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BackgroundHearing impairment is the most frequent sensory deficit in humans, affecting more than 360 million people worldwide. In fact, hearing impairment is not merely a health problem, but it also has a great impact on the educational performance, economic income, and quality of life. Hearing impairment is therefore an important social concern. ObjectiveWe aimed to evaluate and compare the accuracy of self-perception, Hearing Handicap Inventory for the Elderly-Screening (HHIE-S) questionnaire, free-field voice test, and smartphone-based audiometry as tests for screening moderate hearing impairment in older adults in China. MethodsIn this study, 41 patients were recruited through a single otology practice. All patients were older than 65 years. Patients with otorrhea and cognitive impairment were excluded. Moderate hearing impairment was defined as mean hearing thresholds at 500, 1000, 2000, and 4000 Hz >40 dB hearing loss (pure-tone average > 40 dB hearing loss). All patients completed 5 hearing tests, namely, the self-perception test, HHIE-S questionnaire test, free-field voice test, smartphone-based audiometry test, and standard pure-tone audiometry by the same audiologist. We compared the results of these tests to the standard audiogram in the better-hearing ear. ResultsThe sensitivity and the specificity of the self-perception test were 0.58 (95% CI 0.29-0.84) and 0.34 (95% CI 0.19-0.54), respectively. The sensitivity and the specificity of the HHIE-S questionnaire test were 0.67 (95% CI 0.35-0.89) and 0.31 (95% CI 0.316-0.51), respectively. The sensitivity and the specificity of the free-field voice test were 0.83 (95% CI 0.51-0.97) and 0.41 (95% CI 0.24-0.61), respectively. The sensitivity and the specificity of the smartphone-based audiometry test were 0.92 (95% CI 0.60-0.99) and 0.76 (95% CI 0.56-0.89), respectively. Smartphone-based audiometry correctly diagnosed the presence of hearing loss with high sensitivity and high specificity. ConclusionsSmartphone-based audiometry may be a dependable screening test to rule out moderate hearing impairment in the older population.

The molecular underpinnings of acquired resistance to carboplatin are poorly understood and often inconsistent between in vitro modeling studies. After sequential treatment cycles, multiple isogenic clones reached similar levels of resistance, but significant transcriptional heterogeneity. Gene-expression based virtual synchronization of 26,772 single cells from 2 treatment steps and 4 resistant clones was used to evaluate the activity of Hallmark gene sets in proliferative (P) and quiescent (Q) phases. Two behaviors were associated with resistance: (1) broad repression in the P phase observed in all clones in early resistant steps and (2) prevalent induction in Q phase observed in the late treatment step of one clone. Furthermore, the induction of IFNα response in P phase or Wnt-signaling in Q phase were observed in distinct resistant clones. These observations suggest a model of resistance hysteresis, where functional alterations of the P and Q phase states affect the dynamics of the successive transitions between drug exposure and recovery, and prompts for a precise monitoring of single-cell states to develop more effective schedules for, or combination of, chemotherapy treatments.

This paper proposes an online multi-user real-time co-reading (OMURCOR) system to promote the performance of co-reading with collaborative learning. The OMURCOR system utilizes WebSocket to perform synchronization controls on co-reading to allow teachers and students to watch streaming videos together with less delay. Moreover, teachers utilize the system to synchronize control operations of videos on the student site, and the OMURCOR system can be integrated into a learning management system to strengthen students' interaction through co-reading. Unlike traditional platforms, the system supports grouping mechanisms during instruction. A survey was conducted with 104 participants. The bootstrapping square and partial least square approaches of the structural equation modeling (PLS-SEM) are employed via the SmartPLS tool to explore evidence of reliability and validity of the revised TAM. Experimental results reflected that six of the seven hypotheses were supported, and the proposed system has a significant impact on students' learning effectiveness during co-reading.

