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In comparison with responses in recurrent glioblastoma (rGBM), the intracranial response of brain metastases (BrM) to immune checkpoint blockade (ICB) is less well studied. Here, we present an integrated single-cell RNA-Seq (scRNA-Seq) study of 19 ICB-naive and 9 ICB-treated BrM samples from our own and published data sets. We compared them with our previously published scRNA-Seq data from rGBM and found that ICB led to more prominent T cell infiltration into BrM than rGBM. These BrM-infiltrating T cells exhibited a tumor-specific phenotype and displayed greater activated/exhausted features. We also used multiplex immunofluorescence and spatial transcriptomics to reveal that ICB reduced a distinct [CD206.sup.+] macrophage population in the perivascular space, which may modulate T cell entry into BrM. Furthermore, we identified a subset of progenitor exhausted T cells that correlated with longer overall survival in BrM patients. Our study provides a comprehensive immune cellular landscape of ICB's effect on metastatic brain tumors and offers insights into potential strategies for improving ICB efficacy for brain tumor patients., Introduction Brain metastases (BrM) are CNS tumors commonly arising in patients with lung, melanoma, and breast cancer (1). The emergence of BrM usually marks the most advanced stage of a [...]

Objective: Standardised person‐reported outcomes (PRO) data can contextualise clinical outcomes enabling precision diabetes monitoring and care. Comprehensive outcome sets can guide this process, but their implementation in routine diabetes care has remained challenging and unsuccessful at international level. We aimed to address this by developing a person‐centred outcome set for Type 1 and Type 2 diabetes, using a methodology with prospects for increased implementability and sustainability in international health settings. Methods: We used a three‐round questionnaire‐based Delphi study to reach consensus on the outcome set. We invited key stakeholders from 19 countries via purposive snowball sampling, namely people with diabetes (N = 94), healthcare professionals (N = 65), industry (N = 22) and health authorities (N = 3), to vote on the relevance and measurement frequency of 64 previously identified clinical and person‐reported outcomes. Subsequent consensus meetings concluded the study. Results: The list of preliminary outcomes was shortlisted via the consensus process to 46 outcomes (27 clinical outcomes and 19 PROs). Two main collection times were recommended: (1) linked to a medical visit (e.g. diabetes‐specific well‐being, symptoms and psychological health) and (2) annually (e.g. clinical data, general well‐being and diabetes self management‐related outcomes). Conclusions: PROs are often considered in a non‐standardised way in routine diabetes care. We propose a person‐centred outcome set for diabetes, specifically considering psychosocial and behavioural aspects, which was agreed by four international key stakeholder groups. It guides standardised collection of meaningful outcomes at scale, supporting individual and population level healthcare decision making. It will be implemented and tested in Europe as part of the H2O project. [ABSTRACT FROM AUTHOR]

This article, published in the Journal of Neurological Surgery, explores the potential use of basal BCL-2-interacting mediator of cell death (BIM) responsiveness as a predictor of radiosensitivity in meningioma. The study used an in vitro model of meningioma to investigate the correlation between BIM-responsiveness and radiosensitivity. The results showed a wide range of radiosensitivities and basal apoptotic sensitivities in the meningioma cells. The study suggests that targeting BCL-XL and MCL-1, which are involved in apoptotic resistance, may enhance radiosensitivity in meningioma. Further research is needed to understand the mechanisms of apoptosis-evasion and radio-resistance in meningioma. [Extracted from the article]

This article discusses the potential benefits of combining mammalian target of rapamycin (mTOR) inhibition and radiation therapy for the treatment of meningioma, a type of brain tumor. The study found that the combination therapy was more effective in inhibiting tumor growth compared to either treatment alone. Additionally, the combination therapy appeared to disrupt the cell cycle progression of the tumor cells. The researchers suggest that this combination therapy could be a viable option for patients who cannot undergo full-dose radiation due to previous treatments. Further research is needed to validate these findings in animal models. [Extracted from the article]

