Diagnostic performance of PIVKA-II in identifying recurrent hepatocellular carcinoma following curative resection: a retrospective cohort study.

Protein induced by vitamin K absence or antagonist II (PIVKA-II) plays a critical role in the diagnosis of hepatocellular carcinoma (HCC), however, studies on its efficacy in diagnosing recurrent HCC were rarely found. A multicenter, retrospective, and observational study was conducted. During the overall follow-up of 5 years, HCC patients who had curative resection were monitored every 3 months in the first year post-surgery and every 6 months thereafter if no recurrence occurred. Tumor markers were collected at the diagnosis of recurrence for those with recurrence and at the last follow-up for those without recurrence. The median serum levels of PIVKA-II and AFP in the recurrence group were significantly higher than those in the non-recurrence group (PIVKA-II: 84.62 vs. 18.76 mAU/ml, p < 0.001; AFP: 4.90 vs. 3.00 ng/ml, p < 0.001) and there is a significant correlation between PIVKA-II and AFP (R = 0.901, p < 0.001). PIVKA-II showed better accuracy than AFP in the diagnosis of overall recurrent HCC (AUC: 0.883 vs. 0.672; p < 0.0001), but also in patients with negative PIVKA-II before curative resection (AUC: 0.878 vs. 0.680, p = 0.001). Clinician should pay more attention to serum PIVKA-II values when following patients after curative HCC resection to detect early recurrence.Clinical trial registration: ChiCTR2300070874.

A prediction model based on random survival forest analysis of the overall survival of elderly female papillary thyroid carcinoma patients: a SEER-based study.

OBJECTIVE: Papillary thyroid carcinoma (PTC) is a common malignancy whose incidence is three times greater in females than in males. The prognosis of ageing patients is poor. This research was designed to construct models to predict the overall survival of elderly female patients with PTC. METHODS: We developed prediction models based on the random survival forest (RSF) algorithm and traditional Cox regression. The data of 4539 patients were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Twelve variables were analysed to establish the models. The C-index and the Brier score were selected to evaluate the discriminatory ability of the models. Time-dependent receiver operating characteristic (ROC) curves were also drawn to evaluate the accuracy of the models. The clinical benefits of the two models were compared on the basis of the DCA curve. In addition, the Shapley Additive Explanations (SHAP) plot was used to visualize the contribution of the variables in the RSF model. RESULTS: The C-index of the RSF model was 0.811, which was greater than that of the Cox model (0.781). According to the Brier score and the area under the ROC curve (AUC), the RSF model performed better than the Cox model. On the basis of the DCA curve, the RSF model demonstrated fair clinical benefit. The SHAP plot showed that age was the most important variable contributing to the outcome of PTC in elderly female patients. CONCLUSIONS: The RSF model we developed performed better than the Cox model and might be valuable for clinical practice.

Inositol Inclusion Affects Growth, Body Composition, Antioxidant Performance, and Lipid Metabolism of Largemouth Bass (Micropterus salmoides).

