HMG-CoA reductase (HMGCR) protein is usually upregulated after statin (HMGCR inhibitor) treatment, which inevitably diminishes its therapeutic efficacy, provoking the need for higher doses associated with adverse effects. The proteolysis targeting chimera (PROTAC) technology has recently emerged as a powerful approach for inducing protein degradation. Nonetheless, due to their bifunctional nature, developing orally bioavailable PROTACs remains a great challenge. Herein, we identified a powerful HMGCR-targeted PROTAC (

Objective:To explore the relationship among CDH23 gene variation and the risk of noise-induced hearing loss (NIHL) .Methods:The nested case-control study was performed and this study followed a cohort of 6297 noise-exposed workers in a steel factory of Henan province in China from January 1, 2006 to December 31, 2015. In July 2019, subjects whose average hearing threshold were more than 40 dB in high frequency were defined as the case group, and subjects whose average hearing threshold were less than 35 dB in high frequency and less than 25 dB in speech frequency were defined as the control group. A nested case-control study which included 572 subjects was carried out, in which subjects consisted of 286 cases and 286 controls. 18 single nucleotide polymorphisms (SNPs) in CDH23 were selected and genotyped, then we analyzed the association among SNPs in CDH23, haplotypes in CDH23 and NIHL risk. Logistic regression was performed to analyze the main effects of SNPs and the interactions between CNE and SNPs adjusting cumulative noise exposure (CNE) , smoking, drinking, physical exercise and hypertension. Moreover, the association between haplotypes in CDH23 and NIHL risk were also analyzed. We ananlyzed the relationship amongst different SNP groups and NIHL risk using the generalized multifactor dimensionality reduction (GMDR) method.Results:The results suggested that significant associations were observed for rs3802711, rs3752751, rs3752752, rs11592462, rs10762480, rs3747867 for NIHL overall and/or various CNE strata by adjusting CNE, smoking, drinking, physical exercise and blood pressure. For rs3802711, workers exposure to noise carrying the AA/GA genotype of rs3802711 increased risk of NIHL than those carrying GG genotype ( OR=3.121; 95% CI:1.054-9.239, P=0.035) in overall; In the stratified analysis of CNE (>97 dB (A) ·year at rs3802711 locus, workers exposure to noise carrying GA genotype ( OR=2.056; 95% CI:1.226~3.448, P=0.006) and GA+AA/GA genotype ( OR=2.221; 95% CI:1.340~3.681, P=0.002) increased NIHL risk. For rs11592462, workers exposure to noise carrying the GG genotype of rs11592462 increased risk of NIHL than those carrying CC genotype in overall ( OR=3.951; 95% CI:1.104-14.137, P=0.04) ; workers exposure to noise carrying the GG genotype of rs11592462 increased risk of NIHL than those carrying CG+CC genotype in overall ( OR=4.06; 95% CI:1.145-14.391, P=0.03) . After adjusting CNE, smoking, drinking, physical exercise and blood pressure, the haplotypes of CDH23 rs1227049, rs10999947, rs3752752, rs3752751, rs10762480, rs3802711, rs11592462, rs10466026, rs4747194, rs4747195 were not associated with the risk of NIHL. GMDR analysis showed no association between SNP combination and NIHL risk after adjusting CNE, smoking, drinking, physical exercise and blood pressure. Conclusion:Gene polymorphisms in CDH23 might associate significantly with the risk of NIHL.

