Cellular immunotherapy has proven to be effective in the treatment of hematological cancers by donor lymphocyte infusion after allogeneic hematopoietic stem cell transplantation and more recently by ...targeted therapy with chimeric antigen or T-cell receptor-engineered T cells. However, dependent on the tissue distribution of the antigens that are targeted, anti-tumor responses can be accompanied by undesired side effects. Therefore, detailed tissue distribution analysis is essential to estimate potential efficacy and toxicity of candidate targets for immunotherapy of hematological malignancies. We performed microarray gene expression analysis of hematological malignancies of different origins, healthy hematopoietic cells and various non-hematopoietic cell types from organs that are often targeted in detrimental immune responses after allogeneic stem cell transplantation leading to graft-versus-host disease. Non-hematopoietic cells were also cultured in the presence of IFN-γ to analyze gene expression under inflammatory circumstances. Gene expression was investigated by Illumina HT12.0 microarrays and quality control analysis was performed to confirm the cell-type origin and exclude contamination of non-hematopoietic cell samples with peripheral blood cells. Microarray data were validated by quantitative RT-PCR showing strong correlations between both platforms. Detailed gene expression profiles were generated for various minor histocompatibility antigens and B-cell surface antigens to illustrate the value of the microarray dataset to estimate efficacy and toxicity of candidate targets for immunotherapy. In conclusion, our microarray database provides a relevant platform to analyze and select candidate antigens with hematopoietic (lineage)-restricted expression as potential targets for immunotherapy of hematological cancers.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Belatacept, a modified form of CTLA-Ig that blocks CD28-mediated co-stimulation of T cells, is an immune-suppressant that can be used as an alternative to calcineurin inhibitors (CNIs). In kidney ...transplant recipients, belatacept has been associated with improved renal function and reduced cardiovascular toxicity. Monocytes as well as T-lymphocytes play causal roles in the pathophysiology of atherosclerotic disease. We hypothesized that the beneficial impact of the use of belatacept over CNIs on cardiovascular risk could be partly explained by the impact of belatacept therapy on these circulating leukocytes. Hence, we phenotyped circulating leukocytes in transplanted patients with a stable renal function that were randomized between either continuation of CNI or conversion to belatacept in two international studies in which we participated. In 41 patients, we found that belatacept-treated patients consistently showed lower numbers of B-lymphocytes, T-lymphocytes as well as CD14-negative monocytes (CD14NM), especially in non-diabetic patients. Our observation that this decrease was associated to plasma concentrations of TNFα is consistent with a model where CD14NM-production of TNFα is diminished by belatacept-treatment, due to effects on the antigen-presenting cell compartment.
Chronic renal allograft rejection; pathophysiologic considerations. Chronic rejection is currently the most prevalent cause of renal transplant failure. Clinically, chronic rejection presents by ...chronic transplant dysfunction, characterized by a slow loss of function, often in combination with proteinuria and hypertension. The histopathology is not specific in most cases but transplant glomerulopathy and multilayering of the peritubular capillaries are highly characteristic. Several risk factors have been identified such as young recipient age, black race, presensitization, histoincompatability, and acute rejection episodes, especially vascular rejection episodes and rejections that occur late after transplantation. Chronic rejection develops in grafts that undergo intermittent or persistent damage from cellular and humoral responses resulting from indirect recognition of alloantigens. Progression factors such as advanced donor age, renal dysfunction, hypertension, proteinuria, hyperlipidemia, and smoking accelerate deterioration of renal function. At the tissue level, senescence conditioned by ischemia/reperfusion (I/R) may contribute to the development of chronic allograft nephropathy (CAN). The most effective option to prevent renal failure from chronic rejection is to avoid graft injury from both immune and nonimmune mechanism together with nonnephrotoxic maintenance immunosuppression.
The optimal location and configuration of wind farms in a large region is important information for policy makers, electricity system planners and wind farm developers. The model developed in this ...paper uses wind resource data, population data and transmission line locations to find the configuration that produces electricity at minimum cost. Several economic and regulatory scenarios were used to demonstrate the importance of each factor in siting optimally siting wind farms. We demonstrate how gradient based optimization could be applied to discover optimal wind farm location and size. Although the use of gradient based optimization makes the model sensitive to local minima, numerical smoothing is used to reduce this sensitivity.
