Search

Background We previously developed a mobile health (mHealth) app (Roadmap) to promote the resilience of family caregivers during the acute phases of care in patients undergoing hematopoietic cell transplantation (HCT). Objective This study explored users' perspectives on the uptake of Roadmap's multicomponent features and the app's utility in promoting resilience. Methods Fifteen participants were randomized to the full version of the app that included resilience-building activities and the other 15 were randomized to the control version that included a limited view of the app (i.e., without any resilience-building activities). They were instructed to use the app for 120 days. Semistructured qualitative interviews were then conducted with users as part of an ongoing, larger Roadmap study (NCT04094844). During the interview, caregiver participants were asked about their overall experiences with the app, frequency of use, features used, facilitators of and barriers to use, and their perspectives on its utility in promoting resilience. Data were professionally transcribed, coded, and categorized through content analysis. Results Interviews were conducted with 30 participants, which included 23 females and 7 males. The median age of the population was 58 years (range, 23–82). The four main themes that emerged included app use, ease of use, user experiences, and ability to foster resilience. The subthemes identified related to facilitators (convenience and not harmful), barriers (caregiver burden and being too overwhelmed during the acute phases of HCT care), resilience (optimism/positivity and self-care), and app design improvements (personalization and notifications/reminders). Conclusion The qualitative evaluation provided insights into which components were utilized and how one, or a combination of the multicomponent features, may be enhancing users' experiences. Lessons learned suggest that the Roadmap app contributed to promoting resilience during the acute phases of HCT care. Nonetheless, features that provided enhanced personalization may further improve longer-term engagement.

This study aimed to explore the influence of differences in relative skeletal maturity on performance test outcomes in elite youth soccer players from the Middle East.We integrated skeletal age and performance assessments using mixed-longitudinal data available for 199 outfield players (chronological age range, 11.7 to 17.8 yr) enrolled as academy student-athletes (annual screening range, 1 to 5 visits). Skeletal age was determined as per the Tanner-Whitehouse II protocol. Relative maturity was calculated as the difference (∆) between Tanner-Whitehouse II skeletal age minus chronological age. Performance test outcomes of interest were 10-m sprinting, 40-m sprinting, countermovement jump height, and maximal aerobic speed. Separate random-effects generalized additive models quantified differences in performance test outcomes by relative skeletal maturity. Estimated differences were deemed practically relevant based on the location of the confidence interval (95% CI) against minimal detectable change values for each performance test outcome.For 40-m sprinting, differences of +0.51 s (95% CI, +0.35 to +0.67 s) and +0.62 s (95% CI, +0.45 to +0.78 s) were practically relevant for relative maturity status of ∆ = -1.5 yr versus ∆ = +0.5 and ∆ = +1 yr, respectively. For countermovement jump height, a difference of -8 cm (95% CI, -10 to -5 cm) was practically relevant for ∆ = -1.5 yr versus ∆ = +1 yr relative maturity status comparison. Effects for 10-m sprinting and maximal aerobic speed were unclear.Integration of skeletal age and performance assessments indicated that conventional maturity status classification criteria were inconsistent to inform player development processes in our sample. Between-player differences in test performance may depend on a substantial delay in skeletal maturation (∆ ≤ -1.5 yr) and the performance outcome measure.

Applied drama refers to the use of theatrical practices in contexts such as education, therapy, or community-building. We present Robot-Mediated Applied Drama as a medium for safely exploring sensitive topics with children and propose to develop RE-Mind (short for Robots Empowering Minds): a pedagogical platform that aims to use role-playing with robots for fostering anti-bullying peer support among children. We borrow techniques from applied drama to build the human-robot interaction models used in this system. Specifically, we draw from Augusto Boal’s Forum Theatre: a theatrical exercise in which spectators of a drama are invited to become “spect-actors”. That is, they watch the performance twice; the second time, they stop the performance and change its direction and potential conclusion by suggesting different actions to the protagonist. This allows children to use the proposed system to first observe a bullying scenario between two robots, and then intervene by controlling a third robot that is a bystander to bullying, and by doing so practice their intervention strategies. Applied drama engages peers in situated learning and allows them to take reflective, participatory action. In this paper, we argue that using robots provides a buffer for participants to safely explore sensitive topics in a private setting. We present background literature to support using applied drama as an effective vehicle for learning and discuss related work on technology-based anti-bullying interventions. Finally, we define Robot-Mediated Applied Drama and discuss how social robots lend themselves well to this practice.

