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Porcine islet xenografts have the potential to provide an inexhaustible source of islets for β cell replacement. Proof‐of‐concept has been established in nonhuman primates. However, significant barriers to xenoislet transplantation remain, including the poorly understood instant blood‐mediated inflammatory reaction and a thorough understanding of early xeno‐specific immune responses. A paucity of data exist comparing xeno‐specific immune responses with alloislet (AI) responses in primates. We recently developed a dual islet transplant model, which enables direct histologic comparison of early engraftment immunobiology. In this study, we investigate early immune responses to neonatal porcine islet (NPI) xenografts compared with rhesus islet allografts at 1 hour, 24 hours, and 7 days. Within the first 24 hours after intraportal infusion, we identified greater apoptosis (caspase 3 activity and TUNEL[terminal deoxynucleotidyl transferase dUTP nick end labeling])‐positive cells) of NPIs compared with AIs. Macrophage infiltration was significantly greater at 24 hours compared with 1 hour in both NPI(wild‐type) and AIs. At 7 days, IgM and macrophages were highly specific for NPIs (α1,3‐galactosyltransferase knockout) compared with AIs. These findings demonstrate an augmented macrophage and antibody response toward xenografts compared with allografts. These data may inform future immune or genetic manipulations required to improve xenoislet engraftment. A nonhuman primate dual transplant model of islet transplantation compares allogeneic islets to porcine xenogeneic islets and demonstrates an augmented macrophage and antibody response toward xenografts and an early increase in xenograft cell death.

A new pseudoguaiane-type sesquiterpene named litopharbol (1) was isolated from the methanolic extract of the Red Sea soft coral Litophyton arboreum, along with known sesquiterpenoids alismol (2), alismorientol B (3), teuhetenone A (4), and calamusin I (5); steroid, 24-methyl-cholesta-5,24(28)-diene-3β-ol (6), alkyl glyceryl ether, chimyl alcohol (7); sphingolipid, erythro-N-dodecanoyl-docosasphinga-(4E,8E)-dienine (8); and nitrogenous bases, thymine (9) and thymidine (10). The structures were determined on the basis of nuclear magnetic resonance (NMR) spectroscopic (1D and 2D NMR data including heteronuclear single quantum coherence spectroscopy, heteronuclear multiple-bond correlation spectroscopy, and nuclear Overhauser effect spectroscopy) and mass spectrometric analyses. Compounds 1–5were explored for antimicrobial activity and cancer cell line sensitivity tests. Compound 1exhibited antibacterial activity against Bacillus cereuswith a minimum inhibition concentration of 1.8 μg/mL, whereas compound 3showed significant potent cytotoxic effect against MCF-7 (breast cancer cells) with IC504.32 μM.

Early activation of coagulation is an important factor in the initiation of innate immunity, as characterized by thrombotic microangiopathy (TMA). In transplantation, systemic anticoagulation is difficult due to bleeding. A novel “cytotopic” agent, thrombalexin (TLN), combines a cell-membrane-bound (myristoyl tail) anti-thrombin (hirudin-like peptide [HLL]), which can be perfused directly to the donor organ or cells. Thromboelastography was used to measure time to clot formation (r-time) in both rhesus and human blood, comparing TLN versus HLL (without cytotopic tail) versus negative control. Both TLN- and HLL-treated rhesus or human whole blood result in significantly prolonged r-time compared to kaolin controls. Only TLN-treated human endothelial cells and neonatal porcine islets prolonged time to clot formation. Detection of membrane-bound TLN was confirmed by immunohistochemistry and fluorescence activated cell sorter. In vivo, perfusion of a nonhuman primate kidney TLN-supplemented preservation solution in a sensitized model of transplantation demonstrated no evidence of TLN systemically. Histologically, TLN was shown to be present up to 4 days after transplantation. There was no platelet deposition, and TMA severity, as well as microvascular injury scores (glomerulitis + peritubular capillaritis), were less in the TLN-treated animals. Despite promising evidence of localized efficacy, no survival benefit was demonstrated.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. The Oral Rheumatoid Arthritis triaL (ORAL) Strategy aimed to assess the comparative efficacy of tofacitinib monotherapy, tofacitinib plus methotrexate, and adalimumab plus methotrexate for the treatment of rheumatoid arthritis in patients with a previous inadequate response to methotrexate.

Costimulation blockade (CoB) via belatacept is a lower‐morbidity alternative to calcineurin inhibitor (CNI)‐based immunosuppression. However, it has higher rates of early acute rejection. These early rejections are mediated in part by memory T cells, which have reduced dependence on the pathway targeted by belatacept and increased adhesion molecule expression. One such molecule is leukocyte function antigen (LFA)‐1. LFA‐1 exists in two forms: a commonly expressed, low‐affinity form and a transient, high‐affinity form, expressed only during activation. We have shown that antibodies reactive with LFA‐1 regardless of its configuration are effective in eliminating memory T cells but at the cost of impaired protective immunity. Here we test two novel agents, leukotoxin A and AL‐579, each of which targets the high‐affinity form of LFA‐1, to determine whether this more precise targeting prevents belatacept‐resistant rejection. Despite evidence of ex vivoand in vivoligand‐specific activity, neither agent when combined with belatacept proved superior to belatacept monotherapy. Leukotoxin A approached a ceiling of toxicity before efficacy, while AL‐579 failed to significantly alter the peripheral immune response. These data, and prior studies, suggest that LFA‐1 blockade may not be a suitable adjuvant agent for CoB‐resistant rejection. This study examines the use of belatacept with either depletion or inhibition of the high‐affinity form of LFA‐1 in a nonhuman primate model of kidney transplantation.