► Developed a model to optimally place wind farms within a ∼850 km2 region. ► The method uses population density, transmission lines and the wind resource. ► Applies gradient based optimization with numerical smoothing. ► The model shows transmission location has similar impact as wind resource. ► Small increases in the minimum turbine offset distance increases wind energy cost.
Sleep problems are common in adolescents and can have a negative impact on daily functioning and quality of life; therefore recognition of sleep problems is important. The PROMIS (Patient-Reported ...Outcomes Information System) Sleep Disturbance (SD) and Sleep Related Impairment (SRI) items banks are internationally used, well-validated instruments developed for and tested in adults. This study evaluates the content validity of the self- and proxy versions of the PROMIS-SD and the PROMIS-SRI in adolescents.
Experts (n = 6), adolescents (n = 24, 12-18 years) and their parents (n = 7) commented on the relevance and comprehensibility of the item banks.
Experts considered all items relevant, only a few items were found irrelevant by adolescents and parents. The majority of items were comprehensible. The ability of parents to report on their adolescent's sleep was limited.
The PROMIS-SD and PROMIS-SRI have adequate content validity in adolescents. Considering their psychometric robustness and the possibility of Computerized Adaptive Testing, which is efficient as well as patient-friendly, these item banks could prove very useful in the evaluation of adolescent sleep. The validity of the proxy scales, however, is limited considering the difficulties reported by the parents. Further psychometric evaluation of these scales in adolescents is required.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Study Objectives
Children often experience sleep problems, with a negative impact on mood, behavior, cognitive function, and other aspects of mental and physical health. Accelerometers are ...widely used to assess sleep, but general reference values for healthy children do not yet exist. The aim of this meta-analysis was to determine mean values for wake after sleep onset (WASO), sleep efficiency (SE), total sleep time (TST) and sleep onset latency (SOL), and to determine the effect of child and accelerometer-characteristics.
Methods
A search included studies with healthy children, 0–18 years, reporting WASO, SE, TST, and/or SOL, calculated with the Sadeh algorithm. Meta-analyses with random effects produced pooled estimate means per outcome. Meta-regression analyses determined the effect of age, sex, placement site and accelerometer type.
Results
Eighty-three studies (9,068 participants) were included. Pooled means were 63 min (95% CI 57 to 69) for WASO, 88% (95% CI 87 to 89) for SE, 477 min (95% CI 464 to 491) for TST and 19 min (95% CI 17 to 22) for SOL. Heterogeneity was high (95%–99%). TST decreased with age and there was an age-effect on SOL. SE differed between wrist and ankle (used in age 0–24 months) placement, and between piezoelectric and MEMS-type accelerometers. No differences were found between boys and girls, although this number of studies was small.
Conclusions
We found differences in almost all investigated outcomes and heterogeneity was high. Therefore, we advise to use a study-specific control sample until more robust reference values are available. Future research should narrow the methodological heterogeneity and produce larger datasets, needed to establish these reference values.
In the present study, the effect of weather on maize yields in northern China was examined using data from 10 districts in Inner Mongolia and two in Shaanxi province. A regression model with a ...flexible functional form was specified on the basis of agronomic considerations. Explanatory variables included in the model were seasonal growing degree days, precipitation, technological change (e.g. adoption of new crop varieties, improved equipment, better management, etc.) and dummy variables to account for regional fixed effects. Results indicated that a fractional polynomial model in growing degree days could explain variability in maize yields better than a linear or quadratic model. Growing degree days, precipitation in July, August and September, and technological changes were important determinants of maize yields. The results could be used to predict potential maize yields under future climate change scenarios, to construct financial weather products and for policy makers to incentivize technological changes and construction of infrastructure (e.g. irrigation works) that facilitate adaptation to climate change in the agricultural sector.
Acute cellular rejection (ACR) occurs in 10% of renal allograft recipients and is characterized by leukocyte infiltration as observed in needle biopsies. ACR onset is subject to several risk factors, ...including delayed graft function (DGF). As the impact of DGF on the etiology of ACR remains unclear, this study analyzed the association between presence of leukocyte subsets and ACR onset, in DCD kidney biopsies with extensive DGF following transplantation. Immunohistochemical analysis of protocol biopsies taken 10 days after kidney transplantation revealed that patients with high levels of renal CD163+ macrophages have a decreased risk (OR = 0.021, P = 0.008) for ACR in the first 6 months after transplantation. In pre-transplant biopsies of a comparable DCD cohort, with >80% DGF, presence of donor CD163+ macrophages showed no effect on ACR risk. Therefore, leukocyte infiltrate present during the inflammatory response at the time of DGF may contain anti-inflammatory macrophages that exert a protective effect against ACR development.
