GPX4 inhibits apoptosis of thyroid cancer cells through regulating the FKBP8/Bcl-2 axis.

GPX4 has attracted much attention as a key molecule of cell ferroptosis, but its role in cell apoptosis is rarely reported, and its role in apoptosis of thyroid cancer (TC) cell has not been reported. The analysis of TCGA database showed that both GPX4 and FKBP8 were highly expressed in TC tumor tissues; The expression of GPX4 and FKBP8 were positively correlated. The immunohistochemical analysis further confirmed that GPX4 and FKBP8 were highly expressed in TC tumor tissues. In addition, the high expression of GPX4 and FKBP8 were both significantly correlated with the poor prognosis of TC. Silencing GPX4 significantly inhibited the proliferation, induced apoptosis of TC cells, and reduced tumor growth in mice. The co-immunoprecipitation assay revealed a physical interaction between GPX4 and FKBP8 observed in the TC cells. Knockdown of FKBP8 significantly inhibited the proliferation and induced apoptosis of TC cells. Rescue experiments suggested that knockdown of FKBP8 could reverse the strengthens of cell proliferation and apoptosis and the higher expression of FKBP8 and Bcl-2 caused by overexpression of GPX4. Our results suggest that the GPX4/FKBP8/Bcl-2 axis promotes TC development by inhibiting TC cell apoptosis, which provides potential molecular targets for TC therapeutic strategies.

Psychological Distress and Meniere's Disease: A Bidirectional Two-Sample Mendelian Randomization Study.

OBJECTIVE: This study is aim to explore the causal relationship between anxiety, depression, neuroticism, and Meniere's disease (MD). STUDY DESIGN: Two-sample bidirectional Mendelian randomization (MR) analyses. SETTING: IEU, FinnGen, CTG, and UKB databases. METHODS: The genome-wide association studies data for anxiety, depression, neuroticism, and MD involved over 357,957 participants. MR was performed to explore relationships between anxiety, depression, neuroticism, and MD. Sensitivity analyses were performed to assess the robustness of the MR results. Reverse MR was used to exclude the possibility of reverse causality. Finally, multivariate MR was performed to explore the collinear relationships between neuroticism subclusters. RESULTS: MR results showed that anxiety and depression are not causes of MD, nor does MD cause anxiety and depression. Elevated neuroticism sum score is a cause of anxiety, depression, and MD, but MD does not lead to an increase in the level of neuroticism sum score. Further analysis showed that the 5 subclusters of neuroticism often feel lonely, mood often goes up and down, often feel fed-up, feelings easily hurt, and sensitivity to environmental stress and adversity are causes of MD. Multivariate MR analysis results suggested that the 5 neuroticism subclusters have a collinear relationship. CONCLUSION: Anxiety and depression are not causative factors of MD, and vice versa. Elevated neuroticism levels serve as a shared causative factor for anxiety, depression, and MD. Identification and effective management of neuroticism is a potential target for preventing and treating MD.

HMGB1 accumulation in cytoplasm mediates noise-induced cochlear damage.

Damage-associated molecular pattern molecules (DAMPs) play a critical role in mediating cochlear cell death, which leads to noise-induced hearing loss (NIHL). High-mobility group box 1 (HMGB1), a prototypical DAMP released from cells, has been extensively studied in the context of various diseases. However, whether extracellular HMGB1 contributes to cochlear pathogenesis in NIHL and the potential signals initiating HMGB1 release from cochlear cells are not well understood. Here, through the transfection of the adeno-associated virus with HMGB1-HA-tag, we first investigated early cytoplasmic accumulation of HMGB1 in cochlear hair cells after noise exposure. We found that the cochlear administration of HMGB1-neutralizing antibody immediately after noise exposure significantly alleviated hearing loss and outer hair cells (OHCs) death induced by noise exposure. In addition, activation of signal transducer and activators of transcription 1 (STAT1) and cellular hyperacetylation were verified as potential canonical initiators of HMGB1 cytoplasmic accumulation. These findings reveal the adverse effects of extracellular HMGB1 on the cochlea and the potential signaling events mediating HMGB1 release in hair cells, indicating multiple potential pharmacotherapeutic targets for NIHL.