Belatacept is used to prevent allograft rejection but fails to do so in a sizable minority of patients due to inadequate control of costimulation‐resistant T cells. In this study, we report control of costimulation‐resistant rejection when belatacept was combined with perioperative alemtuzumab‐mediated lymphocyte depletion and rapamycin. To assess the means by which the alemtuzumab, belatacept and rapamycin (ABR) regimen controls belatacept‐resistant rejection, we studied 20 ABR‐treated patients and characterized peripheral lymphocyte phenotype and functional responses to donor, third‐party and viral antigens using flow cytometry, intracellular cytokine staining and carboxyfluorescein succinimidyl ester–based lymphocyte proliferation. Compared with conventional immunosuppression in 10 patients, lymphocyte depletion evoked substantial homeostatic lymphocyte activation balanced by regulatory T and B cell phenotypes. The reconstituted T cell repertoire was enriched for CD28+naïve cells, notably diminished in belatacept‐resistant CD28−memory subsets and depleted of polyfunctional donor‐specific T cells but able to respond to third‐party and latent herpes viruses. B cell responses were similarly favorable, without alloantibody development and a reduction in memory subsets—changes not seen in conventionally treated patients. The ABR regimen uniquely altered the immune profile, producing a repertoire enriched for CD28+T cells, hyporesponsive to donor alloantigen and competent in its protective immune capabilities. The resulting repertoire was permissive for control of rejection with belatacept monotherapy.

A new naturally occurring compound based on the dammarane skeleton, i.e. cabralealactone 3-acetate-24-methyl ether, was isolated from the aqueous methanolic extract of Forsythia koreana fruits, along with eight known compounds: cabralealactone 3-acetate, ursolic acid, arctigenin, arctiin, phillyrin, rutin, caffeic acid, and rosmarinic acid. The identifi cation of the isolated compounds was based on their spectral analysis including: HREI-MS, 1D and 2D NMR spectroscopy. The selected compounds and the aqueous methanolic extract were evaluated for their cytotoxic activity against human solid tumour cell lines. Cabralealactone 3-acetate-24-methyl ether and ursolic acid were found to be active against human breast cancer cells (MCF-7). The cytotoxicity was associated with the activation of caspase-8, the induction of the death receptors DR4 and DR5, as well as DNA fragmentation, and was thus due to apoptosis rather than necrosis

The cytotoxicity of the methanol extract of Origanum syriacum against human cerivical adenocarcinoma, Hela cells, was evaluated by the MTT assay. From the crude extract, a new flavone glycoside, acacetin-7-O-[2´´-O-a-L-rhamnopyranosyl-6´´-O-ß -D-glucopyranosyl]-ß -D-glucopyranoside (1), together with the ten known flavonoids luteolin (2), apigenin (3), luteolin-6-C-glucoside (4), luteolin-3´-methylether-6-C-glucoside (5), luteolin-7,4´-dimethyether-6-C-glucoside (6), apigenin-7- methylether-6-C-glucoside (7), apigenin-7-O-glucoside (8), diosmetin-7-O-glucoside (9), acacetin- 7-O-glucoside (10) and acacetin-7-O-rutinoside (11), was isolated from the methanol extract of the aerial parts of Origanum syriacum. The structure elucidation of the isolated compounds was performed by spectroscopic and chromatographic methods.

From the methanol extract of the fruits of Forsythia koreana two new compounds, one phenylethanoid glycoside and one pyrrolidine alkaloid, have been isolated together with six known compounds. The structures of the isolated compounds were elucidated on the basis of 1D and 2D NMR spectroscopic methods and comparison with literature data.

This paper concentrates on the fact that natural materials are variable, and that representation of this variability appears crucial to getting a realistic understanding of certain geotechnical problems. In this case, finite elements have been used to assess the influence of heterogeneity on the stability of a clay slope, characterized by a spatially varying undrained shear strength c_u. For low to intermediate values of the coefficient of variation (e.g. 0.1-0.3), as are often observed in practice, pointwize variability can be approximated by a normal distribution. Data on spatial variability are more scarce, although vertical scales of fluctuation are usually much smaller than horizontal scales of fluctuation, and will often be small relative to the height of a slope. The results show that, for a given factor of safety, reliability is greatest for c_u constant with depth. For c_u increasing linearly with depth, reliability decreases due to the greater range of possible rupture surfaces: hence, in conventional (deterministic) design, higher factors of safety (or lower characteristic values) would be needed. In this study, horizontal anisotropy (of the heterogeneity) causes modest changes in reliability. However, problems are identified in which anisotropy is likely to have a significant influence.

Le cancer du poumon non à petites cellules (CPNPC) est un problème majeur de santé publique. La prédiction du pronostic est très importante dans la prise de décision thérapeutique et la qualité de vie. Cependant, le stade III représente un groupe hétérogène de patients. L’objectif de cette étude est de déterminer les facteurs associés à une mortalité élevée chez les patients atteints de CNPC stade III.

A new pyranone derivative, 3-hydroxy-2-(4-hydroxyphenyl)-6-methyl-4H-pyran-4-one (1), was isolated from the leaves of Livistona australis. The structure was determined by NMR spectral analysis.

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