques. The anionic titanium complex [LTi(OR)Cl]−is proposed as a model for the propagating alkoxide intermediates in the catalytic cycle.

A stereoselective, solvent-free ring-opening polymerisation (ROP) of lactide (LA) in supercritical carbon dioxide (scCO2) is reported for the first time. The key aim is to exploit scCO2 to lower the temperature of traditional melt polymerisations, lowering the energy requirement and leading to cleaner polymeric materials. We have utilised a zirconium amine-trisphenolate initiator-stereoselective catalyst [(iPrO)Zr(OPh(tBu)2-CH2)3N] to yield highly heterotactic poly(lactide) (PLA) homopolymer (Pr = 0.74–0.84) from rac-LA, demonstrating control of the PLA microstructure in scCO2. In addition, high monomer conversion (86–93%) was achieved in short reaction time (1 h), affording poly(lactide) with a very low degree of transesterification and narrow molecular weight distribution. Most importantly, all the reactions were performed at only 80 °C, almost 100 °C lower than the conventional melt process (typically performed at 130–180 °C), representing a very significant potential energy saving.

A tungsten-based polyoxometalate catalyst employing aqueous H2O2 as a benign oxidant has been used for the solvent free catalytic epoxidation of the trisubstituted alkene bonds of a wide range of biorenewable terpene substrates. This epoxidation protocol has been scaled up to produce limonene oxide, 3-carene oxide and α-pinene oxide on a multigram scale, with the catalyst being recycled three times to produce 3-carene oxide. Epoxidation of the less reactive disubstituted alkene bonds of terpene substrates could be achieved by carrying out catalytic epoxidation reactions at 50 °C. Methods have been developed that enable direct epoxidation of untreated crude sulfate turpentine to afford 3-carene oxide, α-pinene oxide and β-pinene oxide. Treatment of crude epoxide products (no work-up) with a heterogeneous acid catalyst (Amberlyst-15) results in clean epoxide hydrolysis to afford their corresponding terpene-anti-diols in good yields.

The demand for self-healing elastomers is increasing due to the potential opportunities such materials offer in reducing down-time and cost through extended product lifetimes and reduction of waste. However, further understanding of self-healing mechanisms and processes is required in order to develop a wider range of commercially applicable materials with self-healing properties. Epoxidized natural rubber (ENR) is a derivative of polyisoprene. ENR25 and ENR50 are commercially available materials with 25 and 50 mol % epoxidation, respectively. Recently, reports of the use of ENR in self-healing materials have begun to emerge. However, to date, there has been limited analysis of the self-healing mechanism at the molecular level. The aim of this work is to gain understanding of the relevant self-healing mechanisms through systematic characterization and analysis of the effect of cross-linking on the self-healing performance of ENR and natural rubber (NR). In our study, cross-linking of ENR and NR with dicumyl peroxide and sulfur to provide realistic models of commercial rubber formulations is described, and a cross-linking density of 5 × 10-5 mol cm-3 in sulfur-cured ENR is demonstrated to achieve a healing efficiency of 143% for the tensile strength. This work provides the foundation for further modification of ENR, with the goal of understanding and controlling ENR's self-healing ability for future applications.

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