T Cells Redirected to EphA2 for the Immunotherapy of Glioblastoma

Outcomes for patients with glioblastoma (GBM) remain poor despite aggressive multimodal therapy. Immunotherapy with genetically modified T cells expressing chimeric antigen receptors (CARs) targeting interleukin (IL)-13Rα2, epidermal growth factor receptor variant III (EGFRvIII), or human epidermal growth factor receptor 2 (HER2) has shown promise for the treatment of gliomas in preclinical models and in a clinical study (IL-13Rα2). However, targeting IL-13Rα2 and EGFRvIII is associated with the development of antigen loss variants, and there are safety concerns with targeting HER2. Erythropoietin-producing hepatocellular carcinoma A2 (EphA2) has emerged as an attractive target for the immunotherapy of GBM as it is overexpressed in glioma and promotes its malignant phenotype. To generate EphA2-specific T cells, we constructed an EphA2-specific CAR with a CD28-ζ endodomain. EphA2-specific T cells recognized EphA2-positive glioma cells as judged by interferon-γ (IFN-γ) and IL-2 production and tumor cell killing. In addition, EphA2-specific T cells had potent activity against human glioma-initiating cells preventing neurosphere formation and destroying intact neurospheres in coculture assays. Adoptive transfer of EphA2-specific T cells resulted in the regression of glioma xenografts in severe combined immunodeficiency (SCID) mice and a significant survival advantage in comparison to untreated mice and mice treated with nontransduced T cells. Thus, EphA2-specific T-cell immunotherapy may be a promising approach for the treatment of EphA2-positive GBM.     

State of the art and recommendationsKangaroo mother care: application in a high‐tech environment

Since Kangaroo Mother Care (KMC) was developed in Colombia in the 1970s, two trends in clinical application emerged. In low income settings, the original KMC model is implemented. This consists of continuous (24 h/day, 7 days/week) and prolonged mother/parent–infant skin‐to‐skin contact; early discharge with the infant in the kangaroo position; (ideally) exclusive breastfeeding; and, adequate follow‐up. In affluent settings, intermittent KMC with sessions of one or a few hours skin‐to‐skin contact for a limited period is common. As a result of the increasing evidence of the benefits of KMC for both infants and families in all intensive care settings, KMC in a high‐tech environment was chosen as the topic for the first European Conference on KMC, and the clinical implementation of the KMC model in all types of settings was discussed at the 7th International Workshop on KMC. Kangaroo Mother Care protocols in high‐tech Neonatal Intensive Care Units (NICU) should specify criteria for initiation, kangaroo position, transfer to/from KMC, transport in kangaroo position, kangaroo nutrition, parents’ role, modification of the NICU environment, performance of care in KMC, and KMC in case of infant instability. Conclusion: Implementation of the original KMC method, with continuous skin‐to‐skin contact whenever possible, is recommended for application in high‐tech environments, although scientific evaluation should continue.     

6种液煤馏分的分离及其元素分析

采用柱层析法将６种不同地区的液煤馏分进行了分离并对其中两种液煤馏分的分离产物进行了元素分析。     

Interleukin-6 predicts hypoalbuminemia, hypocholesterolemia, and mortality in hemodialysis patients

Low serum albumin and low serum cholesterol levels are among the most consistent predictors of mortality in patients with end-stage renal disease (ESRD) undergoing hemodialysis. Hypoalbuminemia is often interpreted as a marker of poor nutrition, but serum albumin and cholesterol levels can also be low as part of a cytokine-mediated acute-phase reaction to acute or chronic inflammation. Here we report the results from a 900-day prospective study designed to determine whether tumor necrosis factor-alfa (TNF-alpha) and interleukin-6 (IL-6) predict serum albumin and cholesterol levels and mortality in a group of 90 ambulatory, adult hemodialysis patients with no acute infection, hospitalization or surgery, and no known acquired immunodeficiency syndrome (AIDS), malignancy, or liver disease. Measurable levels of TNF-alpha and/or IL-6 were found in 89 of 90 patients. Significant relationships were found between TNF-alpha and IL-6 and the degree of hypoalbuminemia and dyslipoproteinemia. IL-6 was the strongest predictor of mortality in univariate and multivariate analysis, followed by age, albumin level, and body mass index (BMI). Although the cause of hypercytokinemia was not addressed in this study, the data support the view that hypoalbuminemia and hypocholesterolemia are negative acute-phase responses to inflammatory stimuli. These results suggest that efforts to identify the nature of the stimuli for cytokine production and to lower cytokine levels in hemodialysis patients might be effective in improving the survival of patients undergoing hemodialysis.     