The present study explored the effects of inositol on growth performance, body composition, antioxidant performance, and lipid metabolism of largemouth bass (Micropterus salmoides). Six isonitrogenous and isolipidic diets containing 0 mg/kg (G1, control), 125 mg/kg (G2), 250 mg/kg (G3), 375 mg/kg (G4), 500 mg/kg (G5), and 625 mg/kg (G6) inositol were prepared and fed to cultured fish (initial weight: 110 ± 1 g) for 8 weeks in recirculating the aquaculture systems. The results indicated that compared with G1 group, the weight gain rate (WGR), specific growth rate (SGR), and feed efficiency rate (FER) in the G3 group were significantly higher. The crude lipid content of the whole fish and the liver of cultured fish was significantly reduced with increasing dietary inositol inclusion. However, no significant effects on moisture, crude protein, and ash contents of fish were observed among the different groups. Dietary inositol supplementation significantly increased muscular crude protein. However, muscular total lipid contents were decreased when the inclusion level was higher than 250 mg/kg (G3-G6 groups). As dietary inositol supplemental level increased, serum triglyceride (TG), and cholesterol (TC) contents showed an increasing trend and reached the maximum value in the G3 group. Additionally, serum low-density lipoprotein cholesterol (LDL-C) in G2, G3, G4, and G5 groups was significantly upregulated by increasing inositol. While, there was no significant change in serum high-density lipoprotein cholesterol (HDL-C) among the treatments. Inositol inclusion also significantly reduced the serum alkaline phosphatase (AKP), glutamic-pyruvic transaminase (ALT), and glutamic-oxaloacetic transaminase (AST) activities as well as serum malondialdehyde (MDA) content but significantly increased serum catalase (CAT), superoxide dismutase (SOD) activities, and total antioxidant capacity (T-AOC). Compared with the control group, the activities of hepatic total lipase (TL) and lipoprotein lipase (LPL) were significantly elevated in the G3, G4, and G5 groups. Above all, dietary inositol supplementation could improve growth performance and antioxidant capacity, and reduce the liver fat content of largemouth bass, and the optimal supplementation level of inositol in feed is estimated to be 250.31-267.27 mg/kg.

The Hippo-YAP signaling pathway drives CD24-mediated immune evasion in esophageal squamous cell carcinoma via macrophage phagocytosis.

Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies in the world with poor prognosis. Despite the promising applications of immunotherapy, the objective response rate is still unsatisfactory. We have previously shown that Hippo/YAP signaling acts as a powerful tumor promoter in ESCC. However, whether Hippo/YAP signaling is involved in tumor immune escape in ESCC remains largely unknown. Here, we show that YAP directly activates transcription of the "don't eat me" signal CD24, and plays a crucial role in driving tumor cells to avoid phagocytosis by macrophages. Mechanistically, YAP regulates CD24 expression by interacting with TEAD and binding the CD24 promoter to initiate transcription, which facilitates tumor cell escape from macrophage-mediated immune attack. Our animal model data and clinical data show that YAP combined with CD24 in tumor microenvironment redefines the impact of TAMs on the prognosis of ESCC patients which will provide a valuable basis for precision medicine. Moreover, treatment with YAP inhibitor altered the distribution of macrophages and suppressed tumorigenesis and progression of ESCC in vivo. Together, our study provides a novel link between Hippo/YAP signaling and macrophage-mediated immune escape, which suggests that the Hippo-YAP-CD24 axis may act as a promising target to improve the prognosis of ESCC patients. A proposed model for the regulatory mechanism of Hippo-YAP-CD24-signaling axis in the tumor-associated macrophages mediated immune escape.

Ferroptosis as a potential target for cancer therapy.

Ferroptosis is a recently discovered essential type of cell death that is mainly characterized by iron overload and lipid peroxidation. Emerging evidence suggests that ferroptosis is a double-edged sword in human cancer. However, the precise underlying molecular mechanisms and their differential roles in tumorigenesis are unclear. Therefore, in this review, we summarize and briefly present the key pathways of ferroptosis, paying special attention to the regulation of ferroptosis as well as its dual role as an oncogenic and as a tumor suppressor event in various human cancers. Moreover, multiple pharmacological ferroptosis activators are summarized, and the prospect of targeting ferroptosis in cancer therapy is further elucidated.

MOF-derived bimetallic coordination polymer@cobalt-aluminum layered double hydroxide for highly selective CO2 adsorption: Experiments, mechanisms.