Aims and objectives To conduct an integrative review of the literature to understand how the incorporation of traditional therapies affect First Nations people's utilisation of palliative care services. Background First Nations peoples face many barriers related to accessing and utilising specialised health services such as palliative care. Whilst culturally appropriate care has been shown to improve these outcomes, there is little evidence regarding how this may be achieved. Design Integrative review. Methods A systematic search was conducted using electronic databases CINAHL, Joanna Briggs, Medline, Scopus, ScienceDirect InformitHealth and ProQuest between the years of 2005 - 2021 databases were searched for papers with full text available and published in English. Papers were included if they were primary-based research and focused on the topics of the use of traditional therapies in a palliative care context by First Nations persons. The Critical Appraisal Skills Programme principles were used to assess the methodological quality of the selected articles. Results Seven studies met the inclusion criteria and were included in the review. The review included six qualitative studies and one quantitative study. From these studies, five themes were identified in the literature: supporting a holistic approach, developing culturally appropriate care, conflict within a Western medical model, regulatory issues, and geographical barriers. Conclusion There is a dearth of current literature available discussing the utilization of traditional therapies in palliative care. From the literature analysed, the benefits of including traditional therapies are overall positive, however, there are barriers including conflict with the Western model of medicine and regulation. More research is required in the provision of traditional therapies in palliative care. Relevance to clinical practice The incorporation of traditional medicines within a palliative care setting could help nurses provide holistic and culturally appropriate care, especially in rural and remote areas where they make up the majority of the healthcare force.

This article reports on the development of a new transition service in Norfolk; ‘Preparing for Adult Life’ (PfAL), led by Adult Services (ASSD). It identifies the strategies that were used to devel...

PURPOSE To provide the first scrutiny of adult height prediction protocols based on automated Greulich-Pyle and Tanner-Whitehouse (TW) skeletal ages applied to elite youth soccer players from the Middle East. METHODS We examined the application of modified Bayley-Pinneau (BoneXpert®), TW-II, and TW-III protocols using mixed-longitudinal data available for 103 subjects (chronological age range, 19.4 to 27.9 yr) previously enrolled as academy student-athletes (annual screening range, one to six visits). Random-effects generalized additive models quantified the presence of systematic mean differences between actual versus predicted adult height. Effects were deemed practically equivalent based on the location of the confidence interval (95% CI) against a realistic difference value of Δ = ± 1 cm. Each model pooled residual standard deviation described the actual precision of height predictions and was used to calculate a 95% prediction interval. RESULTS The BoneXpert® method overpredicted adult height systematically at chronological ages in the range of approximately 13.5 to 14.5 yr (95% CI range, -1.9 to -1 cm) and Greulich-Pyle skeletal ages between 13.5 and 15 yr (95% CI range, -3.1 to -1 cm). Effects based on TW-II were practically equivalent across the chronological and skeletal age measurement ranges, with this protocol yielding adult height predictions with a precision (standard deviation) of approximately ±2.6 cm. The mean TW-III effects indicated systematic adult height overpredictions until the attainment of 14.5 and 15 yr of chronological age (95% CI range, -3.8 to -1.1 cm) and TW-III skeletal age (95% CI range: -5.2 to -2.3 cm), respectively. CONCLUSIONS Tanner-Whitehouse-II adult height prediction method provided more consistent estimates and can be considered the method of choice for talent development purposes in youth soccer players from the Middle East.