Objective:The purpose of this study was to explore the association between gene in the potassium recycling pathway 4 (KCNQ4) polymorphisms and the susceptibility to noise-induced hearing loss (NIHL) , and analysis the effect of cumulative noise exposure (CNE) and noise exposure duration on this association.Methods:A nested case-control study with 1∶1 matched was used based on the cohort of noise exposure in a steel factory. A total of 286 cases were selected as the group of hearing loss and 286 controls were chosen according to the matching standards of same gender, same type of work, age difference ≤ 5 years, noise exposure duration ≤ 2 years. The single nucleotide polymorphisms (SNPs) of rs4660468, rs4660470, rs34287852 in KCNQ4 were genotyped by SNPscan TM method. The codominant, dominant and recessive models were established to study KCNQ4 polymorphisms and the susceptibility to NIHL by single-factor conditional logistic regression analysis. The COX regression analysis was used to analyze the risk of developing NIHL in individuals with different genotypes along with the extending of noise exposure duration or CNE. Results:In the case of CNE≤96 dB (A) ·year, the risk of developing NIHL in individuals with TA genotype of rs4660470 was 2.197 times than individuals with TT genotypes (95% CI: 1.032~4.677) , and those with TA+AA and TT genotypes (HR=2.467, 95% CI: 1.025~5.934) With the increase of noise exposure duration, in rs4660470, individuals with TA genotype had a higher risk of suffering NIHL than those with TT genotype (HR=1.461, 95% CI: 1.061~2.011) , individuals with TA and/or AA genotype had a earlier risk of suffering NIHL than those with TT genotype. Conclusion:The mutant allele A of rs4660470 in KCNQ4 may be a risk factor for developing NIHL, CNE≤100 dB (A) ·year or the increase of noise exposure duration may further increase the risk of NIHL.

Objective:To investigate the association between the single nucleotide polymorphisms (SNPS) at rs1695 and rs6591256 in glutathione S-transferase P1 (GSTP1) gene and susceptibility to noise-induced hearing loss in Chinese Han workers exposed to noise.Methods:Using the 1: 1 nested case-control study and taking 6297 workers exposed to noise in a steel plant in Henan province as the cohort study population in July 2019, we screened those who have been exposed to noise for ≥3 years and whose binaural high frequency (3000, 4000, 6000 Hz) average hearing threshold is ≥40 dB (A) into the case group. The control group was selected according to the matching criteria of the same sex, same type of work, and the age difference was not more than 5 years old, and the working age difference was not more than 2 years. 276 subjects were selected into the case group and the control group respectively. The medium and high throughout single nucleotide polymorphism typing technology (SNPscanTM technology) was used to detect the polymorphism of three nucleotide sites of GSR gene, and conditional logistic regression was used to analyze the relationship between single nucleotide polymorphism (SNP) and NIHL, and the relationship between different polymorphic sites and the risk of NIHL after adjusting covariates. After stratification with different cumulative noise exposure (CNE) , Conditional logistic regression analysis was used to analysis the risk of NIHL at different loci.Results:The mean and standard deviation of age of the selected subjects was (40.28±8.00) , the mean and standard deviation of noise-exposed working years was (18.7±8.92) years. The range of noise exposure levels and comulative noise exposure were 80.05-93.35dB (A) and 86.83-107.92 dB (A) ·year, respectively. Compared with the control group, there were no statistically significant differences in age, noise-exposured working years, intensity of noise exposure, CNE, gender, drinking, hypertension prevalence and noise exposure level in the hearing loss group ( P>0.05) , while there were statistically difference in smoking, binaural high-frequency average hearing threshold and binaural speech frequency ( P<0.05) . After adjusting for smoking, drinking, hypertension and other factors, in the co-dominant model, compared with GGgenotype, the risk of NIHL was higher in rs1002149 GT genotype and rs2251780 GA genotype ( OR=1.558, 95% CI: 1.028-2.361; OR=1.550, 95% CI: 1.020-2.355, P<0.05) ; compared with TT/GT genotype, the rs1002149 TT genotype has a higher risk of developing NIHL ( OR=1.494, 95% CI: 1.002-2.228, P<0.05) , while rs3779647 genotype had no relationship with the risk of NIHL ( P>0.05) . In the equivalent sound level (L Aeq) of noise >85 dB (A) stratification, compared with GG genotype, carrying rs1002149 GT genotype and rs2251780 GT genotype has higher risk of nihl ( OR=1.801, 95% CI: 1.093-2.967; OR=1.720, 95% CI: 1.050-2.817, P<0.05) . Haplotype analysis of two sites, rs1002149 and rs2251780, was not found to be related to NIIHL susceptibility. Conclusion:The allele G of rs1695 and rs6591256 may be risk factors of NIHL.