Selective capture of CO2 is one of the most effective strategies for combating the greenhouse effect. In this study, we report the synthesis of a novel adsorbent-an amine-based cobalt-aluminum layered hydroxide with a hafnium/titanium metal coordination polymer (denoted as Co-Al-LDH@Hf/Ti-MCP-AS)-through the derivatization of metal-organic frameworks (MOFs) for selective CO2 adsorption and separation. Co-Al-LDH@Hf/Ti-MCP-AS achieved the maximum CO2 adsorption capacity of 2.57 mmol g-1 at 25 °C and 0.1 MPa. The adsorption behavior followed the pseudo-second-order kinetics and Freundlich isotherm models, indicating that chemisorption occurs on a non-homogeneous surface. Co-Al-LDH@Hf/Ti-MCP-AS also exhibited selective CO2 adsorption in CO2/N2 and excellent stability over six adsorption-desorption cycles. An in-depth analysis of the adsorption mechanism through X-ray photoelectron spectroscopy and density-functional theory and frontier molecular orbital calculations revealed that adsorption occurs through acid-base interactions between amine functional groups and CO2 and that the tertiary amines (N3) have the highest affinity toward CO2. Our study provides a novel strategy for designing high-performance adsorbents for CO2 adsorption and separation.

Mechanism of the Anti-Influenza Functions of Guizhi Granules Based on Network Pharmacology, Molecular Docking, and in Vitro Experiments.

Guizhi granules mainly treat colds and improve overall health. They are widely used in clinical practice, but their protective effect and anti-inflammatory mechanism against influenza are unclear. In this study, the therapeutic effect of Guizhi granules on influenza was verified in vitro. The active compounds, targets, and cellular pathways of Guizhi granules against influenza were predicted using network pharmacology. The protein-protein interaction and component-target networks identified 5 core targets (JUN, TNF-α, RELA, AKT1, and MAPK1) and components (dihydrocapsaicin, kumatakenin, calycosin, licochalcone A, and berberine). GO and KEGG enrichment analyses revealed the anti-influenza pathways of Guizhi granules as antiviral and anti-inflammatory pathways. Molecular docking further verified that the core targets and components have good or strong binding activity. Therefore, the active ingredients, targets, and molecular mechanisms of Guizhi granules involved in influenza treatment were elucidated.

Correlation between clinical characteristics and tinnitus severity in tinnitus patients of different sexes: an analytic retrospective study.

PURPOSE: This study aimed to explore whether sex is influences tinnitus severity and whether the risk factors for tinnitus severity are the same in tinnitus patients of different sexes. METHODS: This was a retrospective study of data from 1427 patients complaining of tinnitus in a local hospital otolaryngology clinic from November 2019 to January 2022. All patients were interviewed and assessed by otoscopy, pure-tone audiometry, tinnitus handicap inventory (THI), visual analogue scale (VAS), and tinnitus refinement test. RESULTS: THI values were higher in females than in males (P = 0.00). Types of tinnitus sounds (OR 0.667, P = 0.000) and degree of hearing loss (OR 1.318, P = 0.000) were risk factors for tinnitus severity in males. Types of tinnitus sounds (OR 0.789, P = 0.005), sensation level (OR 1.023, P = 0.037), tinnitus types (OR 1.163, P = 0.041), tinnitus location (OR 1.198, P = 0.026), and the degree of hearing loss (OR 1.303, P = 0.000) were risk factors for tinnitus severity in females. Sex was an influencing factor for tinnitus severity. There were different risk factors for the tinnitus severity in different sexes. CONCLUSION: The risk factors for tinnitus severity differed according to sex in tinnitus patients, and the risk factors for tinnitus severity were greater in women than in men. These findings add to the literature on sex differences in tinnitus and suggest that medical and psychological screening of affected individuals and customized tinnitus treatment for each individual with tinnitus are needed. TRIAL REGISTRATION NUMBER/DATE OF REGISTRATION: ChiCTR2200057958, 2022/3/24 (retrospectively registered trials).

Development of an audiological assessment and diagnostic model for high occupational noise exposure.