Genetic and clinical phenotypic analysis of carney complex with external auditory canal myxoma.

Background: Mutations in PRKAR1A gene can lead to Carney complex (CNC), and most CNC patients develop cardiac and cutaneous myxomas. In particular, cardiac myxomas are a common cause of mortality in CNC patients. Cutaneous myxomas of the external ear are extremely rare, and do not have any specific clinical features Methods: In this retrospective study, we analyzed the clinical and genetic data of the proband and his family and fifty whole blood control samples selected from the molecular genetic database of our hospital. Whole exome DNA sequencing analysis was used to detect the mutation in the peripheral blood samples. Results: The results of the clinical analysis showed the presence of spotty skin pigmentation and external auditory canal myxoma in the proband as well as in his sister and mother. Whole-exome DNA sequencing showed a novel heterozygous mutation in the PRKAR1A gene i.e., c.824_825delAG (p.Gln275Leufs*2), in the proband and his sister and mother. Conclusion: In conclusion, the family members had the same autosomal dominant PRKAR1A mutation. DNA sequencing revealed a novel c.824_825delAG in exon 9 of PRKAR1A. This pathogenic mutation has not been reported previously, and may be related to the occurrence of external auditory canal myxomas and spotty pigmentation. This study broadens the genotypic spectrum of PRKAR1A mutations in CNC.

A novel mutation of X-linked recessive deafness gene POU3F4 in a boy with congenital deafness.

Purpose: To report an interstitial deletion of Xq21.1 in chromosome X in a boy with congenital deafness. Methods: The proband underwent a thorough physical examination and a detailed audiological and temporal bone computed tomography (CT) scan. Cochlear implantation was performed on the proband, and follow-up was conducted. High throughput sequencing and copy number analysis was made of peripheral blood samples from the proband, family members, and control subjects. Results: Sensorineural hearing loss was present in the boy and temporal bone CT scan showed a bilateral incomplete partition type III anomaly (IP-III). Q21.1 (79.40-83.32 Mb) of chromosome X in the proband had a copy number deletion with a fragment size of about 3.92 Mb. Categories of auditory performance scores and SIR scores of the cochlea in this child improved after surgery. Conclusion: Through the analysis of POU3F4, a novel mutation site with potentially pathogenic significance was found.Level of Evidence: 5.

Prognostic Analysis of Differentially Expressed DNA Damage Repair Genes in Bladder Cancer.

Bladder cancer (BCa) is the tenth most common tumor in humans. DNA damage repair genes (DDRGs) play important roles in many malignant tumors; thus, their functions in BCa should also be explored. We performed a comprehensive analysis of the expression profiles of DDRGs in 410 BCa tumors and 19 normal tissues from The Cancer Genome Atlas database. We identified 123 DDRGs differentially expressed between BCa tumors and normal tissues, including 95 upregulated and 28 downregulated genes. We detected 22 DDRGs associated with overall survival (OS) of patients with BCa by performing univariate Cox regression analysis. To explore the interactions between OS-associated DDRGs, we constructed a PPI network, which showed that the top six DDRGs (CDCA2, FOXM1, PBK, RRM2, ORC1, and HDAC4) with the highest scores in the PPI network might play significant roles in OS of BCa. Moreover, to investigate the latent regulatory mechanism of these OS-associated DDRGs, we analyzed the transcription factors (TFs)-DDRGs regulatory network. The core seven TFs (NCAPG, DNMT1, LMNB1, BRCA1, E2H2, CENPA, and E2F7) were shown to be critical regulators of the OS-related DDRGs. The 22 DDRGs were incorporated into a stepwise multivariable Cox analysis. Then, we built the index of risk score based on the expression of 8 DDRGs (CAD, HDAC10, JDP2, LDLR, PDGFRA, POLA2, SREBF1, and STAT1). The p-value < 0.0001 in the Kaplan-Meier survival plot and an area under the ROC curve (AUC) of 0.771 in TCGA-BLCA training dataset suggested the high specificity and sensitivity of the prognostic index. Furthermore, we validated the risk score in the internal TCGA-BLCA and an independent GSE32894 dataset, with AUC of 0.743 and 0.827, respectively. More importantly, the multivariate Cox regression and stratification analysis demonstrated that the predictor was independent of various clinical parameters, including age, tumor stage, grade, and number of positive tumor lymph nodes. In summary, a panel of 8 DNA damage repair genes associated with overall survival in bladder cancer may be a useful prognostic tool.