Objective:To investigate the relationship between SNP and noise-induced hearing loss (NIHL) susceptibility in occupational noise exposure population in China.Methods:From 6297 for a certain steel works in contact with noise, contact length of 3 years or more and workplace noise exposure intensity of 80 dB (A) , ears or high frequency (3 000, 4 000, 6 000 Hz) average of hearing acuity 40 dB (HL) , or high frequency loss in both ears, on the basis of single whisper frequency (500, 1, 000, 2 000 Hz) average threshold of 26 dB (HL) or object as case group. A case-control study was designed with 1:1 matching. Subjects with the same gender, the same type of work, age ±5 years old, and working age ±2 years after noise exposure were selected as the control group. Subjects with any whisper frequency (500, 1, 000, 2, 000 Hz) whose hearing threshold in any frequency band was ≤25 dB (A) and whose average high-frequency hearing threshold in pure tone hearing test was <35 dB (A) were selected as the control group. Four sites of PON2 gene were genotyped by medium-and high-throughput SNP genotyping. Univariate logistic regression was used to analyze the relationship between single SNP polymorphism and NIHL.Results:A total of 286 case-control pairs were included. Smoking was statistically significant difference between cases and controls ( P<0.001) . Conclusion:No statistical difference has been found between single SNP polymorphism and NIHL. At the level of greater than 92 dB of high noise exposure, rs7785846 (CT+TT) genotype is a risk factor for occupational noise deafness, and its OR is 2.74 (95% CI: 1.09-6.89) compared with wild homozygous type (CC) . Conclusion. The rs7785846 (CT+TT) genotype carriers of PON2 gene are more susceptible to hearing impairment when exposed to high noise intensity.

Objective:To identify association between genetic polymorphism in the Glutathione peroxidase 1 gene (GPX1) and noise-induced hearing loss (NIHL) .Methods:A nested case control study was conducted based on a cohort of noise-exposed subjects. 392 cases were selected from the steel factory in Henan Province, 392 matched control subjects for each case were designated on the basis of the matched criterion including same gender, age (±5years) and duration of exposure to noise (±2years) . Two single nucleotide polymorphisms (SNPs) of GPX1 were genotyped by SNPscanTM multiplex SNP genotyping kit. Hardy-Weinberg equilibrium (HWE) tests were performed using Pearson's χ 2 for each SNP among control group, effects of genotypes of GPX1 on NIHL were analyzed by logistic regression. Results:All two SNPs were in HWE. After adjustment for covariates including smoking status, rs1987628 polymorphism was statistically significantly associated with the NIHL risk under codominant and Dominant inheritance models; In the subjects carrying rs1987628 GA genotype had a higher NIHL risk than those carrying the GG genotype, the adjusted OR value was 1.803 (95% CI 1.215-2.676, P=0.003) . And meanwhile, rs1987628 GA+AA genotype had a higher NIHL risk than those carrying the GG genotype, the adjusted OR value was 1.762 (95% CI 1.197-2.593, P=0.004) . Conclusion:It was suggested that genetic polymorphism in the GPX1 gene might be the genetic susceptible factor for NIHL.