APTO-253 is a small molecule with antiproliferative activity against cell lines derived from a wide range of human malignancies. We sought to determine the mechanisms of action and basis for resistance to APTO-253 so as to identify synthetic lethal interactions that can guide combination studies. The cellular pharmacology of APTO-253 was analyzed in Raji lymphoma cells and a subline selected for resistance (Raji/253R). Using LC/MS/ESI analysis, APTO-253 was found to convert intracellularly to a complex containing one molecule of iron and three molecules of APTO-253 [Fe(253)3]. The intracellular content of Fe(253)3 exceeded that of the native drug by approximately 18-fold, and Fe(253)3 appears to be the most active form. Treatment of cells with APTO-253 caused DNA damage, which led us to ask whether cells deficient in homologous recombination (i.e., loss of BRCA1/2 function) were hypersensitive to this drug. It was found that loss of either BRCA1 or BRCA2 function in multiple isogenic paired cell lines resulted in hypersensitivity to APTO-253 of a magnitude similar to the effects of PARP inhibitors, olaparib. Raji cells selected for 16-fold acquired resistance had 16-fold reduced accumulation of Fe(253)3 RNA-seq analysis revealed that overexpression of the ABCG2 drug efflux pump is a key mechanism of resistance. ABCG2-overexpressed HEK-293 cells were resistant to APTO-253, and inhibition of ABCG2 reversed resistance to APTO-253 in Raji/253R. APTO-253 joins the limited repertoire of drugs that can exploit defects in homologous recombination and is of particular interest because it does not produce myelosuppression. Mol Cancer Ther; 17(6); 1167-76. ©2018 AACR.

APTO-253 is a phase I clinical stage small molecule that selectively induces CDKN1A (p21), promotes G0-G1 cell-cycle arrest, and triggers apoptosis in acute myeloid leukemia (AML) cells without producing myelosuppression in various animal species and humans. Differential gene expression analysis identified a pharmacodynamic effect on MYC expression, as well as induction of DNA repair and stress response pathways. APTO-253 was found to elicit a concentration- and time-dependent reduction in MYC mRNA expression and protein levels. Gene ontogeny and structural informatic analyses suggested a mechanism involving G-quadruplex (G4) stabilization. Intracellular pharmacokinetic studies in AML cells revealed that APTO-253 is converted intracellularly from a monomer to a ferrous complex [Fe(253)3]. FRET assays demonstrated that both monomeric APTO-253 and Fe(253)3 stabilize G4 structures from telomeres, MYC, and KIT promoters but do not bind to non-G4 double-stranded DNA. Although APTO-253 exerts a host of mechanistic sequelae, the effect of APTO-253 on MYC expression and its downstream target genes, on cell-cycle arrest, DNA damage, and stress responses can be explained by the action of Fe(253)3 and APTO-253 on G-quadruplex DNA motifs. Mol Cancer Ther; 17(6); 1177-86. ©2018 AACR.

The development of resistance to cisplatin (cDDP) is commonly accompanied by reduced drug uptake or increased efflux. Previous studies in yeast and murine embryonic fibroblasts have reported that the copper (Cu) transporters and chaperones participate in the uptake, efflux, and intracellular distribution of cDDP. However, there is conflicting data from studies in human cells. We used CRISPR-Cas9 genome editing to individually knock out the human copper transporters CTR1 and CTR2 and the copper chaperones ATOX1 and CCS. Isogenic knockout cell lines were generated in both human HEK-293T and ovarian carcinoma OVCAR8 cells. All knockout cell lines had slowed growth compared to parental cells, small changes in basal Cu levels, and varying sensitivities to Cu depending on the gene targeted. However, all of the knockouts demonstrated only modest 2 to 5-fold changes in cDDP sensitivity that did not differ from the range of sensitivities of 10 wild type clones grown from the same parental cell population. We conclude that, under basal conditions, loss of CTR1, CTR2, ATOX1, or CCS does not produce a change in cisplatin sensitivity that exceeds the variance found within the parental population, suggesting that they are not essential to the mechanism by which cDDP enters these cell lines and is transported to the nucleus.