Epigenetic Induction of Cancer-Testis Antigens and Endogenous Retroviruses at Single-Cell Level Enhances Immune Recognition and Response in Glioma

Glioblastoma (GBM) is the most common malignant primary brain tumor and remains incurable. Previous work has shown that systemic administration of Decitabine (DAC) induces sufficient expression of cancer-testis antigens (CTA) in GBM for targeting by adoptive T-cell therapy in vivo. However, the mechanisms by which DAC enhances immunogenicity in GBM remain to be elucidated. Using New York esophageal squamous cell carcinoma 1 (NY-ESO-1) as a representative inducible CTA, we demonstrate in patient tissue, immortalized glioma cells, and primary patient-derived gliomaspheres that basal CTA expression is restricted by promoter hypermethylation in gliomas. DAC treatment of glioma cells specifically inhibits DNA methylation silencing to render NY-ESO-1 and other CTA into inducible tumor antigens at single-cell resolution. Functionally, NY-ESO-1 T-cell receptor-engineered effector cell targeting of DAC-induced antigen in primary glioma cells promotes specific and polyfunctional T-cell cytokine profiles. In addition to induction of CTA, DAC concomitantly reactivates tumor-intrinsic human endogenous retroviruses, interferon response signatures, and MHC-I. Overall, we demonstrate that DAC induces targetable tumor antigen and enhances T-cell functionality against GBM, ultimately contributing to the improvement of targeted immune therapies in glioma.SignificanceThis study dissects the tumor-intrinsic epigenetic and transcriptional mechanisms underlying enhanced T-cell functionality targeting decitabine-induced cancer-testis antigens in glioma. Our findings demonstrate concomitant induction of tumor antigens, reactivation of human endogenous retroviruses, and stimulation of interferon signaling as a mechanistic rationale to epigenetically prime human gliomas to immunotherapeutic targeting

A framework for analysing learning health systems: Are we removing the most impactful barriers?

Objective: Learning Health Systems (LHS) are one of the major computing advances in healthcare. However, no prior research has systematically analysed barriers and facilitators for LHS. This paper presents an investigation into the barriers, benefits and facilitating factors for LHS in order to create a basis for their successful implementation and adoption. Method: First, the ITPOSMO-BBF framework was developed based on the established ITPOSMO (Information, Technology, Processes, Objectives, Staffing, Management and Other factors) framework, extending it for analysing barriers, benefits and facilitators. Second, the new framework was applied to LHS. Results: We found that LHS shares similar barriers and facilitators with Electronic Health Records (EHR); in particular, most facilitator effort in implementing EHR and LHS goes towards barriers categorised as human factors, even though they were seen to carry fewer benefits. Barriers whose resolution would bring significant benefits in safety, quality and health outcomes remain. Discussion: LHS envisage constant generation of new clinical knowledge and practice based on the central role of collections of EHR. Once LHS are constructed and operational, they trigger new data streams into the EHR. So LHS and EHR have a symbiotic relationship. The implementation and adoption of EHRs has proved and continues to prove challenging and there are many lessons for LHS arising from these challenges. Conclusion: Successful adoption of LHS should take account of the framework proposed in this paper, especially with respect to its focus on removing barriers that have the most impact

How stable is the tuft structure of a mesic Drakensberg grassland under various burning regimes?

Management options to maintain the stability of Drakensberg grasslands need to incorporate their dynamic nature in response to fire. This study addressed the lack of information on the spatial and temporal changes of these grasslands at a small (tuft) scale. The basal area of every tuft in three 0.25 m2 quadrats per replicate (3) of four burning treatments was mapped over two years in a long-term burning trial using a pantograph. The extent of change in size and shape of tufts indicated the dynamic nature of these grasslands from year to year. Basal cover of Themeda triandra was high in the annual winter (62.5%) and biennial spring (50.5%) burns, lower in the five-year burn (36.1%) and low in the biennial summer burn (11.5%). The bare area in the biennial summer burn increased by 5.6%, remained the same in the annual winter, and decreased in the biennial spring (6.1%) and five-year (7.8%) burns. The disappearance of Stiburus alopecuroides from the summer burn and increase in basal cover of Tristachya leucothrix indicates a directional change in composition that is likely to be irreversible. The biennial spring burn, where the three dominant species were in a state of equilibrium, is recommended for stability.https://www.tandfonline.com/loi/tarf202021-11-18hj2021Plant Production and Soil Scienc

