Magnetite nanoparticles as a kinetically favorable source of iron to enhance GBM response to chemoradiosensitization with pharmacological ascorbate.

Ferumoxytol (FMX) is an FDA-approved magnetite (Fe3O4) nanoparticle used to treat iron deficiency anemia that can also be used as an MR imaging agent in patients that can't receive gadolinium. Pharmacological ascorbate (P-AscH-; IV delivery; plasma levels ≈ 20 mM) has shown promise as an adjuvant to standard of care chemo-radiotherapy in glioblastoma (GBM). Since ascorbate toxicity mediated by H2O2 is enhanced by Fe redox cycling, the current study determined if ascorbate catalyzed the release of ferrous iron (Fe2+) from FMX for enhancing GBM responses to chemo-radiotherapy. Ascorbate interacted with Fe3O4 in FMX to produce redox-active Fe2+ while simultaneously generating increased H2O2 fluxes, that selectively enhanced GBM cell killing (relative to normal human astrocytes) as opposed to a more catalytically active Fe complex (EDTA-Fe3+) in an H2O2 - dependent manner. In vivo, FMX was able to improve GBM xenograft tumor control when combined with pharmacological ascorbate and chemoradiation in U251 tumors that were unresponsive to pharmacological ascorbate therapy. These data support the hypothesis that FMX combined with P-AscH- represents a novel combined modality therapeutic approach to enhance cancer cell selective chemoradiosentization in the management of glioblastoma.

Quantum chemical insight into the effects of the local electron environment on T2*-based MRI.

T2* relaxation is an intrinsic magnetic resonance imaging (MRI) parameter that is sensitive to local magnetic field inhomogeneities created by the deposition of endogenous paramagnetic material (e.g. iron). Recent studies suggest that T2* mapping is sensitive to iron oxidation state. In this study, we evaluate the spin state-dependence of T2* relaxation using T2* mapping. We experimentally tested this physical principle using a series of phantom experiments showing that T2* relaxation times are directly proportional to the spin magnetic moment of different transition metals along with their associated magnetic susceptibility. We previously showed that T2* relaxation time can detect the oxidation of Fe2+. In this paper, we demonstrate that T2* relaxation times are significantly longer for the diamagnetic, d10 metal Ga3+, compared to the paramagnetic, d5 metal Fe3+. We also show in a cell culture model that cells supplemented with Ga3+ (S = 0) have a significantly longer relaxation time compared to cells supplemented with Fe3+ (S = 5/2). These data support the hypothesis that dipole-dipole interactions between protons and electrons are driven by the strength of the electron spin magnetic moment in the surrounding environment giving rise to T2* relaxation.

Follow-up of occupational asthma caused by crab and various agents.

Sixty-three subjects with occupational asthma caused by crab (n = 31) and various other agents (n = 32) were studied after cessation of exposure at work for mean +/- SD intervals of 12.3 +/- 5.5 and 24.5 +/- 18.7 months (greater than 6 months in every subject), respectively. Nineteen of the subjects with asthma caused by crab and 30 of the subjects with asthma caused by various agents were still symptomatic of asthma, nine subjects of the latter group requiring bronchodilators (with inhaled beclomethasone in five) regularly. No significant changes in baseline spirometry were observed at the time of follow-up as compared with initial assessment, nine subjects (all in the asthma group caused by various agents) demonstrating significant bronchial obstruction. Improvement in bronchial responsiveness to histamine was significant (p less than 0.01) in the group with asthma caused by crab but not in the other group. Forty-eight of 52 subjects still had significant airway hyperexcitability. Subjects with asthma caused by crab who were asymptomatic and those subjects with asthma caused by various agents who used bronchodilators only if they were needed had worked for shorter intervals after onset of symptoms (p less than 0.01 and p less than 0.05, respectively). It is concluded that subjects with occupational asthma caused by various agents can remain symptomatic of asthma and demonstrate a persistence of bronchial obstruction and hyperexcitability for prolonged intervals after cessation of exposure.

Occupational asthma in snow crab-processing workers.

The prevalence of occupational asthma was studied in two snow crab-processing industries in operation since 1980. Before the 1982 season, all except 10 of the 313 employees were investigated by a questionnaire, prick skin tests with common allergens, crab n and crab-boiling water extracts, and spirometry. The diagnosis was confirmed in 46 (15.6%) workers (including 33 of 64 subjects with a history highly suggestive of occupational asthma in the previous seasons) by (1) specific inhalation challenges in 33 subjects (one immediate, nine dual, and 23 late asthmatic responses) and/or (2) a combination of monitoring of peak expiratory flow rates (n = 12) and significant changes in bronchial responsiveness to histamine (n = 16) as well as in spirometry (n = 18) after reappearance of symptoms on return to work. Positive skin tests to crab (p less than 0.001) and, to a lesser degree, smoking history (p = 0.03) but not atopy (p greater than 0.05) were related to the presence of occupational asthma. A high prevalence of rhinoconjunctivitis (35 of 46) and urticaria (16 of 46) was also documented in the affected individuals.