PURPOSE: To explore the diagnostic auditory indicators of high noise exposure and combine them into a diagnostic model of high noise exposure and possible development of hidden hearing loss (HHL). METHODS: We recruited 101 young adult subjects and divided them according to noise exposure history into high-risk and low-risk groups. All subjects completed demographic characteristic collection (including age, noise exposure, self-reported hearing status, and headset use) and related hearing examination. RESULTS: The 8 kHz (P = 0.039) and 10 kHz (P = 0.005) distortion product otoacoustic emission amplitudes (DPOAE) (DPs) in the high-risk group were lower than those in the low-risk group. The amplitudes of the summating potential (SP) (P = 0.017) and action potential (AP) (P = 0.012) of the electrocochleography (ECochG) in the high-risk group were smaller than those in the low-risk group. The auditory brainstem response (ABR) wave III amplitude in the high-risk group was higher than that in the low-risk group. When SNR = - 7.5 dB (P = 0.030) and - 5 dB (P = 0.000), the high-risk group had a lower speech discrimination score than that of the low-risk group. The 10 kHz DPOAE DP, ABR wave III amplitude and speech discrimination score under noise with SNR = - 5 dB were combined to construct a combination diagnostic indicator. The area under the ROC curve was 0.804 (95% CI 0.713-0.876), the sensitivity was 80.39%, and the specificity was 68.00%. CONCLUSIONS: We expect that high noise exposure can be detected early with this combined diagnostic indicator to prevent HHL or sensorineural hearing loss (SNHL). TRIAL REGISTRATION NUMBER/DATE OF REGISTRATION: ChiCTR2200057989, 2022/3/25.

Treatment with the Ferroptosis Inhibitor Ferrostatin-1 Attenuates Noise-Induced Hearing Loss by Suppressing Ferroptosis and Apoptosis.

Hair cell death induced by excessive reactive oxygen species (ROS) has been identified as the major pathogenesis of noise-induced hearing loss (NIHL). Recent studies have demonstrated that cisplatin- and neomycin-induced ototoxicity can be alleviated by ferroptosis inhibitors. However, whether ferroptosis inhibitors have a protective effect against NIHL remains unknown. We investigated the protective effect of the ferroptosis inhibitor ferrostatin-1 (Fer-1) on NIHL in vivo in CBA/J mice and investigated the protective effect of Fer-1 on tert-butyl hydroperoxide (TBHP)-induced hair cell damage in vitro in cochlear explants and HEI-OC1 cells. We observed ROS overload and lipid peroxidation, which led to outer hair cell (OHC) apoptosis and ferroptosis, in the mouse cochlea after noise exposure. The expression level of apoptosis-inducing factor mitochondria-associated 2 (AIFM2) was substantially increased following elevation of the expression of its upstream protein P53 after noise exposure. The ferroptosis inhibitor Fer-1was demonstrated to enter the inner ear after the systemic administration. Administration of Fer-1 significantly alleviated noise-induced auditory threshold elevation and reduced the loss of OHCs, inner hair cell (IHC) ribbon synapses, and auditory nerve fibers (ANFs) caused by noise. Mechanistically, Fer-1 significantly reduced noise- and TBHP-induced lipid peroxidation and iron accumulation in hair cells, alleviating ferroptosis in cochlear cells consequently. Furthermore, Fer-1 treatment decreased the levels of TfR1, P53, and AIFM2. These results suggest that Fer-1 exerted its protective effects by scavenging of ROS and inhibition of TfR1-mediated ferroptosis and P53-AIFM2 signaling pathway-mediated apoptosis. Our findings suggest that Fer-1 is a promising drug for treating NIHL because of its ability to inhibit noise-induced hair cell apoptosis and ferroptosis, opening new avenues for the treatment of NIHL.

Systemic steroid administration combined with intratympanic steroid injection in the treatment of a unilateral sudden hearing loss prognosis prediction model: A retrospective observational study.