T follicular helper (TFH) cells are crucial for B cell-mediated humoral immunity1. Although transcription factors such as BCL6 drive the differentiation of TFH cells2,3, it is unclear whether and how post-transcriptional and metabolic programs enforce TFH cell programming. Here we show that the cytidine diphosphate (CDP)–ethanolamine pathway co-ordinates the expression and localization of CXCR5 with the responses of TFH cells and humoral immunity. Using in vivo CRISPR–Cas9 screening and functional validation in mice, we identify ETNK1, PCYT2, and SELENOI—enzymes in the CDP–ethanolamine pathway for de novo synthesis of phosphatidylethanolamine (PE)—as selective post-transcriptional regulators of TFH cell differentiation that act by promoting the surface expression and functional effects of CXCR5. TFH cells exhibit unique lipid metabolic programs and PE is distributed to the outer layer of the plasma membrane, where it colocalizes with CXCR5. De novo synthesis of PE through the CDP–ethanolamine pathway co-ordinates these events to prevent the internalization and degradation of CXCR5. Genetic deletion of Pcyt2, but not of Pcyt1a (which mediates the CDP–choline pathway), in activated T cells impairs the differentiation of TFH cells, and this is associated with reduced humoral immune responses. Surface levels of PE and CXCR5 expression on B cells also depend on Pcyt2. Our results reveal that phospholipid metabolism orchestrates post-transcriptional mechanisms for TFH cell differentiation and humoral immunity, highlighting the metabolic control of context-dependent immune signalling and effector programs. Enzymes in the cytidine diphosphate–ethanolamine metabolic pathway, which promotes de novo synthesis of phosphatidylethanolamine, are shown to act as post-transcriptional mediators of the differentiation of T follicular helper (TFH) cells, by regulating the chemokine receptor CXCR5.

Accurate estimates of the causal effect of air pollution on health outcomes, are critical when calculating attributable disease burdens. Brazil has a large population exposed to fast-growing emissions of air pollutants, however no national level studies have been conducted to examine the causal effect of PM

Glioblastoma (GBM) is the most lethal and aggressive primary brain malignancy with high recurrence rates and virtually no long-term survival. Despite our expanding knowledge regarding GBM at the genomic/molecular level, we still don’t fully comprehend the molecular mechanisms responsible for GBM recurrence. Current knowledge implicates tumor-propagating Glioma Stem Cells (GSCs) in the evolution of treatment resistance and tumor recurrence. Understanding these cellular/molecular events will inform strategies for preventing and/or treating recurrent GBM (rGBM). Gene set enrichment analysis (GSEA) of RNA sequencing datasets obtained from GSCs and clinical rGBM specimens identified TGFBR2 signaling as a high frequency and potentially targetable pathway in rGBM. We show that SMAD2/3 signaling, a downstream effector of TGFBR2, is enriched in rGBM and that patients with elevated TGFBR2 have statistically shorter long-term survival outlooks. The functional relevance of these findings was supported using ITD1, a selective TGFBR2 inhibitor, which decreased the GSC phenotype and cell viability of cells derived from clinical rGBM (rGBM cells), while simultaneously re-sensitizing them to temozolomide (TMZ) in-vitro. Since GBM is known to efficiently develop resistance to receptor-targeting monotherapies, we sought to simultaneously target multiple putative oncogenic drivers downstream of TGFBR2. To achieve this, we applied an unbiased miRNA-based network analysis that identified miR-590-3p as an inhibitor of SMAD2/3 signaling at multiple nodes and thus a potential tumor suppressor in rGBM. Transgenic miR-590-3p robustly decreased the expression of >30 putative oncogenes, reduced the GSC phenotype and cell viability, as well as re-sensitized rGBM cells to TMZ. These results predict that blocking TGFBR2 signaling will negatively impact the tumor phenotype of rGBM as well as its GSC capacity. Ongoing directions for this research include comparing the efficacy of ITD1 monotherapy with miR-590-3p therapy in rGBM models in-vivo. These results identify a significant role of TGFBR2 signaling in both TMZ resistance and the GSC phenotype in rGBM and provide a miRNA-based strategy for simultaneously targeting multiple oncogenic nodes within the TGFBR2 and potentially other oncogenic signaling pathways. Citation Format: Sophie Sall, Jack Korleski, Amanda Johnson, Maya Johnson, Hernando Lopez-Bertoni. miR-590-3p inhibits multiple oncogenic nodes within the TGFBR2:SMAD2/3 pathway in recurrent GBM cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3750.