Single-Cell RNA-Seq Reveals Heterogeneity of Cell Communications between Schwann Cells and Fibroblasts within Vestibular Schwannoma Microenvironment.

Vestibular schwannomas (VSs), which develop from Schwann cells (SCs) of the vestibular nerve, are the most prevalent benign tumors of the cerebellopontine angle and internal auditory canal. Despite advances in treatment, the cellular components and mechanisms of VS tumor progression remain unclear. Herein, single-cell RNA-sequencing was performed on clinically surgically isolated VS samples and their cellular composition, including the heterogeneous SC subtypes, was determined. Advanced bioinformatics analysis revealed the associated biological functions, pseudotime trajectory, and transcriptional network of the SC subgroups. A tight intercellular communication between SCs and tumor-associated fibroblasts via integrin and growth factor signaling was observed and the gene expression differences in SCs and fibroblasts were shown to determine the heterogeneity of cellular communication in different individuals. These findings suggest a microenvironmental mechanism underlying the development of VS.

Novel Immune-Related Ferroptosis Signature in Esophageal Cancer: An Informatics Exploration of Biological Processes Related to the TMEM161B-AS1/hsa-miR-27a-3p/GCH1 Regulatory Network.

Background: Considering the role of immunity and ferroptosis in the invasion, proliferation and treatment of cancer, it is of interest to construct a model of prognostic-related differential expressed immune-related ferroptosis genes (PR-DE-IRFeGs), and explore the ferroptosis-related biological processes in esophageal cancer (ESCA). Methods: Four ESCA datasets were used to identify three PR-DE-IRFeGs for constructing the prognostic model. Validation of our model was based on analyses of internal and external data sets, and comparisons with past models. With the biological-based enrichment analysis as a guide, exploration for ESCA-related biological processes was undertaken with respect to the immune microenvironment, mutations, competing endogenous RNAs (ceRNA), and copy number variation (CNV). The model's clinical applicability was measured by nomogram and correlation analysis between risk score and gene expression, and also immune-based and chemotherapeutic sensitivity. Results: Three PR-DE-IRFeGs (DDIT3, SLC2A3, and GCH1), risk factors for prognosis of ESCA patients, were the basis for constructing the prognostic model. Validation of our model shows a meaningful capability for prognosis prediction. Furthermore, many biological functions and pathways related to immunity and ferroptosis were enriched in the high-risk group, and the role of the TMEM161B-AS1/hsa-miR-27a-3p/GCH1 network in ESCA is supported. Also, the KMT2D mutation is associated with our risk score and SLC2A3 expression. Overall, the prognostic model was associated with treatment sensitivity and levels of gene expression. Conclusion: A novel, prognostic model was shown to have high predictive value. Biological processes related to immune functions, KMT2D mutation, CNV and the TMEM161B-AS1/hsa-miR-27a-3p/GCH1 network were involved in ESCA progression.

Trehalose protects against cisplatin-induced cochlear hair cell damage by activating TFEB-mediated autophagy.

Cisplatin is a widely used chemotherapeutic agent for the treatment of various tumors, but its side effects limit its application. Ototoxicity, a major adverse effect of cisplatin, causes irreversible sensorineural hearing loss. Unfortunately, there are no effective approaches to protect against this damage. Autophagy has been shown to exert beneficial effects in various diseases models. However, the role of autophagy in cisplatin-induced ototoxicity has been not well elucidated. In this study, we aimed to investigate whether the novel autophagy activator trehalose could prevent cisplatin-induced damage in the auditory cell line HEI-OC1 and mouse cochlear explants and to further explore its mechanisms. Our data demonstrated that trehalose alleviated cisplatin-induced hair cell (HC) damage by inhibiting apoptosis, attenuating oxidative stress and rescuing mitochondrial dysfunction. Additionally, trehalose significantly enhanced autophagy levels in HCs, and inhibiting autophagy with 3-methyladenine (3-MA) abolished these protective effects. Mechanistically, we showed that the effect of trehalose was attributed to increased nuclear translocation of transcription factor EB (TFEB), and this effect could be mimicked by TFEB overexpression and inhibited by TFEB gene silencing or treatment with cyclosporin A (CsA), a calcineurin inhibitor. Taken together, our findings suggest that trehalose and autophagy play a role in protecting against cisplatin-induced ototoxicity and that pharmacological enhancement of TFEB-mediated autophagy is a potential treatment for cisplatin-induced damage in cochlear HCs and HEI-OC1 cells.

