Browsing by Subject "peripheral neuropathy"

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    Adverse Health Outcomes among U.S. Testicular Cancer Survivors after Cisplatin-Based Chemotherapy vs. Surgical Management
    (Oxford, 2019-10) Agrawal, Vaibhav; Dinh, Paul C., Jr.; Fung, Chunkit; Monahan, Patrick O.; Althouse, Sandra K.; Norton, Kelli; Cary, Clint; Einhorn, Lawrence; Fossa, Sophie D.; Adra, Nabil; Travis, Lois B.; Medicine, School of Medicine
    We evaluated for the first time adverse health outcomes (AHOs) among U.S. testicular cancer survivors (TCS) given chemotherapy (n = 381) vs. surgery-only patients (n = 98) managed at a single institution, accounting for non-treatment-related risk factors to delineate chemotherapy’s impact. Chemotherapy consisted largely of bleomycin-etoposide-cisplatin (BEP) administered in 3 or 4 cycles (BEPX3, n = 235; BEPX4, n = 82). Incidence of ≥ 3 AHOs was lowest in surgery-only TCS and increased with BEPX3, BEPX4 and other cisplatin-based regimens (12.2%, 40.8%, 52.5%, 54.8%; P<0.0001). Multivariate modeling assessed associations of risk factors and treatment with hearing impairment, tinnitus, peripheral neuropathy, and Raynaud phenomenon. Risk for each AHO significantly increased with both increasing chemotherapy burden (P < 0.0001) and selected modifiable risk factors (P < 0.05): hypertension (OR = 2.40) and noise exposure (OR ≥ 2.3) for hearing impairment; noise exposure for tinnitus (OR ≥ 1.69); peripheral vascular disease for neuropathy (OR = 8.72), and current smoking for Raynaud phenomenon (OR = 2.41). Clinicians should manage modifiable risk factors for AHOs among TCS.
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    Paclitaxel inhibits the activity and membrane localization of PKCα and PKCβI/II to elicit a decrease in stimulated calcitonin gene-related peptide release from cultured sensory neurons
    (Elsevier, 2017) Darby, Lisa M.; Meng, Hongdi; Fehrenbacher, Jill C.; Department of Pharmacology and Toxicology, IU School of Medicine
    Peripheral neuropathy is a dose-limiting and debilitating side effect of the chemotherapeutic drug, paclitaxel. Consequently, elucidating the mechanisms by which this drug alters sensory neuronal function is essential for the development of successful therapeutics for peripheral neuropathy. We previously demonstrated that chronic treatment with paclitaxel (3–5 days) reduces neuropeptide release stimulated by agonists of TRPV1. Because the activity of TRPV1 channels is modulated by conventional and novel PKC isozymes (c/nPKC), we investigated whether c/nPKC mediate the loss of neuropeptide release following chronic treatment with paclitaxel (300 nM; 3 and 5 days). Release of the neuropeptide, calcitonin gene-related peptide (CGRP), was measured as an index of neuronal sensitivity. Following paclitaxel treatment, cultured dorsal root ganglia sensory neurons were stimulated with a c/nPKC activator, phorbol 12,13-dibutyrate (PDBu), or a TRPV1 agonist, capsaicin, in the absence and presence of selective inhibitors of conventional PKCα and PKCβI/II isozymes (cPKC). Paclitaxel (300 nM; 3 days and 5 days) attenuated both PDBu- and capsaicin-stimulated release in a cPKC-dependent manner. Under basal conditions, there were no changes in the protein expression, phosphorylation or membrane localization of PKC α, βI or βII, however, paclitaxel decreased cPKC activity as indicated by a reduction in the phosphorylation of cPKC substrates. Under stimulatory conditions, paclitaxel attenuated the membrane translocation of phosphorylated PKC α, βI and βII, providing a rationale for the attenuation in PDBu- and capsaicin-stimulated release. Our findings suggest that a decrease in cPKC activity and membrane localization are responsible for the reduction in stimulated peptide release following chronic treatment with paclitaxel in sensory neurons.