Glioblastoma (GBM), the most aggressive and lethal form of brain tumors, recurs in 90% of cases and the standard protocol of care—temozolomide (TMZ)—is an ineffective method to combat chemo-resistant GBM. It is therefore imperative that we identify, develop, and design novel therapeutics to effectively combat recurrent GBM (rGBM). Multi-potent stem-like cell subpopulations within GBM (also referred to as glioma stem cells or GSCs) play important roles in tumor propagation, therapeutic resistance, and recurrence following treatment. Understanding the molecular mechanisms that drive resistance in GSCs can lead to novel therapeutic approaches for rGBM. Bioinformatics analyses of transcriptome data sets from rGBM clinical specimens identified transforming growth factor-beta receptor type 2 (TGFBR2) as a putative driver of resistance and recurrence in GBM. We show that TMZ-resistant cells become more stem-like concurrent with higher expression of TGFBR2 protein and mRNA. Importantly, shRNA-mediated inhibition of TGFBR2 decreases proliferation of TMZ-resistant cells and enhances the effects of TMZ. We hypothesize that by developing targeted therapeutics to reduce TGFBR2 expression we will inhibit the growth capacity and/or re-sensitize rGBM cells to ionizing radiation (IR) or TMZ treatment by simultaneously targeting multiple putative oncogenes implicated in the induction of stem-like resistant GBM cell subsets. Future directions include inhibiting TGFBR2 signaling in clinical specimens derived from rGBM patients using two translatable approaches: (1) ITD1, a small molecule TGFBR2 inhibitor predicted to cross the blood-brain-barrier and (2) microRNAs to target multiple TGFBR2 target genes up-regulated in rGBM. Citation Format: Maya K. Johnson, Jack Korleski, Amanda Johnson, Sophie Sall, John Laterra, Hernando Lopez-Bertoni. Inhibition of TGFBR2 signaling re-sensitizes TMZ-resistant glioblastoma cells to therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5009.

The advent of immunotherapy has transformed our approach to cancer treatment; however, it is virtually ineffective in glioblastoma (GBM), the most common & malignant brain cancer in adults, due in part to the inherently immunosuppressive tumor microenvironment (TME). Recent research has identified GBM cancer stem cells (GSCs) as key modulators of the TME, mainly through activation and recruitment of pro-tumor immune cells (e.g., TAMs, regulatory T-cells (Tregs), MDSCs). We identified a novel immunosuppressive phenotype whereby GSCs mimic Treg function via TGF-b type II receptor (TGFBR2) signaling to suppress the immune response with the potential to promote tumor propagation and resist immunotherapy. Preliminary experiments revealed that TGFBR2 drives GBM cells to a CD44-high, mesenchymal-like GSC state. Transgenic TGFBR2 was found to induce a Treg-like transcriptional profile defined by expression of canonical Treg effector genes (e.g., CD274, ENTPD1, NT5E, LGALS1, TGFB1, PDCD1LG2) in human GBM neurospheres. Single-cell RNA-Seq and bioinformatics analyses confirmed the presence of this TGFBR2-mediated transcriptional signature in both patient-derived GSCs and patient tumors. Notably, in silico deconvolution of bulk GBM sequencing predicts that high expression of a TGFBR2-induced transcriptome associates with an immunosuppressive TME characterized by high infiltration of pro-tumor immune cells (e.g., TAMs, neutrophils). To target this Treg-like, immunosuppressive GSC phenotype, we utilized ITD-1, a small molecule inhibitor of TGFBR2. In vitro ITD-1 treatment reduced GSC proliferation capacity and downregulated expression of CD44 and Treg effectors. In T-cell co-cultures, pre-treating GSCs with ITD-1 increased T-cell viability and T-cell-mediated tumor cell killing. Administration of ITD-1 in tumor-bearing, immunocompetent mice reduced tumor volume and increased anti-tumor immune cell infiltration relative to vehicle controls. In all, ITD-1-mediated TGFBR2 inhibition attenuates a unique, Treg-like immunosuppressive and potentially tumor-protective phenotype in GSCs. Future studies will combine ITD-1 and checkpoint inhibitor therapy in an effort to increase the efficacy of immunotherapy in GBM.

