Early Changes in Tumor Perfusion from T1-Weighted Dynamic Contrast-Enhanced MRI following Neural Stem Cell-Mediated Therapy of Recurrent High-Grade Glioma Correlate with Overall Survival

Background. The aim of this study was to correlate T1-weighted dynamic contrast-enhanced MRI- (DCE-MRI-) derived perfusion parameters with overall survival of recurrent high-grade glioma patients who received neural stem cell- (NSC-) mediated enzyme/prodrug gene therapy. Methods. A total of 12 patients were included in this retrospective study. All patients were enrolled in a first-in-human study (NCT01172964) of NSC-mediated therapy for recurrent high-grade glioma. DCE-MRI data from all patients were collected and analyzed at three time points: MRI#1—day 1 postsurgery/treatment, MRI#2— day 7 ± 3 posttreatment, and MRI#3—one-month follow-up. Plasma volume (Vp), permeability (Ktr), and leakage (λtr) perfusion parameters were calculated by fitting a pharmacokinetic model to the DCE-MRI data. The contrast-enhancing (CE) volume was measured from the last dynamic phase acquired in the DCE sequence. Perfusion parameters and CE at each MRI time point were recorded along with their relative change between MRI#2 and MRI#3 (Δ32). Cox regression was used to analyze patient survival. Results. At MRI#1 and at MRI#3, none of the parameters showed a significant correlation with overall survival (OS). However, at MRI#2, CE and λtr were significantly associated with OS (p<0.05). The relative λtr and Vp from timepoint 2 to timepoint 3 (Δ32λtr and Δ32Vp) were each associated with a higher hazard ratio (p<0.05). All parameters were highly correlated, resulting in a multivariate model for OS including only CE at MRI#2 and Δ32Vp, with an R2 of 0.89. Conclusion. The change in perfusion parameter values from 1 week to 1 month following NSC-mediated therapy combined with contrast-enhancing volume may be a useful biomarker to predict overall survival in patients with recurrent high-grade glioma

The Science Performance of JWST as Characterized in Commissioning

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies.Comment: 5th version as accepted to PASP; 31 pages, 18 figures; https://iopscience.iop.org/article/10.1088/1538-3873/acb29

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Detection of the Dietary xenoglycan N-glycolylneuraminic Acid (Neu5Gc) and anti-Neu5Gc Antibodies within Reproductive Tracts of Male and Female Infertility Subjects

Objective To assess the frequency of dietary xenoglycanNeu5Gc and antibodies in males and females and its impact on fertility. Design Prospective study of semen, uterine lavage, and follicular fluid from subjects undergoing infertility evaluation or in vitro fertilization (IVF) and fertile controls. Setting University based infertility program. Participants Males (n=23) and females (n=27) undergoing semen analysis and saline infusion sonography as part of their diagnostic evaluation and 37 women undergoing IVF were compared to fertile male (n=15) and female (n=14) controls. Intervention Neu5Gc was measured by affinity purified antibody staining on Western blots, flow cytometry, and by high performance liquid chromatography. Anti-Neu5Gc antibodies were determined by ELISA. Main parameters measured Frequency and levels of Neu5Gc antigen within sperm and endometrial cells and antibodies in semen, uterine lavage, and follicular fluid. Semen quality and IVF outcomes were assessed between antigen and antibody positive and negative subjects. Results In infertile subjects, Neu5Gc was detected in 26% of sperm and 54% of endometrial cells compared to 0% in male and 0% female controls. Anti-Neu5Gc antibodies were identified in 54% of seminal fluid, 41% in uterine lavage and 43% of follicular fluid samples. There were no differences in semen parameters, oocyte quality, and embryo development in the presence or absence of Neu5Gc antigen or antibody. However, clinical pregnancy rate was significantly lower in the presence of anti-Neu5Gc antibodies intrauterine lavage (0% vs. 54.5.0%, p\u3c0.05). Conclusions Neu5Gc and directed antibodies are present in reproductive tracts of both male and female infertility subjects. Our results suggest their presence may interfere with fertility within the uterine environment

Detection of the Dietary xenoglycan N-glycolylneuraminic Acid (Neu5Gc) and anti-Neu5Gc Antibodies within Reproductive Tracts of Male and Female Infertility Subjects

