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Objective We sought to determine the biocompatibility of electrospun regenerated silk fibroin (RSF) mats with inner ear progenitors, especially their effect on the differentiation of inner ear progenitors into hair cells. Methods Neonatal mouse cochleae (n = 20) were collected and digested and allowed to form spheres over several days. Cells digested from the spheres were then seeded onto aligned or random RSF mats, with laminin-coated coverslips serving as controls. The inner ear progenitor cell mortality was examined by TUNEL labeling, and the adhesion of cells to the RSF mats or coverslip was determined by scanning electron microscopy. Finally, the number of hair cells that differentiated from inner ear progenitors was determined by Myosin7a expression. Unpaired Student’s t-tests and one-way ANOVA followed by a Dunnett’s multiple comparisons test were used in this study ( p < 0.05). Results After 5 days of culture, the inner ear progenitors had good adhesion to both the aligned and random RSF mats and there was no significant difference in TUNEL+ cells between the mats compared to the coverslip ( p > 0.05). After 7 days of in vitro differentiation culture, the percentage of differentiated hair cells on the control, aligned, and random RSF mats was 2.5 ± 0.5%, 2.7 ± 0.4%, and 2.4 ± 0.2%, respectively, and there was no significant difference between Myosin7a+ cells on either RSF mat compared to controls ( p > 0.05). Conclusion The aligned and random RSF mats had excellent biocompatibility with inner ear progenitors and helped the inner ear progenitors maintain their stemness. Our results thus indicate that RSF mats represent a useful scaffold for the development of new strategies for inner ear tissue engineering research.

It has been claimed that salvianolic acid B (Sal B), a natural bioactive antioxidant, exerts protective effects in various types of cells. This study aims to evaluate the antioxidant and anti‐apoptosis effects of Sal B in a cultured HEI‐OC1 cell line and in transgenic zebrafish (Brn3C: EGFP). A CCK‐8 assay, Annexin V Apoptosis Detection Kit, TUNEL and caspase‐3/7 staining, respectively, examined apoptosis and cell viability. The levels of reactive oxygen species (ROS) were evaluated by CellROX and MitoSOX Red staining. JC‐1 staining was employed to detect the mitochondrial membrane potential (ΔΨm). Western blotting was used to assess expressions of Bax and Bcl‐2. The expression pattern of p‐PI3K and p‐Akt was determined by immunofluorescent staining. We found that Sal B protected against neomycin‐ and cisplatin‐induced apoptotic features, enhanced cell viability and accompanied with decreased caspase‐3 activity in the HEI‐OC1 cells. Supplementary experiments determined that Sal B reduced ROS production (increased ΔΨm), promoted Bcl‐2 expression and down‐regulated the expression of Bax, as well as activated PI3K/AKT signalling pathways in neomycin‐ and cisplatin‐injured HEI‐OC1 cells. Moreover, Sal B markedly decreased the TUNEL signal and protected against neomycin‐ and cisplatin‐induced neuromast HC loss in the transgenic zebrafish. These results unravel a novel role for Sal B as an otoprotective agent against ototoxic drug–induced HC apoptosis, offering a potential use in the treatment of hearing loss.

Background: KCNKs, potassium two pore domain channel family K members, can maintain the resting potential, regulate the amplitude and duration of the plateau of the action potential, and change the membrane potential and membrane excitability. Evidence from many studies indicates that KCNKs is abnormally expressed in many solid tumors and plays a regulatory role in the development and malignant progression of cancer. However, the expression pattern and prognostic value of KCNK factors in papillary thyroid carcinoma have not been reported. Methods: In this study, we used the data from databases such as ONCOMINE, GEPIA, Kaplan-Meier Plotter, and cBioPortal to perform bioinformatics analysis of KCNK factors in patients with thyroid cancer. Results: We found that the mRNA expression of KCNK1, KCNK5, KCNK6, KCNK7, and KCNK15 were significantly higher in thyroid cancer tissues than that in normal tissues, while KCNK2, KCNK4, KCNK9, KCNK16 and KCNK17 mRNA levels were decreased compared to normal tissues. And the expression levels of KCNK1/2/4/5/6/7/15 were correlated with the tumor stage. Survival analysis using the Kaplan-Meier Plotter database revealed that KCNK2/3/4/5/12/15 were associated with overall survival (OS) in patients with thyroid cancer. Conclusion: Finally, the results of ROC curves, immunohistochemical staining, immune cell infiltration and kinase / miRNA / transcription factor regulation showed that KCNK2, KCNK4, KCNK5 and KCNK15 levels could be used as biomarkers for PTC diagnosis. This study implied that KCNK2, KCNK4, KCNK5 and KCNK15 are potential targets of precision therapy for patients with thyroid cancer and these genes are new biomarkers for the therapeutic target for thyroid cancer.