Sonic Hedgehog (SHH) signaling is an essential driver of embryonic patterning that, when corrupted, leads to developmental disorders and cancers. SHH effector responses are organized through nonmotile primary cilia that grow and retract with the cell cycle and in response to distinct extracellular cues. Destabilization of primary cilium length corrupts SHH pathway regulation, which places significant pressure on SHH to maintain ciliary architecture. Herein, we investigate whether SHH signaling promotes ciliary length control. We reveal a signal crosstalk circuit induced by SHH activation of Phospholipase A2 (cPLA2) that drives ciliary EP4signaling to stabilize primary cilium length. We demonstrate that chemical or genetic blockade of SHH-EP4crosstalk leads to destabilized primary cilium cyclic AMP (cAMP) control, reduced ciliary length, and attenuated SHH pathway induction. Accordingly, we find thatEp-/-mice display shortened neuroepithelial primary cilia and altered SHH-dependent neuronal cell fate specification. Thus, SHH initiates a signaling crosstalk circuit that maintains primary cilium length for a robust downstream signaling response.

Instructor Talk-noncontent and nonlogistical language that is focused on shaping the classroom learning environment-is a recently defined variable that may play an important role in how undergraduates experience courses. Previous research characterized Instructor Talk used by faculty teaching in biology lecture classrooms. However, graduate teaching assistants (GTAs) and laboratory classrooms represent critical factors in undergraduate education, and Instructor Talk in this context has yet to be explored. Here, we present findings analyzing Instructor Talk used by GTAs teaching in undergraduate biology laboratory classrooms. We characterized the Instructor Talk used by 22 GTA instructors across 24 undergraduate biology laboratory courses in the context of a single, urban, Hispanic-serving and Asian American and Pacific Islander-serving Institution. We found that Instructor Talk was present in every course studied, GTAs with pedagogical training and prior teaching experience used more Instructor Talk than those without, and GTAs teaching laboratory courses used more Instructor Talk than previous observations of faculty teaching lecture courses. Given the widespread use of Instructor Talk and its varying use across contexts, we predict that Instructor Talk may be a critical variable in teaching, specifically in promoting equity and inclusion, which merits continued study in undergraduate science education.

A rare lymphoproliferative disorder involving thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O), so called TAFRO syndrome, was first reported in 2010.1 Considered a variant of idiopathic multicentric Castleman’s disease, the recent discovery and rarity of this syndrome poses significant challenges to diagnosis and management. In this case report, we review the youngest patient to be reported in the literature with TAFRO syndrome. We highlight the patient’s diagnosis, management, and follow-up in the context of current recommendations for treatment and management of TAFRO syndrome.