The population dynamics of four grass species in relation to burning in the KwaZulu-Natal Drakensberg

Marked tillers of Heteropogon contortus, Trachypogon spicatus, Tristachya leucothrix and Harpochloa falx were sampled regularly over a two-year period in Highland Sourveld burnt annually in winter and biennially in spring. Parameters recorded were height of shoot apex, tiller mass, number of new lateral tillers and time of flowering. Monitoring of marked tillers before and after each burn enabled the life history of populations of tillers to be followed. In all species investigated, flowering was found to be of minimal importance with most tillers remaining vegetative until death. Shoot apices remained close to the soil surface (<20 mm) enabling them to survive frequentburns. All species exhibited smooth survivorship curves, suggesting that dramatic fluctuations in climate and severe defoliation, as by fire, had little impact on mortality. The differential response of the four grass species was explained by their different reproductive capacities and reproductive rates. The predicted responses to fire regime were verified by changes that took place at the study area from 1981 to 2019, showing the importance of applying appropriate burning regimes to maintain the bud bank. A biennial spring burn was best for maintaining these important grass species at current levels of abundance in the KwaZulu-Natal Drakensberg. Keywords: bud banks, Leslie matrix, mortality, survivorshi

Frequent burning maintained a stable grassland over four decades in the Drakensberg, South Africa

The mesic montane grasslands of the uKhahlamba-Drakensberg, which produce cured flammable fuel, have evolved under and are sustained by recurrent fires. The Brotherton burning trial (12 replicated treatments) was established at Cathedral Peak (1 890 m asl) in 1980 to understand how burn season and frequency control the composition and diversity of the montane catchment grassland. Multivariate methods were used to examine the long-term (almost 40 years). compositional stability under different burning regimes. The species composition deviated steadily and markedly from the initial state (Bray–Curtis dissimilarity) by 43.4 ± 9.32% with quinquennial burning (alternating autumn/spring) and by 64.6 ± 2.24% with attempted fire exclusion (three unplanned burns). Composition was rapidly transformed (by 53.1 ± 4.6%) by biennial summer burning (discontinued in 1991). Dominance shifted from Themeda triandra to other grasses (Stiburus alopecuroides, Tristachya leucothrix, Harpochloa falx) with biennial summer and infrequent burning. In contrast, regular dormant season burning annually or biennially (in autumn, winter, or spring) maintained a stable grassland close to the original composition (mean deviation 23.08%). Burning homogenised the composition, overriding the initial extant small-scale spatial variation. Results support the current practice to burn biennially in the dormant season to maintain stable grassland in the Drakensberg catchments. Keywords: change, dominance, montane, species composition, stabilit

The value of rested sourveld in a communal grazing area in the Eastern Cape, South Africa

The potential for forage accumulated during periodic long rests to provide valuable winter grazing for livestock in heavily stocked communal rangelands in sourveld was assessed. In a continuously-grazed commonage at Ntshiqo in the Eastern Cape, South Africa, we measured seasonal patterns of biomass accumulation and forage quality under a short season rest (October–January), a full summer rest (October–June), and an extended year rest (June 2014–October 2015). Forage quality was expected to decline with increasing biomass accumulation. The full seasonrest produced twice as much (almost 1 ton ha−1) biomass than the short season rest. Up to 1.5 tons ha−1 more forage accumulated in the exclosures in the extended year rest, compared with the surrounding grazed grassland, but about 15% of the standing dry matter was lost through frost and senescence from the rested areas during winter. Forage quality (crude protein, phosphorus) declined from summer to winter and was similar in all rested and grazed areas, except for 4% higher acid detergent fibre (ADF) for the full- versus the short-summer rest. For commonage insourveld, periodic full season rests (spring to autumn), followed by winter grazing with a protein lick and a spring burn, are recommended. Keywords: biomass, forage quality, protein lick, winter utilisatio