Circular RNAs (circRNAs) are novel RNA molecules that play important roles in chemoresistance in different cancers, including breast and gastric cancers. However, whether circRNAs are involved in the response to chemotherapy in small cell lung cancer (SCLC) remains largely unknown. In this study, we observed that cESRP1 (circular RNA epithelial splicing regulatory protein-1) expression was significantly downregulated in the chemoresistant cells compared with the parental chemosensitive cells. cESRP1 enhanced drug sensitivity by repressing miR-93-5p in SCLC. Cytoplasmic cESRP1 could directly bind to miR-93-5p and inhibit the posttranscriptional repression mediated by miR-93-5p, thereby upregulating the expression of the miR-93-5p downstream targets Smad7/p21(CDKN1A) and forming a negative feedback loop to regulate transforming growth factor-β (TGF-β) mediated epithelial-mesenchymal transition. Furthermore, cESRP1 overexpression and TGF-β pathway inhibition both altered tumour responsiveness to chemotherapy in an acquired chemoresistant patient-derived xenograft model. Importantly, cESRP1 expression was downregulated in SCLC patient tissues and was associated with survival. Our findings reveal, for the first time, that cESRP1 plays crucial a role in SCLC chemosensitivity by sponging miR-93-5p to inhibit the TGF-β pathway, suggesting that cESRP1 may serve as a valuable prognostic biomarker and a potential therapeutic target in SCLC patients.

Background: Recent research showed that abnormal lipid metabolism was associated with cancers. As one of the genes that can regulate the level of lipid metabolism, abnormal APOE expression was associated with carcinogenesis. However, the biological role of APOE in papillary thyroid carcinoma (PTC) remains to be determined.Methods: ONCOMINE, GEPIA, UALCAN, STRING, GeneMANIA, LinkedOmics, GSCALite, TISIDB, EPIC and TIMER were utilized to achieve comprehensively bioinformatics analysis of APOE in this study. And the immunohistochemical staining of APOE was used to verify the predicted results.Results: The mRNA level and protein level of APOE of PTC tissues were significantly elevated in TCGA cohort and Shanghai cohort. And APOE expression was positively correlated with the pathological stage and lymph node metastasis in PTC. PTC patients with low mRNA level of APOE were associated with a bad prognosis. The functions of APOE co-expressed genes were mainly enriched in adaptive immune response, protein-lipid complex subunit organization, actin cytoskeleton reorganization, cell chemotaxis, protein activation cascade and transcriptional misregulation in cancer. APOE level was significantly correlated with tumor-infiltrating cells (B cells, CD8+ T cells, neutrophils, and dendritic) and immune biomarkers in PTC.Conclusions: APOE is a potential independent biomarker for PTC and APOE expression is positively correlated with immune cell infiltration in PTC.

