Dual IGF1R/IR inhibitors in combination with GD2-CAR T-cells display a potent anti-tumor activity in diffuse midline glioma H3K27M-mutant

BackgroundDiffuse midline gliomas (DMG) H3K27M-mutant, including diffuse intrinsic pontine glioma (DIPG), are pediatric brain tumors associated with grim prognosis. Although GD2-CAR T-cells demonstrated significant anti-tumor activity against DMG H3K27M-mutant in vivo, a multimodal approach may be needed to more effectively treat patients. We investigated GD2 expression in DMG/DIPG and other pediatric high-grade gliomas (pHGG) and sought to identify chemical compounds that would enhance GD2-CAR T-cell anti-tumor efficacy.MethodsImmunohistochemistry in tumor tissue samples and immunofluorescence in primary patient-derived cell lines were performed to study GD2 expression. We developed a high-throughput cell-based assay to screen 42 kinase inhibitors in combination with GD2-CAR T-cells. Cell viability, western blots, flow-cytometry, real time PCR experiments, DIPG 3D culture models, and orthotopic xenograft model were applied to investigate the effect of selected compounds on DIPG cell death and CAR T-cell function.ResultsGD2 was heterogeneously, but widely, expressed in the tissue tested, while its expression was homogeneous and restricted to DMG/DIPG H3K27M-mutant cell lines. We identified dual IGF1R/IR antagonists, BMS-754807 and linsitinib, able to inhibit tumor cell viability at concentrations that do not affect CAR T-cells. Linsitinib, but not BMS-754807, decreases activation/exhaustion of GD2-CAR T-cells and increases their central memory profile. The enhanced anti-tumor activity of linsitinib/GD2-CAR T-cell combination was confirmed in DIPG models in vitro, ex vivo, and in vivo.ConclusionOur study supports the development of IGF1R/IR inhibitors to be used in combination with GD2-CAR T-cells for treating patients affected by DMG/DIPG and, potentially, by pHGG.     

Discriminative Aspects of SF-36 and QQL-EPM Related to Asthma Control

Aim. To study any discriminative properties of SF-36 and QQL-EPM in stable and non-controlled moderate asthmatic patients. Methods. A total of 63 asthmatic patients were assessed regarding asthma symptoms, FEV1 % predicted value, PEF, ED visits and hospitalizations, QQL-EPM and SF-36 questionnaires. Results. QQL-EPM highlighted significance in all domains to distinguish stable from non-controlled patients (p = 0.0001) while SF-36 was only significant in 3 of its 7 domains (p = 0.009). Conclusion. The study showed that the specific quality of life questionnaire for asthma (QQL-EPM) demonstrates better discriminative properties that characterize asthma control when compared with the more generic SF-36 questionnaire.     

Validation of the Sexual Inhibition/Sexual Excitation Scales (SIS/SES) in Italy: Assessing Gender and Age Differences of Sexual Functioning

The Sexual Inhibition Scales and Sexual Excitation Scales (Janssen et al., 2002a), based on the dual control model by Bancroft and Janssen (2000), are part of a 45-item self-report questionnaire evaluating individual tendencies to sexual inhibition or excitation according to three factors: two inhibition factors, SIS1, threat of performance failure, and SIS2, threat of performance consequences, and one excitation factor, SES. In this paper, we aimed to validate and explore psychometric properties of the SIS/SES in a sample of 2260 Italian men and women aged 18 to 75 years. Confirmatory factor analyses showed that the three-factor structure proposed in the original version of the scales fit with our sample. Moreover, our data confirmed the results of the original validation sample: Women scored higher on the SIS and lower on the SES than men did, but no significant differences appeared in the factor scores by age group, except for a gender × age interaction, where younger women had higher SIS2 scores. The SIS/SES appeared to be an effective, appropriate cross-cultural measurement of human sexuality in Italian samples, also shedding light on sexual arousal differences in women and men in our country. We also discuss clinical and therapeutic aspects.

     

Internal patterned injuries in trauma

Patterned bruising of the internal organs is unusual. In these cases a cutaneous pattern of bruising is not observed but the underlying tissue may show unusual injuries that may even be recognizable as a tramline pattern. We report the suicide of a 23-year-old man by jumping off a bridge. At autopsy, an unusual finding was “tramline” bruising of the right liver lobe. The “blunt objects” that inflicted the bruising were determined to be the right ribs which were pushed against the liver capsule as a consequence of the extensive thoracic and vertebral trauma after a fall from a height with intermediate impact.     

A mixture of pesticides at environmental concentrations induces oxidative stress and cholinergic effects in the neotropical fish Rhamdia quelen

The insecticides imidacloprid (IMI), a neonicotinoid, and propoxur (PRO), an N-methylcarbamate compound, are pesticides widely used throughout the world. Although they are not used together to combat pests, both are often found in freshwater near agricultural areas. Thereby, the goal of this study was to evaluate the additive effects of IMI and PRO mixtures at environmental concentrations in relation to isolated compounds on Rhamdia quelen, a neotropical fish. The fish was exposed to IMI (0.11 µg/L), PRO (0.039 µg/L), or Mix (0.11 µg/L IMI plus 0.039 µg/L PRO) during 96 h. Glutathione S-transferase (GST), superoxide dismutase (SOD), catalase (CAT), acetylcholinesterase (AChE) activities were determined. To verify oxidative damage thiobarbituric acid reactive substances (TBARS), protein carbonyl (PC), reactive oxygen species contents (ROS), antioxidant capacity against peroxides (ACAP) were determined in gills, liver, brain and muscle. The results shows that a mixture of these pesticides at environmental concentrations inhibited acetylcholinesterase activity in the brain and induced oxidative damage in all analyzed tissues. These results reinforce the hypothesis that mixture of contaminants present in environment could induce additive or synergistic effects on fish species.