Using Patient-Derived Xenografts to Explore the Efficacy of Treating Head-and-Neck Squamous Cell Carcinoma With Anlotinib.

Objective: The efficacy of anlotinib as a treatment for head-and-neck squamous cell carcinoma (HNSCC) has been little explored. Here, we used patient-derived xenografts (PDXs) to this end. Methods: Fresh tumor tissues of HNSCC patients were screened in terms of in vitro drug sensitivity using the MTT assay. Patient PDXs were used to confirm the anti-tumor effects of anlotinib in vivo. After the medication regimen was complete, the tumor volume changes in mice were calculated. Apoptosis was measured using the TUNEL assay. The cell proliferation and apoptosis levels of PDXs yielded data on the utility of anlotinib treatment in vivo. Results: Anlotinib suppressed the in vitro proliferation of nine tumor tissues by an average of 51.05 ± 13.74%. Anlotinib also significantly inhibited the growth of three PDXs in mice (tumor growth inhibition 79.02%). The expression levels of Ki-67 and proliferating cell nuclear antigen after anlotinib treatment were significantly lower than those in the controls. The negative and positive controls exhibited no and some apoptosis, respectively, whereas the anlotinib group evidenced extensive apoptosis. Conclusion: Anlotinib suppressed HNSCC growth in vitro and in vivo (by inhibiting cell proliferation and promoting apoptosis), suggesting that anlotinib can potentially treat HNSCC.

Gene Expression Profiles of Circular RNAs and MicroRNAs in Chronic Rhinosinusitis With Nasal Polyps.

Introduction: Chronic rhinosinusitis (CRS) is often classified primarily on the basis of the absence or presence of nasal polyps (NPs), that is, as CRS with nasal polyps (CRSwNP) or CRS without nasal polyps (CRSsNP). Additionally, according to the percentage of eosinophils, CRSwNP can be further divided into eosinophilic CRSwNP (ECRSwNP) and non-ECRSwNP. CRSwNP is a significant public health problem with a considerable socioeconomic burden. Previous research reported that the pathophysiology of CRSwNP is a complex, multifactorial disease. There have been many studies on its etiology, but its pathogenesis remains unclear. Dysregulated expression of microRNAs (miRNAs) has been shown in psoriasis, rheumatoid arthritis, pulmonary fibrosis, and allergic asthma. Circular RNAs (circRNAs) are also involved in inflammatory diseases such as rheumatoid arthritis, septic acute kidney injury, myocardial ischemia/reperfusion injury, and sepsis-induced liver damage. The function of miRNAs in various diseases, including CRSwNP, is a research hotspot. In contrast, there have been no studies on circRNAs in CRSwNP. Overall, little is known about the functions of circRNAs and miRNAs in CRSwNP. This study aimed to investigate the expression of circRNAs and miRNAs in a CRSwNP group and a control group to determine whether these molecules are related to the occurrence and development of CRSwNP. Methods: Nine nasal mucosa samples were collected, namely, three ECRSwNP samples, three non-ECRSwNP samples, and three control samples, for genomic microarray analysis of circRNA and microRNA expression. All of the tissue samples were from patients who were undergoing functional endoscopic sinus surgery in our department. Then we selected some differentially expressed miRNAs and circRNAs for qPCR verification. Meanwhile, GO enrichment analysis and KEGG pathway analysis were applied to predict the biological functions of aberrantly expressed circRNAs and miRNAs based on the GO and KEGG databases. Receiver operating characteristic (ROC) curve analysis and principal component analysis (PCA) were performed to confirm these molecules are involved in the occurrence and development of CRSwNP. Results: In total, 2,875 circRNAs showed significant differential expression in the CRSwNP group. Specifically, 1794 circRNAs were downregulated and 1,081 circRNAs were upregulated. In the CRSwNP group, the expression of 192 miRNAs was significantly downregulated, and none of the miRNAs were significantly upregulated. GO and KEGG analysis showed differential circRNAs and miRNAs were enriched in "amoebiasis," "salivary secretion," "pathways in cancer," and "endocytosis." Through qRT-PCR verification, the expression profiles of hsa-circ-0031593, hsa-circ-0031594, hsa-miR-132-3p, hsa-miR-145-5p, hsa-miR-146a-5p, and hsa-miR-27b-3p were shown to have statistical differences. In addition, ROC curve analysis showed that the molecules with the two highest AUCs were hsa-circ-0031593 with AUC 0.8353 and hsa-miR-145-5p with AUC 0.8690. Through PCA with the six ncRNAs, the first principal component explained variance ratio was 98.87%. The AUC of the six ncRNAs was 0.8657. Conclusion: In our study, the expression profiles of ECRSwNP and non-ECRSwNP had no statistical differences. The differentially expressed circRNAs and miRNAs between CRSwNP and control may play important roles in the pathogenesis of CRSwNP. Altered expression of hsa-circ-0031593 and hsa-miR-145-5p have the strongest evidence for involvement in the occurrence and development of CRSwNP because their AUCs are higher than the other molecules tested in this study.

