In preclinical models of glioblastoma, antigen escape variants can lead to tumor recurrence after treatment with CAR T cells that are redirected to single tumor antigens. Given the heterogeneous ...expression of antigens on glioblastomas, we hypothesized that a bispecific CAR molecule would mitigate antigen escape and improve the antitumor activity of T cells. Here, we created a CAR that joins a HER2-binding scFv and an IL13Rα2-binding IL-13 mutein to make a tandem CAR exodomain (TanCAR) and a CD28.ζ endodomain. We determined that patient TanCAR T cells showed distinct binding to HER2 or IL13Rα2 and had the capability to lyse autologous glioblastoma. TanCAR T cells exhibited activation dynamics that were comparable to those of single CAR T cells upon encounter of HER2 or IL13Rα2. We observed that TanCARs engaged HER2 and IL13Rα2 simultaneously by inducing HER2-IL13Rα2 heterodimers, which promoted superadditive T cell activation when both antigens were encountered concurrently. TanCAR T cell activity was more sustained but not more exhaustible than that of T cells that coexpressed a HER2 CAR and an IL13Rα2 CAR, T cells with a unispecific CAR, or a pooled product. In a murine glioblastoma model, TanCAR T cells mitigated antigen escape, displayed enhanced antitumor efficacy, and improved animal survival. Thus, TanCAR T cells show therapeutic potential to improve glioblastoma control by coengaging HER2 and IL13Rα2 in an augmented, bivalent immune synapse that enhances T cell functionality and reduces antigen escape.
Abstract
Medulloblastoma (MB) is the most common brain tumor of childhood. Current therapies are toxic and often not curative that necessitates development of targeted immunotherapy. However, little ...is known about immunobiology of this tumor. In this study, we show that MB cells in 9 of 20 primary tumors express CD1d, an antigen-presenting molecule for Natural Killer T cells (NKTs). Quantitative RT-PCR analysis of 61 primary tumors revealed a high level of CD1d mRNA expression in a molecular subgroup characterized by overactivation of Sonic Hedgehog (SHH) oncogene. CD1d-positive MB cells cross-presented glycolipid antigens to activate NKT-cell cytotoxicity. Intracranial injection of human NKTs resulted in regression of orthotopic MB xenografts in NOD/SCID mice. Importantly, the numbers and functional properties of peripheral blood type-I NKTs were preserved in MB patients. Therefore, CD1d is expressed on tumor cells in a subset of MB patients and represents a novel target for immunotherapy of this brain tumor.
Comparative study of clonidine Ahmed Nabil Ibrahim; Manal Mohamed Kamal; Azza Lotfy
Egyptian journal of anaesthesia,
01/2016, Volume:
32, Issue:
1
Journal Article
Peer reviewed
Open access
Background: Laparoscopic surgical procedures have various benefits to the patient in terms of decreased tissue damage, early ambulation, decreased hospital stay and reduced analgesic needs. ...Pneumoperitoneum with carbon dioxide (CO2) leads to stimulation of the sympathetic nervous system which can be a risk factor in patients with cardiovascular diseases. Moreover, reverse Trendelenburg position affects homeostasis in laparoscopic surgeries. In this study, we compared the efficacy of clonidine (which is α2 adrenergic agonist) versus esmolol (which is ultra short acting cardio-selective β1-receptor antagonist) on the hemodynamic response during laparoscopic cholecystectomy. Materials and methods: A total of 60 patients scheduled to undergo laparoscopic cholecystectomy were randomly assigned into two groups: Group C: received 2 μg/kg of clonidine diluted in 20 ml normal saline, given with slow intravenous infusion over 10 min just before induction of GA and Group E: received 1.5 mg/kg of esmolol as a loading dose over a period of 5 min just before induction of GA followed by 10 μg/kg/min as a maintenance dose throughout the procedure. No hypnotic medication was given on the evening before surgery. Systolic, diastolic, mean arterial blood pressures and heart rate were recorded at (1) baseline, (2) three minutes after endotracheal intubation, (3) before pneumoperitoneum, (4) fifteen minutes after pneumoperitoneum, (5) thirty minutes after pneumoperitoneum, (6) five minutes after release of CO2 and (7) five minutes after extubation. Degree of sedation according to Ramsay sedation score was assessed 15 min after reaching PACU. Results: Both groups were similar with respect to demographic data. Clonidine group showed more stability in hemodynamic responses than esmolol