•Infiltrating leukocyte subsets characterize day 10 protocol biopsies of DCD kidney transplants.•Increased numbers of CD163 macrophages in these day 10 biopsies reduce the risk for subsequent acute cellular rejection•Presence of donor CD163 macrophages in DCD pre-transplant renal biopsies does not predict risk for acute cellular rejection
In general, humoral immune responses depend critically upon T cell help. In transplantation, prevention or treatment of humoral rejection therefore require drugs that ideally inhibit both B cell and ...T helper cell activity. Here, we studied the effects of commonly used immunosuppressive drugs tacrolimus, cyclosporin, mycophenolic acid (MPA) and rapamycin on T cell helper activity and on T cell-dependent B cell responses. T cells were activated polyclonally in the presence of immunosuppressive drugs in order to analyse the effect of these drugs on T cell proliferation, co-stimulatory ligand expression and cytokines. The impact of immunosuppressive drugs on T cell-dependent immunoglobulin production by B cells was addressed in T-B cell co-cultures. All drugs affected T cell proliferation and attenuated T cell co-stimulatory ligand (CD154 and CD278) expression when T cells were activated polyclonally. Tacrolimus, cyclosporin and rapamycin also attenuated B cell stimulatory cytokine mRNA levels in T cells. As a consequence, a decrease in immunoglobulin levels was observed in autologous T-B cell co-cultures, where T cell help is essential for immunoglobulin production. In contrast, when pre-activated T cells were used to stimulate autologous B cells, calcineurin inhibitors failed to inhibit B cell immunoglobulin production, whereas MPA and rapamycin did show inhibition. From these studies, it is evident that calcineurin inhibitors affect the humoral immune response by interfering with T helper signals, but not by targeting B cells directly. Furthermore, our studies support the necessity of intervening in T cell helper function to attenuate humoral responses.
In obesity, B cells accumulate in white adipose tissue (WAT) and produce IgG, which may contribute to the development of glucose intolerance. IgG signals by binding to Fcγ receptors (FcγR) and by ...activating the complement system. The aim of our study was to investigate whether activation of FcγR and/or complement C3 mediates the development of high-fat diet-induced glucose intolerance.
We studied mice lacking all four FcγRs (FcγRI/II/III/IV
), only the inhibitory FcγRIIb (FcγRIIb
), only the central component of the complement system C3 (C3
), and mice lacking both FcγRs and C3 (FcγRI/II/III/IV/C3
). All mouse models and wild-type controls were fed a high-fat diet (HFD) for 15 weeks to induce obesity. Glucose metabolism was assessed and adipose tissue was characterized for inflammation and adipocyte functionality.
In obese WAT of wild-type mice, B cells (+142%, P<0.01) and IgG (+128% P<0.01) were increased compared to lean WAT. Macrophages of FcγRI/II/III/IV
mice released lower levels of cytokines compared to wild-type mice upon IgG stimulation. Only C3
mice showed reduced HFD-induced weight gain as compared to controls (-18%, P<0.01). Surprisingly, FcγRI/II/III/IV
mice had deteriorated glucose tolerance (AUC +125%, P<0.001) despite reduced leukocyte number (-30%, P<0.05) in gonadal WAT (gWAT), whereas glucose tolerance and leukocytes within gWAT in the other models were unaffected compared to controls. Although IgG in gWAT was increased (+44 to +174%, P<0.05) in all mouse models lacking FcγRIIb, only FcγRI/II/III/IV/C3
mice exhibited appreciable alterations in immune cells in gWAT, for example, increased macrophages (+36%, P<0.001).
Lack of FcγRs reduces the activity of macrophages upon IgG stimulation, but neither FcγR nor C3 deficiency protects against HFD-induced glucose intolerance or reduces adipose tissue inflammation. This indicates that if obesity-induced IgG contributes to the development of glucose intolerance, this is not mediated by FcγR or complement activation.
PDF