Volume quantification of endolymphatic hydrops in patients with vestibular schwannoma.

OBJECTIVE: The origin of vestibular symptoms in patients with vestibular schwannoma (VS) is uncertain. We used intratympanic gadolinium-enhanced magnetic resonance imaging (MRI) to confirm the labyrinthine lesions in patients with VS and to explore the features of endolymphatic hydrops (EH) in these patients. METHODS: In total, 66 patients diagnosed with unilateral VS were enrolled in this study and underwent intratympanic gadolinium-enhanced MRI. The borders of the vestibule and endolymph were mapped on the axial MRI images, and the area and volume of vestibule and endolymph were automatically calculated using Osirix software, and the area and volume percentage of vestibular endolymph were obtained. RESULTS: The area and volume percentages of vestibular endolymph on the affected side were significantly larger than those on the healthy side (both p < 0.001). Using Kendall's W test, we found that the area and volume percentages of vestibular endolymph on the affected side were consistent (p < 0.001), but the consistency was moderate (k = 0.574). The healthy side was also consistent (p < 0.001), and the degree of consistency was moderate (k = 0.444). We used 19.1% as the cut-off point to distinguish the presence or absence of vestibular EH; that is, the volume percentage of vestibular endolymph that was more than 19.1% were defined as the subgroup with hydrops, while the subgroup without hydrops included patients with a baseline level below 19.1%. No volume classification for vestibular EH was proposed. Based on this standard, 11/66 (16.7%) of the patients with VS in this study had vestibular EH. CONCLUSIONS: The volume percentage of the vestibular endolymph was more accurate than the area percentage for assessing vestibular EH. Using 19.1% as the cut-off point to distinguish the presence or absence of vestibular EH, we found that 16.7% of patients with VS had varying degrees of vestibular EH. We believe that the vestibular symptoms in patients with VS may originate from the peripheral lesions.

FGF19/FGFR4 signaling axis confines and switches the role of melatonin in head and neck cancer metastasis.