Background: In recent years, the annual incidence of thyroid cancer (TC) has increased, with papillary thyroid cancer (PTC) identified as the most commonwinwordpathological type accounting for approximately 80% of all thyroid cancer cases. The tumor microenvironment is known to play a vital role in tumor information transmission and immune detection. Methods: In the present study, we examined gene expression data from 518 patients with PTC. The ESTIMATE algorithm was used to calculate immune and stromal scores of PTC patients. Based on a protein–protein interaction (PPI) network, functional enrichment and overall survival analyses, C-X-C motif chemokine ligand 10 (CXCL10) was identified as a core gene. We further investigated the roles of core genes of PTC in the tumor immune microenvironment using LinkedOmics, GSEA, and TIMER tools. Results: Immune, stromal and ESTIMATE scores were related to clinicopathological variables of patients with PTC, but not survival outcomes. Eight differentially expressed genes (DEGs) were associated with survival outcome. In addition, immunochemical staining experiments revealed lower expression of CXCL10 in PTC than paracancerous tissues. GSEA pathway enrichment analysis revealed downregulation of CXCL10 in multiple cancer pathways. CXCL10 and related genes were enriched in pathways related to adaptive immune response, cellular defense response and regulation of innate immune response. Conclusion: The tumor microenvironment plays a critical role in development of PTC and CXCL10 may serve as a novel target of precision therapy for this patient population.

OBJECTIVES To determine the clinical characteristics of papilloma involving the external auditory canal (PEAC) in a region of China. STUDY DESIGN A retrospective study. METHODS Demographics, manifestations, imaging results, histopathology, and treatment of 67 patients diagnosed with PEAC in a period of 6 years were analyzed at Shanghai Eye, Ear, Nose and Throat Hospital in China. RESULTS PEAC were encountered in patients between the ages of 12 and 82 years (mean 53.8 years). It was more prevalent in men (82%) than in women (18%) (P

Background:Papillary thyroid carcinoma (PTC) is one of the fastest-growing malignant tumor types of thyroid cancer. Therefore, identifying the interaction of genes in PTC is crucial for elucidating its pathogenesis and finding more specific molecular biomarkers. Methods:In this study, 4 pairs of PTC tissues and adjacent tissues were sequenced using RNA-Seq, and 3745 differentially expressed genes (DEGs) were screened. The results of GO and KEGG enrichment analysis indicate that the vast majority of DEGs may play a positive role in the development of cancer. Then, the significant modules were analysed using Cytoscape software in the protein-protein interaction (PPI) network. Survival analysis, TNM analysis, and immune infiltration analysis of key genes are all analyzed. And the expression of ADORA1, APOE and LPAR5 genes was verified by qPCR in papillary thyroid carcinoma compared to their matching adjacent tissues.Results: A total of 25 genes were identified as hub genes with nodes greater than 10. The expression of 25 key genes in PTC were verified by the GEPIA database, and the overall survival and disease free survival analyses of these key genes were conducted with Kaplan–Meier plots. We found that only three genes were confirmed with our validation and were statistically significant in PTC, namely ADORA1, APOE, and LPAR5. Further analysis found that the mRNA levels and methylation degree of these three genes are significantly correlated with the TNM staging of PTC, and these three genes are related to PTC immune infiltration. Verification of the expression of these three genes by RT-qPCR further confirmed the reliability of our results. Conclusion: Our study identified three genes that may play key regulatory roles in the development, metastasis, and immune infiltration of papillary thyroid carcinoma.Key words :RNA-Seq, papillary thyroid carcinoma, key gene, bioinformatics

Objectives To investigate the role of dibenzazepine (DBZ) in promoting supporting cell (SC) proliferation and hair cell (HC) regeneration in the inner ear. Materials and Methods Postnatal day 1 wild‐type or neomycin‐damaged mouse cochleae were cultured with DBZ. Immunohistochemistry and scanning electron microscopy were used to examine the morphology of cochlear cells, and high‐throughput RNA‐sequencing was used to measure gene expression levels. Results We found that DBZ promoted SC proliferation and HC regeneration in a dose‐dependent manner in both normal and damaged cochleae. In addition, most of the newly regenerated HCs induced by DBZ had visible and relatively mature stereocilia bundle structures. Finally, RNA sequencing detected the differentially expressed genes between DBZ treatment and controls, and interaction networks were constructed for the most highly differentially expressed genes. Conclusions Our study demonstrates that DBZ can significantly promote SC proliferation and increase the number of mitotically regenerated HCs with relatively mature stereocilia bundles in the neonatal mouse cochlea by inhibiting Notch signalling and activating Wnt signalling, suggesting the DBZ might be a new therapeutic target for stimulating HC regeneration., Hair cell (HC) damage is the main cause of permanent hearing loss in mammals. To investigate the role of DBZ in the neonatal mouse cochlea, we cultured postnatal day 1 mouse cochleae with DBZ. We found that DBZ promoted SC proliferation and new HC generation in a dose‐dependent manner in both intact and damaged cochleae. In addition, most of the newly generated HCs induced by DBZ had visible and relatively mature stereocilia bundle structures. Our study demonstrates that DBZ can significantly promote SC proliferation and increase the number of mitotically regenerated HCs with relatively mature stereocilia bundles in the neonatal mouse cochlea by inhibiting Notch signalling and activating Wnt signalling, suggesting the DBZ might be a new therapeutic target for stimulating HC regeneration.

