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Background To analyze mechanisms of action of glucocorticoid treatment for endoplasmic reticulum stress (ERS) in sensorineural hearing loss (SNHL), we aimed to evaluate the expression and activation status of the protein kinase RNA-like ER kinase (PERK)–C/EBP homologous protein (CHOP) pathway, which is the major pathway in the ERS. Methods In the present study, we established an in vitro ERS model using tunicamycin-treated hair-cell-like HEI-OC1 cells. The effect of dexamethasone on proliferation inhibition, apoptosis, and ATF4–CHOP pathway in HEI-OC1 cells was examined by CCK-8 assay, flow cytometry, western blotting, and reverse transcription PCR, respectively. Results In HEI-OC1 cells, dexamethasone was shown to significantly reduce the tunicamycin-induced expression of ATF4 and CHOP in the context of sustained viability and proliferation, a therapeutic effect that was reversible by co-treatment with a glucocorticoid antagonist. Conclusion Dexamethasone can protect hair-cell-like HEI-OC1 cells from ERS damage, which may be one of the mechanisms of action for GCs in SNHL treatment.

Single nucleotide polymorphisms (SNPs) within binding sites of microRNAs (miRNAs) could modify cancer susceptibility by changing the binding affinity of miRNAs on their target mRNA 3ʹ‐untranslated regions (UTRs). MicroRNA‐21 (miR‐21) is involved in the development of colorectal cancer. However, the relationship between SNPs within the binding sites of miR‐21 and colorectal cancer risk has not been widely investigated. A case‐control study including 1147 patients and 1203 controls was performed to evaluate the association of SNPs in miR‐21 binding sites and colorectal cancer risk. Dual‐luciferase reporter assays and functional assays were performed to evaluate the effects of miR‐21. The SNP rs6504593 C allele conferred an increased risk of colorectal cancer compared with the T allele in an additive model (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04‐1.36, P = 0.011). Dual‐luciferase reporter assays demonstrated that the rs6504593 T allele negatively post‐transcriptionally regulated IGF2BP1 by altering the binding affinity of miR‐21. Additionally, colorectal cancer cells transiently transfected with miR‐21 mimics promoted cell proliferation and suppressed apoptosis, whereas inhibition of miR‐21 decreased cell growth. These data suggest that the miR‐21 binding site SNP rs6504593 in the IGF2BP1 3ʹ‐UTR may alter IGF2BP1 expression and contribute to colorectal cancer risk.

Cisplatin‑induced cytotoxicity, such as nephrotoxicity, neurotoxicity and ototoxicity, restricts the clinical application of this compound. Panax notoginseng Saponins (PNS) exhibit potent free radical scavenging and antioxidant activity. PNS have been demonstrated to reduce cisplatin‑induced nephrotoxicity and neurotoxicity. The present study investigated the ability of PNS to protect the auditory HEI‑OC1 cell line against ototoxicity induced by cisplatin. PNS induced activation of the AKT/nuclear factor erythroid 2‑related factor 2 (Nrf2) signaling pathway. Following pretreatment with PNS, HEI‑OC1 cells were treated with cisplatin and cultured for 24 h. The viability of HEI‑OC1 cells was examined using a Cell Counting Kit‑8 assay. Double staining analysis was used to measure cell apoptosis. The ability of PNS to reduce reactive oxygen species (ROS) levels was assessed by flow cytometry. The levels of phosphorylated (p)‑AKT, heme oxygenase 1 (HO‑1), NAD(P)H quinone dehydrogenase 1 (NQO1), glutamate‑cysteine ligase catalytic (GCLC) and Nrf2 were measured by western blotting. HEI‑OC1 cells that were pretreated with PNS exhibited significantly increased cell viability compared with that noted in cells treated only with cisplatin. In addition, PNS suppressed the induction of apoptosis and ROS production following cisplatin treatment. The upregulation of NQO1, HO‑1 and GCLC expression in PNS‑pretreated cells was associated with p‑AKT levels and the activation of Nrf2. These findings suggested that PNS protected auditory cells against ototoxicity induced by cisplatin by activating AKT/Nrf2 signaling. PNS may serve as a potential candidate in regulating cisplatin‑induced cytotoxicity.