BACKGROUND: There is no consensus about the effective dosages of melatonin in cancer management, thus, it is imperative to fully understand the dose-dependent responsiveness of cancer cells to melatonin and the underlying mechanisms. METHODS: Head and neck squamous cell carcinoma (HNSCC) cells with or without melatonin treatment were used as a research platform. Gene depletion was achieved by short hairpin RNA, small interfering RNA, and CRISPR/Cas9. Molecular changes and regulations were assessed by Western blotting, quantitative RT-PCR (qRT-PCR), immunohistochemistry, and chromatin Immunoprecipitation coupled with qPCR (ChIP-qPCR). The therapeutic efficacy of FGF19/FGFR4 inhibition in melatonin-mediated tumor growth and metastasis was evaluated in orthotopic tongue tumor mice. RESULTS: The effect of melatonin on controlling cell motility and metastasis varies in HNSCC cells, which is dose-dependent. Mechanistically, high-dose melatonin facilitates the upregulation of FGF19 expression through activating endoplasmic stress (ER)-associated protein kinase RNA-like endoplasmic reticulum kinase (PERK)-Eukaryotic initiation factor 2 alpha (eIF2α)-activating transcription factor 4 (ATF4) pathway, which in turn promotes FGFR4-Vimentin invasive signaling and attenuates the role of melatonin in repressing metastasis. Intriguingly, following long-term exposure to high-dose melatonin, epithelial HNSCC cells revert the process towards mesenchymal transition and turn more aggressive, which is enabled by FGF19/FGFR4 upregulation and alleviated by genetic depletion of the FGF19 and FGFR4 genes or the treatment of FGFR4 inhibitor H3B-6527. CONCLUSIONS: Our study gains novel mechanistic insights into melatonin-mediated modulation of FGF19/FGFR4 signaling in HNSCC, demonstrating that activating this molecular node confines the role of melatonin in suppressing metastasis and even triggers the switch of its function from anti-metastasis to metastasis promotion. The blockade of FGF19/FGFR4 signaling would have great potential in improving the efficacy of melatonin supplements in cancer treatment.

Simultaneously inactivating Src and AKT by saracatinib/capivasertib co-delivery nanoparticles to improve the efficacy of anti-Src therapy in head and neck squamous cell carcinoma.

BACKGROUND: Src, an oncoprotein that drives progression of head and neck squamous cell carcinoma (HNSCC), is commonly hyperactivated in this disease. Unfortunately, the clinical benefit of targeting Src is significantly dampened in HNSCC patients, because the cytotoxic effects of anti-Src therapy and tumor resistance to it are less predictable. Thus, understanding the mechanism of tumor resistance to Src inhibition and seeking a way to overcome it are warranted. METHODS: Dual drug-loaded nanoparticles (NPs) were developed to co-deliver Src inhibitor saracatinib (AZD0530) and AKT inhibitor capivasertib (AZD5363) into the same population of tumor cells. An orthotopic tongue tumor model was generated to evaluate the in vivo therapeutic effects. Cell growth was determined by CellTiter-Glo® Luminescent Cell Viability Kit, colony formation, and 3D culture, and tumor growth was determined by bioluminescence and tumor size. The molecular changes induced by the treatments were assessed by Western blotting and immunohistochemistry. RESULTS: Capivasertib inactivated the AKT-S6 signaling and re-sensitized saracatinib-resistant HNSCC cells to saracatinib. Combination of capivasertib with saracatinib suppressed HNSCC growth more efficiently than either drug alone. Cathepsin B-sensitive NPs for co-delivering saracatinib and capivasertib significantly improved the efficacy of tumor repression without increasing side effects, which were due to highly specific tumor-targeting drug delivery system and synergistic anticancer effects by co-inactivation of AKT and Src in HNSCC cells. CONCLUSIONS: Addition of AKT blockade improves anti-HNSCC efficacy of anti-Src therapy, and co-delivery of capivasertib and saracatinib by tumor-targeting NPs has the potential to achieve better treatment outcomes than the free drug combination.

Nck-associated protein 1 associates with HSP90 to drive metastasis in human non-small-cell lung cancer.

