Epigenetic Suppression of Transgenic T-cell Receptor Expression via Gamma-Retroviral Vector Methylation in Adoptive Cell Transfer Therapy

Transgenic T-cell receptor (TCR) adoptive cell therapies recognizing tumor antigens are associated with robust initial response rates, but frequent disease relapse. This usually occurs in the setting of poor long-term persistence of cells expressing the transgenic TCR, generated using murine stem cell virus (MSCV) y-retroviral vectors. Analysis of clinical transgenic adoptive cell therapy products in vivo revealed that despite strong persistence of the transgenic TCR DNA sequence over time, its expression was profoundly decreased over time at the RNA and protein levels. Patients with the greatest degrees of expression suppression displayed significant increases in DNA methylation over time within the MSCV promoter region, as well as progressive increases in DNA methylation within the entire MSCV vector over time. These increases in vector methylation occurred independently of its integration site within the host genomes. These results have significant implications for the design of future viral-vector gene engineered adoptive cell transfer therapies

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Ocean carbon from space: Current status and priorities for the next decade

This is the final version. Available on open access from Elsevier via the DOI in this recordData availability: Data for Fig. 1a were generated from a free Scopus (https://www.scopus.com/) search of the terms "Ocean carbon satellite" (using All fields) in March 2022. Data from Fig. 1b and 1c were generated from the workshop registration and are available within the figure (participation number, geographical representation and gender split).The ocean plays a central role in modulating the Earth’s carbon cycle. Monitoring how the ocean carbon cycle is changing is fundamental to managing climate change. Satellite remote sensing is currently our best tool for viewing the ocean surface globally and systematically, at high spatial and temporal resolutions, and the past few decades have seen an exponential growth in studies utilising satellite data for ocean carbon research. Satellite-based observations must be combined with in-situ observations and models, to obtain a comprehensive view of ocean carbon pools and fluxes. To help prioritise future research in this area, a workshop was organised that assembled leading experts working on the topic, from around the world, including remote-sensing scientists, field scientists and modellers, with the goal to articulate a collective view of the current status of ocean carbon research, identify gaps in knowledge, and formulate a scientific roadmap for the next decade, with an emphasis on evaluating where satellite remote sensing may contribute. A total of 449 scientists and stakeholders participated (with balanced gender representation), from North and South America, Europe, Asia, Africa, and Oceania. Sessions targeted both inorganic and organic pools of carbon in the ocean, in both dissolved and particulate form, as well as major fluxes of carbon between reservoirs (e.g., primary production) and at interfaces (e.g., air-sea and land–ocean). Extreme events, blue carbon and carbon budgeting were also key topics discussed. Emerging priorities identified include: expanding the networks and quality of in-situ observations; improved satellite retrievals; improved uncertainty quantification; improved understanding of vertical distributions; integration with models; improved techniques to bridge spatial and temporal scales of the different data sources; and improved fundamental understanding of the ocean carbon cycle, and of the interactions among pools of carbon and light. We also report on priorities for the specific pools and fluxes studied, and highlight issues and concerns that arose during discussions, such as the need to consider the environmental impact of satellites or space activities; the role satellites can play in monitoring ocean carbon dioxide removal approaches; economic valuation of the satellite based information; to consider how satellites can contribute to monitoring cycles of other important climatically-relevant compounds and elements; to promote diversity and inclusivity in ocean carbon research; to bring together communities working on different aspects of planetary carbon; maximising use of international bodies; to follow an open science approach; to explore new and innovative ways to remotely monitor ocean carbon; and to harness quantum computing. Overall, this paper provides a comprehensive scientific roadmap for the next decade on how satellite remote sensing could help monitor the ocean carbon cycle, and its links to the other domains, such as terrestrial and atmosphere.European Space AgencySimons FoundationUK National Centre for Earth Observation (NCEO)UKRIAtlantic Meridional Transect ProgrammeSwiss National Science Foundatio

IL-15 mediated expansion of rare durable memory T cells following adoptive cellular therapy.

Background Synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) are ideal solid tumors for the development of adoptive cellular therapy (ACT) targeting NY-ESO-1, as a high frequency of tumors homogeneously express this cancer-testes antigen. Data from early phase clinical trials have shown antitumor activity after the adoptive transfer of NY-ESO-1-specific T cells. In these studies, persistence of NY-ESO-1 specific T cells is highly correlated with response to ACT, but patients often continue to have detectable transferred cells in their peripheral blood following progression.Method We performed a phase I clinical trial evaluating the safety of NY-ESO-1-specific endogenous T cells (ETC) following cyclophosphamide conditioning. Peripheral blood mononuclear cells (PBMCs) from treated patients were evaluated by flow cytometry and gene expression analysis as well as through ex vivo culture assays with and without IL-15.Results Four patients were treated in a cohort using ETC targeting NY-ESO-1 following cyclophosphamide conditioning. Treatment was well tolerated without significant toxicity, but all patients ultimately had disease progression. In two of four patients, we obtained post-treatment tumor tissue and in both, NY-ESO-1 antigen was retained despite clear detectable persisting NY-ESO-1-specific T cells in the peripheral blood. Despite a memory phenotype, these persisting cells lacked markers of proliferation or activation. However, in ex vivo culture assays, they could be induced to proliferate and kill tumor using IL-15. These results were also seen in PBMCs from two patients who received gene-engineered T-cell receptor-based products at other centers.Conclusions ETC targeting NY-ESO-1 with single-agent cyclophosphamide alone conditioning was well tolerated in patients with SS and those with MRCL. IL-15 can induce proliferation and activity in persisting NY-ESO-1-specific T cells even in patients with disease progression following ACT. These results support future work evaluating whether IL-15 could be incorporated into ACT trials post-infusion or at the time of progression

Writing More Informative Letters of Reference

Writing a meaningful and valuable letter of reference is not an easy task. Several factors influence the quality of any letter of reference. First, the accuracy and reliability of the writer's impressions and judgment depend on how well he knows the individual being described. Second, the writer's frame of reference, which is determined by the number of persons at the same level that he has worked with, will impact the context and significance of his beliefs and estimations. Third, the letter-writing skills of the person composing the letter will naturally affect the letter. To support the other components of a candidate's application, a letter of reference should provide specific examples of how an individual's behavior or attitude compares to a reference group and should assess “intangibles” that are hard to glean from a curriculum vitae or from test scores. This report offers suggestions that should help physicians write more informative letters of reference