ObjectivesTo describe the injury characteristics of male youth athletes exposed to year-round athletics programmes.MethodsInjury surveillance data were prospectively collected by medical staff in a cohort of youth athletics athletes participating in a full-time sports academy from 2014–2015 to 2018–2019. Time-loss injuries (>1 day) were recorded following consensus procedures for athletics. Athletes were clustered into five event groups (sprints, jumps, endurance, throws and non-specialised) and the number of completed training and competition sessions (athletics exposures (AE)) were calculated for each athlete per completed season (one athlete season). Injury characteristics were reported overall and by event groups as injury incidence (injuries per 1000 AE) and injury burden (days lost per 1000 AE).ResultsOne-hundred and seventy-eight boys (14.9±1.8 years old) completed 391 athlete seasons, sustaining 290 injuries. The overall incidence was 4.0 injuries per 1000 AE and the overall burden was 79.1 days lost per 1000 AE. The thigh was the most common injury location (19%). Muscle strains (0.7 injuries per 1000 AE) and bone stress injuries (0.5 injuries per 1000 AE) presented the highest incidence and stress fractures the highest burden (17.6 days lost per 1000 AE). The most burdensome injury types by event group were: bone stress injuries for endurance, hamstring strains for sprints, stress fractures for jumps, lesion of meniscus/cartilage for throws and growth plate injuries for non-specialised athletes.ConclusionAcute muscle strains, stress fractures and bone stress injuries were identified as the main injury concerns in this cohort of young male athletics athletes. The injury characteristics differed between event groups.

Introduction: Somatic KRAS mutations occur in 25% of patients with NSCLC. Treatment with MEK inhibitor monotherapy has not been successful in clinical trials to date. Compensatory activation of FGFR1 was identified as a mechanism of trametinib resistance in KRAS-mutant NSCLC, and combination therapy with trametinib and ponatinib was synergistic in in vitro and in vivo models. This study sought to evaluate this drug combination in patients with KRAS-mutant NSCLC. Methods: A phase 1 dose escalation study of trametinib and ponatinib was conducted in patients with advanced NSCLC with KRAS mutations. A standard 3-plus-3 dose escalation was done. Patients were treated with the study therapy until intolerable toxicity or disease progression. Results: A total of 12 patients with KRAS-mutant NSCLC were treated (seven at trametinib 2 mg and ponatinib 15 mg, five at trametinib 2 mg and ponatinib 30 mg). Common toxicities observed were rash, diarrhea, and fever. Serious adverse events potentially related to therapy were reported in five patients, including one death in the study and four cardiovascular events. Serious events were observed at both dose levels. Of note, 75% (9 of 12) were assessable for radiographic response and no confirmed partial responses were observed. The median time on study was 43 days. Conclusions: In this phase 1 study, in patients with KRAS-mutant advanced NSCLC, combined treatment with trametinib and ponatinib was associated with cardiovascular and bleeding toxicities. Exploring the combination of MEK and FGFR1 inhibition in future studies is potentially warranted but alternative agents should be considered to improve safety and tolerability.

Introduction Age and sport specialization are two of the most important factors that can impact an athlete's flexibility, but their influence during adolescence in youth athletics hasn’t yet been investigated. Material and methods Retrospective analysis of the lower limb flexibility assessments in the athletics squad of a full-time sports academy in the Middle East for nine consecutive seasons (2006/07 to 2014/15). Flexibility data were analyzed for eight lower limb muscle groups (mean value±standard deviation) in four athletics events (throws, sprints & jumps, distance running and non-specialized) and seven age groups (categorized yearly from under 13 to above 18 years old). Total lower limb flexibility (TF) was calculated by summating all individual muscle group values and comparisons were made between age groups and athletics events with statistical significance set at p0.05). A weak inverse correlation (r=−0.21, p 0.05). Throwers were found to be significantly less flexible (1091±93) than distance runners (1227±95), sprints & jumps (1186±80) and non-specialized athletes (1178±78); distance runners displayed greater hip external rotators flexibility than any other group (p

