Contribution of macrophages to neural survival and intracochlear tissue remodeling responses following cochlear implantation.

BACKGROUND: Cochlear implants (CIs) restore hearing to deafened patients. The foreign body response (FBR) following cochlear implantation (post-CI) comprises an infiltration of macrophages, other immune and non-immune cells, and fibrosis into the scala tympani, a space that is normally devoid of cells. This FBR is associated with negative effects on CI outcomes including increased electrode impedances and loss of residual acoustic hearing. This study investigates the extent to which macrophage depletion by an orally administered CSF-1R specific kinase (c-FMS) inhibitor, PLX-5622, modulates the tissue response to CI and neural health. MAIN TEXT: 10- to 12-week-old CX3CR1 + /GFP Thy1 + /YFP mice on C57BL/6J/B6 background was fed chow containing 1200 mg/kg PLX5622 or control chow for the duration of the study. 7 days after starting the diet, 3-channel cochlear implants were implanted in the ear via the round window. Serial impedance and neural response telemetry (NRT) measurements were acquired throughout the study. Electric stimulation began 7 days post-CI until 28 days post-CI for 5 h/day, 5 days/week, with programming guided by NRT and behavioral responses. Cochleae harvested at 10, 28 or 56 days post-CI were cryosectioned and labeled with an antibody against α-smooth muscle actin (α-SMA) to identify myofibroblasts and quantify the fibrotic response. Using IMARIS image analysis software, the outlines of scala tympani, Rosenthal canal, modiolus, and lateral wall for each turn were traced manually to measure region volume. The density of nuclei, CX3CR1 + macrophages, Thy1 + spiral ganglion neuron (SGN) numbers, and the ratio of the α-SMA + volume/scala tympani volume were calculated. Cochlear implantation in control diet subjects caused infiltration of cells, including macrophages, into the cochlea. Fibrosis was evident in the scala tympani adjacent to the electrode array. Mice fed PLX5622 chow showed reduced macrophage infiltration throughout the implanted cochleae across all time points. However, scala tympani fibrosis was not reduced relative to control diet subjects. Further, mice treated with PLX5622 showed increased electrode impedances compared to controls. Finally, treatment with PLX5622 decreased SGN survival in implanted and contralateral cochleae. CONCLUSION: The data suggest that macrophages play an important role in modulating the intracochlear tissue response following CI and neural survival.

Organic Functionalization of Uranyl Peroxide Clusters to Impact Solubility.

Benzene-1,2-diphosphonic acid (Ppb) was introduced into the uranyl peroxide cluster system, resulting in three Ppb-functionalized uranyl peroxide clusters, (UO2)20(O2)20(C6H4P2O6)1040- (U20Ppb10), (UO2)26(O2)33(C6H4P2O6)638- (U26Ppb6), and (UO2)20(O2)24(C6H4P2O6)632- (U20Ppb6). Dissolution experiments were performed for the potassium salts of U20Ppb10 and U26Ppb6, which revealed the capacity of U20Ppb10 to dissolve in the organic solvent dimethyl sulfoxide (DMSO). Unlike U20Ppb10, the K salt of U26Ppb6 did not dissolve in DMSO but was more soluble in water, perhaps due to the lower proportion of Ppb ligands in its structure. In this work, U20Ppb10 and U20Ppb6 formed as potassium salts and both adopt the fullerene topology of previously reported U20. U20 contains 20 uranyl peroxide units and encapsulates 12 Na cations. It is not possible for unfunctionalized U20 to incorporate 12 K cations owing to space constraints, as is the case in the new clusters reported here. Transformation of U20Ppb10 in water over time to produce U24 was observed, possibly owing to its ability to incorporate K cations, which have been associated with the formation of U24.

Design and semisynthesis of novel fredericamycin A derivatives with an improved antitumor profile.

We report the design, semisynthesis, and biological activity of a series of fredericamycin (1) derivatives. Within this series compound 1e combines low nanomolar cytotoxic potency in vitro, increased tumor cell line selectivity, and in vivo activity in a human xenograft model.