The utricle is one of the five sensory organs in the mammalian vestibular system, and while the utricle has a limited ability to repair itself, this is not sufficient for the recovery of vestibular function after hair cell (HC) loss induced by ototoxic drugs. In order to further explore the possible self-recovery mechanism of the adult mouse vestibular system, we established a reliable utricle epithelium injury model for studying the regeneration of HCs and examined the toxic effects of 3,3′-iminodiproprionitrile (IDPN) on the utriclein vivoin C57BL/6J mice, which is one of the most commonly used strains in inner ear research. This work focused on the epithelial cell loss, vestibular dysfunction, and spontaneous cell regeneration after IDPN administration. HC loss and supporting cell (SC) loss after IDPN treatment was dose-dependent and resulted in dysfunction of the vestibular system, as indicated by the swim test and the rotating vestibular ocular reflex (VOR) test. EdU-positive SCs were observed only in severely injured utricles wherein above 47% SCs were dead. No EdU-positive HCs were observed in either control or injured utricles. RT-qPCR showed transient upregulation ofHes5andHey1and fluctuating upregulation ofAxin2andβ-cateninafter IDPN administration. We conclude that a single intraperitoneal injection of IDPN is a practical way to establish an injured utricle model in adult C57BL/6J micein vivo. We observed activation of Notch and Wnt signaling during the limited spontaneous HC regeneration after vestibular sensory epithelium damage, and such signaling might act as the promoting factors for tissue self-repair in the inner ear.

Trefoil factor 3 (TFF3) was found to be overexpressed in many types of tumours. Evidence has shown that TFF3 plays an important role in tumour proliferation, migration and invasion metastasis. However, the impact of TFF3 on patients' clinicopathological characteristics and underlying mechanisms remain unknown in papillary thyroid carcinoma (PTC). In this study, the expression of TFF3 and the epithelial-mesenchymal transition (EMT) transcriptional factor Snail in PTC and para-carcinoma specimens was evaluated by immunohistochemistry (IHC) and Western blot, and the possible associations with lymph node (LN) metastasis and other clinicopathological parameters were analysed. In vitro, the effect of TFF3 on the malignant behaviour of TPC-1 cells was evaluated by cell proliferation assays, cell adhesion assays, colony formation assays, wound-healing assays and transwell chamber invasion assays. EMT markers and regulatory molecules were detected by quantitative RT-PCR (qRT-PCR) and Western blot analysis in the TFF3-knockdown groups and shRNA control group. The results showed that TFF3 was upregulated in PTC tissue and was associated with lymph node metastasis (P=0.0001), pathological grade (P=0.0002) and Snail expression (P=0.0001). The knockdown of TFF3 markedly inhibited the abilities of TPC-1 cell proliferation, adhesion, colony formation, migration and invasion. Mechanically, the results demonstrated that TFF3 might activate the MAPK/ERK signalling pathways, affect the expression of the transcription factors snail and slug in addition to affecting EMT associated markers E-cadherin and N-cadherin, and accelerate the progression of EMT in TPC-1 cells. These findings indicate that TFF3 might promote the metastatic potential of PTC by promoting the EMT process through cascades of MAPK/ERK pathways.