Idiopathic sudden sensorineural hearing loss (ISSNHL) is an emergency ear disease that is referred to as a sensorineural hearing loss of at least 30 dB in three sequential frequencies and occurs over a period of < 72 h. Because of its etiology, pathogenesis, and prognostic factors, the current treatment methods are not ideal. Previous studies have developed prognostic models to predict hearing recovery from ISSNHL, but few studies have incorporated serum biochemical indicators into previous models. The aim of this study was to explore the factors influencing the ISSNHL prognosis of combination therapy (combined intratympanic and systemic use of steroids, CT), among the patient population data, the serum biochemical indicators before the treatment, and the clinical features of ISSNHL. The new prediction model was developed through these factors. From November 2015 to April 2022, 430 patients who underwent CT at the Department of Otorhinolaryngology Head and Neck Surgery, Tangdu Hospital, Air Force Medical University for ISSNHL, were reviewed retrospectively. We found significant differences in age (P = 0.018), glucose (P = 0.035), white blood cell (WBC) (P = 0.021), vertigo (P = 0.000) and type (P = 0.000) with different therapeutic efficacies. Multivariate logistic regression analysis showed that age (OR = 0.715, P = 0.023), WBC (OR = 0.527, P = 0.01), platelet to lymphocyte ratio (PLR) (OR = 0.995, P = 0.038), vertigo (OR = 0.48, P = 0.004), course (time from onset to treatment) (OR = 0.681, P = 0.016) and type (OR = 0.409, P = 0.000) were independent risk factors for ISSNHL prognosis. Based on independent risk factors, a predictive model and nomogram were developed to predict hearing outcomes in ISSNHL patients. The area under the curve (AUC) value of the model developed in this study was 0.773 (95% CI = 0.730-0.812), which has a certain predictive ability. The calibration curve indicated good consistency between the actual diagnosed therapeutic effectiveness and the predicted probability. The model and nomogram can predict the hearing prognosis of ISSNHL patients treated with CT and can provide help for medical staff to make the best clinical decision. This study has been registered with the registration number ChiCTR2200061379.

Association of sleep duration, sleep apnea, and shift work with risk of colorectal neoplasms: a systematic review and meta-analysis.

Background: Although studies have reported that certain sleep characteristics, such as sleep duration and sleep apnea, are linked to the risk of colorectal cancer (CRC), this link remains contentious because of the limited evidence from individual studies. Furthermore, evidence indicated that shift work involving circadian disruption as a probable human carcinogen. This systematic review and meta-analysis aimed to examine the associations between sleep duration, sleep apnea, and shift work with the risk of colorectal neoplasms, including CRC and colorectal adenoma (CRA). Methods: We conducted a comprehensive literature search in PubMed, Embase, and Web of Science databases. The inclusion criteria were determined using PICOS principles. Observational studies reporting associations of sleep duration, sleep apnea, or shift work with risk of CRC or CRA were included. We assessed the risk of bias on the basis of the Newcastle-Ottawa Scale. Results: A total of 18 observational studies were included. Of these studies, nine studies reported the effect of sleep duration on risk of colorectal neoplasms, five reported the effect of sleep apnea, and six reported the effect of shift work. The relative risk (RR) for colorectal neoplasms was 1.06 [95% confidence interval (CI): 0.94, 1.20] in the short sleep duration group compared with the moderate sleep duration group. Long sleep duration was associated with an increased risk of colorectal neoplasms (RR: 1.33, 95% CI: 1.07, 1.65). The pooled results showed that sleep apnea was associated with an increased risk of colorectal neoplasms (RR: 1.75, 95% CI: 1.56, 1.97). Furthermore, results showed that the association between shift work and the risk of colorectal neoplasms was not significant (RR: 1.06, 95% CI: 0.95, 1.17). No publication bias was observed in all the analyses (all P>0.05). The sensitivity analysis showed that no individual study substantially influenced the pooled RRs for colorectal neoplasms and CRC. Conclusions: Our findings suggest the significant positive association of long sleep duration and sleep apnea with risk of colorectal neoplasms and CRC. Given that sleep characteristics may be a potentially modifiable risk factor for colorectal neoplasms, further understanding of its role in carcinogenesis will provide valuable insight for cancer prevention.

