To redirect T cells against tumor cells, T cells can be engineered ex vivo to express cancer-antigen specific T cell receptors (TCRs), generating products known as TCR-engineered T cells (TCR T). Unlike chimeric antigen receptors (CARs), TCRs recognize HLA-presented peptides derived from proteins of all cellular compartments. The use of TCR T cells for adoptive cellular therapies (ACT) has gained increased attention, especially as efforts to treat solid cancers with ACTs have intensified. In this review, we describe the differing mechanisms of T cell antigen recognition and signal transduction mediated through CARs and TCRs. We describe the classes of cancer antigens recognized by current TCR T therapies and discuss both classical and emerging pre-clinical strategies for antigen-specific TCR discovery, enhancement, and validation. Finally, we review the current landscape of clinical trials for TCR T therapy and discuss what these current results indicate for the development of future engineered TCR approaches.

Findings revealed that preadolescent differences between groups were maintained for several adjustment variables, indicating that adolescents with SB have enduring academic and attention problems and difficulties with social development (e.g., fewer friends and less influence during family interactions). For other outcomes, trajectories of adjustment levels for adolescents with SB converged on levels observed in comparison adolescents, indicating some areas of resilience. Girls with SB were at risk for increasing levels of social difficulties and negative perceptions of their physical appearance. Clinical implications are discussed.

Night work increases diabetes risk. Misalignment between the central circadian "clock" and daily behaviors, typical in night workers, impairs glucose tolerance, likely due to internal misalignment between central and peripheral circadian rhythms. Whether appropriate circadian alignment of eating can prevent internal circadian misalignment and glucose intolerance is unknown. In a 14-day circadian paradigm, we assessed glycemic control during simulated night work with either nighttime or daytime eating. Assessment of central (body temperature) and peripheral (glucose and insulin) endogenous circadian rhythms happened during constant routine protocols before and after simulated night work. Nighttime eating led to misalignment between central and peripheral (glucose) endogenous circadian rhythms and impaired glucose tolerance, whereas restricting meals to daytime prevented it. These findings offer a behavioral approach to preventing glucose intolerance in shift workers.

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BackgroundSuccessful targeting of solid tumors such as breast cancer (BC) using chimeric antigen receptor (CAR) T cells has proven challenging, largely attributed to the immunosuppressive tumor microenvironment (TME). Myeloid-derived suppressor cells (MDSCs) inhibit CAR T cell function and persistence within the breast TME. To overcome this challenge, we have developed CAR T cells targeting tumor-associated mucin 1 (MUC1) with a novel chimeric costimulatory receptor that targets tumor necrosis factor–related apoptosis-inducing ligand receptor 2 (TR2) expressed on MDSCs.MethodsThe function of the TR2.41BB costimulatory receptor was assessed by exposing non-transduced (NT) and TR2.41BB transduced T cells to recombinant TR2, after which nuclear translocation of NFκB was measured by ELISA and western blot. The cytolytic activity of CAR.MUC1/TR2.41BB T cells was measured in a 5-hour cytotoxicity assay using MUC1+ tumor cells as targets in the presence or absence of MDSCs. In vivo antitumor activity was assessed using MDSC-enriched tumor-bearing mice treated with CAR T cells with or without TR2.41BB.ResultsNuclear translocation of NFκB in response to recombinant TR2 was detected only in TR2.41BB T cells. The presence of MDSCs diminished the cytotoxic potential of CAR.MUC1 T cells against MUC1+ BC cell lines by 25%. However, TR2.41BB expression on CAR.MUC1 T cells induced MDSC apoptosis, thereby restoring the cytotoxic activity of CAR.MUC1 T cells against MUC1+ BC lines. The presence of MDSCs resulted in an approximately twofold increase in tumor growth due to enhanced angiogenesis and fibroblast accumulation compared with mice with tumor alone. Treatment of these MDSC-enriched tumors with CAR.MUC1.TR2.41BB T cells led to superior tumor cell killing and significant reduction in tumor growth (24.54±8.55 mm3) compared with CAR.MUC1 (469.79±81.46 mm3) or TR2.41BB (434.86±64.25 mm3) T cells alone. CAR.MUC1.TR2.41BB T cells also demonstrated improved T cell proliferation and persistence at the tumor site, thereby preventing metastases. We observed similar results using CAR.HER2.TR2.41BB T cells in a HER2+ BC model.ConclusionsOur findings demonstrate that CAR T cells that coexpress the TR2.4-1BB receptor exhibit superior antitumor potential against breast tumors containing immunosuppressive and tumor promoting MDSCs, resulting in TME remodeling and improved T cell proliferation at the tumor site.

BackgroundEvidence on heterogeneity in outcomes of surgical quality interventions in low-income and middle-income countries is limited. We explored factors driving performance in the Safe Surgery 2020 intervention in Tanzania’s Lake Zone to distil implementation lessons for low-resource settings.MethodsWe identified higher (n=3) and lower (n=3) performers from quantitative data on improvement from 14 safety and teamwork and communication indicators at 0 and 12 months from 10 intervention facilities, using a positive deviance framework. From 72 key informant interviews with surgical providers across facilities at 1, 6 and 12 months, we used a grounded theory approach to identify practices of higher and lower performers.ResultsPerformance experiences of higher and lower performers differed on the following themes: (1) preintervention context, (2) engagement with Safe Surgery 2020 interventions, (3) teamwork and communication orientation, (4) collective learning orientation, (5) role of leadership, and (6) perceived impact of Safe Surgery 2020 and beyond. Higher performers had a culture of teamwork which helped them capitalise on Safe Surgery 2020 to improve surgical ecosystems holistically on safety practices, teamwork and communication. Lower performers prioritised overhauling safety practices and began considering organisational cultural changes much later. Thus, while also improving, lower performers prioritised different goals and trailed higher performers on the change continuum.ConclusionFuture interventions should be tailored to facility context and invest in strengthening teamwork, communication and collective learning and facilitate leadership engagement to build a receptive climate for successful implementation of safe surgery interventions.

This modified measure of parental EE can be used in future pediatric research that focuses on precursors or outcomes of this important parenting construct.

SARS-CoV-2 RNA loads can be detected in the excreta of individuals with COVID-19 and have demonstrated positive correlations with clinical infection trends. Consequently, wastewater-based epidemiology (WBE) approaches have been implemented globally as a public health surveillance tool to monitor community-level prevalence of infections. The majority of wastewater specimens are gathered as either composite samples via automatic samplers (autosamplers) or grab samples. However, autosamplers are expensive and can be challenging to maintain in cold weather, while grab samples are particularly susceptible to temporal variation when sampling sewage directly from complex matrices outside residential buildings. Passive sampling can provide an affordable, practical, and scalable sampling system while maintaining a reproducible SARS-CoV-2 signal. In this regard, we deployed tampons as passive samplers outside of a COVID-19 isolation unit (a segregated residence hall) at a university campus from 1 February 2021–21 May 2021. Samples (n = 64) were collected 3–5 times weekly and remained within the sewer for a median duration of 24 h. SARS-CoV-2 RNA was quantified using reverse-transcription quantitative polymerase chain reaction (RT-qPCR) targeting the N1 and N2 gene fragments. We quantified the mean viral load captured per individual and the association between the daily viral load and total persons, adjusting for covariates using multivariable models to provide a baseline estimate of viral shedding. Samples were processed through two distinct laboratory pipelines on campus, yielding highly correlated N2 concentrations. Data obtained here highlight the success of passive sampling utilizing tampons to capture SARS-CoV-2 in wastewater coming from a COVID-19 isolation residence, indicating that this method can help inform building-level public health responses.