The generation of hair cells (HCs) from the differentiation of proliferating supporting cells (SCs) appears to be an ideal approach for replacing lost HCs in the cochlea and is promising for restoring hearing after damage to the organ of Corti. We show here that extensive proliferation of SCs followed by mitotic HC generation is achieved through a genetic reprogramming process involving the activation of β-catenin to upregulate Wnt signaling, the deletion of Notch1 to downregulate Notch signaling, and the overexpression of Atoh1 in Sox2(+) SCs in neonatal mouse cochleae. We used RNA sequencing to compare the transcripts of the cochleae from control mice and from mice with β-catenin activation, Notch1 deletion, and β-catenin activation combined with Notch1 deletion in Sox2(+) SCs. We identified the genes involved in the proliferation and transdifferentiation process that are either controlled by individual signaling pathways or by the combination of Wnt and Notch signaling. Moreover, the proliferation of SCs induced by Notch1 deletion disappears after deleting β-catenin in Notch1 knock-out Sox2(+) cells, which further demonstrates that Notch signaling is an upstream and negative regulator of Wnt signaling. SIGNIFICANCE STATEMENT We show here that the extensive proliferation of supporting cells (SCs) and the subsequent mitotic hair cell (HC) generation is achieved through a genetic reprogramming process involving activation of β-catenin to upregulate Wnt signaling, deletion of Notch1 to downregulate Notch signaling, and overexpression of Atoh1 in Sox2(+) SCs in neonatal mice cochleae. By comparing the transcripts of the cochleae among controls, β-catenin activation, Notch1 deletion, and β-catenin activation combined with Notch1 deletion group, we identified multiple genes involved in the proliferation and transdifferentiation process that are either controlled by individual signaling pathways or by the combination of Wnt and Notch signaling. This provides a better understanding of the mechanisms behind mitotic HC generation and might provide new approaches to stimulating mitotic HC regeneration.

Neuroblastoma (NB) is one of the most common malignant tumors derived from pluripotent cells of the neural crest. Nodal is an important embryonic morphogen which can re-express in cancer cells. The roles of Nodal in the progression of NB are not illustrated. Our present study reveals that Nodal is upregulated in NB cells and tissues. Targeted inhibition of Nodal can suppress the in vitro migration and invasion of NB cells while increase its chemo-sensitivity to doxorubicin (Dox) treatment. Nodal positively regulates the expression of Zeb1, one well-known transcription factors of epithelial to mesenchymal transition (EMT) of cancer cells. Knockdown of Zeb1 can attenuate Nodal-induced malignancy of NB cells. Mechanistically, Nodal increases the protein stability of Zeb1 while has no effect on its mRNA expression. It is due to that Nodal can increase the expression of Ataxia telangiectasia mutated kinase (ATM), which can phosphorylate and stabilize Zeb1 in cancer cells. Collectively, our data revealed that Nodal can increase the malignancy of NB cells via increasing the expression of Zeb1. It suggests that targeted inhibition of Nodal might be a potential therapy approach for NB treatment. © 2019 BioFactors, 45(3):355-363, 2019.

Yanqin Sun,1,* Bingshuang Hu,2,* Yanhong Wang,3 Zhen Li,1 Jingfang Wu,4 Yunchu Yang,4 Yue Wei,5 Xiaofeng Peng,5 Hongling Chen,5 Rongqi Chen,5 Pingyan Jiang,5 Sixian Fang,5 Zhiwu Yu,6 Linlang Guo4 1Department of Pathology, Guangdong Medical University, Dongguan, China; 2Department of Radiotherapy, Zhongshan People’s Hospital, Zhongshan, China; 3Department of Gynecology, Jinxiang People’s Hospital, Jining, China; 4Department of Pathology, Zhujiang Hospital, Southern Medical University, Guangzhou, China; 5College of Pharmacy, Guangdong Medical University, Dongguan, China; 6Division of Laboratory Science, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China *These authors contributed equally to this work Objective: microRNAs are regulatory molecules regarded as important in the pathogenesis of different types of tumors. microRNA-216a (miR-216a-5p) has been identified as a tumor suppressor in multiple malignancies. However, the role of miR-216a-5p in the pathogenesis of small cell lung cancer (SCLC) remains obscure. The objective of this study was to investigate the role of the miR-216a-5p/Bcl-2 axis in SCLC pathogenesis. Materials and methods: All the experimental methods used were as follows: microarray analysis, cell culture, transient, and stable gene transfection; real-time fluorescence PCR; Western blot; flow cytometry for cell cycle analysis; in vitro proliferation assay; in vitro wound healing experiment; in vivo xenograft model in nude mice; and dual luciferase reporter assay. All statistical analyses were carried out using GraphPad Prism 7 software. Statistical significance was analyzed by Student’s t-test or one-way ANOVA. P