Background Coal industry is one of the national pillar industries in China. A large number of coal miners are exposed to various occupational hazards, which might cause occupational disease. The aim of the study was to assess the quality of life (QOL) of coal miners in Xuzhou, China and explore influencing factors to QOL of coal miners. Methods Six hundred and twelve underground miners and 354 ground workers in one of coal mines of Xuzhou were enrolled in our study. The 36-item Short-Form Health Survey (SF-36) questionnaires were applied to evaluate the QOL of coal miners. Multivariate stepwise regression analysis was used to assess the potential impact factors on QOL. Results The score of role limitations due to physical health problems (RP) dimension in underground miners was significantly lower than that of ground workers (P=0.005). Multivariate stepwise regression analysis showed that longer job tenure for dust exposure significantly lower coal miners' RP score. Comparing with normal populations, our subjects scored lower in both the physical health components (PHC) and the mental health components (MHC), and many factors accounted for it including job tenure for dust exposure, chronic disease, medical insurance, etc. Conclusions QOL of coal miners has been affected. Some measures might be taken by enterprise and coal miners themselves to protect the health of coal miners and improve their quality of life.

Sensorineural hearing loss is a health problem with global prevalence. Aminoglycoside antibiotics, for instance gentamicin, may cause ototoxicity in mammals as a result of apoptosis and elevated oxidative stress in cochlear hair cells. Our study aimed to examine the potential effects of theophylline, an HDAC2 agonist, on gentamicin-induced cytotoxicity to sensory hair cells. Mouse cochlear explants and HEI-OC1 cells were in vitro cultured and challenged by gentamicin to induce ototoxicity, with or without theophylline. Cochlear hair cells were evaluated by fluorescent microscopy, and their mechanotransduction was assessed by electrophysiology. Expression levels of HDAC2 and apoptosis pathway factors were also evaluated following gentamicin and theophylline treatments. The functional role of HDAC2 in this setting was investigated by siRNA targeted silencing. Theophylline protected cochlear hair cells from ototoxicity induced by gentamicin, in terms of preserving cochlear structure and mechanotransduction ability, and preventing the activation of the intrinsic apoptosis pathway dose-dependently. HDAC2 expression was downregulated by gentamicin, which could be restored by theophylline. HDAC2 silencing in HEI-OC1 cells negated the beneficial effect of theophylline against gentamicin-induced growth defect and apoptosis activation. Theophylline protects sensory hair cells from gentamicin ototoxicity by maintaining HDAC2 expression. Our study thereby discovers a critical role of HDAC2 in gentamicin-induced ototoxicity, which could shine light on potential therapeutic options for treatment against sensorineural hearing loss.

Objective Mesothelin is a cell surface protein and overexpressed in many cancers. However, the potential value of mesothelin as plasma biomarker in colorectal cancer has not been explored. The purpose of this study was to identify whether plasma mesothelin is a suitable diagnostic and prognostic biomarker for colorectal cancer. Methods We performed a two-stage case-control study to evaluate plasma mesothelin levels in colorectal cancer using enzyme-linked immunosorbent assay (ELISA). Preoperative and postoperative plasma were collected to examine the level changes influenced by surgery. Receiver operating characteristic (ROC) curves were applied to identify the diagnostic value of plasma mesothelin. We also conducted univariate Kaplan-Meier survival analysis and Cox regression analysis of patients with survival information. Results We found that the plasma mesothelin levels in colorectal cancer patients were significantly higher than that in the controls (P < 0.001) with an AUC value of 0.690 (95% CI = 0.625 to 0.752). Individuals with lower mesothelin level had a longer survival time (adjusted HR = 4.43, 95% CI = 1.93-10.15, P < 0.001). Furthermore, Patients had slightly decreased mesothelin levels in postoperative plasma than preoperative plasma, although the alteration was not statistically significant (P = 0.052). Conclusion Our findings highlight the correlative relationship between plasma mesothelin levels and the presence and progression of colorectal cancer. Plasma mesothelin may be a potential diagnostic and, or prognostic biomarker for colorectal cancer.