Objective:Through the investigation of the injured persons in explosion accidents, the impact of wearing the ear protectors device (anti-noise earplugs) on the auditory organs and hearing loss of the injured person was understood, which could provide reference for the clinical diagnosis, treatment and prevention of the explosive hearing impairment.Methods:A retrospective survey was conducted on 39 directly injured persons who were injured in 23 explosion accidents involving a steel plant from 1990 to 2016 as the explosive hearing loss, taking the time of the patient＇s injury and 3-6 months after the injury as the time of investigation and evidence collection, and according to whether to wear the ear protectors device for group comparison and statistical analysis.Results:There was no significant difference between the two groups in hearing loss, tinnitus, earache, headache, some patients with dizziness and craniocerebral injury, regardless of whether the injured person wore anti-noise earplugs or not ( P=0.444-1) , the shock (coma) patients in the non-protected group were more common (34.8%, 8/23) , and the difference was statistically significant ( P=0.012) ; Although auricle injury was detected in both groups and there was no significant difference between the two groups ( P=1) , but the external ear canal injury, tympanic membrane perforation were more common in the non-protected group, and there was no external ear canal and tympanic membrane perforation in the wearing earplug group, and the difference between the two groups was significant ( P=0.000) . After 3-6 months, the rehabilitation of auditory system and other symptoms in patients showed that the hearing loss, tinnitus, earache, headache, dizziness and other symptoms all disappeared in patients wearing earplugs, while the above symptoms in the non-protected group were improved but more persisted, and the difference between the two groups was statistically significant ( P=0.000-0.012) , and there was no significant difference in rehabilitation conditions such as craniocerebral injury between the two groups ( P=1) ; There were patients with unhealed auricle injury in both groups in 3-6 months after the injury, and there was no significant difference between the two groups ( P=1) , however, in the non-protected group, 69.57% (16/23) of the patients with external auditory canal injury were still unhealed and none of the patients with tympanic membrane perforation recovered, and the difference between the two groups was obvious ( P=0.000~0.001) ; Pure tone air conduction examination showed that the hearing of the earplugs wearers was well recovered at the time of the explosion, while irreversible hearing impairment was common in the non-protective group, the difference was statistically significant ( P=0.000) . Conclusion:Ear protector plays an important role in protecting the auditory organs and hearing of workers in explosion accident, and it is an effective protective measure to prevent and reduce the damage of external ear canal, perforation of tympanic membrane and explosive hearing loss caused by explosion accidents.

Objective:To investigate the association between the single nucleotide polymorphisms (SNPS) at rs1695 and rs6591256 in glutathione S-transferase P1 (GSTP1) gene and susceptibility to noise-induced hearing loss in Chinese Han workers exposed to noise.Methods:A 1: 2 matched nested case-control study was performed, which based on the cohort of 6297 workers exposed to noise in an iron and steel plant in Henan, China, who were followed up from January 1, 2006 to December 31, 2015. According to the criteria of binaural average high-frequency hearing threshold ≥40 dB, a total of 292 workers were enrolled as hearing loss group; after the adjustment for sex, type of work, age (difference≤5 years) , and working years of noise exposure (difference≤2 years) , according to the criteria of binaural average high-frequency hearing threshold <35 dB, and the speech frequency hearing threshold of any ear at any frequency band ≤25 dB, a total of 584 workers were enrolled as control group. The single nucleotide polymorphisms (SNPs) of rs1695 and rs6591256 in GSTP1 were genotyped by high throughput SNP genotyping assay. Hardy-Weinberg equilibrium of control group was checked. The association between the SNPs at the two loci and susceptibility to NIHL was analyzed.Results:The L Aeq, 8 h range of workers exposed to noise was 80.2-98.8 dB (A) . The risk of NIHL in individuals with allele G of rs1695 was 1.291 times of those with allele A (95% CI: 1.042-1.598, P<0.05) . The risk of NIHL in individuals with allele G of rs6591256 was 1.390 times of those with allele A (95% CI: 1.119-1.728, P<0.05) . The risk of NIHL in individuals with AG and GG genotypes of rs6591256 was 1.437 times of those with AA genotype (95% CI: 1.057-1.952, P<0.05) . With the increase of noise exposure duration, individuals with AG and GG genotypes of rs6591256 had a higher risk of NIHL than those with AA genotype (HR=1.273, 95% CI: 1.002-1.616, P<0.05) . Conclusion:The allele G of rs1695 and rs6591256 may be risk factors of NIHL.