Cisplatin is widely used for chemotherapy of a variety of malignancies. However, the clinical application of cisplatin is hampered by the resultant irreversible hearing loss due to hair cell apoptosis. To date, no practical regimen to resolve this has been developed. Meanwhile, the role of microRNA in protecting hair cells from cisplatin-induced apoptosis in the inner ear has not been extensively investigated. In this study, we monitored miR-183, -96, and -182 turnover in the cochlea during cisplatin treatment in vitro. We found that overexpression of miR-182, but not miR-183 and -96, improved hair cell survival after 3 μM cisplatin treatment in vitro. We demonstrated that overexpression of miR-182 repressed the intrinsic apoptotic pathway by inhibiting the translation of FOXO3a. Our study offers a new therapeutic target for alleviating cisplatin-induced hair cell apoptosis in a rapid and tissue-specific manner.

The activation of cochlear progenitor cells is a promising approach for hair cell (HC) regeneration and hearing recovery. The mechanisms underlying the initiation of proliferation of postnatal cochlear progenitor cells and their transdifferentiation to HCs remain to be determined. We show that Notch inhibition initiates proliferation of supporting cells (SCs) and mitotic regeneration of HCs in neonatal mouse cochlea in vivo and in vitro. Through lineage tracing, we identify that a majority of the proliferating SCs and mitotic-generated HCs induced by Notch inhibition are derived from the Wnt-responsive leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5(+)) progenitor cells. We demonstrate that Notch inhibition removes the brakes on the canonical Wnt signaling and promotes Lgr5(+) progenitor cells to mitotically generate new HCs. Our study reveals a new function of Notch signaling in limiting proliferation and regeneration potential of postnatal cochlear progenitor cells, and provides a new route to regenerate HCs from progenitor cells by interrupting the interaction between the Notch and Wnt pathways.

The ability of nonmammalian vertebrates to regenerate hair cells (HCs) after damage-induced HC loss has stimulated and inspired research in the field of HC regeneration. The protein pRb encoded by retinoblastoma gene Rb1 forces sensory progenitor cells to exit cell cycle and maintain differentiated HCs and supporting cells (SCs) in a quiescent state. pRb function is regulated by phosphorylation through the MEK/ERK or the pRb/Raf-1 signaling pathway. In our previous study, we have shown that pRb phosphorylation is crucial for progenitor cell proliferation and survival during the early embryonic stage of avian otocyst sensory epithelium development. However, in damaged avian utricle, the role of pRb in regulating the cell cycling of SCs or HCs regeneration still remains unclear. To further elucidate the function of pRb phosphorylation on SCs re-entering the cell cycle triggered by gentamycin-induced HCs damage, we isolated neonatal chicken utricles and treated them with the MEK inhibitor U0126 or the pRb/Raf-1 inhibitor RRD-251, respectively in vitro. We found that after gentamycin-induced HCs damage, pRb phosphorylation is important for the quiescent SCs re-entering the cell cycle in the neonatal chicken utricle. In addition, the proliferation of SCs decreased in a dose-dependent manner in response to both U0126 and RRD-251, which indicates that both the MEK/ERK and the pRb/Raf-1 signaling pathway play important roles in pRb phosphorylation in damaged neonatal chicken utricle. Together, these findings on the function of pRb in damaged neonatal chicken utricle improve our understanding of the regulation of the cell cycle of SCs after HCs loss and may shed light on the mammalian HC regeneration from SCs in damaged organs.