group in all hemodynamic variables but with more postoperative sedation. Conclusion: This study concluded that clonidine and esmolol provide hemodynamic stability in laparoscopic cholecystectomy but clonidine provides more stability with postoperative sedation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Glioblastoma (GBM) is the most common primary brain cancer in adults and is virtually incurable. Recent studies have shown that cytomegalovirus (CMV) is present in majority of GBMs. To evaluate ...whether the CMV antigens pp65 and IE1, which are expressed in GBMs, could be targeted by CMV-specific T cells, we measured the frequency of T cells targeting pp65 and IE1 in the peripheral blood of a cohort of 11 sequentially diagnosed CMV-seropositive GBM patients, and evaluated whether it was feasible to expand autologous CMV-specific T cells for future clinical studies. All 11 CMV-seropositive GBM patients had T cells specific for pp65 and IE1 in their peripheral blood assessed by IFNγ enzyme-linked immunospot assay. However, the precursor frequency of pp65-specific T cells was decreased in comparison with healthy donors (P=0.001). We successfully reactivated and expanded CMV-specific T cells from 6 out of 6 GBM patients using antigen-presenting cells transduced with an adenoviral vector encoding pp65 and IE1. CMV-specific T-cell lines contained CD4 as well as CD8 T cells, recognized pp65 and IE1 targets and killed CMV-infected autologous GBM cells. Infusion of such CMV-specific T-cell lines may extend the benefits of T-cell therapy to patients with CMV GBMs.
The purpose of this research is to examine the impact of electronic human resources management practices (E-HRM) across the dimensions represented in the (E-Recruitment, E-Selection, E-Training, ...E-Performance appraisal, E-Communication, and E-Compensation) on Human Resources Management Service Quality (HRMSQ) across the dimensions represented in (HR Strategic services, HR Supportive services, HR Executive (Administrative) services, and HR Change-related services). This research was conducted in the Fast-Moving Consumer Goods (FMCG) sector in the multinational companies in Egypt represented by all users of the E-HRM system at PepsiCo Egypt. Informal face-to-face structure interviews were first conducted in one of the companies of the FMCG sector that implement the E-HRM system. The research used questionnaire forms that consisted of 53 items and was distributed to 323 PepsiCo employees in Egypt who use the company E-HRM system. Descriptive analyses were then conducted to examine the correlation coefficients between variables of the research and testing hypotheses. The results revealed that there is a statistically significant impact of the dimensions of E-HRM practices on HRMSQ cross the dimensions represented in (HR Strategic services, HR Supportive services, HR Executive (Administrative) services, and HR Change-related services). It was also determined that there is a difference in employee’s perception towards the E-HRM Practices variable according to the demographic variables (age, educational qualifications, years of experiences, and job title). Finally, it revealed that there is a difference in employees’ perception towards the HRMSQ variable according to the demographic variables (age, educational qualifications, years of experiences, and job title).
PWM controlled rectifiers can efficiently and economically be employed in low and medium power applications of dc drives and in front-end converters of rectifier–inverter systems while maintaining ...the advantages of design simplicity and operation reliability of naturally commutated schemes. Due to the high dc voltage that is produced which is greater than the peak voltage of the utility supply, the ac–dc buck-boost converter is especially suited as a front-end power source in variable-speed drive systems to convert the utility supply voltage into a variable dc link voltage where a single-phase or a three-phase utilities power supply is available. In this paper, the dynamic model and steady state equivalent circuit of a single-phase ac–dc buck-boost converter fed dc motor with uniform PWM control is presented. The waveforms of voltage and current, the input and output characteristics of the converter are discussed and verified. Measured, computed and simulated results are shown to be very close and the model is proved to be efficient and accurate.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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