Smoke exposure from landscape and coal mine fires can have severe impacts on human health. The ability of health studies to accurately identify potential associations between smoke exposure and health is dependent on the techniques utilised to quantify exposure concentrations for the population at risk. The evolution of spatial modelling techniques capable of better characterising this association has potential to provide more precise health effect estimates. We reviewed the literature to identify and assess the spatial modelling techniques available to estimate smoke PM2.5 or PM10 concentrations from open biomass or coal mine fires. Four electronic databases were searched: MEDLINE, EMBASE, Scopus and Web of Science. Studies were included if they utilised any method for modelling the spatial distribution of PM2.5 or PM10 concentrations from open biomass or coal mine fires and had applied the modelled PM to health data. Studies based on un-adjusted monitoring data, or which were not in English, were excluded. We identified 28 studies which utilised five spatial modelling techniques to assess exposure from open biomass fires: dispersion models, land use regression, satellite remote sensing, spatial interpolation and blended models. No studies of coal mine fires were identified. We found the most effective models combined multiple techniques to enhance the strengths and mitigate the weaknesses of the underlying individual techniques. “Blended” models have the potential to facilitate research in regions currently under represented in biomass or coal mine fire studies as well as enhancing the power of studies to identify associations with health outcomes.

Navigating romantic transgressions in older adulthood is imperative for both relationship quality and longevity, making forgiveness a critical process. The current study examined marital transgressions and forgiveness among 64 older (age range = 56–89), higher-functioning, primarily White, married couples studied at two time points spaced 16.4 months apart. More than half the spouses did not report a transgression in the past year, and not doing so was associated with better marital functioning at both time points. Of the transgressions reported, thematic analyses revealed they fell into six categories (e.g., spouse behaving badly, financial issues), but were overall relatively minor in nature. If husbands engaged in greater avoidance after a transgression, both spouses were less maritally satisfied a year later. Findings suggest more attention to not only forgiveness approaches employed (avoidance of the issue versus avoidance of the person) but also to the potential role of gender and timing in these associations.

Solid malignancies, including GBM, contain small subsets of cells that display stem-like properties (i.e. glioma stem cells or GSCs) and act as key determinants of therapeutic resistance and tumor recurrence. Mechanisms of GSC immune escape are considered fundamental to clinical GBM growth and recurrence. GBM cells escape antitumor immunity by modifying the tumor microenvironment by secreting immune-suppressive factors and recruiting anti-inflammatory/pro-oncogenic cells (e.g. T-regulatory cells, M2-like macrophages). However, whether subsets of GSCs can mimic T-reg-like functions by expressing proteins associated with T-reg immune-suppression remains unknown. Single-cell RNA sequencing analysis of GBM neurospheres revealed a previously unrecognized Oct4/Sox2high/FOXP3- cell subpopulation with high expression of TGFb1, CD39, CD73, PD-L1, and Galectin-1, a gene expression fingerprint typically associated with T-reg cells and their immune suppressive functions within the tumor microenvironment. Bioinformatics analysis of public databases shows that the above-mentioned genes are enriched in the mesenchymal GBM subtype and highly correlated with CD44 and TGFb type II receptor (TGFBR2) expression in both clinical GBM and primary GSCs. Mechanistically, Oct4 and Sox2 were found to directly induce TGFBR2 transcription concurrent with chromatin architectural changes (i.e. heterochromatin-to-euchromatin transition) involving the TGFBR2 gene. Transgenic TGFBR2 expression increased neurosphere cell growth capacity, upregulated expression of T-reg-like effector genes and enriched for CD44+ GSCs. Functionally, neurospheres expressing transgenic Oct4/Sox2 or transgenic TGFBR2 possess increased immunosuppressive capacity, and pharmacological inhibition of TGFBR2 depleted CD44+ GSCs and reduced immunosuppression in Jurkat cell co-cultures. Taken together, we show that reprogramming events initiated by Oct4 and Sox2 induce a CD44+/FOX3P- GSC cell subset with a T-reg-like immunosuppressive transcriptional profile via a TGFBR2-dependent mechanism. This research provides the first description of such neoplastic cells in any malignancy and has high potential translational impact since targeting these tumor cell subsets and their immunosuppressive mechanisms may be critical to the successful development of GBM immunotherapies.