Doxorubicin (Dox) could trigger a large amount of apoptotic cells in the myocardium, which leads to dilated cardiomyopathy and heart failure. S-propargyl-cysteine (SPRC), a producing agent of endogenous hydrogen sulfide (H2S), possesses cardioprotective efficacy. However, the specific effect and mechanism of SPRC in Dox-induced cardiotoxicity remain elusive. Given gp130 with its main downstream signaling molecule, signal transducer and activator of transcription 3 (STAT3), is involved in cardiac myocyte survival and growth; the present study was performed to elucidate whether SPRC counteracts Dox-induced cardiotoxicity, and if so, whether the gp130/STAT3 pathway is involved in this cardioprotective activity. SPRC stimulated the activation of STAT3 via gp130-mediated transduction tunnel in vitro and in vivo. In Dox-stimulated cardiotoxicity, SPRC enhanced cell viability, restored expression of gp130/STAT3-regulated downstream genes, inhibited apoptosis and oxidative stress, and antagonized mitochondrial dysfunction and intracellular Ca2+ overload. Intriguingly, blockade of gp130/STAT3 signaling abrogated all these beneficial capacities of SPRC. Our findings present the first piece of evidence for the therapeutic properties of SPRC in alleviating Dox cardiotoxicity, which could be attributed to the activation of gp130-mediated STAT3 signaling. This will offer a novel molecular basis and therapeutic strategy of H2S donor for the treatment of heart failure.

The stability and hydrolysis kinetics of a phosphate prodrug, adefovir dipivoxil, in solid formulations were studied. The stability relationship between five solid formulations was explored. An autocatalytic mechanism for hydrolysis could be proposed according to the kinetic behavior which fits the Prout-Tompkins model well. For the classical kinetic models could hardly describe and predict the hydrolysis kinetics of adefovir dipivoxil in solid formulations accurately when the temperature is high, a feedforward multilayer perceptron (MLP) neural network was constructed to model the hydrolysis kinetics. The build-in approaches in Weka, such as lazy classifiers and rule-based learners (IBk, KStar, DecisionTable and M5Rules), were used to verify the performance of MLP. The predictability of the models was evaluated by 10-fold cross-validation and an external test set. It reveals that MLP should be of general applicability proposing an alternative efficient way to model and predict autocatalytic hydrolysis kinetics for phosphate prodrugs.

The recent genome-wide association study identified a link between vitiligo and genetic variants in the ribonuclease T2 (RNASET2) gene; however, the functional roles of RNASET2 in vitiligo pathogenesis or in melanocyte apoptosis have yet to be determined. The current study was designed to investigate the vitiligo-related expression pattern of RNASET2 and its molecular function involving apoptosis-related signaling proteins and pathways. The results showed overexpression of RNASET2 in epidermis specimens from 40 vitiligo patients compared with that from matched healthy controls. In addition, in vitro analyses indicated that overexpression of RNASET2 was inducible in cultured primary human melanocytes and keratinocytes by stress conditions, that is, exposure to UV irradiation, hydrogen peroxide, and inflammatory factors, respectively, and led to increased cell apoptosis via the tumor necrosis factor receptor-associated factor 2 (TRAF2)–caspases pathway through the physical interaction of RNASET2 with TRAF2. Thus, RNASET2 may contribute to vitiligo pathogenesis by inhibiting TRAF2 expression and, as such, RNASET2 may represent a potential therapeutic target of vitiligo.

An earring compatible telephone handset receiver (20) having a side sound outlet (22) and a center sound outlet (24) located on the receiver's front surface. A selection switch (38) is used to determine either the side sound outlet (22), the center sound outlet (24), or both of the side and center sound outlets (22 and 24) to be active for transmitting sound. When the side sound outlet (22) is active and aligned with the user's ear canal (202), the receiver (20) is kept away from the user's ear lobe (206) and the attached earring (204) to accommodate uses wearing earrings. When the center sound outlet (24) is active, the receiver (20) can be used in its normal way to accommodate users without earrings.