ObjectiveTo examine the relationship between the therapeutic effect of intratympanic methylprednisolone perfusion and histone acetylation in refractory sudden sensorineural hearing loss.MethodsThirty-four refractory sudden sensorineural hearing loss patients were enrolled and treated with intratympanic methylprednisolone perfusion. Pure tone average, acetylated histone H3, acetylated histone H4 and histone deacetylase 2 (HDAC2) were measured in peripheral blood mononuclear cells before and after intratympanic methylprednisolone perfusion. Sixteen healthy volunteers were recruited to obtain normal reference values.ResultsPure tone average in sudden sensorineural hearing loss patients improved from 84.14 ± 13.54 dB to 73.56 ± 18.45 dB after intratympanic methylprednisolone perfusion. Up-regulations in HDAC2 protein level, and down-regulations in histone H3 and H4 acetylation were observed in the intratympanic methylprednisolone perfusion sensitive group (pure tone average gain of 15 dB or more), while no significant changes were observed in the intratympanic methylprednisolone perfusion insensitive group (pure tone average gain of less than 15 dB).ConclusionIntratympanic methylprednisolone perfusion can improve hearing in a considerable number of refractory sudden sensorineural hearing loss patients. The therapeutic effect is closely related to reduced histone acetylation.

Objective: The different incidence of colorectal cancer between the sexes suggests that sex hormones may be involved in the susceptibility to colorectal cancer. The association between sex hormones and genetic variants in hormone metabolic pathways and the colorectal cancer risk remains unclear. Methods: We detected sex hormone levels in plasma from colorectal cancer patients and controls in males by ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). We evaluated the clinical significance of sex hormones on colorectal cancer diagnosis with the area under the receiver operating characteristic curve (AUC). The role of genetic variants in hormone metabolic pathways in the colorectal cancer risk was assessed by a logistic regression model. The biological functions were detected by luciferase reporter assays and cell behavior experiments. Results: We found that 2-methoxyestrone (2-MeO-E1) was highly expressed in cases (PFDR = 3.48 × 10−19). The expression of 2-MeO-E1 in plasma showed improved accuracy for predicting colorectal cancer (AUC = 0.88). In the 2-MeO-E1 metabolic pathway, rs165599 in COMT was significantly associated with an increased risk of colorectal cancer (P = 0.009). Mechanistically, we found that the rs165599 G allele could decrease the binding ability of miR-22-3p to the COMT 3′-UTR. Furthermore, knockdown of COMT inhibited cell proliferation, induced cell apoptosis and arrested the cell cycle in the G1 phase. Conclusion: This is the first study to show that 2-MeO-E1 and a genetic variant in COMT contribute to the susceptibility to colorectal cancer. These results shed light on the different incidence of colorectal cancer between the sexes. Keywords: Sex hormone, UPLC-MS/MS, Colorectal cancer, Genetic variants

Oxaliplatin (L-OHP) is a commonly used first-line chemotherapy for colorectal cancer. Genetic variants in nucleotide excision repair (NER) pathway genes may alter genomic integrity and the efficacy of oxaliplatin-based chemotherapy in colorectal cancer. We investigated the association between genetic variants in 19 NER pathway genes and the disease control rate (DCR) and progression-free survival (PFS) among 166 colorectal cancer patients who received oxaliplatin-based chemotherapy. Expression quantitative trait loci (eQTL) analysis was performed using the Genotype-Tissue Expression (GTEx) portal. Gene harboring significant SNP was overexpressed or knocked down to demonstrate the effect on cell phenotypes with or without oxaliplatin treatment. We found that rs5030740, located in the 3′-untranslated region (3′-UTR) of RPA1, was associated with DCR [OR = 2.99 (1.33–5.69), P = 4.00 × 10−3] and PFS [HR = 1.86 (1.30–2.68), P = 7.39 × 10−4]. The C allele was significantly associated with higher RPA1 mRNA expression levels according to eQTL analysis (P = 0.010 for sigmoid colon and P = 0.004 for transverse colon). The C allele of rs5030740 disrupted let-7e-5p binding to enhance RPA1 expression. Functionally, RPA1 knockdown inhibited cell proliferation and promoted cell apoptosis, whereas RPA1 overexpression promoted proliferation and suppressed apoptosis. Furthermore, low RPA1 expression increased sensitivity to oxaliplatin in colon cancer cells and inhibited proliferation after oxaliplatin treatment. Our findings demonstrate an association between rs5030740 and the DCR and PFS of colorectal cancer patients. RPA1 functions as a putative oncogene in tumorigenesis by reducing sensitivity to oxaliplatin and could serve as a potential prognostic biomarker in colorectal cancer.

