Basiliximab induction therapy in kidney transplantation: Benefits for long term allograft function after 10 years?

The interleukin-2 receptor antagonist basiliximab has proven in large clinical trials to be safe and effective to reduce acute rejections in the first year after renal transplantation. Since acute rejections are a risk factor for chronic graft loss, their effective reduction might have a positive effect on long term allograft survival. So far data is spares to prove this hypothesis and 10-year follow up on basiliximab induction therapy is not available. In our center, 41 patients were enrolled in the multicenter trial CHIB201 in 1995/96 comparing basiliximab vs no induction therapy after renal transplantation. We retrospectively analyzed the outcome of these patients after 10 years. The main reason for patient death with functioning graft were infectious complications (basiliximab: 3/20, placebo 1/19), 21% of all patients developed cancer without an obvious correlation to specific immunosuppression. Death censored 10-year graft survival was equivalent in both groups: 65% in the basiliximab and 68% in the placebo group with a mean s-creatinine-clearance of 60 and 44 ml/min. In this small study patient and graft survival was equivalent 10 years after transplantation comparing basiliximab induction therapy and placebo

Two diffusion photopolymer for sharp diffractive optical elements recording

Photopolymers as recording media are widely used in optical applications. In such materials, changes in the phase of the transmittance function are generated during exposure due to refractive index and thickness modulations. These changes arise primarily as a consequence of photopolymerization and mass transport processes. Characterizing polymers’ performance, for example, quantifying the value of monomer diffusion, is therefore very important. Applying index matching, the volume and surface optical effect are separated in an acrylamide/polyvinylalcohol (AA/PVA) material. Using a simplified model that includes the effects of the holes produced during polymerization, both hole and monomer diffusion are analyzed. The analysis presented indicates higher material sensitivity than previously estimated. The results also indicate the possibility of recording sharper diffractive optical elements profiles, like blazed gratings, having diffraction efficiencies higher than 80%.Enterprise Ireland; Generalitat Valenciana of Spain (ISIC/2012/013, PROMETEOII/2015/015); Irish Research Council for Science, Engineering and Technology (National Development Fund); Ministerio de Economía y Competitividad of Spain (FIS2011-29803-C02-01); Science Foundation Ireland

Non-local photo-polymerization kinetics including multiple termination mechanisms and dark reactions : part III. Primary radical generation and inhibition

Photopolymers are playing an ever more important role in diverse areas of research such as holographic data storage, hybrid photonic circuits, and solitary waves. In each of these applications, the production of primary radicals is the driving force of the polymerization processes. Therefore an understanding of the production, removal, and scavenging processes of free radicals in a photopolymer system is crucial in determining a material’s response to a given exposure. One such scavenging process is inhibition. In this paper the non-local photo-polymerization driven diffusion model is extended to more accurately model the effects of (i) time varying primary radical production, (ii) the rate of removal of photosensitizer, and (iii) inhibition. The model is presented to specifically analyze the effects of inhibition, which occur most predominantly at the start of grating growth, and comparisons between theory and experiment are performed which quantify these effects.Science Foundation IrelandIrish Research Council for Science, Engineering and TechnologyEnterprise Irelandpe, la, sp, ke, ab, is, en - kpw17/11/1

T-cell depletion of allogeneic bone marrow using anti-αβTCR monoclonal antibody: Prevention of graft-versus-host disease without affecting engraftment potential in rats

Bone marrow chimerism may solve two major limitations in the transplantation of solid organs and cellular grafts: (1) the requirement for life-long immunosuppressive therapy, and (2) acute and chronic rejection. When untreated bone marrow is transplanted into major histocompatibility complex (MHC)– disparate rats, lethal graft-vs-host disease (GVHD) occurs in the majority of recipients. T-cell depletion using anti-CD3 and anti-CD5 monoclonal antibody (mAb) to avoid GVHD led to an increased occurrence of failure of engraftment. We previously identified a cellular population in mouse bone marrow that facilitates engraftment of highly purified hematopoietic stem cells (HSC) across complete MHC barriers. In light of the fact that facilitating cells have a CD8 + /CD3 + /TCR − phenotype and mostly coexpress CD5, we evaluated in this study whether T-cell depletion of rat bone marrow using anti-αβTCR mAb would retain engraftment potential yet avoid GVHD. T-cell depletion of bone marrow was performed using anti-αβTCR mAb and immunomagnetic beads. Recipients were conditioned with 1100 or 1000 cGy of total body irradiation and reconstituted with 100 × 10 6 T-cell depleted (TCD) MHC- and minor antigen-disparate bone marrow cells. Animals were monitored clinically and histologically for GVHD. Chimerism was assessed by flow cytometry. Immunomagnetic bead depletion resulted in a reduction of T cells from 1.92% ± 0.21% to 0.10% ± 0.04% of total bone marrow. T-cell depletion did not remove facilitating cells (CD8 + /αβTCR − /γδTCR − /NK3.2.3 − ) from bone marrow. Further, the engraftment potential of TCD bone marrow was not affected, as 100% of animals engrafted and high levels of donor chimerism were detectable. Animals reconstituted with TCD bone marrow showed no clinical evidence of GVHD and histology revealed none to minimal changes, whereas recipients transplanted with untreated bone marrow succumbed to severe lethal GVHD. T-cell depletion using anti-αβTCR mAb and immunomagnetic beads selectively removes T cells from the bone marrow graft while sparing facilitating cells that are required for engraftment of allogeneic bone marrow across MHC barriers. Moreover, the cells required for engraftment of HSC do not produce GVHD

