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IntroductionBrain metastases are a significant source of morbidity and mortality for patients with lung cancer. Lung cancer can induce local and systemic immunosuppression, promoting tumor growth and dissemination. One mechanism of immunosuppression is tumor-induced expansion of programmed death-ligand 1 (PD-L1) expressing myeloid cells. Here, we investigate peripheral blood immune phenotype in NSCLC patients with or without brain metastasis.MethodsPeripheral blood was collected from patients with lung metastatic brain tumors and pre-metastatic lung cancer. Immunosuppressive monocytes, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs) were quantified through flow cytometry. T cell reactivity was analyzed via ELISpot. Brain metastasis conditioned media was collected from tumor-derived cell cultures and analyzed for cytokines by ELISA. Naïve monocytes were stimulated with brain metastasis conditioned media to evaluate PD-L1 stimulation.ResultsPatients with brain metastatic lung carcinoma demonstrated increased peripheral monocyte PD-L1, MDSC abundance, and Treg percentage compared to early stage pre-metastatic patients and healthy controls. Patients with elevated peripheral monocyte PD-L1 had less reactive T cells and worse survival. Brain metastasis conditioned media stimulation increased monocyte PD-L1, and conditioned media IL-6 levels correlated with PD-L1 induction. Treatment with anti-IL-6 or anti-IL-6 receptor antibodies reduced PD-L1 expression. In summary, patients with lung cancer and brain metastases exhibit multiple markers of peripheral immunosuppression.ConclusionsThe frequency of PD-L1+ myeloid cells correlated with the presence of brain metastases. Tumor-derived IL-6 was capable of inducing PD-L1+ myeloid cells in vitro, suggesting that monitoring of immunosuppressive factors in peripheral blood may identify new targets for therapeutic intervention in selected patients.

AimDespite current treatments, high-grade meningiomas continue to have a poor prognosis. Immunotherapy targeting immune checkpoints, such as PD-L1, has demonstrated significant success in controlling numerous malignancies. In this study, we investigate the extent of systemic and local immunosuppression in meningiomas to assess the potential benefit of immune checkpoint inhibitors for the treatment of high-grade meningiomas.MethodsPeripheral blood was collected from patients undergoing resection of meningiomas (WHO grade I, n = 18; grade II, n = 25; grade III, n = 10). Immunosuppressive myeloid cells (CD45+CD11b+PD-L1+), myeloid-derived suppressor cells (MDSCs) (CD11b+CD33+HLA-DRlow), and regulatory T cells (Tregs) (CD3+CD4+CD25+FoxP3+) were quantified through flow cytometry. Tissue sections from the same patients were assessed for PD-L1 expression and T cell infiltration via immunohistochemistry.ResultsPatients with grade III meningiomas demonstrated increased peripheral monocyte PD-L1 compared to patients with grade I/II meningiomas and healthy controls. Peripheral MDSC abundance was increased in grades II and III meningioma patients. PD-L1 staining of meningioma tissue demonstrated increased positivity in grade III meningiomas. Intratumoral PD-L1 was not associated with progression-free survival. High-grade meningiomas had increased T-cell infiltration. However, a significant proportion of these T cells were exhausted PD1+ T cells and immunosuppressive Tregs.ConclusionsPatients with meningiomas exhibit signs of peripheral immunosuppression, including increased PD-L1 on myeloid cells and elevated MDSC abundance proportional to tumor grade. Additionally, the tumors express substantial PD-L1 proportional to tumor grade. These results suggest a role for immune checkpoint inhibitors targeting the PD-L1/PD-1 pathway in combination with standard therapies for the treatment of high-grade meningiomas.

The excellence of educational institutions can be developed and improved by the teachers' consistent and effective communication in classrooms. This study embarks to investigate the effect of teachers' communication style (CS) on their communication effectiveness (CE), based on self-assessment, during classroom teaching. The results indicate that CS has significant influence on CE, with "Expressiveness" and "Preciseness" emerging as best styles of communication, whereas "Verbal Aggressiveness" has negative impact on faculties' CE. It also investigates the differences in CE of the faculty based on their gender and subject specialization. Findings indicate gender differences on the basis of two CE variables--"Listening" and "Ability to get the Message Across." But there is no difference in instructors' CE when compared on basis of subject specialization. The findings of the study have implications for the faculty members to enhance their CE, by understanding their CS, which will further have an impact on students' satisfaction and learning.

Glioblastoma (GBM) promotes immunosuppression through upregulation of PD-L1 and regulatory T cell (Treg) expansion, but the association of these suppressive factors has not been well elucidated. Here, we investigate a role of PD-L1 in expanding Tregs and the value of targeting the PD-1 receptor to inhibit Treg expansion. Quantitative RNA sequencing data from The Cancer Genome Atlas were evaluated for an association between CD274 and FOXP3 transcript expressions and impact of FOXP3 on clinical outcomes. Peripheral leukocytes from patients with newly diagnosed GBM were profiled for PD-L1+ myeloid expressions and Treg abundance. Healthy lymphocytes were assessed for impact of recombinant PD-L1 on expansion of the inducible Treg (iTreg) population. iTreg function was evaluated by the capacity to suppress effector T cell proliferation. Specificity of responses were confirmed by pharmacologic inhibition of the PD-1 receptor. Increased PD-L1 mRNA expression in GBM corresponded to increased FOXP3 mRNA (p = 0.028). FOXP3 elevation had a negative impact on overall survival (HR = 2.0; p < 0.001). Peripheral PD-L1 positivity was associated with an increased Treg fraction (p = 0.008). Lymphocyte activation with PD-L1 co-stimulation resulted in greater iTreg expansion compared to activation alone (18.3% vs. 6.5%; p < 0.001) and improved preservation of the Treg phenotype. Suppressive capacity on naïve T cell proliferation was sustained. Nivolumab inhibited PD-L1-induced Treg expansion (p < 0.001). These results suggest that PD-L1 may expand and maintain immunosuppressive Tregs, which are associated with decreased survival in glioma patients. Blockade of the PD-L1/PD-1 axis may reduce Treg expansion and further improve T cell function beyond the direct impact on effector cells.