Objective To assess the frequency of dietary xenoglycanNeu5Gc and antibodies in males and females and its impact on fertility. Design Prospective study of semen, uterine lavage, and follicular fluid from subjects undergoing infertility evaluation or in vitro fertilization (IVF) and fertile controls. Setting University based infertility program. Participants Males (n=23) and females (n=27) undergoing semen analysis and saline infusion sonography as part of their diagnostic evaluation and 37 women undergoing IVF were compared to fertile male (n=15) and female (n=14) controls. Intervention Neu5Gc was measured by affinity purified antibody staining on Western blots, flow cytometry, and by high performance liquid chromatography. Anti-Neu5Gc antibodies were determined by ELISA. Main parameters measured Frequency and levels of Neu5Gc antigen within sperm and endometrial cells and antibodies in semen, uterine lavage, and follicular fluid. Semen quality and IVF outcomes were assessed between antigen and antibody positive and negative subjects. Results In infertile subjects, Neu5Gc was detected in 26% of sperm and 54% of endometrial cells compared to 0% in male and 0% female controls. Anti-Neu5Gc antibodies were identified in 54% of seminal fluid, 41% in uterine lavage and 43% of follicular fluid samples. There were no differences in semen parameters, oocyte quality, and embryo development in the presence or absence of Neu5Gc antigen or antibody. However, clinical pregnancy rate was significantly lower in the presence of anti-Neu5Gc antibodies intrauterine lavage (0% vs. 54.5.0%, p\u3c0.05). Conclusions Neu5Gc and directed antibodies are present in reproductive tracts of both male and female infertility subjects. Our results suggest their presence may interfere with fertility within the uterine environment

Early Changes in Tumor Perfusion from T1-Weighted Dynamic Contrast-Enhanced MRI following Neural Stem Cell-Mediated Therapy of Recurrent High-Grade Glioma Correlate with Overall Survival

Background. The aim of this study was to correlate T1-weighted dynamic contrast-enhanced MRI- (DCE-MRI-) derived perfusion parameters with overall survival of recurrent high-grade glioma patients who received neural stem cell- (NSC-) mediated enzyme/prodrug gene therapy. Methods. A total of 12 patients were included in this retrospective study. All patients were enrolled in a first-in-human study (NCT01172964) of NSC-mediated therapy for recurrent high-grade glioma. DCE-MRI data from all patients were collected and analyzed at three time points: MRI#1—day 1 postsurgery/treatment, MRI#2— day 7 ± 3 posttreatment, and MRI#3—one-month follow-up. Plasma volume (Vp), permeability (Ktr), and leakage (λtr) perfusion parameters were calculated by fitting a pharmacokinetic model to the DCE-MRI data. The contrast-enhancing (CE) volume was measured from the last dynamic phase acquired in the DCE sequence. Perfusion parameters and CE at each MRI time point were recorded along with their relative change between MRI#2 and MRI#3 (Δ32). Cox regression was used to analyze patient survival. Results. At MRI#1 and at MRI#3, none of the parameters showed a significant correlation with overall survival (OS). However, at MRI#2, CE and λtr were significantly associated with OS (p<0.05). The relative λtr and Vp from timepoint 2 to timepoint 3 (Δ32λtr and Δ32Vp) were each associated with a higher hazard ratio (p<0.05). All parameters were highly correlated, resulting in a multivariate model for OS including only CE at MRI#2 and Δ32Vp, with an R2 of 0.89. Conclusion. The change in perfusion parameter values from 1 week to 1 month following NSC-mediated therapy combined with contrast-enhancing volume may be a useful biomarker to predict overall survival in patients with recurrent high-grade glioma

Locoregional delivery of IL-13Rα2-targeting CAR-T cells in recurrent high-grade glioma: a phase 1 trial

Chimeric antigen receptor T cell (CAR-T) therapy is an emerging strategy to improve treatment outcomes for recurrent high-grade glioma, a cancer that responds poorly to current therapies. Here we report a completed phase I trial evaluating IL-13Rα2-targeted CAR-T cells in 65 patients with recurrent high-grade glioma, the majority being recurrent glioblastoma (rGBM). Primary objectives were safety and feasibility, maximum tolerated dose/maximum feasible dose and a recommended phase 2 dose plan. Secondary objectives included overall survival, disease response, cytokine dynamics and tumor immune contexture biomarkers. This trial evolved to evaluate three routes of locoregional T cell administration (intratumoral (ICT), intraventricular (ICV) and dual ICT/ICV) and two manufacturing platforms, culminating in arm 5, which utilized dual ICT/ICV delivery and an optimized manufacturing process. Locoregional CAR-T cell administration was feasible and well tolerated, and as there were no dose-limiting toxicities across all arms, a maximum tolerated dose was not determined. Probable treatment-related grade 3+ toxicities were one grade 3 encephalopathy and one grade 3 ataxia. A clinical maximum feasible dose of 200 × 106 CAR-T cells per infusion cycle was achieved for arm 5; however, other arms either did not test or achieve this dose due to manufacturing feasibility. A recommended phase 2 dose will be refined in future studies based on data from this trial. Stable disease or better was achieved in 50% (29/58) of patients, with two partial responses, one complete response and a second complete response after additional CAR-T cycles off protocol. For rGBM, median overall survival for all patients was 7.7 months and for arm 5 was 10.2 months. Central nervous system increases in inflammatory cytokines, including IFNγ, CXCL9 and CXCL10, were associated with CAR-T cell administration and bioactivity. Pretreatment intratumoral CD3 T cell levels were positively associated with survival. These findings demonstrate that locoregional IL-13Rα2-targeted CAR-T therapy is safe with promising clinical activity in a subset of patients. ClinicalTrials.gov Identifier: NCT02208362