Glioblastoma (GBM) is a highly aggressive primary brain cancer with dismal prognoses despite current standards of care. Immunotherapy is being explored for GBM, given its promising results in other solid malignancies; however, the results from early clinical studies in GBM are disappointing. It has been discovered that GBM has numerous mechanisms of immune resistance, including the physical blood–brain barrier, high intratumoral and intertumoral heterogeneity, and numerous cellular and molecular components in the tumor microenvironment (TME) that promote immunosuppression. Furthermore, GBM utilizes numerous metabolic pathways to establish a survival advantage in the TME. Recently, it has begun to become evident that these complex metabolic pathways that promote GBM growth and invasion also contribute to tumor immune resistance. Aerobic glycolysis provides tumor cells with ample ATP while depleting key glucose and increasing acidity in the TME. Increased glutamine, tryptophan, and arginine metabolism deprives T cells of these necessary amino acids for proper anti-tumor function. Sphingolipid metabolism promotes an immunosuppressive phenotype in the TME and affects immune cell trafficking. This review will discuss, in detail, the key metabolic pathways relevant to GBM pathophysiology which also modulate host immunosuppression.

The rapid spread of SARS-CoV-2 virus has overwhelmed hospitals with patients in need of intensive care, which is often limited in capacity and is generally reserved for patients with critical conditions. This has led to higher chances of infection being spread to non-COVID-19 patients and healthcare workers and an overall increased probability of cross contamination. The effects of design parameters on the performance of ventilation systems to control the spread of airborne particles in intensive care units are studied numerically. Four different cases are considered, and the spread of particles is studied. Two new criteria for the ventilation system—viz., dimensionless timescale and extraction timescale—are introduced and their performances are compared. Furthermore, an optimization process is performed to understand the effects of design variables (inlet width, velocity, and temperature) on the thermal comfort conditions (predicted mean vote, percentage of people dissatisfied, and air change effectiveness) according to suggested standard values and the relations for calculating these parameters based on the design variables are proposed. Desirability functions that are comprised of all three thermal condition parameters are used to determine the range of variables that result in thermally comfortable conditions and a maximum desirability of 0.865 is obtained. The results show that a poorly designed ventilation system acts like a perfectly stirred reactor—which enormously increases the possibilities of contamination—and that when air is injected from the ceiling and extracted from behind the patient beds, the infection spread is least probable since the particles exit the room orders of magnitude faster.

Underlying inflammation is associated with an increased risk of depression in older adults. In this study, we examined the role of inflammatory biomarkers in antidepressant response in depressed older adults undergoing adjunct Tai Chi Chih (TCC) or Health education interventions. Older adults aged 60 years and above with a diagnosis of major depression were randomized to 12 weeks of TCC versus Health and Wellness Education (HEW) as an adjunct therapy to their stable antidepressant treatment regimen. A panel of 19 cytokine/chemokines was measured at baseline and 12 weeks. Five factors were derived using factor analysis. General linear models were estimated to examine the change in factor scores and the association of these changes on depression remission rates, controlling for age, sex, and body mass index. Of the 170 randomized participants (TCC: n = 85 and HEW: n = 85), 55 TCC and 58 HEW completed the 3-month assessment. The groups did not differ at baseline in any measure. At follow-up, neither the changes in cytokine/chemokines scores nor the depression remission rate differed significantly between TCC and HEW. However, remitters and non-remitters differed significantly in changes in a factor composed of growth-regulated oncogene protein-alpha (GRO-alpha), epidermal growth factor (EGF), and soluble CD40 ligand (sCD40L). GRO-alpha and EGF levels (in both groups) were significantly increased in remitters compared to non-remitters. Changes in certain cytokines/chemokines may accompany improvement in depressive symptoms in older adults. Future studies will need to explore the role of these molecules in remission of late-life depression.

Glioblastoma multiforme (GBM) is the most common malignant primary tumor of the central nervous system (CNS), accounting for the majority of brain tissue tumors and CNS neoplasms. GBM has an incidence rate of 3.2/100,000 people in the United States, with an abysmal survival rate of 15 months with treatment and under 3 months for untreated patients. GBM remains incurable, with no disease-modifying treatment available. As a grade IV astrocytoma, GBM is highly aggressive, characterized by rapid proliferation, high metabolic demands, substantial angiogenesis, and diffuse infiltration of healthy parenchyma. The GBM genome is highly heterogeneous, with unpredictable amplification patterns, dysregulation, and mutational activation of receptor tyrosine kinase genes, tumor suppressor genes, and growth factor signaling. GBM’s indistinct tumor margins, its highly adaptive interaction with the brain microenvironment, and the existence of the blood-brain barrier and the blood-brain tumor barrier further limit effective anti-GBM therapeutic strategies. Hence, anti-GBM drug discoveries and molecular techniques that aim for patient-specific treatment stratification are of profound clinical and therapeutic significance. The current paper aims to outline the fundamental pathophysiology, tumorigenicity, and immunosuppressive mechanism of GBMs, review current treatment options for GBMs, and examine the contemporary challenges and advances in anti-GBM drug discovery and delivery. Finally, the paper aims to shed light on the emergence of small-molecule inhibitors, immune checkpoint inhibitors, and vaccination therapy as potentially efficacious therapeutic strategies for treating GBM.

Glioblastoma (GBM) is a universally fatal cancer for which the standard of care has remained largely unchanged for the last 20 years. Recent work has demonstrated that most therapeutic trials for GBM fail due to complex mechanisms of immunosuppression mediated by both the innate and adaptive immune systems. Various metabolic alterations in the tumor microenvironment help maintain this local and systemic immunosuppression, of which the axis of hypoxia-driven tryptophan degradation has garnered substantial attention over the last decade. This paper synthesizes a much-needed elucidation of the immunometabolic reshaping of glioma, myeloid, endothelial, and lymphoid cell lineages induced by hypoxia. The current paper critically evaluates the role of IDO1/TDO2-mediated breakdown of tryptophan and the consequent accumulation of kynurenine, a metabolite that triggers GCN2- and AHR-mediated CD8+ T-cell exhaustion and supports regulatory T-cell differentiation and expansion. Furthermore, we propose a synthesis of mechanistic evidence that establishes a role for the Trp-GCN2-ATF4-VEGFA axis in hypoxia-induced immunosuppression, supporting that pro-tumoral metabolic dysregulation is directly linked to angiogenesis. In GBM, hypoxia and tryptophan–kynurenine pathway dysregulation operate as an integrated metabolic circuit that drives widespread immunosuppression. These mechanisms can be captured by a metabolic signature shared across nearly every cell type in the GBM microenvironment. Drawing on recent spatial transcriptomic, metabolomic, and pharmacologic studies, we outline how this metabolic axis shapes disease biology and how it can be targeted to restore effective antitumor immunity.