Analysis of the temporal effects on grating evolution in photopolymer

The nonlocal polymerization driven diffusion model is used to describe holographic grating formation in acrylamidebased photopolymer. The free radical chain polymerization process results in polymer being generated nonlocal both in space and time to the point of chain initiation. A Gaussian spatial material response function and an exponential temporal material response function are used to account for these effects. In this paper we firstly examine the nature of the temporal evolution of grating formation for short recording periods. It is shown that in this case, temporal effects become most notable and the inclusion of the nonlocal temporal response function is shown to be necessary to accurately describe the process. In particular, brief post exposure self-amplification of the refractive index modulation is noted. This is attributed to continued chain growth for a brief period after exposure. Following this a slight decay in the grating amplitude also occurs. This we believe is due to the continued diffusion of monomer after exposure. Since the sinusoidal recording pattern generates a monomer concentration gradient during the recording process monomer diffusion occurs both during and after exposure. The evolution of the refractive index modulation is determined by the respective refractive index values of the recording material components. From independent measurements it is noted that the refractive index value of the monomer is slightly less than that of the background material. Therefore as monomer diffuses back into the dark regions, a reduction in overall refractive index modulation occurs. Volume changes occurring within the material also affect the nature of grating evolution. To model these effects we employ a free volume concept. Due to the fact that the covalent single carbon bond in the polymer is up to 50% shorter than the van der Waals bond in the liquid monomer state, free volume is created when monomer is converted to polymer. For each bond conversion we assume a hole is generated which then collapses at some characteristic rate constant. Incorporating each of these effects into our model, the model is then solved using a Finite-Difference Time- Domain method (FDTD). The Lorentz-Lorenz relation is used to determine the overall evolution refractive index modulation and the corresponding diffraction efficiency of the resulting grating is calculated using Rigorous Coupled Wave Analysis (RCWA). Fits are then carried out to experimental data for 1 second exposures. Good quality fits are achieved and material parameters extracted. Monomer diffusion rates are determined to be of the order of D ~ 10-10 cm2/s and the time constant of the nonlocal material temporal response function being of the order of τn ~ 10-2s. Material shrinkage occurring over these recording periods is also determined.Support of enterprise Ireland and Science Foundation through the Research Innovation Fund, the Basic Research Program and the Research Frontiers Program and of the Irish Research Council for Science, Engineering and Technology

Temporal response and first order volume changes during grating formation in photopolymers

We examine the evolution of the refractive index modulation when recording gratings in an acrylamide based photopolymer. A nonlocal diffusion model is used to predict theoretically the grating evolution. The model has been developed to account for both nonlocal spatial and temporal effects in the medium, which can be attributed to polymer chain growth. Previously it was assumed that the temporal effect of chain growth could be neglected. However, temporal effects due to chain growth and monomer diffusion are shown to be significant, particularly over short recording periods where dark field amplification is observed. The diffusion model is solved using a finite-difference technique to predict the evolution of the monomer and polymer concentrations throughout grating recording. Using independently measured refractive index values for each component of the recording medium, the Lorentz-Lorenz relation is used to determine the corresponding refractive index modulation. The corresponding diffraction efficiency is then determined using rigorous coupled wave analysis. The diffraction efficiency curves are presented for gratings recorded using short exposure times, monitored in real time, both during and after recording. The effect of volume shrinkage of polymer on grating evolution is also examined. Both the nonlocal temporal response of the material and monomer diffusion are shown to influence refractive index modulation postexposure.Science Foundation IrelandIrish Research Council for Science, Engineering and TechnologyEnterprise IrelandIreland Canada University Foundation (ICUF)pe, al, sp, ke, ab, st, en - kpw1/12/1

DOG1 overexpression is associated with mismatch repair deficiency and BRAF mutations but unrelated to cancer progression in colorectal cancer

Introduction. The transmembrane channel protein DOG1 (Discovered on GIST1) is normally expressed in the gastrointestinal interstitial cells of Cajal and also in gastrointestinal stroma tumors arising from these cells. However, there is also evidence for a relevant role of DOG1 expression in colorectal cancers. This study was undertaken to search for associations between DOG1 expression and colon cancer phenotype and key molecular alterations. Methods. A tissue microarray containing samples from more than 1,800 colorectal cancer patients was analyzed by immunohistochemistry. Results. DOG1 immunostaining was detected in 503 (30.2%) of 1,666 analyzable colorectal cancers and considered weak in 360 (21.6%), moderate in 78 (4.7%), and strong in 65 (3.9%). Strong DOG1 immunostaining was associated with advanced pT stage (p=0.0367) and nodal metastases (p=0.0145) but these associations were not retained in subgroups of 1,135 mismatch repair proficient and 86 mismatch repair deficient tumors. DOG1 positivity was significantly linked to several molecular tumor features including mismatch repair deficiency (p=0.0034), BRAF mutations (p<0.0001), nuclear p53 accumulation (p=0.0157), and PD-L1 expression (p=0.0199) but unrelated to KRAS mutations and the density of tumor infiltrating CD8 positive lymphocytes. Conclusion. Elevated DOG1 expression is frequent in colorectal cancer and significantly linked to important molecular alterations. However, DOG1 overexpression is largely unrelated to histopathological parameters of cancer aggressiveness and may thus not serve as a prognostic parameter for this tumor entity