Nrf2 Knockout Affected the Ferroptosis Signaling Pathway against Cisplatin-Induced Hair Cell-Like HEI-OC1 Cell Death.

Cisplatin is a well-known and widely used anticancer drug with high therapeutic efficacy in solid tumors; however, side effects are common with its use. Because cisplatin can be retained in the cochlea, ototoxicity leading to hearing loss limits its clinical applications. Here, we report that Nrf2 knockout (KO) strongly increased cisplatin resistance in HEI-OC1 cells, which are immortalized cells from the murine organ of Corti. The underlying mechanism of this phenomenon was uncovered, and an important novel therapeutic target for combating cisplatin-induced hearing loss was identified. Preliminary investigations determined that Nrf2 KO markedly decreased TfR1 protein levels and increased GPX4 protein levels. Thus, ferroptosis may protect organisms from cisplatin-induced cell death. Furthermore, Nrf2 KO cells were resistant to the classical ferroptosis inducers RSL3 and erastin, providing solid evidence that Nrf2 KO inhibits ferroptosis and that knocking out Nrf2 may be a new clinical strategy to prevent cisplatin-induced hearing loss.

N-acetylcysteine protect inner hair cells from cisplatin by alleviated celluar oxidative stress and apoptosis.

Cisplatin is a well-known platinum-based chemotherapy drug widely used to treat a variety of malignant tumors. However, cisplatin has serious side-effects include nephrotoxicity and ototoxicity, Cisplatin chemotherapy causes permanent hearing loss at least 40% of treated patients. Our results showed that 20 mM N-acetylcysteine (NAC) can completely protect 50 µM cisplatin-induced hair cell loss in rat cochlear culture and protects against cisplatin-induced hair cell loss in zebrafish in vivo. The fluorescence intensity of mitochondrial ROS significantly increased after the cultures were treated with 15 µM cisplatin for 48 h and was decreased in the group treated with 15 µM cisplatin add 20 mM NAC. In addition, the number of TUNEL positive hair cells was increased after the cultures were treated with 15 µM cisplatin for 48 h and there are null in cisplatin and NAC co-treated group.

[A cross-sectional study and risk factors analysis of tinnitus in flight support personnel of PLA air force].

Objective:The aim of this study is to understand the epidemiological characteristics of tinnitus among flight support personnel and analyze its audiological characteristics and related risk factors. Methods:The information of tinnitus was collected by a method of cross-sectional investigation using questionnaire survey and audiology test among the flight support personnel of two stations of PLA air force. Results:The incidence of tinnitus among 666 subjects included was 24.2%, the THI grade was mainly grade 1 and grade 2. There were differences in THI scores among groups with different working years, but only differences in tinnitus incidence among groups with different frequency of hearing loss. Multivariate logistic regression analysis showed that grade of high frequency hearing loss（OR=1.39）, conscious hearing loss（OR=1.79） and frequency of asking others to repeat words（OR=1.64） were independent risk factors of tinnitus. The incidence of HF-HL and EHF-HL in ears with tinnitus among 0-5 working years was higher than that without tinnitus, while the incidence of EHF-HL in ears with tinnitus was not different from that without tinnitus among 6-10 and >10 working years. There was moderate correlation between THI scores and SAS standard scores（r=0.759）, and weak correlation between THI scores and PSQI scores（r=0.445）. Conclusion:The risk of tinnitus in high-frequency hearing loss and recessive hearing loss is increased; working years can affect the severity of tinnitus, while hearing conditions at different frequencies only affect the incidence of tinnitus; with increasing age, noise exposure plays a role in the occurrence of tinnitus decreasing gradually.

Regulation of Hippo/YAP signaling and Esophageal Squamous Carcinoma progression by an E3 ubiquitin ligase PARK2.