Neonatal treatment with 192 IgG-saporin produces long-term forebrain cholinergic deficits and reduces dendritic branching and spine density of neocortical pyramidal neurons

The role of basal forebrain-derived cholinergic afferents in the development of neocortex was studied in postnatal rats. Newborn rat pups received intraventricular injections of 192 IgG-saporin. Following survival periods ranging from 2 days to 6 months, the brains were processed to document the cholinergic lesion and to examine morphological consequences. Immunocytochemistry for choline acetyltransferase (ChAT) and in situ hybridization for ChAT mRNA demonstrate a loss of approximately 75% of the cholinergic neurons in the medial septum and nucleus of the diagonal band of Broca in the basal forebrain. In situ hybridization for glutamic acid decarboxylase mRNA reveals no loss of basal forebrain GABAergic neurons. Acetylcholinesterase histochemistry demonstrates a marked reduction of the cholinergic axons in neocortex. Cholinergic axons are reduced throughout the cortical layers; this reduction is more marked in medial than in lateral cortical areas. The thickness of neocortex is reduced by approximately 10%. Retrograde labeling of layer V cortico-collicular pyramidal cells reveals a reduction in cell body size and also a reduction in numbers of branches of apical dendrites. Spine densities on apical dendrites are reduced by approximately 20-25% in 192 IgG- saporin-treated cases; no change was detected in number of spines on basal dendrites. These results indicate a developmental or maintenance role for cholinergic afferents to cerebral cortical neurons.      

Optic disc oval ness,refractive error and axial length of Hong Kong Chinese

Myopic crescent, refractive error and axial length were previously investigated in Hong Kong Chinese subjects. The myopic crescent was found to correlate with axial length and myopic refraction. In this study, three groups of Hong Kong Chinese with different degrees of myopia were assessed for optic disc ovalness, refractive error and axial length. The axial length was significantly correlated with the degree of myopia, indicating that the myopia was axial in nature. The regression line shows that 0.44 mm of axial elongation would give about one dioptre of increase in myopia. The elliptical ratio of the optic disc was defined as the maximal disc diameter divided by the minimal disc diameter. All three groups showed an oval disc with vertical axis greater and an increased ovalness for the high myopic group with an elliptical ratio from 1.11 in low myopia to 1.29 in high myopia. There is a small amount (about four degrees) of temporal rotation of this vertical oval orientation, which is independent of the amount of myopia. This result shows an association between axial elongation of the globe and optic disc ovalness, in addition to the previously described temporal myopic crescent. Therefore, in myopic subjects, a vertically oval disc may be associated with a myopic refraction rather than glaucoma.     

Artificial neural network for predicting intracranial haemorrhage in preterm neonates

Intraventricular haemorrhage (IVH) incidence is used to assess peri-/neonatal therapy, and to make intra-and inter-hospital quality assessments. Unbiased assessment is complicated by the amount of confounding factors. Is an artificial neural network (ANN) able to early and accurately forecast the occurrence of severe IVH in an individual patient? Is it superior to classic multiple logistic regression? We conducted an observational study on pre-existing routine data. Admission data were available from 890 preterm neonates (gestational age < 32 weeks, birthweight < 1500 g). Patients were randomly assigned to either a training, or a validation set (50%/50%). Using the training set data an ANN was trained. A second predictive model was developed by stepwise multiple logistic regression analysis. Using the validation set input data both models delivered estimates of the probability for severe IVH to occur in each individual patient. Receiver operating characteristic (ROC) curves were used to compare prognostic performance. The optimal ANN processed 13 input variables, whereas stepwise logistic regression analysis only identified five independent predictor variables. The area under the ROC curve was 0.935 for the ANN and 0.884 for the logistic regression model (p= 0:001). Adjusted for 95%, 90%, 85%, 80% and 75% specificity, the sensitivity of the ANN was significantly superior to that of the logistic regression model. Due to its ability to give an accurate prognosis based solely on admission data, a trained ANN qualifies as a tool for local quality control.