Motivation research has shown significant relations of students' mastery goal orientation and perceived competence to educational outcomes, but has not simultaneously scrutinized their relative influences on various educational outcomes. In the present investigation, a sample of Australian students from 6 secondary schools in Western Sydney (N = 1519) responded to survey items that measured mastery goal orientation and sense of competence. They were also asked to rate their status in class and self-efficacy in life. Their achievement scores were obtained by conducting both a reading and a numeracy test. Structural equation modeling (SEM) was applied to relate the motivational constructs (mastery and competence) to the outcomes (achievement, status, and self-efficacy). Results showed that students' sense of competence was a stronger predictor of all three outcomes - achievement, status, and self-efficacy whereas mastery was a strong predictor of status and self-efficacy. Given that a sense of competence was found to be a strong predictor of achievement, it seems that educators should pay more attention to enhancing secondary students' sense of competence if the purpose is solely to improve achievement. However, if the goal is to enhance long-term and whole-person outcomes, then both a mastery goal orientation and a positive sense of competence should be nurtured in secondary education.

Introduction: Despite extensive research, comprehensive characterization of leukaemic stem cells (LSC) and information on their immunophenotypic differences from normal haematopoietic stem cells (HSC) is lacking. Herein, we attempted to unravel the immunophenotypic (IPT) characteristics and heterogeneity of LSC using multiparametric flow cytometry (MFC) and single‐cell sequencing. Materials and Methods: Bone marrow aspirate samples from patients with acute myeloid leukaemia (AML) were evaluated using MFC at diagnostic and post induction time points using a single tube‐10‐colour‐panel containing LSC‐associated antibodies CD123, CD45RA, CD44, CD33 and COMPOSITE (CLL‐1, TIM‐3, CD25, CD11b, CD22, CD7, CD56) with backbone markers that is, CD45, CD34, CD38, CD117, sCD3. Single‐cell sequencing of the whole transcriptome was also done in a bone marrow sample. Results: LSCs and HSCs were identified in 225/255 (88.2%) and 183/255 (71.6%) samples, respectively. Significantly higher expression was noted for COMPOSITE, CD45RA, CD123, CD33, and CD44 in LSCs than HSCs (p < 0.0001). On comparing the LSC specific antigen expressions between CD34+ (n = 184) and CD34‐ LSCs (n = 41), no difference was observed between the groups. More than one sub‐population of LSC was demonstrated in 4.4% of cases, which further revealed high concordance between MFC and single cell transcriptomic analysis in one of the cases displaying three LSC subpopulations by both methods. Conclusion: A single tube‐10‐colour MFC panel is proposed as an easy and reproducible tool to identify and discriminate LSCs from HSCs. LSCs display both inter‐ and intra‐sample heterogeneity in terms of antigen expressions, which opens the facets for single cell molecular analysis to elucidate the role of subpopulations of LSCs in AML progression. [ABSTRACT FROM AUTHOR]

Background/Aim: This study examined the effects of tocotrienols (TT) in conjunction with statin on glucose homeostasis, bone microstructure, gut microbiome, and systemic and liver inflammatory markers in obese C57BL/6J mice. Materials and Methods: Forty male C57BL/6J mice were fed a high-fat diet (HFD) and assigned into four groups in a 2 (no statin vs. 120 mg statin/kg diet)×2 (no TT vs. 400 mg TT/kg diet) factorial design for 14 weeks. Results: Statin and TT improved glucose tolerance only when each was given alone, and only statin supplementation decreased insulin resistance. Consistently, only statin supplementation decreased serum insulin levels and HOMA-IR. Pancreatic insulin was also increased with statin treatment. Statin and TT, alone or in combination, reduced the levels of serum IL-6, but only TT attenuated the increased serum leptin levels induced by a HFD. Statin supplementation increased bone area/total area and connectivity density at LV-4, while TT supplementation increased bone area/total area and trabecular number, but decreased trabecular separation at the distal femur. Statin supplementation, but not TT, reduced hepatic inflammatory cytokine gene expression. Neither TT supplementation nor statin supplementation statistically altered microbiome species evenness or richness. However, they altered the relative abundance of certain microbiome species. Most notably, both TT and statin supplementation increased the relative abundance of Lachnospiraceae UCG-006. Conclusion: TT and statin collectively benefit bone microstructure, glucose homeostasis, and microbial ecology in obese mice. Such changes may be, in part, associated with suppression of inflammation in the host. [ABSTRACT FROM AUTHOR]

Central nervous system (CNS) teratomas are very rare neoplasms that contain tissues derived from all three germ cell layers (endoderm, mesoderm, and ectoderm). Patients with teratomas usually have a good prognosis. Given the paucity of cases in the literature, we present a retrospective review of 15 CNS teratomas treated over a 25 year period at the University of California, San Francisco. We describe the presentation, location, treatment, and adjuvant therapy for these patients, and highlight three unique cases that emphasize the diverse presentation and treatment of these rare tumors.