Objective: Esophageal squamous cell carcinoma (ESCC) is one of the most commonly diagnosed cancer types in China. Recent genomic sequencing analysis indicated the over-activation of Hippo/YAP signaling might play important roles for the carcinogenic process and progression for ESCC patients. However, little is known about the molecular mechanisms that controls Hippo signaling activity in ESCC. Our previous studies indicated that PLCE1-an important risk factor for ESCC-linked to ESCC progression through snail signaling, during this period, we found PARK2 was an important downstream target of PLCE1-snail axis. PARK2 was decreased in ESCC human samples, and correlated with good prognosis in ESCC patients. Further research showed that PARK2 could inhibit YAP, which functions as key downstream effectors of the Hippo pathway. Here, we aim to reveal the molecular mechanisms of PARK2 modulated Hippo pathway in ESCC. Methods: To evaluate the function of PARK2 in ESCC, we used a tissue microarray (TMA) of 223 human ESCC patients and immunohistochemistry to analyze the correlation between PARK2 expression and clinicopathologic variables. Depletion of endogenous PARK2 and YAP from ESCC cells using CRISPR/Cas9 technologies. Flow cytometry and EdU cell proliferation assay were used to detect proliferation of ESCC cells. Nude mice subcutaneous injection and Ki-67 staining were used to evaluate tumor growth in vivo. Migration and invasion assays were performed. In addition, lung metastasis models in mice were used to validate the function of PARK2 in vivo. Identification of PARK2 involved in hippo pathway was achieved by expression microarray screening, double immunofluorescence staining and co-immunoprecipitation assays. The RNA-seq analysis results were validated through quantitative real-time PCR (qRT-PCR) analysis. The protein half-life of YAP was analyzed by Cycloheximide assay, and the TEAD activity was detected by Luciferase reporter assays. Results: Clinical sample of ESCC revealed that low PARK2 expression correlated with late tumor stage (P < 0.001), poor differentiation (P < 0.04), lymph node (P < 0.001) and distant metastasis (P = 0.0087). Multivariate Cox proportional regression analysis further revealed that PARK2 expression (P = 0.032) is an independent prognostic factor for the overall survival of ESCC patients. Besides, the immunohistochemistry results showed that PARK2 negatively correlated with YAP protein level (P < 0.001). PARK2 depletion promotes ESCC progression both through Hippo/YAP axis, while PARK2 overexpression suppresses ESCC tumor progression by Hippo signaling. Co-IP and ubiquitination assays revealed that PARK2 could interact with YAP in the cytosol and promotes YAP K48-linked ubiquitination at K90 sites. Conclusion: Clinical sample analysis and mechanistic study have validated PARK2 as a tumor suppressor for ESCC. Multivariate Cox proportional regression analysis further revealed that PARK2 is an independent prognostic factor for the overall survival of ESCC patients. Cellular and molecular mechanisms in this study showed that PARK2 associated with YAP protein in the cytosol, promoted YAP ubiquitination and proteasome-dependent degradation in ESCC cells. Therefore, as a novel modulator for Hippo signaling, modulation of PARK2 activity or gene expression level could be an appealing strategy to treat esophageal.

RACO-1 modulates Hippo signalling in oesophageal squamous cell carcinoma.

Oesophageal cancer is one of the most lethal malignancies worldwide, whereas the 5-year survival is less than 20%. Although the detailed carcinogenic mechanisms are not totally clear, recent genomic sequencing data showed dysregulation of Hippo signalling could be a critical factor for oesophageal squamous cell carcinoma (ESCC) progression. Therefore, understanding of the molecular mechanisms that control Hippo signalling activity is of great importance to improve ESCC diagnostics and therapeutics. Our current study revealed RACO-1 as an inhibitory protein for YAP/TEAD axis. Depletion of RACO-1 increases the protein level of YAP and expression of YAP/TEAD target gene. Besides, RACO-1 silencing could promote ESCC cell invasion and migration, which effect could be rescued by YAP depletion in ESCC cells. Immunoprecipitation showed that RACO-1 associated with YAP and promote ubiquitination and degradation of YAP at k48 poly-ubiquitination site. Our research discovered a new regulator of Hippo signalling via modulating YAP stability. RACO-1 could be a promising factor, which serves cancer diagnostics and therapeutics in ESCC patients.