Oxidative phosphorylation and glycolysis are the dominant ATP‐generating pathways in mammalian metabolism. The balance between these two pathways is often shifted to execute cell‐specific functions in response to stimuli that promote activation, proliferation, or differentiation. However, measurement of these metabolic switches has remained mostly qualitative, making it difficult to discriminate between healthy, physiological changes in energy transduction or compensatory responses due to metabolic dysfunction. We therefore present a broadly applicable method to calculate ATP production rates from oxidative phosphorylation and glycolysis using Seahorse XF Analyzer data and empirical conversion factors. We quantify the bioenergetic changes observed during macrophage polarization as well as cancer cell adaptation to in vitro culture conditions. Additionally, we detect substantive changes in ATP utilization upon neuronal depolarization and T cell receptor activation that are not evident from steady‐state ATP measurements. This method generates a single readout that allows the direct comparison of ATP produced from oxidative phosphorylation and glycolysis in live cells. Additionally, the manuscript provides a framework for tailoring the calculations to specific cell systems or experimental conditions. Synopsis: This manuscript details a method to calculate ATP production rates using OCR and ECAR data obtained from the Seahorse XF Analyzer. This generates a single readout measuring real‐time rates of ATP produced from oxidative phosphorylation and glycolysis in live cells. ECAR can quantitatively reflect lactate efflux after adjusting for buffering power of the experimental medium, respiratory acidification, and sensor coverage of the measurement well.The approach quantifies changes in ATP produced from oxidative phosphorylation and glycolysis in response to physiologically relevant stimuli.Real‐time ATP production rates capture changes in ATP utilization that steady‐state ATP levels do not.Examples are given for acute activation of neurons, adipocytes, macrophages, and T cells. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM), the most common primary malignant brain tumor, is a highly lethal form of cancer with a very limited set of treatment options. High heterogeneity in the tumor cell population and the invasive nature of these cells decrease the likely efficacy of traditional cancer treatments, thus requiring research into novel treatment options. The use of oncolytic viruses as potential therapeutics has been researched for some time. Zika virus (ZIKV) has demonstrated oncotropism and oncolytic effects on GBM stem cells (GSCs). To address the need for safe and effective GBM treatments, we designed an attenuated ZIKV strain (ZOL-1) that does not cause paralytic or neurological diseases in mouse models compared with unmodified ZIKV. Importantly, we found that patient-derived GBM tumors exhibited susceptibility (responders) and non-susceptibility (non-responders) to ZOL-1-mediated tumor cell killing, as evidenced by differential apoptotic cell death and cell viability upon ZOL-1 treatment. The oncolytic effect observed in responder cells was seen both in vitro in neurosphere models and in vivo upon xenograft. Finally, we observed that the use of ZOL-1 as combination therapy with multiple PI3K-AKT inhibitors in non-responder GBM resulted in enhanced chemotherapeutic efficacy. Altogether, this study establishes ZOL-1 as a safe and effective treatment against GBM and provides a foundation to conduct further studies evaluating its potential as an effective adjuvant with other chemotherapies and kinase inhibitors. [ABSTRACT FROM AUTHOR]

Cross-talk among oncogenic signaling and metabolic pathways may create opportunities for new therapeutic strategies in cancer. Here we show that although acute inhibition of EGFR-driven glucose metabolism induces only minimal cell death, it lowers the apoptotic threshold in a subset of patient-derived glioblastoma (GBM) cells. Mechanistic studies revealed that after attenuated glucose consumption, Bcl-xL blocks cytoplasmic p53 from triggering intrinsic apoptosis. Consequently, targeting of EGFR-driven glucose metabolism in combination with pharmacological stabilization of p53 with the brain-penetrant small molecule idasanutlin resulted in synthetic lethality in orthotopic glioblastoma xenograft models. Notably, neither the degree of EGFR-signaling inhibition nor genetic analysis of EGFR was sufficient to predict sensitivity to this therapeutic combination. However, detection of rapid inhibitory effects on [[sup.18]F]fluorodeoxyglucose uptake, assessed through noninvasive positron emission tomography, was an effective predictive biomarker of response in vivo. Together, these studies identify a crucial link among oncogene signaling, glucose metabolism, and cytoplasmic p53, which may potentially be exploited for combination therapy in GBM and possibly other malignancies., Author(s): Wilson X Mai [1]; Laura Gosa [1]; Veerle W Daniels [2]; Lisa Ta [1]; Jonathan E Tsang [1]; Brian Higgins [3]; W Blake Gilmore [1]; Nicholas A Bayley [1]; [...]

Amine‐weighted chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) is particularly valuable as an amine‐ and pH‐sensitive imaging technique in brain tumors, targeting the intrinsically high concentration of amino acids with exchangeable amine protons and reduced extracellular pH in brain tumors. Amine‐weighted CEST MRI contrast is dependent on the glioma genotype, likely related to differences in degree of malignancy and metabolic behavior. Amine‐weighted CEST MRI may provide complementary value to anatomic imaging in conventional and exploratory therapies in brain tumors, including chemoradiation, antiangiogenic therapies, and immunotherapies. Continual improvement and clinical testing of amine‐weighted CEST MRI has the potential to greatly impact patients with brain tumors by understanding vulnerabilities in the tumor microenvironment that may be therapeutically exploited. [ABSTRACT FROM AUTHOR]

