James Connor

The association between anemia and outcomes in glioblastoma patients is unclear. We analyzed data from 1346 histologically confirmed adult glioblastoma patients in the TriNetX Research Network. Median hemoglobin and hematocrit levels were quantified for 6 months following diagnosis and used to classify patients as anemic or non-anemic. Associations of anemia and iron supplementation of anemic patients with median overall survival (median-OS) were then studied. Among 1346 glioblastoma patients, 35.9% of male and 40.5% of female patients were classified as anemic using hemoglobin-based WHO guidelines. Among males, anemia was associated with reduced median-OS compared to matched non-anemic males using hemoglobin (HR 1.24; 95% CI 1.00–1.53) or hematocrit-based cutoffs (HR 1.28; 95% CI 1.03–1.59). Among females, anemia was not associated with median-OS using hemoglobin …

Iron deficiency (ID) and iron‐deficiency anaemia (IDA) are global public health concerns, most commonly afflicting children, pregnant women and women of childbearing age. Pathological outcomes of ID include delayed cognitive development in children, adverse pregnancy outcomes and decreased work capacity in adults. IDA is usually treated by oral iron supplementation, typically using iron salts (e.g. FeSO4); however, dosing at several‐fold above the RDA may be required due to less efficient absorption. Excess enteral iron causes adverse gastrointestinal side effects, thus reducing compliance, and negatively impacts the gut microbiome. Recent research has sought to identify new iron formulations with better absorption so that lower effective dosing can be utilized. This article outlines emerging research on oral iron supplementation and focuses on molecular mechanisms by which different supplemental …

Adequate and timely delivery of iron is essential for brain development. The uptake of transferrin‐bound (Tf) iron into the brain peaks at the time of myelination, whereas the recently discovered H‐ferritin (FTH1) transport of iron into the brain continues to increase beyond the peak in myelination. Here, we interrogate the impact of dietary iron deficiency (ID) on the uptake of FTH1‐ and Tf‐bound iron. In the present study, we used C57BL/6J male and female mice at a developing (post‐natal day (PND) 15) and adult age (PND 85). In developing mice, ID results in increased iron delivery from both FTH1 and Tf for both males and females. The amount of iron uptake from FTH1 was higher than the Tf and this difference between the iron delivery was much greater in females. In contrast, in the adult model, ID was associated with increased brain iron uptake by both FTH1 and Tf but only in the males. There was no increased …

Background Glioblastoma (GBM) displays alterations in iron that drive proliferation and tumor growth. Iron regulation is complex and involves many regulatory mechanisms, including the homeostatic iron regulator (HFE) gene, which encodes the homeostatic iron regulatory protein. While HFE is upregulated in GBM and correlates with poor survival outcomes, the function of HFE in GBM remains unclear. Methods We interrogated the impact of cell-intrinsic Hfe expression on proliferation and survival of intracranially implanted animals through genetic gain- and loss-of-function approaches in syngeneic mouse glioma models, along with in vivo immune assessments. We also determined the expression of iron-associated genes and their relationship to survival in GBM using public data sets and used transcriptional profiling to identify differentially expressed pathways in control …

METHODS:An autologous blood infusion model was utilized to create an ICH in the right caudate of H67D (human homolog of the H63D HFE mutation) and WT mice. Motor recovery was assessed using latency to fall from rotarod. 3-days post-ICH, the extent of neurodegeneration and mitochondrial damage in glial cells in the perihematomal area were measured using Fluorojade-B (FJB) and Cytochrome-C (CytC) immunofluorescent staining respectively. Levels of key regulatory proteins in the antioxidant and iron storage systems (Nrf2, GPX4, and FTH1) were evaluated using immunoblotting.RESULTS:H67D mice demonstrated significantly increased motor recovery at two-and three-days post-ICH compared to WT. H67D mice displayed significantly decreased degenerated neurons and CytC+ glial cells in the perihematomal region compared to WT. Furthermore, levels of Nrf2, GPX4, and FTH1 were significantly …

BackgroundIn primary retroperitoneal sarcoma (RPS), loco-regional and distant relapse occur frequently despite optimal surgical management. The role of chemotherapy in improving outcomes is unclear. The Australia and New Zealand Sarcoma Association (ANZSA) sought to develop clinical practice guidelines based on systematic review of the literature using the PICO model.MethodsA systematic review of ‘Does chemotherapy improve outcomes in adults with primary RPS?’was conducted. Three databases were searched (Medline, Embase and Cochrane Central) for publications from 1946 to June 2022. Two independent reviewers screened studies by title and abstract, reviewed full texts for eligibility, and extracted qualitative and quantitative data from eligible studies. Quality assessments were performed using the NHMRC evidence hierarchy and the Newcastle-Ottawa quality assessment scale.Results23 …

BackgroundApo- (iron free) and holo- (iron bound) transferrin (Tf) participate in precise regulation of brain iron uptake at endothelial cells of the blood–brain barrier. Apo-Tf indicates an iron-deficient environment and stimulates iron release, while holo-Tf indicates an iron sufficient environment and suppresses additional iron release. Free iron is exported through ferroportin, with hephaestin as an aid to the process. Until now, the molecular mechanisms of apo- and holo-Tf influence on iron release was largely unknown.MethodsHere we use a variety of cell culture techniques, including co-immunoprecipitation and proximity ligation assay, in iPSC-derived endothelial cells and HEK 293 cells to investigate the mechanism by which apo- and holo-Tf influence cellular iron release. Given the established role of hepcidin in regulating cellular iron release, we further explored the relationship of hepcidin to transferrin in this …

INTRODUCTION Photodynamic therapy (PDT) is an emerging investigational therapeutic for gliomas marked by variable success. Several strategies to increase its efficacy have been attempted, and although promising, challenges that have hindered translational progress persist. The objective of this study was to analyze translational barriers through a systematic review and appraisal of the in vivo literature. Method: PRISMA guidelines were utilized to identify studies that reported translational in vivo data of 5-aminolevulinic acid (5-ALA) PDT in murine glioma models. Databases were searched from inception to 2022, using the terms: “photodynamic therapy” AND (“5-ALA” OR “ALA” OR “PPIX”) AND “in vivo” AND (“glioma” OR “glioblastoma” OR astrocytoma”). Study design parameters were appraised, and mechanistic and translational outcomes across all studies were evaluated and compared …