Caspase inhibitor z-VAD-FMK increases the survival of hair cells after Actinomycin-D-induced damage in vitro.

Actinomycin-D (Act-D) is a highly effective chemotherapeutic agent that induces apoptosis in systemic tissues. Act-D combined with other chemotherapeutic agents exhibits ototoxic effects and causes hearing impairment. To investigate the potential toxic effects of Act-D in the inner ear, we treated cochlear organotypic cultures with varying concentrations of Act-D for different durations. For the first time, we found that Act-D specifically induced HC loss and apoptosis in a dose- and time-dependent manner but not neuronal degeneration. Co-treatment with benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (z-VAD-FMK), a pan cysteine protease inhibitor, significantly reduced HC loss and apoptosis induced by Act-D, indicating increased cell survival. Taken together, Act-D exposure has ototoxic effects on the auditory system, while z-VAD-FMK prevents Act-D-induced hair cell damage.

SHARPIN Inhibits Esophageal Squamous Cell Carcinoma Progression by Modulating Hippo Signaling.

Esophageal cancer is one of the leading malignancies worldwide, while around sixty percent of newly diagnosed cases are in China. In recent years, genome-wide sequencing studies and cancer biology studies show that Hippo signaling functions a critical role in esophageal squamous cell carcinoma (ESCC) progression, which could be a promising therapeutic targets in ESCC treatment. However, the detailed mechanisms of Hippo signaling dys-regulation in ESCC remain not clear. Here we identify SHARPIN protein as an endogenous inhibitor for YAP protein. SHARPIN depletion significantly decreases cell migration and invasion capacity in ESCC, which effects could be rescued by further YAP depletion. Depletion SHARPIN increases YAP protein level and YAP/TEAD target genes, such as CTGF and CYR61 in ESCC. Immuno-precipitation assay shows that SHARPIN associates with YAP, promoting YAP degradation possibly via inducing YAP K48-dependent poly-ubiquitination. Our study reveals a novel post-translational mechanism in modulating Hippo signaling in ESCC. Overexpression or activation of SHARPIN could be a promising strategy to target Hippo signaling for ESCC patients.

Inhibition of DHCR24 increases the cisplatin-induced damage to cochlear hair cells in vitro.

Hearing loss is a common sensory disorder that affects more than 360 million people worldwide, and is primarily caused by the loss of hair cells (HCs). Ototoxic drugs, viral infections, genetic predisposition, aging or noise all damage HCs. 3ß-hydroxysteroid-Δ24 reductase (DHCR24), one enzyme in the cholesterol biosynthetic pathway, is involved in inflammation, oxidative stress and neuroprotection. However, researchers have not determined whether DHCR24 is present in the cochlea and the mechanism by which it exerts its regulatory effect on HC loss. In the present study, we analyzed DHCR24 expression in the postnatal day 1 (P1) rat cochlea and found that DHCR24 was localized in HCs of the organ of Corti. Next, exposure to cisplatin caused HC loss in cochlear organotypic cultures. Then, we inhibited DHCR24 expression with U18666A and observed significantly increased cisplatin-induced damage of cochlear HCs. These findings were consistent with the observed increase in DHCR24 expression in response to cisplatin treatment, and U18666A significantly decreased DHCR24 expression. Finally, DHCR24 inhibition increased the levels of reactive oxygen species and cleaved caspase-3 after cisplatin-induced injury. Collectively, DHCR24 may play a significant role in regulating auditory function and potentially represents a new therapeutic target for the treatment of cisplatin-induced ototoxicity.