BACKGROUND: Metastatic lung cancer is a life-threatening condition that develops when cancer in another area of the body metastasizes, or spreads, to the lung. Despite advances in our understanding of primary lung oncogenesis, the biological basis driving the progression from primary to metastatic lung cancer remains poorly characterized. METHODS: Genetic knockdown of the particular genes in cancer cells were achieved by lentiviral-mediated interference. Invasion potential was determined by Matrigel and three-dimensional invasion. The secretion of matrix metalloproteinase 2 (MMP2) and MMP9 were measured by ELISA. Protein levels were assessed by Western blotting and immunohistochemistry. Protein-protein interactions were determined by immunoprecipitation. An experimental mouse model was generated to investigate the gene regulation in tumor growth and metastasis. RESULTS: Nck-associated protein 1 (NAP1/NCKAP1) is highly expressed in primary non-small-cell lung cancer (NSCLC) when compared with adjacent normal lung tissues, and its expression levels are strongly associated with the histologic tumor grade, metastasis and poor survival rate of NSCLC patients. Overexpression of NAP1 in lowly invasive NSCLC cells enhances MMP9 secretion and invasion potential, whereas NAP1 silencing in highly invasive NSCLC cells produces opposing effects in comparison. Mechanistic studies further reveal that the binding of NAP1 to the cellular chaperone heat shock protein 90 (HSP90) is required for its protein stabilization, and NAP1 plays an essential role in HSP90-mediated invasion and metastasis by provoking MMP9 activation and the epithelial-to-mesenchymal transition in NSCLC cells. CONCLUSIONS: Our insights demonstrate the importance and functional regulation of the HSP90-NAP1 protein complex in cancer metastatic signaling, which spur new avenues to target this interaction as a novel approach to block NSCLC metastasis.

Novel Bougie for the Management of Esophageal Coins in Children: An Observational Study.

OBJECTIVES: To determine the efficacy and safety of a novel bougie for the removal of esophageal coins lodged in the proximal esophagus. SUBJECTS AND METHODS: This was an observational study. Medical records were reviewed of patients who were confirmed with esophageal coins between July 2015 and October 2016 in our department. Sixty-three patients, upper esophageal coins were confirmed by radiographs, were treated by using this novel bougie to remove esophageal coins. RESULTS: A total of 63 children were enrolled in this study. Sixty coins (95%) were removed successfully. The coin was extracted on the first attempt in 56 cases (89%), the second attempt in 3 cases (5%), and the third attempt in 1 case (2%). Two coins retained in the esophagus underwent endoscopy. In the remaining patient, the coin passed into the stomach and was confirmed to be passed in the stool within 48 hours. No serious complications occurred in any subject. CONCLUSIONS: Our novel bougie procedure is likely a safe, highly efficient approach to managing esophageal coins given that no serious complications of the 63 patients were reported. This simple technique may provide another valuable option to physicians.

Intracellular reduction in ATP levels contributes to CYT997-induced suppression of metastasis of head and neck squamous carcinoma.

The incidence rate of head and neck squamous cell carcinoma (HNSCC) has steadily increased over the past decade. However, treatment options for metastatic HNSCC are often limited and the 5-year survival rate has remained static. Therefore, the development and assessment of more efficient but less toxic therapeutic strategies is an unmet need for treatment of more extensive HNSCC. Here, we report that CYT997, a novel microtubule-disrupting agent, exerts strong activity in inhibiting HNSCC cell invasion and metastasis. The loss of invasion capacity by CYT997 was accompanied by an associated increase in cell adhesion and the reversal of epithelial-mesenchymal transition (EMT). Increased expression of E-cadherin protein and decreased expression of Vimentin protein became evident in HNSCC cells following CYT997 exposure, which were consistently observed in HNSCC xenografts from the mice receiving CYT997. Moreover, the capacity of invasive HNSCC cells to form pulmonary metastases was significantly blocked with CYT997 treatment, indicating that the diminishment of EMT traits contributes to CYT997-suppressed metastasis. Intriguingly, CYT997 impaired intracellular ATP levels in HNSCC cells, at least in part, through its inhibitory effect on the mitochondrial protein IF1. The addition of ATP attenuated CYT997-induced suppression of cell invasion, coupled with down-regulation of E-Cadherin and up-regulation of Vimentin. These findings support a critical role of ATP levels in cell invasion and metastasis under the influence of CYT997. Collectively, our data unveil the mechanism involved in mediating CYT997 action, and provide preclinical rationale for possible clinical application of CYT997 as a novel therapeutic strategy against aggressive HNSCC.

FGFR4 provides the conduit to facilitate FGF19 signaling in breast cancer progression.