Objective To evaluate the expression of histone deacetylase 2 (HDAC2) in peripheral blood mononuclear cells (PBMCs) from patients with sudden sensorineural hearing loss (SSNHL) who were refractory to systemic glucocorticoid treatment and to identify the relationship between the level of HDAC2 and glucocorticoid insensitivity. Study design Prospective clinical study. Setting This study was conducted in Nanjing Drum Tower Hospital, Nanjing University Medical School. Subjects and methods PBMCs were collected from 42 refractory SSNHL patients. After a 10-day intratympanic methylprednisolone perfusion (IMP) and systemic Ginkgo biloba extract treatment, the SSNHL patients were divided into 2 groups according to their hearing recovery after IMP (IMP sensitive and insensitive). Real-time polymerase chain reaction and HDAC2 protein assays were used to detect the relative expression levels of HDAC2 in PBMCs. The HDAC2 mRNA expression and protein levels in PBMCs collected from 17 volunteers were used as normal HDAC2 reference levels. Results Compared with normal reference levels, HDAC2 protein levels were significantly reduced, while the HDAC2 mRNA expression was much higher in all refractory SSNHL patients before IMP. HDAC2 mRNA expression and HDAC2 protein levels were significantly elevated in the IMP-sensitive group, while no change was observed in the IMP-insensitive group after IMP plus systemic antioxidant treatment. Conclusions Reduced HDAC2 protein levels may be 1 of the mechanistic underpinnings of corticosteroid insensitivity in refractory SSNHL patients. IMP can increase HDAC2 protein levels and the expression of HDAC2 mRNA in IMP-sensitive patients. HDAC2 protein levels might be regulated through posttranslational modifications.

To observe the role of the dust mites drops sublingual immunotherapy(SLIT) in pediatric allergic rhiriitis caused by dust mites and compare its efficacy between monosensitized and polysensitized children.A total of 77 pediatric allergic rhinitis patients received Dermatophagoides farina extracts sublingual immunotherapy for 2 years were enrolled as desensitization group and were allocated into monosensitized group (41 cases) and polysensitized group (36 cases) according to the number of coexisting allergens. Meanwhile another 33 allergic rhinitis children treated by pharmacotherapy during the period were collected as control group. The total symptom scores (TNSS), total medication scores (TMS) and visual analogue scale(VAS) were assessed at the beginning, six months, 1 year and 2 years of the treatment. SPSS 13. 0 software was used to analyze the data.the score of TNSS and VAS in desensitization was slightly higher than the control after six months treatment, but without difference at l year and 2 years; the score of TMS had significantly improved in desensitization compared with the corresponding points in control. All the parameters in monosensitized group were equivalent with polysensitizend group, except the score of TMS was slightly lower than the polysensitizend group at six months.Dust mite drops sublingual immunotherapy is effective for the allergic rhinitis children caused by mites. And it has similar immunotherapy efficacy between monosensitized and polysensitized children.

Objective: This study aimed to identify factors related to outcomes of the pharyngeal foreign bodies in children and to improve the management protocol of this disease. Methods: The medical records of 131 children with pharyngeal foreign bodies hospitalized in the hospital were retrospectively reviewed. Results: Significant differences were observed between the two groups (dislodgement and removal group) with respect to location of pharyngeal foreign bodies and age, while sex, time of pharyngeal foreign bodies, and nature of pharyngeal foreign bodies had no significant differences. Moreover, results suggested that location of pharyngeal foreign bodies and nature of pharyngeal foreign bodies were risk factors correlated with complications. Conclusion: Pharyngeal foreign body in children has a high rate of dislodgement (>50%). Foreign bodies in the oropharynx were more likely to dislodge compared with the foreign bodies in the laryngopharynx. Younger children were more likely to dislodge compared with older children. Although the risk of complications was very low, attention needs to be paid to the potential risks: local infection, deep abscess, and migration of foreign bodies. Because the possibility of complications caused by bone fragments and foreign bodies in the laryngopharynx increase obviously, hence, it is suggested to remove these kinds of foreign bodies as soon as possible to prevent complications.

The binderless fiberboard was manufactured using defibrated poplar fiber as a raw material, without adding any additives, holding pressure-cooling process was used before unloading the boards out of the press. The effects of hot-pressing temperature, pressure, mat moisture content and hot-pressing time on the physical and mechanical properties of product, were evaluated and the relation between density and product properties in the test range was also discussed. The binderless poplar fiberboard produced under the conditions of hot-pressing temperature 200°, pressure 6MPa and mat moisture content 10% recorded: MOR 52.8MPa, MOE 6413MPa, IB 0.92MPa and 24h TS 7.56%.