Context: Diclofenac is commonly used as pain relief. Hypoglycemia has rarely been reported due to aspirin and indomethacin use but not of any other nonsteroidal anti-inflammatory drugs. Case report: A 69-years old endocrinologist participated as a control in a glucagon-like peptide-1 (GLP-1) study. He decreased his plasma glucose to 1.8 mmol/L and developed full-blown hypoglycemic symptoms during an oral glucose tolerance test (OGTT). He had taken a 50 mg diclofenac tablet at 10 pm the evening before for a harmless muscle stretch in the lower back. Apart from well-controlled hypothyroidism he was healthy. During medical school he often had reactive hypoglycemia which came after intake of a carbohydrate rich but otherwise poor breakfast followed by bicycling. However, he had never experienced problems later in life after more decent meals containing slower absorbable carbohydrates. A 3-day continuous glucose monitoring (CGM) was performed three weeks after the OGTT test. A glucose value of 3.1 mmol/L was registered on the third CGM day in the afternoon after intake of 500 mg aspirin in the early morning the same day. Otherwise, all values were normal. A second OGGT where no medications apart from levothyroxine had been taken during at least a 2-week period adjacent was normal. Detailed analyses of the OGTTs showed that the GLP-1 levels before the test were higher after diclofenac exposure while the insulin levels increased after the glucose challenge which suggesting uncoupling. Conclusion: With this case report we would like to draw attention to that diclofenac may cause hypoglycemia. [ABSTRACT FROM AUTHOR]

An eating disorder prevention program was completed with middle school, high school, and college females. Some successful outcomes included: (1) facilitating an acknowledgement of pressures to attain a model skeletal look; (2) changing attitudes about standards of beauty; and (3) altering the participants' current and future intentional use of pharmaceutical aids or disordered eating behaviors as methods of weight control. (Author/JDM)

Multiple sclerosis (MS) is an autoimmune disease driven by lymphocyte activation against myelin autoantigens in the central nervous system leading to demyelination and neurodegeneration. The deoxyribonucleoside salvage pathway with the rate‐limiting enzyme deoxycytidine kinase (dCK) captures extracellular deoxyribonucleosides for use in intracellular deoxyribonucleotide metabolism. Previous studies have shown that deoxyribonucleoside salvage activity is enriched in lymphocytes and required for early lymphocyte development. However, specific roles for the deoxyribonucleoside salvage pathway and dCK in autoimmune diseases such as MS are unknown. Here we demonstrate that dCK activity is necessary for the development of clinical symptoms in the MOG35–55 and MOG1–125 experimental autoimmune encephalomyelitis (EAE) mouse models of MS. During EAE disease, deoxyribonucleoside salvage activity is elevated in the spleen and lymph nodes. Targeting dCK with the small molecule dCK inhibitor TRE‐515 limits disease severity when treatments are started at disease induction or when symptoms first appear. EAE mice treated with TRE‐515 have significantly fewer infiltrating leukocytes in the spinal cord, and TRE‐515 blocks activation‐induced B and T cell proliferation and MOG35–55‐specific T cell expansion without affecting innate immune cells or naïve T and B cell populations. Our results demonstrate that targeting dCK limits symptoms in EAE mice and suggest that dCK activity is required for MOG35–55‐specific lymphocyte activation‐induced proliferation. [ABSTRACT FROM AUTHOR]

Objective: Patients with diabetes or familial hypercholesterolemia (FH) have an increased incidence of cardiovascular diseases compared with the population, but whether this risk is exacerbated in patients with combined traits is unknown.Research Design and Methods: In this Swedish nationwide, register-based cohort study, patients with diabetes were included between 2002 and 2020. Adjusted Cox proportional hazards models were used to assess the risk of cardiovascular events in patients with or without phenotypic FH (≥6 points for phenotypic FH according to Dutch Lipid Clinic Network criteria) compared with general population control subjects without diabetes as reference.Results: A total of 45,585 patients with type 1 diabetes (227,923 control subjects) and 655,250 patients with type 2 diabetes (655,250 control subjects) were followed for a median of 14.1 and 7.9 years, respectively. Of those, 153 and 7,197, respectively, had phenotypic FH. Compared with control subjects, patients with diabetes and phenotypic FH had higher risk of cardiovascular mortality (type 1: hazard ratio 21.3 [95% CI 14.6-31.0]; type 2: 2.40 [2.19-2.63]) and of a cardiovascular event (type 1: 15.1 [11.1-20.5]; type 2: 2.73 [2.58-2.89]). Further, patients with diabetes and phenotypic FH had higher LDL-cholesterol levels during observation (P < 0.05) and increased risk of all major cardiovascular outcomes (P < 0.0001) than patients with diabetes but without FH. The proportion receiving lipid-lowering treatment was higher in patients with phenotypic FH (P < 0.0001).Conclusions: Patients with both diabetes and phenotypic FH are more at risk for adverse cardiovascular outcomes and have higher LDL-cholesterol levels despite receiving intensified lipid-lowering therapy. [ABSTRACT FROM AUTHOR]