Although genetic amplification and overexpression of the fibroblast growth factor 19 (FGF19) gene are found in human breast cancer, mechanisms that contribute to such functional alterations remain elusive. We report here that high expression of FGF19 is associated with the aggressive malignant behavior and poor survival outcome of breast cancer patients. FGF19 is particularly highly expressed in luminal molecular subtype of breast tumors and its expression levels are positively associated with its secretion levels from breast cancer cells. Genetic knockout of FGF19 significantly induces repression of breast tumor progression and metastasis in either an orthotopic mouse model of breast cancer or an experimental metastasis model. The FGF19 specific receptor, FGFR4, can be activated and subsequently upregulate AKT signaling in breast cancer cell upon FGF19, which is critical for oncogenic role of FGF19. Inactivation of FGFR4 by its inhibitor BLU9931 significantly attenuates FGF19-induced tumor-promoting activity, suggesting interruption of FGFR4 function is sufficient to affect FGF19-driven breast cancer. Overall, these insights support the idea that targeting FGFR4 in breast cancer cells overexpressing FGF19 may represent an effective strategy to suppress cancer development, progression, and metastasis.

Combating head and neck cancer metastases by targeting Src using multifunctional nanoparticle-based saracatinib.

BACKGROUND: Inhibition of metastasis of head and neck squamous cell carcinoma (HNSCC) is one of the most important challenges in cancer treatment. Src, a non-receptor tyrosine kinase, has been implicated as a key promoter in tumor progression and metastasis of HNSCC. However, Src therapy for HNSCC is limited by lack of efficient in vivo delivery and underlying mechanisms remain elusive. METHODS: Src knockdown cells were achieved by lentiviral-mediated interference. Cell migration and invasion were examined by wound healing and Transwell assays. Protein levels were determined by Western blot and/or immunohistochemistry. The Src inhibitor saracatinib was loaded into self-assembling nanoparticles by the solvent evaporation method. An experimental metastasis mouse model was generated to investigate the drug efficacy in metastasis. RESULTS: Blockade of Src kinase activity by saracatinib effectively suppressed invasion and metastasis of HNSCC. Mechanistic assessment of the drug effects in HNSCC cells showed that saracatinib induced suppression of Src-dependent invasion/metastasis through downregulating the expression levels of Vimentin and Snail proteins. In tests in mice, saracatinib loaded into the novel multifunctional nanoparticles exhibited superior effects on suppression of HNSCC metastasis compared with the free drug, which is mainly attributed to highly specific and efficient tumor-targeted drug delivery system. CONCLUSIONS: These findings and advances are of great importance to the development of Src-targeted nanomedicine as a more effective therapy for metastatic HNSCC.

Efficacy and mechanism of mandibular advancement devices for persistent sleep apnea after surgery: a prospective study.

BACKGROUND: To explore the feasibility, the efficacy, and the mechanism of mandibular advancement devices (MAD) in the treatment of persistent sleep apnea after surgery. METHODS: Nineteen patients who failed uvulopalatopharyngoplasty (UPPP) or UPPP plus genioglossus advancement and hyoid myotomy (GAHM) were given a non-adjustable MAD for treatment. All patients had polysomnography (PSG) at least 6 months post-UPPP with and without the MAD. Seventeen patients had computed tomography (CT) examinations. RESULTS: After the application of MAD, the apnea hypopnea index (AHI) decreased significantly from 41.2 ± 13.1/h to 10.1 ± 5.6/h in the responder group. The response rate was 57.9 % (11/19). During sleep apnea/hypopnea acquired from sedated sleep, the cross-sectional area and anterior-posterior and lateral diameters of the velopharynx enlarged significantly from 4.2 ± 6.0 mm2 to 17.5 ± 15.3 mm2, 1.9 ± 2.3 mm to 6.5 ± 4.1 mm, and 1.1 ± 1.3 mm to 2.6 ± 2.1 mm, respectively (P < 0.01) in the responder group with MAD. The velopharyngeal collapsibility also decreased significantly from 83.3 ± 21.8 % to 46.5 ± 27.1 %. The glossopharyngeal collapsibility decreased from 39.8 ± 39.1 % to -22.9 ± 73.2 % (P < 0.05). CONCLUSION: MAD can be an effective alternative treatment for patients with moderate and severe OSAHS after surgery. The principal mechanisms underlying the effect of MAD are expansion of the lateral diameter of the velopharynx, the enlargement of the velopharyngeal area, the reduction of velopharyngeal and glossopharyngeal collapsibility, and the stabilization of the upper airway.