Objective:To investigate the effect of sound insulation improvement on the noise exposure of workers in the operation room of hot rolling line for wide and heavy plate.Methods:From September 2019 to September 2017, based on the occupational health Survey, the data of 25 fixed operation rooms and workers in operation rooms of a steel rolling production line were collected retrospectively, the noise exposure levels before and after the improvement of sound insulation were statistically analyzed.Results:The noise exposure value of the workers, the qualified rate of 0 Grade 8 hours equivalent noise (L EX, 8 h) ≤85 dB (A) and the qualified rate of the design limit value of the operation room were all higher than those before the modification, the difference was statistically significant ( P<0.01) , after the renovation, the Class II and above noise hazards were eliminated, the equivalent continuous a sound level (L Aeq, 8 h) >75 dB (A) of the workers in the operation room was 8h, and the noise level in the operation room still did not meet the Ergonomics limit standard. Conclusion:The improvement of sound insulation can effectively improve the working environment of noise workplace operating room and reduce the workers'noise exposure level.

Objective:To explore the relationship among CDH23 gene variation and the risk of noise-induced hearing loss (NIHL) .Methods:The nested case-control study was performed and this study followed a cohort of 6297 noise-exposed workers in a steel factory of Henan province in China from January 1, 2006 to December 31, 2015. In July 2019, subjects whose average hearing threshold were more than 40 dB in high frequency were defined as the case group, and subjects whose average hearing threshold were less than 35 dB in high frequency and less than 25 dB in speech frequency were defined as the control group. A nested case-control study which included 572 subjects was carried out, in which subjects consisted of 286 cases and 286 controls. 18 single nucleotide polymorphisms (SNPs) in CDH23 were selected and genotyped, then we analyzed the association among SNPs in CDH23, haplotypes in CDH23 and NIHL risk. Logistic regression was performed to analyze the main effects of SNPs and the interactions between CNE and SNPs adjusting cumulative noise exposure (CNE) , smoking, drinking, physical exercise and hypertension. Moreover, the association between haplotypes in CDH23 and NIHL risk were also analyzed. We ananlyzed the relationship amongst different SNP groups and NIHL risk using the generalized multifactor dimensionality reduction (GMDR) method.Results:The results suggested that significant associations were observed for rs3802711, rs3752751, rs3752752, rs11592462, rs10762480, rs3747867 for NIHL overall and/or various CNE strata by adjusting CNE, smoking, drinking, physical exercise and blood pressure. For rs3802711, workers exposure to noise carrying the AA/GA genotype of rs3802711 increased risk of NIHL than those carrying GG genotype ( OR=3.121; 95% CI:1.054-9.239, P=0.035) in overall; In the stratified analysis of CNE (>97 dB (A) ·year at rs3802711 locus, workers exposure to noise carrying GA genotype ( OR=2.056; 95% CI:1.226~3.448, P=0.006) and GA+AA/GA genotype ( OR=2.221; 95% CI:1.340~3.681, P=0.002) increased NIHL risk. For rs11592462, workers exposure to noise carrying the GG genotype of rs11592462 increased risk of NIHL than those carrying CC genotype in overall ( OR=3.951; 95% CI:1.104-14.137, P=0.04) ; workers exposure to noise carrying the GG genotype of rs11592462 increased risk of NIHL than those carrying CG+CC genotype in overall ( OR=4.06; 95% CI:1.145-14.391, P=0.03) . After adjusting CNE, smoking, drinking, physical exercise and blood pressure, the haplotypes of CDH23 rs1227049, rs10999947, rs3752752, rs3752751, rs10762480, rs3802711, rs11592462, rs10466026, rs4747194, rs4747195 were not associated with the risk of NIHL. GMDR analysis showed no association between SNP combination and NIHL risk after adjusting CNE, smoking, drinking, physical exercise and blood pressure. Conclusion:Gene polymorphisms in CDH23 might associate significantly with the risk of NIHL.