Novel therapeutic strategies are needed to address the emerging problem of imatinib resistance. The histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) is being evaluated for imatinib-resistant chronic myelogenous leukemia (CML) and has multiple cellular effects, including the induction of autophagy and apoptosis. Considering that autophagy may promote cancer cell survival, we hypothesized that disrupting autophagy would augment the anticancer activity of SAHA. Here we report that drugs that disrupt the autophagy pathway dramatically augment the antineoplastic effects of SAHA in CML cell lines and primary CML cells expressing wild-type and imatinib-resistant mutant forms of BcrAbl, including T315I. This regimen has selectivity for malignant cells and its efficacy was not diminished by impairing p53 function, another contributing factor in imatinib resistance. IntroductionImatinib (Gleevec; STI-571), a targeted competitive inhibitor of the Bcr-Abl tyrosine kinase, revolutionized the clinical treatment of chronic myelogenous leukemia (CML). 1 However, acquired imatinib resistance during the accelerated and blast crisis phases of the disease is an emerging problem and has been linked to gene amplification, to point mutations in Bcr-Abl that impede drug binding or structurally preclude adoption of the inactive conformation, and to loss of p53 function. [2][3][4] Two novel inhibitors of Bcr-Abl, dasatinib and nilotinib, have been evaluated to address this problem. 5,6 Both agents produce clinical responses in many imatinib-refractory patients but not in those carrying the most drug-resistant T315I mutation, which confers cross-resistance to nilotinib and dasatinib. 7,8 The lack of effective therapeutic regimens for T315I patients thus highlights the dire need for novel therapeutic strategies that are effective in treating these patients.Histone deacetylase (HDAC) inhibitors represent a novel class of anticancer agents currently under investigation in preclinical models and in phase 1/2 clinical trials. [9][10][11][12] Suberoylanilide hydroxamic acid (SAHA) is an orally bioavailable, well-tolerated pan-HDAC inhibitor with anticancer activity in hematologic and solid malignancies. 12,13 SAHA's anticancer effects have been linked to the generation of reactive oxygen species (ROS) and to the induction of apoptosis, growth arrest, polyploidy, and autophagy. 14-17 Whether SAHA's ability to augment autophagy affects its anticancer activity remains unclear. Here we tested the hypotheses that disruption of the autophagy pathway would significantly enhance the anticancer activity of SAHA and that this would prove effective in killing imatinib-resistant CML. Patients, materials, and methods Cells and cell cultureBa/F3 cells and Ba/F3 cells engineered to express comparable levels of wild-type (p210) and mutant forms of Bcr-Abl (E255K, M351T, and T315I) were maintained as previously described. 2 K562 and LAMA 84 CML cells were maintained in RPMI-1640 media with 10% heat-inactivated fetal bovine serum at 3...

Ménière's disease patients' hearing outcomes seem to be worse than the general CI population. However, those with active MD perform similarly to the general CI population.

Partial inactivation of the Ankyrin repeat domain 26 (Ankrd26) gene causes obesity and diabetes in mice and increases spontaneous and induced adipogenesis in mouse embryonic fibroblasts. However, it is not yet known how the Ankrd26 protein carries out its biological functions. We identified by yeast two-hybrid and immunoprecipitation assays the triple functional domain protein (TRIO), the G protein pathway suppressor 2 (GPS2), the delta-interacting protein A (DIPA) and the hyaluronan-mediated motility receptor (HMMR) as ANKRD26 interacting partners. Adipogenesis of 3T3-L1 cells was increased by selective down-regulation of Ankrd26, Trio, Gps2, Hmmr and Dipa. Furthermore, GPS2 and DIPA, which are normally located in the nucleus, were translocated to the cytoplasm, when the C-terminus of ANKRD26 was introduced into these cells. These findings provide biochemical evidence that ANKRD26, TRIO, GPS2 and HMMR are novel and important regulators of adipogenisis and identify new targets for the modulation of adipogenesis.

4.

ObjectiveTo determine if reliable, objective audiologic data can be obtained by nonotolaryngology and nonaudiology practitioners using novel mobile technology in an effort to expand the capacity for early identification and treatment of disabling hearing loss in the developing world.Study DesignCross-sectional, proof-of-concept pilot study.SettingScreenings took place during an annual 2-week otolaryngology surgical mission in October 2016 in semirural Malindi, Kenya.Subject and MethodsEighty-seven patients (174 total ears) were included from 2 deaf schools (n = 12 and 9), a nondeaf school (n = 9), a tuberculosis ward (n = 8), and a walk-in otology clinic at a local hospital (n = 49). An automated, tablet-based, language-independent, clinically validated, play audiometry system and wireless otoscopic endoscopy via an iPhone or laptop platform was administered by Kenyan community health workers (CHWs) and nursing staff.ResultsVarious degrees of hearing loss and otologic pathology were identified, including 1 child presumed to be deaf who was found to have unilaterally normal hearing. Other pathology included 2 active perforations, 2 healed perforations, 2 middle ear effusions, and 1 cholesteatoma. CHWs and nursing staff demonstrated proficiency performing audiograms and endoscopy. Patients screened in a deaf school were more likely to complete an unreliable audiogram than patients screened in other settings (P < .01).ConclusionThis study demonstrates the feasibility of a non–otolaryngology-based hearing screening program. This may become an important tool in reducing the impact of hearing loss and otologic pathology in areas bereft of otolaryngologists and audiologists by allowing CHWs to gather important patient data prior to otolaryngologic evaluation.

Streptococcus pneumoniae vaccinations have dramatically decreased the incidence of serotype-specific invasive pneumococcal disease across all age groups. However, the optimal timing of immunization remains unclear in cochlear implant candidates.

The majority of studies evaluating the safety and efficacy of MEIs are retrospective in nature with limited follow-up. To date, no prospective randomized controlled trial exists comparing contemporary air conduction hearing aid performance and MEI outcomes. Based on available data for patients with sensorineural hearing loss, functional gain and word recognition improvement seems similar between conventional hearing aids and MEIs, whereas patient-perceived outcome measures suggest that MEIs provide enhanced sound quality and eliminate occlusion effect.

Objective: To establish the feasibility of a systematic, community health worker (CHW)-based hearing screening program that gathers Health Insurance Portability and Accountability Act-compliant electronic data (otoscopic images of tympanic membrane and audiometric evaluation) on a smartphone in an effort to streamline treatment options in resource-limited communities.Methods: This is a cross-sectional study in which four schools were screened in Portau-Prince, Haiti, during in April 2018. A total of 122 subjects (61% female) aged 5-17 years underwent an initial brief audiometric screen followed by a more comprehensive air conduction audiometric evaluation if they failed their initial screen. Participants with more than 35-dB loss in any frequency on their comprehensive audiometric evaluation received endoscopic otoscopy.Results: Seventy-five percent of subjects (91/122) passed their initial screen. Of those who failed, 9% (4/44 ears) had a severe or profound hearing loss on comprehensive evaluation. Abnormal otoscopic findings (11/36 ears, 31%) included are cerumen impaction (n = 6), myringosclerosis (n = 3), tympanic membrane perforation (n = 1), and tympanic membrane retraction (n = 1). The average duration of the initial testing was 100 seconds (SD = 74 seconds), whereas the duration of comprehensive testing was 394 seconds (SD = 175 seconds). Extrapolating from these data, we estimate that a group of seven trained CHWs could gather formal audiologic and otologic data points for 100 children per hour using this protocol.